Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([CH3:40])=[C:34]2[CH2:41][C:42](O)=[O:43].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][C:42](=[O:43])[CH2:41][C:34]3[C:33]4[C:37](=[CH:38][CH:39]=[C:31]([O:30][CH3:29])[CH:32]=4)[NH:36][C:35]=3[CH3:40])[N:13]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CN)cc1
Reactant: COc1ccc2[nH]c(C)c(CC(=O)O)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CNC(=O)Cc2c(C)[nH]c3ccc(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (202 mg, 0.50 mmol), in N,N-dimethylformamide (4 ml) was added 5-methoxy-2-methyl-3-indole acetic acid (170 mg, 0.74 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide, hydrochloride (150 mg, 0.75 mmol), and 1-hydroxybenzotriazole (105 mg, 0.74 mmol). The mixture was stirred at room temperature for 12 hours. The crude reaction mixture was diluted with dichloromethane (100 ml) and washed with water (100 ml), brine (100 ml), dried (MgSO4), filtered, and concentrated in vacuo, which afforded 2-amino-6-(4-methoxy-benzyl)-5-((2-(5-methoxy-2-methyl-1H-indol-3-yl)acetylamino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]3[NH:24][C:23](=[O:25])[O:22][C:21]([CH3:27])([CH3:26])[C:20]=3[CH:28]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:29]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]3[NH:24][C:23](=[O:25])[O:22][C:21]([CH3:26])([CH3:27])[C:20]=3[CH:28]=2)=[O:29])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCSc3ccc(Cl)c(Cl)c3)cc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2ccc(OCCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[5-(3,4-dichlorophenylmercapto)-pentoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Br: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][N:14]3[CH:22]=[CH:23][CH:24]=[C:13]3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[Cl:34][C:35]([Cl:40])([Cl:39])[C:36](Cl)=[O:37]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:36](=[O:37])[C:35]([Cl:40])([Cl:39])[Cl:34])=[CH:23][CH:24]=[C:13]3[CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: O=C(c1ccc2n1Cc1ccccc1N(S(=O)(=O)c1ccc(Br)cc1)C2)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 21 h
Yield: 62.9 %

Procedure:
To a solution of 10-[(4-bromophenyl)sulfonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step A (2.32 g, 5.753 mmol) and N,N-dimethylaniline (1.17 mL, 9.204 mmol) in dry dichloromethane (20 mL) at 0° C. under nitrogen was added dropwise trichloroacetyl chloride (0.96 mL, 8.629 mmol). The ice bath was removed and the reaction mixture stirred at room temperature for 21 hours. The reaction mixture was then washed with 2 M hydrochloric acid (2×100 mL) and water (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give an olive foam. Purification by flash chromatography using a solvent gradient of 5-15% ethyl acetate in hexane afforded a cream solid that was recrystallized from diethyl ether/hexane to afford the title compound (1.986 g, 63%) as an off-white crystalline solid, m.p. 182-183 ° C.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][Cl:20].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[ClH:20].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][S:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: ClCc1ccccn1
Reactant: Sc1cnc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(CSc2cnc3ccccc3n2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
In 50 ml of acetone was dissolved 2.0 g of 2-mercaptoquinoxaline. To the solution were added 2.02 g of 2-picolyl chloride hydrochloride, 4.0 g of potassium carbonate and 5 ml of water. The resulting mixture was stirred at room temperature for 0.5 hr., and the solvent was removed under reduced pressure. The residue was extracted with chloroform after addition of chloroform and water. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was placed under reduced pressure to remove the solvent. To the residue were added 20 ml of ethanol and 1.03 ml of conc. hydrochloric acid and then added ether. Thus precipitated crystals were washed with ethanol-ether (1:1) and dried under reduced pressure to give 2.09 g of 2-(2-pyridylmethylthio)quinoxaline hydrochloride as a yellow crystalline powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@:4]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>>[O:10]=[C:8]1[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5][C@:4]([CH2:3][CH2:2][NH:1][S:32]([CH3:31])(=[O:34])=[O:33])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:9]1
Reactant: C[C@@H](c1ccc(-c2cccnc2)cc1)N1CC[C@](CCN)(c2ccccc2)OC1=O
Reactant: CS(=O)(=O)Cl
Product: C[C@@H](c1ccc(-c2cccnc2)cc1)N1CC[C@](CCNS(C)(=O)=O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(2-aminoethyl)-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one by treatment with MeSO2Cl. LC-MS Method 2 tR=1.525 min, m/z=480.2; 1H NMR (CDCl3) 1.52 (d, 3H), 2.05-2.32 (m, 6H), 2.81 (s, 3H), 2.86 (m, 1H), 2.93-3.04 (m, 1H), 3.06-3.20 (m, 1H), 4.73 (s, 1H), 5.63 (q, 1H), 6.95 (d, 2H), 7.05-7.22 (m, 2H), 7.23-7.40 (m, 6H), 7.71 (d, 1H), 8.50 (d, 1H), 8.66 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16]CC)=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=[O:2].[OH-].[Na+:20]>C1COCC1.C(O)C>[CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O-:16])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=[O:2].[Na+:20]
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=Cc1cc(C(=O)[O-])c(=O)n2ccccc12
Reaction time: 4 h

