Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]([CH3:15])([CH2:12][CH:13]=[CH2:14])[C:9]([OH:11])=[O:10].CN(C=O)C.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.C(OCC)C>[CH3:7][C:8]([CH3:15])([CH2:12][CH:13]=[CH2:14])[C:9]([O:11][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:10]
Reactant: C=CCC(C)(C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: C=CCC(C)(C)C(=O)OCc1ccccc1

Procedure:
To a mixture of K2CO3 (1.58 g, 11.5 mmol), 2,2-dimethylpent-4-enoic acid (1.30 g, 10.1 mmol) and DMF (8.1 mL) was added benzyl bromide (1.40 g, 8.19 mmol) slowly over 15 minutes. After 4 hours the mixture was diluted with a mixture of water (80 mL) and diethylether (80 mL). The organic layer was separated and sequentially washed with 80 mL of 5% aqueous sodium bicarbonate, saturated copper sulfate, slightly acidic water, half-saturated brine, and then saturated brine. The organics were then dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound which was used without further purification. MS: m/z=219 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[C:43]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][N:44]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:43]4[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][N:44]=4)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.2 %

Procedure:
A mixture of 59 mg (0.1 mmol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate, 42 mg (0.3 mmol) of 2-chloro-5-nitropyridine and 65 mg (0.2 mmol) of cesium carbonate in 0.5 mL of dimethyl formamide was stirred at rt for 12 h. The mixture was diluted with ethyl acetate and extracted with water. Evaporation of the solvent and chromatography on silica gel (1:1 ethyl acetate/hexane) gave the title compound (38 mg) as a white foam. 1H-NMR:0.83(6H,dd), 1.7(2H,m),1.8(2H,m), 2.8-3.2(7H,m), 3.7(3H.m), 3.8-4(4H,m), 5.0(2H,m), 5.62(1H,d), 6.03(2H,s), 6.85(1H,d), 6.97(1H,d), 7.02(2H,d), 7.18(1h,s), 7.35(2H,d), 7.4(1H,d), 8.42(1H,d), 8.90(1H,d). MS: 715
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:14][CH2:13][CH:12](CCCCC)[CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[CH:20]1[CH2:25][CH2:24][CH:23](C2CCC(O)CC2)[CH2:22][CH2:21]1.[H-].[Na+].Br[CH2:36][CH3:37].[OH2:38]>CN(C)C=O.C1(C)C=CC=CC=1>[F:8][C:7]1[C:2]([F:1])=[C:3]([CH:20]2[CH2:21][CH2:22][CH:23]([CH2:13][CH2:14][CH2:9][CH2:10][CH3:11])[CH2:24][CH2:25]2)[CH:4]=[CH:5][C:6]=1[C:9]1([CH:7]2[CH2:2][CH2:3][CH:4]([O:38][CH2:36][CH3:37])[CH2:5][CH2:6]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CCCCCC1CCC(c2ccc(C3CCC(C4CCC(O)CC4)CC3)c(F)c2F)CC1
Reactant: O
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCC1CCC(c2ccc(C3(C4CCC(OCC)CC4)CCCCC3)c(F)c2F)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
4′-(2,3-Difluoro-4-(4-pentylcylohexyl)phenyl)bi(cyclohexane)-4-ol (48) (5.0 g) synthesized according to the method described in Example 7, sodium hydride (0.59 g) and dimethylformamide (50 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated to 60° C. The mixture was stirred for 1 hour, then bromoethane (49) (1.34 g) dissolved in dimethylformamide (10 ml) was added dropwise thereto, and the mixture was heated to 120° C. The stirring was continued for 2 hours, and cooled slowly to room temperature, and then water (200 ml) and toluene (200 ml) were added and mixed thereto. The mixture was then allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with water and a saturated aqueous solution of sodium hydrogencarbonate and brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and heptane (toluene:heptane=2:1 by volume) as an eluent and silica gel as a stationary phase powder, and further purified by means of recrystallization from a mixed solvent of heptane and Solmix (heptane: Solmix=1:1 by volume), and dried, giving 3.2 g of 4-(2,3-difluoro-4-(4-pentylcyclohexyl)phenyl-4′-ethoxybi(cyclohexane) (No. 168). The yield based on the compound (48) was 59.5%.
Reaction SMILES: Cl.C(O[C:7]([N:9]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:11][CH2:10]1)=[O:8])(C)(C)C.Cl.CO.[CH2:33]([Cl:35])[Cl:34].O1[CH2:40][CH2:39][CH2:38][CH2:37]1>CO>[ClH:34].[Cl:35][C:33]1[CH:37]=[C:38]2[C:26](=[CH:25][CH:24]=1)[NH:27][C:40]([C:7]([N:9]1[CH2:10][CH2:11][N:12]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[CH:22][CH:23]=3)(=[O:16])=[O:17])[CH2:13][CH2:14]1)=[O:8])=[CH:39]2
Reactant: ClCCl
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(-c3ccncc3)cc2)CC1
Agent: Cl
Solvent: CO
Product: O=C(c1cc2cc(Cl)ccc2[nH]1)N1CCN(S(=O)(=O)c2ccc(-c3ccncc3)cc2)CC1
Reaction time: 0.5 h

