Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:29]4[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=4)[CH:7]=[CH:6][CH:5]=3)[CH:13]=2)=[CH:15][CH:16]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)cc(-c2cccc(Br)c2)n1
Product: Nc1ncc(-c2cccc(-c3cc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-trifluoromethyl-pyridine (example E.82) (0.20 g, 0.485 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.118 g, 0.532 mmol) according to the general procedure VI. Obtained as a white solid (0.110 g, 53%). MS (ISP) 427.1 [(M+H)+] and 429 [(M+2+H)+]; mp 239° C.
Reaction SMILES: C[O-].[Na+].[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:18]1[CH2:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:5]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:21]2[CH:20]=[CH:19][CH:18]=[CH:22]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: C1=CCC=C1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: C1=CC(=C(c2ccccc2)c2ccccc2)C=C1
Reaction time: 168 h
Yield: 86.2 %

Procedure:
A 1 liter round bottom flask was charged with sodium methoxide (41.00 grams, 0.759 mol), ethanol (500 mL), benzophenone (125.00 grams, 0.686 mol) and cyclopentadiene (100.0 mL, 1.213 mol). This was stirred for 7 days before the orange precipitate was collected by suction filtration and washed with 50 mL ethanol. The collected solid was boiled in 200 mL methanol and allowed to cool. The precipitate was collected by suction filtration and washed with 75 mL methanol. The orange solid was dried under high vacuum for 48 hours, giving 136.18 grams 6,6-diphenylfulvene (86.2%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]Br.[S:11]([O-:14])([O-:13])=[O:12].[Na+:15].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][S:11]([O-:14])(=[O:13])=[O:12].[Na+:15]
Reactant: O=S([O-])[O-]
Reactant: BrCCc1ccccc1Br
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])CCc1ccccc1Br
Temperature: 100 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A solution of 1-bromo-2-(2-bromoethyl)benzene (6.23 g, 23.6 mmol) in ethanol (20.5 mL) was added to a solution of sodium sulfite (3.12 g, 24.7 mmol) in water (25.0 mL). The mixture was heated at 100° C. for 24 hours. The reaction mixture was filtered, and the filtrate was then left to stand at 3° C. overnight. The resulting white crystals were collected by filtration and dried to give sodium 2-(2-bromo-phenyl)ethanesulfonate (4.00 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].Br[CH2:12][C:13]1[CH:14]=[C:15]([CH2:21][CH:22]([O:26][CH:27]([CH3:29])[CH3:28])[C:23]([O-:25])=[O:24])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][O:5][CH2:12][C:13]1[CH:14]=[C:15]([CH2:21][CH:22]([O:26][CH:27]([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CBr
Reactant: OCc1ccc(Cl)cc1Cl
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COCc1ccc(Cl)cc1Cl

Procedure:
Using 2,4-dichlorobenzyl alcohol and 3-[3-(bromomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(2,4-dichlorobenzyl)oxy]methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 247).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:26]=[CH:25][C:13]([O:14][C:15]([CH3:24])([CH3:23])[C:16]([OH:22])([CH3:21])[CH2:17][CH2:18][CH:19]=[CH2:20])=[CH:12][C:11]=1[CH3:27]>C(Cl)(Cl)Cl>[Br:1][CH2:20][CH:19]1[CH2:18][CH2:17][C:16]([C:15]([O:14][C:13]2[CH:25]=[CH:26][C:10]([Cl:9])=[C:11]([CH3:27])[CH:12]=2)([CH3:23])[CH3:24])([CH3:21])[O:22]1
Reactant: C=CCCC(C)(O)C(C)(C)Oc1ccc(Cl)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1cc(OC(C)(C)C2(C)CCC(CBr)O2)ccc1Cl
Yield: 86.6 %

