Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:13]2([CH2:18][CH2:17][N:16]([C:19]([C@H:21]([NH:31][C:32](=[O:44])[C:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:35])[CH3:34])[CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:20])[CH2:15][CH2:14]2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[N:16]1([C:19]([C@H:21]([NH:31][C:32](=[O:44])[C:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:35])[CH3:34])[CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:20])[CH2:17][CH2:18][C:13]2([C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[NH:11][CH2:12]2)[CH2:14][CH2:15]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CN(C(=O)OCc1ccccc1)c1ccccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CNc1ccccc12
Yield: 72 %

Procedure:
To a solution of 8.10 g of the intermediate obtained from Step A in 80 mL of ethanol was added 1 g of 20% palladium hydroxide/C and hydrogenated with hydrogen balloon for 1 h. The catalyst was filtered off through a pad of celite and washed with ethyl acetate. The filtrate was concentrated to give 4.69 g of the product as a colorless foam.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].S(Cl)([Cl:14])=O>N1C=CC=CC=1.ClCCl>[Cl:14][CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=CCCCCCCCCO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCC=CCl
Reaction time: 8.5 h
Yield: 95.3 %

Procedure:
To 26.0 g of 9-decene-1-ol was added 10 drops of pyridine, and the mixture was placed into an eggplant flask. To the mixture was added dropwise 24.0 g of thionyl chloride, during cooling with ice. After dropping thionyl chloride, reaction was carried out for 8.5 hours at 70° C. After conclusion of the reaction, the reaction solution was diluted with dichloromethane, and then washed with an aqueous potassium carbonate. The washed solution was dried on magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain 27.7 g of 1-chloro-1-decene. (Yield: 95%)
Reaction SMILES: C1([CH2:7][CH2:8][S:9]([N:12]2[CH2:34][CH2:33][CH2:32][C@H:13]2[C:14]([NH:16][C@H:17]([C:25]([O:27]C(C)(C)C)=[O:26])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])(=[O:11])=[O:10])C=CC=CC=1>C(O)=O>[C:19]1([CH:8]([S:9]([N:12]2[CH2:34][CH2:33][CH2:32][C@H:13]2[C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])(=[O:10])=[O:11])[CH3:7])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)CCc1ccccc1
Solvent: O=CO
Product: CC(c1ccccc1)S(=O)(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
PhCH2CH2SH was treated with Cl2 in a rapidly stirred mixture of CHCl3 and H2O, and then the CHCl3 layer was washed with 5% NaHSO3 and sat. NaCl, dried with MgSO4, filtered, and concentrated to give PhCH2CH2SO2Cl. This product was treated with Pro-OtBu and Et3N in CH2Cl2 to give, after aqueous workup, PhCH2CH2SO2-Pro-OtBu. This product was treated with HCO2H, and the mixture was evaporated to give PhCH2CH2SO2-Pro-OH. This product was treated with HCl.Phe-OtBu, EDAC, HOBT, and Et3N in CH2Cl2 to give, after aqueous workup and flash chromatography, PhCH2CH2SO2-Pro-Phe-OtBu. This product was treated with HCO2H, and the mixture was evaporated to give the title compound as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:25][CH:24]=3)[S:16][C:10]=2[NH:11][C:12](=O)[CH2:13][N:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:25][CH:24]=3)[S:16][C:10]=2[NH:11][C:12](=[S:42])[CH2:13][N:14]=1
Reactant: CC(C)Cc1ccc(CCCCc2cc3c(s2)NC(=O)CN=C3c2ccccc2Cl)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc(CCCCc2cc3c(s2)NC(=S)CN=C3c2ccccc2Cl)cc1
Yield: 143.1 %

Procedure:
A suspension of 8.9 g of 5-(2-chlorophenyl)-7-[4-(4-isobutylphenyl)butyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one, melting at 133°-135° C. and 4.7 g of Lawesson reagent in 100 ml of toluene is stirred at 38°-40° C. for an hour. The resultant solution is concentrated under reduced pressure, and the residue is subjected to chromatography on silica gel and then eluted with chloroform-methanol (100:1 to 100:2). The objective fraction is concentrated under reduced pressure to give 8 g of 5-(2-chlorophenyl)-7-[4-(4-isobutylphenyl)butyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione, melting at 169°-171° C. with decomposition.
Reaction SMILES: C(O)C.C(O[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2)=[O:8])C.CC[O-].[Na+].[CH2:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH2:24]([N:31]1[CH2:36][CH2:35][N:34]([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1ccc2c(c1)CCC(=O)N2
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C1CCc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Yield: 9.5 %

