Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([O:8][C@H:9]2[C@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][C@@H:11]([S:12][CH3:13])[C@@H:10]2[NH:20][C:21](=[C:23]2[C:28](=[O:29])[CH2:27][C:26]([CH3:31])([CH3:30])[CH2:25][C:24]2=[O:32])[CH3:22])=[O:7])=[CH:4][CH:3]=1.[Si:35](Cl)([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C1C=CN=CC=1.ClCCCl.C(Cl)(Cl)Cl>[Si:35]([O:19][CH2:18][C@H:15]1[O:14][C@@H:11]([S:12][CH3:13])[C@H:10]([NH:20][C:21](=[C:23]2[C:24](=[O:32])[CH2:25][C:26]([CH3:31])([CH3:30])[CH2:27][C:28]2=[O:29])[CH3:22])[C@@H:9]([O:8][C:6](=[O:7])[C:5]2[CH:33]=[CH:34][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@@H:16]1[OH:17])([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CS[C@@H]1O[C@H](CO)[C@@H](O)[C@H](OC(=O)c2ccc(Cl)cc2)[C@H]1NC(C)=C1C(=O)CC(C)(C)CC1=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CS[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H](OC(=O)c2ccc(Cl)cc2)[C@H]1NC(C)=C1C(=O)CC(C)(C)CC1=O
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A mixture of methyl 3-O-(p-chlorobenzoyl)-2-deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-ethylamino]-1-thio-β-D-glucopyranoside (3) (1.00 g, 1.95 mmol), t-butyldiphenylsilylchloride (536 mg, 1.95) and 4-dimethylaminopyridine (238 mg, 1.95 mmol), in 1,2-dichloroethane (30 mL), was stirred under reflux for 6 hours. The reaction mixture was cooled to room temperature, diluted with chloroform (60 mL) and washed with diluted brine (3×50 mL, brine/water, 1:2), dried over MgSO4. The solvent was removed in vacuo and the residue was chromatographed using hexane—EtOAc 1:1 as the mobile phase to give a white solid, methyl 6-O(t-butyldiphenylsilyl)-3-O-(p-chlorobenzoyl)-2-deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-1-thio-β-D-glucopyranoside (4) (1.1 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:14]=[N:13][N:12]=1.[CH3:20][O:21]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl>[CH2:16]([N:15]1[CH:14]=[N:13][N:12]=[C:11]1[C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([O:9][CH3:10])=[C:6]([CH:5]=1)[CH:20]=[O:21])[CH:17]([CH3:19])[CH3:18]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(-c2nncn2CC(C)C)c(OC)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1cc(OC)c(-c2nncn2CC(C)C)cc1C=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
Ex-109E: To a solution of 3-(2,4-dimethoxy-phenyl)-4-isobutyl-4H-[1,2,4]triazole (Ex-109D, 0.78 g, 2.98 mmol) was added dichloromethyl methyl ether (0.4 mL, 4.48 mmol) followed by addition of titanium tetrachloride (1.0M in dichloromethane, 9.0 mL, 9.0 mmol) over 10 min at 0° C. The reaction mixture was allowed to stir at 0° C. for 30 min and ambient temperature overnight. The reaction mixture was poured into ice. The aqueous solution was extracted with dichloromethane and isopropyl alcohol (33%, v/v, in dichloromethane). The combined dichloromethane and isopropyl alcohol were washed with brine, dried over sodium sulfate and concentrated. The aqueous solution was treated with sodium hydroxide to pH 12 and extracted again with isopropyl alcohol (33%, v/v, in dichloromethane) to give additional product. The crude product was purified by flash chromatography. Elution with methanol (10%, v/v, in dichloromethane) afford 5-(4-isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-benzaldehyde (0.24 g, 28%): 1H NMR (CDCl3) δ 10.30 (s, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 6.51 (s, 1H), 4.00 (s, 3H), 3.87 (s, 3H), 3.58 (d, J=7.2 Hz, 2H), 1.91–1.80 (m, 1H), 0.77 (d, J=6.5 Hz, 6H).
Reaction SMILES: O[C:2]1[C:3]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[N:10]2)=[N:4][CH:5]=[CH:6]C=1.Cl.ClCC1N=C(C)[S:24]C=1.[OH-].[Na+]>>[CH3:6][C:5]1[S:24][CH:2]=[C:3]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[N:10]2)[N:4]=1
Reactant: Cc1nc(CCl)cs1
Reactant: CC(=O)Nc1ccn(Cc2ncccc2O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccn(Cc2csc(C)n2)n1

