Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-])=O)=[N:18][CH:19]=1>C(O)C.[Ni]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(N2CCC[C@@H]2c2cc(F)ccc2F)cn1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(N2CCC[C@@H]2c2cc(F)ccc2F)cn1
Reaction time: 0.08 h
Yield: 93.8 %

Procedure:
To a stirred solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-2-nitropyridine (3.2 g, 10.46 mmol) in Ethanol (32 ml) was cooled to 10° C. and added Raney Ni (640 mg, 20% w/w) portion wise and stirred for 5 min, then added N2H4.2H2O (1.05 g, 20.98 mmol) drop wise for the period of 5 min, then stirred for 20 min at room temperature. After completion of reaction, reaction mixture was filter through celite bed under N2 atmosphere and filtrate was concentration under reduced pressure, the residue was re-dissolved in DCM and washed with water, brine and dried over Na2SO4 and concentration to get desired product as brown solid (2.7 g, 93% yield), MS (ESI): m/z 276.1 (M+H).
Reaction SMILES: [C:1]([CH2:3][CH:4]([C:27]1([C:30]#[N:31])[CH2:29][CH2:28]1)[N:5]1[CH:9]=[C:8]([C:10]2[C:11]3[CH:18]=[CH:17][N:16](COCC[Si](C)(C)C)[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[N:6]1)#[N:2].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[C:1]([CH2:3][CH:4]([C:27]1([C:30]#[N:31])[CH2:29][CH2:28]1)[N:5]1[CH:9]=[C:8]([C:10]2[C:11]3[CH:18]=[CH:17][NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[N:6]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4(C#N)CC4)c3)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCC(n1cc(-c2ncnc3[nH]ccc23)cn1)C1(C#N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
1-{2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}cyclopropanecarbonitrile (48 mg, 0.11 mmol) was stirred in a mixture of DCM (3 mL) and TFA (2 mL) for 3 hours. The solvents were removed in vacuo and the residue was re-dissolved in THF (3 mL). 6N NaOH (2 mL) was added and the resulting mixture was stirred at ambient temperature for 3 hours. The crude reaction mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded product (20 mg, 43%).
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([Cl:19])[C:16]=1[O:17][CH3:18])[C:10]([NH2:13])([CH3:12])[CH3:11].C(N(CC)CC)C.O>CN(C)C(=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([Cl:19])[C:16]=1[O:17][CH3:18])[C:10]([NH:13][CH2:2][C:3](=[O:5])[CH3:4])([CH3:11])[CH3:12]
Reactant: CC(=O)CCl
Reactant: COc1c(Cl)cc(C(C)(C)N)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1c(Cl)cc(C(C)(C)NCC(C)=O)cc1Cl
Temperature: 80 °C
Yield: 54.6 %

Procedure:
10.0 g (0.1 mol) of chloroacetone, 14.1 g (0.06 mol) of 3,5-dichloro-4-methoxy-α,α-dimethylbenzylamine and 7.2 g (0.07 mol) of triethylamine were dissolved in 100 ml of N,N-dimethylacetamide, and the mixture was heated at 80° C. for about three hours under stirring under a nitrogen atmosphere. The reaction solution was cooled, then poured into a large amount of water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magensium sulfate. The solvent was distilled off under reduced pressure to obtain 9.5 g (yield: 89%) of the desired compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:34])[C@@H:5]([NH2:33])[CH2:6][C:7]1[CH:32]=[CH:31][C:10]2[O:11][C@H:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=4)=[CH:17][CH:16]=3)[CH2:13][O:14][C:9]=2[CH:8]=1.C([O-])(O)=O.[Na+].[N+:40]([C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1)([O-:42])=[O:41]>CCOC(C)=O>[CH3:2][O:3][C:4](=[O:34])[C@@H:5]([NH:33][S:49]([C:46]1[CH:45]=[CH:44][C:43]([N+:40]([O-:42])=[O:41])=[CH:48][CH:47]=1)(=[O:50])=[O:51])[CH2:6][C:7]1[CH:32]=[CH:31][C:10]2[O:11][C@H:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=4)=[CH:17][CH:16]=3)[CH2:13][O:14][C:9]=2[CH:8]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.4 %

