Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Reactant: C1CCNC1
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)c2c(c1)OC(CN1CCCC1)OC2

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (7 mg, 0.021 mmol), pyrrolidine (0.5 ml) and EtOH (1.0 ml). MS m/z (rel. intensity, 70 eV) 315 (M+, 0.5), 95 (4), 85 (6), 84 (bp), 75 (4), 55 (7).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]#[C:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([F:14])[C:6]=1[NH:15]C(=O)CCC.CC([O-])(C)C.[K+].O>CN(C=O)C>[C:2]([C:3]1[NH:15][C:6]2[C:5]([CH:4]=1)=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][C:7]=2[F:14])([CH3:22])([CH3:21])[CH3:1]
Reactant: CCCC(=O)Nc1c(F)cc([N+](=O)[O-])cc1C#CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc2cc([N+](=O)[O-])cc(F)c2[nH]1
Temperature: 120 °C
Yield: 84.7 %

Procedure:
To a solution of N-[2-(3,3-dimethyl-but-1-ynyl)-6-fluoro-4-nitro-phenyl]-butyramide (3.2 g, 10 mmol) in DMF (20 mL) was added t-BuOK (2.3 g, 21 mmol) at room temperature. The mixture was heated at 120° C. for 2 g before being cooled down to room temperature. Water (50 mL) was added to the reaction mixture and the resulting mixture was extracted with CH2Cl2 (30 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give 2-tert-butyl-7-fluoro-5-nitro-1H-indole (2.0 g, 81%), which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 9.95 (brs, 1 H), 8.30 (d, J=2.1 Hz, 1 H), 7.74 (dd, J=1.8, 11.1 Hz, 1 H), 6.43 (dd, J=2.4, 3.3 Hz, 1 H), 1.43 (s, 9 H).
Reaction SMILES: [CH:1]([CH:3]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH:4]1[O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[O:2].[CH2:28]([Mg]Br)[CH3:29].C(=O)(O)[O-].[Na+]>C1COCC1.CCOCC>[OH:2][CH:1]([CH:3]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH:4]1[O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[CH2:28][CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O[Si](C)(C)C(C)(C)C)C2C=O)CC1
Reactant: CC[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)C1C(O[Si](C)(C)C(C)(C)C)CCC12CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
A solution of tert-butyl 1-formyl-2-(tert-butyldimethylsilyloxy)-8-azaspiro[4.5]decane-8-carboxylate (0.284 g, 0.714 mmol) from Step C in THF (7 mL) was cooled to −70° C. and ethyl magnesium bromide (3.0M, 0.262 mL, 0.786 mmol) was added. The reaction was stirred for 30 min and then an additional aliquot of ethyl magnesium bromide (3.0M, 0.050 mL, 0.142 mmol) was added. After 5 min, the reaction was diluted with ether, poured into sodium bicarbonate, and extracted three times with ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with 10 to 20% ethyl acetate in hexanes to afford the title compound (0.248 g) as a mixture of isomers. MS/EI (acetonitrile/water): m/z 354 (100%, M+1–74 (t-BuOH)), 372 (M+1–56 (C4H8); 428 (M+1); retention time=4.29 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]([OH:20])=O)[CH:12]=2.[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[CH3:29])[NH2:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:21][C:22]1[CH:23]=[C:24]([NH:25][C:18]([C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:9]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[NH:10]3)=[CH:15][CH:14]=2)=[O:20])[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: Cc1ccc(N)cc1C
Reactant: O=C(O)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc3cc(-c4c(Cl)cccc4Cl)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylic acid (150 mg, 490 μmol), 3,4-dimethylaniline (60 mg, 500 μmol), HATU (280 mg, 740 μmol), and triethylamine (137 μL, 99 mg, 980 μmol) in DMF (10 mL) was stirred 18 h at ambient temperature. The solution was decanted into ethyl acetate and extracted once with water and five times with brine, then dried, filtered, and the solvent removed under reduced pressure to leave an oil, which was purified by chromatography using a gradient of 10-50% heptane/ethyl acetate to give 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylic acid (3,4-dimethylphenyl)-amide. 