Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][C:11]([O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([N+:23]([O-])=O)=[CH:18][C:17]=1[Cl:26])=[CH:10]2)=[O:4].[NH4+].[Cl-]>CCO.C1COCC1.O.[Fe]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][C:11]([O:15][C:16]1[C:17]([Cl:26])=[CH:18][C:19]([NH2:23])=[CH:20][C:21]=1[Cl:22])=[CH:10]2)=[O:4]
Reactant: COC(=O)c1cccc2cc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cnc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc2cc(Oc3c(Cl)cc(N)cc3Cl)cnc12
Temperature: 25 °C
Yield: 118.7 %

Procedure:
To a solution of 3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-8-carboxylic acid methyl ester (314) (1.26 mmol) and NH4Cl (370 mg, 6.91 mmol) in EtOH/THF/H2O=8 ml/4 ml/2 ml was added Iron powder (386 mg, 6.91 mmol). The reaction mixture was refluxed for 3.5 hr. After cooling to room temperature and insoluble materials were filtered by Celite filtration. The filtrate was concentrated and sat NaHCO3 was added to the residue, which was extracted twice with AcOEt. Organic layer was washed by Brine, dried over MgSO4, and concentrated. Crude residue was purified by column chromatography (Hexane/AcOEt=2/1, 80 g of silica gel) to afford compound 315 (543 mg).
Reaction SMILES: Cl.Cl[CH:3]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>O>[N:14]1([CH:3]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: ClC1CCCCc2cccnc21
Agent: Cl
Solvent: O
Product: c1cnc2c(c1)CCCCC2N1CCCC1
Reaction time: 5 h

Procedure:
5 g of 9-chloro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine hydrochloride were dissolved in 12.5 ml of water and 8 ml of pyrrolidine were added. The mixture was refluxed with vigorous stirring for 5 hours and the excess pyrrolidine was evaporated off under reduced pressure. 25 ml of a saturated solution of sodium bicarbonate and then 50 ml of water were added followed by extraction with methylene chloride. The combined organic phases were washed with water, dried and concentrated to dryness under reduced pressure. The residue was chromatographed on silica and eluted with a mixture of methylene chloride and methanol (9-1) to obtain 2.25 g of the expected product with an Rf=0.20. 2.25 g of the product were crystallized from petroleum ether (b.p. 40°-70° C.) to obtain 2 g of the expected product melting about 62° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)([CH3:3])[CH3:2].[Br:18][CH2:19][CH2:20]C>C1COCC1>[Br-:18].[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N+:13]1[CH:17]=[CH:16][N:15]([CH2:19][CH3:20])[CH:14]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1cccc(C(C)C)c1-n1ccnc1
Reactant: CCCBr
Solvent: C1CCOC1
Product: CCn1cc[n+](-c2c(C(C)C)cccc2C(C)C)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 4.4 mmol (1.00 g) 1-(2,6-diisopropylphenyl)imidazole and 5.3 mmol (0.650 g, 0.48 ml) 1-bromopropane are dissolved in 5 ml THF and heated for 20 h to 90° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[C:19](Cl)(Cl)=[S:20]>C1COCC1.O>[N:6]([C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[C:19]=[S:20]
Reactant: S=C(Cl)Cl
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N=C=S)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of 4-methyl-3-nitroaniline (1.00 g, 6.57 mmol) and triethylamine (2.75 ml, 19.7 mmol) in THF (150 ml) was added dropwise thiophosgene (0.55 ml) at 0° C. After addition, the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was diluted with water and extracted with ether. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated under vacuum to afford 1.04 g of the title compound.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6]C(S(O)(=O)=O)=CC=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)[F:14].C1(C[NH:22][C:23]2[C:24]([S:42][CH3:43])=[N:25][N:26]3[C:31]([C:32]4[C:37]([CH3:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=4[O:40][CH3:41])=[CH:30][CH:29]=[CH:28][C:27]=23)CC1>COCCOC>[CH:7]1([CH2:6][CH:16]([NH:22][C:23]2[C:24]([S:42][CH3:43])=[N:25][N:26]3[C:31]([C:32]4[C:37]([CH3:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=4[O:40][CH3:41])=[CH:30][CH:29]=[CH:28][C:27]=23)[CH:15]([OH:17])[CH2:13][F:14])[CH2:2][CH2:12]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: FCC1CO1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NCC3CC3)c(SC)nn12
Solvent: COCCOC
Solvent: O
Product: COc1cc(C)cc(C)c1-c1cccc2c(NC(CC3CC3)C(O)CF)c(SC)nn12
Temperature: 25 °C

