Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)C.[C:7]([O:11][C:12]([NH:14][C:15]1([CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[H][H]>[C].[Pd].CO>[C:7]([O:11][C:12]([NH:14][C:15]1([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCOC(=O)C=CC1(NC(=O)OC(C)(C)C)CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)CCC1(NC(=O)OC(C)(C)C)CCOCC1

Procedure:
In the ethyl acetate (30 mL) and methanol (12 mL) mixed solution of ethyl 3-(4-t-butoxycarbonylamino-tetrahydro-pyran-4-yl)-acrylate which had been obtained in 3), 5% palladium carbon catalyst was added at room temperature. The reaction mixture was stirred under the hydrogen gas stream at room temperature for 75 minutes. The palladium catalyst was removed by filtration with Celite, and the filtrate was concentrated and dried up to give colorless oily matter (2.69 g).
Reaction SMILES: [H][H].[C:3](#[N:12])[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1>[Ni]>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([CH2:3][NH2:12])=[CH:5][CH:6]=1)#[N:9]
Reactant: [H][H]
Reactant: N#Cc1ccc(C#N)cc1
Agent: [Ni]
Product: N#Cc1ccc(CN)cc1

Procedure:
168 kg of p-cyanobenzylamine crude product (p-cyanobenzylamine 92% by weight, p-xylylenediamine 8% by weight) obtained by hydrogen reduction of terephthalonitrile in the presence of sponge metal nickel catalyst was mixed with 680 kg of water while stirring at 40° C. or less and the mixture was stirred for 3 hours. The crystals which precipitated were separated by centrifugation while washing with water to obtain 155 kg of p-cyanobenzylamine hydrate (water content: 21% by weight).
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[CH2:3][C:4]#[CH:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:7][C:8]1[C:9]([C:5]#[C:4][CH2:3][C@H:2]([OH:6])[CH3:1])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC[C@@H](C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC[C@@H](C)O)c21

Procedure:
Using Method C above, (R)-pent-4-yn-2-ol (44 mg, 0.52 mmol) (see below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mol) and Cul (2 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 7 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-1,3-Dihydro-5-fluoro-4-(4-hydroxy-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-70% EtOAc in hexanes gradient and trituration with Et2O. (Yield 20 mg, 45%).
Reaction SMILES: B(F)(F)F.CCOCC.[BH4-].[Na+].[C:12]1([S:18]([N:21]2[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][N+:28]([O-])=O)=[CH:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[C:12]1([S:18]([N:21]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:28])=[CH:22]2)(=[O:19])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])C=Cc1ccn(S(=O)(=O)c2ccccc2)c1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCc1ccn(S(=O)(=O)c2ccccc2)c1

Procedure:
Boron trifluoride etherate (17.7 g) was added under nitrogen with ice-cooling to sodium borohydride (3.94 g) suspended in tetrahydrofuran (150 ml). After stirring at room temperature for fifteen minutes 2-(1-phenylsulphonyl-3-pyrrolyl)-1-nitroethylene (5.78 g) (prepared according to Synthetic Communications, 15 (1), 71-74 (1985)), dissolved in tetrahydrofuran (80 ml) was added dropwise. The mixture was refluxed overnight, quenched by the addition of ice-water, acidified with 5M hydrochloric acid and refluxed for a further two hours. The aqueous layer was washed with ether and the amine liberated by the addition of 0.880 ammonia solution which was extracted into dichloromethane. The extracts were washed with water, dried and evaporated to give pure product as an oil.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12]>N1C=CC=CC=1>[OH:1][CH:2]([CH:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12]
Reactant: COc1cccc(C(O)c2ccncc2)c1OC
Solvent: c1ccncc1
Product: COc1cccc(C(O)C2CCNCC2)c1OC

