Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=3)[C:10]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24].N1CCCCC1>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.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:15]=3)[C:10]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C(=O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CN(C)C(=O)c1nn(-c2ccnc(N)n2)c2cc(C#C[Si](C)(C)C)ccc12
Temperature: 65 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
To a mixture of 1-(2-aminopyrimidin-4-yl)-6-bromo-N,N-dimethylindazole-3-carboxamide (61-b) (500 mg, 1.27 mmol), tetrakis(triphenylphosphine)palladium (118 mg, 0.102 mmol), copper(I) iodide (19.4 mg, 0.102 mmol) and ethynyl(trimethyl)silane 0.39 ml, 2.54 mmol) was added piperidine (3.1 mL). The mixture was purged with nitrogen for 2 minutes and then stirred at 65° C. for 4 hr. The reaction mixture was concentrated in vacuo, DCM (5 mL) was added and the concentration repeated (×2). The crude product was purified by flash chromatography (Biotage, 2-8% methanol in DCM) to give the title intermediate (250 mg): LC-MS: m/z=+379.45 (M+H)+.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8]([C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[C:15](Cl)=[O:16])([CH3:11])([CH3:10])[CH3:9]>O1CCCC1.C1C=CC=CC=1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][O:7][C:15](=[O:16])[C:14]1[CH:18]=[C:19]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:20]([OH:21])=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:13]=1)[C:15](=[O:16])[C:14]1[CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:20]([OH:21])=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: OCCNCCO
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)OCCN(CCO)C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reaction time: 1 h

Procedure:
To a cold (5° C.) solution of 3 moles of diethanolamine in tetrahydrofuran was added dropwise a solution of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in benzene. The reaction mixture was stirred for about 1 hour, washed with water, separating the benzene layer from the aqueous layer. The benzene solution was evaporated to yieldan oil, which, after crystallization with aqueous ethanol, yielded a white solid. Small amounts of by-product compounds of Examples 1 and 3 were removed by fractional crystallization to yield N-hydroxyethyl-N-(3',5'-di-t-butyl-4'-hydroxybenzoyloxyethyl)-3,5-di-t-butyl-4-hydroxybenzamide; melting point 174°-178° C. When testedby the procedure of Example 2, the sample containing this compound lasted 1,200 hours, about 2.2 times as long as the control.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)[OH:19]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=1)(=[O:19])[NH2:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(-c2nc3cccnc3o2)cc1
Product: NC(=O)c1ccc(-c2nc3cccnc3o2)cc1
Reaction time: 16 h

Procedure:
A solution of 600 mg. of 2-(4-cyanophenyl)oxazolo[ 5,4-b]pyridine in 8 ml. of concentrated sulfuric acid was allowed to stand at room temperature for 16 hours. The solution was poured onto ice and the white precipitate was collected on a filter to give 2-(4-carbamylphenyl)oxazolo[ 5,4-b]pyridine, m.p. 315° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[O:11][CH2:10][CH:9]1[C:16](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH2:34][C:35]1[CH:39]=[C:38]([Br:40])[S:37][C:36]=1[C:41]([NH2:43])=[O:42]>O1CCCC1.O>[Br:40][C:38]1[S:37][C:36]2[C:41](=[O:42])[NH:43][C:16]([CH:9]3[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][C:12]([CH3:14])([CH3:15])[O:11][CH2:10]3)=[N:34][C:35]=2[CH:39]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)OCC1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(C)(C)OCC1c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 60 °C
Yield: 55.2 %