Procedure:
Title compound was prepared by a method analogous to that described for Intermediate 41, replacing the benzyl halide by 4-(chloromethyl)-2-methyl-1,3-thiazole hydrochloride (MAYBRIDGE). 4-(chloromethyl)-2-methyl-1,3-thiazole hydrochloride (MAYBRIDGE) was also liberated using NaOH (1N, aq) at room temperature. 1H NMR (300 MHz, DMSO-d6) ppm: 10.37 (s, 1H), 7.62-7.63 (m, 1H), 7.25 (s, 1H), 6.43-6.44 (m, 1H), 5.20 (s, 2H), 2.59 (s, 3H), 1.93 (s, 3H). [ES+MS] m/z 237 (MH+).
Reaction SMILES: [NH3:1].[C:2]12([C:12]3[CH:24]=[CH:23][C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21])=[CH:14][CH:13]=3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2>C1C=CC=CC=1>[C:2]12([C:12]3[CH:24]=[CH:23][C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20]([NH2:1])=[O:21])=[CH:14][CH:13]=3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: N
Reactant: O=C(Cl)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Solvent: c1ccccc1
Product: NC(=O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
A strong stream of dry ammonia is passed (for 15 minutes) into a solution of 16.5 g of 4-[4-(1-adamantyl)-phenoxy]-butyric acid chloride in 150 ml of absolute benzene under anhydrous conditions, whilst stirring. The product formed is now filtered off and washed with ether. Recrystallisation from a large amount of acetone yields pure 4-[4-(1-adamantyl)-phenoxy]-butyric acid amide of melting point 176°-177° C (needles).
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Li]CCCC.[CH3:32][N:33]1[C:37]([C:38]([C:40]2[N:44]([CH3:45])[N:43]=[N:42][CH:41]=2)=[O:39])=[CH:36][N:35]=[N:34]1.C(=O)=O.CC(C)=O>C1COCC1>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:38]([C:37]3[N:33]([CH3:32])[N:34]=[N:35][CH:36]=3)([C:40]3[N:44]([CH3:45])[N:43]=[N:42][CH:41]=3)[OH:39])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cn1nncc1C(=O)c1cnnn1C
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cnnn3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reaction time: 0.03 h

Procedure:
A solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (0.271 g, 0.632 mmol; Intermediate 16) in THF (6 mL) was stirred under argon at ˜−70° C. while n-BuLi (1.63 M in hexanes, 0.368 mL, 0.6 mmol) was added dropwise by syringe over 1 minute. After another 2 minutes, a solution of bis(1-methyl-1H-1,2,3-triazol-5-yl)methanone (0.128 g, 0.664 mmol; Intermediate 43) in THF (6 mL) was added dropwise over 2 minutes, and the reaction was allowed to warm to room temperature overnight as the dry ice/acetone bath slowly warmed (11 hours). The resulting yellow mixture was quenched in one portion at 0° C. with 5 M aqueous NH4Cl (1 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was dry load flash chromatographed with a DCM to 100% EtOAc gradient to yield the impure title compound. This was then triturated from ˜0.5 mL DMSO+˜2 mL MeOH at 70° C., and the opaque milky mixture was allowed to cool to room temperature, filtered, and the white filter cake washed with MeOH (2×2 mL). The filter cake was air dried at 110° C. to provide the title compound as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (d, J=2.53 Hz, 1H), 8.16 (d, J=2.02 Hz, 1H), 7.96 (s, 1H), 7.90 (d, J=8.59 Hz, 1H), 7.74 (s, 1H), 7.71 (d, J=4.55 Hz, 2H), 7.46 (dd, J=2.27, 8.84 Hz, 1H), 7.36 (d, J=8.59 Hz, 2H), 7.19 (s, 2H), 6.51 (s, 1H), 4.30 (s, 2H), 4.06 (s, 3H), 3.84 (s, 6H); MS m/e 542.3 [M+H]+.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1/[CH:17]=[CH:18]/[C:19](O)=[O:20]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:19](=[O:20])/[CH:18]=[CH:17]/[C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1cccs1
Agent: Cl
Product: O=C(/C=C/c1cccs1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(2-thienyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 263 (MH+).
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([S:14]([CH3:16])=[O:15])[C:11]([CH3:17])=[CH:10][C:9]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].ClCC(=O)C.[I-].[K+]>CC(C)=O.[I-].[K+]>[CH3:6][O:7][C:8]1[CH:13]=[C:12]([S:14]([CH3:16])=[O:15])[C:11]([CH3:17])=[CH:10][C:9]=1[O:18][CH2:2][C:3](=[O:5])[CH3:4]
Reactant: CC(=O)CCl
Reactant: COc1cc(S(C)=O)c(C)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(S(C)=O)c(C)cc1OCC(C)=O
Reaction time: 16 h