Procedure:
In Scheme F, step e, the pyridine functionality of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10) is reduced to give 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:19]=[CH:20][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([NH:6][C:7]([N:26]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:16]([O:15][CH3:14])[CH:17]=1)[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(F)cccc1Cl
Reactant: COC(=O)c1ccc(NNC(=O)OC(C)(C)C)cc1OC
Solvent: ClCCl
Product: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2c(F)cccc2Cl)cc1OC
Yield: 89.6 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-9 by using 2-chloro-6-fluorobenzoyl isocyanate (Intermediate-8, 2.0 g, 6.75 mmol), tert-butyl 2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (Intermediate-14, 2.0 g, 10.10 mmol) and DCM (30 mL) to afford 3.0 g of desired product. 1H NMR (300 MHz, DMSO do): δ 1.42 (s, 9H), 3.76 (s, 6H), 6.99 (d, J=8.1 Hz, 1H), 7.11 (s, 1H), 7.2-7.50 (m, 4H), 9.88 (s, 1H), 11.32 (s, 1H); MS (m/z): 493.92 (M−H)−.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([C:18]2[S:19][C:20]([CH3:33])=[C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[C:26]([O:30][CH3:31])=[CH:25][C:24]=3[Cl:32])[N:22]=2)[CH2:17][CH2:16]1)C1C=CC=CC=1.C(O)C.C1CC=CCC=1>>[Cl:32][C:24]1[CH:25]=[C:26]([O:30][CH3:31])[C:27]([CH3:29])=[CH:28][C:23]=1[C:21]1[N:22]=[C:18]([C:15]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[OH:8])[CH2:17][CH2:16]2)[S:19][C:20]=1[CH3:33]
Reactant: COc1cc(Cl)c(-c2nc(C3(c4ccccc4OCc4ccccc4)CC3)sc2C)cc1C
Solvent: CCO
Solvent: C1=CCC=CC1
Product: COc1cc(Cl)c(-c2nc(C3(c4ccccc4O)CC3)sc2C)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-[1-(2-Benzyloxy-phenyl)-cyclopropyl)-4-(2-chloro-4-methoxy-5-methyl-phenyl)-5-methyl-thiazole (0.95 g, 2 mmol) was dissolved in dry ethanol (100 mL) 30% palladium on carbon (0.39 g, 1.1 mmol) and 1,4-cyclohexadiene (20 mL, 210 mmol) was added. The reaction mixture was stirred for 2 d at room temperature. The mixture was filtered through Celite concentrated, and purified by chromatography on silica using an ethyl acetate/hexane gradient, the title compound was obtained as a white powder. Yield: 0.41 g (53%). [MH]+ =386.2, 388.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-])=O)[CH3:2].[CH2:16](C1C=CC(C(O)=O)=CC=1)C.COC(OC)N(C)C>CN(C)C=O>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]2[C:3]([C:1]([CH3:16])=[CH:2][NH:13]2)=[CH:12][CH:11]=1)=[O:8]
Reactant: CCc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Reactant: CCc1ccc(C(=O)O)cc1
Agent: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C)c[nH]c2c1
Temperature: 130 °C
Reaction time: 72 h

Procedure:
Methyl 4-ethyl-3-nitrobenzoate (5.0 g), which had been prepared through nitration followed by methyl-esterification of 4-ethylbenzoic acid, is dissolved in N,N-dimethylformamide (50 ml), to which is added N,N-dimethylformamide dimethyl acetal (8.45 g), and stirred under heat at 130° C. for 3 hours. The reaction mixture is concentrated under reduced pressure, and the resulting red oily residue is dissolved in methanol (50 ml), to which is added palladium-carbon (5%, 0.400 g), and stirred in a hydrogen atmosphere at room temperature for 2.5 hours. Then, this is further stirred at 50° C. for 2 hours and thereafter at room temperature for 3 days. The catalyst is removed through filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is recrystallized from t-butyl methyl ether to obtain a pale yellow crystal of the intended product (2.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([SH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.[CH2:20]([N:22]=[C:23]=[S:24])[CH3:21]>ClCCl.C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([S:17][C:23](=[S:24])[NH:22][CH2:20][CH3:21])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Br)cc1F
Reactant: CCN=C=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=S)SC1C2=C(CCCC2)C(=O)N1c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.1 %

Procedure:
In 20 ml of dichloromethane was dissolved 3.4 g of 2-(4-bromo-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindol-1-one, and 1.0 g of ethyl isothiocyanate, together with one drop of triethylamine, was added to the solution, followed by stirring at room temperature for 5 hours. The dichloromethane was distilled off under reduced pressure, and the resulting crystals were washed with cold ethanol and dried, thereby producing 3.8 g (yield of 88%) of the subject compound. Recrystallization from ethanol yielded white crystals, m.p. 130°-131° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([N:9]([CH3:13])[C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Br:8])[CH:7]=1.Cl.N([O-])=O.[Na+].[Na].[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[Br:8][C:6]1[CH:5]=[C:4]([N:9]([CH3:13])[C:10](=[O:12])[CH3:11])[CH:3]=[C:2]([S:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=1
Reactant: CC(=O)N(C)c1cc(N)cc(Br)c1
Reactant: Sc1ccccc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)N(C)c1cc(Br)cc(Sc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 25.3 %