Procedure:
To a solution of ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (see Example 1, 10.1 g, 41.0 mmol) in a mixture of 137 mL of THF and 68 mL of ethanol was added aqueous sodium hydroxide (1N, 43.1 mL, 43.1 mmol). After 4 h, the reaction was concentrated in vacuo to provide sodium 1-formyl-4-oxo-4H-quinolizine-3-carboxylate that gave a mass ion (ES+) of 218.1 for [M+H]+.
Reaction SMILES: [Cu][C:2]#[N:3].Cl[C:5]1[CH:6]=[C:7]2[C:23]([CH3:24])=[C:22]([CH3:25])[NH:21][C:8]2=[C:9]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)[N:10]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[C:9]1[N:10]=[C:5]([C:2]#[N:3])[CH:6]=[C:7]2[C:23]([CH3:24])=[C:22]([CH3:25])[NH:21][C:8]=12
Reactant: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(Cl)cc2c1C
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(C#N)cc2c1C
Temperature: 25 °C
Yield: 24.1 %

Procedure:
Copper(I) cyanide (9.3 g, 102.6 mmol) was added to a solution of 2-(5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline (3.2 g, 10.3 mmol) prepared in Example 656 in anhydrous N,N-dimethylformamide (100 ml). The reaction mixture was refluxed for 24 hours and then cooled to room temperature. Ethyl acetate was added to the reaction mixture, which was then filtered to discard insoluble matertals. The reaction mixture washed with water. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 750 mg of the titled compound as a white solid. (Yield: 26%)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:23])[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[C:20]([OH:22])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][NH2:49].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][NH:49][C:20]([C@@H:15]1[CH2:16][CH2:17][CH2:18][CH2:19][N:14]1[CH2:13][CH2:12][N:11]([CH3:23])[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:22]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCN
Reactant: CN(CCN1CCCC[C@H]1C(=O)O)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCCOCCOCCOCCOCCOCCOCCNC(=O)[C@@H]1CCCCN1CCN(C)C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of (S)-1-(2-(((benzyloxy)carbonyl)(methyl)amino)ethyl)piperidine-2-carboxylic acid (0.145 mmol, 46.4 mg), 2,5,8,11,14,17,20,23-octaoxapentacosan-25-amine (0.145 mmol, 55.6 mg), DIEA (0.725 mmol, 94 mg) in DMF (0.3 mL) was added HATU (0.16 mmol, 61 mg). The mixture was stirred at 60° C. for 1 h. The crude mixture was used in next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[N:10]([CH2:16][CH3:17])[CH:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27]/[CH:28]=[C:29]1/[C:30]2[CH:43]=[C:42]([C:44]([OH:47])([CH3:46])[CH3:45])[CH:41]=[CH:40][C:31]=2[O:32][CH2:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][C:35]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[N:10]([CH2:16][CH3:17])[CH:11]2[CH2:15][CH2:14][N:13]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Reactant: CCN(C(=O)Nc1ccc(Cl)cc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN(C(=O)Nc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(4-chloro-phenyl)-1-ethyl-1-pyrrolidin-3-yl-urea (0.21 g, 0.8 mmol) in acetonitrile:water (4:1) was added potassium carbonate (0.16 g, 0.8 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) and the resulting mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by flash chromatography on silica using gradient elution from ethyl acetate/methanol (5%) to ethyl acetate/methanol (10%) to give the desired product as yellow solid. 1H-NMR (CDCl3) δ: 1.05 (3H, t), 1.40 (6H, s), 1.80 (1H, m), 2.20-2.40 (3H, m), 2.50-3.00 (8H, m), 3.40 (4H, q and m), 4.20 (1H, m), 5.20 (2H, br, s), 6.20 (1H, t), 6.65 (1H, d), 7.00 (2H, dd), 7.20-7.40 (5H, m), 7.70 (1H, dd), 8.50 (1H, dd) 9.80 (1H, br s). ESI-MS m/z: 561 (M+1), UV retention time: 1.45 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](/[C:17](=C\C(C)C)/[C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CS(C)=O.[OH-:33].[Na+]>CO>[CH2:10]([O:33][CH:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:18]([CH3:24])([CH3:23])[C:19]([OH:21])=[O:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C(C)(C)/C(=C/C(C)C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)(C(=O)O)C(OCc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 8 h

