Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:13]=[O:14])[C:11]=2[N:12]=1.[BH4-].[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([N:12]=1)=[C:10]([CH2:13][OH:14])[CH:9]=[CH:8][CH:7]=2
Reactant: COc1cnc2cccc(C=O)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cnc2cccc(CO)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a stirred suspension of 3-methoxy-quinoxaline-5-carbaldehyde (4.05 g, 21.5 mmol; see WO 2006/032466) in EtOH (150 mL) cooled at 0° C., NaBH4 (814 mg, 21.5 mmol) was added in one portion. The reaction mixture was warmed to rt and stirred for 1 h. The mixture was quenched at 0° C. by addition of 1M HCl until H2 evolvement ceased, then concentrated under reduced pressure. The phases were separated between EA and sat. aq. NaHCO3, the org. layer was dried over MgSO4 and concentrated under reduced pressure. The residue was chromatographed on SiO2 (DCM-MeOH—NH4OH: 1000:50:4) to afford the title alcohol as a dark yellow solid (2.92 g, 71% yield).
Reaction SMILES: I.[CH2:2]([N:9]1[CH2:17][CH:16]2[C:11](=[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=3[CH2:15]2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)(=O)C>[CH2:2]([N:9]1[CH2:17][CH:16]2[CH:11]([CH:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=3[CH2:15]2)[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=C1CN(Cc3ccccc3)CC1C2
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)C(c1ccccc1)C1CN(Cc3ccccc3)CC1C2

Procedure:
190 cc of 57% hydriodic acid are added dropwise to a suspension of 30 g of (9aRS)-2-benzyl-6-chloro-9,9a-dihydro-4-phenyl-benz[f]isoindoline and 46.8 g of red phosphorus in 400 cc of glacial acetic acid, the mixture is subsequently heated to 110° for 5 1/2 hours, is then poured on ice and made alkaline with caustic soda solution. After extraction with ethyl acetate, the organic phase is filtered through Celite, the filtrate is dried and concentrated by evaporation, whereby the title compound, having a M.P. of 115-117° (after crystallization from pentane), is obtained.
Reaction SMILES: Cl.C(OC([NH:9][CH:10]([C:53]([OH:55])=[O:54])[CH2:11][CH2:12][NH:13][S:14]([C:17]1[C:30]2[C:31]3=[C:32]4[C:27](=[CH:28][CH:29]=2)[C:26]([OH:33])=[CH:25][C:24]([OH:34])=[C:23]4[CH:22]=[CH:21][C:20]3=[C:19]([S:35](=[O:52])(=[O:51])[NH:36][CH2:37][CH2:38][CH:39]([C:48]([OH:50])=[O:49])[NH:40]C(OC(C)(C)C)=O)[CH:18]=1)(=[O:16])=[O:15])=O)(C)(C)C>C1COCC1>[NH2:40][CH:39]([C:48]([OH:50])=[O:49])[CH2:38][CH2:37][NH:36][S:35]([C:19]1[C:20]2[C:31]3=[C:32]4[C:23](=[CH:22][CH:21]=2)[C:24]([OH:34])=[CH:25][C:26]([OH:33])=[C:27]4[CH:28]=[CH:29][C:30]3=[C:17]([S:14](=[O:16])(=[O:15])[NH:13][CH2:12][CH2:11][CH:10]([C:53]([OH:55])=[O:54])[NH2:9])[CH:18]=1)(=[O:52])=[O:51]
Reactant: CC(C)(C)OC(=O)NC(CCNS(=O)(=O)c1cc(S(=O)(=O)NCCC(NC(=O)OC(C)(C)C)C(=O)O)c2ccc3c(O)cc(O)c4ccc1c2c43)C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: NC(CCNS(=O)(=O)c1cc(S(=O)(=O)NCCC(N)C(=O)O)c2ccc3c(O)cc(O)c4ccc1c2c43)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 2 N aqueous solution of HCl was added in one portion to a solution of the bis-Boc derivative (8) synthesized above (1.658 g, 2.09 mmol) in THF (200 mL) and the mixture was stirred for 24 h at room temperature. The mixture was then evaporated to dryness under reduced pressure.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[NH:7][C:8](=O)[C:9]2[NH:10][CH:11]=[N:12][C:13]=2[N:14]=1)[CH3:3].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O.C(=O)([O-])O.[Na+]>>[CH3:1][N:2]([CH:4]=[N:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8]([Cl:27])[N:7]=1)[CH3:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Product: CN(C)C=Nc1nc(Cl)c2[nH]cnc2n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
20.6 g (0.1 mol) of N-dimethylaminomethyleneguanine obtained in Example 15, and 12.1 g (0.1 mol) of N,N-dimethylaniline were added to 38.3 g (0.25 mol) of phosphorus oxychloride, followed by stirring at 80° C. for 2 hours. After cooling, the reaction mixture was added to 500 ml of ice water, and then neutralized with 126.0 g (1.5 mol) of sodium hydrogen carbonate. The precipitating crystal was collected by filtration and then washed with 50 ml of water, subsequently with 50 ml of methanol to yield 18.0 g (0.08 mol) of a crystal of 2-dimethylaminomethyleneamino-6-chloropurine (yield 80%). Comparative Example (method disclosed in Japanese Patent Laid-Open No. 227583/1986)
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH2:12][Cl:13])(=[O:11])=[O:10])=[CH:6][C:5]([NH:14][C:15]([N:17]2[CH2:21][C@H:20]([OH:22])[CH2:19][C@@H:18]2[C:23](O)=[O:24])=[O:16])=[C:4]([F:26])[CH:3]=1.S(=O)(=O)(O)O>C(C(C)=O)C(C)C>[Cl:13][CH2:12][S:9]([NH:8][C:7]1[CH:6]=[C:5]([N:14]2[C:23](=[O:24])[C@H:18]3[CH2:19][C@@H:20]([OH:22])[CH2:21][N:17]3[C:15]2=[O:16])[C:4]([F:26])=[CH:3][C:2]=1[Cl:1])(=[O:11])=[O:10]
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1C(=O)Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Agent: O=S(=O)(O)O
Solvent: CC(=O)CC(C)C
Product: O=C1[C@H]2C[C@@H](O)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.9 %

