Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](O)=[C:6](OC)[CH:5]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].COCCl>>[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: COc1cc(C(C)=O)ccc1O
Agent: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)c1ccccc1

Procedure:
Analogs in series 3, which contain a 3-carbon spacer, were prepared as shown in Schemes 28-37. Analogs 45a and 45b contain two identical aryl rings separated by an unsaturated 3-carbon spacer having a single carbonyl and were designed to test the importance of the length of the spacer. Analog 45a was prepared as shown in Scheme 28 following the procedures described by Masuda (Masuda et al., Phytochemistry 32(6), 1557-1560 (1993)) and by Kohler and Chadwell (Kohler et al., Org. Synth., Coll. Vol. 178-80 (1932)). 4-Hydroxy-3-methoxyacetophenone (44a) was reacted with potassium carbonate and chloromethyl methyl ether (18) in a substitution reaction to give compound 44j. The formation of the product was verified by proton NMR by the appearance of signals at 3.33 ppm and 5.12 ppm for the protons of the protecting group. Compound 1j, prepared as shown in Scheme 12, was reacted with compound 44j and barium hydroxide in an aldol reaction to give compound 45j. The formation of the product was verified by proton NMR by the appearance of a pair of doublets in the aromatic region with J values of 15.5 Hz for the alkene protons on the spacer. Also observed in the proton NMR was the loss of a signal at 2.38 ppm for the methyl protons of the starting acetophenone (44j) and the loss of a signal at 9.75 ppm for the aldehyde proton of the starting benzaldehyde (1j). Compound 45j was then reacted with a catalytic amount of concentrated hydrochloric acid to give the phenol, analog 45a. The formation of the product was verified by proton NMR by the appearance of signals at 6.00 ppm and 6.19 ppm for the phenolic protons. Also observed in the proton NMR was the loss of signals at 3.50 ppm, 5.25 ppm
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[C:7]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[H][H]>C(O)C.[C].[Pd]>[OH:6][CH:3]([CH2:4][CH3:5])[CH2:2][NH:1][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C1CCCCC1
Reactant: [H][H]
Reactant: CCC(O)CN
Agent: [Pd]
Solvent: CCO
Product: CCC(O)CNC1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.8 %

Procedure:
1-Amino-2-butanol (120 g) is added dropwise into a solution of cyclohexanone (132 g) in ethanol (600 ml) at room temperature, and the mixture is stirred at room temperature for one day. To the reaction solution is added 10% palladium-carbon (6 g), and the mixture is subjected to catalytic hydrogenation at 60° C. under 4 atms of hydrogen gas. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure, and distilled under reduced pressure to give N-(2-hydroxybutyl)-N-cyclohexylamine (223 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13](=O)[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([F:12])[F:11].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([F:12])[F:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OCC(F)F)c(Cl)c1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)F)c(Cl)c1
Yield: 62 %

