Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([C@@H:28]([NH2:30])[CH3:29])=[CH:24][N:23]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:30][C@H:28]([C:25]4[CH:24]=[N:23][C:22]([CH3:21])=[N:27][CH:26]=4)[CH3:29])[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: Cc1ncc([C@H](C)N)cn1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(N[C@@H](C)c4cnc(C)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (60 mg, 0.21 mmol) and (S)-1-(2-methylpyrimidin-5-yl)ethanamine (29 mg, 0.21 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (74 μL, 0.42 mmol) was subjected to microwave irradiation at 180° C. for 1 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to yield an off-white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[CH:7]1([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:7]1([C:10]2[CH:16]=[CH:15][C:13]([NH:14][C:4](=[O:5])[CH2:3][O:2][CH3:1])=[CH:12][CH:11]=2)[CH2:9][CH2:8]1
Reactant: COCC(=O)Cl
Reactant: Nc1ccc(C2CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)Nc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methoxyacetyl chloride (0.55 mL, 6.0 mmol) was added to a solution of 4-cyclopropylaniline (800 mg, 6.0 mmol) and DIEA (1.05 mL, 6.0 mmol) in DCM, and the reaction was stirred at r.t. for 2 h. The reaction was washed with brine, dried (MgSO4), and concentrated to give crude N-(4-cyclopropylphenyl)-2-methoxyacetamide.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:32](O)=[O:33])=[C:21]([CH3:31])[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]=23)[CH2:3][CH2:2]1.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:32]([NH:35][C@H:36]4[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:38][CH2:37]4)=[O:33])=[C:21]([CH3:31])[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]=23)[CH2:2][CH2:3]1
Reactant: COc1ccc(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c4) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C@H:12]([N:14]([CH2:22][C@@H:23]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[O:24][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[C@@H:55]([CH3:64])[C:56]([N:58]2[CH2:63][CH2:62][O:61][CH2:60][CH2:59]2)=[O:57])(=O)=O)=CC=1.C(OCC)(=O)C>CN(C)C=O>[CH3:13][C@@H:12]([N:14]([CH2:22][C@@H:23]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[O:24][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][C:7]1[C:6]2[C:10](=[C:2]([O:1][C@H:55]([CH3:64])[C:56]([N:58]3[CH2:63][CH2:62][O:61][CH2:60][CH2:59]3)=[O:57])[CH:3]=[CH:4][CH:5]=2)[NH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H](C)C(=O)N2CCOCC2)cc1
Reactant: CC[Si](CC)(CC)O[C@@H](CN(C(=O)OC(C)(C)C)[C@H](C)Cc1c[nH]c2c(O)cccc12)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@@H](CN(C(=O)OC(C)(C)C)[C@H](C)Cc1c[nH]c2c(O[C@H](C)C(=O)N3CCOCC3)cccc12)c1cccnc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of tert-butyl (1R)-2-(7-hydroxy-1H-indol-3-yl)-1-methylethyl((2R)-2-pyridin-3-yl-2-((triethylsilyl)oxy)ethyl)carbamate (300 mg, 0.570 mmol) in N,N-dimethylformamide-(1.0 mL) are added potassium carbonate (98.5 mg, 0.714 mmol), (1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl 4-methylbenzenesulfonate (JP-A-2000-273085) (196 mg, 0.627 mmol), and the mixture is stirred at 50° C. for one hour. To the reaction solution are added potassium carbonate (45 mg), (1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl 4-methylbenzene-sulfonate (120 mg), and the mixture is stirred at 60° C. for 10 hours. After allowed to cool, to the reaction solution is added ethyl acetate (50 mL), and the mixture is filtered, washed with water and a saturated brine, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (chloroform/methanol=100/1→20/1) to give tert-butyl (1R)-1-methyl-2-(7-(((1R)-1-methyl-2-morpholin-4-yl-2-oxo-ethyl)oxy)-1H-indol-3-yl)ethyl((2R)-2-pyridin-3-yl-2-((triethylsilyl)oxy)-ethyl)carbamate (209 mg, yield: 55%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N+:6]([O-:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([NH2:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[Cl:9][C:4]1[N:3]=[C:2]([NH:18][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[N+:6]([O-:8])[CH:5]=1
Reactant: NCCc1ccccc1
Reactant: [O-][n+]1cc(Cl)nc(Cl)c1
Solvent: O
Product: [O-][n+]1cc(Cl)nc(NCCc2ccccc2)c1