Procedure:
295.5 g (0.25 mol) of (2R-cis)-1-[[[4-chloro-5-[[(chloromethyl)sulfonyl]amino]-2-fluorophenyl]amino]carbonyl]4-hydroxy-2-pyrrolidinecarboxylic acid was suspended in 150 g of methyl isobutyl ketone at room temperature. 12.75 g (0.125 mol) of concentrated sulfuric acid was added and the clear solution was heated to reflux. At 90° C. a precipitate appeared. After an additional 20 minutes of stirring at reflux the suspension was cooled to 0° C. and allowed to stir for 1 hour at this temperature. After filtration and drying at 60° C., 91.65 g (86.6%) of the title compound was obtained as beige crystals melting at 198-200° C. (purity: 97%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[CH3:15][O:16][C:17]([C:19]1[O:23][NH:22][C:21](=O)[CH:20]=1)=[O:18]>>[CH3:15][O:16][C:17]([C:19]1[O:23][N:22]=[C:21]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])[CH:20]=1)=[O:18]
Reactant: COC(=O)c1cc(=O)[nH]o1
Reactant: Cc1onc(-c2ccccc2)c1CO
Product: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)no1
Yield: 62.4 %

Procedure:
As described for Intermediate 1, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (1.0 g, 5.3 mmol) was converted, using 3-oxo-2,3-dihydro-isoxazole-5-carboxylic acid methyl ester (756 mg, 5.3 mmol) instead of 3-hydroxy-5-methylisoxazole, to the title compound (1.04 g, 63%) which was obtained as a colourless gum after purification by chromatography (silica, heptane:ethyl acetate=4:1 to 0:1). MS: m/e=315.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH2:14][CH3:15])([CH2:12][OH:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](OC=C)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(OC(C)C)(C)C>[C:1]([O:5][C:6]([NH:8][C@@:9]([CH2:14][CH3:15])([CH2:10][O:11][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(CO)(CO)NC(=O)OC(C)(C)C
Reactant: C=COC(=O)CCCCC
Solvent: CC(C)OC(C)C
Product: CCCCCC(=O)OC[C@@](CC)(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.3 %

Procedure:
2-t-Butoxycarbonylamino-2-ethylpropane-1,3-diol (52.9 g, 241 mmol) was suspended in isopropyl ether (1.0 L) and vinyl hexanoate (41.0 mL, 254 mmol) and lipase [Immobilized lipase from Pseudomonas sp., manufactured by TOYOBO Limited, 0.67 U/mg] (2.1 g) was added thereto, followed by stirring of the mixture at room temperature for 4 hours. After the reaction mixture was filtered, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 7:1-4:1-2:1) to obtain the title compound (66.8 g, yield: 87%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=1.CN(C)C=O.C(Cl)(=O)C([Cl:26])=O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([Cl:26])=[O:17])=[CH:11][CH:10]=1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(C)c1-c1ccc(C(=O)Cl)cc1

