Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][OH:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38]>>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][O:29][CH2:28][CH2:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3([C:4]([OH:3])=[O:5])[CH2:8][CH2:7]3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1
Reactant: Clc1ccccc1CBr
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCO)cc3)cc2)CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCOCc1ccccc1Cl

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-{4′-[4-(2-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 1-bromomethyl-2-chloro-benzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:21])[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.C[O:23][C:24](=[O:47])[C@H:25]([C@@H:44]([CH3:46])O)[NH:26]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([O:21][C@H:44]([CH3:46])[C@@H:25]([C:24]([OH:47])=[O:23])[NH2:26])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]2[C:20]1=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: OC1(c2ccccc2F)c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Product: C[C@@H](OC1(c2ccccc2F)c2ccccc2-c2ccccc21)[C@H](N)C(=O)O

Procedure:
from 9-(2-fluorophenyl)-9H-fluoren-9-ol (Example 3c) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH:41]([CH3:43])[CH3:42])=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH:41]([CH3:42])[CH3:43])=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: CC(C)c1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(6-isopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K22) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous brown substance (266 mg, 65%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH2:14])[CH2:6][C:7]([F:13])([F:12])[CH2:8][CH:9]([CH3:11])[CH3:10].C(NC(C)C)(C)C.[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>ClCCl>[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH:14][C:29]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:30])[CH2:6][C:7]([F:13])([F:12])[CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: COC(=O)[C@@H](N)CC(F)(F)CC(C)C
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CC(F)(F)CC(C)C)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 65.9 %

Procedure:
To a mixture of (S)-2-amino-4,4-difluoro-6-methyl-heptanoic acid methyl ester hydrochloride (238 mg, 0.97 mmol) and diisopropyl amine (2.42 mmol, 313 mg) in dry dichloromethane (5 mL) under N2 is added drop wise morpholine carbonyl chloride (1.45 mmol, 218 mg). The mixture is stirred at room temperature for 23 h, then diluted with dichloromethane (25 mL) and washed with dilute HCl (30 mL), and saturated NaHCO3 (30 mL). The organic layers are dried over magnesium sulfate and concentrated in vacuum. Purification over 12 g silica gel, eluting with EtOAc:Heptane (1:1, then 2:1) affords (S)-4,4-Difluoro-6-methyl-2-[(morpholine-4-carbonyl)-amino]-heptanoic acid methyl ester (206 mg, 66%).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[CH:7][C:8]=1[Cl:9].[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(N(CC)CC)C>C(O)C>[Cl:10][C:4]1[C:3]([CH2:2][S:18][C:16]2[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=2)=[C:8]([Cl:9])[CH:7]=[CH:6][N:5]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Clc1ccnc(Cl)c1CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2c(Cl)ccnc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To a solution of 3-(bromomethyl)-2,4-dichloropyridine (1.41 g, 5.86 mmol) in anhydrous ethanol (20 mL) was added 6-methyl-2-sulfanylpyrimidin-4-ol (0.58 g, 4.09 mmol) and triethylamine (0.65 g, 6.43 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to precipitate the product. The white solid was filtered and washed with water and ether to provide 2-{[(2,4-dichloropyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (0.795 g, 45% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.23 (s, 3H), 2.31 (s, 3H), 4.68 (s, 2H), 6.04 (bs, 1H), 7.67 (d, J=5.3 Hz, 1H), 8.35 (d, J=5.3 Hz, 1H); M+ 302.3.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[CH:4][N:3]=1.[CH2:10]([OH:14])[C:11]#[C:12][CH3:13].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:10]([O:14][C:6]1[C:7]([F:8])=[C:2]([F:1])[N:3]=[CH:4][N:5]=1)[C:11]#[C:12][CH3:13]
Reactant: CC#CCO
Reactant: Fc1ncnc(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC#CCOc1ncnc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
0.5 g of 4,5,6-trifluoropyrimidine, 0.31 g of 2-butyn-1-ol and 0.62 ml of N,N-diisopropylethylamine were added to 1 ml of tetrahydrofuran, then the mixture was stirred at room temperature for 1 hour. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.52 g of 4-(2-butynyloxy)-5,6-difluoropyrimidine.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:22](F)=[CH:21][C:20]([F:24])=[CH:19][N:18]=2)=O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][NH:26][NH2:27].CC(O)C>O>[F:24][C:20]1[CH:21]=[C:22]2[N:26]([CH3:25])[N:27]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[C:17]2=[N:18][CH:19]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1ncc(F)cc1F
Reactant: CNN
Solvent: O
Solvent: CC(C)O
Product: Cn1nc(-c2ccc(O)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
A mixture of [4-(benzyloxy)phenyl](3,5-difluoropyridin-2-yl)methanone (300 mg), methylhydrazine (212 mg) and 2-propanol (5 mL) was stirred at room temperature for 30 min, and then at 90° C. for 12 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude material was dissolved in EtOH (20 mL) and 10% Pd—C (50% wet, 98 mg) was added. The mixture was stirred for 1 h under H2 atmosphere, filtered and evaporated. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (125 mg).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][CH2:38][NH2:39]>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:5])[N:39]([CH2:38][CH2:37][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[Cl:30])[CH2:23][CH2:22]2)[CH2:7][CH2:8]1)(=[O:13])=[O:14]
Reactant: NCCc1ccccc1Cl
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(CCc2ccccc2Cl)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 2-(2-Chloro-phenyl)-ethylamine. MS (ESI): 467.3 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH3:11])[NH:10][C:5]2=[CH:4][CH:3]=1.[Cu][C:13]#[N:14]>CN(C)C=O>[CH3:11][C:9]1[N:8]=[C:6]2[NH:7][C:2]([C:13]#[N:14])=[CH:3][CH:4]=[C:5]2[N:10]=1
Reactant: Cc1nc2nc(Br)ccc2[nH]1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: Cc1nc2ccc(C#N)[nH]c-2n1
Temperature: 150 °C
Reaction time: 9 h
Yield: 64.7 %

