Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8](Br)[CH:7]=1)=[O:5])C.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Sn](C)(C)C)[CH:23]=1.BrC1C=NC=CC=1.[Li+].[Cl-]>C1(C)C=CC=CC=1.CO.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:3][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8]([C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)=[O:5]
Reactant: C[Sn](C)(C)c1cccnc1
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)OCC)n2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)OC)n2n1

Procedure:
A mixture of 7-bromo-2-(3-ethyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester (8)(240 mg, 0.67 mmol), (Ph3P)2PdCl2 (24 mg, 0.03 mmol) and CuI (13 mg, 0.07 mg) were suspended in dry toluene (5 mL). A solution of 3-pyridyltrimethylstannane [195 mg, 0.81 mmol; prepared from 3-bromopyridine according to the procedure of J. Org. Chem., 64(19), 6999-7008 (1999)] in toluene (5 mL) was added, followed by LiCl (143 mg, 3.37 mmol) as a single portion. The entire mixture was heated at reflux under nitrogen for 2 h. The reaction mixture was allowed to cool, then diluted with 10% MeOH/CH2Cl2 (80 mL). This organic solution was washed with water (80 mL), 1 M KF solution (80 mL) and brine (80 mL). The organic layer was filtered to remove inorganic solids, dried (Na2SO4), and the solvent removed under reduced pressure to give a solid which was purified by chromatography on silica (2% MeOH/CH2Cl2 as eluant). Transesterification from the ethyl to the methyl ester occurred during workup and chromatography. 2-(3-Ethyl-ureido)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid methyl ester was isolated; mp. 211-213° C. LCMS (APCI+) 341. HRMS (FAB+) calcd C16H17N6O3 (MH+) 341.1362, found 341.1358.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]2[O:12][CH:11]([CH2:13][CH2:14][CH2:15]O)[S:10][C:9]=2[C:17]=1[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[Br:46]Br>C1C=CC=CC=1.O>[Br:46][CH2:15][CH2:14][CH2:13][CH:11]1[S:10][C:9]2[C:17]([CH3:18])=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]=2[O:12]1
Reactant: BrBr
Reactant: COCOc1c(C)c(C)c2c(c1C)SC(CCCO)O2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: COCOc1c(C)c(C)c2c(c1C)SC(CCCBr)O2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
2.6 g of 3-(5-methoxymethoxy-4,6,7-trimethyl-1,3-benzoxathiole-2-yl)propanol (prepared as described in Example 85) and 4.6 g of triphenylphosphine were dissolved in 30 ml of benzene, and 3 ml of dry pyridine were added to the solution. 4.4 g of bromine were then added dropwise at room temperature to this reaction mixture. The temperature rose as the bromine was added, and the mixture was allowed to stand until this temperature rise had finished and the mixture had returned to room temperature. The reaction mixture was then stirred for 40 minutes at room temperature, whereupon crystals formed. Water was added to the reaction mixture, which was then extracted with benzene. The extract was washed with water and then dried over anhydrous sodium sulfate. The benzene was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography. The title compound was obtained from the fraction eluted with a 2:3 by volume mixture of cyclohexane and benzene.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH:23]2[CH2:25][CH2:24]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].CC1C(C)OB(B2OC(C)C(C)O2)O1.Br[C:46]1[CH:51]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:49]=[CH:48][C:47]=1[F:56].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23]1([C:9]2[N:8]([CH2:7][C:5]3[O:6][C:2]([C:46]4[CH:51]=[C:50]([C:52]([F:54])([F:55])[F:53])[CH:49]=[CH:48][C:47]=4[F:56])=[CH:3][CH:4]=3)[C:16]3[C:11]([CH:10]=2)=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:25][CH2:24]1
Reactant: N#Cc1ccc2c(cc(C3CC3)n2Cc2ccc(Br)o2)c1C(F)(F)F
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2ccc(-c3cc(C(F)(F)F)ccc3F)o2)c1C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h
Yield: 1.7 %