Procedure:
A stirred solution of 2′,6′-dimethyl-1,1′-biphenyl-4-carboxylic acid of Step A (0.790 g, 3.5 mmol) in dichloromethane (15 mL) was treated under nitrogen with a catalytic amount of N,N-dimethylformamide followed by dropwise addition of 2N oxalyl chloride in dichloromethane (2.8 mL). After the gas evolution ceased the mixture was refluxed for 4 hours, cooled, and evaporated. The residue was azeotroped twice with benzene and dried in vacuo to provide 2′,6′-dimethyl-1,1′-biphenyl-4-carboxylic acid chloride. The crude 2′,6′-dimethyl-1,1′-biphenyl-4-carboxylic acid chloride (0.856 g, 3.5 mmol) was dissolved in dichloromethane (7 mL) and added dropwise to a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 12 (0.450 g, 1.41 mmol) in anhydrous tetrahydrofuran 10 mL) containing N,N-diisopropylethyl amine (0.860 mL). The mixture was stirred for 18 hours at room temperature and evaporated to dryness. The residue was dissolved in dichloromethane, the solution washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous potassium carbonate and evaporated. The residue was chromatographed over silica gel Merck-60 eluting with a gradient from 0 to 4% methanol in 1:1 hexane-ethyl acetate to provide the title compound (0.452 g) as a white solid after trituration with hexane, m.p. 216-218° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=O)[NH:9]2)=[CH:4][CH:3]=1>O1CCCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(F)cc2N1
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)NCCC2
Temperature: 60 °C
Reaction time: 24 h
Yield: 65.6 %

Procedure:
To a solution of 7-fluoro-1,2,3,4-tetrahydroquinolin-2-one (1.5 g, 9.08 mmol) in tetrahydrofuran (50 ml) was dropwise BH3 in THF (1M, 90 ml), the solution was stirred for 24 h at 60° C. The reaction mixture was cooled and then quenched by the addition of methanol (15 ml) and HCl (conc) (5 ml), then stirred for 1 h at 60° C. The reaction mixture was cooled to room temperature and adjusted to pH 12 with sodium hydroxide (4 mol/L), extracted with (3×15 ml) of ethyl acetate and the organic layers were combined and dried over anhydrous magnesium sulfate, concentrated in vacuo to give a residue, which was purified by a silica gel column chromatography with 3% ethyl acetate in petroleum ether to afford 7-fluoro-1,2,3,4-tetrahydroquinoline as a yellow solid (0.9 g, 66%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12].B#B>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[CH2:11][OH:12]
Reactant: O=C(O)c1ccccc1CCCCCCCBr
Agent: B#B
Solvent: C1CCOC1
Product: OCc1ccccc1CCCCCCCBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2-(7-bromoheptyl) benzoic acid (8.0 g, 0.027 mole) and distilled tetrahydrofuran (75 ml) was added diborane (40 ml, 0.04 mole) at room temperature under argon. The reaction mixture was stirred at room temperature for approximately 18 hours under argon, cooled to 0° C. and quenched with ethanol. The solvents were evaporated to give a colorless oil which was partitioned between methylene chloride and water. The organic layer was dried over magnesium sulfate and filtered. The resulting oil was flash chromatographed on silica using 10% ethyl acetate in hexane to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[C:21]1([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:27]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:28]=[CH:29][C:30]([CH2:31][NH:32][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:6]([Cl:20])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:16])=[CH:33][CH:34]=1
Reactant: NCc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCc1ccc(-c2ccccc2)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (100 mg, 0.28 mmol) and 4-phenyl benzylamine (55 mg, 0.32 mmol). The title compound was obtained as a yellow solid (65 mg, 45% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.41 (1H, m), 8.98 (2H, m), 8.49 (1H, s), 7.63 (4H, m), 7.46 (2H, m), 7.35 (3H, m), 7.38 (1H, m), 4.44 (2H, m). MS m/z: 514.03, 516.08 [M+H]+
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16].[CH2:18](C([Sn])=C(CCCC)CCCC)[CH2:19]CC>C(OCC)(=O)C.CCCCCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:15]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:7]=1[CH:18]=[CH2:19])[C:11]#[N:12])([O-:17])=[O:16]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 82.5 %

