Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7]S(C)(=O)=O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[C:19]([C:26]2[C:35]3[C:30](=[CH:31][C:32](O)=[CH:33][CH:34]=3)[N:29]=[CH:28][CH:27]=2)=[C:20]2[CH2:25][CH2:24][CH2:23][N:21]2[N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[C:19]([C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:7][CH2:6][CH:2]4[CH2:3][CH2:4][CH2:5][O:1]4)=[CH:33][CH:34]=3)[N:29]=[CH:28][CH:27]=2)=[C:20]2[CH2:25][CH2:24][CH2:23][N:21]2[N:22]=1
Reactant: CS(=O)(=O)OCC1CCCO1
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nn3c(c2-c2ccnc4cc(OCC5CCCO5)ccc24)CCC3)nc1
Temperature: 60 °C

Procedure:
A mixture of methanesulfonic acid tetrahydro-furan-2-ylmethyl ester (0.70 g, 3.66 mmol), 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol (400 mg, 1.22 mmol), and cesium carbonate (2.38 g, 7.32 mmol) in N,N-dimethylformamide (2.5 mL) is heated at 60° C. for 42 h. The mixture is concentrated in vacuo and the residue chromatographed to yield the title compound, 79 mg (15%), as a tan solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[CH2:16][C:17]1[NH:21][C:20]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:19]=2[N:18]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:29]>CN(C)C=O.O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[CH2:16][C:17]1[N:18]([CH3:29])[C:19]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:20]=2[N:21]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCCCC1Cc1nc2cc(F)c(F)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(CC2CCCCN2C(=O)OC(C)(C)C)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of sodium hydride (0.46 g, 60% dispersion in mineral oil) in dimethylformamide (30 ml) at 0° C., under argon, was added (RS)-2-(5,6-difluoro-1H-benzoimidazol-2-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester, D59 (2 g) and the reaction mixture stirred for a further 30 min. before the addition of iodomethane (0.78 ml). The reaction mixture was then stirred at room temperature for 18 h, a further equivalent of iodomethane (0.35 ml) was added and stirring continued for 24 h. Further portions of sodium hydride (0.23 g, 60% dispersion in mineral oil) and iodomethane (0.35 ml) were added and the reaction stirred for an additional 24 h. After diluting with water, the aqueous layer was extracted with diethyl ether (3×). The combined organics were dried (MgSO4) and solvent removed in vacuo to afford the title compound (0.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH:5]=[N:6][OH:7].N1C=CC=CC=1.ClN1C(=O)CCC1=O.[CH2:26]=[C:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:26][C:27]3([CH2:31][CH2:30][CH2:29][CH2:28]3)[O:7][N:6]=2)[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccc(C=NO)cc1Br
Reactant: C=C1CCCC1
Agent: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C2=NOC3(CCCC3)C2)cc1Br
Yield: 58.6 %

Procedure:
To a solution of 3-bromo-4-methylbenzaldehyde oxime (0.85 g, 4 mmol, 1.0 eq) in THF (50 mL) was added pyridine (0.2 mL, 2.4 mmol, 0.6 eq) followed by N-chlorosuccinimide (530 mg, 4 mmol, 1.0 eq) and the resulting mixture was refluxed for 1 h. The reaction was cooled to room temperature before the addition of a solution of methylenecyclopentane (0.42 mL, 4 mmol, 1.0 eq) in THF (5 mL) followed by triethyl amine (0.94 mL, 7 mmol, 1.7 eq). The resulting solution was refluxed for 1 h. The solvent was evaporated under vacuum and usual work up afforded 690 mg of the title product as a white solid. 1HNMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 3.22 (s, 2H), 2.41 (s, 3H), 2.14-2.11 (m, 2H), 1.88-1.84 (m, 2H), 1.77-1.72 (m, 4H); ESI-MS (m/z) 294, 296 [(MH)+, Br79,81].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[NH:13])[CH2:4][CH2:3]1.C(NC1N=[C:23]([C:25]2[C:26]([CH:34]([CH3:36])[CH3:35])=[N:27][N:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=23)[CH:22]=[CH:21]N=1)(C)C>>[CH:34]([C:26]1[C:25]([C:23]2[CH:22]=[CH:21][N:14]=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[N:13]=2)=[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]2[N:27]=1)([CH3:36])[CH3:35]
Reactant: CC(C)Nc1nccc(-c2c(C(C)C)nn3ccccc23)n1
Reactant: CN1CCN(CCCNC(=N)N)CC1
Product: CC(C)c1nn2ccccc2c1-c1ccnc(NCCCN2CCN(C)CC2)n1