Procedure:
p-Toluenesulfonic acid hydrate (40 mg) and epifluorohydrin (0.15 mL) [CAS No. 503-09-3] were added to a solution of N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (50 mg) in 1,2-dimethoxyethane (0.40 mL), and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate:n-hexane=1:5) to obtain the title compound (24 mg) as a brownish oil.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:27]=[O:28])=[C:10]2[C:14]=1[N:13]=[C:12]1[N:15]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[CH2:16][CH2:17][CH2:18][N:11]21>O1CCCC1>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[Cl:26])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:27]([OH:28])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Ethylmagnesium bromide (3.0 M solution in diethyl ether, 1.1 mL, 3.3 mmol) was added to a stirred solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (1.00 g, 2.63 mmol) in tetrahydrofuran (13 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from ethanol to give the title compound as a colorless crystal (992 mg, 2.42 mmol, 92%).
Reaction SMILES: CS([O:5][CH2:6][CH:7]1[CH2:11][O:10][C:9](=[O:12])[N:8]1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=O)=O.O[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([N:8]2[CH:7]([CH2:6][O:5][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)[CH2:11][O:10][C:9]2=[O:12])=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)OCC1COC(=O)N1c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2COC(=O)N2c2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
In 20 ml of N,N-dimethylformamide was dissolved 1.50 g of 3-(4-chlorophenyl)-2-oxooxazolidin-4-ylmethyl methanesulfonate and 0.80 g of methyl 4-hydroxybenzoate. To the solution was added 0.80 g of anhydrous potassium carbonate, and the mixture was stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure and water was added thereto. The obtained residue was recrystallized from methanol to give 1.60 g of the title compound (compound 176) in a yield of 90%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]#[N:12])=[N:2]1.[Cl-:13].[Al+3].[Cl-].[Cl-].[NH3:17]>Cl>[ClH:13].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]([NH2:17])=[NH:12])=[N:2]1
Reactant: N
Reactant: N#CCc1noc2ccccc12
Reactant: [Cl-]
Agent: Cl
Agent: [Al+3]
Product: N=C(N)Cc1noc2ccccc12

Procedure:
A mixture of 1,2-benzisoxazole-3-acetonitrile (0.34 g) and aluminum chloride (0.54 g) was melted at 90° to 100°C, while dry ammonia gas was passed through thereto for 10 minutes. The reaction mixture was dissolved in aqueous ethanolic hydrochloric acid under cooling and then the solvent was distilled off. The residue was dissolved in a small amount of ethanol-chloroform and subjected to silica gel column chromatography and eluted with 10 % methanol-chloroform. The eluates were collected and recrystallized from ethanol to give the desired compound (0.08 g). m.p. 209° to 212°C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)#[N:2].[OH:19]O.[OH-].[Na+].CO>O>[NH2:2][C:1](=[O:19])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1
Reactant: OO
Reactant: CC(C)(C)OC(=O)N1CCN(CCCC#N)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCCC(N)=O)CC1
Yield: 7 %