Procedure:
60 g (0.37 mol) of N-bromosuccinimide are added in portions to 88.8 g (0.3 mol) of 6-(4-chloro-3-methylphenoxy)-5-hydroxy-5,6,6-trimethyl-1-hexene in 600 ml of absolute chloroform, while stirring and cooling, so that the reaction temperature does not exceed 40° C. When the addition has ended, the mixture is stirred at room temperature for a further 14 hours and then washed twice with water and dried over sodium sulphate and the solvent is removed in vacuo. 94 g (82% of theory) of 2-bromomethyl-5-[2-(4-chloro-3-methylphenoxy)-prop-2-yl]-5-methyl-tetrahydrofuran are obtained and are further reacted without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].[C:16]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:25])[CH2:23]Br>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:23][C:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccccc1-c1ccccc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCC(=O)c2ccccc2-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
4-Hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.721 g) in dimethylformamide (8 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 30 minutes and then 1-[1,1'-biphenyl]-2-yl-2-bromoethanone (1.1 g) in dimethylformamide (4 mL). The mixture was stirred at room temperature overnight and worked up as in Example 20. The residual oil (1.5 g) was purified by flash chromatography over silica gel (dichloromethane) to afford of 0.62 g of 4-[2-[[1,1'-biphenyl]-2-yl]-2-oxoethoxy]-alpha-oxobenzeneacetic acid methyl ester as an oil.
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.[Li]CCCC.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1.C1COCC1>[Si:11]([C:5]#[C:4][CH:1]1[CH2:3][CH2:2]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: C#CC1CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)C#CC1CC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 42 %

Procedure:
To a stirred, cooled (0° C.) solution of 188 mL (658 mmol) of a 3.5 M solution of cyclopropylacetylene in toluene was added 200 mL of THF. The solution was re-cooled to 0° C. and treated with 264 mL (660 mmol) of a 2.5 M solution of n-BuLi in hexanes over 15 min. The solution was stirred an additional 40 min. at 0° C. and treated with 100 g(663 mmol) of t-butyldimethylsilyl chloride in 60 mL of THF over 10 min. After stirring 90 min. at 0° C. the reaction was quenched with saturated aq. NH4Cl and poured into 500 mL of water. The mixture was extracted with 500 mL of ether, and the organic extract was washed three times with water and once with brine. Concentration under reduced pressure followed by distillation afforded 49 g(42%) of 1-(t-butyldimethylsilyl)-2-cyclopropylacetylene as a colorless oil (b.p. 39-42° C. at 0.5 torr). 1H NMR(CDCl3, 300 MHz) δ1.17-1.24(m, 1H); 0.95(s, 9H); 0.61-0.75(m, 4H); 0.00(s, 6H).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O-:14])=O)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.O>CN(C)C=O>[O:18]1[CH2:19][CH2:20][N:15]([C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[NH:1][C:2](=[O:3])[CH2:4][CH2:5]3)=[O:14])[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: O=C1CCc2cc(C(=O)[O-])ccc2N1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc(C(=O)N3CCOCC3)ccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.0 Gram of succenimide 3,4-dihydrocarbostyril-6-carboxylate and 0.37 g of morpholine were dissolved in 2 ml of dimethylformamide and stirred at room temperature for 3 hours. Then water was added to the reaction mixture and extracted with chloroform, the chloroform layer was washed with water and a saturated sodium chloride aqueous solution in this order. After drying the chloroform layer with anhydrous sodium sulfate, then chloroform was removed by distillation under a reduced pressure, then acetone was added to the thus obtained residue to crystallize the product. 150 Milligrams of 6-morpholinocarbonyl-3,4-dihydrocarbostyril was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][N:34]=2)[C:29]([CH:36]=O)=[CH:28]1.N1CCCCC1>CO>[NH:27]1[C:35]2=[N:34][CH:33]=[CH:32][CH:31]=[C:30]2[C:29](/[CH:36]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[CH:28]1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1c[nH]c3ncccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
A solution of tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.107 g, 0.295 mmol) synthesized in Example A40, Step 1 in methanol (1.2 mL) was added with 7-aza-1H-indole-3-carboxaldehyde (0.0517 g, 0.354 mmol) and piperidine (0.00251 g, 0.0295 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the precipitated solid was collected by filtration to obtain the objective tert-butyl (Z)-4-({2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0654 g, 45%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)(C)(C)C.[ClH:18]>O1CCOCC1>[ClH:18].[S:12]1[C:8]([NH2:7])=[CH:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]1=2
Reactant: CC(C)(C)OC(=O)Nc1cc2ccccc2s1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cc2ccccc2s1
Temperature: 25 °C
Yield: 83 %