Procedure:
A suspension of 0.330 g (2.0 mmol) of 2,6-dichloro-pyrazine 4-oxide in 0.485 g (4.0 mmol) of phenethylamine was allowed to stir under reflux for 10 min. pCooled water was added and the mixture extracted with dichloromethane, dried over sodium sulfate and evaporated to dryness. pThe residue obtained was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/diethylamine in the proportions 97/3/0.3 to give after trituration with diethyl ether 0.370 g (74%) of pure product as a grey solid.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([O:16][Si](C)(C)C)=[CH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]N1C(=O)CCC1=O>O1CCCC1>[Br:21][CH:10]([C:9](=[O:16])[CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CC=C(C=Cc1ccccc1)O[Si](C)(C)C
Solvent: C1CCOC1
Product: COC(=O)CC(Br)C(=O)C=Cc1ccccc1
Reaction time: 1 h
Yield: 44.2 %

Procedure:
A mixture of 4.2 g of the product of Step C., 40 ml of tetrahydrofuran and 2.7 g of N-bromo-succinimide was cooled to 0° C. and stirred for one hour at this temperature, then brought to dryness. The residue was chromatographed on silica, eluting with a hexane-ethyl acetate mixture (8-2) to obtain 1.9 g of the expected product. Thin layer chromatography; Rf=0.28 [eluant: hexane-ethyl acetate (8-2)].
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([CH:10]([CH3:12])[CH3:11])=[N:5][N:6]([CH2:8]Cl)[CH:7]=1.[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:2][C:3]1[C:4]([CH:10]([CH3:12])[CH3:11])=[N:5][N:6]([CH2:8][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21])[CH:7]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CC(C)c1nn(CCl)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nn(CC(C#N)(C#N)CCC(F)(F)F)cc1Br
Yield: 50.1 %

Procedure:
1.38 g of 4-bromo-3-i-propyl-1-(chloromethyl)-1H-pyrazole hydrochloride and 0.81 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 15 ml of N,N-dimethylformamide. 1.38 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.91 g of [(4-bromo-3-i-propyl-1H-pyrazole-1-yl)methyl] (3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (11), hereinafter) shown by below formula.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[N:15]=[N:16][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18].ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[N+:15]([O-:31])=[N:16][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18]
Reactant: COc1ccc(-c2ccccc2)cc1N=NC(=O)OC(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2ccccc2)cc1[N+]([O-])=NC(=O)OC(C)C
Yield: 90.6 %

