Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH2:28][CH2:29][OH:30].[CH2:31]([O:33][C:34](=[O:44])[C:35]1[CH:40]=[C:39](O)[C:38]([Br:42])=[C:37]([OH:43])[CH:36]=1)[CH3:32].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:31]([O:33][C:34](=[O:44])[C:35]1[CH:36]=[C:37]([OH:43])[C:38]([Br:42])=[C:39]([O:30][CH2:29][CH2:28][C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[Cl:20])[CH:40]=1)[CH3:32]
Reactant: OCCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1cc(O)c(Br)c(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(O)c(Br)c(OCCc2ccc(Cl)cc2Cl)c1
Yield: 96.2 %

Procedure:
To a solution of 17.8 g (67.9 mmol) of triphenylphosphane, 8.8 ml (67.9 mmol) of 2-(2,4-dichlorophenyl)ethanol and 16 g (61.3 mmol) of 4-bromo-3,5-dihydroxybenzoic acid ethyl ester in 25 ml of THF was added a solution of 10.6 ml (67.9 mmol) of DEAD in 40 ml of THF within 45 min between 6° and 18° C. After 16 h at room temperature the solvent was removed and the residue was stirred with cyclohexane/ethyl acetate (1/1) and filtered. The solid residue was stirred with cyclohexane and filtered. The remaining solid was separated by chromatography (cyclohexane/ethyl acetate (1/1)) to give 25.6 g (96%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[C:10]1[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:10]1[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: Fc1ccccc1S
Product: O=C(O)c1coc(Sc2ccccc2F)c1

Procedure:
Following the procedure of Example 13, o-fluorothiophenol (4.02 g., 31.4 mmoles) was reacted with 5-bromofuran-3-carboxylic acid. Isolation according to the procedure of Example 16 gave crude product as an oil. The product was chromatographed on silica gel with ethyl acetate-1/hexane-5/5% acetic acid as eluant. Combination of clean middle cuts, evaporation to dryness and recrystallization from methanol/water gave purified 5-(2-fluorophenylthio)furan-3-carboxylic acid (266 mg., m.p. 100°-103° C., m/e 238).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:5]2=[CH:4][CH:3]=1.C[Si]([C:45]#[CH:46])(C)C.C(N(CC)CC)C.[OH-].[Na+]>CN(C)C=O.CO.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:45]#[CH:46])[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: C#Cc1ccc(Oc2ccc(OC)cc2)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Yield: 61.2 %