Procedure:
[4-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-[3-(4-methyl-piperazin-1-yl)-propyl]-amine was prepared from 3-dimethylamino-1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-propenone and N-[3-(4-methyl-piperazin-1-yl)-propyl]-guanidine following the method used in Step 4 of the synthesis of Isopropyl-[4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-amine (Example 66), except preparative-HPLC purification was used in the place of recrystallization (162 mg, 19%). 1H-NMR (250 MHz, DMSO-d6) δ 8.72 (d, J=6.8 Hz, 1H), 8.28-8.20 (m, 2H), 7.37 (t, J=7.8 Hz, 1H), 7.16-7.10 (m, 1H), 6.99 (t, J=6.6 Hz, 1H), 6.80 (d, J=7.3 Hz, 1H), 3.78 (sept, J=7.3 Hz, 1H), 2.56-2.32 (m, 10H), 2.22 (s, 3H), 2.10-2.06 (m, 2H), 1.73 (pent, J=6.9 Hz, 2H), 1.35 (d, J=6.8 Hz, 6H); LC/MS 394.3 m/z (M+H+). Compound 1135.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]([C:15]([F:18])([F:17])[F:16])=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=2)=[CH:6][CH:5]=1.C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[Br:1][C:11]1[C:12]([C:19]([F:22])([F:20])[F:21])=[C:13]([C:15]([F:16])([F:17])[F:18])[NH:14][C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)[nH]c1C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1[nH]c(-c2ccc(Cl)cc2)c(Br)c1C(F)(F)F
Reaction time: 2 h
Yield: 65.4 %

Procedure:
Bromine (0.527 g, 3.3 mmol) is added to a room temperature solution of 5-(p-chlorophenyl)-2,3-bis(trifluoromethyl)pyrrole (0.94 g, 3.0 mmol), acetic acid (5 mL) and sodium acetate (0.492 g, 6 mmol). After stirring for 2 hours the reaction mixture is diluted with water and extracted with ether. The combined organic extracts are washed sequentially with water, sodium metabisulfite solution, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. Crystallization of the solid from hexanes gives the title product as white crystals (0.77 g, mp 64.5°-65.0° C., 65%).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[C:24]=1[F:32])#[N:16]>>[F:32][C:24]1[C:25]([C:2]2[N:6]3[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:26][CH:27]=[CH:28][C:23]=1[C:18]1[C:17]([C:15]#[N:16])=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Reactant: N#Cc1ccccc1-c1cccc(B(O)O)c1F
Product: N#Cc1ccccc1-c1cccc(-c2cnc3nc(C(F)(F)F)cnn23)c1F
Yield: 15 %

Procedure:
7-Bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine was coupled with 2′-cyano-2-fluorobiphenyl-3-boronic acid as described in Example 3, step f, to give 21 mg (15%) of the title compound: mp 167-168° C.; 1H NMR (360 MHz, CDCl3) δ 7.47-7.60 (4H, m), 7.73 (1H, dd, J 1.4, 7.7 Hz), 7.84 (1H, dd, J 0.7, 7.0 Hz), 8.26-8.30 (1H, m), 8.69 (1H, d, J 2.8 Hz), 8.83 (1H, s); MS (ES+) m/z 384 [M+H]+. Anal. Found: C, 59.14; H, 2.75; N, 18.01%. Required for C19H9F4N5.0.2H2O: C, 58.98; H, 2.45; N, 18.10%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH:16]([NH:22]C(OC(C)(C)C)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][CH:16]([CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(Cc1cccc(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(N)Cc1cccc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 84.8 %