Procedure:
A stirred mixture of 5.0 g (0.02 mole) of 1-(3-cyanopropyl)-4-(1,1-dimethylethoxycarbonyl)piperazine, 10 ml of 30% hydrogen peroxide solution and 10 ml of 20% NaOH solution warmed spontaneously to 42°. After the initial exothermic reaction had subsided and the temperature returned to room temperature, 50 ml of methanol was added dropwise; a temperature rise to 38° was noted. After heating two hours at 50° the mixture was diluted with 50 ml of water and extracted with CH2Cl2. The organic extracts were dried (Mg SO4), filtered and evaporated on a rotary evaporator. The crude product was recrystallized from ethyl acetatehexane to yield 0.4 g (7%) of 1-(4-amino-4-oxobutyl)-4-(1,1-dimethylethoxycarbonyl)piperazine, 1/4 hydrate, mp-67.5°-71.5°. Calc. for C13H15N3O3. 1/4 H2O (275.87): C, 56.60; H, 9.32; N, 15.23. Found: C, 56.58; H, 9.41; N, 15.23.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[C:22]([O:40][CH3:41])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:41][O:40][C:22]1[CH:21]=[C:20]([CH:39]=[CH:38][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:19][O:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: COC(=O)Cc1cn(-c2ccccc2)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
A mixture of methyl (3-hydroxy-1-phenyl-1H-pyrazol-4-yl)acetate (406 mg), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (551 mg), potassium carbonate (484 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate-layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give methyl [3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetate (595 mg, yield 55%), which was then recrystallized from ethyl acetate-hexane. melting point: 107–108° C.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[C:12]([CH3:13])=[C:11](F)[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].Cl>C1COCC1>[Cl:3][C:4]1[C:12]([CH3:13])=[C:11]([NH:2][CH3:1])[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Cc1c(F)c([N+](=O)[O-])cc(C(=O)O)c1Cl
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNc1c([N+](=O)[O-])cc(C(=O)O)c(Cl)c1C
Temperature: 25 °C

Procedure:
A mixture of methylamine (2M THF solution, 8.56 mL, 17 mmol), 2-chloro-3-methyl-4-fluoro-5-nitro-benzoic acid (1.00 g, 4.2 mmol) and 20 mL THF is stirred over the weekend at rt. Then the mixture is acidified with 4M aq HCl and concentrated and the residue is washed with water and dried.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[CH:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1C(O)=O)=[O:8].[CH2:18](I)C>C(#N)C>[CH:7]([C:9]1[CH:10]=[C:14]([CH:15]=[CH:16][CH:17]=1)[C:1]([O:2][CH3:18])=[O:4])=[O:8]
Reactant: CCI
Reactant: O=Cc1ccccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cccc(C=O)c1
Yield: 89.3 %

Procedure:
Potasium carbonate (6.84 g) was added to a solution of 3 formylbenzoic acid (5.00 g), ethyl iodide (5.15 g) in acetonitrile (100 ml). The reaction mixture was refluxed for 18 hrs after cooling the mixture was partitioned between ethyl acetate and water, the organic phase separated, washed with saturated brine, dried over MgSO4 and evaporated under reduced pressure to afford the title compound as a yellow oil (4.84 g).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:28]=[CH:27][C:10]([CH2:11][N:12]([CH2:19][CH2:20][C:21]2[S:22][CH:23]=[C:24]([CH3:26])[N:25]=2)C(=O)C(F)(F)F)=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].O>C(O)C>[C:3]([C:7]1[CH:28]=[CH:27][C:10]([CH2:11][NH:12][CH2:19][CH2:20][C:21]2[S:22][CH:23]=[C:24]([CH3:26])[N:25]=2)=[CH:9][CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1csc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)C(F)(F)F)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1csc(CCNCc2ccc(C(C)(C)C)cc2)n1
Reaction time: 3 h

