Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[CH2:6]=O.[CH3:8][O:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][N:16]2[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:12][C:11]=1[OH:28]>CCO>[OH:5][CH2:4][CH2:3][N:2]([CH2:6][C:12]1[C:11]([OH:28])=[C:10]([O:9][CH3:8])[CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][N:16]2[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH3:1]
Reactant: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1O
Reactant: C=O
Reactant: CNCCO
Solvent: CCO
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)c(CN(C)CCO)c1O
Temperature: 65 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
To 2-(methylamino)ethanol (0.37 g, 4.9 mmol) and paraformaldehyde (0.15 g, 4.9 mmol) was ethanol (5 mL) added. The reaction mixture was heated at 65° C. for 5 minutes and a clear solution was formed. 6-methoxy-1-(phenylsulfonyl)-1H-indol-5-ol (Intermediate 15, 0.75 g, 2.5 mmol) in EtOH (10 mL) was added in one portion. The mixture was stirred for 2 hours at 70° C. The solvent was removed under reduced pressure and the crude material was dissolved in DCM and was washed with brine. The organic layer was collected and dried (MgSO4) to give the title compound (400 mg). MS m/z 391 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][C:13]3[CH:24]=[CH:23][C:16]4[N:17]=[C:18](S(C)=O)[S:19][C:15]=4[CH:14]=3)=[CH:10][N:11]=2)[N:8]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][C:13]3[CH:24]=[CH:23][C:16]4[N:17]=[C:18]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]5[OH:32])[S:19][C:15]=4[CH:14]=3)=[CH:10][N:11]=2)[N:8]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COc1ccc2ncc(Cc3ccc4nc(S(C)=O)sc4c3)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc2ncc(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)n2n1
Temperature: 140 °C
Reaction time: 24 h
Yield: 32.9 %

Procedure:
A mixture of 6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (320 mg, 0.89 mmol), (1R,2R)-2-amino cyclohexanol (308 mg, 2.68 mmol) and DIEA (231 mg, 1.79 mmol) in NMP (11 mL) was stirred for 1 d at 140° C. The mixture was cooled to rt and water (50 mL) was added. The mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 10:1 DCM/MeOH, then further purified by preparative HPLC to afford (1R,2R)-2-((6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a brown solid (120 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ 7.97 (d, J=9.6 Hz, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.61 (s, 1H), 7.44 (s, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.18 (d, J=9.9 Hz, 1H), 6.82 (d, J=9.6 Hz, 1H), 4.72 (d, J=5.4 Hz, 1H), 4.23 (s, 2H), 3.95 (s, 3H), 3.52-3.49 (m, 1H), 3.39-3.36 (m, 1H), 2.05-2.01 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59 (m, 2H), 1.28-1.14 (m, 4H). LCMS (ESI) m/z 410 (M+H)+.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:34])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:14]2=[O:33])=[CH:8][CH:7]=1>C1COCC1>[O:33]=[C:14]1[C:15]2[C:20](=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=3)[CH:18]=[CH:17][CH:16]=2)[CH2:21][CH2:22][CH:13]1[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:5]([OH:34])=[O:4])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(CC2CCc3c(cccc3-c3cccc(C(F)(F)F)c3)C2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CC2CCc3c(cccc3-c3cccc(C(F)(F)F)c3)C2=O)cc1
Temperature: 40 °C
Reaction time: 24 h
Yield: 92.2 %

Procedure:
Aqueous lithium hydroxide (1 N, 0.11 mL, 0.11 mmol) was added to a solution of methyl4-((1-oxo-5-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydronaphthalen-2-yl)methyl)benzoate (10 mg, 0.023 mmol) in THF (0.23 mL) in a 1 dram vial. The vial was sealed and heated at 40° C. After 24 h, the reaction mixture was allowed to cool and the volatiles were evaporated under a stream of nitrogen. The residue was diluted with water (0.5 mL), acidified with 1 N aqueous HCl (0.5 mL) and extracted with EtOAc (3×2 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford 9 mg of the title compound.
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH2:17][CH2:18][C:19](Cl)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([CH2:17][CH2:18][C:19]([N:8]2[CH2:9][CH2:10][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(C2CCN2)cc1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccccc1)N1CCC1c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.8 %