Procedure:
(E)-Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhex-3-enoate (52 mg, 0.123 mmol) was dissolved in MeOH (5 mL) and DMSO (5 mL) and treated with 1 M NaOH (5 mL) at 100° C. After stirring overnight, the MeOH was removed in vacuo, the residue acidified with sat KH2PO4 to pH 4-5 and extracted with EtOAc×3. The organic layer was dried with MgSO4, filtered, concentrated in vacuo to give 3-(benzyloxy)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoic acid.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:23])[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH3:29][NH:30][CH3:31].C(N(CC)CC)C>C(#N)C>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:23])[CH2:17][CH2:16][CH:15]([C:18]([N:30]([CH3:31])[CH3:29])=[O:20])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CNC
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)O)C1(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)N(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
To a 20-mL scintillation vial were added the product from Example 96 (118 mg, 0.300 mmol), dimethylamine hydrochloride (Aldrich, 36.7 mg, 0.450 mmol), and 2-(1H-benzo[d][1,2,3]tria-zol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (TBTU, Bachem, 144 mg, 0.450 mmol). Anhydrous acetonitrile (3 mL) was added to form a yellow slurry. Neat triethylamine (Aldrich, 182 mg, 1.80 mmol) was added to form a tan solution. The reaction was stirred at 25° C. in a shaker block for 24 hr. The volatiles removed by rotary evaporator to give a brown oil. The product was purified by flash chromatography (silica gel: 10-45% ethyl acetate in hexanes). The product was recrystallized from hexanes to afford 67.0 mg (53%) of the title compound. 1H NMR (DMSO-d6) δ ppm 0.49 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.25 (s, 3H), 1.26 (s, 3H), 1.28-1.33 (m, 2H), 1.37-1.46 (m, 1H), 1.57 (s, 9H), 1.57-1.70 (m, 3H), 2.01-2.10 (m, 1H), 2.62-2.67 (m, 2H), 2.74-2.83 (m, 1H), 2.83 (s, 3H), 3.05 (s, 3H), 3.33-3.39 (m, 1H), 8.49 (s., 1H). MS (ESI+) m/z 422 (M+H)+. Anal. calcd. for C23H39N3O2S: C, 65.52; H, 9.32; N, 9.97. Found: C, 65.13; H, 9.22; N, 9.55.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.O[CH2:20][CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([CH2:21][CH2:20][O:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=2)=[CH:23][CH:24]=1)#[N:27]
Reactant: N#Cc1ccc(CCO)cc1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Product: N#Cc1ccc(CCOc2ccc(C(=O)NCC(=O)O)cc2)cc1
Yield: 18.2 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (582 mg, 3.83 mmol) prepared in Example 1 (1a) and 4-(2-hydroxyethyl)benzonitrile (592 mg, 4.02 mmol) to give 226 mg of the title compound (white powder, yield: 46%).
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[H-].[Na+].[C:16](Cl)([Cl:18])=[O:17]>ClCCl.C1(C)C=CC=CC=1>[C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][C:4]([O:7][C:16]([Cl:18])=[O:17])=[CH:5][CH:6]=1
Reactant: O=C(Cl)Cl
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Cl)Oc1ccc(-c2ccccc2)cc1
Reaction time: 3 h

Procedure:
2.00 g (11.75 mmol) of [1,1′-biphenyl]-4-ol in suspension in 50 ml of dichloromethane are introduced into a 50-ml three-necked flask, 0.47 g (11.75 mmol) of 60% sodium hydride in mineral oil is added portionwise, and the solvent is evaporated off under reduced pressure. A white solid is obtained which is added over 1 h to 6.84 ml (12.92 mmol) of a 20% solution of phosgene in toluene at 30° C. and left in contact for 3 h.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][C:13]([C:16]([F:28])([F:27])[O:17][C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=3)=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]>C1(C)C=CC=CC=1.C(O)C.[C].[Pd]>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]([F:27])([F:28])[O:17][C:18]3[CH:19]=[C:20]([F:26])[C:21]([F:25])=[C:22]([F:24])[CH:23]=3)[CH2:14][CH2:15]2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](C2CC=C(C(F)(F)Oc3cc(F)c(F)c(F)c3)CC2)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(F)(F)Oc3cc(F)c(F)c(F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a nitrogen-purged 1-L stainless steel autoclave, 7.3 g (18.1 mmol) of 1-(4-(trans-4-propylcyclohexyl)cyclohexene-1-yl-difluoromethoxy)-3,4,5-trifluorobenzene obtained in the second step was dissolved in 250 ml of a mixed solution of equal amount of toluene/ethanol. 0.6 g of 5% palladium carbon catalyst was added thereto, and the mixture was stirred at room temperature under a hydrogen pressure of 0.8 MPa for 5 hours. The catalyst was separated from the reaction mixture by filtration, and then the solvent was distilled off under reduced pressure. The concentrated residue was purified by means of a silica gel column chromatography with heptane as a developing solvent and further recrystallized from a mixed solution of equal amount of heptane/ethanol to obtain 5.1 g of 1-(trans-4-(trans-4-propylcyclohexyl)-cyclohexyldifluoromethoxy)-3,4,5-trifluorobenzene as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2.O.C(=O)([O-])[O-:18].[K+].[K+]>COCCOC>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([OH:18])[CH2:10][CH:9]=[CH:8]2
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1ccc2ncccc2c1
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1ccc2c(c1)C=CCN2O
Reaction time: 2 h