1H NMR (CDCl3, 400 MHz) δ 8.53 (s, broad, 1H), 8.11 (s, 1H), 7.83 (s, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.46 (m, 3H), 7.38 (dd, J=10.4, 2.1 Hz, 1H), 7.31 (m, 1H), 7.13 (d, J=8.2 Hz, 1H), 6.72 (s, 1H), 2.29 (s, 3H), 2.25 (s, 2H). MS (m/z) 409.1 (M+1); retention time=1.68 min (Method 10). High Resolution, MS (M+H): theory, 409.0874; measured 409.0867.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)=O.C(#N)C.CON(C)[C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)=[O:17]>C1COCC1.CCOCC>[NH:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([CH:19]3[CH2:20][CH:18]3[CH:16]=[O:17])[CH:29]=2)[CH:25]=[CH:26]1
Reactant: CON(C)C(=O)C1CC1c1ccc2cc[nH]c2c1
Agent: O=C=O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC#N
Product: O=CC1CC1c1ccc2cc[nH]c2c1
Temperature: 25 °C

Procedure:
Lithium aluminum hydride (30 mg, 7.86 mmol) was suspended in anhydrous THF at −45° C. (dry ice/acetonitrile) with stirring. The 2-(1H-indol-6-yl)-cyclopropanecarboxylic acid methoxy-methyl-amide was dissolved in anhydrous THF and added dropwise over a period of 10 min. The reaction was stirred for 3 h at this temperature, diluted with ether, then quenched with 1.5 mL of 1 N sodium hydroxide solution. The mixture was allowed to warm to room temperature and the resulting white solid was filtered and washed with ether. The ether layer was then concentrated in vacuo to give 2-(1H-indol-6-yl)-cyclopropanecarbaldehyde as a yellow solid. This material was used immediately for the next reaction.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([CH2:29][NH:30][C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH:26]=[CH:25][CH:24]=1>>[C:33]([CH2:32][C:31]([NH:30][CH2:29][C:27]1[N:28]=[C:23]([NH:1][C:2]2[S:3][C:4]([C:10]3[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=3[F:16])=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])[CH:24]=[CH:25][CH:26]=1)=[O:35])#[N:34]
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: N#CCC(=O)NCc1cccc(Br)n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(CNC(=O)CC#N)n3)s2)c(F)c1

Procedure:
The title compound was prepared using the procedure described in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.12 g, 0.38 mmol) and N-[(6-bromopyridin-2-yl)methyl]-2-cyanoacetamide (0.96 g, 0.38 mmol) as starting materials.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:5]=1[C:6](OC)=[O:7])[CH:2]=[CH2:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([C:4]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:5]=1[CH2:6][OH:7])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(F)ccc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCc1cc(F)ccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a mixture of methyl 2-allyl-4-fluorobenzoate (400 mg, 2.060 mmol) in THF (5 mL) was added LAH (4.12 mL, 4.12 mmol) and the reaction was stirred at rt for 1 h. It was then added NH4Cl and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 10% EtOAc/hexane to isolate (2-allyl-4-fluorophenyl)methanol (300 mg, 1.805 mmol, 88% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.37 (dd, J=8.9, 6.0 Hz, 1H), 7.06-6.84 (m, 2H), 6.08-5.88 (m, 1H), 5.24-5.03 (m, 2H), 4.76-4.68 (m, 2H), 3.58-3.39 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]=[C:9]2[C:15]([OH:17])=O)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:51]([Si:55]([CH3:74])([CH3:73])[O:56][CH2:57][CH2:58][N:59]1[C:63]([CH3:64])=[CH:62][C:61]([C:65]2[CH:66]=[CH:67][C:68]([CH3:72])=[C:69]([NH2:71])[CH:70]=2)=[N:60]1)([CH3:54])([CH3:53])[CH3:52]>CN1C(=O)CCC1.O>[C:51]([Si:55]([CH3:74])([CH3:73])[O:56][CH2:57][CH2:58][N:59]1[C:63]([CH3:64])=[CH:62][C:61]([C:65]2[CH:66]=[CH:67][C:68]([CH3:72])=[C:69]([NH:71][C:15]([C:9]3[C@H:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:13][C:12](=[O:14])[NH:11][CH:10]=3)=[O:17])[CH:70]=2)=[N:60]1)([CH3:53])([CH3:52])[CH3:54]
Reactant: O=C1C[C@@H](c2ccc(F)cc2)C(C(=O)O)=CN1