Procedure:
102 mg of sodium borohydride (2.7 mmol) were added to a solution of 260 mg of N-(4-tert-butyl-benzyl)-2,2,2-trifluoro-N-[2-(4-methyl-thiazol-2-yl)-ethyl]-acetamide (0.68 mmol) in ethanol at ambient temperature and the reaction mixture was stirred for 3 h. Then water was added and the mixture was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried with magnesium sulfate, filtered and the solvent was evaporated. The remaining 195 mg (100%) of (4-tert-butyl-benzyl)-[2-(4-methyl-thiazol-2-yl)-ethyl]-amine were used in the following coupling step without further purification. 1H NMR (CDCl3, 300 MHz): δ 1.31 (s, 9H), 2.41 (s, 3H), 3.06 (m, 2H), 3.17 (m, 2H), 3.81 (s, 2H), 6.72 (s, 1H), 7.25 (d, J=8 Hz, 2H), 7.34 (d, J=8 Hz, 2H); MS (ISP) 289.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].Br[Zn][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[C:14]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: Br[Zn]C1CCCC1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Br)c(C#Cc2ccccc2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(C2CCCC2)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-bromo-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]carbamate C2d (60 mg, 0.14 mmol), bromo(cyclopentyl)zinc (0.5 M solution in THF, 1.6 ml, 0.81 mmol), Palladium(II) acetate (1.5 mg, 0.01 mmol), 2-Dicyclohexyl-phosphino-2′,4′,6′-triisopropylbiphenyl (6.4 mg, 0.01 mmol) in toluene (0.25 ml) is stirred at RT for 6 days. The reaction mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 18 mg (31%). HPLC-MS: M+H=434; tR=1.97 min (*Method—5).
Reaction SMILES: ClN1C(=O)CCC1=O.[CH:9](=[N:16][OH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH2:25]([O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[C:26]#[CH:27]>C(Cl)Cl>[C:10]1([C:9]2[CH:27]=[C:26]([CH2:25][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[O:17][N:16]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ON=Cc1ccccc1
Reactant: C#CCOC1CCCCO1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(-c2cc(COC3CCCCO3)on2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.5 %

Procedure:
1.47 g (11 mmol) of N-chlorosuccinimide were added at -30° C. to a solution of 1.21 g of benzaldoxime in 10 ml of methylene chloride. After 2 hours a solution of 1.0 g of triethylamine and 1.4 g of (RS)-tetrahydro-2-(2-propynyloxy)-2H-pyran in 5 ml of methylene chloride was added dropwise. The reaction mixture was stirred at room temperature for 5 hours, the solvent was thereafter distilled off and, for purification, the crude product was chromatographed on silica gel using methylene chloride as the eluent. There were obtained 1.8 g of (RS)-3-phenyl-5-(tetrahydro-pyran-2-yloxymethyl)-isoxazole as a colourless liquid; MS: 259 (M)+.
Reaction SMILES: [CH2:1]([C@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=O)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH:40][CH2:39][C:36]2[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: COc1ccc(CN)cc1
Reactant: C=CC[C@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C=CC[C@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNCc2ccc(OC)cc2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (300 mg, 0.675 mmol; Example 91, Step C) and (4-methoxyphenyl)methanamine (131 μL, 1.01 mmol) in DCE (4.5 mL) was added sodium triacetoxyborohydride (429 mg, 2.03 mmol) at 0° C. in several portions. After being stirred at 25° C. for 18 h, the reaction was quenched by adding ice-cold saturated aqueous NaHCO3 and extracted (2×DCM). The combined organic layers were washed (1×sat. aq. NaCl solution) and concentrated under reduced pressure to provide the title compound as a yellow film. The product was used in the next step without further purification.
Reaction SMILES: [OH:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]1[CH:4]=[C:5]([C:16](O)=[O:17])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1.Cl.Cl.[CH3:27][C:28]1[N:33]=[CH:32][C:31]([C@H:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]1[CH:4]=[C:5]([C:16]([NH:36][C@@H:34]([C:31]2[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=2)[CH3:35])=[O:17])[CH:6]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH:8]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(O)c3ccccc3)c2)cc1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(C)nc3)cc(C(O)c3ccccc3)c2)cc1
Temperature: 30 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(hydroxy(phenyl)methyl)-4′-methylbiphenyl-3-carboxylic acid (50 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (70 mg, 0.34 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (500 μL, 2.87 mmol). The reaction mixture was stirred for 16 hours at 30° C. The reaction mixture was purified by preparative HPLC (100×21.2 mm C18 column, CH3CN/water[1 mM Et2NH]) to afford a light color solid.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([C:9]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:10]=1[N:11]([CH3:14])[CH:12]=[O:13])(=[O:8])[CH3:7].O>ClCCl>[Cl:4][CH2:7][C:6]([C:9]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:10]=1[N:11]([CH3:14])[CH:12]=[O:13])=[O:8]
Reactant: CC(=O)c1cc(F)ccc1N(C)C=O
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CN(C=O)c1ccc(F)cc1C(=O)CCl
Reaction time: 8 h

