Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:9](Cl)(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[Na+].S(=O)(=O)(O)O>O>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCC(=O)N1CCC[C@H]1C(=O)O
Yield: 92.7 %

Procedure:
Proline (manufactured by Ajinomoto Co., Inc., 34.54 g) was dissolved in water (100 g), and decanoyl chloride (manufactured by Tokyo Chemical Industry Co., Ltd., 52.01 g) and 25% aqueous sodium hydroxide solution were added while adjusting to pH 12. The mixture was neutralized with 75% sulfuric acid, and the aqueous layer was removed. Water and ethyl acetate were further added, and the aqueous layer was removed. Ethyl acetate was evaporated under reduced pressure to give decanoyl proline (68.12 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:9]=O)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:11]([O:15][C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:9][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: Cc1cnc(C=O)c(C)c1
Product: Cc1cnc(CNCCCCNC(=O)OC(C)(C)C)c(C)c1

Procedure:
Colorless oil prepared from 3,5-dimethyl-pyridine-2-carbaldehyde and (4-amino-butyl)-carbamic acid tert-butyl ester 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.53-1.60 (m, 4H), 2.27 (s, 6H), 2.65-2.75 (m, 2H), 3.10-3.16 (m, 2H), 3.83 (s, 2H), 4.76 (s, br, 1H), 7.24 (s, 1H), 8.21 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1B(O)O>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1
Reactant: COc1ccc(Cl)c(B(O)O)c1
Reactant: Nc1c(F)cc(Br)cc1Cl
Product: COc1ccc(Cl)c(-c2cc(F)c(N)c(Cl)c2)c1
Yield: 31 %

Procedure:
The title compound (39 mg) was prepared from 4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.44 mmol) and 2-chloro-5-methoxyphenylboronic acid (106 mg, 0.62 mmol) as a pale-yellow solid.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].Br[CH2:30][CH:31]=[CH2:32].[Cl-].[NH4+]>O1CCCC1.O>[CH2:32]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1)[CH:31]=[CH2:30]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 101.6 %

Procedure:
A solution of 1-(1,1-Dimethylethyl) 4-ethyl 1,4-piperidinedicarboxylate (25.0 g, 97 mmol) in tetrahydrofuran (100 mL) was added slowly to a stirred, cooled (−78° C.) solution of potassium hexamethyldisilazide (29.0 g, 145 mmol) in tetrahydrofuran (150 mL), maintaining the internal temperature below −65° C. The mixture was stirred at −78° C. for 30 minutes, then 3-bromopropene (12.6 mL, 145 mmol) was added dropwise over 10 minutes. The mixture was stirred at −78° C. for 1 hour, then saturated aqueous ammonium chloride (400 mL) and water (100 mL) were added and the mixture was warmed to room temperature. The mixture was extracted with ethyl acetate (3×400 mL) and the combined organic fractions were washed with aqueous citric acid (10%, 2×250 mL), saturated aqueous sodium hydrogen carbonate (400 mL) and brine (200 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (29.3 g, 100%). 1H NMR (400 MHz, CDCl3) δ 5.75–5.60 (1H, m), 5.10–5.00 (2H, m), 4.16 (2H, q, J 7 Hz), 3.92–3.78 (2H, m), 2.90 (2H, br t, J 14 Hz), 2.26 (2H, d, J 7 Hz), 2.08 (2H, br d, J 14 Hz), 1.45 (9H, s), 1.45–1.30 (2H, m), and 1.26 (3H, t, J 7 Hz).
Reaction SMILES: Br.Br.[NH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[O:15])[CH2:7][CH2:6]1.[NH2:23][C:24]1[C:32]([Cl:33])=[CH:31][C:27]([C:28](O)=[O:29])=[C:26]([O:34][CH3:35])[CH:25]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[NH2:23][C:24]1[C:32]([Cl:33])=[CH:31][C:27]([C:28]([NH:3][CH2:4][CH:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)=[O:15])[CH2:7][CH2:6]2)=[O:29])=[C:26]([O:34][CH3:35])[CH:25]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: NCC1CCN(CCCC(=O)c2ccc(O)cc2)CC1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCC(=O)c2ccc(O)cc2)CC1
Yield: 78.7 %

