Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([F:11])=[C:4]([Cl:12])[N:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH2:20]([O:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.ClCCl.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:20]([O:27][NH:28][C:8]([C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:12])=[C:5]([F:11])[CH:6]=1)=[O:10])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NOCc1ccccc1)c1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Yield: 49.6 %

Procedure:
To a suspension of 2,6-dichloro-5-fluoro-3-pyridinecarboxylic acid (20.00 g, 95.2 mmol) and a few drops of DMF in dichloromethane (200 mL) was added oxalyl chloride (24.6 mL, 0.282 mol) dropwise. The mixture was stirred at room temperature until evolution of gas ceased, and the reaction mixture was evaporated under reduced pressure to remove excess of the reagent. The residue was dissolved in dichloromethane (200 mL) and O-benzylhydroxylamine hydrochloride (16.71 g, 0.105 mol) in dichloromethane (200 mL) and triethylamine (15.90 mL, 0.114 mmol) were added dropwise at 0° C. The mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium hydrogen carbonate, water, and dried on sodium sulfate. The solid residue was recrystallized from chloroform to give 14.87 g of the title compound as solid, mp 176-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[C:25][Si](C)(C)C)=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:22])[C:15]([O:17]C(C)(C)C)=[O:16])[C:10](=[O:23])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[CH:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:22])[C:15]([OH:17])=[O:16])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)OC(C)(C)C)n1ccc(-c2cc(Cl)ccc2C#C[Si](C)(C)C)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: C#Cc1ccc(Cl)cc1-c1ccn(C(C)C(=O)O)c(=O)c1

Procedure:
55 mg (purity 89%, 0.11 mmol) of tert-butyl 2-[4-{5-chloro-2-[(trimethylsilyl)ethynyl]phenyl}-2-oxopyridin-1(2H)-yl]propanoate (racemate) were hydrolysed with TFA according to General Method 6A. Yield: 50 mg (purity 82%, quant.)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([C:19]4[S:20][C:21]5[CH:27]=[CH:26][CH:25]=[C:24](C(F)(F)F)[C:22]=5[N:23]=4)[C:15]([NH2:18])=[N:16][CH:17]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.Cl[C:33]1SC2C=CC(C#N)=CC=2[N:37]=1>>[NH2:18][C:15]1[C:14]([C:19]2[S:20][C:21]3[CH:27]=[CH:26][C:25]([C:33]#[N:37])=[CH:24][C:22]=3[N:23]=2)=[CH:13][C:12]([C:10]2[CH:9]=[N:8][N:7]([CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[CH:11]=2)=[CH:17][N:16]=1
Reactant: N#Cc1ccc2sc(Cl)nc2c1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)cccc2s1
Product: N#Cc1ccc2sc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)nc2c1

Procedure:
Following the procedure for 5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-3-(4-trifluoromethylbenzothiazol-2-yl)-pyridin-2-ylamine, but using 2-chloro-1,3-benzothiazole-5-carbonitrile, the title compound was obtained as yellow solid. MS (ES+): m/z=402.13 [MH+].
Reaction SMILES: CC(C)[C@H]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:26])C(OC)=O.BrC[C:30]1[CH:35]=[CH:34][C:33](C2C=CC([N+]([O-])=O)=CC=2)=[CH:32][C:31]=1[C:45]([O:47][CH3:48])=[O:46].Cl.NC1CCCC(C(OC)=O)C1>>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][N:8]([CH:35]4[CH2:34][CH2:33][CH2:32][CH:31]([C:45]([O:47][CH3:48])=[O:46])[CH2:30]4)[C:9]3=[O:26])=[CH:14][CH:13]=2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: COC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)ccc1CBr
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O
Agent: COC(=O)C1CCCC(N)C1
Agent: Cl
Product: COC(=O)C1CCCC(N2Cc3ccc(-c4ccc([N+](=O)[O-])cc4)cc3C2=O)C1
Yield: 59 %

