Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]1[CH2:33][OH:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[C:4]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]2[CH2:33][OH:34])[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Reactant: OC[C@H]1COCCN1
Product: CCOC(=O)C1=C(CN2CCOC[C@@H]2CO)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 41.1 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.95 g, 2 mmol) was reacted with (S)-morpholin-3-ylmethanol (0.24 g, 2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a pale yellow solid (0.42 g, 41%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.CC(C)([O-])C.[K+].[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:17]>C1(C)C=CC=CC=1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][C:1]([O:5][CH2:6][CH3:7])=[O:8])=[CH:19][CH:20]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1ccc(F)cc1
Temperature: 78 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Diethyl carbonate (801 mL, 6.79 mole) was added dropwise over a 30 minute period to a stirring slurry of potassium t-butoxide (609.2 g, 5.43 mole) in toluene (9.5 L) under a nitrogen atmosphere. The reaction mixture was heated to 78° C. and 4-fluoroacetophenone (250 g, 1.81 mole) in toluene (250 mL) was added over a one hour time period. Heating of the reaction mixture was continued overnight. Then the reaction mixture was quenched with 1.5 N HCl(aq) and extracted with ethyl acetate (3×1 L). The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo leaving a brown liquid. The liquid was distilled to give the title compound as a colorless liquid (250 g, 79%). MS m/z 209 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1ccnc(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2ccnc(Cl)n2)n[nH]1
Temperature: 50 °C
Reaction time: 18 h
Yield: 25.8 %

Procedure:
A mixture of 2,4-dichloropyrimidine (2.97 g, 20 mmol), 3-amino-5-methyl-1H-pyrazole (2.14 g, 22 mmol), and N,N-diisopropylethylamine (2.82 g, 22 mmol) in dry THF (75 ml) was stirred at 50° C. for 18 hours. The solvent was removed by evaporation, and the residue partitioned between DCM (75 ml) and water (50 ml). The resulting precipitate was collected by filtration washed with water and then ether, and dried under vacuum at 50° C. to give the title compound (1.08 g, 26%) as a colourless crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[CH:10]=[N:11][N:12]([CH:19]([CH3:21])[CH3:20])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH3:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:23][C:24]2[CH:25]=[C:26]([CH3:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=2)[C:9]2[CH:10]=[N:11][N:12]([CH:19]([CH3:21])[CH3:20])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)cnn1C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(Nc2cc(C)c(=O)n(C)c2)c2ccc(Cl)cc2)cnn1C(C)C