Procedure:
To a solution of 4-(tert-butoxycarbonyl)-6,6-dimethylmorpholine-3-carboxylic acid (1.00 g) and triethylamine (1.08 mL) in tetrahydrofuran (20 mL) was added, while stirring under ice-cooling, 2-methylpropyl chlorocarbonate (0.50 mL). After stirring at room temperature for 30 min, a solution of 3-amino-5-bromothiophene-2-carboxamide (568 mg) produced in Example 1, step D, in tetrahydrofuran (3 mL) was added. The reaction system was stirred with heating at 60° C. for 3 hr. Water was poured into the reaction system, and the mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue were added 2M aqueous sodium hydroxide solution (7.7 mL) and ethanol (20 mL), and the mixture was stirred with heating at 80° C. for 5 hr. Brine was poured into the reaction system, the mixture was extracted with 3:1 ethyl acetate/tetrahydrofuran mixture, and the extract was washed with brine, and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate) to give the title compound (630 mg) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1.C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH2:32][C@@H:33]1[CH:38]2[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]2)[CH2:34]1.CO>C(Cl)Cl.CN(C=O)C.CN(C=O)C>[N:35]12[CH2:40][CH2:39][CH:38]([CH2:37][CH2:36]1)[C@@H:33]([NH:32][C:12]([C:10]1[S:11][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][CH:9]=1)=[O:14])[CH2:34]2
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Reactant: N[C@H]1CN2CCC1CC2
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(-c2ccccn2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.9 %

Procedure:
TEA (50 μL, 0.35 mmol) is added to a suspension of 5-(pyridin-2-yl)-2-thiophenecarboxylic acid (72 mg, 0.35 mmol) in CH2Cl2:DMF (2:1, 1.5 mL). Diphenylchlorophosphate (62 μL, 0.3 mmol) is added and the resulting solution is stirred at room temperature for 30 minutes. A solution of (R)-3-aminoquinuclidine (1M, 0.2 mmol, 0.2 mL) in DMF is added and the resulting solution is stirred overnight at room temperature. MeOH is added and the mixture is poured through a column of AG50W×2 ion exchange resin (H+ form). The resin is washed with MeOH then the product is eluted with 5% TEA in MeOH. The eluent is evaporated to dryness to yield the desired product (15 mg, 24%). MS for C17H19N3OS (ESI) (M+H)+ m/z 314.
Reaction SMILES: N1C2C(=NC=CC=2)N(C2C=CC(C(O)=O)=NC=2)N=1.[N+:19]([C:22]1[C:23]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[N:33][CH:34]=2)=[N:24][CH:25]=[CH:26][CH:27]=1)([O-])=O>>[NH2:19][C:22]1[C:23]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[N:33][CH:34]=2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1ccc(Nc2ncccc2[N+](=O)[O-])cn1
Agent: O=C(O)c1ccc(-n2nnc3cccnc32)cn1
Product: CCOC(=O)c1ccc(Nc2ncccc2N)cn1

Procedure:
Prepared according to General Procedure F starting from the compound from Step 2 ethyl 5-((3-nitropyridin-2-yl)amino)picolinate (9.30 g, 32.3 mmol) to afford the title compound as a yellow solid (quantitative yield).
Reaction SMILES: Cl[CH:2]=[C:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].N1C=CN=C1.[Na].C[O-].[Na+].N1C=CN=C1>C(#N)C.CO>[F:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:3]([C:4](=[O:9])[C:5]([CH3:6])([CH3:7])[CH3:8])=[CH2:2])=[CH:12][CH:13]=1
Reactant: CC(C)(C)C(=O)C(=CCl)Oc1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CC#N
Product: C=C(Oc1ccc(F)cc1)C(=O)C(C)(C)C
Temperature: 25 °C

Procedure:
256.7 g (1 mol) of 1-chloro-2-(4-fluorophenoxy)-4,4-dimethyl-penten-3-one in 150 ml of acetonitrile were added dropwise to a suspension of 90 g (1 mol) of sodium imidazole, prepared from sodium methylate and imidazole in methanol, in 2,5000 ml of acetonitrile, while stirring. Thereafter, the reaction mixture was heated to the boil for 6 hours. It was allowed to cool to room temperature and was concentrated by distilling off the solvent in vacuo. The residue was taken up in 1,000 ml of ethyl acetate, the ethyl acetate mixture was washed three times with 200 ml of water each time and the organic phase was dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. 272.4 g (94.5% of theory) of crude 1-imidazol-1-yl)-2-(4-fluorophenoxy)-4,4-dimethyl-penten-3-one were obtained as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].C(O)C>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2ccccc2N)cc1
Reaction time: 4 h
Yield: 89.6 %