Procedure:
To a solution of (1-[(5-bromo-2-furanyl)methyl]-2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 310C) (0.1 g, 0.24 mmol) in dry DMF (5 mL) was added potassium acetate (0.072 g, 0.73 mmol), palladium acetate (0.011 g, 0.048 mmol) and 4,4′,5,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborolane (0.068 g, 0.264 mmol). The reaction is heated to 90° C. for 3 h. To the reaction was then added 2-bromo-1-fluoro-4-(trifluoromethyl)benzene (0.119 g, 0.48 mmol), cesium carbonate (0.159 g, 0.48 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.057 g, 0.048 mmol). The mixture was stirred at 85° C. overnight. Solids were filtered and the filtrate was then concentrated in vacuo. The residue was purified by radial chromatography (0-40% EtOAc-hexanes gradient) and by semipreparative HPLC to afford the title compound (0.002 g, 1.3% yield): MS (ES) m/z 493 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:68])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:67])[NH:26][C@H:27]([C:60]([O:62]C(C)(C)C)=[O:61])[CH2:28][CH2:29][C:30](=[O:59])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][C:39](=[O:58])[NH:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][C:48]([O:50][N:51]1[C:55](=[O:56])[CH2:54][CH2:53][C:52]1=[O:57])=[O:49])(C)(C)C.C(O)(C(F)(F)F)=O>>[C:60]([C@@H:27]([NH:26][C:25]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:68])=[O:5])=[O:67])[CH2:28][CH2:29][C:30](=[O:59])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][C:39](=[O:58])[NH:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][C:48]([O:50][N:51]1[C:55](=[O:56])[CH2:54][CH2:53][C:52]1=[O:57])=[O:49])([OH:62])=[O:61]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)ON1C(=O)CCC1=O)C(=O)O

Procedure:
Alternatively, the acylation reagent can be prepared employing a solid phase method to prepare the intermediate 19-((S)-1-tert-butoxycarbonyl-3-{2-[2-({2-[2-(2,5-dioxo-pyrrolidin-1-yloxycarbonylmethoxy)ethoxy]ethylcarbamoyl}methoxy)ethoxy]ethylcarbamoyl}propyl-carbamoyl)nonadecanoic acid tert-butyl ester (alternative name: tBu-Eicosanedioyl-gGlu(OtBu)-OEG-OEG-OH) as described in WO 2009/022005 followed by activation as N-hydroxysuccinimide ester and TFA cleavage (last two steps above).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH:18]1([NH2:21])[CH2:20][CH2:19]1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH:18]2[CH2:20][CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: NC1CC1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1nc(NC2CC2)c2c(n1)C(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To a solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (170 mg, 0.641 mmol) in NMP (2 mL) was added cyclopropanamine (110 mg, 1.924 mmol) dropwise. The mixture was stirred at RT for 3 hours. 8 mL of water was added to precipitate out the product. The solid was filtered out and air-dried to give a crude 2-chloro-N-cyclopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (175 mg, 0.612 mmol, 96% yield), which was used for the next step without any purification. LC-MS (M+H)+=286.1
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]([OH:21])=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:22]I.[H-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[CH2:12]([O:11][CH2:10][C@H:9]([N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH3:22])[C:19]([OH:21])=[O:20])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@@H](COCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
N-Boc-O-Benzyl-L-Serine (8.86 g, 30.0 mmol) was dissolved in tetrahydrofuran (94 mL) and the resultant solution was cooled with a 0° C. ice bath. Methyl iodide (15.0 mL, 241 mmol) was added in one portion. After 5 min, sodium hydride (60% dispersion in mineral oil, 3.6 g, 90 mmol) was added in three portions during 10 min. The resultant reaction mixture was stirred under nitrogen for 76 h while the cooling bath temperature was maintained at 0° C. The reaction mixture was diluted with cold (0-5° C.) ethyl acetate (150 mL) and water (1.5 mL) was added dropwise over 10 min. The cooling bath temp was allowed to slowly warm to ambient temperature overnight. The reaction mixture was concentrated to a viscous oil on a rotary evaporator without heating. The residue was partitioned between ether (100 mL) and water (300 mL). The ethereal layer was further washed with saturated aqueous sodium bicarbonate (150 mL). The combined aqueous portions were acidified to pH 3 using aqueous citric acid (2 M) and were extracted with ethyl acetate (3×150 mL). The combined extracts were washed with water (2×150 mL) and 5% aqueous sodium thiosulfate (150 mL), dried over magnesium sulfate and concentrated on a rotary evaporator (without heating) to afford (S)-3-Benzyloxy-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid as viscous, colorless oil (8.98 g).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:14]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:22](=[O:30])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:31])[N:15]=1)[CH2:12][CH3:13])C1C=CC=CC=1>C(O)C.[Pd]>[NH2:10][CH:11]([C:14]1[N:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:22](=[O:30])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:31])[N:15]=1)[CH2:12][CH3:13]
Reactant: CCC(NC(=O)OCc1ccccc1)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCC(N)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A catalytic amount of 10% Pd/C was added to a solution of compound 16 (691 mg, 1.62 mmol) in ethanol (8 mL). The resulting mixture was placed under a hydrogen atmosphere (balloon pressure) and allowed to stir at ambient temperature overnight. The reaction was filtered, and the filtrate concentrated in vacuo. The resulting crude residue was purified by flash chromatography to afford the free amine, compound 17, as a pale yellow oil. (ES): m/z 294 (M+H), 237. 1H NMR MHz, DMSO-d6) δ 7.68 (t, 1H, J=7.7 Hz), 7.49-7.63 (m, 3H), 7.43-7.49 (m, 1H), 7.36-7.43 (m, 1H), 7.19-7.34 (m, 2H), 4.03-4.19 (m, 1H), 2.72 (s, 3H), 2.04 (br. s, 2H), 1.63-1.79 (m, 1H), 1.29-1.44 (m, 1H), 0.68 (t, 3H, J=7.3 Hz). The reaction described above and compound 17 are shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([OH:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[NH:12][C:11](=[O:22])[CH:10]=1.[Br:24][CH2:25][CH2:26][CH2:27]Br.ClCCCCCCOC1C(OC)=CC=C2C=1NC(=O)C=C2NC1C(Cl)=CN=CC=1Cl>>[Br:24][CH2:25][CH2:26][CH2:27][O:21][C:14]1[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11](=[O:22])[CH:10]=[C:9]2[NH:8][C:7]1[C:6]([Cl:23])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: BrCCCBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1O
Agent: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCBr