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-isopropyl-1H-pyrazole-5-carboxylate (Step 36.3) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.94 min (HPLC 1); tR: 1.14 min (LC-MS 2); ESI-MS: 443 [M+H]+ (LC-MS 2); Rf=0.23 (EtOAc).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([CH:15]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[C:13]([C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14]
Reactant: CCOC(=O)C(C#N)c1cccc(OC)c1
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C#N)(Cc1ccccc1)c1cccc(OC)c1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a solution of diisopropylamine (7.80 ml, 54.7 mmol) in 100 ml dry tetrahydrofuran at −78° C. was added n-butyl lithium (34.2 ml, 54.7 mmol) and stirred for 1 h while the reaction mixture was allowed to warm up to −40° C. A solution of ethyl 2-cyano-2-(3-methoxyphenyl)acetate (10 g, 45.6 mmol) in 100 ml dry tetrahydrofuran was added and the mixture stirred for 30 min. Then (bromomethyl)benzene (8.13 ml, 68.4 mmol) was added and the reaction was stirred over night. The solvent was evaporated and the residue dissolved in ethyl acetate, which was washed with 10% citric acid, water and brine. The combined organic layers were dried over sodium bicarbonate, filtered and the solvent evaporated to obtain a yellow-orange oil. Purification on 120 g SiO2 using 20% ethyl acetate in cyclohexene afforded a clear colourless oil m=9.4 g (66.6%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH:24]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:25]([C:34]([O:36][CH3:37])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][CH2:2][CH2:3][O:4][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C@H:25]([NH:24][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1
Reactant: OCCBr
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OCCBr)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
2-Bromo-ethanol (0.61 mL, 8.03 mmol), followed by PPh3 (3.16 g, 12.05 mmol) was added to a solution of Boc-Tyr-OMe (2.85 g, 9.64 mmol) in anhydrous THF (50 mL). The mixture was cooled to 0° C. and DEAD (5.5 mL of 40% wt solution in toluene, 12.05 mmol) was added. The mixture was allowed to warm at room temperature and was stirred overnight. After the reaction was finished, the solvent was evaporated and the residue dissolved in EtOAc (100 mL) was washed with NaOH (0.1 M, 2×50 mL), followed by brine. The organic phase was dried over Na2SO4 and evaporated. The crude product was purified by flash column chromatography (SiO2, step-wise gradient from 2-40% EtOAc in Hexanes) to give 1A (1.61 g, 50%) as a white solid. 1H NMR (600 MHz, CDCl3): δ 7.04 (2H, d, J=8.4 Hz), 6.84 (2H, d, J=8.4 Hz), 4.96 (1H, d, J=7.8 Hz), 4.51-4.58 (1H, m), 4.27 (2H, t, J=6.6 Hz), 3.71 (3H, s), 3.62 (2H, t, J=6.6 Hz), 3.06 (1H, dd, J=13.8, 5.4 Hz), 3.00 (1H, dd, J=13.8, 5.4 Hz), 1.42 (9H, s); 13C NMR (150 MHz, CDCl3): δ 172.3, 157.2, 155.1, 130.4, 128.8, 114.8, 79.9, 67.9, 54.5, 52.2, 37.5, 29.1, 28.3; MS (ESI, m/z): 424 (M+Na)+.
Reaction SMILES: [Mg].[CH2:2]([N:9]1[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][N:11]=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.O1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH2:2]([N:9]1[C:13]([C:14]([OH:16])([CH2:19][CH2:20][C:21]2[CH:22]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:15])=[CH:12][N:11]=[CH:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)c1cncn1Cc1ccccc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Mg]
Product: CC(O)(CCc1ccccc1)c1cncn1Cc1ccccc1
Temperature: 25 °C

Procedure:
1.0 g of magnesium turnings are covered with 5 ml of dry tetrahydrofuran. To the mixture is added 7.8 g of (2-bromoethyl)benzehe in 30 ml of dry tetrahydrofuran at such a rate that a smooth reaction is maintained. The mixture is then heated under reflux for one hour. After being cooled to room temperature, 3.0 g of 1-(3-benzyl-3H-imidazol-4-yl)-ethanone in 20 ml of tetrahyrofuran is added dropwise to the Grignard reagent and the reaction mixture is refluxed for one hour. The cooled reaction mixture is poured into a cold dilute hydrochloric acid solution. Work-up of the mixture gives the crude product, which is recrystallized from ethyl acetate. The yield is 3.3 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[OH:12]>CCO.[Pd]>[NH2:9][C:5]1[CH:4]=[C:3]([OH:12])[CH:2]=[CH:7][C:6]=1[F:8]
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(O)ccc1F
Reaction time: 12 h
Yield: 69.9 %

Procedure:
2-Chloro-4-fluoro-5-nitrophenol (85 g, 0.45 mol) and 10% Pd/C (25 g, 0.023 mol) were combined in EtOH and hydrogenated (50 psi) for 12 h. The reaction mixture was filtered, concentrated in vacuo and purified by silica gel chromatography to provide 3-amino-4-fluorophenol (40 g 70% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 6.70 (dd, J=11.2, 8.8 Hz, 1H), 6.14 (dd, J=7.8, 2.4 Hz, 1H), 5.84 (m, 1H), 4.92 (s, 2H); MS (ESI) m/z: 128.2 (M+H+).
Reaction SMILES: O[CH2:2][CH:3]([C:7]1[N:16]=[C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[CH3:24])[CH:14]=[C:13]2[C:8]=1[CH:9]=[C:10]([NH:25][C:26]([CH:28]1[CH2:30][CH2:29]1)=[O:27])[N:11]=[CH:12]2)[CH2:4][CH2:5][OH:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C>[F:23][C:21]1[CH:20]=[CH:19][C:18]([CH3:24])=[C:17]([C:15]2[CH:14]=[C:13]3[C:8]([CH:9]=[C:10]([NH:25][C:26]([CH:28]4[CH2:30][CH2:29]4)=[O:27])[N:11]=[CH:12]3)=[C:7]([CH:3]3[CH2:4][CH2:5][O:6][CH2:2]3)[N:16]=2)[CH:22]=1
Reactant: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(C(CO)CCO)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(C2CCOC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.5 %