Procedure:
(S)-2-Amino-3-{(R)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester hydrochloride (1.2 g) was dissolved in 100 mL EtOAc and 100 mL saturated aqueous NaHCO3 and 1.0 g p-nitrobenzenesulfonyl chloride was added. After stirring at room temperature for 2 hours, the layers were separated and the organic layer was dried over Na2SO4 and evaporated. The residue was purified by silica gel flash chromatography (hexanes to 7:3 hexanes/EtOAc) to give 1.7 g desired product after drying. 1H NMR (400 MHz, CDCl3): 8.27 (m, 2H), 7.89 (m, 2H), 7.54 (d, 1H), 7.45 (d, 1H), 7.35 (m, 2H), 7.28-7.24 (m, 1H), 7.20 (m, 2H), 6.81 (m, 1H), 6.56 (m, 2H) 5.26 (m, 1H), 5.02 (s, 2H), 4.99 (m, 1H), 4.26 (m, 2H), 3.95 (m, 1H), 3.66 (s, 3H), 3.05-2.85 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:15])[C@@H:9]([CH2:16][CH:17]=O)[O:8][C@H:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:6]=2[CH:26]=1.C([O:29][C:30]([CH:32]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:31])C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]([CH3:13])[CH3:14])[C:10](=[O:15])[C@@H:9]([CH2:16]/[CH:17]=[CH:32]/[C:30]([OH:31])=[O:29])[O:8][C@H:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:6]=2[CH:26]=1
Reactant: CC(C)N1C(=O)[C@@H](CC=O)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)N1C(=O)[C@@H](C/C=C/C(=O)O)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
In toluene (20 ml) was dissolved trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetaldehyde (1.5 g). To the solution was added (ethoxycarbonylmethylene)-triphenylphosphorane (2.0 g), and the mixture was stirred for 3 hours at 90° C. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=10:1) to give ethyl ester of trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-crotonic acid (1.28 g) as prisms, m.p.126°-127° C.
Reaction SMILES: [CH3:1][Si:2]([CH:5](O)[CH3:6])([CH3:4])[CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([CH2:29][C:30]([OH:32])=[O:31])[N:28]=1>CN(C)C1C=CN=CC=1.C(#N)C>[NH2:23][C:24]1[S:25][CH:26]=[C:27]([CH2:29][C:30]([O:32][CH2:6][CH2:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[O:31])[N:28]=1
Reactant: CC(O)[Si](C)(C)C
Reactant: Nc1nc(CC(=O)O)cs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: C[Si](C)(C)CCOC(=O)Cc1csc(N)n1
Reaction time: 48 h

Procedure:
11.2 g (15.8 ml, 0.1 mol) of trimethylsilylethanol, 100 mg of 4-dimethylaminopyridine and 11.4 g of dicyclohexylcarbodiimide are added at room temperature to 7.9 g (0.05 mol) of 2-aminothiazol-4-ylacetic acid in 50 ml of acetonitrile and the mixture is stirred for 2 days. The precipitated urea is then filtered off under suction, washed with ether, the washings are concentrated on a rotary evaporator and the residue is taken up in ether and the ethereal solution is washed with 0.5N hydrochloric acid and with NaHCO3 solution, dried over MgSO4 and concentrated on a rotary evaporator. After concentration of the solution and addition of petroleum ether, the desired ester crystallizes out.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][C:5]=2[N:6]=1.[F:16][C:17]([F:31])([F:30])[C:18]1[C:19]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1>>[Cl:11][C:9]1[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][C:5]2[NH:6][C:2]([N:27]3[CH2:28][CH2:29][N:24]([C:19]4[C:18]([C:17]([F:31])([F:16])[F:30])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:25][CH2:26]3)=[N:3][C:4]=2[CH:10]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: FC(F)(F)c1cc2nc(Cl)[nH]c2cc1Cl
Product: FC(F)(F)c1cc2[nH]c(N3CCN(c4ncccc4C(F)(F)F)CC3)nc2cc1Cl