Procedure:
Compound 1-B (1.45 g, 5.81 mmol) was added to a solution of HCl in dioxane (4N, 20 mL), and the mixture was stirred at rt until all the starting material was consumed. The mixture was diluted with diethyl ether, the product collected by filtration, and washed with diethyl ether, to afford compound 1-C as an off-white solid (0.89 g, 83%). 1H-NMR (DMSO-d6): δ 6.43 (s, 1H), 6.8-7.2 (br s, 3H) superimposed on 7.05 (m, 1H) and 7.20 (m, 1H), 7.45 (d, 1H), 7.66 (d, 1H); MS: m/z 150.1 (MH+).
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([O:7][C:8]2[CH:9]=[C:10]([CH3:22])[C:11]3[CH:15]([CH2:16][C:17]([OH:19])=[O:18])[O:14][B:13]([OH:20])[C:12]=3[CH:21]=2)[S:4][N:3]=1.[Li+].C[Si]([N-:28][Si](C)(C)C)(C)C.Cl>C1COCC1.O>[NH2:28][C:2]1[N:6]=[C:5]([O:7][C:8]2[CH:9]=[C:10]([CH3:22])[C:11]3[CH:15]([CH2:16][C:17]([OH:19])=[O:18])[O:14][B:13]([OH:20])[C:12]=3[CH:21]=2)[S:4][N:3]=1
Reactant: Cc1cc(Oc2nc(Cl)ns2)cc2c1C(CC(=O)O)OB2O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2nc(N)ns2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
To a solution of [6-(3-chloro-[1,2,4]thiadiazol-5-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (100 mg, 0.27 mmol) in THF (1.5 mL) was added LHMDS (1M in Hexanes, 0.54 mL, 0.54 mmol). The resulting solution was stirred at room temperature for overnight. LC-MS showed still half starting material left. The mixture was added LHMDS (1M in Hexanes, 0.54 mL, 0.54 mmol) again. After 3 hours, the mixture was diluted with H2O and acidified to pH 3 with 1N HCl at 0° C. The resulting mixture was extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The crude mixture was purified by prep HPLC to give title compound (30 mg, 40%) as a white solid. 1H NMR (CD3OD) δ7.38 (d, 1H), 7.26 (d, 1H), 5.66 (dd, 1H), 3.16 (dd, 1H), 2.39 (s, 3H), 2.34 (dd, 1H). MS found: (M+H)+: 322.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]([OH:17])[C:6]=1[CH:7]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:18][NH2:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[C:1]([C:5]1[C:6]([CH2:7][NH:19][CH3:18])=[C:9]([OH:17])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(O)c(C=O)c(C(C)(C)C)c1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CNCc1c(O)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 0.234 g (1.00 mmol) of the product of Step A, 3 mL of 2 N methylamine in TMF, and 0.5 mL acetic acid dissolved in 4.0 mL 1,2-dichloroethane was stirred at room temperature for 5 h. Sodium triacetoxyborohydride (0.422 g; 2.0 mmol) and 10 mL of 1,2-dichloroethane was then added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was then treated with excess saturated aqueous NaHCO3. The aqueous layer was separated and extracted with CH2Cl2, the organic layers were combined, dried (Na2SO4), filtered, and evaporated. The residue was purified on a silica gel flash chromatography column eluted with CH2Cl2-MeOH—NH4OH (95:5:0.5). Evaporation of the purified fractions and drying in vacuo afforded the title compound. HPLC/MS: 250.2 (M+1); Rt=2.5 min.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]=[CH:54][C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[N+:60]1([O-:65])[CH2:61][CH2:62][CH2:63][CH:64]=1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]3[O:65][N:60]4[CH2:61][CH2:62][CH2:63][CH:64]4[CH:54]3[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C=CC(=O)OCC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: [O-][N+]1=CCCC1
Solvent: Cc1ccccc1
Product: CCCCc1nc2ccc(C3ON4CCCC4C3C(=O)OCC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 53.2 %

