Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][NH:10][C:11]2[S:15][N:14]=[C:13]([C:16]#[N:17])[N:12]=2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:21].[K+].[K+].OO>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][NH:10][C:11]2[S:15][N:14]=[C:13]([C:16]([NH2:17])=[O:21])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(CNc1nc(C#N)ns1)c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(CNc1nc(C(N)=O)ns1)c1ccc(F)cc1
Reaction time: 0.25 h
Yield: 1.6 %

Procedure:
To a 0° C. mixture of 5-(2-(4-fluorophenyl)-2-methylpropylamino)-1,2,4-thiadiazole-3-carbonitrile (100 mg, 3.65 mmol, 1.0 equiv) and K2CO3 (202 mg, 14.6 mmol, 4.0 equiv) in DMSO (1.0 mL) was added hydrogen peroxide (30% in water, 1.1 mL, 36 mmol, 10 equiv) by syringe. After stirring for 15 min, the ice bath was removed, and the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc and washed repeatedly with water and once with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Preparatory thin layer chromatography (5% MeOH/DCM) provided the title compound (17 mg, 16%). m/z=295 [M+H]+.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=[N:16][N:17]1[C:22]([S:23][CH2:24][CH3:25])=[N:21][C:20](=[O:26])[N:19]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:18]1=[O:32])(C)C>C(O)(C)C>[NH2:16][N:17]1[C:22]([S:23][CH2:24][CH3:25])=[N:21][C:20](=[O:26])[N:19]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:18]1=[O:32]
Reactant: CCSc1nc(=O)n(CC(C)(C)C)c(=O)n1N=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CCSc1nc(=O)n(CC(C)(C)C)c(=O)n1N
Temperature: 60 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
1.1 g of p-toluenesulphonic acid and 5.4 ml of water are added to a solution of 34.1 g (0.114 mol) of 1-isopropylideneamino-6-ethylthio-3-neopentyl-1,3,5-triazine-2,4(1H,3H)-dione (V-2) in 150 ml of isopropanol at 60° C. and the mixture is stirred at 60° C. for one hour, during which most of the reaction product crystallises out. About 80 ml of material are distilled off under 200-300 mbar, the concentrate is cooled at 0° C. and the crystals are filtered off with suction and washed with a little methanol. 26.8 g (91% of theory) of 1-amino-6-ethylthio-3-neopentyl-1,3,5-triazine-2,4(1H,3H)-dione (I-1) of melting point 202°-204° C. are obtained. ##STR25## (A) X=Br⃝
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(OCC)(=O)C>C(O)C.[Pd]>[CH2:19]([O:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(CCOCCOc2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1ccc(OCCOCCc2ccccc2)cc1
Yield: 91 %

Procedure:
The 1-benzyloxy-4-(2-phenethyloxyethoxy)benzene obtained according to the preceding paragraph was dissolved in 200 ml of ethanol and 200 ml of ethyl acetate and hydrogenated overnight at atmospheric pressure and room temperature in the presence of 0.4 g of 10% palladium/carbon. The catalyst was removed by filtration and the filtrate was evaporated to give 10.8 g (91%) of 4-(2-phenethyloxyethoxy)phenol in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]([CH3:21])[C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:25][N:24]=1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]([CH3:21])[C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:26]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[N:25][N:24]=4)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1
Reactant: COc1cnc2c(N(C)c3ccc(N)cc3)ccnc2c1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Product: COc1cnc2c(N(C)c3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)ccnc2c1
Temperature: 100 °C

Procedure:
A mixture of N1-(7-methoxy-1,5-naphthyridin-4-yl)-N1-methylbenzene-1,4-diamine (0.061 g, 0.22 mmol) and 1-chloro-4-phenylphthalazine (0.052 g, 0.22 mmol) was heated at 100° C. for 48 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using 1-10% MeOH:CH2Cl2 containing 1% NH4OH to afford N1-(7-methoxy-1,5-naphthyridin-4-yl)-N1-methyl-N4-(4-phenylphthalazin-1-yl)benzene-1,4-diamine as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30](Br)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[OH:40][CH:41]1[CH2:44][NH:43][CH2:42]1>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30]([N:43]4[CH2:44][CH:41]([OH:40])[CH2:42]4)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Reactant: OC1CNC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CC(O)C4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 199 using Diethyl[4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate and 3-hydroxyazetidine. MS (ES+): m/z 621.25 (100) [MH+]; HPLC: tR=0.89 min (UPLC, purity).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)=[O:9])=[CH:4][N:3]=1.[CH3:16][OH:17]>>[CH3:16][O:17][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)=[O:9])=[CH:4][N:3]=1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)nc1
Reactant: CO
Product: COc1ccc(C(=O)c2cncn2C)cn1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
In a 50-mL round-bottom flask was placed a solution of Na (260 mg, 11.3 mmol) in methanol (15 mL) and the solution was stirred for 30 min at room temperature. Then 2-chloro-5-[(1-methyl-1H-imidazol-5-yl)carbonyl]pyridine (250 mg, 1.13 mmol, Intermediate 22, step c) was added. The resulting mixture was stirred for 4 hours at 75° C. and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel column, 100:0-20:1 CH2Cl2/MeOH) to give the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][N:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19].CC(C)=O>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:8]=[CH:9][N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nccn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.4 %

