Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([C:20](O)=[O:21])=[CH:18][C:17]([O:23][CH2:24][C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])=[N:16]1.C(Cl)(=O)C(Cl)=O.CN(C)C=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:13])([F:12])[F:14])=[CH:4][C:3]=1[N:15]1[C:19]([CH2:20][OH:21])=[CH:18][C:17]([O:23][CH2:24][C:25]([F:30])([F:31])[C:26]([F:27])([F:28])[F:29])=[N:16]1
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2C(=O)O)cc1SCC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2CO)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
3.97 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole-5-carboxylic acid was dissolved in 60 mL of dichloromethane, and 0.93 mL of oxalyl dichloride and N,N-dimethylformamide in a catalytic amount were added, followed by stirring at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure, the resulting product was dissolved in 50 mL of tetrahydrofuran, and 1.56 g of sodium borohydride was added, followed by cooling to −20° C. 20 mL of water was slowly dropwise added, and then, stirring was carried out for 12 hours while the temperature was slowly increased to room temperature. Then, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 3.01 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-hydroxymethyl-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[ClH:29].C(O)C>CO.CC(C)=O>[ClH:29].[OH:1][CH:2]([CH2:16][N:26]1[CH2:27][CH2:28][N:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][CH2:25]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2
Reactant: O=C1CCc2c(cccc2OCC2CO2)N1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: CC(C)=O
Product: O=C1CCc2c(cccc2OCC(O)CN2CCN(c3ccccc3)CC2)N1

Procedure:
4.4 grams of 5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril and 3.4 g of 4-phenylpiperazine are dispersed in 60 ml of methanol and reacted at 50°-60° C. for 3 hours. After the reaction is completed, the reaction mixture is concentrated under a reduced pressure. To the residue thus obtained are added 5 ml of concentrated hydrochloric acid and 30 ml of ethanol to dissolve the residue uniformly and further 200 ml of acetone are added. The crystals precipitated are collected by filtration and dried. Recrystallization from water to obtain 6.5 g of 5-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydro carbostyril monohydrochloride in the form of colorless needle-like crystals with a melting point of 239°-241° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].O=[C:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:15]#[N:16].[Cl-].[Ca+2].[Cl-]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:15]#[N:16])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: N#CC1CCCC1=O
Agent: [Ca+2]
Agent: [Cl-]
Product: N#CC1=C(Nc2cccc(F)c2)CCC1

Procedure:
3-Fluoro-aniline (Aldrich Chemicals) (4.6 g, 41 mmol), cyano-ketone (Example 11) (4.4 g, 40 mmol), calcium chloride (5.0 g, 45 mmol) and T.H.F. (60 ml) were heated under reflux for 17 hours. After being allowed to cool, the mixture was filtered and the solvent evaporated. Kugelrohr distillation (125° C., 0.02 mm Hg) gave the product as a pale yellow powder.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.O.[OH-].[Li+]>C1COCC1.O.CO.Cl>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (1.4 g, 4.2 mmol) (538 mg, 1.1 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (94 mg, 2.2 mmol) in water (5 mL) and methanol (1 mL) added and the resulting mixture stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (25%, 3 drops) and methanol (2 drops) added. A gum began to form and the mixture was cooled at 0° C. for 1.5 h and then the aqueous layer decanted off. Trituration with diethylether and hexane afforded the title compound (1.1 g, 78%) which was obtained as a white solid. MS: m/e=327.3 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([CH:18]([Br:20])[Br:19])[C:15]([Cl:21])=[CH:14][C:13]=2[Cl:22])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[Br:23]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[Br:23][CH2:11][N:5]1[C:6]([O:7][CH:8]([F:9])[F:10])=[C:2]([Cl:1])[C:3]([C:12]2[CH:17]=[C:16]([CH:18]([Br:20])[Br:19])[C:15]([Cl:21])=[CH:14][C:13]=2[Cl:22])=[N:4]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1nc(-c2cc(C(Br)Br)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)Oc1c(Cl)c(-c2cc(C(Br)Br)c(Cl)cc2Cl)nn1CBr
Yield: 28.8 %