Procedure:
To a solution of 5-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (1.92 g) in N,N-dimethylformamide (48 ml) was added Copper (I) cyanide (2.04 g), and the mixture was stirred for 9 hr at 150° C. After evaporation of the solvent under reduced pressure, water (45 ml) and ethylenediamine (2.7 g) were added to the residue, and the mixture was heated at 70° C. for 15 min. The solution was concentrated under reduced pressure and the residue was purified by a short silica gel column to give the objective compound (927 mg) as a brown powder. Purification by silica gel column chromatography (dichloromethane/methanol=10/1) gave a purer compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH:26]2[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]2)[S:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1.[BH4-].[Na+].CC(C)=O>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C@@H:26]2[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]2)[S:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1
Reactant: CC(C)c1nnc2ccc(-c3sc(C4CCC(=O)CC4)nc3-c3ccc(F)cc3F)nn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)c1nnc2ccc(-c3sc([C@H]4CC[C@@H](O)CC4)nc3-c3ccc(F)cc3F)nn12
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
The 4-(4-(2,4-difluorophenyl)-5-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiazol-2-yl)cyclohexanone (0.495 g, 1.09 mmol, Example #26, Step B) was dissolved in MeOH (5 mL) then cooled to about −5° C. Sodium borohydride (0.0413 g, 1.09 mmol) was added and the mixture was stirred for about 5 min. Acetone was added then the solvents were concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel with DCM/MeOH (95:5) as an eluent then by RP-HPLC (Table 1, Method f) to give the title compound: (0.029 g, 6%): LC/MS (Table 1, Method a) Rt=2.41 min; MS m/z: 456.2 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:22][CH3:23])=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][C:7]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=O.CN.[C:26]([BH3-])#[N:27].[Na+].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C(O)(=O)C.CO>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[CH3:23][O:22][C:4]1[C:3]([CH2:1][NH:27][CH3:26])=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][C:7]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: COc1c(C=O)cccc1Oc1nc(C(F)(F)F)ccc1C#N
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2nc(C(F)(F)F)ccc2C#N)c1OC
Yield: 64.5 %