Procedure:
4-Aminomethyl-1-(4-(4-hydroxyphenyl)-4-oxobutyl)piperidine dihydrobromide (3.67 g) as a starting compound, 4-amino-5-chloro-2-methoxybenzoic acid (1.69 g), triethylamine (4.65 ml), 1-hydroxybenzotriazole (1.20 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.69 g) were reacted and purified in the same manner as in Example 270 to give 3.03 g of 4-amino-5-chloro-2-methoxy-N-((1-(4-(4-hydroxyphenyl)-4-oxobutyl)piperidin-4-yl)methyl)benzamide, m.p. 199°-201° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]#[N:17])[C:13]([NH2:18])=[N:12]2)=[CH:7][CH:6]=1)[CH3:2].[C:20](Cl)(=[O:22])[CH3:21].N1C=CC=CC=1.O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]#[N:17])[C:13]([NH:18][C:20](=[O:22])[CH3:21])=[N:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(N)n2)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(NC(C)=O)n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.6 %

Procedure:
To a solution of 4-(3-amino-4-cyanopyrazole-1-yl)benzoic acid ethyl ester (0.1 g) in tetrahydrofuran (4 mL) were added acetyl chloride (0.12 g) and pyridine (0.15 g), and this mixture was stirred at room temperature for 12 hours. This reaction mixture was poured into water, and the precipitated solid was collected by filtration. This obtained solid was washed with ethyl acetate, dried under reduced pressure at 50° C. to give the title compound (0.088 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[CH2:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: CN(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1cc(I)cn1
Reaction time: 24 h
Yield: 79.8 %

Procedure:
4-iodo-1H-pyrazole (0.95 g, 4.94 mmol) and 2-bromo-N,N-dimethylacetamide (Preparation 98, 0.82 g, 4.94 mmol) were dissolved in dry DMF (10 ml). To the stirred solution was added potassium carbonate (1 g, 7.35 mmol) and the reaction mixture was stirred for 24 hours. The solid was filtered and the solution was diluted with dichloromethane (50 ml) and water (30 ml). The organic solution was collected, dried and concentrated in vacuum. The crude was purified by silica gel column chromatography eluting with neat ethyl acetate to afford the title compound as a white crystalline solid (1.1 g, 80%). 1H-NMR (500 MHz, CDCl3): δ 3 (s, 3H), 3.09 (s, 3H), 5 (s, 2H), 7.54 (s, 1H), 7.6 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:29]4[C:20](=[CH:21][C:22]5[O:27][CH2:26][CH2:25][O:24][C:23]=5[CH:28]=4)[O:19][CH2:18]3)[C:10]2=[O:30])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:31][S:32]([O-])(=[O:34])=[O:33].[Na+].[Na].N1CCC[C@H]1C(O)=O>CS(C)=O.C(OCC)(=O)C.[Cu](I)I>[CH3:31][S:32]([C:2]1[C:3]([CH2:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:29]4[C:20](=[CH:21][C:22]5[O:27][CH2:26][CH2:25][O:24][C:23]=5[CH:28]=4)[O:19][CH2:18]3)[C:10]2=[O:30])=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:34])=[O:33]
Reactant: O=C1C(Cc2ncccc2Br)c2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: CS(=O)(=O)[O-]
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cccnc1CC1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 95 °C
Reaction time: 30 h
Yield: 44.4 %