Procedure:
10% carbon-palladium (4 g) was added to an ethanol solution of tert-butyl[4-(2-nitrophenylamino)benzyl]carbamate (36 g, 105 mmols). The resulting mixture was hydrogenated at room temperature under atmospheric pressure for 4 hours. The catalyst was removed through filtration, and the filtrate was concentrated under reduced pressure. The residual solid was recrystallized from hexane/ethyl acetate to give a crystal of tert-butyl[4-(2-aminophenylamino)benzyl]carbamate (29.5 g, 89.9%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([N:18]=[C:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[BH4-].[Na+].C(Cl)(Cl)Cl>CO>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH:19]([CH2:20][CH3:21])[CH2:22][CH3:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1N=C(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOCc1nc2cnc3ccccc3c2n1NC(CC)CC
Reaction time: 24 h
Yield: 56.4 %

Procedure:
A solution of N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(1-ethylpropylidene)amine (1.78 g, 5.73 mmol) in 20 mL of methanol was treated with NaBH4 (0.867 g, 22.9 mmol) and CeCl3.7H2O (15 mg, catalytic) and stirred under an atmosphere of nitrogen. After 24 h, the reaction was concentrated under reduced pressure, dissolved CHCl3, washed with water (2×) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield a yellow/green syrup. Chromatography (SiO2, 93:7 CHCl3:MeOH) gave N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(1-ethylpropyl)amine (1.01 g) as a yellow/green oil.
Reaction SMILES: C(OC([N:8]([CH2:53][C:54]1[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=1)[CH2:9][C:10]([C@:12]12[CH2:48][C:47](=[O:49])[C:46]([CH:50]([CH3:52])[CH3:51])=[C:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:45])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C@@H:21]([O:34][C:35](=[O:44])[CH2:36][C:37]([CH3:43])([CH3:42])[CH2:38][C:39]([OH:41])=[O:40])[CH2:20][CH2:19]3)[CH2:16][CH2:15]1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:60][C:57]1[CH:56]=[CH:55][C:54]([CH2:53][NH:8][CH2:9][C:10]([C@:12]23[CH2:48][C:47](=[O:49])[C:46]([CH:50]([CH3:51])[CH3:52])=[C:13]2[C@@H:14]2[C@@:27]([CH3:30])([CH2:28][CH2:29]3)[C@@:26]3([CH3:31])[C@@H:17]([C@:18]4([CH3:45])[C@@H:23]([CH2:24][CH2:25]3)[C:22]([CH3:32])([CH3:33])[C@@H:21]([O:34][C:35](=[O:44])[CH2:36][C:37]([CH3:42])([CH3:43])[CH2:38][C:39]([OH:41])=[O:40])[CH2:20][CH2:19]4)[CH2:16][CH2:15]2)=[O:11])=[CH:59][CH:58]=1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)CC(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(C(=O)CN(Cc2ccc(Cl)cc2)C(=O)OC(C)(C)C)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)CC(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(C(=O)CNCc2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 5-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((tert-butoxycarbonyl)(4-chlorobenzyl)amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid (59) (800 mg, 0.941 mmol) in dichloromethane (6 mL) stirred at rt was added trifluoroacetic acid (2 mL, 0.941 mmol). The reaction mixture was stirred at rt for 1 h. The mixture was evaporated to provide the target compound (600 mg, 81%) which was used without further purification. LC/MS: m/z calculated 749.4. found 750.1 (M+1)+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:31]1[C:32](=[O:60])[N:33](COCC[Si](C)(C)C)[CH:34]=[C:35]([C:37](=[O:51])[NH:38][C:39]2[CH:40]=[N:41][N:42]([CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:43]=2)[CH:36]=1)=O)(C)(C)C.Cl.N>CO>[CH2:44]([N:42]1[CH:43]=[C:39]([NH:38][C:37]([C:35]2[CH:36]=[C:31]([C:9]3[NH:8][C:16]4[C:11]([CH:10]=3)=[CH:12][C:13]([CH2:17][N:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)=[CH:14][CH:15]=4)[C:32](=[O:60])[NH:33][CH:34]=2)=[O:51])[CH:40]=[N:41]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(c2)cc(-c2cc(C(=O)Nc4cnn(Cc5ccccc5)c4)cn(COCC[Si](C)(C)C)c2=O)n3C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: N
Solvent: CO
Product: O=C(Nc1cnn(Cc2ccccc2)c1)c1c[nH]c(=O)c(-c2cc3cc(CN4CCNCC4)ccc3[nH]2)c1
Temperature: 90 °C