Procedure:
A flask charged with 1H-imidazole-2-carboxylic acid ethyl ester (1.03 g, 7.36 mmol), K2CO3 (2.00 g, 14.5 mmol), SEM-Cl (1.56 mL, 8.89 mmol), and 20 mL of acetone was stirred for 10 h at RT. The reaction was diluted with EtOAc (100 mL), washed with NaHCO3 (2×100 mL), brine (100 mL), and the organic layer dried over Na2SO4 and concentrated. The title compound was eluted from a 20-g SPE with 50% EtOAc/hexanes to give 1.50 g (76%) of a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C12H22N3O3Si, 271.1 (M+H). found 271.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:33]([C:32]3[CH:35]=[CH:36][CH:37]=[C:30]([O:29][CH3:28])[CH:31]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1cccc(C=O)c1
Reactant: Cc1cc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)no1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: COc1cccc(-c2nc3c(N4CCN(Cc5cc(C)on5)CC4)c(Br)cnc3[nH]2)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-bromo-4-[4-(5-methyl-isoxazol-3-ylmethyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.040 g, 0.10 mmol) and EtOH (3 ml) was added 3-methoxybenzaldehyde (0.022 g, 0.16 mmol) with the aid of EtOH (1 ml), followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.40 ml, 0.40 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with ethyl acetate/dichloromethane (v:v; 3:7) and then a gradient of methanol (0 to 2%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellowish solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.010 g, 21%); 1H-NMR (500 MHz, DMSO-d6) 2.40 (s, 3H, isoxazole 5-CH3), 2.64 (br s, 4H, piperazine N(CH2)2), 3.60 (s, 2H, NCH2 isoxazole), 3.67 (br s, 4H, piperazine N(CH2)2), 3.85 (s, 3H, OCH3), 6.25 (s, 1H, isoxazole 4-H), 7.09 (dd, J=1.9, 8.3 Hz, 1H, PhH), 7.45 (t, J=8.3 Hz, 1H, Ph 5-H), 7.76 (s, 1H, Ph 2-H), 7.79 (d, J=8.3 Hz, PhH), 8.24 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.50 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:14]=2)=[O:26])=[C:2]([Cl:1])[CH:3]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(NCc1ccccc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
60 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to benzylamine via Procedure G. The crude product was purified on reverse phase HPLC to yield N4-benzyl-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (Q1) 476 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:41]=[CH:40][C:39]([O:42][C:43]([F:46])([F:45])[F:44])=[CH:38][CH:37]=1)=[C:34]=[O:35]>ClCCl>[F:44][C:43]([F:45])([F:46])[O:42][C:39]1[CH:38]=[CH:37][C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])=[CH:41][CH:40]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.21 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (74.3 ul, 0.53 mmol) (Aldrich), followed by the addition of 1-isocyanato-4-trifluoromethoxy-benzene (52.0 mg, 0.26 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-trifluoromethoxy-phenyl)-amide as a white solid. (Yield 82 mg, 66.7%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]2[CH2:16][CH2:15]2)[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]2[CH2:16][CH2:15]2)[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(C2CC2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(C2CC2)c(C(F)(F)F)cc1N

Procedure:
The title compound was prepared from (5-cyclopropyl-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A31) (460 mg, 1.33 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as an orange solid (300 mg, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:22][C:21]([CH:23]=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[OH:8])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)([O-:11])=[O:10]
Reactant: Nc1ccccc1O
Reactant: O=Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Product: O=[N+]([O-])c1ccc(-c2ccc(C=Nc3ccccc3O)o2)cc1