Procedure:
The benzoimidazole from step (c) above (255 mg, 1.0 mmol) reacted with 1-(3-trifluoromethylpyridin-2-yl)piperazine (231 mg, 1.0 mmol, Oakwood) under the conditions of Example 3c to give the title compound as a white solid. M.p. 206.4-208.1° C. MS (ESI, pos. ion) m/z: 450.4 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH3:21])[CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH:9]=2)[N:4]=1.Br>O>[CH3:21][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:9]=[C:10]2[C:5]=1[NH:4][C:3](=[O:2])[CH:12]=[CH:11]2
Reactant: COc1ccc(-c2cc(C)c3nc(OC)ccc3c2)cc1
Agent: Br
Solvent: O
Product: Cc1cc(-c2ccc(O)cc2)cc2ccc(=O)[nH]c12

Procedure:
A mixture of 2-methoxy-8-methyl-6-[4-methoxyphenyl]quinoline (4.82 g) and 48% aqueous HBr (100 cm3) was heated under reflux for 6 hours. The cooled mixture was diluted with water (200 cm3), the solid filtered off, and dissolved in chloroform:methanol, 4:1 (500 cm3). The organic phase was washed with water (2×25 cm3), dried (MgS04) and evaporated in vacuo to give a solid which was recrystallised from propan-2-ol to afford the title compound, m.p. 270°-274°, (2.5 g).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25]([OH:27])=[O:26])=[CH:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].[BH4-].[Na+]>>[CH2:13]([C:12]([C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([C:25]([OH:27])=[O:26])=[CH:22][C:21]=2[CH:28]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:30])[C:2]([CH3:31])([CH3:32])[CH3:1])=[C:7]([CH3:29])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)O)cc2c1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)O)cc2c1
Yield: 95 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-2-carboxylic acid (0.22 g, 0.504 mmol) is reduced with NaBH4 (57 mg, 1.51 mmol) analogous to Example 3 to give the title product (210 mg, 95%).
Reaction SMILES: C([O:4][C:5]1[CH:18]=[CH:17][CH:16]=[C:11]([O:12]C(=O)C)[C:6]=1[O:7]C(=O)C)(=O)C.Cl>C(O)(=O)C>[C:5]1([CH:18]=[CH:17][CH:16]=[C:11]([OH:12])[C:6]=1[OH:7])[OH:4]
Reactant: CC(=O)Oc1cccc(OC(C)=O)c1OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: Oc1cccc(O)c1O
Yield: 87 %

Procedure:
To 100 parts of pyrogallol triacetate as prepared above were added glacial acetic acid (364 parts) and 2 N HCl solution (3640 parts) and the mixture refluxed for three hours under a nitrogen blanket. Continuous ether extraction followed by evaporation of the extract gave an oil which slowly crystallised. Recrystallisation from toluene gave pyrogallol (44 parts, 87% yield).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]2[CH:25]=[CH:24][C:13]([CH:14]=[C:15]([C:20]([O:22][CH3:23])=[O:21])[C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)[C:5]2[CH:26]=[CH:27][C:28]([CH:30]=[CH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:29][C:4]=2[S:3]1.ClCCOC1C=CC(CC(C(OC)=O)C(OC)=O)=CC=1>>[O:1]=[C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]2[CH:25]=[CH:24][C:13]([CH2:14][CH:15]([C:20]([O:22][CH3:23])=[O:21])[C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)[C:5]2[CH:26]=[CH:27][C:28]([CH:30]=[CH:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:29][C:4]=2[S:3]1
Reactant: COC(=O)C(=Cc1ccc(OCCn2c(=O)sc3cc(C=Cc4ccccc4)ccc32)cc1)C(=O)OC
Agent: COC(=O)C(Cc1ccc(OCCCl)cc1)C(=O)OC
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C=Cc4ccccc4)ccc32)cc1)C(=O)OC