Procedure:
A saturated solution of hydrochloride in methanol (10 ml) was added to 1-(tert-butoxycarbonyl)-4-[4-(pyridin-4-yl)phenylsulfonyl]piperazine (180 mg). After stirring for 30 minutes, the solvent was distilled off under reduced pressure. To a solution of the residue in N,N-dimethylformamide (10 ml) were added (5-chloroindol-2-yl)carboxylic acid (90.0 mg), 1-hydroxybenzotriazole (75.5 mg) and 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107 mg) and diisopropylethylamine (233 μg) at room temperature. After stirring for 3 days, methylene chloride (100 ml) and water (500 ml) were added to the reaction mixture to separate it into layers. The water layer was extracted with methylene chloride (50 ml). The organic layers were combined, washed with water (500 ml) and a saturated aqueous solution (100 ml) of sodium bicarbonate, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 20 g, methylene chloride:acetone=3:1→1:1), whereby the title compound (97.5 mg) was obtained as a white solid. The resulting compound was dissolved in hydrochloric acid-methanol-methylene chloride-tetrahydrofuran, followed by concentration, whereby the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.Cl.O[NH2:18].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)#[N:18]
Reactant: Cc1ccc(-c2ccccc2C=O)cc1
Reactant: NO
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
A mixture of 4′-methyl-2-biphenylcarbaldehyde (2.0 g) and hydroxyamine hydrochloride (1.0 g) in pyridine (10 ml) was Stirred at room temperature for 15 min., followed by addition of acetic anhydride (4.1 g). The reaction mixture was stirred at 90–100° C. for 1 hr. and concentrated to dryness. After addition of water to the residue, the precipitated crystals were collected by filtration. Recrystallization from hexane gave colorless needles (1.5 g, 79%).
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[CH3:30][N:31]1[CH2:35][CH2:34][CH2:33][CH:32]1[CH2:36][CH2:37][NH2:38]>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:38][CH2:37][CH2:36][CH:32]2[CH2:33][CH2:34][CH2:35][N:31]2[CH3:30])=[O:29])[S:14][N:13]=1
Reactant: CN1CCCC1CCN
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCC3CCCN3C)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-(1-methyl-pyrrolidin-2-yl)-ethylamine by the procedure analogous to Example 1. MS (APCl, m/z): 454 [M+H]+.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([O:14][C:15](=[O:18])[CH2:16][SH:17])[CH3:13].F[C:20]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:21]=1[CH:22]=O>C1COCC1.[NH4+].[Cl-].CCOC(C)=O>[F:29][C:28]([F:30])([F:31])[C:26]1[CH:27]=[CH:20][C:21]2[CH:22]=[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:18])[S:17][C:24]=2[CH:25]=1
Reactant: CCOC(=O)CS
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2s1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 5 equiv) in THF (1 M) at 0° C. was added a solution of ethyl-2-mercaptoacetate (1.15 equiv) and the reaction stirred at 0° C. for 20 min. A solution of 2-fluoro4-(trifluoromethyl)benzaldehyde (1 equiv) in THF (2 M) was added and the reaction was stirred for an additional 2 h at 0° C. The reaction was diluted with half-saturated NH4Cl and EtOAc. The organic layer was washed with brine and dried over magnesium sulfate. The volatiles were removed under reduced pressure to obtain the title compound as a viscous oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:38][CH3:39])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:40]1(NCC(F)(C)C(OCC)=O)CCCCC1.CC1(C(OC)=O)CO1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:38][CH3:39])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:40][CH2:5]1
Reactant: CCOC(=O)C(C)(F)CNC1CCCCC1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(F)C(=O)N2C
Agent: COC(=O)C1(C)CO1
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(C)(F)C(=O)N2C