Procedure:
8-(3-Bromopropoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one was prepared from 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one (Intermediate 3) and 1,3-dibromopropane following the procedure outlined for Intermediate 4 (modifications: 1.0 equiv KHMDS and 5.0 equiv of dibromide used; reaction run at room temperature). MS (ESI): 472.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C:15]([C:25](=O)[CH3:26])=[CH:16][C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([CH2:31][CH2:32][O:33][C:34](=[O:39])/[CH:35]=[C:36](\[NH2:38])/[CH3:37])#[N:30]>CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:15]2[CH:16]([C:17]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=3)[C:35]([C:34]([O:33][CH2:32][CH2:31][C:29]#[N:30])=[O:39])=[C:36]([CH3:37])[NH:38][C:25]=2[CH3:26])=[O:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C/C(N)=C/C(=O)OCCC#N
Reactant: CC(=O)C(=Cc1cc(Cl)cc(Cl)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CC(C)O
Product: CC1=C(C(=O)OCCC#N)C(c2cc(Cl)cc(Cl)c2)C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)=C(C)N1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
1.66 g (3.88 mmol) of 4-[2-acetyl-3-(3,5-dichlorophenyl)-2-propenoyl] piperazine-1-carboxylic acid t-butyl ester and 598 mg (3.88 mmol) of 3-aminocrotonate 2-cyanoethyl ester were stirred in 30 ml of 2-propanol at 80° C. overnight and then stirred at 120° C. for 2 hours. After concentration under reduced pressure, ethyl acetate was added and the residue was washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=100/1 to 30/1) to obtain the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][N:6]=[C:7]([NH2:19])[C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=2F)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1.C(OCC)(=O)C>C1C=CC=CC=1>[CH:1]1([CH2:4][O:5][N:6]=[C:7]([NH:19][C:29](=[O:30])[CH2:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]([F:17])([F:16])[F:15])[CH2:3][CH2:2]1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: NC(=NOCC1CC1)c1c(F)cccc1C(F)(F)F
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CC(=O)NC(=NOCC2CC2)c2ccccc2C(F)(F)F)cc1
Yield: 75.2 %