Procedure:
A solution of 6 g (12 mmol) of 4-chloro-3-(2,4-dichloro-5-(di-bromomethyl)phenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole and 6.4 g (36 mmol) of N-bromosuccinimide in 800 ml of tetrachloromethane was irradiated for 2 hours with a 150 W high-pressure mercury lamp and a UV lamp. The solids were then removed by filtration, and the filtrate was concentrated. Silica gel chromatography of the residue (eluent: hexane/ethyl acetate=4:1) gave 2 g of the target product. 1H-NMR (250 MHz, in CDCl3): δ [ppm]=5.87(s,2H); 6.82(t,1H); 7.03(s,1H); 7.52(s,1H); 8.08(s,1H).
Reaction SMILES: C[C:2]1[N:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]1[N:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[CH:21][CH:20]=2)=[CH:15][N:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[F:28][CH:26]([F:27])[O:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:17]=[N:18][C:13]([NH:11][C:8]3[CH:9]=[N:10][CH:2]=[C:3]([CH:7]=3)[C:4]([OH:6])=[O:5])=[N:14][CH:15]=2)=[CH:24][CH:23]=1
Reactant: FC(F)Oc1ccc(-c2cnc(Cl)nc2)cc1
Reactant: Cc1ncc(N)cc1C(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: O=C(O)c1cncc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Temperature: 100 °C

Procedure:
A vial is charged with methyl 5-aminonicotinic acid 18 (1.45 mmol), 2-chloro-5-(4-(difluoromethoxy)phenyl)pyrimidine 17 (1.45 mmol), Pd(OAc)2 (0.22 mmol), xanthphos (0.22 mmol), Cs2CO3 (1.45 mmol) and anhydrous 1,4-dioxane (5 mL). The vial is evacuated and refilled with N2 twice and the mixture is heated in an oil bath at 100° C. for 3 h. The vial is cooled down to it and the reaction mixture is diluted with water (20 mL) and pH neutralized with 10% Na2CO3. The resulting suspension is extracted with DCM:IPA=3:1 (3×50 mL). The organic layer is washed once with brine and dried over Na2SO4. The solvent is removed in vacuum and the orange crude is purified by preparative HPLC (MeCN gradient 20-70%) to afford 5 5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)nicotinic acid 19. MS (m/z) (M+1)+: 359.1.
Reaction SMILES: C([N:20]([CH2:34][CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[O:45][C:46]3[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=3[N:48]=2)=[CH:40][CH:39]=1)[CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.[ClH:56]>C(Cl)Cl.CCO.CO>[ClH:56].[O:45]1[C:46]2[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=2[N:48]=[C:44]1[C:41]1[CH:42]=[CH:43][C:38]([CH2:37][O:36][CH2:35][CH2:34][NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:39][CH:40]=1
Reactant: c1ccc(CCCCOCCN(CCOCc2ccc(-c3nc4ccccc4o3)cc2)C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: c1ccc(CCCCOCCNCCOCc2ccc(-c3nc4ccccc4o3)cc2)cc1