Procedure:
2-(3-Formyl-2-methoxyphenoxy)-6-(trifluoromethyl)nicotinonitrile (0.50 g, 1.6 mmol), methylamine (33% in ethanol, 0.9 mL, 7.2 mmol) and sodium cyanoborohydride (120 mg, 1.9 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (80 mL) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.20 g, 1.7 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 2-(2-methoxy-3-methylaminomethyl-phenoxy)-6-trifluoromethyl-nicotinonitrile fumarate (468 mg, 67%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11]C)[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>>[N+:13]([C:16]1[CH:21]=[C:20]([C:2]2[CH:8]=[C:7]([CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:19]=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: CCCCc1ccc(N)c(Br)c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: CCCc1ccc(N)c(-c2cccc([N+](=O)[O-])c2)c1

Procedure:
2-bromo-4-(n-butyl)aniline and 3-nitrobenzene boronic acid can be combined to form 2-(3-nitrophenyl)-4-propylaniline,
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11])[CH3:2].[CH2:12](N)[CH2:13][NH2:14]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[NH:11][CH2:12][CH2:13][N:14]=1)[CH3:2]
Reactant: CCc1ccccc1CC#N
Reactant: NCCN
Product: CCc1ccccc1CC1=NCCN1

Procedure:
2-(2-Ethyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2-ethylphenyl)-acetonitrile and ethylene diamine in analogy to Example 19 b): light yellow powder; MS (ISP): 189.4 ((M+H)+.).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:5]([CH:27]=[O:28])=[C:6]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[C:16]([NH:21][C:22]([CH:24]4[CH2:26][CH2:25]4)=[O:23])[N:17]=[CH:18]3)=[CH:13][CH:12]=2)[C:7]([CH3:10])=[CH:8][CH:9]=1>C1COCC1.C(OCC)(=O)C>[F:3][C:4]1[C:5]([CH2:27][OH:28])=[C:6]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[C:16]([NH:21][C:22]([CH:24]4[CH2:25][CH2:26]4)=[O:23])[N:17]=[CH:18]3)=[CH:13][CH:12]=2)[C:7]([CH3:10])=[CH:8][CH:9]=1
Reactant: Cc1ccc(F)c(C=O)c1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(F)c(CO)c1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 40 °C
Yield: 40.8 %