Procedure:
In a manner similar to the method described in example 6a, racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(4-methoxy-phenoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.29 g, 0.42 mmol) was reacted with trimethylsilyl acetylene (0.41 g, 4.2 mmol), CuI (5 mg), triethylamine (1.76 mL, 12.7 mmol), and dichlorobis(triphenylphosphine) palladium (0) (23.4 mg, 0.034 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-(4-methoxy-phenoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.15 g, 61%)
Reaction SMILES: C(OC([N:8]1[CH2:13][C:12]([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:29][C:30]([C:32]2[N:33](COCC[Si](C)(C)C)[CH:34]=[C:35]([C:37]#[N:38])[N:36]=2)=[O:31])=[CH:11][CH2:10][CH2:9]1)=O)(C)(C)C.CCO.[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51]>C(Cl)Cl>[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51].[F:53][C:52]([F:55])([F:54])[C:50]([OH:56])=[O:51].[C:26]([N:23]1[CH2:22][CH2:21][CH:20]([C:18]2[CH:17]=[CH:16][C:15]([NH:29][C:30]([C:32]3[NH:33][CH:34]=[C:35]([C:37]#[N:38])[N:36]=3)=[O:31])=[C:14]([C:12]3[CH2:13][NH:8][CH2:9][CH2:10][CH:11]=3)[CH:19]=2)[CH2:25][CH2:24]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCN(C(=O)OC(C)(C)C)C3)c2)CC1
Solvent: ClCCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCNC3)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
A solution of 5-(5-(1-acetyl-piperidin-4-yl)-2-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared in the previous step, 0.40 g, 0.61 mmol) in CH2Cl2 (20 mL) and EtOH (0.4 mL) was treated with TFA (3 mL). The solution was stirred at room temperature for 0.5 h. The solvents were evaporated in vacuo, and the residue was immediately taken up in EtOH (25 mL) and stored at 5° C. for 11 h. The solution was concentrated in vacuo, and the residue was taken up in CH2Cl2 (20 mL) and EtOH (0.4 mL) then treated with TFA (6 mL). The reaction was stirred at room temperature for 2 h, and the solvents were evaporated in vacuo. Reverse phase HPLC (C-18 column) (10 to 80% acetonitrile in water with 0.1% TFA over 30 min) afforded the title compound (56.9 mg, 22%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 8.06 (s, 1H), 7.81 (d, 1H, J=8.4 Hz), 7.32 (d, 1H, J=8.4 Hz), 7.22 (s, 1H), 6.10-6.03 (m, 1H), 4.74-4.64 (m, 2H), 4.11-4.02 (m, 1H), 3.95 (s, 2H), 3.50-3.37 (m, 2H), 3.29-3.20 (m, 1H), 2.93-2.82 (m, 1H), 2.80-2.69 (m, 1H), 2.62-2.53 (m, 2H), 2.16 (s, 3H), 1.98-1.84 (m, 2H), 1.78-1.54 (m, 2H). LC-MS (ESI, m/z): Calcd. for C23H26N6O2 419.2 (M+H). found 419.2.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=N)CCCCC1.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>ClCCl.CN(C)C=O>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][C:20]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[O:21])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCCOc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: C1COCCN1
Agent: N=C=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCCOc1ccc2c(c1)CCN(C1CCC1)CC2)N1CCOCC1
Reaction time: 0.75 h

Procedure:
4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]butanoic acid (E283, Step 1) (0.15 g, 0.50 mmole) was dissolved in dry dichloromethane (5 ml) and dry dimethylformamide (2 ml) was treated with 1-hydroxybenzotriazole hydrate (0.14 g, 1.0 mmole) and N-cyclohexylcarbodiimide, N′-methyl polystyrene HL (0.53 g, 1.0 mmol, 1.7 mmol/g) and stirred for 45 minutes. Morpholine (0.056 ml, 0.65 mmol) was added and the mixture stirred for 3 hours at ambient temperature. The crude reaction mixture was applied to a SCX ion exchange cartridge (Varian bond-elute) and washed with water, methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were reduced in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95 to 1:9:90) to afford the title compound (E283); MS (ES+) m/e 373 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)#[CH:2].I[C:21]1[CH:22]=[N:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:25]=1[CH3:26].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:19][O:18][C:8]1[C:7]2[N:6]([N:5]=[CH:4][C:3]=2[C:1]#[C:2][C:21]2[CH:22]=[N:23][N:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:25]=2[CH3:26])[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)[CH:9]=1
Reactant: Cc1c(I)cnn1-c1ccccc1
Reactant: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3cnn(-c4ccccc4)c3C)c12
Temperature: 80 °C