Procedure:
The procedure is as in Step B of Example 37 starting from the compound obtained in Example 85, with the replacement of dimethyl 2-[4-(2-chloroethoxy)benzylidene]malonate with dimethyl 2-[4-(2-chloroethoxy)benzyl]malonate.
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH2:13](Cl)/[CH:14]=[CH:15]/[CH2:16]Cl>CO>[CH:14]([CH:15]1[CH2:16][C:5]1([C:4]([O:11][CH3:12])=[O:10])[C:6]([O:8][CH3:9])=[O:7])=[CH2:13]
Reactant: COC(=O)CC(=O)OC
Reactant: ClC/C=C/CCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=CC1CC1(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.8 %

Procedure:
Sodium methoxide (108.02 g, 2.0 moles) 25% in MeOH was added in 40 minutes to dimethyl malonate (132.12 g, 1.0 mole), 1,4-dichlorobutene-2 (150 g, 1.2 moles), and 50 mL MeOH and allowed to stir at ambient temperature overnight. The mixture was vacuum filtered, neutralized with concentrated HCl to 3.5-4.0 pH, and filtered a second time. Solvent was then removed under vacuum to give 194.8 g of light yellow crude product. Vacuum distillation (55°/0.25 mm-72°/0.4 mm) with 0.064 g of hydroquinone added gave 142.5 g of product (77.4% yield) and 30.4 g of residue.
Reaction SMILES: [CH:1]1([OH:4])[CH2:3][CH2:2]1.[CH3:5][C:6]1([CH3:33])[C@@H:8](/[CH:9]=[CH:10]\[C:11](O)=[O:12])[C@H:7]1[C:14]([O:16][C@H:17]([C:31]#[N:32])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:15].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:5][C:6]1([CH3:33])[C@@H:8](/[CH:9]=[CH:10]\[C:11]([O:4][CH:1]2[CH2:3][CH2:2]2)=[O:12])[C@H:7]1[C:14]([O:16][C@H:17]([C:31]#[N:32])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:15]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Reactant: OC1CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OC1CC1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
0.9 ml of cyclopropanol were added to a mixture of 5.5 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[Z-2-carboxy-ethenyl]-cyclopropane-carboxylate in 26 ml of methylene chloride and 1 g of 4-dimethylamino-pyridine and 3 g of dicyclohexylcarbodiimide were added thereto at 0° C. The mixture was stirred at 20° C. for 90 minutes and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with an 85-15 cyclohexane-ethyl acetate mixture yielded 3.6 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[Z-2-(cyclopropyloxycarbonyl)-ethenyl]-cyclopropane-carboxylate melting at 62° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:9](=[O:12])[NH:10][N:11]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:9](=[O:12])[N:10]([CH2:22][C:23]#[N:24])[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)s2)n1Cc1ccccc1F
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O

Procedure:
A mixture of 250 mg (0.81 mmol) of 5-(5-chloro-2-thienyl)-4-(2-fluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [preparation according to WO 2007/134862 Example 154A], 67 μl (0.97 mmol) of bromoacetonitrile and 223 mg (1.61 mmol) of potassium carbonate was stirred in 8 ml of dry DMF at an oil bath temperature of 100° C. for 1 h. After cooling, the mixture was filtered through kieselguhr, the filtrate was concentrated under reduced pressure and the residue was partitioned between MTBE and water. The organic phase was washed successively with 10 ml of water and 10 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). This gave 258 mg (92% of theory) of the target compound as a slightly yellowish solid.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([CH:14]=[CH2:15])([OH:13])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1>[Pd].C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:14][CH3:15])([OH:13])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:16][CH:17]=1
Reactant: C=CC(O)(c1ccccc1)c1ccc(Br)cc1
Agent: [Pd]
Solvent: c1ccccc1
Product: CCC(O)(c1ccccc1)c1ccc(Br)cc1