Procedure:
A mixture of 3′-[(3-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one (0.233 g, 0.50 mmol), sodium methanesulfonate (0.071 g, 0.60 mmol), copper iodide (0.010 g, 0.05 mmol), and the sodium salt of L-proline (0.014 g, 0.10 mmol) were combined in dimethyl sulfoxide (1 mL) and heated at 95° C. for 48 h, then stirred at ambient temperature for 30 h. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated from methanol and further purified by column chromatography, and eluted with a 0% to 50% gradient of ethyl acetate in dichloromethane to yield 3′-{[3-(methylsulfonyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one (0.103 g, 44%) as a colorless solid: mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J=4.2 Hz, 1H), 8.35 (dd, J=8.0, 0.5 Hz, 1H), 7.64 (dd, J=7.9, 4.7 Hz, 1H), 7.24 (dd, J=7.7, 7.7 Hz, 1H), 7.18 (d, J=7.3 Hz, 1H), 7.05-6.99 (m, 2H), 6.50 (s, 1H), 6.39 (s, 1H), 5.50 (ABq, 2H), 4.76 (ABq, 2H), 4.19-4.12 (m, 4H), 3.52 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.6, 155.0, 153.7, 153.6, 144.6, 143.4, 138.4, 138.2, 135.9, 132.4, 129.1, 124.1, 123.9, 123.3, 122.1, 112.2, 109.8, 99.1, 79.6, 64.7, 64.1, 57.7, 44.2, 42.7; MS (ES+) m/z 465.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@H:13]([OH:18])[C@@H:12]2[OH:19])=[C:4]([NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[N:3]=1.O.[NH2:27][NH2:28]>>[NH:27]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:12]([OH:19])[C@H:13]([OH:18])[C@@H:14]([CH2:16][OH:17])[O:15]2)=[C:4]([NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[N:3]=1)[NH2:28]
Reactant: NN
Reactant: OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(Cl)nc32)[C@@H](O)[C@H]1O
Solvent: O
Product: NNc1nc(NC2CCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(4S,2R,3R,5R) 5-[2-chloro-6-(cyclopentylamino)purin-9-yl]-2-(hydroxymethyl)oxolane-3,4-diol, a compound of formula (2) as prepared in Example 1A, was suspended in hydrazine hydrate (5 mL), and the mixture was allowed to stir at room temperature for 24 hours. The hydrazine was removed under reduced pressure and the residue triturated with ether and filtered, to afford (4S,2R,3R,5R)-2-[2-hydrazino-6-(cyclopentylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol, a compound of formula (3), as a white solid.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:13]2[N:14]=[CH:15][N:16]([CH3:17])[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1>>[CH3:1][NH:2][C:4]1[C:13]2[N:14]=[CH:15][N:16]([CH3:17])[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: CN
Product: CNc1nc2ccccc2c2c1ncn2C
Temperature: 112 °C

Procedure:
A mixture of 40% aqueous methylamine (25 ml) and 5.0 g (0.023 mole) of 4-chloro-1-methyl-1H-imidazo[4,5-c]quinoline (from Example 114) was placed in a metal pressure reactor and heated at 112° C. for about 16 hours. After cooling, the solid was separated by filtration, washed with water, dried and recrystallized from ethanol to provide N,1-dimethyl-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 216°-218° C. Analysis: Calculated for C12H12N4 : %C, 67.9; %H, 5.7; %N, 26.4; Found: %C, 67.9; %H, 5.6; %N, 26.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18](O)[CH3:19])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[N:9]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18]([N:25]2[C:21](=[O:31])[C:22]3[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:24]2=[O:26])[CH3:19])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[N:9]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)c1cc2ncccc2nc1-c1ccccc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1cc2ncccc2nc1-c1ccccc1F)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.12 h

Procedure:
1-(2-(2-Fluorophenyl)-1,5-naphthyridin-3-yl)ethanol (550 mg, 2.04 mmol) and phthalimide (600 mg, 4.09 mmol) were dissolved in THF (20 mL) and the mixture was cooled to 0° C. To the cooled mixture was added PPh3 (1.07 g, 4.09 mmol) and the mixture was stirred for 5-10 min at 0° C. Then DIAD (800 mg, 4.09 mmol) was added dropwise to the above reaction mixture at 0° C., and the reaction mixture was slowly allowed to warm to rt and maintained at rt for 3 h. After completion of reaction, the reaction mixture was quenched with water and ethyl acetate. The organic layer was separated and the aqueous layer was back extracted with ethyl acetate. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 2-(1-(2-(2-fluorophenyl)-1,5-naphthyridin-3-yl)ethyl)-1H-isoindole-1,3(2H)-dione as a white solid: 1H-NMR (CDCl3) δ: 1.8 (s, 3H), 5.0 (brs, 1H), 6.4 (s, 2H), 7.7-7.2 (m, 7H), 8.4 (d, 1H), 9.0-8.8 (d, 2H).
Reaction SMILES: N12CCC(C[OH:10])(CC1)CC2.FC1C=CC(C#N)=CC=1.[N:20]12[CH2:27][CH2:26][C:23]([CH2:28][O:29][C:30]3[CH:37]=[CH:36][C:33]([C:34]#N)=[CH:32][CH:31]=3)([CH2:24][CH2:25]1)[CH2:22][CH2:21]2>>[N:20]12[CH2:27][CH2:26][C:23]([CH2:28][O:29][C:30]3[CH:37]=[CH:36][C:33]([CH:34]=[O:10])=[CH:32][CH:31]=3)([CH2:24][CH2:25]1)[CH2:22][CH2:21]2
Reactant: OCC12CCN(CC1)CC2
Reactant: N#Cc1ccc(OCC23CCN(CC2)CC3)cc1
Agent: N#Cc1ccc(F)cc1
Product: O=Cc1ccc(OCC23CCN(CC2)CC3)cc1