Procedure:
To 100 ml of ethanol was added 2.0 g of 6-ethoxycarbonyl-3,4-dihydrocarbostyril, 0.5 g of sodium ethylate and 1.6 g of benzylpiperazine, the mixture was reacted in an autoclave under 110 atmospheric pressure at 140°-150° C. for 6 hours. After the reaction was completed, the reaction mixture was cooled and concentrated under a reduced pressure. The residue thus obtained was dissolved in 200 ml of chloroform and the chloroform solution was washed with 1%-potassium carbonate aqueous solution, a diluted hydrochloric acid and water in this order, then dried with anhydrous sodium sulfate. The solvent was removed by distillation and the residue was treated by means of a silica gel column chromatography (Silica gel: Wako C-200, eluate:chloroform:methanol (volume/volume)=20:1) and the crude crystals were recrystallized from ethanol to obtain 300 mg of 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 198°-200° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].Cl.[F:18][C:19]([F:32])([F:31])[C:20]1[S:24][C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:22][CH:21]=1>>[CH2:1]([S:3][C:4]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6]([N:28]1[CH2:29][CH2:30][N:25]([C:23]2[S:24][C:20]([C:19]([F:32])([F:18])[F:31])=[CH:21][N:22]=2)[CH2:26][CH2:27]1)=[O:8])[CH3:2]
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Reactant: CCSc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CCSc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1
Yield: 41 %

Procedure:
Prepared in analogy to example 1 (b) from 2-ethylsulfanyl-5-methanesulfonyl-benzoic acid (Example A23) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white foam (yield 41%). MS (m/e): 479.8 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:16][C:3]=1[O:4][C:5]1(S(C)(=O)=O)[CH2:10][CH:9]=[CH:8][NH:7][C:6]1=[O:11]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:16][C:3]=1[O:4][C:5]1[C:6](=[O:11])[NH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC3(S(C)(=O)=O)CC=CNC3=O)c(Cl)cc2F)c1=O
Solvent: Cc1ccccc1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc[nH]c3=O)c(Cl)cc2F)c1=O

Procedure:
A mixture of one equivalent of 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-3-(methylsulfonyl)-3,4-dihydro-1H-pyridin-2-one, 0.1 equivalent of p-toluenesulsonic acid and toluene is refluxed under stirring. After the reaction, the reaction liquid is concentrated and the residue is subjected to silica gel column chromatography to give 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-1H-pyridin-2-one.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[N+:14]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20])([O-:16])=[O:15].C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:5]([CH3:7])=[C:6]1[C:19](=[O:20])[C:18]1[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=1[N+:14]([O-:16])=[O:15]
Reactant: CCOC(=O)Cc1cc(C)cn1C
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccccc2[N+](=O)[O-])n1C
Yield: 93.7 %

Procedure:
A solution of 5.7 g (0.032 mole) of ethyl 1,4-dimethylpyrrole-2-acetate and 7.0 g (0.038 mole) of 2-nitrobenzoyl chloride in 130 ml xylene is heated at reflux under nitrogen for 18 hours. The mixture is stirred vigorously over a saturated sodium bicarbonate solution for 3 hours at room temperature. The xylene layer is separated from the aqueous layer, washed with brine, dried and filtered. The filtrate is concentrated in vacuo to give 9.9 g (95%) crude ethyl 1,3-dimethyl-2-(2-nitrobenzoyl)-pyrrole-5-acetate which can be used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[NH:18])[C:10]2[C:15]([CH3:16])=[C:14]([F:17])[CH:13]=[N:12][CH:11]=2)[CH:3]=1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:18]=[C:9]([C:10]3[CH:11]=[N:12][CH:13]=[C:14]([F:17])[C:15]=3[CH3:16])[N:8]=[C:4]2[CH:3]=1
Reactant: Cc1c(F)cncc1C(=N)Nc1cc(Cl)ccn1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(F)cncc1-c1nc2cc(Cl)ccn2n1
Temperature: 150 °C