Procedure:
To a solution of N-(5-(1,4-dihydroxybutan-2-yl)-7-(5-fluoro-2-methylphenyl)-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (45 mg, 0.1 mmol) in tetrahydrofuran (1 mL) was added triphenylphosphine (61 mg, 0.23 mmol) followed by diisopropyl azodicarboxylate (0.028 mL, 0.14 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-60% ethyl acetate in heptane) and then repurified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (10 mg, 20% over two steps). 1H NMR (400 MHz, DMSO) δ 11.18 (s, 1H), 9.30 (s, 1H), 8.83 (s, 1H), 8.03 (s, 1H), 7.41-7.31 (m, 2H), 7.19 (td, J=8.5, 2.8 Hz, 1H), 4.31-4.23 (m, 1H), 4.20 (t, J=7.7 Hz, 1H), 4.00-3.95 (m, 1H), 3.94-3.86 (m, 2H), 2.42-2.35 (m, 5H), 2.10 (m, 1H), 0.95-0.82 (m, 4H). LCMS (Method E): RT=5.416 min, M+H+=392.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:13])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([I:13])=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(Cl)c(I)cc1O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c(I)c([N+](=O)[O-])c1O
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
To a mixture of methyl 5-chloro-2-hydroxy-4-iodobenzoate (5.1 g, 16 mmol) in acetic acid (50 mL) was added nitric acid (6.8 mL) at room temperature. The reaction was stirred at 60° C. for 90 min and then cooled and poured into ice water. The precipitate was collected by filtration, washed with water and air dried to give the desired product (5.15 g, 88%).
Reaction SMILES: CO.C([O:6][C@@H:7]1[CH2:42][N:10]2[C:11]3[C:16]([N:17]([C:19](=[O:41])[C:20]4[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:40])[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:22][CH:21]=4)[CH2:18][C@@H:9]2[CH2:8]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[OH:6][C@@H:7]1[CH2:42][N:10]2[C:11]3[C:16]([N:17]([C:19](=[O:41])[C:20]4[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:40])[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)=[CH:24][CH:25]=4)[CH2:18][C@@H:9]2[CH2:8]1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: CC(=O)O[C@H]1C[C@H]2CN(C(=O)c3ccc(NC(=O)c4ccccc4-c4ccccc4)cc3)c3ccccc3N2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc(C(=O)N2C[C@@H]3C[C@H](O)CN3c3ccccc32)cc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.1 %

Procedure:
To 20 ml of methanol, there were added 0.57 g of (2S, 3aS)-2-acetoxy-5-[4-[(2-phenylbenzoyl)amino]benzoyl]-1,2,3,3a,4,5-hexahydro-pyrrolo [1,2-a]quinoxaline prepared in Example 5 and 0.2 g of anhydrous potassium carbonate and the reaction solution was stirred at room temperature for 15 hours. After concentration of the reaction solution, the resulting residue was diluted with water and then extracted with ethyl acetate. The resulting organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was recrystallized from ethyl acetate-hexane to give 0.52 g (yield 88.0%) of the title compound.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:7]=[CH:6][N:5]=1.[F:20][CH2:21][CH2:22][NH:23][C:24](=O)[O:25]C1C=CC=CC=1.O>CN(C)C=O>[F:20][CH2:21][CH2:22][NH:23][C:24]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([NH2:3])[CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1)=[O:25]
Reactant: O=C(NCCF)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Oc2ccc3c(ccn3C(=O)NCCF)c2)ccn1
Reaction time: 0.08 h
Yield: 69.2 %