Procedure:
The compound of example 542 was prepared analogous to compound of example 5 by reaction of compound of example 4 with methyl 3-aminocyclohexanecarboxylate hydrochloride.
Reaction SMILES: [NH2:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:6]([S:9]/[CH:10]=[CH:11]\[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][S:8][C@H:3]12.[C:36]([NH:55][C:56]1[S:57][CH:58]=[C:59]([CH:61]([CH2:65][OH:66])[C:62](O)=[O:63])[N:60]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:36]([NH:55][C:56]1[S:57][CH:58]=[C:59]([CH:61]([CH2:65][OH:66])[C:62]([NH:1][CH:2]2[C:34](=[O:35])[N:4]3[C:5]([C:18]([O:20][CH:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])=[C:6]([S:9]/[CH:10]=[CH:11]\[C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[CH2:7][S:8][C@H:3]23)=[O:63])[N:60]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C\c3cccnc3)CS[C@H]12
Reactant: O=C(O)C(CO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(S/C=C\c2cccnc2)CS[C@@H]2C(NC(=O)C(CO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
To a solution of benzhydryl 7-amino-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (1.50 g) and 2-(2-tritylaminothiazol-4-yl)-3-hydroxypropionic acid (1.42 g) in tetrahydrofuran was added N,N'-dicyclohexylcarbodiimide (925 mg) under ice-cooling. The resultant mixture was stirred for 1 hour at the same temperature and stirred for 2 hours at ambient temperature. The resultant precipitate was filtered off. To the filtrate was added ethyl acetate (100 ml) and the organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel (120 g) and eluted with a mixture of ethyl acetate and diisopropyl ether (3:1). The fractions containing the object compound were combined and concentrated in vacuo to give benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-3-hydroxypropionamido]-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (1.10 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](OCC)=[O:10])=[CH:4][CH:3]=1.[H-].CC(C[AlH]CC(C)C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: [H-]
Product: O=CCc1ccc(Br)cc1
Temperature: -78 °C

Procedure:
To a cold solution (-78° C.) of 15 g (62 mmol) of ethyl (4-bromophenyl)acetate (Compound A) in 150 ml of CH1Cl2 was added dropwise (over a span of 1 hour) 65 ml (65 mmol) of dffsobutylaluminum hydride (DIBAL-H, 1M solution in hexane). After the DIBAL-H addition was complete, the reaction was stirred at -78° C. for an additional hour. The reaction was quenched by the dropwise addition of methanol (10 ml), followed by water (10 ml) and 10% HCl (40 ml). The mixture was then warmed to 0° C., stirred for 10 minutes and then washed with water (15 ml), 10% aqueous NaHCO3 (10 ml) and brine (10 ml). The organic phase was dried over MgSO4 and the solvent distilled off at ambient temperature to give crude (4-bromophenyl)acetaldehyde. To a cold solution (0° C.) of this crude aldehyde in 150 ml of CH2Cl2 was added a solution of 26 g (74.6 mmol) of (carbethoxymethylene)triphenylphosphorane in 50 ml of CH2Cl2. The mixture was stirred for 16 hours, concentrated in vacuo and purified by flash chromatography (silica, 10% EtOAc-hexane) to give ethyl 4-(4-bromophenyl)but-2-enoate as a mixture of E:Z isomers. This isomeric mixture was dissolved in 150 ml of EtOAc and hydrogenated over 1 g of 10% Pd/C for 6 hours. The catalyst was filtered off and the filtrate concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1>C(O)C.O1CCCC1.[Pd]>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc2[nH]cc(C3CCN4CCCC4C3)c2c1
Reaction time: 24 h
Yield: 85.7 %

