Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[CH2:9][S:10]([CH3:12])=O.FC(F)(F)C(O)=O>C1C=CC=CC=1>[CH3:12][S:10][CH:9]1[C:8](=[O:13])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1]1
Reactant: CS(=O)CC(=O)c1ccccc1O
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: CSC1Oc2ccccc2C1=O

Procedure:
2-Hydroxy-1-[(methylsulfinyl)acetyl] benzene (1.5 g 0.0075m) and trifluoroacetic acid (1.5 g) are refluxed in benzene (25 ml) for one hour under nitrogen. The solvent is removed under reduced pressure to give a pale yellow oil which crystallizes on standing. Recrystallization from ethanol gave white crystals, (0.611 g 45%), m.p. 81°-82° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([N:11]=1)=[CH:9][NH:8][C:7](=O)[N:6]=2.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:7]1[N:8]=[CH:9][C:10]2[N:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc2ccc(Cl)nc2c[nH]1
Product: Clc1ccc2nc(Cl)ncc2n1
Temperature: 0 °C

Procedure:
6-chloro-3H-pyrido[3,2-d]pyrimidin-2-one (3.4 g, 5.2 mmol) are taken up in POCl3 (55 mL) and the mixture is heated for 3 h to 105° C. Then the reaction mixture is added dropwise to ice water, extracted with DCM, the organic phase is dried on MgSO4, the solvent is eliminated in vacuo and 2,6-dichloro-pyrido[3,2-d]pyrimidine (HPLC-MS: MS(M+H)+=200; method AFEC) is obtained.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:12]=2)[N:7]([CH3:19])[CH:6]=1.[OH-].[Na+].Cl>CO>[CH3:19][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:9]=2)[C:5]([CH2:4][C:3]([OH:20])=[O:2])=[CH:6]1
Reactant: COC(=O)Cc1cn(C)c2cc(N3CCCC3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(CC(=O)O)c2ccc(N3CCCC3)cc21
Temperature: 0 °C
Yield: 70.7 %

Procedure:
(1-Methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)acetic acid methyl ester (360 mg, 1.32 mmol) and NaOH (132 mg, 3.3 mmol) in methanol (8 mL) were heated at reflux for 30 min. The reaction mixture was cooled to 0° C. and acidified using 1 N HCl. The mixture was extracted with EtOAc (3×100 mL) and CH2Cl2 (3×100 mL). The combined organic extracts were dried (MgSO4) and concentrated. Chromatography of the crude product over silica gel using 5-20% MeOH in CH2Cl2 gave (1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)acetic acid (241 mg, 71%).
Reaction SMILES: [CH3:1][O:2][CH2:3][NH:4][C:5]([NH:7][CH:8]1[C:16]2[CH:15]=[CH:14][S:13][C:12]=2[CH:11]([OH:17])[CH2:10][CH2:9]1)=[O:6]>CC(C)=O.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][CH2:3][NH:4][C:5]([NH:7][CH:8]1[C:16]2[CH:15]=[CH:14][S:13][C:12]=2[C:11](=[O:17])[CH2:10][CH2:9]1)=[O:6]
Reactant: COCNC(=O)NC1CCC(O)c2sccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: COCNC(=O)NC1CCC(=O)c2sccc21
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A solution of 1-(methoxymethyl)-3-(4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl)urea (0.35 g., 1.37 mmole) in acetone (40 ml.) is treated with manganese dioxide (3.5 g.). After 2 hours stirring the reaction mixture is filtered through celite, the cake washed thoroughly with acetone and the filtrate and washings evaporated to furnish 0.32 g. on 90.7% yield of the title compound as a crystalline solid, m.p. 155°-158° C. Recrystallization from hot acetone affords the analytical sample, m.p. 159°-162° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1.CC1(C)C(C)(C)OB([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)O1.CC(=O)OCC>O1CCOCC1.C([O-])([O-])=O.[K+].[K+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:28]([O:27][C:25]([N:22]1[CH2:21][CH:20]=[C:19]([C:2]2[CH:3]=[N:4][N:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=2)[CH2:24][CH2:23]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(O)Cn1cc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cnn(CC(=O)O)c2)CC1
Temperature: 100 °C
Yield: 88 %