Procedure:
Potassium iodide (0.075 g) was added to a stirred solution of chloroacetone (3 ml) in dry acetone (3.5 ml) and the mixture was stirred for 16 hours. 2-Methoxy-5-methyl-4-methylsulphinylphenol (5.0 g) and potassium carbonate (0.85 g) were heated at reflux with stirring in dry acetone (25 ml). The chloroacetone/potassium iodide solution and potassium carbonate (3.4 g) were then added in four equal portions over 2 hours. The mixture was heated at reflux for a further 2 hours, cooled and filtered, the filter cake being washed well with acetone. The acetone was removed under reduced pressure and the residue chromatographed on a column of silica gel eluting with methylene chloride/methanol mixtures (gradient I to 3% v/v methanol). Trituration with diethyl ether gave the ketone (4.6 g) as colourless crystals, m.p. 104°-106°.
Reaction SMILES: CN(C)C=O.C[O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1.CC(C)([O-])C.[K+].Br[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=1>O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[C:8]([OH:7])=[O:16])=[N:25][CH:26]=1
Reactant: Clc1ccc(Br)nc1
Reactant: COC(=O)c1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccc(Oc2ccc(Cl)cn2)c1
Temperature: 130 °C

Procedure:
To a dimethylformamide (100 mL) solution of 3-hydroxy-benzoic acid methyl ester (3.5 g, 23 mmol) was added potassium t-butoxide (3.2 g, 28 mmol). Upon stirring the reaction at room temperature for 15 min, 2-bromo-5-chloro-pyridine was added. The reaction was heated to 130° C. for 15 h. Crude reaction mass was added to water, and extracted with diethyl ether to remove unhydrolyzed methyl ester, 3-(5-chloro-pyridin-2-yloxy)-benzoic acid methyl ester (2.5 g). The aqueous layer was acidified to pH 4.0 and product was extracted with ethyl acetate to give 3-(5-chloro-pyridin-2-yloxy)-benzoic acid (2.0 g). Saponification of methyl ester (2.5 g, 9.4 mmol) using NaOH (1.0 g, 25 mmol) in methanol:THF:water (1:1:1, 60 mL) furnished additional 2.0 g of 3-(5-chloro-pyridin-2-yloxy)-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[CH2:29]Br)=[O:19])=[CH:4][CH:3]=1.Cl.[CH3:33][NH:34][CH3:35]>C(Cl)Cl.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[CH2:29][N:34]([CH3:35])[CH3:33])=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc2ccccc2c1CBr
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Product: CN(C)Cc1c(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cc2)sc2ccccc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 43 %

Procedure:
To a suspension of N-(4-chlorophenyl)-2-[((3-(bromomethyl)benzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide (0.075 g, 0.14 mmol) in methylene chloride (1.5 mL) in a pressure vessel was added dimethylamine hydrochloride (0.035 g, 0.43 mmol), followed by Bio-Rad AG1-X8 anion exchange resin (0.55 g, 0.7 mmol equivalents, OH− form). The vessel was sealed and the mixture was stirred at ambient temperature for 3.5 hours. The vessel was opened and the reaction mixture diluted with methylene chloride (25 mL) and acetonitrile (25 mL), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel, followed by crystallization from acetonitrile afforded 0.030 g (43% yield) of N-(4-chlorophenyl)-2-[((3-(dimethylamino)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide, as a crystalline solid; NMR (DMSO-d6/TFA) 13.2 (s, 1), 10.7 (s, 1), 7.3-8.1 (m, 11), 3.9 (s, 2), 2.1 (s, 6) ppm.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[C:6]2[S:13][CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1.O>CN(C=O)C>[CH3:1][S:2][C:5]1[C:6]2[S:13][CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: C[S-]
Reactant: Clc1ncnc2ccsc12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncnc2ccsc12
Reaction time: 1.5 h
Yield: 69 %