Procedure:
A solution of 2-phenylazetidine (266 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3-phenylpropionyl chloride (421.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 3-phenyl-1-(2-phenylazetidin-1-yl)propan-1-one are collected and the solvent is removed in vacuo to give 397 mg of colorless oil.
Reaction SMILES: Br/[CH:2]=[CH:3]\[CH3:4].[CH2:5]=[CH:6][C:7](=[CH2:9])[CH3:8].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[CH3:9][C:7](=[CH:6][CH2:5][CH:2]=[CH:3][CH3:4])[CH2:8][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C1COCCN1
Reactant: C/C=C\Br
Reactant: C=CC(=C)C
Product: CC=CCC=C(C)CN1CCOCC1
Yield: 40 %

Procedure:
In a much slower reaction than Example 19, Z-1-bromopropene, isoprene and morpholine gave 2-methyl-1-morpholino-2,5-heptadiene in 40% yield along with higher boiling unidentified products and polymers. The major point of interest in this Example was to determine whether or not the stereochemistry of the Z-1-bromopropene was retained in the product. The product appeared homogeneous by GLC (gas liquid chromatography) and NMR (nuclear magnetic resonance); however, IR (infrared) showed bands characteristic of both cis and trans olefinic groups. Therefore, the product may be a mixture of isomers. Aside from the stereochemistry with respect to the double bonds, the structure can be assigned conclusively from the NMR spectrum. The addition of the 1-propenyl group, therefore, was completely regio-selective, adding to the terminal carbon of the less-substituted double bond of the isoprene. This contrasts with the mixture of positional isomers obtained when this halide was added to 1-hexene (refer Example 4, supra).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([OH:27])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]4)=[O:27])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow foam.
Reaction SMILES: C[Si](C)(C)[O:3][C:4](OC)([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:5]([F:8])([F:7])[F:6].Cl.O.[Cl-].[Na+]>O1CCOCC1>[F:6][C:5]([F:7])([F:8])[C:4]([C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)=[O:3]
Reactant: COC(O[Si](C)(C)C)(c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Yield: 120.7 %

Procedure:
A mixture of trimethyl-[2,2,2-trifluoro-1-methoxy-1-(4-nitro-phenyl)-ethoxy]-silane (5.5 g), a solution of hydrogen chloride in dioxane (4 M, 15 ml), and water (5 ml) was stirred for 4 hours. The mixture was treated with saturated aqueous sodium chloride solution (100 ml) and extracted with ethyl acetate (100 ml). The organic extract was concentrated under reduced pressure to afford 2,2,2-trifluoro-1-(4-nitro-phenyl)-ethanone (4.5 g, 85% yield)
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29]([O:31][CH3:32])=[O:30])[CH:23]=3)[NH:18]2)[CH:14]=[CH:15][CH:16]=1)=[O:10])C1C=CC=CC=1.C(OCC)(=O)C>CO.O1CCCC1.[Pd]>[CH3:32][O:31][C:29]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:9]([OH:10])=[O:8])[C:26]([CH3:28])([CH3:27])[CH2:25]2)=[O:30]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)OCc3ccccc3)c1)N2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Yield: 91.4 %

Procedure:
A mixture of methyl 2-(3-(benzyloxycarbonyl)-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (10.2 g, 23.7 mmol, 1.0 eq.), 2.04 g Pd/C in methanol/tetrahydrofuran (V/V=1/1, 102 mL) was treated with H2 at room temperature overnight. Thin layer chromatography (petroleum ether: ethyl acetate=3:1) showed the reaction was complete. The mixture was separated by filtration and the filtrate was concentrated in vacuo to give 7.35 g of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid as a white solid, yield: 91.2%. MS (ESI+APCI) M+1=340.1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: COc1ccccc1I
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Product: COc1ccccc1-n1ccc2cc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)ccc21