Procedure:
A mixture of 2-(4-bromo-1H-pyrazol-1-yl)acetic acid (867 mg), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.2 g) and Pd(PPh3)4 (232 mg) in dioxane (15 mL) and sat. K2CO3 (7.5 mL) was heated at 100° C. overnight. After cooling down, EA was added and the mixture was washed with water and brine. The combined aq. layers were acidified to pH=2 with NaHSO4 and extracted with EA. The org. layers from the second extraction were dried (MgSO4), filtered off and evaporated in vacuo to afford 1.05 g of brown resin that was used without purification. LC-MS (B): tR=0.72 min; [M+H]+: 308.26.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=O)=[CH:15][CH:14]=1>C(O)(C)C>[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]2[O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:9])[N:10]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NC(=O)c1ccccc1O
Solvent: CC(C)O
Product: COc1ccc(-c2nc(=O)c3ccccc3o2)cc1
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
6.85 g (50 mmol) of salicylic acid amide are added, dropwise, to 18.1 g of p-methoxybenzoyl chloride and the mixture is heated to 150° C. The mixture is then stirred for 30 minutes at this temperature. After cooling, the honey-like mass is stirred with 100 ml of isopropanol, the precipitated solid filtered off and dried to yield 10.2 g of 2-(4-methoxyphenyl)-4H-1,3-benzoxazin-4-one as a white solid melting at 175-178° C. and having the following elemental analysis:
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C:13](=[O:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>O.C(O)(=O)C.S(=O)(=O)(O)O>[CH3:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[N:5]=[N:1][C:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[C:13]2[OH:21]
Reactant: O=N[O-]
Reactant: Cc1cccc(C(=O)Cc2ccccc2)c1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc2c(O)c(-c3ccccc3)nnc12
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 22.3 %

Procedure:
A solution of sodium nitrite (0.20 g, 2.8 mmol) in water (0.5 mL) was added dropwise, to a solution of 1-(2-amino-3-methylphenyl)-2-phenylethanone (0.42 g, 1.9 mmol) in acetic acid (9 mL) and sulfuric acid (1.5 mL). After the solution was stirred for 20 min at 80° C., the solution was poured into iced water. After the pH was adjusted to 6 with 2 N sodium hydroxide. The aqueous layer was extracted with ethyl acetate. The combined organics was dried over MgSO4 and concentrated. The material was purified via column chromatography using 5-50% ethyl actetate in hexane as the eluent to yield 0.10 g of 8-methyl-3-phenylcinnolin-4-ol as a gum. MS (ESI) m/z 237; HRMS (ESI, [M+H]+) 237.102;
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH:14]=1)([O-:3])=[O:2].CC(O)=O.Cl.[CH3:25][NH2:26].[OH-].[Na+]>ClCCCl>[CH3:25][NH:26][CH:16]1[CH2:17][CH2:18][C:13]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)=[CH:14][CH2:15]1
Reactant: O=C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reactant: CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CNC1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reaction time: 14 h
Yield: 99.9 %

Procedure:
A solution of compound 79 (0.07 g, 0.273 mmol) in 1,2-dichloroethane (3 mL) was treated with AcOH (0.015 mL, 0.273 mmol), methylamine hydrochloride (0.018 g, 0.273 mmol), NaBH(OAC)3 (0.086 g, 0.409 mmol) at room temperature and stirred for over night (14 h). The reaction was basified with 2 N NaOH (25 mL) and product was extracted into ethyl acetate (2×20 mL). The combined ethyl acetate layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 80 (0.074 g, quantitative) as a solid. mp 208-210° C.; 1H NMR (DMSO-d6) δ 1.44-1.53 (m, 1H), 1.97-2.01 (m, 2H), 2.35 (s, 3H), 2.40-2.57 (m, 3H), 2.60-2.70 (m, 1H), 6.13 (brs, 1H), 7.54 (d, 1H, J=9.0 Hz), 7.63 (s, 1H), 8.00 (d, 1H, J=7.5 Hz), 8.67 (s, 1H), 11.85 (brs, 1H); ESI-MS m/z (%): 272 (M+, 100).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=2)=[CH:10][O:9][N:8]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][C:14]([O:13][CH2:12][C:11]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][O:9][CH:10]=3)=[N:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccccn2)nc1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccc(OCc2conc2-c2ccccn2)nc1
Yield: 82 %