Procedure:
Sodium borohydride (11 mg, 0.29 mmol) was added to a solution of N-[7-(3-fluoro-2-formyl-6-methyl-phenyl)-3-isoquinolyl]cyclopropanecarboxamide (50 mg, 0.14 mmol) in THF (1 mL). The reaction mixture was heated at 40° C. for 1 hour and then diluted with ethyl acetate (40 mL) and washed with water (40 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water w/0.1% NH4OH, 14 minutes). Desired fractions were combined and evaporated in vacuo to afford the title compound as an off-white solid (20 mg, 40%). 1H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 9.14 (s, 1H), 8.50 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.89 (s, 1H), 7.54 (dd, J=8.5, 1.4 Hz, 1H), 7.31 (dd, J=8.3, 5.8 Hz, 1H), 7.20-7.12 (m, 1H), 4.79 (t, J=4.9 Hz, 1H), 4.25-4.10 (m, 2H), 2.13-2.03 (m, 1H), 1.99 (s, 3H), 0.91-0.79 (m, 4H). LCMS (Method E): RT=4.648 min, M+H+=351.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]2)=[C:4]([C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.[B]1OC2C(=CC=CC=2)O1>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[C:3]([N:17]2[CH2:18][CH2:19][C:20]([CH3:23])([CH3:24])[CH2:21][CH2:22]2)=[C:4]([C@H:10]([OH:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)C(=O)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [B]1Oc2ccccc2O1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](O)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Temperature: -15 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To stirred yellow solution of ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (2.25 g, 5.66 mmol) and (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (0.314 g, 1.133 mmol) in toluene (30 mL) at −35° C. was added drop wise 50% catecholborane (1.819 ml, 8.49 mmol) over 10 min. The reaction mixture was slowly warmed to −15° C. over 1 h and then left for 2 h at −15° C. Then, diluted with EtOAc (100 mL), washed with sat Na2CO3 (4×25 mL) by vigorously stirring and separating aqueous layers. The organic layer dried (MgSO4), filtered, concentrated and purified by flash chromatography using 10, 20 and 25% EtOAc/Hex to afford desired (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (2.2596 g, 5.66 mmol, 100% yield) contaminated with about 10% of (S)-ethyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate. Used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 5.71 (d, J=7.3 Hz, 1H), 5.54 (d, J=7.4 Hz, 1H), 4.29 (dq, J=10.8, 7.1 Hz, 1H), 4.16 (dq, J=10.8, 7.1 Hz, 1H), 3.94-3.83 (m, 2H), 2.71 (d, J=11.9 Hz, 1H), 2.67 (s, 3H), 2.59 (s, 3H), 2.54 (d, J=12.0 Hz, 1H), 1.71 (td, J=12.7, 4.7 Hz, 1H), 1.62 (td, J=13.0, 4.7 Hz, 1H), 1.42 (dd, J=13.1, 2.2 Hz, 1H), 1.37 (dd, J=12.9, 2.4 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H), 1.09 (s, 3H), 1.04 (s, 3H). LCMS (M+H)=401.3.
Reaction SMILES: COC([C@@H]1[C@H](O)CCN1C(OC(C)(C)C)=O)=O.C(OC(N1CC[C@H](O[Si](C(C)(C)C)(C)C)[C@H]1CO)=O)(C)(C)C.[OH:40][C@H:41]1[CH2:48][CH2:47][N:46]2[C@@H:42]1[CH2:43][N:44]([C:51]1[CH:58]=[CH:57][C:54]([C:55]#[N:56])=[C:53]([Cl:59])[C:52]=1[CH3:60])[S:45]2(=[O:50])=[O:49]>>[Cl:59][C:53]1[C:52]([CH3:60])=[C:51]([N:44]2[CH2:43][C@H:42]3[N:46]([CH2:47][CH2:48][C@H:41]3[OH:40])[S:45]2(=[O:49])=[O:50])[CH:58]=[CH:57][C:54]=1[C:55]#[N:56]
Reactant: Cc1c(N2C[C@@H]3[C@@H](O)CCN3S2(=O)=O)ccc(C#N)c1Cl
Agent: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Agent: COC(=O)[C@@H]1[C@H](O)CCN1C(=O)OC(C)(C)C
Product: Cc1c(N2C[C@@H]3[C@H](O)CCN3S2(=O)=O)ccc(C#N)c1Cl