Procedure:
3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (30.0 mg, 0.119 mmol), 4-iodo-5-methyl-1-phenyl-1H-pyrazole (67.6 mg, 0.238 mmol), and bis(triphenylphosphine)palladium(II) chloride (8.4 mg, 0.012 mmol) were combined into one vial fitted with a Teflon septum. The vial was flushed with nitrogen and tetra-n-butylammonium fluoride (0.36 mL, 0.36 mmol, 1M in THF) and tetrahydrofuran (0.2 mL) were added. After sparging with nitrogen for 5 minutes, the reaction was heated to 80° C. for one hour. The reaction was cooled to ambient temperature, then diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate. The organic layer was separated, and the aqueous layer was back extracted with ethyl acetate two times. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 4-methoxy-3-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethynyl]-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[S:3].Br[CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].N12CCCNC1C=CCCC2>CN(C)C=O>[NH2:6][C:5]1[CH:7]=[CH:8][N:1]=[C:2]([S:3][CH2:10][CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[N:4]=1
Reactant: Nc1cc[nH]c(=S)n1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: C1=CC2NCCCN2CCC1
Solvent: CN(C)C=O
Product: Nc1ccnc(SCCN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-thiocytosine (0.51 g.), dimethylformamide (5 ml.), N-(2-bromoethyl)phthalimide (1.12 g.) and 1,8-diazabicyclo[5,4,0]undec-5-ene (0.67 g.) was stirred at room temperature for 6 hours and then evaporated to dryness. The residue was stirred with a mixture of water and ethyl acetate and the insoluble material collected to give 4-amino-2-(2-phthalimidoethylthio)pyrimidine which was used without further purification.
Reaction SMILES: [Cl:1]C1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:36]=[CH:35][C:16]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([S:30][CH2:31][CH2:32][O:33][CH3:34])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[C:15]([F:37])[CH:14]=1>C(Cl)Cl>[ClH:1].[Cl:12][C:13]1[CH:36]=[CH:35][C:16]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([S:30]([CH2:31][CH2:32][O:33][CH3:34])=[O:9])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[C:15]([F:37])[CH:14]=1
Reactant: COCCSc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COCCS(=O)c1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
3-Chloroperbenzoic acid (188 mg, 1.05 mmol) was added in portions to a solution of 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methoxyethylthio)quinazoline (275 mg, 0.7 mmol), (prepared as described in Example 11), in methylene chloride (6 ml). The mixture was stirred for 30 minutes at ambient temperature, diluted with methylene chloride (20 ml), washed with aqueous sodium hydrogen carbonate solution and then brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/acetone (8/2 followed by 7/3 and 6/4). The purified product was dissolved in methylene chloride and 3M ethereal hydrogen chloride (0.5 ml) was added. The mixture was diluted with ether and the resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methoxyethylsulphinyl)quinazoline hydrochloride (100 mg 38%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:16])[C:12]([NH:14][NH2:15])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[C:18]1[N:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=1>C(O)CCC>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]2[N:14]([C:12]([CH:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[CH3:16])=[N:20][N:19]=2)[N:15]=1
Reactant: CC(C(=O)NN)c1ccc2ncccc2c1
Reactant: Cc1ccc(Cl)nn1
Solvent: CCCCO
Product: Cc1ccc2nnc(C(C)c3ccc4ncccc4c3)n2n1
Temperature: 120 °C
Yield: 53 %