Procedure:
As described for example 358 g, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.24 mmol) was converted using cyclopropylamine instead of 4-aminotetrahydropyran to the title compound (65 mg, 82%) which was obtained as a white solid. MS: m/e=337.3 [M+H]+.
Reaction SMILES: [CH:1]([NH2:3])=O.[CH3:4][C:5]1([CH3:12])[C:8](=O)[C:7](C)([CH3:10])[S:6]1.B(O)(O)O>O>[NH2:3][CH:1]1[C:7]([CH3:10])([CH3:8])[S:6][C:5]1([CH3:12])[CH3:4]
Reactant: CC1(C)SC(C)(C)C1=O
Reactant: NC=O
Agent: OB(O)O
Solvent: O
Product: CC1(C)SC(C)(C)C1N
Temperature: 175 °C
Yield: 5 %

Procedure:
Formamide (4.0 g, 89 mmol), 2,2,4,4-tetramethyl-3-oxothietane (1.0 g, 6933 mmol) and boric acid (100 mg) were combined in a Teflon lined Parr bomb which was heated for 15 hours in a 175° C. oil bath. The reaction was cooled and the light brown mixture taken up in water (40 ml). The aqueous solution was extracted with methylene chloride (4×20 ml) and the combined extracts dried (MgSO4) and evaporated under reduced pressure to a light brown oil (1.02 g). The residue was hydrolyzed and the hydrolyzate worked up according to the procedure of Example 1 to give the title product 650 mg (65%), verified by its 1H-NMR spectrum.
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[N:6][C:5]([SH:8])=[N:4]1.[CH2:9](Br)[C:10]#[CH:11]>CO>[CH2:11]([S:8][C:5]1[N:6]=[CH:7][NH:3][N:4]=1)[C:10]#[CH:9]
Reactant: C#CCBr
Reactant: Sc1nc[nH]n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#CCSc1nc[nH]n1
Temperature: 25 °C

Procedure:
To a solution of 21.8 g of potassium hydroxide in 400 ml of methanol under nitrogen was added 33.37 g of 1,2,4-triazole-3-thiol. The resulting mixture was stirred at ambient temperature for ~1 hour. To this mixture was added 33.4 ml of propargyl bromide dropwise while keeping the reaction temperature below 30° C. After the addition, the resulting mixture was stirred at ambient temperature for ~4 hours and was then concentrated under reduced pressure. The residue was triturated in 300 ml of water. The precipitate was collected by filtration, washed with water and then hexanes, air dried and then dried in oven to give 24.6 g of the title product as a solid, m.p. 102°-104° C. NMR (DMSO-d6): 3.14 (t, 1H); 3.92 (d, 2H); 8.48 (s, 1H); 14.2 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[N+](C1C=CC(S(O[C@@H:36]2[CH2:40][N:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:38]([C:48]([O:50][CH3:51])=[O:49])[CH2:37]2)(=O)=O)=CC=1)([O-])=O.[F-].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][C@H:36]3[CH2:40][N:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:38]([C:48]([O:50][CH3:51])=[O:49])[CH2:37]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.9 %