Procedure:
To a solution of intermediate (4d), 2-[5-(1-benzyl-1H-pyrazol-4-ylcarbamoyl)-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(4-tert-butoxycarbonyl-piperazin-1-ylmethyl)-indole-1-carboxylic acid tert-butyl ester, 120 mg, 0.14 mmol) in methanol (4 mL) was added hydrochloric acid, 37% (0.75 mL). The mixture was heated at 90° C. for 3 hours. The reaction was allowed to attain ambient temperature and the pH adjusted to 7 by the careful addition of ammonia solution 7N in methanol. The mixture was concentrated in vacuo and the resultant crude residue was purified via preparative HPLC at pH9, to furnish the title compound as a yellow solid, 1.83 mg, 3%.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:11]Br)=[N:4][C:5]([O:9][CH3:10])=[CH:6][C:7]=1[CH3:8].CCCC[N+](CCCC)(CCCC)CCCC.[F-:30]>>[Br:1][C:2]1[C:3]([CH2:11][F:30])=[N:4][C:5]([O:9][CH3:10])=[CH:6][C:7]=1[CH3:8]
Reactant: [F-]
Reactant: COc1cc(C)c(Br)c(CBr)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: COc1cc(C)c(Br)c(CF)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-2-(bromomethyl)-6-methoxy-4-methylpyridine (126 mg) and TBAF (1.71 mL, 1 M solution in THF) was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 10%) to give the title compound (37 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17]([CH:19]=[CH2:20])=[O:18]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:20][C:19]([CH:17]=[O:18])=[CH:7][C:6]=2[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: C=CC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=CC1=Cc2cc(Br)ccc2OC1

Procedure:
The starting material is prepared as follows: A mixture of 5-bromosalicylaldehyde (10.3 g, 51.1 mmol) and potassium carbonate (7.0 g, 51.1 mmol) in 30 ml of 1,4-dioxane is treated with acrolein (4.3 g, 76.6 mmol). The mixture is heated at reflux for 2 hours and allowed to cool. This is partitioned between ether and water, and separated. The aqueous layer is extracted once with ether, and the organic phases are combined, dried (MgSO4) and evaporated. Flash chromatography (silica gel, 8% ethyl acetate/hexane) yields 6-bromo-2H-1-benzopyran-3-carboxaldehyde, m.p. 103°-104° C., which is converted to the final product as described above.
Reaction SMILES: C(O)(=[S:3])C.[C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)#[N:6].C(O)(=O)C>C(O)(C)C.O>[C:11]([C:10]1[CH:15]=[CH:16][C:7]([C:5](=[S:3])[NH2:6])=[CH:8][CH:9]=1)([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: CC(O)=S
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(C(N)=S)cc1
Yield: 77.7 %