Procedure:
N-trityl-N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-(4-phenylbutoxy)ethanamine (600 mg) is dissolved in a solution of CH2Cl2 (10 ml) and EtOH (10 ml) and treated with a solution of EtOH/HCl until acidic by pH paper. The solution is concentrated in vacuo, then purified by column chromatography using 5% MeOH/CH2Cl2. The residue is isolated, dissolved in methanol and acidified with acidic methanol. The solution is concentrated to obtain N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-(4-phenylbutoxy)ethanamine hydrochloride (m.p. 121°-125° C.).
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:10]=[C:11]2[CH:17]=[CH:16][O:15][C:12]2=[CH:13][N:14]=1)[CH2:3]C(OCC)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:2]([C:9]1[CH:10]=[C:11]2[CH:17]=[CH:16][O:15][C:12]2=[CH:13][N:14]=1)(=[O:1])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cc2ccoc2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2ccoc2cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
Ethyl β-oxo-5-furo[2,3-c]pyridinepropionate (583 mg, 2.5 mmol) obtained in Example 7 was dissolved in 10 mL of toluene, and 3 g of 10% sodium hydroxide aqueous solution was added with stirring. After addition, the reaction mixture was heated to 60° C., and a reaction was carried out for 8 hours with stirring. It was then cooled to room temperature, the organic layer was separated, the aqueous layer was extracted twice with 5 mL of methylene chloride, and the combined organic layer was dried with anhydrous magnesium sulfate and then concentrated in a rotary evaporator. The resulting solids were recrystallized from a mixed solvent of toluene-hexane, giving 205 mg (51% yield) of 5-acetylfuro[2,3-c]pyridine in a purity of 99% by HPLC.
Reaction SMILES: [CH:1]1([C:4]([N:6]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=O)=[CH:14][CH:13]=2)[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+].Cl.Cl.Cl.[CH2:28]([O:30][C:31]1[CH:32]=[C:33]([CH:50]=[CH:51][CH:52]=1)[CH2:34][N:35]1[C:39]2=[N:40][CH:41]=[N:42][C:43]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[C:38]2[CH:37]=[N:36]1)[CH3:29].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>C(O)C.C(Cl)(Cl)Cl.C(N(CC)CC)C.C(Cl)Cl>[CH2:28]([O:30][C:31]1[CH:32]=[C:33]([CH:50]=[CH:51][CH:52]=1)[CH2:34][N:35]1[C:39]2=[N:40][CH:41]=[N:42][C:43]([N:44]3[CH2:45][CH2:46][N:47]([C:16](=[O:18])[C:15]4[CH:14]=[CH:13][C:12]([N:6]([C:4]([CH:1]5[CH2:2][CH2:3]5)=[O:5])[CH2:7][CH2:8][N:9]([CH3:10])[CH3:11])=[CH:22][CH:21]=4)[CH2:48][CH2:49]3)=[C:38]2[CH:37]=[N:36]1)[CH3:29]
Reactant: CCOc1cccc(Cn2ncc3c(N4CCNCC4)ncnc32)c1
Reactant: CCOC(=O)c1ccc(N(CCN(C)C)C(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOc1cccc(Cn2ncc3c(N4CCN(C(=O)c5ccc(N(CCN(C)C)C(=O)C6CC6)cc5)CC4)ncnc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a solution of ethyl 4-[N-(cyclopropylcarbonyl)-N-[2-(dimethylamino)ethyl]-amino]benzoate (106 mg; compound obtained in Reference Example 11) in ethanol (3 mL) is added 2N sodium hydroxide solution (21 μL) and the mixture is stirred at room temperature overnight. To the reaction mixture is added 2N HCl (42 μL) and the mixture is concentrated to give a crude carboxylic acid compound. To the compound is added successively methylene chloride (2 mL), 1-(3-ethoxybenzyl)-4-piperazin-1-yl-1H-pyrazolo[3,4-d]pyrimidine dihydrochloride (105 mg, compound described in WO02/79189), 1-hydroxybenzotriazole (51.7 mg), triethylamine (124.5 μL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (73.4 mg) and the mixture is stirred at room temperature for 19 hours. The reaction mixture is diluted with chloroform (5 mL) and thereto is added a saturated sodium hydrogencarbonate solution (10 mL). After stirring, the organic layer is separated and concentrated. The resultant crude product is purified by flash column chromatography on NH-silica gel (Chromatorex NH silica gel; Fuji Silicia Chemical Ltd., Solvent; ethyl acetate:chloroform=1:0→0:1) to give 1-(3-ethoxybenzyl)-4-[4-[4-[N-(cyclopropyl-carbonyl)-N-[2-(dimethylamino)ethyl]amino]benzoyl]piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine (127 mg, yield; 84%) as an amorphous powder. MS (APCI) m/z: 597 [M+H]+
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([S:16]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:5]=1[F:24])(=O)[CH3:2].II.[NH2:27][C:28]([NH2:30])=[S:29]>CCO>[NH2:30][C:28]1[S:29][CH:2]=[C:1]([C:4]2[CH:9]=[CH:8][C:7]([C:10]3[C:11]([S:16]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:6][C:5]=2[F:24])[N:27]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Agent: II
Solvent: CCO
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2csc(N)n2)c(F)c1
Temperature: 25 °C