Procedure:
0.243 g (0.001 mol) of N-(3-amino-5-bromophenyl)-N-methylacetamide was suspended in 5 ml of water, treated with 0.2 ml (0.002 mol) of HCl (37%) and cooled to 0° C. A solution of 0.069 g (0.001 mol) of NaNO2 in 1 ml of water was added thereto, the mixture was stirred at 0° C. for 5 min. and subsequently at room temperature for 10 min. and finally treated with a suspension of 0.35 g (0.0025 mol) of thiophenol sodium salt. The reaction mixture was treated in an ultrasound bath for 10 min. and subsequently partitioned in water/ethyl acetate. The organic phase was washed with sat. sodium chloride solution, dried over MgSO4 filtered and freed from solvent. The residue was then heated to 120-130° C. for 20 min., taken up in ethyl acetate and chromatographed on silica gel with ethyl acetate/hexane 1:9 and 1:2. There was obtained 0.085 g (21%) of N-(3-bromo-5-phenylsulphanylphenyl)-N-methylacetamide as a yellow oil. MS (EI): me/e=337, 335 (C15H14BrNOS+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]=1[CH3:9])(=[O:3])[CH3:2].Cl.[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH:29]=[CH:28]C=N2)[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH2:29][CH2:28][N:7]([CH2:10][CH2:2][C:1]([C:4]3[CH:5]=[N:6][N:7]([C:10]4[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=4)[C:8]=3[CH3:9])=[O:3])[CH2:8][CH2:4]2)[CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cccc(-n2cccn2)c1
Reactant: CC(=O)c1cnn(-c2ncccc2Cl)c1C
Agent: Cl
Product: Cc1c(C(=O)CCN2CCN(c3cccc(Cl)c3)CC2)cnn1-c1ncccc1Cl
Yield: 71.9 %

Procedure:
4-Acetyl-1-(3-chloro-2-pyridyl)-5-methylpyrazole (648 mg), 1-(3-chlorophenyl)pyrazole hydrochloride (641 mg), and p-formaldehyde (1.65 g) were reacted, and the product was worked up in the same manner as in Example 5-(4) to yield 439 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH2:22]([C@H:29]1[CH2:33][O:32][C:31](=[O:34])[NH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([Li])CCC>CCCCCC>[CH2:22]([C@H:29]1[CH2:33][O:32][C:31](=[O:34])[N:30]1[C:11](=[O:13])[CH2:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:15][CH:14]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(OCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1

Procedure:
The target compound (28.3 g) was obtained as colorless crystals by carrying out the reaction and the post-treatment according to Reference example 20(a) using 4-t-butylphenoxyacetic acid (17.0 g), oxalyl chloride (17.8 ml), (S)-4-benzyl-2-oxazolidinone (14.2 g) and a solution of n-butyl lithium in hexane (1.61N, 50.4 ml).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH:11]([CH3:13])[CH3:12])[C:3]=1[CH:4]=O.C(N)CN.C(O)(=O)C.CC1(C)O[C:28](=[O:29])[CH2:27][C:25](=[O:26])[O:24]1>CO>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:3]=1[CH:4]=[C:27]([C:25]([OH:26])=[O:24])[C:28](=[O:29])[N:10]2[CH:11]([CH3:13])[CH3:12]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)Nc1cccc(Cl)c1C=O
Solvent: NCCN
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)n1c(=O)c(C(=O)O)cc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.5 %