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-2-methoxybenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 482.2 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]2[CH2:15][NH:14][C:13]2=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[P:22](Cl)(Cl)([O:24][CH3:25])=[O:23].[CH2:28]([NH2:31])[CH2:29][CH3:30].P([O-])([O-])([O-])=O>O1CCCC1.CCCCCC.C(#N)C>[C:1]1([CH2:7][O:8][C:9]([NH:11][CH:12]2[CH2:15][N:14]([P@@:22]([NH:31][CH2:28][CH2:29][CH3:30])(=[O:23])[O:24][CH3:25])[C:13]2=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COP(=O)(Cl)Cl
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Reactant: CCCN
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCN[P@](=O)(OC)N1CC(NC(=O)OCc2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
(S)-3-[[(Phenylmethoxy)carbonyl]amino]-2-azetidinone (5.0 g) was dissolved in dry tetrahydrofuran (140 ml) and cooled to -78° C. in a dry ice-acetone bath under a nitrogen atmosphere. This mixture was treated with 1 equivalent of a 1.56 M solution of n-butyl lithium in hexane (14.2 ml) and was stirred for 30 minutes at -78° C. Methyl dichlorophosphate (3.38 g) was added and the mixture stirred for 1 hour at -78° C., followed by the addition of 2 equivalents of distilled n-propylamine (2.68 g) and stirring for an additional 2 hours at -78° C. The reaction was treated with 0.5 M phosphate buffer pH 5.5 (150 ml), allowed to warm to 5° C., and extracted with three 125 ml portions of ethyl acetate. The extracts were combined, dried over anhydrous Na2SO4 and the solvent removed in vacuo yielding an oily residue. The residue was dissolved in acetonitrile (60 ml) and applied to 500 g column of silica gel eluting with acetonitrile. Removal of solvent in vacuo yielded 4.6 g of the title compound, melting point 121°-123° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:19]=[C:18]2[C:14](=[N:15][CH:16]=[N:17]2)[C:13](=[O:20])[N:12]=1)[CH2:2][CH3:3].Cl[S:22]([OH:25])(=O)=[O:23].[NH3:26]>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:22](=[O:25])(=[O:23])[NH2:26])=[CH:7][C:6]=1[C:11]1[N:19]=[C:18]2[C:14](=[N:15][CH:16]=[N:17]2)[C:13](=[O:20])[N:12]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C1=NC(=O)C2=NC=NC2=N1
Reactant: N
Reactant: O=S(=O)(O)Cl
Product: CCCOc1ccc(S(N)(=O)=O)cc1C1=NC(=O)C2=NC=NC2=N1

Procedure:
In a similar manner to Example 18 reaction of 2-(2-propoxyphenyl)purin-6-one (0.95 g) with chlorosulphonic acid (4.5 ml), followed by reaction with saturated methanolic ammonia (50 ml), yielded a crude product (0.92 g) which was recrystallised from aqueous ethanol and then from dimethylformamide to yield the pure title compound, 0.59 g, m.p. 276°-278° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.OCC1CCN(CC2C=CC=CC=2)C1.C([O:33][C@H:34]1[CH2:38][N:37]([C:39](=[O:60])[CH2:40][C:41]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:36]([C:61]([N:63]2[CH2:67][CH2:66][CH2:65][C@@H:64]2[C:68](O)=[O:69])=[O:62])[CH2:35]1)(C)(C)C>>[OH:33][C@H:34]1[CH2:38][N:37]([C:39](=[O:60])[CH2:40][C:41]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C@H:36]([C:61]([N:63]2[CH2:67][CH2:66][CH2:65][C@@H:64]2[C:68]([NH:1][CH2:2][CH:3]2[CH2:7][CH2:6][NH:5][CH2:4]2)=[O:69])=[O:62])[CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)O)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: OCC1CCN(Cc2ccccc2)C1
Product: O=C(NCC1CCNC1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by successively conducting procedures similar to Step 5 of Example 1 and Example 46, using 3-aminomethyl-1-(t-butoxycarbonyl)pyrrolidine [which was synthesized by a method similar to the one described in Japan Kokai Hei 11(1999)-193232, using 3-hydroxymethyl-1-benzylpyrrolidine [taught in Japan Kokai (laid-open) Hei 4(1992)-112868]] and (2R)-1-{(2S,4R)-4-(tert-butoxy)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-pyrrolidine-2-carboxylic acid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](OCC)=[O:14])[N:10]=[C:9]2[S:18][CH3:19])=[CH:4][CH:3]=1.[Li+].[BH4-].O.CCOC(C)=O>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[C:9]2[S:18][CH3:19])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(-c2ccc(I)cc2)c(SC)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CSc1nc(CO)cn1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of ethyl 1-(4-iodophenyl)-2-(methylthio)-1H-imidazole-4-carboxylate (0.49 g, 1.26 mmol) in anhydrous THF (10 mL) at room temperature, LiBH4 (2M in THF, 3.2 mL, 6.4 mmol) was added. The mixture was stirred at room temperature overnight. H2O and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methanol (0.41 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@@H:4]([CH3:36])[NH:5][C:6](=[O:35])[C@H:7]([CH2:19][CH2:20]/[CH:21]=[C:22](/[C:31]([O:33][CH3:34])=[O:32])\[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[H][H]>C(O)(=O)C.C1COCC1.Cl([O-])(=O)(=O)=O.[Rh+]>[CH3:1][O:2][C:3](=[O:37])[C@@H:4]([CH3:36])[NH:5][C:6](=[O:35])[C@@H:7]([CH2:19][CH2:20][CH2:21][CH:22]([C:31]([O:33][CH3:34])=[O:32])[NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: [H][H]
Reactant: COC(=O)/C(=C/CC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C)C(=O)OC)NC(=O)OC(C)(C)C
Agent: [Rh+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C(CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C)C(=O)OC)NC(=O)OC(C)(C)C
Yield: 92.6 %