Procedure:
To a solution of 0.300 g of ethyl 3-[2-butyl-3,4-dihydro-4-oxo-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-6-quinazolinyl]-2-propenoate in 20 ml of toluene is added 0.293 g of 3,4-dihydro-2H-pyrrole 1-oxide and the reaction mixture heated at reflux for 6 hours. The reaction mixture is cooled and concentrated in vacuo to a residue which is purified by chromatography on silica gel by elution with 1:1 ethyl acetate-hexanes to give 0.177 g of the desired product. FAB mass spec 620 (M+H, -ph3C).
Reaction SMILES: Cl.Cl.[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH2:11])[CH2:7]1)([CH3:5])[CH3:4].[CH3:30][O:31][CH:32]1[C:37](=O)[CH2:36][CH2:35][O:34][CH2:33]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH:11][CH:37]2[CH2:36][CH2:35][O:34][CH2:33][CH:32]2[O:31][CH3:30])[CH2:7]1)([CH3:5])[CH3:4]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)CC[C@@H](N)C1
Reactant: COC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine dihydrochloride (135.0 mg, 0.2945 mmol), 3-methoxytetrahydro-4H-pyran-4-one (110 mg, 0.88 mmol) and triethylamine (0.16 mL, 1.2 mmol) in methylene chloride (8 mL) was added sodium triacetoxyborohydride (190 mg, 0.88 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated. The residue was purified by flash chromatography on silica gel (EtOAc to EtOAc/Et3N=10:0.1) to give 123 mg of desired product as a mixture of two isomers. The two isomers were separated by chiral HPLC to give isomer 1 (65 mg after converting to TFA salt) and isomer 2 (45 mg after converting to TFA salt). LCMS calculated for C24H36F3N5O3: (M+1) 500; found 500.1 for both isomers.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])=[C:11]([N+:35]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>CO>[NH2:35][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([O:15][CH3:16])=[CH:13][C:12]=1[C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1)=[O:18]
Reactant: COc1cc(C(=O)N2CCN(c3ncnc4ccccc34)CC2)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)N2CCN(c3ncnc4ccccc34)CC2)c(N)cc1OCc1ccccc1
Yield: 119.3 %

Procedure:
[4-(Benzyloxy)-5-methoxy-2-nitrophenyl][4-(4-quinazolinyl)piperazino]methanone (600 mg, 1.2 mmol) was dissolved in methanol (10 mL), SnCl2.2H2O (810 mg, 3.6 mmol) was added and refluxed until the TLC indicated the completion of the reaction. The methanol was evaporated by vacuum and the aqueous layer was then adjusted to pH 8 with 10% NaHCO3 solution and extracted with ethyl acetate (2×30 mL). The combined organic phase was dried over Na2SO4 and evaporated under vacuum to afford the crude (450 mg, 95% yield). This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (8d) (672 mg, 80% yield). 1H NMR (CDCl3) δ 3.20-3.30 (m, 4H), 3.65-3.75 (m, 4H), 3.95 (s, 3H), 5.20 (s, 2H), 6.20 (s, broad NH2), 6.45-6.55, (t, 1H) 6.70 (s, 1H), 7.30-7.50 (m, 5H), 7.55-7.65 (t, 1H), 7.65 (s, 1H), 7.70-7.90, (m, 2H), 7.85-7.95, (m, 2H); FABMS: 470 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:24])OC2C=CC=CC=2)=[CH:11][N:10]=1.[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH2:30][CH2:29]2>>[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:16](=[O:24])[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][CH:11]=1)[CH2:30][CH2:29]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: O=C(Nc1ccc(OCc2ccccn2)nc1)Oc1ccccc1
Product: O=C(Nc1ccc(OCc2ccccn2)nc1)N1CCc2cc(Br)ccc21