Reactant: Cc1ccc(-c2cc(C)n(CCO[Si](C)(C)C(C)(C)C)n2)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C)n(CCO[Si](C)(C)C(C)(C)C)n2)cc1NC(=O)C1=CNC(=O)C[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
A solution of (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid (138 mg), N,N-Diisopropylethylamine (155 mg) and HATU (152 mg) in NMP (1 ml) was stirred at room temperature for 10 minutes. A solution of 5-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-phenylamine (94 mg) in NMP (1 ml) was added, and the reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by “flash chromatography” (0 to 5% MeOH in CH2Cl2) to give 62.2 mg of (S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid (5-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-phenyl)-amide as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([N:11]=[N+:12]=[N-:13])[CH2:6]1)=[O:4].Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C@H:8]([O:10][CH2:15][CH:16]2[CH2:18][CH2:17]2)[C@@H:7]([N:11]=[N+:12]=[N-:13])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Reactant: BrCC1CC1
Product: COC(=O)C1C[C@H](N=[N+]=[N-])[C@@H](OCC2CC2)C1

Procedure:
In analogy to example 11A (1R,3S,4S)-3-azido-4-hydroxy-cyclopentanecarboxylic acid methyl ester (CAS 213742-85-9) was reacted with (bromomethyl)cyclopropane to give (3S,4S)-3-azido-4-cyclopropylmethoxy-cyclopentanecarboxylic acid methyl ester. Colorless oil.
Reaction SMILES: Cl.[Br:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][C:14]2[C:5](=[C:6]([O:19][C@H:20]3[CH2:24][NH:23][C@H:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21]3)[N:7]=[C:8]3[C:13]=2[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:4]=1.[CH:30]1([C@H:36]([NH:40][C:41]([O:43][CH2:44][C:45]([CH3:50])([CH3:49])[CH2:46][CH:47]=[CH2:48])=[O:42])[C:37](O)=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.CN(C1C=CN=CC=1)C>[Br:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][C:14]2[C:5](=[C:6]([O:19][C@H:20]3[CH2:24][N:23]([C:37](=[O:38])[C@H:36]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[NH:40][C:41]([O:43][CH2:44][C:45]([CH3:50])([CH3:49])[CH2:46][CH:47]=[CH2:48])=[O:42])[C@H:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21]3)[N:7]=[C:8]3[C:13]=2[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:4]=1
Reactant: CCOC(=O)[C@@H]1C[C@@H](Oc2nc3c(c4cc(OC)c(Br)cc24)CCCC3)CN1
Reactant: C=CCC(C)(C)COC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@H](Oc2nc3c(c4cc(OC)c(Br)cc24)CCCC3)C[C@H]1C(=O)OCC)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the product from Step 2, ethyl (4R)-4-[(8-bromo-9-methoxy-1,2,3,4-tetrahydrophenanthridin-6-yl)oxy]-L-prolinate hydrochloride (466 mg, 0.96 mmol) in DMF (8 mL) was added linker intermediate B20, (2S)-cyclohexyl({[(2,2-dimethylpent-4-en-1-yl)oxy]carbonyl}amino)acetic acid (300 mg, 1.0 mmol)), DIPEA (0.50 mL, 2.88 mmol), HATU (547 mg, 1.44 mmol), and DMAP (59 mg, 0.48 mmol) were added. The mixture was stirred at r.t. for 18 h and then the mixture was poured into 120 mL of aqueous citric acid. The resulting solid was removed by filtration and washed with water. The solid was then dissolved in EtOAc, dried over Na2SO4, and the solvent was removed in vacuo. The crude material was then purified on silica (gradient elution, 20-50% EtOAc/hexanes) to yield the title compound. LRMS (M+H)+=728.0.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:21])[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C:15]1=[O:20].I[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(O[Na])(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:21])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:23]2[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=2)[CH2:16][C:15]1=[O:20]
Reactant: Cc1cccc(I)c1
Reactant: O=C1CNCCN1CC(O)CN1CCc2ccccc2C1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: Cc1cccc(N2CCN(CC(O)CN3CCc4ccccc4C3)C(=O)C2)c1
Yield: 28 %

Procedure:
A mixture of 1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)piperazin-2-one (50 mg, 0.17 mmol), 1-iodo-3-methylbenzene (55.3 mg, 0.25 mmol), Pd2(dba)3 (10 mg, 0.01 mmol), Xantphos (20 mg, 0.02 mmol) and t-BuONa (30 mg, 0.3 mmol) were placed in the three-neck reactor with a condenser and magnetic stirring bar, the system was degassed 3 times (N2) and dioxane (10 mL) was added. The mixture was heated at reflux for 16 h, cooled, filtered and concentrated. The residue was purified by preparative HPLC purification. (18.0 mg, yield 28.0%) MS (ESI+) e/z: 380.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.10 (br. s., 5H), 6.85-6.65 (m, 3H), 4.33-4.14 (m, 1H), 3.88-3.81 (m, 2H), 3.81-3.68 (m, 4H), 3.67-3.58 (m, 1H), 3.56-3.44 (m, 2H), 3.32-3.25 (m, 1H), 3.02-2.76 (m, 4H), 2.68-2.54 (m, 2H), 2.32 (s, 3H).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:7]([NH:9][NH:10]C(OC(C)(C)C)=O)=[O:8]>C(OCC)(=O)C>[ClH:2].[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:7]([NH:9][NH2:10])=[O:8]
Reactant: Cc1ccc(C(CCCCl)C(=O)NNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(C(CCCCl)C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4 N hydrochloric acid in ethyl acetate (10 mL) was added to tert-butyl N′-(5-chloro-2-p-tolylpentanoyl)hydrazinecarboxylate (600 mg), and the reaction solution was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure to obtain a crude product of 5-chloro-2-p-tolylpentanoic acid hydrazide hydrochloride. A solution of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride (2.03 g) and triethylamine (1 mL) in ethanol (8 mL) was added to a solution of the resulting crude product of 5-chloro-2-p-tolylpentanoic acid hydrazide 2hydrochloride and triethylamine (0.87 mL) in ethanol (8 mL), and the reaction solution was stirred at 80° C. in a nitrogen atmosphere for 19.5 hours. The reaction solution was cooled to room temperature, and then the solvent was evaporated from the reaction solution under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the resulting residue, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1→ethyl acetate→ethyl acetate:methanol=9:1) and further purified by silica gel column chromatography (elution solvent: ethyl acetate→ethyl acetate:methanol=9:1) to obtain 221 mg of a racemate of the title compound. The resulting racemate (100 mg) was separated by CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1) to obtain the title optically active compound with a retention time of 17 minutes and positive optical rotation (48.6 mg) and the title optically active compound with a retention time of 23 minutes and negative optical rotation (48 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH3:8][O:9][N:10]=[C:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27].CCOCC>CN(C=O)C>[CH3:8][O:9][N:10]=[C:11]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27]
Reactant: c1c[nH]cn1
Reactant: CON=C(Cl)c1ccccc1OCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CON=C(c1ccccc1OCc1ccc(Cl)cc1Cl)n1ccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.5 %

Procedure:
Imidazole (2.04 g) was dissolved in DMF (30 ml), and 60% sodium hydride (1.20 g) was added. The mixture was stirred at room temperature for 10 minutes, then α-chloro-2-(2,4-dichlorobenzyloxy)benzaldehyde O-methyloxime (5.17 g) was added, and the mixture was stirred at 120° C. for 2 hours. After completion of the reaction, ether (200 ml) was added, and the mixture was washed with brine (200 ml) twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography and recrystallized from ethyl acetate/n-hexane to give 2-(2,4-dichlorobenzyloxy)-α-(1-imidazolyl)benzaldehyde O-methyloxime (2.74 g) as colorless crystals. mp. 122°-123° C.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:29][C:30](=[O:36])[NH:31][CH:32]2[CH2:35][NH:34][CH2:33]2)=[N:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:37]([CH:39]1[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]1)#[N:38]>>[C:8]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:26])([F:25])[F:27])=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:29][C:30](=[O:36])[NH:31][CH:32]2[CH2:33][N:34]([CH:42]3[CH2:43][CH2:44][CH:39]([C:37]#[N:38])[CH2:40][CH2:41]3)[CH2:35]2)=[N:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: N#CC1CCC(=O)CC1