Procedure:
The title compound was synthesized using an analogous procedure to that described in connection with Compound 87 except that ethyl 3-(cyclohexylamino)-2-fluoro-2-methylpropanoate, made from commercially available starting material methyl 2-methyloxirane-2-carboxylate, was used and the final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.36 (m, 2H) 1.28-2.08 (m, 17H) 2.19 (s, 3H) 2.81 (d, J=10.6 Hz, 2H) 3.26 (s, 3H) 3.60-3.85 (m, 3H) 3.95 (s, 3H) 4.45 (m, 1H) 7.47 (d, J=8.3 Hz, 1H) 7.50 (s, 1H) 7.75 (s, 1H) 7.97-8.20 (m, 2H) 8.32 (d, J=8.3 Hz, 1H). [M+H] calc'd for C29H40FN7O3, 554. found 554.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C@@H:7]([C:16](O)=[O:17])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C@H:7]([NH:8][C:9](=[O:10])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:16][OH:17])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)cc1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 4-bromo-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-phenylalanine (72.6 mmol), in anhydrous diethyl ether (550 mL) at 0° C. was added slowly lithium aluminum hydride, 95% (108.9 mmol). The resulting solution was stirred for an additional 2 h at 0° C. The reaction was then carefully quenched with a saturated aqueous solution of sodium bicarbonate (73 mL) which stirred at RT for half an hour. Lithium aluminium salts crashed out of solution and were removed by filtration. The filtrate was concentrated and vacuum pumped for 24 h to afford the title product as a white solid (97%). ESMS [M+H]+: 331.2.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=1>>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: C[C@H](N)C(=O)O
Product: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O

Procedure:
The title compound was prepared using L-alanine (Nova Biochem) and 3-chlorophenyl acetic acid (Aldrich) by following General Procedures F' or G', followed by hydrolysis using General Procedure D'.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[S:3].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:21]1([C:19]2[N:1]=[C:2]([CH:4]3[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]3)[S:3][CH:18]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccccc3)cs2)CC1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
A mixture of tert-butyl 4-(aminocarbonothioyl)piperidine-1-carboxylate (1.00 g, 7.24 mmol), 2-bromoacetophenone (1.58 g, 7.96 mmol), potassium carbonate (1.00 g, 7.24 mmol) and N,N-dimethylformamide (30 ml) was stirred at 110° C. for 1.5 hours. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) to obtain the desired product (1.38 g, 55.2%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:9][CH2:10][N:11]([CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[CH:4][CH:3]=1.CS[C:29]([NH:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH:40]=1)=[CH:30][N+:31]([O-:33])=[O:32].C(OCC)(=O)C.CO>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:29]([NH:34][CH2:35][CH2:36][CH2:37][O:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)[CH:40]=2)=[CH:30][N+:31]([O-:33])=[O:32])[CH3:20])=[CH:4][CH:3]=1.[NH3:11]
Reactant: CN(CCCCCCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Reactant: CSC(=C[N+](=O)[O-])NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(CCCCCCCNC(=C[N+](=O)[O-])NCCCOc1cccc(CN2CCCCC2)c1)CCC(c1ccc(Cl)cc1)c1ccccn1
Product: N