Procedure:
159 (850 mg) was dissolved in 4 ml of DCM and 4 ml of TFA was added then the reaction mixture was let 1 h at room temperature. The reaction mixture is concentrated and 50 ml of AcOEt are added. The organic phase are washed with saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated to afford 160 as a white solid (540 mg, 86%). 1H NMR (DMSO): δ 1.26 (t, 3H, J=6.5 Hz), 1.89 (s, 2H), 2.89 (dd, 1H, J=13.1, 6.1 Hz), 2.97 (dd, 1H, J=13.1, 6.1 Hz), 3.68 (t, 1H, J=6.1 Hz), 4.16 (q, 2H, J=6.5 Hz), 5.21 (s, 2H), 6.90 (d, 1H, J=7.6 Hz), 6.99 (s, 2H), 7.32 (t, 1H, J=7.8 Hz), 7.47 (m, 1H), 7.53 (t, 2H, J=7.0 Hz), 7.58 (d, 2H, J=7.6 Hz).
Reaction SMILES: F[C:2]1[N:26]=[CH:25][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)=[C:13]([CH3:24])[CH:12]=3)[C:4]=2[CH:3]=1.C(OC(=O)[NH:33][CH:34]1[CH:39]2[CH:35]1[CH2:36][NH:37][CH2:38]2)(C)(C)C>C(O)C.C(Cl)(Cl)Cl>[NH2:33][CH:34]1[CH:39]2[CH:35]1[CH2:36][N:37]([C:2]1[N:26]=[CH:25][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([O:17][C:18]5[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=5)=[C:13]([CH3:24])[CH:12]=4)[C:4]=3[CH:3]=1)[CH2:38]2
Reactant: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1Oc1cccnc1
Reactant: CC(C)(C)OC(=O)NC1C2CNCC21
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2ncnc3cnc(N4CC5C(N)C5C4)cc23)ccc1Oc1cccnc1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A solution of 2.71 g (7.83 mmol) of (6-fluoro-pyrido[3,4-d]pyrimidin-4-yl)-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-amine and 31.0 g (156.5 mmol) of (3-aza-bicyclo[3.1.0]hex-6-yl)-carbamic acid tert-butyl ester in 20 mL of ethanol in a sealed tube was heated at 105° C. for 24 hours. The mixture was cooled to room temperature and diluted with chloroform. The organics were washed sequentially with 3×150 mL saturated sodium bicarbonate and 1×50 mL of saturated sodium chloride, dried over sodium sulfate and evaporated. Chromatography over silica gel, eluting with 5% methanol/chloroform afforded 1.79 g (43%) of the title compound. 1H NMR (CDCl3): δ 8.93 (s, 1), 8.53 (s, 1), 8.33 (m, 2), 7.60 (m, 3), 7.21 (m, 2), 6.96 (d, 1), 6.24 (m, 1), 4.83 (m, 1), 3.81 (m, 2), 3.51 (m, 2), 3.47 (m, 1), 2.36 (m, 1), 2.26 (s, 3), 1.88 (m, 1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=2)[CH:3]=1
Reactant: Fc1ccc2[nH]ncc2c1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1cc2cc(F)ccc2n1

Procedure:
The title compound was prepared according to the method described for Preparation 93 using 5-fluoro-1H-indazole and ethyl bromoacetate to afford the title compound as an off-white solid in 27% yield, 130 mg.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[C:4]2[CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:3]=12.[CH2:16](OCC)C>C[Li]>[CH3:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:16])=[C:4]2[CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:3]=12
Reactant: CCOCC
Reactant: Cc1sc(C(=O)O)c2c1CC(C)(C)CC2
Agent: [Li]C
Product: CC(=O)c1sc(C)c2c1CCC(C)(C)C2
Temperature: 26 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (4.10 g, 18.28 mmol) in diethyl ether (300 mL), methyllithium (23 mL, 1.6 M solution in diethyl ether) is slowly added at rt. The reaction mixture becomes clear, yellow and slightly warm (26° C.), and is stirred for 15 min before it is quenched with water. The organic layer is separated, washed once more with water, dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (2.80 g) as a pale yellow crystalline solid; LC-MS: tR=1.06 min; [M+1]=223.17; 1H NMR (CDCl3): δ 3.00 (t, J=7.0 Hz, 2H), 2.43 (s, 3H), 2.31 (s, 3H), 2.26 (s, 2H), 1.51 (t, J=7.0 Hz, 2H), 0.95 (s, 6H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:27]3[N:23]([C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25][N:26]=3)[C:22]3[CH:34]=[C:35]([F:39])[C:36]([F:38])=[CH:37][C:21]=3[N:20]([CH2:40][C:41](=[O:53])[N:42]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:43]([CH3:45])[CH3:44])[C:19]2=[O:54])=[N:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH2:46]([N:42]([CH:43]([CH3:45])[CH3:44])[C:41](=[O:53])[CH2:40][N:20]1[C:19](=[O:54])[CH:18]([CH2:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8][N:9]=2)[C:27]2[N:23]([C:24]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[N:25][N:26]=2)[C:22]2[CH:34]=[C:35]([F:39])[C:36]([F:38])=[CH:37][C:21]1=2)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)c2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)C(Cc2n[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
To a solution of 3-{6-[(benzyl-isopropyl-carbamoyl)-methyl]-8,9-difluoro-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl}-indazole-1-carboxylic acid tert-butyl ester (100 mg, 0.137 mmol) in dioxane (1 mL) was added HCl (4.0M in dioxane, 2 mL). The reaction was stirred at room temperature for 24 hours. The volatiles were concentrated in vacuo and the residue was dissolved in CH2Cl2. The organic solution was washed with aqueous NaHCO3 (1×), dried (Na2SO4), filtered and concentrated in vacuo. Purification by preparative chromatography eluting with 5% MeOH in CH2Cl2 provided 45 mg of N-benzyl-2-[8,9-difluoro-4-(1H-indazol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. 1H NMR (CD2Cl2) δ 7.92 (m, 1H), 7.04-7.66 (m, 14H), 6.67 (s, 1H), 4.22-4.96 (m, 6H), 3.91-4.13 (m, 2H), 1.01-1.22 (m, 6H); MS 632.3 (M+1), 630.2 (M−1).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:14][CH3:15])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:14]([O:13][C@@H:10]1[CH2:11][CH2:12][C@H:8]([NH2:7])[CH2:9]1)[CH3:15]
Reactant: CCO[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCO[C@@H]1CC[C@H](N)C1