Reactant: CC(C)(C)NC(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)n1nc(NCC(=O)NC2CN(C3CCC(C#N)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of 3-[(azetidin-3-ylcarbamoylmethyl)-amino]-5-trifluoromethyl-indazole-1-carboxylic acid tert-butyl amide TFA salt (as prepared in Example 81, Step D) and 4-cyano-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:38]=[C:5]2[N:6]=[CH:7][C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11]([C:20]4[CH:37]=[CH:36][C:23]([CH2:24][N:25]5[CH2:30][CH2:29][CH:28]([C:31]([O:33]CC)=[O:32])[CH2:27][CH2:26]5)=[CH:22][CH:21]=4)=[N:10][C:9]=3[N:4]2[N:3]=1.O.[Li+].[OH-]>C1COCC1>[CH3:1][C:2]1[CH:38]=[C:5]2[N:6]=[CH:7][C:8]3[CH:13]=[C:12]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:11]([C:20]4[CH:37]=[CH:36][C:23]([CH2:24][N:25]5[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]5)=[CH:22][CH:21]=4)=[N:10][C:9]=3[N:4]2[N:3]=1
Reactant: CCOC(=O)C1CCN(Cc2ccc(-c3nc4c(cnc5cc(C)nn54)cc3-c3ccccc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2ncc3cc(-c4ccccc4)c(-c4ccc(CN5CCC(C(=O)O)CC5)cc4)nc3n2n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Compound (13-1) (1.78 g, 3.52 mmol, 1.0 eq) was dissolved in THF (35 mL) and then added H2O (35 mL) and LiOH (178 mg, 10% w/w). The reaction was stirred at room temperature for 20 hours. After that time, the THF was removed in vacuo, and the remaining solvent was diluted with additional water and the pH adjusted to 7 with dilute HCl (5% aq). The mixture was extracted with CHCl3/MeOH (4:1, ×5). The combined organic phases were dried with brine and Na2SO4, and then concentrated onto Celite in vacuo. The material was purified by silica gel chromatography by eluting with a gradient of CHCl3 to CHCl3/MeOH (1:1) to give Compound (14-1).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32][NH2:33]>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:33][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: CN(C)CCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCCN(C)C)sc2Br)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (200 mg; 0.48 mmol; 1 eq), is dissolved in anhydrous DCM (10 ml). The reaction mixture is cooled down to 0° C. and put under nitrogen. Triethylamine (0.33 ml; 2.41 mmol; 5 eq) and N,N-dimethyl-1,3-propanediamine (0.3 ml; 2.41 mmol; 5 eq) are added successively and the reaction mixture is stirred at 0° C. for 1 hour. It is then washed with water, NaHCO3 and dried over MgSO4, affording the title compound (200 mg; 86%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][C:12]=2[N:13]=1.[F:22][C@@H:23]1[CH2:27][NH:26][C@H:25]([CH2:28][O:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[CH2:24]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.O>[F:22][C@@H:23]1[CH2:27][N:26]([C:19](=[O:20])[CH2:18][C:15]2[CH:16]=[CH:17][C:11]3[O:10][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])=[N:13][C:12]=3[CH:14]=2)[C@H:25]([CH2:28][O:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[CH2:24]1
Reactant: Cc1ccccc1Nc1nc2cc(CC(=O)O)ccc2o1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](F)CN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](F)CN2C(=O)Cc2ccc3oc(Nc4ccccc4C)nc3c2)cc1
Yield: 78.3 %

Procedure:
In DMF (5 ml), 2-(2-methylphenylamino)-5-benzoxazolylacetic acid (282 mg, 1.0 mmol), methyl 4-((2S,4S)-4-fluoro-1-2-pyrrolidinylmethoxy)benzoate (253 mg, 1.0 mmol), EDC•HCl (288 mg, 1.5 mmol), HOBT (203 mg, 1.5 mmol) and triethylamine (0.70 ml, 5.0 mmol) were stirred at room temperature for 18 hours. The reaction mixture was poured in water, followed by extraction with ethyl acetate. The extract was washed with ice water and saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 50 g), whereby from chloroform/acetone (10/1) eluate fractions, the title compound (405 mg, 78%) was obtained as a pale brown amorphous substance.