Procedure:
A mixture of 0.73 g (1.9 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,7-heptanediamine and an equimolar amount of 1-methylthio-1-[3-[3-(piperidinomethyl)phenoxy]propyl]amino-2-nitro-ethene is heated under reflux for 12 hours in 20 ml of acetonitrile. The batch is then freed of solvent and the title compound is isolated in the form of a viscous oil by means of preparative thick-layer chromatography (eluant: ethyl acetate/methanol 9+1, ammonia atmosphere); MS (+FAB method): m/z (rel. int. [%])=691 ([M+H]30 12), 230 (100).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][C:21]2([CH3:25])[CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:26][C:27]1[O:28][C:29]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[CH:32][C:30]=2[N:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:1][C:2]1[N:3]=[C:4]([O:20][C:21]2([CH3:25])[CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:34]3[CH:33]=[CH:32][C:30]4[N:31]=[C:27]([CH3:26])[O:28][C:29]=4[CH:35]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: Cc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2o1
Reactant: CC1(Oc2nc(Cl)nc3c2c(I)cn3COCC[Si](C)(C)C)CCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5(C)CCC5)c34)cc2o1
Temperature: 70 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
To a degassed mixture of 2-chloro-5-iodo-4-(1-methylcyclobutoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (1.1 equiv) and tripotassium phosphate trihydrorate (3.0 equiv) in a 9:1 mixture of 1,4-dioxane and water (0.45 M) was added palladium 1,1-bis(diphenylphosphion)-ferrocene dicholoride (0.1 equiv). The reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-25% ethyl acetate in petroleum ether) to afford the title compound (49% yield) as a yellow solid. MS (ESI) m/z 499.2 [M+H]+.
Reaction SMILES: O=[C:2]1[C:11]2[C:10]([C:12](OC)=O)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH2:28].[NH2:29][NH2:30]>O>[C:16]1([CH:4]2[NH:5][C:6]3[C:11]4[C:2](=[N:29][NH:30][C:12](=[O:28])[C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH:3]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccccc1)C(c1ccccc1)N2
Reactant: NN
Reactant: O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1ccccc1
Yield: 16 %

Procedure:
A mixture of methyl 4-oxo-2,3-diphenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (100 mg, mmol) in hydrazine monohydrate (25 mL) was heated to reflux for 20 hr. The mixture was diluted with water (30 mL), extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=20:1 to 8:1) to give 8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (15.6 mg, yield 16%) as a white solid. MS (ESI) m/z: 340(M+1)+. 1H-NMR (400 MHz, CDCl3) δ 4.22-4.25 (d, J=9.6 Hz, 1H), 4.66-4.69 (d, J=9.6 Hz, 1H), 7.02-7.06 (m, 3H), 7.16-7.26 (m, 8H), 7.57-7.61 (t, J=7.8 Hz, 1H), 7.74-7.76 (d, J=7.6 Hz, 1H), 9.82 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=O)[CH3:7].C[N:10]([CH:12]=O)C.CC([N:17](C)C)=O.CC(O)=O.NN>C(Cl)Cl>[NH:17]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[CH:7][CH:12]=[N:10]1
Reactant: CC(=O)N(C)C
Reactant: CN(C)C=O
Reactant: CC(=O)c1nccs1
Agent: NN
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1cc(-c2nccs2)[nH]n1
Temperature: 25 °C
Yield: 100 %