Procedure:
2-Quinolin-6-yl-propionic acid hydrazide (intermediate 63) (500 mg, 2.32 mmol) was added to a stirred solution of 3-chloro-6-methylpyridazine (299 mg, 2.32 mmol) in n-butanol. The reaction mixture was heated at 120° C., overnight. The volatiles were removed in vacuo and the residue absorbed onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-90:10) to obtain 6-[1-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-quinoline (356 mg, 53% yield). To 6-[1-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-quinoline (356 mg, 1.23 mmol) was added a dropwise solution of bromine (1.73 uL, 3.69 mmol) in acetic acid (3 mL). The reaction was heated at 100° C. for 2 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. A solution of 10% aq. NaSH (10 mL) was added and the product extracted with 10% methanol in dichloromethane. The organic phase was washed with 5% aqueous sodium sulfite. The filtrate was then concentrated in vacuo onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-90:10) to return the title compound (168 mg, 37% yield). Analytical data presented in Table 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[H][H].[Cl:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([Cl:27])=[CH:20][C:19]=1Cl>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:12])[CH:5]([CH2:11][C:19]1[CH:20]=[C:21]([Cl:27])[C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=1[Cl:17])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cc(Cl)c([N+](=O)[O-])cc1Cl)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
86.5 ml (0.5 mole) of methylmalonic acid diethyl ester are added dropwise with good stirring under nitrogen at room temperature to a suspension of 12 g (0.5 mole) of sodium hydride in 500 ml of dimethylformamide. After cessation of evolution of hydrogen, 113.5 g (0.5 mole) of 1,2,4-trichloro-5-nitrobenzene are added dropwise and subsequently stirred for a further 2 hours at room temperature. Pouring onto 1 kg of ice is effected, followed by extracting five times with (in each case) 200 ml of cyclohexane, washing of the organic phase with water, drying, and distilling off the solvent. (2,5-dichloro-4-nitrophenyl)methylmalonic acid diethyl ester is thus obtained. This is boiled under reflux for 5 days in 2 liters of 6 N hydrochloric acid. Subsequently, cooling to room temperature is effected, followed by extracting with chloroform, and extracting the organic phase with sodium hydroxide solution. The aqueous phase is acidified with hydrochloric acid, and extraction with chloroform is effected. The organic phase is dried and concentrated in a vacuum to yield 109 g (82.5% of theory) of 2-(2,5-dichloro-4-nitrophenyl)propionic acid (m.p. 143° C.).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:14].C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=CN2)C1C=CC=CC=1)C>>[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[C:18]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:14]
Reactant: CCOC(=O)C=Cc1ccccn1
Reactant: COc1n[nH]c2cc(Br)ccc12
Agent: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1ccc2c(OC)n[nH]c2c1)c1ccccn1

Procedure:
3-(3-Methoxy-1H-indazol-6-yl)-3-pyridin-2yl-acrylic acid ethyl ester CCXLIII was prepared from 6-bromo-3-methoxy-1H-indazole and 3-pyridin-2-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH:7]=[CH:6][CH2:5][N:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]1=[O:17].[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.S(Cl)(Cl)(=O)=O>ClCCl.N1C=CC=CC=1>[CH2:10]([O:9][N:4]1[CH2:5][CH:6]=[CH:7][CH2:8][C@@H:2]([NH:1][S:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[C:3]1=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N[C@@H]1CC=CCN(OCc2ccccc2)C1=O
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Product: O=C1[C@H](NS(=O)(=O)c2ccc(F)cc2)CC=CCN1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.2 %

Procedure:
To a solution of 551 mg of 3-(R)-amino-1-benzyloxy-1,3,4,7-tetrahydro-azepin-2-one from example 1 Step D in 4 mL of dichloromethane and 4 mL of pyridine was added 565 mg of 4-fluorophenyl sulfonyl chloride. The reaction was stirred at room temperature for 24 hours, and an additional 495 mg of the sulfonyl chloride was added. The reaction was stirred for an additional 24 hours, and then the reaction was extracted with ethyl acetate. The mixture was washed with 5% HCl(aq.), NaHCO3(aq.), and NaCl(aq.) solutions. The aqueous layers were re-extracted with ethyl acetate, and the organic layers combined and dried over Na2SO4(s). Filtration and solvent removal gave a light brown solid. Dilution with ethyl ether, filtration, washing of the solids with ethyl ether and drying gave 548 mg of a light brown solid. MS: 391 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([N:13]1[C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][NH:15][C:14]1=[S:23])[CH2:7]2.[OH-].[K+]>C(O)C.O>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([N:13]1[C:17]([C:18]([OH:20])=[O:19])=[CH:16][NH:15][C:14]1=[S:23])[CH2:7]2
Reactant: CCOC(=O)c1c[nH]c(=S)n1C1CCc2c(F)cc(F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1c[nH]c(=S)n1C1CCc2c(F)cc(F)cc2C1
Reaction time: 5 h
Yield: 91.9 %