Procedure:
Lead tetra acetate (0.15 g, 0.00034 mol) was added at RT to a solution of N-(4-chloropyridin-2-yl)-5-fluoro-4-methylnicotinimidamide (40-1; 0.09 g, 0.00034 mol) in toluene (10 mL) in a 40 mL microwave vial. The reaction mixture was heated to 150° C. for 1.5 h under microwave irradiation. It was then cooled to RT, diluted with water (20 mL), and extracted with ethyl acetate (2×30 mL). the combined organic layers were dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was purified by Prep TLC to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.10-9.086 (d, J=8 Hz, 1H), 9.01 (s, 1H), 8.6 (s, 1H), 8.17 (s, 1H), 7.37-7.35 (d, J=8 Hz, 1H), 2.64 (s, 3H), MS (M+1): 263.7.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:17]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[C:26]4[NH:30][N:29]=[CH:28][CH:27]=4)=[O:18])[CH2:15]3)[CH2:10]2)[N:3]=1.[H-].[Na+].[CH3:33]I.O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:17]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[C:26]4[CH:27]=[CH:28][N:29]([CH3:33])[N:30]=4)=[O:18])[CH2:15]3)[CH2:10]2)[N:3]=1
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-c4ccn[nH]4)C[C@@H]32)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)nc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-c4ccn(C)n4)C[C@@H]32)n1
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
A solution of the (1R,6S)-8-(4,6-dimethylpyrimidin-2-yl)-3-{[5-fluoro-2-(1H-pyrazol-3-yl)phenyl]carbonyl}-3,8-diazabicyclo[4.2.0]octane (Example 171) in DMF was treated with NaH at RT and stirred for 15 minutes until no more gas evolution occurred. The solution was cooled to −5° C. and then treated with MeI. Reaction allowed to stir for 20 min and then worked up by the addition of water followed by multiple extractions with EtOAc. Purified on 12 g SiO2 with 0-3.5% NH3 MeOH in CH2Cl2. MS (ESI) mass calcd. for C23H25FN6O, 420.5; m/z found, 421.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:40]=[CH:39][C:7]2[CH2:8][CH2:9][CH2:10][CH:11]([N:13]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:14][C@H:15]([O:24][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][C:6]=2[CH:5]=1.[CH2:41](I)[CH3:42].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:41]([O:3][C:4]1[CH:40]=[CH:39][C:7]2[CH2:8][CH2:9][CH2:10][CH:11]([N:13]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:14][C@H:15]([O:24][Si:25]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:30][CH3:31])[CH2:16][O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:12][C:6]=2[CH:5]=1)[CH3:42]
Reactant: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(O)cc2C1
Reactant: CCI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)CC(N(C[C@@H](COc1ccccc1)O[Si](CC)(CC)CC)C(=O)OC(C)(C)C)CCC2
Reaction time: 0.5 h

Procedure:
Under nitrogen, to a suspension of sodium hydride (60% in oil, 12 mg) in N,N-dimethylformamide (2 ml) was dropwise added N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (150 mg) in N,N-dimethylformamide (1 ml) at 5° C., and the mixture was stirred at the same temperature for 30 minutes. To this one was added ethyl iodide (27 μl), and the mixture was stirred at room temperature for 2 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=20:1) to give N-(3-ethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (130 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9][N:10]=1)=[O:5])C.[OH-].[Na+]>CCO>[C:12]1([S:11][C:8]2[S:7][C:6]([C:4]([OH:5])=[O:3])=[N:10][N:9]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1nnc(Sc2ccccc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nnc(Sc2ccccc2)s1

Procedure:
The 5-phenylsulfanyl-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester from Step 64a (1.0 g, 3.76 mmol, 1 eq) is dissolved in EtOH (40 mL), and cooled in an ice bath. To this, 2N NaOH (1.88 mL, 3.76 mmol, 1 eq) is added drop wise. The sodium salt of the acid precipitates out of solution. The reaction mixture is concentrated in vacuo to give a white crystalline product. The reaction mixture is carried through to the next step in its crude form to make the acid chloride. MS (ESI) for C9H6N2S2O2 m/z 237.0 (M−H)−.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])C.[F:17][C:18]([F:23])([F:22])[CH2:19][NH:20]N>C(O)(=O)C.C(O)CCC>[F:17][C:18]([F:23])([F:22])[CH2:19][N:20]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])=[N:5][CH:4]=[N:2]1
Reactant: NNCC(F)(F)F
Reactant: CN(C)C=NC(=O)c1ccccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CCCCO
Product: O=[N+]([O-])c1ccccc1-c1ncnn1CC(F)(F)F

Procedure:
N-[(Dimethylamino)methylene]-2-nitrobenzamide (1.0 g, 4.5 mmol) in acetic acid (25 mL) and n-butanol (15 mL) was treated with 70% aqueous 1,1,1-trifluoroethylhydrazine (1 mL, 11.3 mmol), and heated to reflux for 2 hours, at which time the volume was reduced by ˜25 mL by distillation. The remaining solvent was removed in vacuo, and the residue chromatographed on silica eluting with 3:1-1:1 hexane:ethyl acetate to afford 1-(2,2,2-trifluoroethyl)-5-(2-nitrophenyl)-1,2,4-triazole, which was reduced as in Example 64 to give crude 1-(2,2,2-trifluoroethyl)-5-(2-aminophenyl)-1,2,4-triazole (430 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4](Cl)[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].O.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([C:50]([F:53])([F:52])[F:51])[C:31]([O:34][CH2:35][CH2:36][CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]3)=[N:32][CH:33]=2)O1>O1CCOCC1.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>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([C:28]2[CH:29]=[C:30]([C:50]([F:53])([F:51])[F:52])[C:31]([O:34][CH2:35][CH2:36][CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[CH2:39][CH2:38]3)=[N:32][CH:33]=2)[N:3]=1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ncc(B3OC(C)(C)C(C)(C)O3)cc2C(F)(F)F)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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cnc2c(-c3cnc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)c3)nc(Cl)nc21
Temperature: 85 °C
Reaction time: 5 h
Yield: 63.7 %