Procedure:
The title compound was prepared from (2S,3R)—N-tert-Butyloxycarbonyl-3-hydroxy-2-pyrrolidinecarboxylic acid methyl ester by procedures analogous to those described in Example 7 (7A to 7F). HRMS (ES) m/z 328.0528 [M+1]+.
Reaction SMILES: C(O)C.Br[C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=1[CH:11]=[O:12].[N+:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[N+:13]([C:16]1[CH:21]=[C:20]([C:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:11]=[O:12])[CH:19]=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: O=CC1=C(Br)CCCC1
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: CCO
Solvent: Cc1ccccc1
Product: O=CC1=C(c2cccc([N+](=O)[O-])c2)CCCC1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
Ethanol (11.1 mL) was added to a solution of 2-bromocyclohex-1-enecarbaldehyde (2.22 g) in toluene (22.2 mL). 3-Nitrophenylboronic acid (2.34 g), tetrakis(triphenylphosphine)palladium (270 mg) and a 1 N sodium carbonate solution (14.0 mL) were added to the mixture. The atmosphere of the reaction system was replaced with nitrogen. Then, the reaction solution was stirred with heating under reflux for three hours. The reaction solution was cooled to room temperature, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain the title compound (2.00 g).
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)=[N:11][C:10]=1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)C=C.C1([SiH3])C=CC=CC=1>ClCCl.C(O)(=O)C>[CH2:24]([C:10]1[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)[S:13][C:9]=1[C:5]1[NH:6][CH:7]=[CH:8][N:4]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=CCn1ccnc1-c1sc(-c2ccnc(NC(C)=O)c2)nc1Cc1ccccc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(-c2nc(Cc3ccccc3)c(-c3ncc[nH]3)s2)ccn1
Temperature: 40 °C
Reaction time: 3 h
Yield: 52.7 %

Procedure:
To a solution of N-{4-[5-(1-allyl-1H-imidazol-2-yl)-4-benzyl-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.210 g, 0.0505 mmol) in dichloromethane (0.38 mL) and acetic acid (0.13 mL) was added tetrakis (triphenylphosphine)palladium(0) (0.00292 g, 0.00253 mmol) followed by phenylsilane (0.0318 mL, 0.258 mmol). The solution was stirred at 40° C. for 3 hours. The solution was cooled to room temperature then concentrated in vacuo and diluted with ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted three more times with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (0.0100 g, 53%). LCMS: (FA) ES+ , 376. 1H NMR (400 MHz, d4-methanol) δ: 8.67-8.63 (m, 1H), 8.38-8.35 (m, 1H), 7.63-7.59 (m, 1H), 7.25-7.07 (m, 7H), 4.42 (s, 2H), 2.20 (s, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[O:8]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH:2]1[CH2:3][CH2:4][C:5]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[O:8]2)[CH2:6][CH2:7]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1OC2(CCC(O)CC2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCC2(CC1)OC(=O)c1ccccc12
Yield: 88 %

Procedure:
At r.t to the mixture of 4′-hydroxy-3H-spiro[2-benzofuran-1,1′-cyclohexan]-3-one (100 mg, 0.46 mmol), triethylamine (192 μL, 1.37 mmol) in methylene chloride (2 mL) was added methanesulfonyl chloride (42.6 μL, 0.55 mmol) with stirring. The mixture was stirred at r.t. overnight, then quenched with water and extracted with ethyl acetate. The extract was washed with water, then brine once; and dried over anhydrous sodium sulfate. After removal of solid, the solution was concentrated to yield 120 mg of 3-oxo-3H-spiro[2-benzofuran-1,1′-cyclohexan]-4′-yl methanesulfonate (yield: 88%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:13]=[N:14][NH:15][CH:16]=1)[CH:8]=[CH:7][CH:6]=2.[H-].[Na+].Br[CH2:20][CH2:21][O:22][CH3:23]>CN(C=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:16]=[N:15][N:14]([CH2:20][CH2:21][O:22][CH3:23])[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: COCCBr
Reactant: Clc1cc2c(-c3cn[nH]c3)cccc2cn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1cc(-c2cccc3cnc(Cl)cc23)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-chloro-5-(1H-pyrazol-4-yl)isoquinoline (Preparation 3, 10 mg, 0.42 mmol) in DMF (3 mL) was added NaH (60%, 28 mg, 0.122 mmol). After stirring at room temperature for 15 minutes, 1-bromo-2-methoxyethane (25.4 mg, 0.183 mmol) was added and the reaction mixture was stirred at 80° C. for 60 minutes. The reaction was diluted with brine and extracted with EtOAc, the organic layers were dried with Na2SO4 and concentrated in vacuo to afford the title compound that was used in the next step without further purification (15 mg).