Procedure:
A solution of 8.5 g of 47c in 25 mL of acetic acid and 250 mL of THF is hydrogenated at 48 psi of hydrogen over 0.5 g of (bicyclo(2.2.1.)hepta-2,5-diene[2S,3S]bis(diphenylphosphino)butane)rhodium (I) perchlorate for 18 h. The reaction is filtered and evaporated to a residue. The residue is chromatographed using variable gradient hexane-ethyl acetate to give 7.9 g of reduced product as a residue. Multiple crystallizations give 2.6 g of diastereomerically pure 40c. NMR(CDCl3) δ1.40(d,J=6Hz,3H); 1.43(s,9H); 1.60-1.97(m,6H); 3.73(s,3H); 3.74(s,3H); 4.12-4.37 (m, 2H); 4.52-4.61 (m, 1H); 5.12 (bs, 3H); 5.44-5.55 (b s, 1H); 6.73 (b s, 1H); 7.36 (b s, 5H); 13C-NMR: δ18.02(CH--CH3); 21.12(CH2 --CH2 --CH2); 28.23(--OC(--CH3)3); 31.87 (--CH2 --CH2 --); 32.29 (--CH2CH2 --); 47.99 (--CHCH3); 52.23(--OCH3); 52.38(--OCH3); 52.75(OCCHN); 54.41(OCCHN); 67.01(--OCH2Ar); 79.97(--OC(CH3)3); 127.99 (phenyl ring carbon); 128.09 (phenyl ring carbon); 128.44 (ArCH); 136.13(ArCC); 155.48(OCONH); 156.23(OCONH); 171.10 (--CONH--); 173.03 (--CO2 --2X); IR(KBr) (cm-1): 3340(s); 1760(s); 1740(s); 1680(s); 1660(s); 1660(s); 1520(s); MS(FAB) m/z 546(M+Na)+ ; 524 (MH)+ ; 424 (MH--C4H8CO2)+ ; Anal. Calcd: C, 57.35; H, 7.12; N, 8.03; Found: C, 57.23; H, 7.27; N, 8.03; rotation [α]D26 -9±1; m.p. 120°-121° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=3)[NH:30][N:29]=2)=[CH:23][CH:22]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH:37][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:35]=3)[NH:30][N:29]=2)=[CH:25][CH:26]=1
Reactant: Nc1ccc2[nH]nc(Nc3ccc(F)cc3)c2c1
Reactant: CC1=C(C(=O)O)C(c2cc(F)cc(F)c2)NC(=O)N1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4ccc(F)cc4)c3c2)C(c2cc(F)cc(F)c2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(3,5-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(4-fluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=493 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: Fc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(COc2ccccn2)cc1
Temperature: 54 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of 4-bromobenzyl alcohol (25 g, 130 mmol) in N,N-dimethyl formamide (125 mL) was added potassium tert-butoxide (15.8 g, 141 mmol) at room temperature, which was stirred at 54° C. for 10 minutes. To this reaction solution was added 2-fluoropyridine (15 mL, 154 mmol) at from 40° C. to 58° C., which was further stirred for 30 minutes at 65° C. The reaction solution was allowed to room temperature, water and ethyl acetate were added, and liquid separation was carried out. The aqueous layer was further extracted with ethyl acetate (twice). The ethyl acetate layers were combined, washed with water (3 times) and sodium chloride water (once), dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure. Diethyl ether was added to the residue, which was concentrated under a reduced pressure to obtain the title compound (34 g) as a crude product.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.Cl[CH2:10][C:11]1[O:15][C:14]([C:16]2[CH:24]=[C:23]([C:25]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:26]=3[CH:27]=[CH:28][NH:29]4)[CH:22]=[C:21]3[C:17]=2[CH:18]=[N:19][N:20]3S(C2C=CC=CC=2)(=O)=O)=[N:13][N:12]=1.C(N(CC)C(C)C)(C)C.[I-].[Na+].[OH-].[Na+]>C(#N)C.C(O)(C)C>[CH3:8][C@H:6]1[O:7][C@@H:2]([CH3:1])[CH2:3][N:4]([CH2:10][C:11]2[O:15][C:14]([C:16]3[CH:24]=[C:23]([C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)[CH:22]=[C:21]4[C:17]=3[CH:18]=[N:19][NH:20]4)=[N:13][N:12]=2)[CH2:5]1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(-c3cccc4[nH]ccc34)cc21
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CC(C)O
Product: C[C@@H]1CN(Cc2nnc(-c3cc(-c4cccc5[nH]ccc45)cc4[nH]ncc34)o2)C[C@H](C)O1
Temperature: 70 °C
Reaction time: 18 h
Yield: 9 %