Procedure:
To a solution of 2-chloro-6-(isopropylamino)benzaldehyde (1.1 g, 5.57 mmol, step 3) in methanol (10 mL) was added ethylenediamine (0.186 mL, 2.78 mmol) and acetic acid (0.319 mL, 5.57 mmol). Meldrum's acid (1.6 g, 11.1 mmol) was added to the mixture at 0° C. Then, the mixture was stirred at room temperature for 16 h. The formed precipitate was filtrated and washed with methanol. The filtrate was evaporated and crystallized from methanol to give 200 mg (14%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([O:25]C(=O)C)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])(=[O:4])=[O:3].CS(C(CC#C[C@@H](OC(=O)C)CCCCC)CCCCCCC(OC)=O)(=O)=O>>[CH3:1][S:2]([CH:5]([CH2:16][C:17]#[C:18][C@@H:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OC)S(C)(=O)=O)OC(C)=O
Agent: CCCCC[C@@H](C#CCC(CCCCCCC(=O)OC)S(C)(=O)=O)OC(C)=O
Product: CCCCC[C@H](O)C#CCC(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out by the method of Example 3, Step E, except that methyl 8-methylsulfonyl-12-acetoxyheptadecanoate is replaced by an equivalent quantity of methyl 8-methylsulfonyl-12(S)-acetoxy-10-heptadecynoate.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[CH2:31][OH:32])=[CH:26][CH:25]=1.[OH-].[Na+]>ClCCl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)[CH:31]=[O:32])=[CH:26][CH:25]=1
Reactant: OCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Dess-Martin periodinane (3.17 g, 7.49 mmol) was added to a solution of 2,2-Bis-(4-chloro-phenyl)-ethanol in dichloromethane (40 ml). The reaction mixture was stirred at room temperature for 17 hours under nitrogen, 2N NaOH added (15 ml) and the organic layer was separated, dried (MgSO4), filtered and concentrated to afford the title compounds which was used in the next step without further purification. LC/MS: (PS-B3) Rt 3.62 [M+H]+ 262.91.
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.N.C(OC(C1[CH:21]([C:22]2C=CC=C[N+:23]=2[O-:28])C(C(OCC)=O)=C(C)NC=1C)=O)C>C(O)C>[N+:23]1([O-:28])[C:2]([CH:1]=[O:7])=[CH:3][CH:5]=[CH:21][CH:22]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cccc[n+]1[O-]
Agent: N
Solvent: CCO
Product: O=Cc1cccc[n+]1[O-]

Procedure:
Analogously to the process described in Example 1 there is obtained from 22.5 g of pyridine-2-carboxaldehyde-1-oxide, 37 ml of ethyl acetoacetate and 14.5 ml of 30% aqueous ammonia in 29 ml of absolute ethanol, 2,6-dimethyl-4-(1-oxido-2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dietyl ester which, after recrystallisation from 250 ml of acetonitrile, melts at 198°-200°.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[C:16]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)=[C:17]([C:22]([O:24]C)=[O:23])[N:18]([CH3:21])[C:19](=[O:20])[C:8]2=3)=[CH:4][CH:3]=1.[Li+].[OH-].Cl>CO.O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[C:16]([C:26]4[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=4)=[C:17]([C:22]([OH:24])=[O:23])[N:18]([CH3:21])[C:19](=[O:20])[C:8]2=3)=[CH:33][CH:34]=1
Reactant: COC(=O)c1c(-c2ccc(C)cc2)c2c3ccccc3n(Cc3ccc(F)cc3)c2c(=O)n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2c(C(=O)O)n(C)c(=O)c3c2c2ccccc2n3Cc2ccc(F)cc2)cc1
Temperature: 0 °C
Yield: 98.2 %

Procedure:
A mixture of methyl 9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-3-carboxylate (625 mg, 1.375 mmol) in Methanol (10 mL) and Tetrahydrofuran (THF) (10.00 mL) was treated with 2M LiOH (20 mL, 40.0 mmol) and then refluxed overnight. The mixture was cooled to 0° C., treated with HCl (1M) until pH<2 and then filtered to afford 9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-3-carboxylic acid as a white solid (595 mg, 1.35 mmol, 98% yield). A suspension of 9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-3-carboxylic acid (595 mg, 1.35 mmol) in thionyl chloride (10 mL, 137 mmol) was heated at 70° C. for 2 hours and then concentrated. The residue was dissolved in Tetrahydrofuran (THF) (10.00 mL), treated with sodium borohydride (520 mg, 13.75 mmol) and then heated at 70° C. for 2 hours. Additional NaBH4 (15 eq.) was added and then mixture was heated at 70° C. overnight. The mixture was concentrated, treated with NH4Cl (sat. aq) slowly at 0° C. and then extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and concentrated to afford 9-(4-fluorobenzyl)-3-(hydroxymethyl)-2-methyl-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one (520 mg, 1.22 mmol, 90% yield) as a white solid which was used in the next step without any further purification. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.30-7.44 (m, 7H) 7.19-7.27 (m, 3H) 6.95 (s, 4H) 6.62-6.70 (m, 1H) 6.14 (s, 3H) 4.57 (s, 2H) 3.92 (s, 3H) 2.52 (s, 3H); LCMS (m/z) ES+=427 (M+1).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:15]=3[CH:16]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>C(O)CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:14]2[O:13][C:12]([CH:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)=[CH:16][C:15]=2[CH:17]=1
Reactant: CCOC(=O)N1CCC(c2cc3cc(Cl)ccc3o2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: Clc1ccc2oc(C3CCNCC3)cc2c1