Procedure:
A mixture of ethyl 3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate (4.6 g, 13.6 mmol), prepared as in Example 24, and potassium hydroxide (3.14 g, 47.6 mmol) in 130 mL of ethanol/water (10:3) was stirred at 85°-90° C. for 5 hours. The solvent was removed by evaporation and the residue was dissolved in water. The solution was acidified with 1N hydrochloric acid to a pH of 1 giving a crystalline material. Isolation of the material by filtration gave 3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic acid (3.86 g, 12.5 mmol), m.p. 250°-252° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([O:22]CC)=O)[N:16]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:25]([NH2:28])[CH2:26][CH3:27]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([NH:28][CH2:25][CH2:26][CH3:27])=[O:22])[N:16]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: CCCN
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 125 °C
Yield: 69.8 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(ethoxycarbonyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 4) (107 mg, 0.31 mmol) in toluene (2 ml) was treated with n-propylamine (250 μl, 3.10 mmol) and the mixture was heated at 125° C. in a sealed vessel for 2 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and washed sequentially with aqueous citric acid solution (5%w/v), water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (80:20) gradually changing to dichloromethane:ethyl acetate (60:40) then to dichloromethane:methanol (90:10) to afford the title compound as an oil (76 mg).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21]([OH:24])(=[O:23])[CH3:22].OO.C(OC(=O)C)(=O)C>O>[C:21]([O:24][CH:9]1[C:10]2[N:1]=[C:2]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)(=[O:23])[CH3:22]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1cc2c(nc1C(=O)OCC)CCCC2
Agent: OO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC(=O)c1cc2c(nc1C(=O)OCC)C(OC(C)=O)CCC2
Temperature: 75 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture comprising 2.8 g of diethyl 5,6,7,8-tetrahydroquinoline-2,3-dicarboxylate, 10 ml of acetic acid and 1.1 ml of a 35% hydrogen peroxide aqueous solution, was stirred at 75° C. for 3 hours under heating. 1.0 ml of a 35% hydrogen peroxide aqueous solution was added thereto, and the mixture was further reacted at 75° C. for 9 hours. After cooling the mixture, water was added thereto, and the mixture was extracted with chloroform. The organic layer was dried, and then the solvent was distilled off to obtain an oily substance. This oily substance was added to 50 ml of acetic anhydride under reflux, and refluxed for 15 minutes. The solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with diethyl ether. The organic layer was dried, and then the solvent was distilled off. The residue was purified by column chromatography to obtain 2.3 g (yield: 69%) of diethyl 8-acetoxy-5,6,7,8-tetrahydroquinoline-2,3-dicarboxylate.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[S:5])[NH2:4].[C:7]([O:10][CH2:11][CH3:12])(=[O:9])[CH3:8].[CH3:13]CCCCC.CO>C(Cl)(Cl)Cl>[CH:2]([C:3]1[S:5][C:8]([C:7]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][N:4]=1)([CH3:6])[CH3:1]
Reactant: CCCCCC
Reactant: CC(C)C(N)=S
Reactant: CCOC(C)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc(C(C)C)s1
Yield: 83 %

Procedure:
Using the procedure of Example 1J but replacing thioformamide with 2-methylpropane-thioamide provided, after silica gel chromatography using 9:1 ethyl acetate:hexane, the desired compound, Rf 0.8, (5% methanol in chloroform) in 83% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)[N:14]=1>O.C(#N)C>[CH3:24][O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: COc1ccc2ccc(N)nc2n1
Solvent: O
Solvent: CC#N
Product: COc1cccc(C(=O)Nc2ccc3ccc(OC)nc3n2)c1
Temperature: 4 °C
Yield: 70.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-methoxybenzoic acid (9.1 g), N,N'-carbonyldiimidazole (9.7 g) and 2-amino-7-methoxy-1,8-naphthyridine (7 g). The product produced by precipitation in water (13 g; m.p. approximately 75° C.) is dissolved in 90 cc of boiling acetonitrile. After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (3×10 cc) and dried at 50° C. under reduced pressure (0.067 kPa). N-(7-methoxy-1,8-naphthyridin-2-yl)-3-methoxybenzamide (8.7 g) is produced, m.p. 135° C.).