Procedure:
A solution of 1-methylethyl (4-methoxy-[1,1′-biphenyl]-3-yl)diazenecarboxylate (10.25 g) in dichloromethane (160 mL) was cooled in an ice bath and meta-chloroperbenzoic acid (14.8 g) was added in portions with stirring. Additional dichloromethane (90 mL) was added and the solution left to stir at room temperature for 3 days. To the mixture, dichloromethane (200 mL) was added and washed with saturated potassium bicarbonate (300 mL), followed by saturated sodium sulfite (2×200 mL) and finally saturated potassium bicarbonate (200 mL). The organic phase was dried with sodium sulfate and evaporated to give the product as a brown-orange solid (9.78 g). The product was purified using silica gel chromatography (1:5 ethyl acetate:hexane). Evaporation of the desired fractions gave purified product as an orange solid (6.19 g), with melting point 102-106° C. The product was analyzed by NMR (CDCl3) which showed 1.4 d (6H), 3.9 s (3H), 5.2 m (1H), 7.1-7.9 m (8H), where d signifies doublet, s signifies singlet, and m signifies multiplet; and by LC/MS which showed m/z: 315.8 (M+H)+, (M)+ 314.7.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[Cl:23]
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Reactant: O=C(Cl)c1ccccc1Cl
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccccc2Cl)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.182 mmol) was used in general procedure 1 with 2-chlorobenzoyl chloride (0.228 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(2-chlorobenzamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide. MS (Q1) 469 (M)+
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15].[CH3:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31](O)[CH:30]=2)[C:18]=1[C:19]([O:21][CH3:22])=[O:20]>>[CH3:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:15][CH2:14][CH2:13][C:3]3[N:4]=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[O:6][C:2]=3[CH3:1])[CH:30]=2)[C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: COC(=O)c1c(C)cccc1COc1cccc(O)c1
Product: COC(=O)c1c(C)cccc1COc1cccc(OCCc2nc(-c3ccccc3)oc2C)c1

Procedure:
MS (ESI) 458 (M+H)+. Prepared from 2-(5-methyl-2-phenyloxazol-4-yl)ethanol (example 11a) and methyl 2-(3-hydroxyphenoxymethyl)-6-methylbenzoate (example 5).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]([CH2:28][NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:6]([CH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([N:21]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]2[CH3:27])[N:15]=1)[C:7](OC(C)C)=[O:8])[CH:2]=[CH2:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([O:4][C@@H:5]([CH2:28][NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:6]([CH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([N:21]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]2[CH3:27])[N:15]=1)[CH2:7][OH:8])[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H](CNCc1ccccc1)[C@H](Cc1cc(C)cc(-n2c(C)ccc2C)n1)C(=O)OC(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCO[C@@H](CNCc1ccccc1)[C@@H](CO)Cc1cc(C)cc(-n2c(C)ccc2C)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
To a solution of 19 (400 mg, 0.82 mmol) in THF (20 mL) at 0° C. was added LiAlH4 (48 mg, 1.2 mmol) in several portions. The reaction mixture was allowed to stir at 0° C. for an additional 10 min then quenched with H2O (25 μL). The solvent was removed by rotary evaporation, and the crude product was purified by flash column chromatography (EtOAc:hexanes, 2:1-4:1) to give 20 (280 mg, 0.66 mmol, 80%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 2.12 (s, 6H), 2.39 (s, 3H), 2.64-2.67 (dd, J=2.0, 12.0 Hz, 1H), 2.70-2.90 (m, 2H), 2.98-3.03 (dd, J=5.5, 12.5, Hz, 1H), 3.40-3.44 (dd, J=3.0, 11.5 Hz, 1H), 3.56-3.58 (dd, J=3.0, 6.0 Hz, 1H), 3.65-3.69 (dd, J=7.5, 11.5 Hz, 1H), 3.76-3.79 (d, J=13.0 Hz, 1H), 3.83-3.86 (d, J=13.0 Hz, 1H), 3.90-3.94 (dd, J=5.0, 12.5 Hz, 1H), 3.99-4.03 (dd, J=5.5, 12.5 Hz, 1H), 5.15-5.17 (dd, J=1.0, 10.5 Hz, 1H), 5.23-5.27 (dd, J=1.0, 18.5 Hz, 1H), 5.80-5.96 (m, 3H), 6.86 (s, 1H), 6.99 (s, 1H), 7.24-7.40 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 13.5, 21.2, 37.7, 46.4, 49.5, 54.0, 60.8, 70.9, 79.4, 98.9, 106.9, 117.2, 120.4, 123.7, 127.6, 128.6, 128.7, 128.9, 135.0, 139.2, 149.8, 151.8, 160.6; LCQ-MS (M+H+) calcd for C27H36N3O2 434. found 434; LC-TOF-MS (M+H+) calcd for C27H36N3O2 434.28075. found 434.28071.
Reaction SMILES: [C:1]1([C:7]2[CH2:13][C:12](=[S:14])[NH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:21]I>C1C=CC=CC=1>[CH3:21][S:14][C:12]1[CH2:13][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[N:11]=1
Reactant: S=C1CC(c2ccccc2)=Nc2ccccc2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CSC1=Nc2ccccc2N=C(c2ccccc2)C1
Temperature: 25 °C