Procedure:
Dissolved 1-(thiazol-2-yl)ethanone (1-BA-1, 5 g, 39.7 mmole) in DMF DMA (9.5 g, 2 eq). The resulting mixture was warmed to 100° C. until all the ketone starting material was consumed. This material was concentrated under reduced pressure to give 6.5 g of crude intermediate. This material was dissolved in 25 mL of DCM and 5 mL of HOAc was added, followed by hydrazine (5 g, 4 eq) at 0° C. The resulting mixture was heated at reflux until all the starting material was consumed. The reaction mixture was cooled to rt and neutralized with 30 mL of a saturated NaHCO3 solution. The layers were separated and the aqueous layer was extracted with DCM (2×50 mL). The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by MPLC (eluted with 0-20% MeOH/DCM) to give 2-(1H-pyrazol-5-yl)thiazole (Compound 2-BA-1, ˜6 g). LC/MS: 152.0 m/z (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[CH:13]=[C:12]([NH2:14])[C:11]([NH2:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].[Cl:17][C:18]1[C:31]([N:32]=[C:33]=S)=[C:30]([Cl:35])[CH:29]=[CH:28][C:19]=1[CH2:20][NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].FC(F)(F)C(=N[Si](C)(C)C)O[Si](C)(C)C.CC(C)N=C=NC(C)C>CC(O)=O.CC#N>[Cl:17][C:18]1[C:19]([CH2:20][NH:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:28][CH:29]=[C:30]([Cl:35])[C:31]=1[NH:32][C:33]1[NH:14][C:12]2[CH:13]=[C:5]([O:4][CH2:3][CH:2]([F:16])[F:1])[C:6]([C:7]([OH:9])=[O:8])=[CH:10][C:11]=2[N:15]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: Nc1cc(OCC(F)F)c(C(=O)O)cc1N
Agent: CC(C)N=C=NC(C)C
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)O)c(OCC(F)F)cc3[nH]2)c1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-(2,2-difluoro-ethoxy)-4,5-diamino-benzoic acid (732 mg, 3.15 mmol), N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (1.00 g, 3.15 mmol) and MeCN (15 mL) is stirred for 48 h, then BSTFA (1.03 mL, 3.15 mmol) is added and it is stirred at reflux for 10 min. Then DIC (0.494 mL, 3.15 mmol) is added and it is stirred for another 4 h. The mixture is cooled to rt, diluted with HOAc and concentrated. The residue is stirred with 1N NaOH, filtered and the filtrate is acidified with 4N HCl, extracted with EtOAc and purified via chromatography [DCM→DCM+10% EtOH/HOAc (95:5)] to give the subtitle compound.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:5]=[C:4]1[CH3:18].[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C.O>C1COCC1>[CH3:18][C:4]1[C:3](=[N:2][O:1][S:20]([CH3:19])(=[O:22])=[O:21])[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]#[N:11])[CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1=CC(=C(C#N)c2ccccc2)C=CC1=NO
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1=CC(=C(C#N)c2ccccc2)C=CC1=NOS(C)(=O)=O
Temperature: 0 °C
Yield: 52.3 %

Procedure:
16.7 g (70 mmol) of crude (4-Hydroxyimino-3-methyl-cyclohexa-2,5-dienylidene)-phenylacetonitrile are dissolved in 100 ml of THF and cooled in an ice bath. After adding 6.0 ml (77 mmol) of methanesulfonyl chloride, 14.8 ml (106 mmol) of triethylamine are added dropwise to the solution, keeping the temperature below 10° C. The reaction mixture is stirred in the ice bath for 30 min., poured into 250 ml of iced water, and extracted with ethyl acetate. The organic phase is washed with 0.2 N hydrochloric acid, water, and saturated aqueous sodium chloride. The organic phase is dried over MgSO4, the solvent is distilled off, and the residue is purified by recrystallization from toluene. 11.5 g (52%) of (3-Methyl-4-methylsulfonyloxyimino-cyclohexa-2,5-dienylidene)-phenyl-acetonitrile are obtained in the form of bright yellow crystals having a melting point of 136-138° C.(dec.).