Procedure:
Sodium thiomethoxide (9.1 g) was added to a solution of 4-chlorothieno[3,2-d]pyrimidine (WO9849899, example 3A; WO9924440, example 1C) (17.0 g) in DMF (100 mL). After stirring for 90 minutes the mixture was poured into water (400 mL), extracted into EtOAc, washed with water, dried (MgSO4), and the solvent removed. Purification by flash chromatography on silica eluting with DCM:EtOAc (4:1) gave the title compound as a pale yellow solid (16.5 g, 69%);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[C:7]([C:16](OC)=[O:17])=[C:6]2[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[OH:17][CH2:16][C:7]1[C:8]([CH3:15])=[N:9][C:10]2[C:5]([C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2
Reactant: COC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2c(CO)c(C)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.7 %

Procedure:
A solution of methyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-methylquinoline-3-carboxylate (0.4 g) in tetrahydrofuran (10 ml) was added dropwise to a suspension of lithium aluminium hydride (LiAlH4)(0.114 g) in tetrahydrofuran (10 ml) at room temperature. The mixture was stirred at room temperature for 1.5 hours, and water was added. The resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, the solvent was evaporated, and the resulting crystals were collected by filtration and recrystallized from methanol to give 3-hydroxymethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-methylquinoline (0.326 g, 88%). mp. 200°-201° C.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1([Li])C=CC=CC=1.C1CCCCC1.[Br:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[C:40]([O:46][C:47]([F:50])([F:49])[F:48])[CH:39]=1>CCOCC>[Br:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][CH:2]=[O:3])=[C:40]([O:46][C:47]([F:50])([F:49])[F:48])[CH:39]=1
Reactant: O=Cc1ccc(Br)cc1OC(F)(F)F
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: O=CCc1ccc(Br)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.6 %

Procedure:
To a suspension of (methoxymethyl) triphenylphosphonium chloride (5.29 g, 14.9 mol) in Et2O (50 mL) was added 1.8 M phenyl lithium in 30% Et2O in cyclohexane (8.58 mL, 15.5 mmol). The mixture was stirred at ambient temperature for 10 min. To the reaction mixture was added 4-bromo-2-trifluoromethoxy-benzaldehyde (4 g, 14.9 mmol) in Et2O (18 mL). The mixture was stirred at ambient temperature for 4 hr, filtrated, and concentrated. To the above residue was added 10% H2SO4 in AcOH (40 mL). The mixture was stirred at ambient temperature for 90 min. The solution was poured into H2O, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was washed with saturated aqueous NaHCO3, washed with brine, dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel, 9% EtOAc in hexane) to give (4-bromo-2-trifluoromethoxy-phenyl)-acetaldehyde (1.25 g, 30%) as a pale brown oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>O1CCCC1>[CH3:2][CH:1]([O:4][C:5]1[CH:6]=[C:7]([NH:8][C:23]([C:22]2[C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH:9]=[CH:10][CH:11]=1)[CH3:3]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)Oc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(NC(=O)c2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a tetrahydrofuran solution containing 1.5 g (0.01 mole) of m-isopropoxyaniline and 1.2 g (0.011 mole) of triethylamine, while being cooled in ice water, was added slowly 2.3 g (0.011 mole) of o-trifluoromethylbenzoyl chloride. After having been stirred for 2 hours at room temperature, the reaction mixture was freed from triethylamine hydrochloride by filtration and then from the solvent by distillation under reduced pressure. The residue was recrystallized from n-hexane to obtain 2.9 g (91% yield) of the intended product melting at 95° to 97° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[N+:17]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni].O.[H][H]>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[NH2:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: O
Solvent: CO
Product: COc1cccc(NC(=O)OC(C)(C)C)c1N
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of the N-tert-Butyloxycarbonyl-3-methoxy-2-nitro aniline (4 mmol) in MeOH was added catalytic amount of Raney Nickel in water, hydrogen was applied at 40 psi and the mixture was stirred overnight. The mixture was filtered over Celite and the solvent was evaporated to give the desired product in 55% yield. MS (ESI)=239 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)CCl.C1C=CC2N(O)N=[N:23]C=2C=1.N>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5]([NH2:23])=[O:6]
Reactant: On1nnc2ccccc21
Reactant: COc1cc(C)ccc1C(=O)O
Agent: N
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc(C)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a mixture of 2-methoxy-4-methylbenzoic acid (20 g, 120.4 mmol), EDC (23.1 g, 120.4 mmol) and HOBt (16.3 g, 120.4 mmol) in dichloromethane (1 L) was added NH3 (7N in MeOH, 52 mL, 3 eq) dropwise. The reaction mixture was stirred at room temperature overnight then washed successively with HCl (1N), saturated aq.NaHCO3, water and brine, dried over MgSO4, filtered and evaporated. The residue was recrystallized from ethyl acetate/hexane to give 16.5 gr of 2-methoxy-4-methylbenzamide (83% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C@@H:7]([OH:14])[C@@H:6]2[N:15]=[N+]=[N-])#[N:2].C(N(CC)CC)C.C(S)CCS>CO>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C@@H:7]([OH:14])[C@@H:6]2[NH2:15])#[N:2]
Reactant: CC1(C)c2ccc(C#N)cc2[C@@H](N=[N+]=[N-])[C@@H]1O
Agent: SCCCS
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1(C)c2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Yield: 95.9 %