Procedure:
The title compound is prepared in 62% yield (780 mg, clear colorless oil) from 1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethanone (860 mg, 3.7 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28](C(OCC)=O)=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:37].[CH3:38][Mg]I.[Cl-].[NH4+].[O:43]1[CH2:47][CH2:46]CC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([C:47]([OH:43])([CH3:46])[CH3:38])=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:37]
Reactant: C[Mg]I
Reactant: CCOC(=O)c1cc(C)c2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCCc5ccccc54)ccc3Cl)c2n1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1cc(C(C)(C)O)nc2c1[nH]c(=O)n2-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[2-chloro-5-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-ylsulfonyl)-phenyl]-5-ethoxycarbonyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (30 mg) in tetrahydrofuran (3 mL) was added methylmagnesium iodide (3 mol/L diethyl ether solution, 0.061 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=2/3) to give the title compound (4 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])=[O:5].[C:22](#[N:25])[CH:23]=[CH2:24].Cl>C(OCC)C>[ClH:21].[C:22]([CH2:23][CH2:24][N:2]([CH3:1])[CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])=[O:5])#[N:25]
Reactant: CNCC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: C=CC#N
Agent: Cl
Solvent: CCOCC
Product: CN(CCC#N)CC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.0 g of 2-(methylamino-acetamido)-5-chloro-benzophenone were dissolved in 30 mls. of anhydrous alcohol and then mixed with 2.0 g of freshly distilled acrylonitrile. The mixture was stirred for 2 hours at room temperature and then heated under reflux for a further 8 hours. After being allowed to stand overnight at room temperature a further 2.0 g of freshly distilled acrylonitrile was added and the mixture heated under reflux with stirring for a further 4 hours. At this point a sample showed in a thin-layer chromatogram a uniform point which differed from that of the initial product. The turbid solution was filtered and concentrated in vacuo (approx. 0.1 mm Hg), 3.0 g of a colourless oil being obtained. This residue was dissolved in anhydrous diethyl ether. After passing dry hydrogen chloride into this solution, 3.6 g of 2-(5-cyano-3-methyl-3-aza-pentanamido)-5-chloro-benzophenone hydrochloride were obtained, corresponding to 92% of theory. The product had a melting point of 166°-168°. The RF value in a thin-layer chromatogram in methanol as flow medium was 0.85.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](Br)=[CH:7][CH:6]=1)=[O:4].[CH2:16]([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH2:18]>C1(C)C=CC=CC=1.CCOCC.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>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:18][CH:17]=[CH2:16])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(Br)c2ccccc12
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CCc1ccc(C(=O)OC)c2ccccc12
Temperature: 120 °C
Yield: 89 %

Procedure:
To a solution of 4-bromo-naphthalene-1-carboxylic acid methyl ester (2.0 g, 7.9 mmol) in toluene (20 mL) was added allyltributyltin (2.7 mL), tetrakis(triphenylphosphine)palladium(0) (183 mg, 0.16 mmol) and 2 crystals of BHT. The system was purged under vacuum and nitrogen and allowed to heat to 120° C. under N2 for 4 h. TLC analysis (silica, 1:1 ethyl acetate-hexanes) showed the reaction to be completed with only one new fluorescent spot present. The mixture was diluted with ether, washed with H2O, 10% HCl, and then saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 9:1 hexanes-ether) to give (1.6 g, 89%) 4-allylnaphthalene-1-carboxylic acid methyl ester as a colorless liquid. MS m/z 227.1 (M+1). 1H NMR (400 mHz) CDCl3 8.95(d 1H), 8.11(d, 1H), 8.08(d, 1H), 7.58(m, 2H), 7.37(d, 1H), 6.09(m, 1H), 5.11(m, 2H), 3.99(s, 3H), 3.88(d, 2H).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[CH:10][N:9]=1.[CH2:19]([C:21]1[CH:22]=[C:23]([CH3:33])[C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:25][CH:26]=1)[CH3:20]>>[O:18]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[N:9]=[CH:10][C:11]([C:12]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[C:23]([CH3:33])=[CH:22][C:21]([CH2:19][CH3:20])=[CH:26][N:25]=3)[CH2:28][CH2:29]2)=[O:14])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(CN2CCCS2(=O)=O)nc1
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)nc3)CC2)c(C)c1
Yield: 46.3 %

Procedure:
Using methyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)nicotinate (107 mg) described in Preparation Example 45 and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (81 mg) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Example 109, [6-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)pyridin-3-yl][4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (81 mg) was obtained. The obtained [6-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)pyridin-3-yl][4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (81 mg) was dissolved in ethyl acetate/methanol, 2N hydrogen chloride/ethanol solution was added, and the solvent was evaporated under reduced pressure. The obtained residue was suspension washed with diisopropyl ether to give the title compound (83 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2Cl)=[O:8])[N:5]=[C:4]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.N[C:25]1N(C(NC2C=CC=C(Cl)C=2)=O)N=C(NC2C=NC=CC=2)N=1.NC1N=C(NC2C=NC=CC=2)N(C(NC2C=CC=CC=2Cl)=O)N=1.NC1N(C(NC2C=CC(C)=CC=2)=O)N=C(NC2C=NC=CC=2)N=1>>[NH2:1][C:2]1[N:6]([C:7]([NH:9][CH2:10][C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:25]=2)=[O:8])[N:5]=[C:4]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1
Reactant: Nc1nc(Nc2cccnc2)nn1C(=O)Nc1cccc(Cl)c1
Reactant: Nc1nc(Nc2cccnc2)nn1C(=O)Nc1ccccc1Cl
Agent: Cc1ccc(NC(=O)n2nc(Nc3cccnc3)nc2N)cc1
Agent: Nc1nc(Nc2cccnc2)n(C(=O)Nc2ccccc2Cl)n1
Product: Nc1nc(Nc2cccnc2)nn1C(=O)NCc1ccccc1