Procedure:
A solution of 4′-acetyl-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide (100 mg, 0.29 mmol), iodine (94.6 mg, 0.37 mmol), thiourea (44.01, 0.57 mmol) in EtOH (1.1 mL) was heated at 100 Celcius for 48 h. The reaction mixture was cooled to rt and the precipitate collected by filtration thus providing the title compound. MS (ESI): mass calcd. for C19H20FN3O2S2, 405.10; m/z found, 406.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.71 (s, 2H), 8.19 (d, J=7.9, 1H), 7.94 (m, 1H), 7.59 (m, 1H), 7.54 (dd, J=11.6, 3.8, 1H), 7.44 (dd, J=12.1, 1.6, 1H), 7.38 (dd, J=8.1, 1.7, 1H), 7.33 (dd, J=7.5, 1.3, 1H), 6.96 (d, J=1.3, 1H), 1.08 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:5])C.[H-].[Na+].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23](OS(C)(=O)=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:8]2[CH:9]=[N:10][C:6]([C:4]([O:3][CH3:1])=[O:5])=[N:7]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CCOC(=O)c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ncn(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1H-[1,2,4]triazole-3-carboxylic acid ethyl ester (1.05 g, 8.23 mmol) in dimethylformamide (50 mL) was added sodium hydride (60%, 0.395 g, 9.88 mmol). The solution was stirred at room temperature for 20 minutes followed by 1 hour at 70° C. 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.3 g, 8.23 mmol) was then added in a single portion and heated at 70° C. for 40 hours. The solution was cooled to 0° C. and the salt precipitate was removed by filtration. The filtrate was diluted with dichloromethane and washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatograph on silica gel with Hexanes and EtOAc to afford the desired product. 1H NMR (CDCl3): δ 8.18 (1H, s), 4.40 (1H, m), 4.22 (2H, m), 3.96 (3H, s), 2.82 (2H, m), 2.12 (2H, m), 1.94 (2H, m), 1.41 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)(=[O:15])=[O:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Sn](Cl)Cl>Cl>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:9]1[CH:10]=[CH:11][C:2]([CH3:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2)(=[O:15])=[O:14]
Reactant: Cc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c2ncccc12
Agent: Cl
Agent: Cl[Sn]Cl
Product: Cc1ccc(NS(=O)(=O)c2ccccc2N)c2ncccc12
Yield: 56.7 %

Procedure:
In a similar fashion using route 1 general procedure 4, N-(5-methylquinolin-8-yl)-2-nitrobenzenesulfonamide (Intermediate 159) (830 mg, 2.42 mmol), tin (II) chloride (1.83 g, 9.68 mmol) and 6 N HCl (3 drops) gave the title compound (430 mg, 58%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])[C:9](=[O:21])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH3:12])[C:5]2=[CH:4][N:3]=1.[NH2:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38][O:39][C:40](=[O:42])[CH3:41])[CH:34]=[CH:35][CH:36]=1>>[C:25]([C:24]1[CH:23]=[C:22]([N:8]2[C:6]3[N:7]=[C:2]([NH:30][C:31]4[CH:32]=[C:33]([CH2:37][CH2:38][O:39][C:40](=[O:42])[CH3:41])[CH:34]=[CH:35][CH:36]=4)[N:3]=[CH:4][C:5]=3[CH:11]([CH3:12])[N:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[C:9]2=[O:21])[CH:29]=[CH:28][CH:27]=1)#[N:26]
Reactant: CC(=O)OCCc1cccc(N)c1
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Cl)ncc3C2C)cc1
Product: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCOC(C)=O)c4)ncc3C2C)cc1
Temperature: 110 °C

Procedure:
A mixture of (±)-3-[7-chloro-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile (1.00 g; 2.42 mmol) (from Example 2 supra) and acetic acid 2-(3-amino-phenyl)-ethyl ester (2.03 g; 11.3 mmol) (from Example 3b supra) was heated in an oil bath at 110° C. for 1.5 hours. Upon cooling, the mixture was triturated with hexanes containing a small volume of ethyl acetate. The supernatant was decanted away and the residue was purified, in two runs, by flash chromatography (Biotage 40M; 50:50 to 70:30 ethyl acetate-hexanes gradient). The purified material was crystallized from ethyl acetate-hexanes to give (±)-acetic acid 2-{3-[8-(3-cyano-phenyl)-6-(4-methoxy-phenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydro-pyrimido[4,5-d]pyrimidin-2-ylamino]-phenyl}-ethyl ester as a white solid. (1.03 g; 77.5%). Melting Point: 170–172° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:20]([C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29]Br)[CH2:25][CH2:24]1)[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:20]([C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[N:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][N:9]=3)=[CH:6][CH:7]=2)[CH2:25][CH2:24]1)[CH2:21][CH3:22]
Reactant: CCCCCCc1cnc(-c2ccc(O)cc2)cn1
Reactant: CCC[C@H]1CC[C@H](CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCc1cnc(-c2ccc(OC[C@H]3CC[C@H](CCC)CC3)cc2)cn1