Procedure:
To N,N-dimethylformamide (50 ml) were added 4-chloro-3-nitrobenzonitrile (2.81 g, 15.39 mmol), tri-n-butylvinyltin (5.23 g, 16.49 mmol) and bis(triphenylphosphine)palladium(II) dichloride (701 mg, 0.999 mmol), and the mixture was stirred with heating at 100° C. for 160 min. The reaction mixture was cooled, diluted with an ethyl acetate-hexane=1:1 mixed solvent, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (2.21 g, yield 82%) as a yellow solid.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25]1([CH:31](Cl)[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:8][CH2:9][CH2:10][NH:11][CH:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCNC(c1ccccc1)c1ccccc1
Reactant: CC(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(NCCNC(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
11 g of N-diphenylmethyl-ethylenediamine, 10.1 g of triethylamine and 7.0 g of 1-phenylethyl chloride are dissolved, while stirring, in 85 ml of acetonitrile and heated under reflux for 30 hours. The solution is concentrated by evaporation under reduced pressure, 50 ml of 10% sodium hydroxide solution are added and the mixture is extracted thoroughly by shaking with diethyl ether. The ether extracts are combined, dried over sodium sulphate and concentrated by evaporation. N-diphenylmethyl-N'-(1-phenylethyl)-ethylenediamine is obtained in the form of a yellow oil which can be purified chromatographically over silica gel with methanol/ethyl acetate (1:1) as the eluant and, for characterisation, can be converted into the dihydrochloride, having a melting point of 160° C., as described in Example 4.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.CC(C)([O-])C.[K+].[C:12]([C:14]1([C:17]2([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][O:18]2)[CH2:16][CH2:15]1)#[N:13].CN(C=O)C>C(OCC)(=O)C>[C:12]([C:14]1([C:17]([OH:18])([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:19][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH2:15][CH2:16]1)#[N:13]
Reactant: c1nc[nH]n1
Reactant: N#CC1(C2(CCc3ccccc3)CO2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CC1(C(O)(CCc2ccccc2)Cn2cncn2)CC1
Yield: 26.6 %

Procedure:
0.8 g (12 mmol) of 1,2,4-triazole, 0.1 g (1 mmol) of potassium tert.-butoxide and 0.8 g (4 mmol) of 2-(1-cyanocyclopropyl)-2-(2-phenylethyl)oxirane (IV-16, Example 34) are heated to 80° C. for 6 h in 10 ml of abs. DMF. The solvent is stripped off in vacuo, and the residue is taken up in ethyl acetate and washed with water. After drying over Na2SO4, the solvent is evaporated in vacuo and the residue is chromatographed on silica gel (CH2Cl3 containing 2% ethanol). 0.3 g (28% of theory) of 2-(1-cyanocyclopropyl)-4-phenyl-1-(1,2,4-triazol- 1-yl)butan-2-ol is obtained in the form of a colorless oil, 1H--NMR (CDCl3):
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[OH:13])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[OH:13]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(N)c1O
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A mixture of 2,6-dinitrophenol (2.50 g, 13.6 mmol) and 10% Pd/C (300 mg) in MeOH was shaken under H2 (40 psi) overnight and filtered. The filtrate was concentrated in vacuo to provide the title compound (1.50 g, 89%), characterized by NMR and mass spectral analyses.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=[S:3])[NH2:2].CO[CH:16](OC)[CH2:17]Cl.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[S:3]1[CH:17]=[CH:16][N:2]=[C:1]1[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cccc(C(N)=S)c1
Reactant: COC(CCl)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: COC(=O)c1cccc(-c2nccs2)c1
Temperature: 100 °C
Yield: 76 %