Procedure:
Synthesized from (1-azabicyclo[2.2.2]oct-4-yl)methanol and 4-fluorobenzonitrile according to an analogous synthetic method to Preparation Example 15, 4-(1-azabicyclo[2.2.2]oct-4-ylmethoxy)benzonitrile (200 mg) was used according to an analogous synthetic method to Preparation Example 16 to provide the title compound (120 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10]C(C)=O)=[CH:6][CH:5]=1)=[O:3].C(OC1C=CC(C(O)=O)=CC=1)(=O)C>>[CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)Oc1ccc(C(C)=O)cc1
Agent: CC(=O)Oc1ccc(C(=O)O)cc1
Product: CC(=O)c1ccc(O)cc1

Procedure:
The 4-acetoxyacetophenone (4-AAP) used as the starting material for the catalytic oxidation to 4-acetoxybenzoic acid may be obtained as a co-product with the 4-hydroxyacetophenone (4-HAP) produced by the Fries rearrangement of phenyl acetate or the Friedel-Crafts acetylation of phenol, e.g., when the reaction is carried out in the presence of HF and an acid anhydide, or it may be produced from the 4-HAP by reacting the latter with an acetylating agent such as acetic anhydride, as indicated by equation (III), by contacting the 4-HAP with, for example, about 1 to 5 moles of the anhydride per mole of 4-HAP at a temperature, for example, in the range of 120° to 140° C. for a period, for example, in the range of 1 to 4 hours.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH2:32])[CH:20]=[CH:21][C:22]=1[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].O>CN(C)C(=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:32][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])[CH:20]=[CH:21][C:22]=1[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:24])=[O:25]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: COc1cc(N)ccc1S(=O)(=O)c1ccccc1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: COc1cc(NC(=O)C(C)(O)C(F)(F)F)ccc1S(=O)(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.80 g, 11.4 mmol) in N,N-dimethylacetamide (40 mL) was added thionyl chloride (1.36 g, 11.4 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 3-Methoxy-4-(phenylsulfonyl)benzeneamine (2.00 g, 7.6 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and the aqueous solution filtered through a pad of Celite. The Celite was washed with methylene chloride (200 mL), the organic extract dried (MgSO4), and the solvent removed in vacuo to yield a brown oil which was purified by flash column chromatography (10% v/v ethyl acetate/methylene chloride). The resulting white solid (2.52 g, 82%) melted at 202°-204° C. 1H-NMR (250 MHz, d6-DMSO): 1.56 (s, 3H, CH3) 3.87 (s, 3H, OCH3) 7.70-7.54 (m, 6H, aromatic+OH) 7.85-7.88 (m, 2H, aromatic) 7.93 (d, 1H, J=8.7 Hz, aromatic) 10.32 (s, 1H, NH). MS (CI, CH4): 404 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:4]=1[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([CH:18]([CH3:20])[CH3:19])[CH:16]=[CH:17][C:10]=2[NH:9][C:8](=O)[CH2:7]1.CN(C)C1C=CC(C)=CC=1.P(Cl)(Cl)([Cl:40])=O>C1(C)C=CC=CC=1>[Cl:40][C:8]1[CH2:7][N:6]([CH2:5][C:4]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:3]=2[O:2][CH3:1])[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([CH:18]([CH3:20])[CH3:19])[CH:16]=[CH:17][C:10]=2[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(CN2CC(=O)Nc3ccc(C(C)C)cc3C2=O)c(OC)c1
Solvent: Cc1ccccc1
Solvent: Cc1ccc(N(C)C)cc1
Product: COc1ccc(CN2CC(Cl)=Nc3ccc(C(C)C)cc3C2=O)c(OC)c1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
4-(2,4-Dimethoxy-benzyl)-7-isopropyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (1.5 g, 4.1 mmol) and N,N-dimethyl-p-toluidine (1.76 mL, 12.2 mmol) were mixed in toluene (8 mL) and heated to 100° C. Then phosphorus oxychloride (559 μL, 6.1 mmol) was added dropwise and heating at 100° C. was continued for 2.5 h. After cooling, the mixture was evaporated and dissolved in THF (10 mL) and was used directly in the subsequent step.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)OCC[O:20]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C(O)(C)C>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[N:11][C:2]=1[N:30]1[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][CH2:24][C:19]([C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=2)=[O:20])[CH2:32][CH2:31]1
Reactant: Fc1ccc(C2(CCCN3CCNCC3)OCCO2)cc1
Reactant: Clc1ncc2ccccc2n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C(CCCN1CCN(c2ncc3ccccc3n2)CC1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2.25 g 2-Chloroquinazoline, 4.2 g 1-(3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-propyl)piperazine and 2 ml triethylamine in 8 ml isopropanol are stirred and heated 21/2 hours at 80° C. The solvent is then evaporated in vacuo and the residue is taken up in hexane. The hexane solution is treated with charcoal, filtered and concentrated whereby the ketal of the title compound crystallizes out. The resulting precipitate is dissolved in 40 ml aqueous 1N hydrochloric acid. After 1 hour the acidic solution is made alkaline with aqueous ammonia. The resulting precipitate is filtered off and recrystallized from ethyl acetate to give the title compound, m.p. 129°-131° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cncc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.6 %