Procedure:
A mixture of 11 g of 2-p-hydroxyphenyl-5-n-hexylpyrazine, 7.8 g of trans-4-n-propyl-1-bromomethylcyclohexane, 8.6 g of potassium carbonate and 50 ml of dimethylformamide is heated at 90° for 10 hours. Customary working up gives 4-(5-n-hexylpyrazin-2-yl)-phenyl trans-4-n-propylcyclohexylmethyl ether.
Reaction SMILES: [N:1]([C:4]1[CH:15]=[CH:14][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:17]([CH2:24][CH2:25][CH3:26])[CH2:18][C:19]([O:21]CC)=[O:20].[O-]CC.[Na+].O>C(O)C>[CH2:24]([C:17]1[N:1]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])=[CH:14][CH:15]=2)[N:2]=[N:3][C:18]=1[C:19]([OH:21])=[O:20])[CH2:25][CH3:26]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: CCCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
4-Azido-N-propylbenzamide (2.0 g) obtained in Example 55a) and ethyl 3-oxohexanoate (1.09 ml, 6.50 mmol, 1.25 eq.) were dissolved in ethanol (20 ml), sodium ethoxide (491 mg, 6.50 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 60° C. for 14 hr. Water (20 ml) was added to the reaction mixture. After concentration, the mixture was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-yellow powder (1.58 g, 4.99 mmol, 96.0%).
Reaction SMILES: Cl.[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25](/[C:27](=[N:31]/[O:32][CH3:33])/[C:28](O)=[O:29])[N:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[NH2:48][C@@H:49]1[C:82](=[O:83])[N:51]2[C:52]([C:66]([O:68][CH:69]([C:76]3[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=3)[C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)=[O:67])=[C:53]([CH2:56][S:57][C:58]3[CH:63]=[C:62]([CH3:64])[O:61][C:60](=[O:65])[CH:59]=3)[CH2:54][S:55][C@H:50]12>CN(C)C=O.N1C=CC=CC=1>[CH3:64][C:62]1[O:61][C:60](=[O:65])[CH:59]=[C:58]([S:57][CH2:56][C:53]2[CH2:54][S:55][C@@H:50]3[C@H:49]([NH:48][C:28](=[O:29])/[C:27](/[C:25]4[N:26]=[C:22]([NH:21][C:2]([C:3]5[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=5)([C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)[S:23][CH:24]=4)=[N:31]\[O:32][CH3:33])[C:82](=[O:83])[N:51]3[C:52]=2[C:66]([O:68][CH:69]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[O:67])[CH:63]=1
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](N)[C@H]3SC2)cc(=O)o1
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3cc(C)oc(=O)c3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
A stirred solution of 2-(2-tritylaminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid hydrochloride (470 mg) and N,N-diisopropylethylamine (0.34 ml) in dimethylformamide (4 ml) was cooled to -55° to -60° C. and methanesulphonyl chloride (0.075 ml) was added. The mixture was stirred at the same temperature for 0.5 h and then a solution of diphenymethyl 7β-amino-3-(6-methyl-2-oxo-2H-pyran-4-ylthiomethyl)ceph-3-em-4-carboxylate (450 mg) in dimethylformamide (4 ml) was added, followed by pyridine (0.071 ml). The mixture was stirred at 0° C. for 1.5 h and then partitioned between ethyl acetate and citric acid solution. The organic phase was then washed successively with water, sodium bicarbonate solution, water and brine. The solution was dried over magnesium sulphate and evaporated. The product (576 mg) was isolated by column chromatography of the residue using gradient elution (Kieselgel 1:1 hexane:ethyl acetate going to neat ethyl acetate). υmax (CHCl3) 3400, 1780, 1710 and 1680(s). δ(CDCl3) 2.18 (3H, s), 3.46 (1H, d, J 18.3Hz), 3.61 (1H, d, J 18.4Hz), 3.85 (1H, d, J 12.3Hz), 3.96 (1H, d, J 12.3Hz), 4.08 (3H, s), 5.08 (1H, d, J 4.9Hz), 5.69 (1H, s), 5.78 (1H, s), 5.96 (1H, dd, J 4.9 and 8.9Hz), 6.74 (1H, s), 6.81 (1H, d, J 8.8Hz), 6.97 (1H, s), 7.02 (1H, s), 7.2-7.5 (25H, m). [Mass spectrum: +ve ion (3NOBA, Na+) MNa+ 1196].