Procedure:
5-amino-N-(2-chlorophenyl)-3-(pyridin-3-ylamino)-1H-1,2,4-triazole-1-carboxamide; 5-amino-N-(3-chlorophenyl)-3-(pyridin-3-ylamino)-1H-1,2,4-triazole-1-carboxamide; 3-amino-N-(2-chlorophenyl)-5-(pyridin-3-ylamino)-1H-1,2,4-triazole-1-carboxamide; and 5-amino-N-(4-methylphenyl)-3-(pyridin-3-ylamino)-1H-1,2,4-triazole-1-carboxamide.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([Cl:11])[C:8]2[N:7]([CH3:12])[C:6]3[CH2:13][CH:14]4[NH:18][CH:17]([C:5]=3[C:4]=2[C:3]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]4.[C:26]1([S:32](C2C=CC=CC=2)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([S:32]([C:2]2[CH:10]=[C:9]([Cl:11])[C:8]3[N:7]([CH3:12])[C:6]4[CH2:13][CH:14]5[NH:18][CH:17]([C:5]=4[C:4]=3[C:3]=2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]5)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(c1ccccc1)c1ccccc1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)cc(Cl)c31)C1CCC(C2)N1
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccccc4)cc(Cl)c31)C1CCC(C2)N1
Yield: 63 %

Procedure:
The product of step E was converted to the phenylsulfone derivative following the procedure of Example 71, step D. The crude product was purified by flash column chromatography (SiO2, 75:25 hexanes/ethyl acetate) to give tert-butyl 2-phenylsulfonyl-4-chloro-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (165 mg, 63%) as an off-white solid: 1H NMR (CDCl3, 300 MHz): δ 8.02-8.07 (m, 1H), 7.91-7.97 (m, 2H), 7.42-7.62 (m, 4H), 5.10-5.32 (m, 1H), 4.55-4.80 (m, 1H), 3.94 (s, 3H), 3.15-3.48 (m, 1H), 2.47 (d, J=16.2 Hz, 1H), 2.10-2.40 (m, 2H), 1.85-1.96 (m, 1H), 1.52-1.65 (m, 1H), 1.38 (br s, 9H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]([F:22])([F:21])[F:20])=[N:6][CH:7]=1.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(N)CN>O1CCOCC1.[Cu]I.CCOC(C)=O>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:30][C:2]2[CH:7]=[N:6][C:5]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=4[N:10]=[C:9]3[C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(Br)cn1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: NCCN
Solvent: C1COCCO1
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2ccc(F)cc2)cn1

Procedure:
Into a 50 mL 3-necked round bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole (iv) (100 mg, 0.27 mmol) in 1,4-dioxane (30 mL). To this was added 4-fluorobenzamide (80 mg, 0.58 mmol), K3PO4 (250 mg, 1.18 mmol), CuI (10 mg, 0.05 mmol) and ethane-1,2-diamine (EDA) (5 mg, 0.08 mmol). The resulting solution was stirred at reflux overnight. The reaction progress was monitored by TLC (EtOAc/PE=1:2). When the reaction had gone to completion, the mixture was filtered to remove the solid components, then concentrated under vacuum. The residue was dissolved in EtOAc, then washed with water. The organic layer was dried over Na2SO4, then concentrated to yield a crude product. The crude product was purified by eluting through a column with a 1:6 EtOAc/PE solvent system. This resulted in 60 mg (52%) of 4-fluoro-N-(5-(5-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)pyrazin-2-yl)benzamide (Compound 86) as a white solid.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Na].[Cl:8][C:9]1[C:10]([NH:15][NH2:16])=[N:11][CH:12]=[CH:13][CH:14]=1.[C:17](OC)(=[O:24])/[CH:18]=[CH:19]\[C:20](OC)=[O:21].C(O)(=O)C>O>[Cl:8][C:9]1[C:10]([N:15]2[CH:19]([C:20]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:21])[CH2:18][C:17](=[O:24])[NH:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)/C=C\C(=O)OC
Reactant: CCCCCO
Reactant: NNc1ncccc1Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Temperature: 100 °C
Yield: 42 %