Procedure:
A solution of cyclopent-3-enecarboxylic acid (2.25 g), diphenylphosphoryl azide (4.7 mL), and triethylamine (2.8 mL) in 25 mL toluene was refluxed for 7 h. The mixture was cooled to rt and treated with 10 mL of tert-butanol. The resulting mixture was refluxed for an additional 16 h. The solvents were evaporated and the crude residue was chromatographed with silica gel (1:10 ethyl acetate:hexanes) to give Cyclopent-3-enylcarbamic acid tert-butyl ester (racemic): (2.37 g). Borane-tetrahydrofuran (1.5 M in THF, 20 mL) was added dropwise to a solution of cyclopent-3-enylcarbamic acid tert-butyl ester (1.83 g) in tetrahydrofuran (30 mL) at 0° C. The solution was gradually warmed to rt and stirred for 16 h. The reaction solution was cooled to 0° C. and sodium hydroxide (1 N, 33 mL) was slowly added followed by 30% hydrogen peroxide (33 mL). The resulting mixture was stirred at rt for an additional 5 h and diluted with ethyl acetate (70 mL). The aqueous layer was separated and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated via rotary evaporator. Silica gel chromatography (1:1 ethyl acetate:hexanes) provided 0.25 g of cis-(3-hydroxycyclopentyl)carbamic acid tert-butyl ester (racemic) followed by 1.07 g of the trans isomer. A solution of cis-(3-hydroxycyclopentyl)-carbamic acid tert-butyl ester (201 mg) in dimethylformamide (3 mL) was treated with sodium hydride (60% in mineral oil, 95 mg) at 0° C. After gas evolution had ceased, the mixture was stirred for 30 min at rt. Iodoethane (88 μL) was added to the mixture and the reaction was stirred at rt for 16 h. The excess sodium hydride was destroyed at 0° C. by the careful addition of aqueous ammonium chloride. The resulting mixture was partitioned between ethyl acetate and ammonium chloride and the organic layer was separated and washed with brine. The organic layer was dried over Na2SO4 and concentrated via rotary evaporator. Silica gel chromatography (1:4 ethyl acetate:hexanes) provided cis-(3-ethoxycyclopentyl)carbamic acid tert-butyl ester (racemic) (102 mg). Cis-(3-ethoxycyclopentyl)carbamic acid tert-butyl ester was stirred in 1:1 trifluoroacetic acid:dichloromethane for 0.5 h. The solvent was removed by evaporation to provide cis-3-ethoxycyclopentylamine (racemic).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[C:9]([C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:10][NH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])=[C:4]([N+:28]([O-])=O)[CH:3]=1>B#[Ni]>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[C:9]([C:18](=[O:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:10][NH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])=[C:4]([NH2:28])[CH:3]=1
Reactant: CCOC(=O)c1[nH]nc(C(=O)c2ccccc2)c1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: B#[Ni]
Product: CCOC(=O)c1[nH]nc(C(=O)c2ccccc2)c1C(=O)c1ccc(Cl)cc1N
Yield: 55.5 %