Procedure:
The 3-(1,2,3,4,5,8-hexahydroindolizin-7-yl)-5-nitro-1H-indole (2.21 g, 6.90 mmol) was dissolved in 95 ml of ethanol and 50 ml of tetrahydrofuran. 5% palladium over carbon was added (550 mg) and the mixture was placed under an atmosphere of hydrogen, at an initial pressure of 60 psi, at room temperature, for 24 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give 1.51 g of a purple foam. (85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([C:49]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[O:50])[CH:45]=[CH:46][C:47]=1[Cl:48]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:46]5[CH:45]=[C:44]([C:49]([N:51]6[CH2:52][CH2:53][O:54][CH2:55][CH2:56]6)=[O:50])[CH:43]=[CH:42][C:47]=5[Cl:48])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: O=C(c1ccc(Cl)c(Br)c1)N1CCOCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cc(C(=O)N4CCOCC4)ccc3Cl)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (70 mg) and (3-bromo-4-chloro-phenyl)-morpholin-4-yl-methanone (59 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-chloro-phenyl]-morpholin-4-yl-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-310) as a pale brown powder (16 mg, 24%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]([CH3:26])[NH:21][CH2:20][CH2:19]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][CH:25]=[C:16]([O:15][CH3:14])[CH:17]=4)[CH:22]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: COc1ccc2c(c1)CCNC2C
Product: COc1ccc2c(c1)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:8][CH2:7][C:6](=O)[NH:5][C:4]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:3]1=2.CO>C1COCC1>[CH3:1][C:2]1([CH3:17])[CH2:8][CH2:7][CH2:6][NH:5][C:4]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:3]1=2
Reactant: CC1(C)CCC(=O)Nc2ccc([N+](=O)[O-])cc21
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CCCNc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 71.7 %

Procedure:
Combined 5,5-Dimethyl-7-nitro-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (89 mg, 0.38 mmol), Borane-THF complex, 1M in THF (1.9 mL, 1.9 mmol) and 3 mL anhydrous THF. Heated reaction to reflux for 1 hour. Let reaction cool to room temperature, added methanol and concentrated under reduced pressure. Dissolved residue in methylene chloride and washed with saturated sodium bicarbonate solution. Purified with normal phase chromatography eluting with 10% ethyl acetate in hexane to yield a yellow solid, 5,5-Dimethyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (60 mg, 72%). mp 99° C.; LCMS: m/z=221.06 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.26 (d, 1H, J=2.3 Hz), 7.91 (dd, 1H, J=8.6, 2.5 Hz), 6.68 (d, 1H, J=8.8 Hz), 4.28 (br s, 1H), 3.16 (m, 2H), 1.91 (m, 2H), 1.72 (m, 2H), 1.41 (s, 6H).
Reaction SMILES: Cl.NC1CCN(C2C=C(C=C(Cl)N=2)C(N)=O)CC1.[Cl:19][C:20]1[C:24]([Cl:25])=[C:23]([CH3:26])[NH:22][C:21]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[C:40]([C:42]([NH:44][O:45][CH3:46])=[O:43])[N:39]=[C:38]([O:47][CH2:48][CH2:49][NH:50]C(=O)OC(C)(C)C)[N:37]=2)[CH2:32][CH2:31]1)=[O:28]>>[NH2:50][CH2:49][CH2:48][O:47][C:38]1[N:39]=[C:40]([C:42]([NH:44][O:45][CH3:46])=[O:43])[CH:41]=[C:36]([N:33]2[CH2:34][CH2:35][CH:30]([NH:29][C:27]([C:21]3[NH:22][C:23]([CH3:26])=[C:24]([Cl:25])[C:20]=3[Cl:19])=[O:28])[CH2:31][CH2:32]2)[N:37]=1
Reactant: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(OCCNC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(OCCN)n1

Procedure:
The title compound was synthesized by a method analogous to Intermediate 70 starting from tert-butyl 2-({4-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-6-[(methoxyamino)carbonyl]pyrimidin-2-yl}oxy)ethylcarbamate (Example 322).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH3:19][C:20]1([CH3:27])[CH2:25][C:24](=[O:26])[O:23][C:21]1=[O:22].C(N(CC)CC)C.O1CCCC1>O>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:24](=[O:26])[CH2:25][C:20]([CH3:27])([CH3:19])[C:21]([OH:23])=[O:22])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: CC1(C)CC(=O)OC1=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(CC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1)C(=O)O
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (400 mg), 2,2-dimethylsuccinic anhydride (400 mg), triethylamine (1.39 mL), and tetrahydrofuran (20 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (1.03 g, 95%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:7]1[N:8]=[CH:9][C:10]([NH:13]C(=O)C(C)(C)C)=[N:11][CH:12]=1)([O:5][CH3:6])[CH3:4].[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:7]1[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1)([O:5][CH3:6])[CH3:4]
Reactant: COC(C)(OC)c1cnc(NC(=O)C(C)(C)C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(C)(OC)c1cnc(N)cn1
Temperature: 25 °C
Reaction time: 63 h