Procedure:
12.6 parts of 2,3-dihydro-4-phenyl-1H-1,5-benzodiazepine-2-thione is suspended in 1000 parts by volume of dry benzene. To this suspension is added 3 parts of 57% sodium hydride and the resultant mixture is stirred for about 2 hours at reflux temperature. 10 Parts of methyl iodide is then added to the reaction mixture and stirring is continued at reflux temperature overnight. The reaction mixture is then cooled to room temperature, filtered and the filtrate concentrated under reduced pressure to afford 2-methylthio-4-phenyl-3H-1,5-benzodiazepine, as an oil. This compound has the formula ##STR15##
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[OH:11]O.[CH3:13][O:14][C:15]1[C:16]([CH3:38])=[C:17]([C:29]([O:36][CH3:37])=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH3:28])=[C:23]([CH:26]=1)[CH:24]=[O:25]>O.C(#N)C>[CH3:13][O:14][C:15]1[C:16]([CH3:38])=[C:17]([C:29]([O:36][CH3:37])=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH3:28])=[C:23]([CH:26]=1)[C:24]([OH:11])=[O:25]
Reactant: COc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C=O
Reactant: OO
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
An aqueous solution (5 ml) of sodium dihydrogenphosphate (1.06 g, 8.86 mmol), an aqueous solution (7 ml) of sodium chlorite (0.460 g, 5.11 mmol) and aqueous hydrogen peroxide (0.502 ml, 30%) were added to an acetonitrile solution (10 ml) of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-methoxybenzaldehyde (0.409 g, 1.14 mmol) and the resulting solution was stirred at room temperature for 5 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium hydrosulfite (Na2S2O4) solution and saturated brine, then dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the titled compound (0.260 g, 0.691 mmol, 61%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH2:25][CH3:26])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:27][N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[CH2:25]([C:21]1[CH:22]=[C:23]([CH3:24])[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:5]3[CH:4]=[CH:3][C:2]([N:30]4[CH2:31][CH2:32][N:28]([CH3:27])[C:29]4=[O:33])=[CH:9][C:6]=3[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=1)[CH3:26]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3C#N)CC2)c(C)c1
Yield: 85.7 %

Procedure:
Using 5-bromo-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (827 mg) described in Preparation Example 246 and 1-methylimidazolidin-2-one (240 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (742 mg) was obtained.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][O:11][C:10]=1[CH:14]=O)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[C:1]([C:9]1[CH:13]=[CH:12][O:11][C:10]=1[CH:14]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]([O:24][CH2:25][CH3:26])=[O:23])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1ccoc1C=O
Reactant: CCOC(=O)CC(=O)OCC
Product: CCCCCCC#Cc1ccoc1C=C(C(=O)OCC)C(=O)OCC

Procedure:
Reaction of 3-(1-octynyl)furan-2-carboxaldehyde (2.04 g, 10 mmole from Example 14) with diethyl malonate (1.98 g, 1.25 eq) as described in Example 3 gave, after chromatography on silica (DCM:Hexane 1:1) 1.96 (57%) of the title compound as an oil, νmax (film) 2930, 2230, 1740, 1725, 1625, 1240, 1210, 1100 cm-1 ; δ(CDCl3) 0.89(3H, distorted t), 1.32(3H, t, J=7.5 Hz), 1.35(3H, t, J=7.5 Hz), 1.40(8H, m), 2.40(2H, t, J=6.5 Hz), 4.28(2H, q, J=7.5 Hz), 4.36(2H, q, J=7.5 Hz), 6.45(1H, d, J=2 Hz), 7.40(1H, d, J=2 Hz), 7.60(1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:17]O>>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: Cc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Agent: Cl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C)c1Cl