Procedure:
0.6 g. of 10% palladium-on-carbon and added to a solution of 29 g. of 4-bromo-α-vinyl-benzhydrol in 300 ml. of benzene, and the mixture is hydrogenated at room temperature under atmospheric pressure. After the uptake of the calculated amount of hydrogen the catalyst is filtered off, and the benzene is evaporated from the clear filtrate under reduced pressure. 25 g. of clear, viscous oil, boiling at 140° C (0.8 mmHG.) are obtained as residue.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C[O-].C([Sn+](CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C([O:38][C:39]([CH3:41])=[CH2:40])(=O)C>C(OCC)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.Cl[Pd]Cl>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([CH2:40][C:39](=[O:38])[CH3:41])[N:11]=[C:10]([Cl:12])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: C=C(C)OC(C)=O
Agent: Cl[Pd]Cl
Agent: CCCC[Sn+](CCCC)CCCC
Agent: C[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)nc(CC(C)=O)c1
Yield: 29 %

Procedure:
Add methyl 2,6-dichloroisonicotinate (3.0 g, 15.0 mmol), trans-dichlorobis(tri-o-tolylphosphine)palladium (II) (196 mg, 0.25 mmol), tributyltin methoxide (2.4 g, 7.5 mmol) and toluene (20 mL) in a previously nitrogen filled sealed vessel. Flush the reactants with nitrogen again. Add isopropenyl acetate (0.85 mL, 7.75 mmol) under nitrogen and heat the sealed mixture at 100° C. overnight with vigorous stirring. Cool the reaction to room temperature, dilute with diethyl ether and filter through a filtering agent. Concentrate and purify (silica gel chromatography, eluting with 0:100 to 20:80 ethyl acetate:hexanes) to give the title compound (29%).
Reaction SMILES: [C:1](=[O:42])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C@H:3]1[CH2:7][C@H:6]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17](S(C5C=CC(C)=CC=5)(=O)=O)[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[C@H:5]([CH2:30][CH3:31])[CH2:4]1.[CH:43]1([NH2:46])[CH2:45][CH2:44]1.[OH-].[Na+]>O1CCOCC1>[CH:43]1([NH:46][C:1](=[O:42])[O:2][C@H:3]2[CH2:7][C@H:6]([C:8]3[N:12]4[C:13]5[CH:19]=[CH:18][NH:17][C:14]=5[N:15]=[CH:16][C:11]4=[N:10][N:9]=3)[C@H:5]([CH2:30][CH3:31])[CH2:4]2)[CH2:45][CH2:44]1
Reactant: NC1CC1
Reactant: CC[C@@H]1C[C@@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@@H](OC(=O)NC2CC2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 60 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a scalemic mixture enriched in (1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl 4-nitrophenyl carbonate (Example #41 Step O, 0.211 g, 0.357 mmol) in 1,4-dioxane (1.5 mL) was added cyclopropylamine (0.102 g, 1.79 mmol). After about 1 h, 1N aqueous sodium hydroxide (1.5 mL, 1.5 mmol) was added and the reaction mixture was heated at about 60° C. for about 30 min then cooled to ambient temperature. The layers were separated and the aqueous layer was extracted with DCM (3×5 mL). The combined organic layers were concd under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-10% MeOH in EtOAc to give (1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl cyclopropylcarbamate (0.085 g, 67%): LC/MS (Table 1, Method b) Rt=1.73 min; MS m/z: 355 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)OCC[O:15]2)=[CH:10][C:9]=1[C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:6])=[N+]=[N-]>C1COCC1.[Pd].C(O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:14]([C:11]2[CH:12]=[CH:13][C:8]3[NH:7][C:5](=[O:6])[CH2:4][N:1]=[C:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:9]=3[CH:10]=2)=[O:15])=[CH:20][CH:21]=1
Reactant: [N-]=[N+]=NCC(=O)Nc1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(=O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C1CN=C(c2ccccc2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2N1
Yield: 2.4 %