Procedure:
Sodium hydride (60% in oil) (360 mg) was added to a solution of 2.0 g of 5-[(2-amino-4-pyridyl)oxy]-1H-indole in 30 ml of dimethylformamide at room temperature. After stirring for 5 minutes, the mixture was placed in an ice bath and 1.8 g of phenyl N-(2-fluoroethyl)carbamate was added while cooling. The mixture was returned to room temperature and stirred for 30 minutes, after which water was added and extraction was performed with ethyl acetate. The extract was passed through a glass filter coated with silica gel. The ethyl acetate layer was washed once with bicarbonate water and dried over magnesium sulfate. The drying agent was filtered off to obtain 1.93 g of a faint brown powder.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].[C:12]1([Si:18]2(CCCCC)[CH2:23][CH2:22][CH:21]([SiH:24]3[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)C=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][C@H:27]2[CH2:28][CH2:29][Si@H:24]([CH:21]3[CH2:22][CH2:23][SiH:18]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:19][CH2:20]3)[CH2:25][CH2:26]2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CCCCC[Si]1(c2ccccc2)CCC([SiH]2CCC(O)CC2)CC1
Product: CCCCC[SiH]1CCC([Si@H]2CC[C@H](OC(=O)c3ccc(C#N)cc3)CC2)CC1

Procedure:
The general procedure of Example 31 was repeated using 4-cyanobenzoic acid and 4-(4-phenyl-4-n-pentyl-4-silacyclohexyl)-4-silacyclohexanol, thereby obtaining the intended product.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[CH2:15]([O:19][C:20](Cl)=[O:21])[CH:16]([CH3:18])[CH3:17].Cl>O>[CH2:15]([O:19][C:20]([NH:1][CH:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11])=[O:21])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)COC(=O)Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)COC(=O)NC(Cc1ccccc1)C(=O)O
Temperature: 12.5 °C
Reaction time: 3.5 h

Procedure:
L-phenylalanine (50 gm) in water (50 mL) was stirred for about 30 minutes and reaction mass was cooled to 10-15° C. To the resulting solution, aq. NaOH was added followed by addition of isobutylchloroformate (45.5 gm). The reaction mass was stirred at about 25° C. for about 3-4 h and pH was adjusted to 2-3 by addition of conc. HCl at 10-15° C. Reaction mass was stirred at 10-15° C. for 1 h, filtered, washed with water and dried to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[C:19]1([NH:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:28][CH2:27][CH2:26][NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: NCCNc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCCNc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and N-phenylethylenediamine in DME. ES-MS m/e (%): 321 (M+H+, 100).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[OH-].[Na+].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+]>>[CH2:9]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@H](N)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
L-Alanine (44.6 g, 0.5 mole)) was taken up in 250 mL 2N-NaOH to which was added benzaldehyde (50 mL, 0.5 mole). The resulting suspension was stirred at room temperature for approximately 20 minutes. After this period a pale yellow solution resulted. This solution was cooled in an ice/acetone bath and sodium borohydride (5.7 g, 0.15 mole) added in 1.0 g portions while keeping the temperature below 15° C. A large flask is necessary as a good deal of foaming takes place during the course of the reaction. The above process was repeated with the same quantities of benzaldehyde and sodium borohydride. However, this time after the addition of the sodium borohydride, the resulting solution was stirred for about 11/2 hours at room temperature and then washed with either (100 mL, ×2). The ether extracts were discarded and the aqueous phase acidified with 6N-HCl to pH 6-7. The product precipitated out of the solution. The resulting mixture was left overnight in the refrigerator and filtered the following morning. The product was washed with a little cold water and air dried. Yield 67 g (75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH2:14][CH2:15][CH2:16][CH2:17]Cl)[CH3:13].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH2:14][CH2:15][CH2:16][CH2:17][N:29]1[CH2:28][CH2:27][N:26]([C:23]2[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=2)[CH2:31][CH2:30]1)[CH3:13]
Reactant: CC1(CCCCCl)C(=O)Nc2c(Cl)cc(Cl)cc21
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: CC1(CCCCN2CCN(c3ccc(Cl)cc3)CC2)C(=O)Nc2c(Cl)cc(Cl)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 5,7-dichloro-3-(4-chlorobutyl)-3-methyl-1,3-dihydro-2H-indol-2-one and 1-(4-chlorophenyl)-piperazine.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:9])[C:4]1[O:8][CH:7]=[CH:6][CH:5]=1.[Cl:10][C:11]1[S:15][C:14]([S:16]([NH:19][C:20]2[C:25](Br)=[N:24][CH:23]=[C:22]([Cl:27])[N:21]=2)(=[O:18])=[O:17])=[CH:13][CH:12]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>COCCOC>[Cl:10][C:11]1[S:15][C:14]([S:16]([NH:19][C:20]2[C:25]([O:9][CH2:3][C:4]3[O:8][CH:7]=[CH:6][CH:5]=3)=[N:24][CH:23]=[C:22]([Cl:27])[N:21]=2)(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: OCc1ccco1
Reactant: O=S(=O)(Nc1nc(Cl)cnc1Br)c1ccc(Cl)s1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=S(=O)(Nc1nc(Cl)cnc1OCc1ccco1)c1ccc(Cl)s1
Temperature: 40 °C
Reaction time: 16 h
Yield: 28.7 %