Procedure:
A solution of N-[5-(1,1-dimethoxy-ethyl)-pyrazin-2-yl]-2,2-dimethyl-propionamide (1.73 g, 6.47 mmol) in ethanol (13 mL) was treated with a 2N aqueous sodium hydroxide solution (11 mL, 22 mmol). The reaction was stirred at 25° C. for 63 h and then was heated at 65° C. for 1.5 h. The reaction mixture was then diluted with ethyl acetate (200 mL) and washed with a saturated aqueous sodium chloride solution (75 mL). The aqueous layer was back-extracted with ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4% methanol/methylene chloride) afforded impure 5-(1,1-dimethoxy-ethyl)-pyrazin-2-ylamine as a yellow solid. This material was re-purified via Biotage chromatography (FLASH 40L, Silica, 7/3 ethyl acetate/hexanes) to afford still impure 5-(1,1-dimethoxy-ethyl)-pyrazin-2-ylamine as a light yellow solid (880.4 mg, 74%) which used without further purification and characterization.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([Cl:12])[C:3]=1[NH2:13].[F-].[Cs+].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CS(C)=O>[CH2:16]([NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([Cl:12])[C:3]=1[NH2:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: Nc1c(Br)cc(C(F)(F)F)nc1Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Solvent: O
Product: Nc1c(NCc2ccccc2)cc(C(F)(F)F)nc1Cl
Temperature: 150 °C
Yield: 17.5 %

Procedure:
4-Bromo-2-chloro-6-trifluoromethyl-pyridin-3-ylamine (84 g, 300 mmol) was stirred in 500 ml DMSO in the presence of caesium fluoride (46.3 g, 305 mmol) and benzylamine (66.6 ml, 610 mmol). The resulting brown suspension was heated at 150° C. for 16 h. Added to the cooled suspension was 1500ml water and the mixture extracted with 2×500 ml diethyl ether. The combined organic extracts were dried (MgSO4), concentrated in vacuo and purified by column chromatography on silica, eluting with Hept:EtOAc, 4:1 to 2:1 to give the title compound (15.8 g, 17%) as a pale brown solid. The undesired isomer was similarly isolated as a brown oil (51.0 g, 48%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([CH3:23])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].C(O)C>[Fe].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([CH3:23])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Yield: 67.3 %

Procedure:
4-(3-Methyl-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (2 g, Example 36a), iron powder (1.74 g), ammonium chloride (1.67 g), ethanol (50 ml) and water (50 ml) were refluxed together under nitrogen for 2 h. The mixture was cooled and the iron was filtered off. Water (200 ml) was added to the residue and the product extracted into ethyl acetate (3×200 ml), dried (MgSO4), and concentrated to give the subtitle compound (1.22 g).
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(N(C(C)C)CC)(C)C.Br[CH2:36][CH2:37][CH2:38][OH:39]>C(O)CCC>[CH:1]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:36][CH2:37][CH2:38][OH:39])[CH2:16][CH2:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: OCCCN1CCC(C(c2ccccc2)c2ccccc2)CC1