Procedure:
Dimethylformamide (15 ml) was added to 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-hydroxyquinazoline (0.66 g; prepared as described in Example 22-preparation of starting materials), 1-tert-butyl 2-methyl (2S,4S)-4-[(4-nitrophenyl)sulfonyloxy]pyrrolidine-1,2-dicarboxylate (0.889 g) and cesium fluoride (0.941 g). The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was evaporated under vacuum and the residue partitioned between ethyl acetate and water. The organics were washed with water and saturated brine and dried over magnesium sulfate. The product was then purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5). The fractions containing the expected product were combined and evaporated under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-[(2S,4R)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline as a colourless gum (0.36 g); Mass Spectrum: (M+H)+ 547.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[CH2:19][N:20]([CH2:31][C:32]([O:34][CH3:35])=[O:33])S(C1C=CC(C)=CC=1)(=O)=O)=O.C[O-].[Na+].Cl>CO.[Cl-].[Na+].O>[CH3:35][O:34][C:32]([C:31]1[C:3]([OH:2])=[C:5]2[C:6](=[CH:19][N:20]=1)[N:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8](=[O:12])[C:9]([Br:11])=[CH:10]2)=[O:33]
Reactant: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1-c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COC(=O)c1ncc2c(cc(Br)c(=O)n2-c2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.6 %

Procedure:
5-Bromo-2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.67 g, 4.74 mmol) was dissolved in 80 mL of MeOH and placed in ice bath. NaOMe solution (3.3 mL, 14.2 mmol, 4.375 M in MeOH) was added and the mixture was stirred for 16 h at r.t. 1 M HCl was added to acidify the mixture, followed by addition of 100 mL of brine. The resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-20% EtOAc/CH2Cl2) to give 1.54 g of the title compound as a light yellow solid. MS: (−) m/z 373.15, 375.16 (M-1, 79/81Br).
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1.CC1C([O:44]CC(F)(F)F)=CC=NC=1CSC1NC2C=CC=CC=2N=1>>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S+:11]([O-:44])[C:9]2[NH:8][C:7]3[CH:23]=[CH:24][C:4]([O:3][CH:2]([F:1])[F:25])=[CH:5][C:6]=3[N:10]=2)[C:18]=1[O:19][CH3:20]
Reactant: COc1ccnc(CSc2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Yield: 78 %

Procedure:
The experiment described in example 2 was repeated using 52.2 g 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl]methyl]thio]-1H-benzimidazole as substrate instead of Lansoprazole sulfide. 42.3 g of crystallized Pantoprazole are isolated after crystallization and drying (yield 78%).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[NH2:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14]>>[N:2]1([CH2:7][C:8]([NH:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)=[O:14])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: N[C@@H](COCc1ccccc1Cl)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(Cn1cncn1)N[C@@H](COCc1ccccc1Cl)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 50 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(2-chlorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 181, (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-3-(2-chlorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (100 mg, 50%). 1H-NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 8.20 (s, 1H), 8.00 (s, 1H), 7.50-7.25 (m, 7H), 7.15-6.90 (m, 6H), 5.00 (s, 2H), 4.79-4.60 (m, 3H), 4.00 (m, 1H), 3.70-3.60 (m, 1H). MS (EI) for C26H23ClFN5O4 found 524 (MH+).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(P(N(C)C)(N(C)C)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])=[CH:35][CH:34]=1>C1COCC1>[Si:41]([O:40][CH2:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]#[N:9])=[CH:38][CH:37]=1)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:43]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CBr)cc1
Reactant: N#CCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CC(C#N)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
A solution of phenylacetonitrile (1.5 mL, 12.7 mmol) in THF (40 mL) containing HMPA (11 mL, 63.4 mmol) was cooled to -78° C. and treated with 16 mL (16 mmol) of a 1.0M THF solution of lithium bis(trimethylsilyl)amide dropwise while the temperature was maintained at -78° C. The reaction was stirred at -78° C. for 1.5 hours, and a solution of the product of Step B (2.00 g, 6.34 mmol) in THF (8 mL) was added dropwise with the temperature maintained below -70° C. The reaction temperature was maintained below -68° C. for 3 hours. The reaction was quenched at this temperature by addition of 1N Na2HSO4. After warming to room temperature, the mixture was partitioned between EtOAc and water, and the combined organic layers were washed with water, saturated NaHCO3, brine, dried (MgSO4), filtered, then concentrated in vacuo. The residue was chromatographed on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 1.5 g (67%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[C:12]([O:20][CH2:21][CH2:22][O:23][CH2:24]Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:24][O:23][CH2:22][CH2:21][O:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([Cl:11])[N:3]=1
Reactant: O=C(OCCOCCl)c1ccccc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Product: O=C(OCCOCn1cnc2c(Cl)nc(Cl)nc21)c1ccccc1
Yield: 41 %