Procedure:
Intermediate (26) (0.1052 mol) in THF (220 ml) was hydrogenated with Pd/C (0.6 g) as a catalyst at room temperature for 8 h under a 2 bar pressure in a Parr apparatus. After uptake of H2, the catalyst was filtered over celite and the filtrate was evaporated till dryness. The residue (47.9 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 98/2/0.1) (35–70 μm). The pure fractions were collected and evaporated and the residue was crystallized from 2-propanone/DIPE giving 14.86 g (31%). A sample (1.35 g) was taken up in hot ethanol and filtered off, yielding 0.93 g (70%) of 7-(4-chlorobenzoyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (intermediate 27), mp. 230° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:4]=2[CH:3]=1.[Li]CCCC.[CH3:19][Si:20]([CH3:23])(Cl)[Cl:21]>CCOCC.CCCCCC>[Cl:21][Si:20]([CH3:23])([CH3:19])[CH:7]1[C:5]2[S:6][C:2]([CH3:1])=[CH:3][C:4]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: Cc1cc2c(s1)Cc1ccccc1-2
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cc2c(s1)C([Si](C)(C)Cl)c1ccccc1-2
Temperature: 25 °C
Yield: 88.6 %

Procedure:
Suspension of 1.86 g (0.01 mol) 2-methyl-8H-indeno[2,1-b]thiophene in 25 mL ether was treated dropwise with 6.25 mL (0.01 mol) of 1.6M BuLi in hexane at −40° C. under stirring. Then the mixture was stirred in additional 3 h. The resulting mixture was treated with 1.20 mL (0.01 mol) of dimethyldichlorosilane in 5 mL of ether at −70° C.; then it was allowed to warm to r.t. and stirred overnight. The solution was isolated and evaporated to give 2.47 g (89%) of the crude product that was used without further purification.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:25][C:26](=[O:40])[C:27]([NH:29][C:30]([CH3:39])([CH3:38])[CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[O:28])[CH:17]=[CH:18][C:19]=1[C:20]1[O:24][CH:23]=[N:22][CH:21]=1>ClCCl.C(OCC)(=O)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:25][C:26](=[O:40])[C:27]([NH:29][C:30]([CH3:38])([CH3:39])[CH2:31][C:32]2[CH:33]=[CH:34][N+:35]([O-:6])=[CH:36][CH:37]=2)=[O:28])[CH:17]=[CH:18][C:19]=1[C:20]1[O:24][CH:23]=[N:22][CH:21]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)Cc2ccncc2)ccc1-c1cnco1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)C(=O)NC(C)(C)Cc2cc[n+]([O-])cc2)ccc1-c1cnco1
Reaction time: 1 h
Yield: 62.1 %

Procedure:
30 mg (0.1 mmol) of 60% 3-chloroperoxybenzoic acid were added to a stirred solution of 20 mg (0.051 mmol) of N-[3-methoxy-4-(5-oxazolyl)phenyl]-N′-[1,1-dimethyl-2-(4-pyridyl)ethyl]oxalamide in 1 ml of dichloromethane. The mixture was stirred for 1 hour then diluted with ethyl acetate, washed with sodium bisulphite solution, sodium bicarbonate solution and brine. The organic solution was dried over magnesium sulphate, evaporated to dryness and the residue triturated with diethyl ether to give 13 mg of N-[3-methoxy-4-(5-oxazolyl)phenyl]-N′-[1,1-dimethyl-2-(1-oxido-4-pyridyl)ethyl]oxalamide as an off-white solid. MS: m/e 411 [M+]+.