Procedure:
4-Benzhydrylpiperidine (10 mmol, 2.87 g) is slurried in n-butanol (30 mL), and K2CO3 (s) (2.76 g, 10 mmol) or diisopropylethylamine (20 mmol, 2.5 g) and 3-bromopropanol (10 mmol, 1.39 g) are added to the slurry. The stirred mixture is refluxed for about 7 hours under N2 (g), filtered, and concentrated in vacuo. The residue is dissolved in hot CHCl3, filtered and concentrated in vacuo to yield crude product as an oil (3.0-3.1 g) which is used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]([NH:27][NH2:28])=[O:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[C:35](OC)(OC)(OC)[CH3:36].C1CCN2C(=NCCC2)CC1.C(O)(=O)C>C(O)CCC>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([C:25]1[O:26][C:35]([CH3:36])=[N:28][N:27]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C(=O)NN)ccc2c1=O
Reactant: COC(C)(OC)OC
Solvent: CC(=O)O
Solvent: CCCCO
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nnc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)o1
Yield: 90.1 %

Procedure:
A mixture of tert-butyl[6-(hydrazinocarbonyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.23 g, 0.50 mmol) and trimethyl orthoacetate (2.0 mL, 11 mmol) in 1-butanol (10 mL) was refluxed for 20 min. To the reaction mixture was added 1,8-diazabicyclo[5.4.0]-7-undecene (0.075 mL, 0.50 mmol), and then the mixture was refluxed for 1 h. The resulting reaction mixture was neutralized with acetic acid (0.040 mL, 0.70 mmol) and concentrated under reduced pressure. The residue was partitioned between water (10 mL) and ethyl acetate (30 mL). The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1 (v/v)) to give tert-butyl[2-isobutyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.22 g, 91%) as crystals.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].[Cl-].[NH4+]>O.[Fe]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([S:5]([NH:4][CH:1]([CH3:3])[CH3:2])(=[O:7])=[O:6])=[CH:9][CH:10]=1
Reactant: CC(C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(C)NS(=O)(=O)c1ccc(N)cc1
Yield: 88.3 %

Procedure:
To a stirred solution of N-isopropyl-4-nitro-benzenesulfonamide (9.0 g, 37.0 mmol) ethanol (500 mL) was added iron powder (11.0 g, 196.0 mmol) and the solution of ammonium chloride (22.0 g, 392.0 mmol) in water (150 mL). After the reaction mixture was refluxed for 3 h, the iron was filtered off and the filtrate was basified to pH 9 by addition of sodium carbonate. The reaction mixture was extracted with ethyl acetate (300 mL×2). The extract was washed with water (130 mL×2) and brine (130 mL×2), dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 20-60% ethyl acetate in petroleum ether) to afford 4-amino-N-isopropyl-benzenesulfonamide (7.0 g, 89%) as a yellow powder: MS (ESI) M+1=215.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])[CH:12]=[CH:13][C:14]=1/[CH:15]=[CH:16]/[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][S:25]([CH2:28][CH2:29][CH2:30][CH3:31])(=[O:27])=[O:26])=[C:20]([O:32][CH3:33])[CH:19]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:28]([S:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][CH2:15][C:14]2[CH:13]=[CH:12][C:11]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:10][C:9]=2[OH:8])=[CH:19][C:20]=1[O:32][CH3:33])(=[O:27])=[O:26])[CH2:29][CH2:30][CH3:31]
Reactant: [H][H]
Reactant: CCCCS(=O)(=O)Oc1ccc(C/C=C/c2ccc(/C=C/C(=O)OC)cc2OCc2ccccc2)cc1OC
Agent: [Pd]
Solvent: CO
Product: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)OC)cc2O)cc1OC
Yield: 86.1 %

Procedure:
11 g (20 mmol) of methyl(E)-3-(3-benzyloxy-4-{(E)-3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propenyl}phenyl)acrylate are dissolved in 100 ml of methanol and 1.1 g (10% massique) palladium-on-charcoal are then added. The reaction medium est placed under 1 atmosphere of hydrogen for 24 hours, and then filtered through Celite and rinsed with dichloromethane, and the filtration liquors are concentrated. The residue is purified by chromatography on a column of silica eluted with an 8/2 heptane/ethyl acetate mixture. 8 g (73%) of methyl 3-(4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-3-hydroxyphenyl)propanoate are obtained.