Procedure:
Following a procedure similar to that described in Example 23(d), ethyl 4-(4-chloro-2-nitrobenzoyl)-3-benzoyl-1H-pyrazole-5-carboxylate (1.2 g, 2.81 mmol) was treated with nickel boride to afford crude product. The crude product was purified by flash chromatography eluting with hexanes:ethyl acetate (75:25-50:50) to give the title compound as a solid (620 mg, 56%).
Reaction SMILES: [N:1]([CH2:4][C:5]([F:27])([F:26])[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=2)[CH:9]=[C:8]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N+]=[N-]>CO.C(Cl)Cl.[Pd]>[NH2:1][CH2:4][C:5]([F:27])([F:26])[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=2)[CH:9]=[C:8]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(F)(F)CN=[N+]=[N-])c2c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(F)(F)CN)c2c1
Reaction time: 3.5 h
Yield: 83.2 %

Procedure:
To a solution of diethyl 1-(3-azido-2,2-difluoropropyl)-1H-indole-2,6-dicarboxylate (2.5 g, 7.8 mmol) in methanol:CH2Cl2 (1:1, 60 mL) is added 10% palladium on carbon (1.4 g, 1.3 mmol). The reaction mixture is stirred for 3.5 h under H2 atmosphere. The reaction mixture is filtered and the filtrate is concentrated to afford the title crude compound (2.3 g) which is used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][N:6]=1.N1C=CC=CC=1.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:22][S:19]([NH:1][C:2]1[S:3][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][N:6]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1cnc(N)s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Cc1cnc(NS(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of ethyl 2-aminothiazol-5-ylacetate (32 g.) in methylene chloride (160 ml.) was added pyridine (27.2 g.) under ice-cooling, and to the mixture was dropwise added mesyl chloride (29.6 g.) in methylene chloride (29.6 ml.) over 30 minutes at 8° to 10° C. The mixture was further stirred for 8 hours at room temperature. After the reaction, methylene chloride was distilled off from the reaction mixture, and to the residue were added water (300 ml.) and ethyl acetate (300 ml.). The resulting mixture was adjusted to pH 2 with 10% hydrochloric acid under ice-cooling, and the precipitates were collected by filtration and washed with ethyl acetate. The precipitates were recrystallized from ethanol (600 ml.) to give ethyl 2-methanesulfonamidothiazol-5-ylacetate (27.3 g.), mp 153° to 155° C.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>O.CO>[C:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:11]=1)(=[O:5])[CH:4]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)CCCc1ccc(C(C)=O)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCc1ccc(C(=O)C=Cc2ccccc2)cc1
Reaction time: 3 h
Yield: 70.6 %

Procedure:
To a solution of 0.40 g of sodium hydroxide in 6 ml of water, a solution of 1.00 g of methyl 4-(4-acetylphenyl)butyrate in 2 ml of methanol was added under ice-cooling. Then, a solution of 0.48 g of benzaldehyde in 2 ml of methanol was added dropwise and stirring was continued at room temperature for 3 hours. The reaction mixture was diluted with water and acidified with dilute hydrochloric acid. Precipitated crystals were collected by filtration, washed successively with water and n-hexane to yield 0.94 g of colorless crystals. Recrystallization from 80% aqueous methanol gave colorless needles, mp 111°~112° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26](Br)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[CH3:37][C:38]1([CH3:45])[C:42]([CH3:44])([CH3:43])[O:41][BH:40][O:39]1>O1CCCC1.C(N(CC)CC)C.CC#N>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([B:40]3[O:41][C:42]([CH3:44])([CH3:43])[C:38]([CH3:45])([CH3:37])[O:39]3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1Br
Reactant: CC1(C)OBOC1(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1B1OC(C)(C)C(C)(C)O1

Procedure:
A mixture of EXAMPLE 1D (1.2 g), 1.0 M 4,4,5,5-tetramethyl-1,3,2-dioxaborolane in tetrahydrofuran (4.24 mL), triethylamine (0.92 mL), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane (0.087 g) in CH3CN (15 mL) was heated at 100° C. in a Biotage Initiator microwave reactor for 30 minutes. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to provide the title compound.