Procedure:
Phenyl N-[2-(pyridin-2-ylmethyloxy)pyridin-5-yl]carbamate (D3) and 5-bromoindoline were converted into the title compound using a method similar to that of Example 1, m.p. 138-139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([S:16]([CH3:19])(=[O:18])=[O:17])[CH2:13][CH2:14][CH3:15])[N:11]=1)[C:5](OC)=[O:6].[BH4-].[Li+]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([CH2:13][CH2:14][CH3:15])[S:16]([CH3:19])(=[O:17])=[O:18])[CH:9]=[C:4]([CH2:5][OH:6])[CH:3]=1
Reactant: CCCN(c1cc(C(=O)OC)cc(Cl)n1)S(C)(=O)=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCN(c1cc(CO)cc(Cl)n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-chloro-6-[(methylsulfonyl)(propyl)amino]isonicotinate (3.52 g, 11.47 mmol) in THF (50 mL), cooled to 0° C., was added lithium borohydride (17.3 mL, 34.4 mmol, 2M THF) slowly via serynge. The reaction mixture was allowed to warm to RT by itself and stirred at RT for 3 h. The reaction mixture was carefully quenched with EtOAc, MeOH and water sequentially. The reaction mixture was diluted with EtOAc, the organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give N-[6-chloro-4(hydroxymethyl)pyridin-2-yl]-N-propylmethanesulfonamide as a yellow thick oil. 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H), 7.23 (s, 1H), 4.72 (s, 2H), 3.80 (t, J=8 Hz, 2H), 3.00 (s, 3H), 2.02 (s, 1H), 1.59-1.46 (m, 2H), 0.90 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:13][C:12]=2[CH:11]=[C:10]([O:29][CH3:30])[CH:9]=1.[CH3:31][NH2:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH:32][CH3:31])[CH2:13][C:12]=2[CH:11]=[C:10]([O:29][CH3:30])[CH:9]=1
Reactant: COc1cc2c(c(-c3ccccc3Cl)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cc(OC)cc(-c3ccccc3Cl)c2O1

Procedure:
The title compound was prepared (0.040 g, 52%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2-chlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.102 g, 0.23 mmol) and methylamine (0.071 g, 2.3 mmol). mp 185-186° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1.Br[C:28]1[CH:29]=[C:30]([NH2:37])[CH:31]=[N:32][C:33]=1[CH:34]1[CH2:36][CH2:35]1.COCCOC.C([O-])([O-])=O.[Cs+].[Cs+]>O>[NH2:37][C:30]1[CH:29]=[C:28]([C:9]2[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:26])[CH:8]=2)[C:33]([CH:34]2[CH2:36][CH2:35]2)=[N:32][CH:31]=1
Reactant: Nc1cnc(C2CC2)c(Br)c1
Reactant: Cc1noc(C)c1-c1cc(B2OC(C)(C)C(C)(C)O2)c2[nH]c(=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1noc(C)c1-c1cc(-c2cc(N)cnc2C2CC2)c2[nH]c(=O)[nH]c2c1
Temperature: 130 °C
Yield: 85 %

Procedure:
6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (150 mg, 0.42 mmol) and 5-bromo-6-cyclopropylpyridin-3-amine (180 mg, 0.84 mmol) were added to a solvent mixture of 1,2-dimethoxyethane (2 mL) and water (1 mL). To the mixture were added PEPPSI-Ipr (29 mg, 0.03 mmol) and Cs2CO3 (413 mg, 1 mmol). The reaction mixture was heated at 130° C. in microwave reactor for 30 mins. The reaction mixture was then filtered and organic solvent was evaporated and the residue was purified with Prep HPLC (0-100% CH3CN/H2O) to afford 129 mg of 4-(5-amino-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]([NH2:13])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1COCC1>[Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11](=[S:23])[NH2:13]
Reactant: CC(C)(C)n1ncc(C(N)=O)c1Br
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(C(N)=S)c1Br
Yield: 81.3 %

Procedure:
A solution of the compound (3.59 g, 14.59 mmol) obtained in step 4 and Lawesson's reagent (5.31 g, 13.13 mmol) in THF (60 mL) was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (solvent gradient; 2→50% ethyl acetate/hexane) to give 5-bromo-1-tert-butyl-1H-pyrazole-4-carbothioamide (2.8 g, 10.68 mmol, 73%) as a pale-yellow powder.