Procedure:
A solution of trans-5-cyano-1,1-dimethyl-3-azido-indan-2-ol (0.93g), triethylamine (1.2 ml) and 1,3-propanedithiol (0.9 ml) in dry methanol (20 ml) was stirred at room temperature for 48h. After filtration, the solution was evaporated in vacuo to give the title compound (0.79g) as a gum.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[C:37]([O:38][CH3:39])=[CH:36][C:26]([C:27]([NH:29][C@@H:30]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31]2)=[O:28])=[C:25]([F:40])[CH:24]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[C:37]([O:38][CH3:39])=[CH:36][C:26]([C:27]([NH:29][C@@H:30]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31]5)=[O:28])=[C:25]([F:40])[CH:24]=4)=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)N[C@@H]2CCN(C)C2)c(F)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)CC(C)O
Product: COc1cc(C(=O)N[C@@H]2CCN(C)C2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Yield: 46.5 %

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 100 mg, 0.32 mmol), 4-amino-2-fluoro-5-methoxy-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide (Intermediate 182; 87 mg, 0.32 mmol) and 4-toluenesulphonic acid monohydrate (154 mg, 0.81 mmol) were heated in 4-methyl-2-pentanol (3 mL) at 140° C. for 3 hours. The mixture was cooled and absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (80 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])/[C:10](/[CH3:27])=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]#[N:26])[CH:20]=3)[CH:13]=2)=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[CH2:33](N)[CH2:34][NH2:35]>C(O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])/[C:10](/[CH3:27])=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[NH:35][CH2:34][CH2:33][N:26]=4)[CH:20]=3)[CH:13]=2)=[CH:4][C:3]=1[C:29]([F:32])([F:30])[F:31]
Reactant: C/C(=C\c1cccc(Oc2ccnc(C#N)c2)c1)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NCCN
Solvent: CCO
Solvent: CCOC(C)=O
Product: C/C(=C\c1cccc(Oc2ccnc(C3=NCCN3)c2)c1)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
(E)-N-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-(2-cyanopyridin-4-yloxy)phenyl)-2-methylacrylamide (500 mg, 1.09 mmol) and TEA (456 μL, 3.27 mmol) were combined and stirred in ethanol. H2S was bubbled into the solution for 2 min then the reaction mixture was sealed and allowed to stir at rt. Reaction completion was checked by LCMS and TLC. The mixture was diluted with EtOAc and washed with brine. The aqueous phase was extracted with EtOAc, and the organic solutions were combined, dried over Na2SO4, filtered, and concentrated to provide a yellow residue. The residue was redissolved in ethylene diamine (3 mL), heated to 60° C. for 5 min, and then allowed to cool to rt. The mixture was diluted with EtOAc and washed with brine. The aqueous phase was extracted with EtOAc, and the organic solutions were combined, dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, 0-10% MeOH with 1% NH4OH in DCM) provided B-12 (415 mg). LCMS, FA: Rt=1.34 min, [MH+ 501.0]. 1H NMR (400 MHz, CD3OD): δ 8.49 (d, 1H), 8.18 (d, 1H), 7.91-7.89 (dd, 1H), 7.57-7.53 (m, 3H), 7.40 (d, 1H), 7.35 (s, 1H), 7.23 (m, 1H), 7.16-7.13 (dd, 1H), 7.09-7.07 (m, 1H), 3.77 (s, 4H), and 2.16 (d, 3H).