Procedure:
A solution of 0.6 g (0.003 mol) of methyl 3-carbamothioylbenzoate in 6 ml of acetic acid was charged with 1.15 g (0.009 mol) of chloroacetaldehyde dimethyl acetal and a catalytic amount of PTSA. The RM was heated to 100° C. over night. Acetic acid was removed under vacuum and the crude product was purified by 60-120 silica gel column using 5% of ethyl acetate in pet ether as eluent to provide methyl 3-(thiazol-2-yl)benzoate (0.5 g) as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:1]([C:8]1[N:9]=[N:10][C:11]([N:16]2[CH2:17][CH2:18][N:19]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:20][CH2:21]2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCNCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1c(Cc2ccccc2)nnc(N2CCN(Cc3ccccc3)CC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
To a solution of 3-benzyl-4,5-dimethyl-6-piperazin-1-yl-pyridazine (40 mg, 0.14 mmol)) in CH2Cl2 (1.6 mL) and THF (1.6 mL) at 25° C. is added benzaldehyde (23 mg, 0.21 mmol), acetic acid (2 drops) and sodium triacetoxyborohydride (90 mg, 0.43 mmol). After being stirred at 25° C. for 2 h, the mixture is diluted with CH2Cl2 (10 mL) and washed with saturated sodium bicarbonate (2 mL) and water (5 mL). The organic layer is concentrated and purified by HPLC (CH3CN/H2O: 22% 45% with 0.1% TFA) to give 3-benzyl-6-(4-benzyl-piperazin-1-yl)-4,5-dimethyl-pyridazine (20 mg, 37%).
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].CCCCCCC>C1(C)C=CC=CC=1.CN(C)C=O>[CH:13]1([CH2:12][O:11][C:3]2[C:2]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=2)[CH2:15][CH2:14]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(O)c1cnc(OCC2CC2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
5-Bromo-6-cyclopropylmethoxy-nicotinic acid (2.28 g, 8 mmol) was dissolved in a mixture of toluene (40 mL) and dimethylformamide (4 mL). To this solution was added [4-fluoro-phenyl]-boronic acid (1.2 g, 8 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) dichloro-methane complex (307 mg), and 2 N sodium carbonate solution (33 mL). The whole mixture was heated with stirring at 90° C. for 4 h, cooled to room temperature and filtered. Phases were separated; the organic phase was discarded and the water phase was acidified with 1 N hydrochloric acid (pH 2) and extracted with ethylacetate. Etylacetate phases were pooled, dried with Na2SO4 and filtered over a small silica gel pad (20 g). The solvent was removed to yield a solid which was stirred with heptane (200 mL), filtered, washed with heptane and dried to yield 1.77 g of the title compound as beige solid, MS (ISP) 286.0 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1>[OH-].[Na+].O.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Product: Clc1ccc(NNc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
A suspension of 4-chloronitrobenzene (2.5 g, 15.9 mM) in 50% aqueous NaOH (1 mL, 12.5 mM) was warmed to 60° C. Zinc dust (3 g, 46 mM) was added in portions at such a rate as to keep the reaction temperature below 80° C. After all the zinc had been added, the reaction mixture was diluted with 20% NaOH (6 mL, 30 mM) and water (10 mL). A second portion of zinc dust (4 g, 62 mM) was then added in one portion. The resulting reaction mixture was stirred at 80° C. for approximately 18 hrs. The mixture was cooled to room temperature, the solid was filtered, and washed several times with ether. The combined filtrates were concentrated and purified by flash column chromatography. This afforded the title compound as a yellow solid (1.25 g, 5 mM) which contained approximately 25% of an impurity. This mixture was used directly in the next step. NMR (d6 -DMSO, 250 MHz): 7.14 (d, J=9 Hz, 4H), 6.76 (d, J=9 Hz, 4H), 5.63 (br s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1Br.[CH3:14][C:15]1([CH3:24])[CH2:20][CH2:19][C:18](B(O)O)=[CH:17][CH2:16]1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:18]1[CH2:19][CH2:20][C:15]([CH3:24])([CH3:14])[CH2:16][CH:17]=1
Reactant: CC1(C)CC=C(B(O)O)CC1
Reactant: N#CC1(c2ccc(N)c(Br)c2)CC1
Product: CC1(C)CC=C(c2cc(C3(C#N)CC3)ccc2N)CC1

Procedure:
The title compound was prepared from 1-(4-amino-3-bromo-phenyl)-cyclopropanecarbonitrile (as prepared in this step) and 4,4-dimethylcyclohexen-1-yl boronic acid using the conditions described in Example 1, step (e). 1H NMR (CD3OD; 400 MHz): δ 6.95 (dd, 1H, J=8.2, 2.3 Hz), 6.88 (d, 1H, J=2.3 Hz,), 6.71 (d, 1H, J=8.2 Hz), 5.62 (m, 1H), 2.52-2.23 (m, 2H), 1.98-1.97 (m, 2H), 1.55-1.51 (m, 4H), 1.31-1.28 (m, 2H), 1.01 (s, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][N:15]=[N+:16]=[N-:17])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:15]([CH2:14][C@@H:9]1[CH2:10][C@@H:11]([F:13])[CH2:12][NH:8]1)=[N+:16]=[N-:17]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1CN=[N+]=[N-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@@H]1C[C@@H](F)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,4R)-2-azidomethyl-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (600 mg, 2.45 mmol) in CH2Cl2 (2.5 mL) was added TFA (1.88 mL, 24.6 mmol) and the solution was stirred at RT for 2 h. CH2Cl2 was concentrated and the crude was dried under high vacuum to give the desired material which was used without further purification in the next step.