Procedure:
Using 2-aminophenol and 5-(4-nitrophenyl)furan-2-carbaldehyde, 3.62 g of 2-{[5-(4-nitrophenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.COCCOC.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=1>O>[Cl:17][C:18]1[CH:23]=[C:22]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:21]=[CH:20][N:19]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1cccc(F)c1
Solvent: COCCOC
Solvent: O
Product: Fc1cccc(-c2cc(Cl)ncn2)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 24.7 %

Procedure:
A reaction vessel was charged with 0.303 g of tetrakistriphenylphosphine palladium, 1.344 g of 3-fluorophenylboronic acid, and 3.707 g of tripotassium phosphate n-hydrate, to which 36 ml of 1,2-dimethoxyethane, 9 ml of water, and 1.301 g of 4,6-dichloropyrimidine were added, followed by stirring at 80° C. under an atmosphere of a nitrogen gas for 7 hours. The reaction mixture was then left for cooling to room temperature, and water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.45 g of 4-chloro-6-(3-fluorophenyl)pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH:11]3[CH2:13][CH2:12]3)=[N:10][C:3]=12.Br[CH2:15][C:16]1[CH:35]=[CH:34][C:19]2/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:15][C:16]3[CH:35]=[CH:34][C:19]4/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=5[O:23][CH2:24][C:18]=4[CH:17]=3)[C:9]([CH:11]3[CH2:13][CH2:12]3)=[N:10][C:3]=12
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: Clc1ccnc2[nH]c(C3CC3)nc12
Product: C/C(C#N)=C1/c2ccc(Cn3c(C4CC4)nc4c(Cl)ccnc43)cc2COc2cc(F)ccc21
Yield: 54.2 %

Procedure:
Using 7-chloro-2-cyclopropyl-3H-imidazo[4,5-b]pyridine (EP1988091, 81 mg, 0.419 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (150 mg, 0.419 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (107 mg, 54%) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:13]=2)[O:3]1.[CH3:21][S:22]([CH:25]=[CH2:26])(=[O:24])=[O:23].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][S:22]([CH2:25][CH2:26][N:17]1[CH2:18][CH2:19][CH:14]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:20])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:15][CH2:16]1)(=[O:24])=[O:23]
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Reactant: C=CS(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(C3CCN(CCS(C)(=O)=O)CC3)c2)OC1(C)C
Yield: 10.8 %

Procedure:
A solution of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine (500 mg, 1.80 mmol), (methylsulfonyl)ethene (212 mg, 1.99 mmol), and DIPEA (500 mL, 2.87 mmol) in DMF (6 mL) was stirred at 25° C. for 30 min. The reaction mixture was then concentrated in vacuo to a solid and then purified by flash chromatography (0 to 5% MeOH:EtOAc) to yield 74.5 mg (11%) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 7.98 (s, 1H), 7.59 (s, 1H), 4.17 (tt, J=10.36, 5.05 Hz, 1H), 3.30 (s, 2H), 3.05 (s, 3H), 2.98 (d, J=11.62 Hz, 2H), 2.74 (t, J=6.57 Hz, 2H), 2.13 (td, J=11.37, 3.28 Hz, 2H), 1.88-2.00 (m, 4H), 1.25 (s, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18](Cl)=[O:19].Cl[CH2:29][CH2:30][Mg].[NH4+].[Cl-].O>C1COCC1>[Cl:16][C:4]1[CH:5]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:7]=[C:2]([Cl:1])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18](=[O:19])[CH2:29][CH3:30]
Reactant: [Mg]CCCl
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: -75 °C
Yield: 17.3 %

Procedure:
A mixture of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4,-triazin-2(3H)-yl)-benzeneacetyl chloride (0.05 mol) in THF (200 ml) was stirred at −75° C. A solution of chloroethyl magnesium (0.1 mol; 2 M/THF) in THF (50 ml) was added dropwise at −75° C. The reaction mixture was stirred for 90 minutes, then the temperature was raised to −20° C. A saturated aqueous NH4Cl solution was added dropwise. Water was added and the product was extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was filtered over silica gel (eluent: CH2Cl2/CH3OH 98/2). Two fractions were collected and the solvent was evaporated, yielding 3.8 g (±)-2-[3,5-dichloro-4-[1-(4-chlorophenyl)-2-oxobutyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (interm. 69).
Reaction SMILES: N(OCCC(C)C)=O.[Br:9][C:10]1[CH:16]=[CH:15][C:13](N)=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=1.[CH3:21][S:22]C>C(#N)C>[Br:9][C:10]1[CH:16]=[CH:15][C:13]([S:22][CH3:21])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=1
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: CSC
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CSc1ccc(Br)cc1C(F)(F)F