Procedure:
(2R,6S)-2,6-Dimethylmorpholine (12.57 mg, 0.11 mmol) and 4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazole (51 mg, 0.104 mmol) were dissolved in acetonitrile (0.5 ml) and N,N-diisopropylethylamine (0.0262 ml, 0.15 mmol) was added, followed by sodium iodide (14.99 mg, 0.1 mmol). The solution was stirred at 70° C. for 18 h and blown to dryness under a stream of nitrogen. Isopropanol (0.5 ml) was added followed by 2M sodium hydroxide (0.5 ml) and stirred for 18 h when the mixture was neutralised and the solvent removed under a stream of nitrogen. The crude product was dissolved in dimethylsulphoxide (0.5 ml) and purified by Mass Directed Automated Preparative HPLC (Method F) and the solvent was evaporated in vacuo using Genevac to give the title compound (4 mg).
Reaction SMILES: S(=O)(O)[O-].[Na+].[CH:6](=O)[CH3:7].[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10].[C-:14]#[N:15].[Na+]>O>[C:9]([NH:13][CH:6]([CH3:7])[C:14]#[N:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC=O
Reactant: CC(C)(C)N
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C#N)NC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
A solution of 106 g of sodium bisulfite in 250 ml of water is combined with 44 g of acetaldehyde and the mixture is stirred for one hour at 60°-65° C. The mixture is then cooled to room temperature, 73.1 g of tert-butylamine is added dropwise thereto, and the mixture is stirred for 2 hours at room temperature. Then a solution of 150 g of sodium cyanide in 160 ml of water is added to the reaction mixture, and the latter is stirred for another 2 hours and then allowed to stand at room temperature for 16 hours. The mixture is thereafter extracted with diethyl ether, the ether extract is dried over sodium sulfate, the solvent is evaporated under vacuum, and the residue is distilled at 14 torr, thus obtaining 73.5 g of 2-tert-butylaminopropionitrile, bp 61°-63° C. at 14 torr.