Procedure:
130 g (1.7 moles) of thioacetic acid, 50 g (0.3 mole) of methyl 4-cyanobenzoate and 12 ml of glacial acetic acid were stirred for 2 hours at 80° C. The mixture was allowed to cool, 200 ml of 1:1 isopropanol/water was added, the mixture was stirred for a short time and the crystals formed were filtered off under suction. 45.5 g of 4-carbomethoxybenzothiamide of melting point 188°-190° C. were obtained in this manner.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[NH:9]1)=[O:7])(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][CH:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1NC(CC2CCOCC2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(c2ccc(Cl)cc2F)C(CC2CCOCC2)NC(C(=O)O)C1c1cccc(Cl)c1F
Yield: 80 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 101b (0.45 g, 0.81 mmol) was vented with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.4 g, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[O:8][C:9]([CH3:28])=[C:10]([CH3:27])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1>C(Cl)Cl>[Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[O:8][C:9]([CH3:28])=[C:10]([CH3:27])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2c(Cc3ccc(Br)cc3)oc(C)c2C)cc1C1CCCC1
Solvent: ClCCl
Product: Cc1oc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Yield: 50.6 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using [2-(4bromo-benzyl)4,5-dimethyl-furan-3-yl]-(3-cyclopentyl-4-methoxy-phenyl)-methanone (3.38 g, 7.23 mmol) and 1M boron tribromide/CH2Cl (15.2 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 1.66 g (51%) of the title compound. 1H NMR (DMSO-d6) δ 1.39-1.48 (m, 2H), 1.59-1.65 (m, 2H), 1.68-1.76 (m, 2H), 1.79 (s, 3H), 1.88-1.95 (m, 2H), 2.18 (s, 3H), 3.18 (quintet, 1H), 3.81 (s, 2H), 6.87 (d, 1H), 7.04 (d, 2H), 7.43-7.47 (m, 3H), 7.53 (s, 1H), 10.35 (s, 1H). IR (KBr) 3300, 2950, 1650, 1575 and 1280 cm−1. mass spectrum (+ESI) m/z 453 (M+H). Anal. Calcd. for C25H2,BrO 3: C, 66.23; H, 5.56; N, 0.00. Found: C, 66.12; H, 5.49; N, 0.03.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:16]([C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:16][C:18]3[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=3)[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cccc(C=O)c1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)c1cccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)c1

Procedure:
A solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (70 mg, 287 μmol) and and tert-butyl 3-formylbenzoate (150 mg, 727 μmol) in MeOH (3 ml) was stirred at 45° C. for 2 days, added more tert-butyl 3-formylbenzoate (30 mg, 145 μmol) and stirring continued for 6 more days. NaBH4 (65.1 mg, 1.72 mmol) was added and the reaction was stirred for 1 hour. The solvent was removed, and the reaction mixture was redissolved in EtOAc (5 ml) and washed with water (2×4 ml), dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 2% to 5% MeOH in DCM) to afford a colorless gum (91.5 mg) which was used for the next reaction.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>C1COCC1>[CH:2]([C:1]([O:8][CH3:9])=[O:7])([C:3]([O:5][CH3:6])=[O:4])[CH2:14][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: COC(=O)CC(=O)OC
Reactant: C=CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.6 %

Procedure:
To a solution of dimethyl malonate (2.5 g, 18.9 mmol) in anhydrous THF (20 mL) was added NaH (0.038 g, 0.95 mmol, 60% in mineral oil). The reaction was stirred at ambient temperature for 15 minutes. In a separate flask, ethyl acrylate (1.02 mL, 9.45 mmol) was dissolved in anhydro is THF (1 mL) and then added dropwise over 30 minutes to the dimethyl malonate solution. The reaction was stirred at ambient temperature overnight and then concentrated under vacuum. The residue was dissolved in EtOAc, washed with saturated NH4Cl solution and brine. The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by column chromatography (silica gel) using an EtOAc/hexanes gradient to yield the desired compound (1.68 g, 77%).