Procedure:
In 80 ml of benzene was dissolved 10.4 g of N'-cyclopropylmethyloxy-2-fluoro-6-trifluoromethylbenzamidine, and to the solution was added 8.9 g of 4-methoxyphenylacetylchloride. The solution was heated under refluxing for 3 hours. After cooling, ethyl acetate was added to the solution, followed by washing with water and drying over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue obtained in crystal was washed with a mixed solvent hexane and ether to thereby obtain 13.7 g of crude crystal. The crystal was then re-crystallized in hexane, thereby affording 11.5 g of the objective compound.m.p. 88-90° C.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([NH:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9]>>[CH2:6]([N:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:2][C:1]([OH:5])=[O:4])[CH2:7][CH2:8][CH3:9]
Reactant: C=CC(=O)O
Reactant: CCCCNCCCC
Product: CCCCN(CCCC)CCC(=O)O
Yield: 98 %

Procedure:
After completion of the reaction, acrylic acid and di-n-butylamine were assayed by gas chromatography. As a result, formation of 152.5 g (yield 98%) of N,N-di-n-butyl-β-alanine was confirmed, with the rates of conversion of acrylic acid and di-n-butylamine being 98% and 98%, respectively.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=1)[O:7][C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[CH3:24][N:25]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][C:27]([OH:34])=[N:26]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH3:24][N:25]1[C:29]([C:30]([F:31])([F:32])[F:33])=[CH:28][C:27]([O:34][C:2]2[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=2)[O:7][C:8]2[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=2[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:26]1
Reactant: COC(=O)COc1ccccc1Oc1cc(F)ccc1[N+](=O)[O-]
Reactant: Cn1nc(O)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1Oc1cc(Oc2cc(C(F)(F)F)n(C)n2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 18 h
Yield: 31.5 %

Procedure:
A mixture of methyl [o-(5-fluoro-2-nitrophenoxy)phenoxy]acetate (1.1 g, 3.4 mmol), 1-methyl-5-(trifluoromethyl)pyrazol-3-ol (0.63 g, 3.8 mmol) and potassium carbonate (0.53 g, 3.8 mmol) in N,N-dimethylformamide is stirred at 100° C. for 18 hours, cooled to room temperature, poured into water and extracted with ethyl acetate. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an orange oil. Column chromatography of the oil using silica gel and a 30% ethyl acetate in hexanes solution gives the title product as a yellow oil (0.5 g) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: FC([C:4]([O:10][C:11]([C:14]([C:17]([C:20](F)=[O:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([C:6]([F:9])([F:8])[F:7])[F:5])=O.[C:23](=O)([O-])[O-:24].[Na+].[Na+].C(=O)=O.S(=O)(=O)(O)O.CO>O.COCCOCCOC>[C:6]([CH:4]([O:10][C:11]([C:14]([C:17]([C:20]([O:24][CH3:23])=[O:21])([F:18])[F:19])([F:16])[F:15])([F:12])[F:13])[F:5])([F:9])([F:7])[F:8]
Reactant: O=C(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(C(=O)F)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COCCOCCOC
Product: COC(=O)C(F)(F)C(F)(F)C(F)(F)OC(F)C(F)(F)F
Temperature: 165 °C
Yield: 56.5 %

Procedure:
FC(O)CF(CF3)—O—(CF2)3COF (503 grams, 1.4 mole), prepared as described in U.S. Pat. App. Pub. No. 2004/0116742, was added over a period of two hours to a stirred mixture of sodium carbonate (387 grams, 3.7 moles) and diglyme (650 grams) at 78° C. The reaction liberated carbon dioxide gas. Distilled water (35 grams, 1.9 mole) was added at 85° C., and then the reaction mixture was heated to 165° C. and maintained at that temperature for 30 minutes. The reaction was allowed to cool, and sulfuric acid (250 grams, 2.6 moles) in 1250 grams of water was added. Two layers formed, and the top layer was washed with 33% sulfuric acid and then esterified at 65° C. with methanol (200 grams, 6.3 moles) and concentrated sulfuric acid (200 grams, 2.0 moles). The reaction mixture was washed with water and distilled at 52° C. at 15 mmHg (2.0×103 Pa) to give 258 grams of CF3CFH—O—(CF2)3COOCH3.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH2:8]([O:15][C:16]([N:18]([CH2:23][C:24]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=1[NH3+:32])[CH2:19][C:20](O)=[O:21])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[F:30][C:28]1[C:27]([F:31])=[CH:26][C:25]2[NH:32][C:20](=[O:21])[CH2:19][N:18]([C:16]([O:15][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:17])[CH2:23][C:24]=2[CH:29]=1
Reactant: [NH3+]c1cc(F)c(F)cc1CN(CC(=O)O)C(=O)OCc1ccccc1
Agent: O=C([O-])C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(C(=O)OCc2ccccc2)Cc2cc(F)c(F)cc2N1
Reaction time: 0.08 h
Yield: 59.9 %