Procedure:
A solution of sulphuryl chloride (3.2 ml) in dichloromethane (20 ml) was added dropwise over a period of 10 minutes to the solution of 2'-acetyl-4'-fluoro-N-methylformanilide at 0° under a nitrogen atmosphere and the mixture stored overnight at 0 to 5°. Water (25 ml) was added whilst maintaining the temperature below 1 0°. The dichloromethane layer was separated, washed with water (1 25 ml) and dried over magnesium sulphate to give a solution of 2'-(2-chloroacetyl)-4'-fluoro-N-methylformanilide.
Reaction SMILES: [F:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](I)[CH:20]=[CH2:21].O>CN(C=O)C>[F:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][C:8](=[O:10])[N:9]([CH2:21][CH:20]=[CH2:19])[C:4]=2[CH:3]=1
Reactant: O=c1cnc2ncc(F)cc2[nH]1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)cnc2ncc(F)cc21
Yield: 46.5 %

Procedure:
7-Fluoropyrido[2,3-b]pyrazin-2(1H)-one (306 mg, 1.855 mmol) was suspended in dry DMF (10 mL) under argon at rt, and the stirred suspension was treated with K2CO3 (845 mg, 6.12 mmol) and allyl iodide (223 μl, 2.41 mmol). It was then stirred for 1 h before addition of water (100 ml). The mixture was then extracted with DCM (2×200 ml) and 5% MeOH/DCM (100 ml). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated and purified by column chromatography on silica with a 0-10% MeOH in DCM gradient to give the desired product as a yellow solid (177 mg, 47%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][CH:6]1[C:11]([C:12]2[CH:26]=[CH:25][C:15]3[N:16]=[C:17]([C:19]4[O:20][C:21]([NH2:24])=[CH:22][CH:23]=4)[NH:18][C:14]=3[CH:13]=2)=[N:10][NH:9][C:8](=[O:27])[CH2:7]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:5][CH:6]1[C:11]([C:12]2[CH:26]=[CH:25][C:15]3[N:16]=[C:17]([C:19]4[O:20][C:21]([NH:24][C:1](=[O:3])[CH3:2])=[CH:22][CH:23]=4)[NH:18][C:14]=3[CH:13]=2)=[N:10][NH:9][C:8](=[O:27])[CH2:7]1
Reactant: CC(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc2nc(-c3ccc(N)o3)[nH]c2c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(-c2nc3ccc(C4=NNC(=O)CC4C)cc3[nH]2)o1
Reaction time: 3 h

Procedure:
0.3 ml of acetyl chloride in 3 ml of chloroform is added to a solution of 309 mg of 5-methyl-6-[2-(5-amino-2-furyl)-5-benzimidazolyl]-4,5-dihydropyridazin-3-one and 0.2 ml of triethylamine in 10 ml of chloroform, and the mixture is boiled for 3 hours. The usual working up is carried out, and 5-methyl-6-[2-(5-acetamido-2-furyl)-5-benzimidazolyl]-4,5-dihydropyridazin-3-one is obtained.