Procedure:
2,6-Dichloro-9-methyl-9H-purine (5.6 g), Na2CO3 (11.7 g), water (16.8 mL), and tetrakis(triphenylphosphine)palladium (0) (1.6 g) were added to a solution of tert-butyl 4-(2-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)piperidine-1-carboxylate (13.8 g) in dioxane (112 mL) at room temperature in an argon atmosphere, and the mixture was stirred at an internal temperature of 85° C. for 5 hours. After the reaction mixture was cooled to room temperature, water (700 mL) was added thereto, and the mixture was stirred for 3 hours. The precipitate was collected by filtration, then, washed with water and diisopropyl ether, and dried. The obtained solid was purified by silica gel column chromatography (Hex:EtOAc:CHCl3=1:1:1), whereby tert-butyl 4-(2-{[5-(2-chloro-9-methyl-9H-purin-6-yl)-3-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)piperidine-1-carboxylate (9.5 g) was obtained as a solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:3]1.C1COCC1.[BH4-].[Na+]>CO.O.[Co](Cl)Cl>[NH2:13][CH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:3][C:2]2=[O:1]
Reactant: N#Cc1ccc2nc(-c3ccccc3)[nH]c(=O)c2c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: NCc1ccc2nc(-c3ccccc3)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Prepared from INT-87. To a stirring solution of 4-oxo-2-phenyl-3,4-dihydroquinazoline-6-carbonitrile INT-87 (540 mg, 2.18 mmol) in MeOH (30 mL) and THF (10 mL) was added cobalt(II) chloride hydrate (646 mg, 4.37 mmol) and sodium borohydride (826 mg, 21.8 mmol) portionwise. After stirring at room temperature for 30 min the reaction mixture was quenched with 1 M HCl (5 mL) and filtered through a celite plug, washing with THF (50 mL). The mixture was diluted with EA (100 mL) and washed with NaHCO3 (120 mL) and brine (20 mL). The organics were dried over MgSO4 and concentrated in vacuo to afford 306 mg (56%) of 6-(aminomethyl)-2-phenylquinazolin-4(3H)-one INT-88 as a white powder. LCMS-ESI (m/z) calculated for C15H13N3O: 251; found 250 [M−H]−, tR=0.80 min (Method 10).
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[O:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][C:2]1([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[O:3]1
Reactant: CCOC(=O)CC1(C)CCc2c(C)cc(C)c(C)c2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(c1C)OC(C)(CCO)CC2
Yield: 73.7 %

Procedure:
A solution of ethyl (2,5,7,8-tetramethylchroman-2-yl)acetate (8.00 g) in tetrahydrofuran (THF) (16 ml) was added dropwise to the suspension of lithium aluminum hydride (1.10 g) in THF (40 ml) under reflux. After refluxing for 2 hours, a solution of water (1 ml) in THF (5 ml) was added to the reaction mixture. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by chromatography over silica gel (AcOEt-hexane 10:90) to give 2-(2,5,7,8-tetramethylchroman-2-yl)ethanol as a solid (5.00 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:28]1[CH:27]=[N:26][N:25]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Reactant: CC1(C)OB(c2cnn(C3CCCCO3)c2)OC1(C)C
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1ccc2c(cc(-c3cnn(C4CCCCO4)c3)n2Cc2ccccc2)n1
Temperature: 25 °C

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.120 g, 0.373 mmol, from Example 62, Step 2), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.11 g, 0.41 mmol, Aldrich) and Na2CO3 (0.20 g, 1.9 mmol) in 1,2-dimethoxyethane (4 mL) and water (0.7 mL) was degassed by a stream of nitrogen through the solution for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.043 g, 0.037 mmol) was added, and the reaction was heated to reflux for 1.5 hours. Upon cooling to room temperature, the mixture was partitioned between water and EtOAc, and the aqueous layer was extracted a total of three times. The combined extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-50% EtOAc in hexanes afforded product. Yield: (0.106 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]>C(O)C.[Ni]>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 932.5 %

Procedure:
To a solution of 5-chloro-2-nitrobenzoic acid (20 g, 10 mmol) in ethanol was added freshly activated raney nickel (2 g). The mixture was stirred overnight at room temperature under hydrogen atmosphere. The solution was filtered through celite and evaporated under reduced pressure to yield 16 g (96%) of white solids. 1H NMR (DMSO-d6): δ 6.77 (d, J=8.9 Hz, 1H), 7.24 (dd, J=2.9, 8.9 Hz, 1H), 7.62 (d, J=2.9 Hz, 1H), 8.7 (b, 3H); EIMS: 170 (M−H).