Procedure:
Isopentyl nitrite (0.67 ml) was added dropwise to a solution of 4-bromo-2-(trifluoromethyl)aniline (1.2 g) and dimethyl sulfide (0.45 ml) in acetonitrile (12 ml). The reaction was slowly heated to reflux and then refluxed until gas evolution ceased. The volatiles were evaporated, the residue absorbed onto silica and the product eluted off with isohexane. Yield 0.8 g.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[NH2:8][OH:9]>>[OH:9]/[N:8]=[C:6](\[NH2:7])/[CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCCC#N
Reactant: NO
Product: COCCC/C(N)=N/O

Procedure:
In analogy to the procedure described for example D28 4-methoxybutanenitrile (3.1 g) and hydroxylamine (2.07 g, 50 wt % in water) yield the title compound as a solid.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[C:15]([O-:20])(=[O:19])[C:16]([CH3:18])=[CH2:17].[K+].[I-].[K+].C1(C=CC(O)=CC=1)O>>[C:15]([O:20][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: COc1ccc2c(ccn2CCCl)c1
Reactant: C=C(C)C(=O)[O-]
Agent: Oc1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Product: C=C(C)C(=O)OCCn1ccc2cc(OC)ccc21
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 86.5 %

Procedure:
Next, into a flask of 200 ml capacity fitted with a stirrer and cooling tube, there were introduced 15.7 g of 1-(2-chloroethyl)-5-methoxyindole, 18.6 g of potassium methacrylate, 6.2 g of potassium iodide, 40 ml of N,N-dimethylsulfoxide, and a small amount of hydroquinone. They were heated to 100° C., and stirred for 2.5 hours. After completion of the reaction, the insoluble material was removed by infiltration, and concentration was performed under reduced pressure. Further, this reaction mixture was purified by column chromatography using silica gel, to obtain a 16.8 g of 1-(2-methacryloyloxyethyl)-5-methoxyindole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:16])[CH2:11][CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([CH3:17])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]=[O:35]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([C:9]2[C:10](=[O:16])[CH:11]([CH:34]([OH:35])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:6]([CH3:8])[CH:7]=1
Reactant: COC1=C(c2c(C)cc(Br)cc2C)C(=O)CC1
Reactant: O=Cc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C(C(O)c2ccccn2)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-(4-bromo-2,6-dimethylphenyl)-3-methoxycyclopent-2-enone (5 g, 17 mmol) in anhydrous tetrahydrofuran (50 ml) under nitrogen atmosphere is added lithium bis(trimethylsilyl)amide (22.4 ml, 20 mmol, 0.9M solution in tetrahydrofuran) dropwise at −75°C. The resulting solution is stirred at this temperature for 40 minutes, then a second solution of pyridine-2-carboxaldehyde (2.18 g, 20 mmol) in anhydrous tetrahydrofuran (50 ml) is added over 20 minutes. The resulting solution is stirred at −75°C. for 2 hours, then allowed to warm to room temperature and stir for a further 2 hours. The reaction mixture is quenched with ice cold water (30 ml), extracted with ethyl acetate (3×100 ml), then dried over sodium sulfate, filtered and the filtrate is concentrated in vacuo to afford 2-(4-bromo-2,6-dimethylphenyl)-5-(hydroxypyridin-2-ylmethyl)-3-methoxycyclopent-2-enone. This material is used directly in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20]N(CCN(C)C)C.C([Li])(CC)C.COS(OC)(=O)=O>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:12][CH:13]1[CH3:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCCC2)CC1
Reactant: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Product: CC1CC(N2CCCCC2)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 1′-tert-Butoxycarbonyl-[1,4′]-Bipiperidine 1 (5.1 g, 19.0 mmol), TMEDA (19 ml) in dry Et2O (40 ml) at −78° C. is slowly added a solution of sec-butyllithium (19.0 ml, 24.7 mmol, 1.3 M in cyclohexanes) over a period of 30 min. The mixture is stirred at −78° C. for 3 hr, and then is treated with a solution of Dimethylsulfate (3.6 g, 28.5 mmol) in Et2O (5 ml). The cooling bath is removed and the reaction mixture is stirred at ambient temperature for 16 hr. After cooling to 0° C., the reaction mixture is quenched with water, extracted with Et2O (5×100 ml), and the combined ether layers is dried over K2CO3. The solvent is removed in vacuo and the residue is purified on silica gel chromatography (eluting 40% ethyl acetate in hexane) to give 2.51 g of 1′-tert-Butoxycarbonyl-2′-methyl-[1,4′]-Bipiperidine, 2.