Procedure:
To a three-necked flask, pentan-1-ol (150 mL) was added. And the sodium (3.0 g, 0.13 mol) was added partially. The reaction mixture was heated to reflux for 30 minutes at 100° C. When the sodium reacted completely, the mixture was cooled to 60° C. Then 3-chloro-2-hydrazinylpyridine (12.75 g, 98%, 0.09 mol) were added and reacted for 30 minutes. The dimethyl maleate (12.50 g, 0.11 mol) was added dropwise. The reaction mixture was heated to reflux for 10 minutes. After cooled to 65° C., the reaction mixture was neutralized with glacial acetic acid (13.04 g, 0.23 mol) and diluted with water (300 mL). After cooled to room temperature, solid is separated out to be filtered and, washed with 40% aqueous solution of ethanol (3×50 mL) and dried to give pentyl 2-(3-chloro-2-pyridinyl)-5-oxopyrazolidine-3-carboxylate (12.00 g) as a orange solid in 42% yield. HPLC area normalization method content is 95% (Analytical condition: chromatographic column: ZORBAX Eclipse XDB-C8 4.6×150 mm 5 μm, mobile phase:the ratio of acetonitrile to water is 70:30).
Reaction SMILES: [C:1]([CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[O:17]2)[CH2:13][CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O1CCCC1.[BH4-].[Na+]>O>[OH:8][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][C:14]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[O:17]2)[CH2:15][CH2:16]1
Reactant: O=C(CCN1CCC2(CC1)OC(=O)c1ccccc12)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C1OC2(CCN(CCC(O)c3ccccc3)CC2)c2ccccc21

Procedure:
A solution of 2.5 g. of 1'-(2-benzoylethyl)-1,3-dihydrospiro[isobenzofuran-1,4'-piperidine]-3-one, 30 ml. of methanol, 10 ml. of tetrahydrofuran, and 0.35 g. of sodium borohydride is stirred for 4 hours, diluted with water, and extracted with chloroform. The chloroform solution is dried over sodium sulfate and concentrated to a solid. Recrystallization from benzene yields colorless crystals, m.p. 144°-146°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](O)=[O:27].C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)(Cl)Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:19]([NH:20][C:26]([C:22]2[O:21][CH:25]=[CH:24][CH:23]=2)=[O:27])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: O=C(O)c1ccco1
Reactant: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Product: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)c3ccco3)nc2n1
Temperature: 40 °C

Procedure:
A suspension of 3.0 g of 6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-amine and 1.8 g of 2-furoic acid in 50 ml of chloroform is boiled on a steam bath until the distilling vapors reach a temperature of 61° C. The mixture is cooled to about 40° C. and 2.6 g of carbonyldiimidazole is added cautiously. Gas is evolved. When gas evolution has ceased, the resulting solution is heated at reflux for 30 hours. The cooled reaction mixture is chromatographed directly on a column of 150 g of silica gel. The crude product is eluted with a 99/1 chloroform/methanol mixture. This is purified by trituration with ether and recrystallization of the resulting solid from a chloroform/ether mixture. N-[6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-yl]-2-furancarboxamide is obtained as yellow crystals, mp 228°-230.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:31])[C:22]1[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:24](N)=[O:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:24](=[O:25])[C:23]4[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]3=[O:31])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2c[nH]cn2)cc1
Reactant: NC(=O)c1ccccc1C(=O)NCCCCBr
Agent: [H-]
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)N1CCCCn1cnc(-c2ccc(Cl)cc2)c1
Yield: 37.4 %