Procedure:
53.02 g (0.21 mol) of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid were dissolved in 400 ml of methanol and HCl was passed in at reflux temperature for 3 h. The mixture was then allowed to cool and completely concentrated on a rotary evaporator.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]2[CH2:9][O:8]2)=[CH:5][S:4][C:3]=1[C:10]#[N:11].[OH:12][CH2:13][C@H:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1>CCO>[C:10]([C:3]1[S:4][CH:5]=[C:6]([CH:7]([OH:8])[CH2:9][N:19]2[CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:15][C@H:14]2[CH2:13][OH:12])[C:2]=1[CH3:1])#[N:11]
Reactant: Cc1c(C2CO2)csc1C#N
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)csc1C#N
Temperature: 140 °C

Procedure:
A mixture of 3-methyl-4-(oxiran-2-yl)thiophene-2-carbonitrile (1.3 g, 7.9 mmol) and tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (2.0 g, 9.5 mmol) in 5 mL of EtOH was heated in a microwave apparatus at 140° C. for 90 minutes and then cooled down. The reaction mixture was concentrated, and the residue was purified by column chromatography (DCM:MeOH=10:1) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1.[Br:18]Br.CCOCC>C(O)(=O)C>[Br:18][CH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)[N:3]=1
Reactant: Cc1ccnc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: BrBr
Solvent: CCOCC
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(-c2nccc(CBr)n2)cc1
Temperature: 80 °C
Yield: 82.6 %

Procedure:
A mixture of 4-methyl-2-(4-trifluoromethylphenyl)pyrimidine (3 g) and bromine (2.11 g) in 20 ml of acetic acid was warmed to 80° C. for 1 hour, and then allowed to cool to room temperature. Ether (10 ml) was added, and the precipitate filtered off and washed with ether, giving 3.3 g of 4-bromomethyl-2-(4-trifluoromethylphenyl)pyrimidine, m.p. 125° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:17]([O:19][CH3:20])=[O:18])[CH2:3]1.[CH3:21]I.[H-].[Na+]>C1COCC1>[CH3:21][O:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH:4]([C:17]([O:19][CH3:20])=[O:18])[CH2:3]1
Reactant: CI
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CC(OC)CN1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a mixture of 1-benzyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (500 mg, 1.79 mmol) in THF (6 mL) was added methyl iodide (0.385 mL) followed by sodium hydride (95 mg, 3.94 mmol). The reaction was stirred for 1 hour, then quenched with ice and diluted with diethyl ether. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-benzyl 2-methyl 4-methoxypyrrolidine-1,2-dicarboxylate. MS ESI calc'd. for C15H19NO5 [M+H]+ 294. found 294.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:44]#[N:45])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:38][CH:39]3[CH2:42][CH2:41][CH2:40]3)[C:17]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([C:24](=[O:37])[N:25]([CH3:36])[N:26]4C(OC(C)(C)C)=O)=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:43])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:44]#[N:45])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:38][CH:39]3[CH2:40][CH2:41][CH2:42]3)[C:17]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([C:24](=[O:37])[N:25]([CH3:36])[NH:26]4)=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:43])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CCC2)C(=O)Nc2ccc3c(=O)n(C)n(C(=O)OC(C)(C)C)c3c2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2CCC2)C(=O)Nc2ccc3c(=O)n(C)[nH]c3c2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
101 mg (0.16 mmol) of tert-butyl 6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoyl}amino)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (racemate) were hydrolysed with TFA according to General Method 2. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 52 mg (62% of theory)