Procedure:
Sodium hydride (0.04 g of a 60% dispersion in oil) was added to furfurylalcohol (0.034 g) in 1,2-dimethoxyethane (1.0 mL). After 5 minutes 5-chloro-N-(3-bromo-6-chloro-2-pyrazinyl)-2-thiophenesulphonamide (0.1 g) was added and the mixture heated at 40° C. After 16 h, 5% aqueous citric acid (5.0 mL) was added and the mixture extracted with ethyl acetate (2×20 mL). The combined extracts were washed with brine, dried (MgSO4) and the solvent evaporated. Chromatography on silica gel eluting with dichloromethane gave the title compound as a white solid (0.03 g).
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[CH3:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH2:12]([O:13][C:14]1[CH:15]=[C:16]([NH:20][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:2](=[O:3])[CH3:1])[CH:17]=[CH:18][CH:19]=1)[CH3:11]
Reactant: CCOc1cccc(N)c1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cccc(Nc2ccccc2C(C)=O)c1

Procedure:
5 g of phenacyl bromide and 3.78 g of m-phenetidine are stirred at 50° C. for 2.5 h in 50 ml of ethanol in the presence of 5.85 g of powdered Na2CO3. The mixture is then cooled and concentrated in an RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na2SO4 and concentrated. The residue is slurried with ether and the crystals are filtered off, 2'-(3-ethoxyphenylamino)acetophenone being obtained. Further product is again obtained from the mother liquor after addition of petroleum ether.
Reaction SMILES: [OH:1][CH:2]([CH2:21][OH:22])[CH2:3][NH:4][CH2:5][CH2:6][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][CH3:20].[OH-].[K+].C[O:26][C:27](=O)[CH:28]([OH:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[OH:1][CH:2]([CH2:21][OH:22])[CH2:3][N:4]([CH2:5][CH2:6][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][CH3:20])[C:27](=[O:26])[CH:28]([OH:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCCCCCNCC(O)CO
Reactant: CCCCCCC(O)C(=O)OC
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCN(CC(O)CO)C(=O)C(O)CCCCCC

Procedure:
N-(2,3-dihydroxypropyl)-N-hexadecylamine (1.0 g, 0.0032 mole) and potassium hydroxide (0.01 g, 0.18 mmole) were heated to 85° C. under vacuum and methyl-2-hydroxyoctanoate (0.55 g, 0.0032 mole) was heated and added dropwise to the reaction. The reaction was heated under vacuum for 6 hours. A waxy off-white solid was obtained (crude yield=1.39 g). The waxy solid was recrystalized from hot hexane (yield=0.88 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](O)=[O:14])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:27]>C1(C)C=CC=CC=1.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([Cl:27])=[O:14])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(=O)O)sc2-c2ccc(F)cc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2cc(C(=O)Cl)sc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.8 %

Procedure:
A mixture of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxylic acid (7.1 g) and phosphorus pentachloride (4.1 g) in toluene (100 ml) and tetrahydrofuran (25 ml) was stirred at ambient temperature for 1 hour. The mixture was concentrated to dryness to give pale yellow crystals of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carbonyl chloride (8.1 g).