Procedure:
11.5 g of 4-(5-chloro-2-benzofuranyl)-1-piperidinecarboxylic acid ethyl ester is dissolved in 75 ml of ethylene glycol. After the addition of 50 ml of a 50% aqueous potassium hydroxide solution, the formed cloudy solution is heated, with vigorous stirring, for 15 hours at 160°; the reaction solution is thereupon cooled to 20°, and extracted twice with 500 ml of ethyl acetate each time. The organic phases are washed five times with 1 liter of water each time, dried over sodium sulphate, filtered, and concentrated by evaporation. The residue is dissolved in 300 ml of a 10% solution of methanesulphonic acid in water, and the acid solution extracted with ether. The aqueous solution is then adjusted by addition of 10% sodium hydroxide solution to have a pH value of 12, and extracted with 1 liter of chloroform. The chloroform solution is dried with sodium sulphate, filtered, and concentrated by evaporation to obtain crude 4-(5-chloro-2-benzofuranyl)-piperidine. The free base melts at 77°-78° after recrystallisation from hexane. The hydrochloride is prepared with hydrogen chloride in ethyl acetate, and recrystallised from ethyl acetate, whereupon its melts at 252°-254°.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]=[CH2:3].C(Cl)C=C.[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.C1(C)C=CC=CC=1>[C:11]1([CH2:10][CH2:3][CH:2]=[CH2:1])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: C=CC[Mg]Cl
Solvent: Cc1ccccc1
Solvent: C=CCCl
Solvent: C1CCOC1
Product: C=CCCc1ccccc1
Reaction time: 1 h
Yield: 90 %

Procedure:
Example 8 was repeated to form allyl magnesium chloride. The allyl magnesium chloride which flowed out of the flask through the branch was accumulated in a 3 L four-necked flask equipped with a stirrer, a thermometer, a condenser and a dropping funnel placed under a nitrogen atmosphere. A mixed solvent of toluene and tetrahydrofuran dissolving allyl chloride was started to be added dropweise thereto. 2 hours after the start of the addition of the mixed solvent, 300 ml of a mixed solvent of toluene and tetrahydrofuran (a content of terahydrofuran 25% by weight) dissolving 156 g (1.23 mole) of benzyl chloride was added dropwise in the 3 L four-necked flask at a rate of 15 ml per hour at a temperature of 0 to 20° C. After the completion of the dropwise addition, the reaction mixture was stirred for 1 hour at the same temperature. After the completion of the reaction, an aftertreatment was effected in a similar manner to that in Example 1 to obtain 146.9 g (yield 90%, based on benzyl chloride) of 4-phenyl-1-butene which was a colorless liquid. An analysis of the product by gas chromatography indicated the purity of 98.7%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[CH:14][C:13]=2[F:20])[N:6]=1)=[O:4].[Cl:21]N1C(=O)CCC1=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:21])=[C:9]([NH2:11])[N:8]=[C:7]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[CH:14][C:13]=2[F:20])[N:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(N)nc(-c2cc(F)c(Cl)cc2F)n1
Solvent: CC#N
Product: COC(=O)c1nc(-c2cc(F)c(Cl)cc2F)nc(N)c1Cl
Temperature: 40 °C
Yield: 49.9 %

Procedure:
6-Amino-2-(4-chloro-2,5-difluorophenyl)pyrimidine-4-carboxylic acid methyl ester (0.090 g, 0.3 mmol) and N-chlorosuccinimide (0.05 g, 0.37 mmol) were combined in 10 mL acetonitrile and heated at 40° C. for 18 hours. The reaction mixture was concentrated and the product purified by column chromatography (ethyl acetate/hexane gradient) to yield the title compound as an off-white solid (0.050 g, 50% yield): 1H NMR (CDCl3): δ 7.85 (dd, 1H), 7.22 (dd, 1H), 5.62 (br s, 2H), 4.01 (s, 3H).