Procedure:
Using the procedure of Stage A of Example 1, 12.2 g of the product of Stage A, 4.96 g of sodium hydride and 23.83 g of N-4-bromobutyl-phthalamide were reacted to obtain 9.7 g of the expected product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([P:14]([O:19]CC)(=[O:18])[O:15]CC)[P:6]([O:11]CC)(=[O:10])[O:7]CC.[N+]([O-])(O)=O.C[C:27]1C=C(C)[N:29](C(N)=N)[N:28]=1>CN(C=O)C>[NH2:29][N:28]=[CH:27][NH:1][CH2:2][CH2:3][CH2:4][CH:5]([P:14]([OH:19])(=[O:18])[OH:15])[P:6]([OH:11])(=[O:10])[OH:7]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: CCOP(=O)(OCC)C(CCCN)P(=O)(OCC)OCC
Solvent: CN(C)C=O
Solvent: O=[N+]([O-])O
Product: NN=CNCCCC(P(=O)(O)O)P(=O)(O)O

Procedure:
A solution of 0.69 g (2 mmol) of tetraethyl 4-aminobutane-1,1-bisphosphonate (according to DE 3,225,469 A1, 01.05.1984) and 0.402 g (2 mmol) of 3,5-dimethylpyrazole-1-carboxamidine nitrate in 10 ml of DMF is heated at boiling point for 3 hours. The DMF is then distilled off in vacuo and the residue is dissolved in a little water. After extraction with diethyl ether and ethyl acetate (the organic extracts are discarded), the aqueous phase is distilled in vacuo. A dark oil (0.89 g) remains. This is heated at boiling point for 8 hours in 15 ml of concentrated hydrochloric acid. The excess hydrochloric acid is distilled off and the residue is treated with a little water, DMF and acetone. The precipitate is filtered off with suction and dried in vacuo.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.CN(C)[CH:16]=[O:17].[BH4-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:16][OH:17])=[N:8][CH:9]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: OCc1ccc(F)cn1
Temperature: 25 °C

Procedure:
Add butyllithium (10.9 mL, 27.22 mmol, 2.5 M solution in hexanes) to a −78° C. solution of 2-bromo-5-fluoro-pyridine (3.99 g, 22.68 mmol) in toluene (200 mL). Stir the reaction at −78° C. for 90 min and then add N,N-dimethylformamide (2.3 mL, 29.71 mmol) via syringe. Stir the reaction for an additional 2 h at −78° C. and then add sodium borohydride (1.72 g, 45.36 mmol) and allow the reaction to warm to room temperature over a 12 h period. Quench the reaction with saturated aqueous sodium bicarbonate (20 mL) and dilute with ethyl acetate (100 mL). Separate the organic phase and dry (magnesium sulfate), filter and concentrate in vacuo to give a yellow oil. Purify the oil by column chromatography (silica gel; 10% to 50% ethyl acetate in hexanes) to give 1.30 g (45%) as a clear colorless oil. 1H NMR (300 MHz, CDCl3): δ 8.41s, 1H), 7.46-7.37 (m, 1H), 7.32-7.27 (m, 1H), 4.75 (s, 2H), 3.64 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.Br[CH2:14][CH2:15][OH:16].[OH-].[K+]>CN(C)C=O.O>[OH:16][CH2:15][CH2:14][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: OCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: OCCOc1ccc2cc(Br)ccc2c1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To a solution of 6-bromo-2-naphthol (15.1 g, 67.7 mmol), 2-bromoethanol (10.11 g, 80.9 mmol) in N,N-dimethylformamide (60 ml) was added a solution of KOH (5.41 g, 81.9 mmol) and KI (0.37 g, 2.20 mmol) in water (10 ml). Upon stirring at 85° C. for 4 hours, the reaction mixture was filtered. The filtrate was shaken with diethyl ether (400 ml) and water (400 ml). The organic layer was washed with 2% KOH (100 ml water). The solvent was evaporated off to obtain crude product. Recrystallization from a mixed solvent of methanol (20 ml) and water (200 ml) yielded (h) in 10.0 g (55%). Proton-NMR spectral data (CDCl3), δ (ppm): 2.16 (t, HOCH2, 1H), 4.10 (m, HOCH2CH2, 2H), 4.22 (t, ArOCH2CH2,2H), 7.10-7.95 (m, aromatic, 6H).