Procedure:
Following the procedure of Example 1, 2,6-dichloro-purine was condensed with 1-benzoyloxy-2-chloromethoxyethane to give a 41% yield of 2,6-dichloro-9-(2-benzoyloxy ethoxymethyl)purine, m.p. 121°-125° C. This was treated according to the procedure of Example 2 to give simultaneous ammonolysis of the 6-chloro and benzoyloxy groups yielding 2-chloro-9-(hydroxyethoxymethyl)adenine, in 94% yield, m.p. 188°-190° C. after recrystallization from isopropanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH2:11][C:10]([C:20]([OH:22])=O)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH2:11][C:10]([C:20]([Cl:25])=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1=NN(c2ccc(Br)cc2)C(c2ccccc2Cl)C1
Product: O=C(Cl)C1=NN(c2ccc(Br)cc2)C(c2ccccc2Cl)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
1-(4-Bromo-phenyl)-5-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (5.4 g, 14.3 mmol) prepared in Step 4 was added to thionyl chloride (50.0 mL). The reaction mixture was stirred at 100° C. for 2 hours and then concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure three times, along with using toluene, to give 1-(4-bromo-phenyl)-5-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carbonyl chloride as a dark brown liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[C:5]([CH3:9])=[CH:4][N:3]=1.[S:10]1[CH:14]=[CH:13][C:12]2[CH:15]=[CH:16][CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[C:11]1=2.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.C(O)(C)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[S:10]1[CH:14]=[CH:13][C:12]2[CH:15]=[CH:16][CH:17]=[C:18]([C:6]3[C:5]([CH3:9])=[CH:4][N:3]=[C:2]([F:1])[CH:7]=3)[C:11]1=2
Reactant: CC1(C)OB(c2cccc3ccsc23)OC1(C)C
Reactant: Cc1cnc(F)cc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1cnc(F)cc1-c1cccc2ccsc12
Temperature: 100 °C
Yield: 82.2 %

Procedure:
In a flask, combine 2-fluoro-4-iodo-5-methyl-pyridine (355 mg, 1.5 mmol), 2-benzo[b]thiophen-7-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (282 mg, 1.8 mmol), Pd(dppf)Cl2 (61 mg, 0.07 mmol), 2-(di-tert-butylphos-phino)biphenyl (13 mg, 0.04 mmol), sodium carbonate (2 M, 1.5 mL, 3 mmol) and THF (10 mL). Heat the mixture at 100° C. for 3 h in an oil bath. Dilute the mixture with chloroform/IPA (3/1). Wash the solution with aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate in vacuo to a dark residue. Purify by column chromatography (20% ethyl acetate in hexane) to afford the title compound (300 mg, 82%) as a yellow oil. MS (ES) m/z 244 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[NH:12][CH:11]3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:5]2=[CH:4][CH:3]=1.[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36].[C:41]([O:45][C:46](=[O:49])[CH2:47]Br)([CH3:44])([CH3:43])[CH3:42].C(=O)([O-])[O-].[Cs+].[Cs+].[NH4+].[Cl-]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[N:12]([CH2:47][C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:49])[CH:11]3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:5]2=[CH:4][CH:3]=1.[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(F)cc1C1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: COC(C)[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1CC(=O)N(CC(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 4 h
Yield: 28.4 %

Procedure:
To a solution of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (2.5 g, 4.18 mmol) prepared in example 146b in N,N-dimethyl-formamide (20 mL) at room temperature was added bromo-acetic acid tert-butyl ester (2.0 g, 10.4 mmol) and cesium carbonate (7.5 g, 23.0 mmol). The reaction mixture was stirred under nitrogen for 4 h, then was poured into saturated aqueous NH4Cl solution. The mixture was extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by chromatography (EtOAc:Hexanes=1:4) to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a yellow solid (Yield 0.85 g).