Procedure:
To a stirred solution of methyl 5-hydroxynicotinate (8.5 g, 55.6 mmol) and K2CO3 (11.5 g, 83.3 mmol) in DMF (20 mL) at 0° C. was added (bromomethyl)benzene (8 mL, 66.7 mmol) drop wise over 5 min. The resulting mixture was stirred at room temperature for 2 hours. The mixture was quenched with water (100 mL) and extracted with EA (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4. After filtration and evaporation of the solvent, the residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (4:1) to give methyl 5-(benzyloxy)nicotinate (4 g, 30.7%) as a yellow oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[N:12]1([C:18]2[C:23]([CH3:24])=[CH:22][N:21]=[C:20]([CH2:25][S:26][C:27]3[NH:31][C:30]4[CH:32]=[CH:33][C:34]([O:36][C:37]([F:42])([F:41])[CH:38]([F:40])[F:39])=[CH:35][C:29]=4[N:28]=3)[C:19]=2[Cl:43])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.N.C(#N)C>ClCCl>[N:12]1([C:18]2[C:23]([CH3:24])=[CH:22][N:21]=[C:20]([CH2:25][S:26]([C:27]3[NH:31][C:30]4[CH:32]=[CH:33][C:34]([O:36][C:37]([F:41])([F:42])[CH:38]([F:39])[F:40])=[CH:35][C:29]=4[N:28]=3)=[O:9])[C:19]=2[Cl:43])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1cnc(CSc2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)c(Cl)c1N1CCCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: N
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cnc(CS(=O)c2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)c(Cl)c1N1CCCCC1

Procedure:
m-Chloroperbenzoic acid (0.75 g total) in dichloromethane (40 ml) was added to a solution of 2-(4-piperidino-3-chloro-5-methyl-2-pyridylmethylthio)-5-(1, 1,2,2-tetrafluoroethoxy)-(1H)-benzimidazole (1.5 g) in dichloromethane (30 ml) at -40° to -50° over a period of 2.5 hours. After a further 0.5 hour ammonia was passed through the solution and the precipitate filtered off and washed well with dichloromethane. The filtrates were evaporated under reduced pressure to give an oil which, on treatment with acetonitrile, gave 2-(4-piperidino-3-chloro-5-methyl-2-pyridylmethylsulphinyl)-5-(1, 1,2,2-tetrafluoroethoxy)-(1H)-benzimidazole, 0.77 g. m.p. 155°-56° (dec).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([CH:34]2[CH2:37][CH2:36][NH:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[C:28]1([CH:34]2[CH2:37][CH2:36][N:35]2[C:23]([C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:8]3)(=[O:18])=[O:17])=[CH:27][CH:26]=2)=[O:24])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(C2CCN2)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1)N1CCC1c1ccccc1
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
Combine 4-(3-phenyl-indole-1-sulfonyl)-benzoic acid (125 mg, 0.33 mmol) and 2-phenyl-azetidine (100 mg, 0.75 mmol, excess) in dichloromethane (1.0 mL) and triethylamine (0.300 mL, 2.15 mmol, excess) and add benzotriazol-1-yloxytris(dimethylamino)phosphonium hexfluorophosphate (BOP Reagent) (150 mg, 0.33 mmol) at room temperature. Stir for 30 minutes, load entire reaction directly onto pre-packed silica gel column and purify by flash column chromatography (EtOAc/Hexanes) to yield 149 mg of (2-Phenyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone as a glassy solid (92%). LRMS: MH+ 493.08.