Procedure:
To a solution of 2-[(benzyloxycarbonyl-carboxymethyl-amino)-methyl]-4,5-difluoro-phenyl-ammonium trifluoroacetate (4.75 g, 10.25 mmol) in DCM (40 mL) was added EDC (2.55 g, 13.32 mmol) and HOBT (1.7.9 g, 13.32 mmol) at 0° C. The resulting solution was stirred for 5 min and DIPEA (5.35 mL, 30.75 mmol) was added to it. The reaction mixture was stirred overnight at r.t. under argon. After completion of the reaction as confirmed by TLC, water (60 mL) was added to the reaction mixture and crude compound was extracted with DCM (3×50 mL). The combined organic layers were dried over Na2SO4 and the solvents were removed in vacuo to afford the crude compound which was purified by column chromatography (silica gel: 2:8 EtOAc:Pet. ether) to afford pure benzyl 7,8-difluoro-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate (2.04 g, 60%) as thick gel.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:9]([O:13][C:14](=[O:23])[NH:15][C@H:16]1[CH2:21][CH2:20][C@@H:19](O)[CH2:18][CH2:17]1)([CH3:12])([CH3:11])[CH3:10].C1C(COC(/N=N\C(OCC2C=CC(Cl)=CC=2)=O)=O)=CC=C(Cl)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([O:8][C@H:19]2[CH2:18][CH2:17][C@H:16]([NH:15][C:14](=[O:23])[O:13][C:9]([CH3:11])([CH3:10])[CH3:12])[CH2:21][CH2:20]2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Reactant: Oc1cncc(Br)c1
Agent: O=C(/N=N\C(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2cncc(Br)c2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-7, 5-bromopyridin-3-ol was reacted with (cis)-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as a colorless solid. MS: 371.3 and 373.3 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([O:15]CC)=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+:19]>C(O)C.O>[CH2:1]([N:8]1[C:12]([C:13]([O-:15])=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[K+:19]
Reactant: CCOC(=O)c1nnnn1Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])c1nnnn1Cc1ccccc1

Procedure:
To a solution of 1-benzyl-5-carboethoxy tetrazole prepared in Example 1, in warm absolute ethanol is added a stoichiometric excess of KOH in water to precipitate crystalline 1-benzyl-1H-tetrazole-5-carboxylic acid potassium salt.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH2:16]1[CH2:26][C:24](=O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21]C=2)[CH2:17]1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][C:8]2([C:23]3[C:18](=[CH:17][CH:16]=[CH:26][CH:24]=3)[CH2:19][CH2:20][CH2:21]2)[O:7][C:1](=[O:6])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C1CCCc2ccccc21
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(O)CC2(CCCc3ccccc32)O1

Procedure:
The title compound was prepared as described in General Method 1 using 25 mmol of methyl acetoacetate, 27.5 mmol of NaH 60% dispersion in oil, 26.25 mmol of 1.6M n-butyl lithium in hexane, 25 mmol of α-tetralone and 70 mL of tetrahydrofuran. The product was recrystallized from ethyl acetate/diethyl ether (m.p. 117°-119° C.). 1H NMR (CDCl3) δ1.7-1.9 (m, 1H), 1.9-2.1 (m, 2H), 2.1-2.3 (m, 1H), 2.7-3.0 (m, 2H), 2.95 (d, 1H), 3.1 (d, 1H), 3.5 (s, 2H), 7.1-7.2 (m, 1H), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 1H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([OH:13])=O)[CH2:3][CH2:2]1.[CH2:14]([N:16]1[CH:20]=[C:19]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[CH:18]=[N:17]1)[CH3:15]>>[CH2:14]([N:16]1[CH:20]=[C:19]([CH2:21][N:22]([C:23]2[CH:24]=[CH:25][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:27][CH:28]=2)[C:11]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[O:1][CH2:2][CH2:3]2)=[O:13])[CH:18]=[N:17]1)[CH3:15]
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Reactant: O=C(O)C1CCOc2ccccc21
Product: CCn1cc(CN(C(=O)C2CCOc3ccccc32)c2ccc(C(C)C)cc2)cn1
Yield: 85 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using chroman-4-carboxylic acid (0.27 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (0.52 g) was obtained.