Procedure:
m-Perchlorobenzoic acid (6.85 g, 39.8 mmol) was added to a solution of commercially available quinolin-6-yl-acetic acid methyl ester (5.00 g, 24.8 mmol) in 1,2-dimethoxyethane at room temperature and stirred for 2 hours. Water was added and the solution was basified to pH 9-10 with saturated potassium carbonate and the product was extracted with ethyl acetate to give quantitative yield of (1-hydroxy-quinolin -6-yl)-acetic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, 1H, J=8.4 Hz), 7.93 (d, 1H, J=8.4 Hz), 7.65 (m, 1H), 7.60 (m, 1H), 7.32 (d, 1H, J=8.8 Hz), 7.19 (s, 1H), 3.74 (s, 2H), 3.65 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[O:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CO>[C:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[O:11])[NH:8][C:9]=1[CH:10]=[CH:16][N:17]([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C
Solvent: CO
Product: CC(=O)c1cc(C#N)c(=O)[nH]c1C=CN(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture containing 35.2 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile, 300 ml of methanol and 30 ml of dimethylformamide dimethyl acetal was heated with stirring on a steam bath for 4 and 1/2 hours and then allowed to cool to room temperature. The precipitated yellow solid was collected, washed with methanol and dried in an oven under reduced pressure at 95° C. to yield 16.4 g of 5-acetyl-1,2-dihydro-6-(2-dimethylaminoethenyl)-2-oxo-3-pyridinecarbonitrile, m.p. 267°-270° C.
Reaction SMILES: C[Si](Cl)(C)C.[Na+].[I-].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:20]=[C:19]([O:21]C)[C:18](=[O:23])[C:17]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:26][CH:25]=2)=[N:16]1.O>CC#N>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:20]=[C:19]([OH:21])[C:18](=[O:23])[C:17]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:26][CH:25]=2)=[N:16]1
Reactant: COc1cn(-c2ccccc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=c1c(O)cn(-c2ccccc2F)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
TMSCl (1.27 mL, 10 mmol) was added at room temperature to a solution of NaI (1.50 g, 10 mmol) in CH3CN (60 mL). After stirring for 30 min, 1-(2-fluorophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (0.725 g, 2 mmol) was added to the resulting suspension. The mixture was stirred for 30 min at room temperature and then refluxed for 1 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with hexane/AcOEt (1/1) and recrystallized from MeOH/H2O to give the title compound (0.648 g, 93% yield) as off-white prisms: mp 218-220° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 6.99 (1H, d, J=1.9 Hz), 7.10 (1H, dt, J=1.5, 7.9 Hz), 7.21-7.26 (1H, m), 7.32-7.54 (7H, m), 7.80 (1H, d, J=1.9 Hz), 8.44 (1H, d, J=2.6 Hz). Anal. Calcd for C19H13FN4O2: C, 65.51; H, 3.76; N, 16.08. Found: C, 65.73; H, 3.88; N, 16.24.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH3:13])=[CH:7][C:6]=1[C:15]([F:18])([F:17])[F:16])(=[O:4])=[O:3].[Cl:19][C:20]1[N:25]=[C:24]([NH:26][C:27]([NH2:29])=[S:28])[CH:23]=[N:22][CH:21]=1>>[Cl:19][C:20]1[N:25]=[C:24]([NH:26][C:27]2[S:28][C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[C:6]([C:15]([F:18])([F:17])[F:16])[CH:7]=3)=[C:12]([CH3:13])[N:29]=2)[CH:23]=[N:22][CH:21]=1
Reactant: CC(=O)Cc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Reactant: NC(=S)Nc1cncc(Cl)n1
Product: Cc1nc(Nc2cncc(Cl)n2)sc1-c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1

Procedure:
The titled compound is prepared from 1-(4-methanesulfonyl-3-trifluoromethyl-phenyl) propan-2-one (59c) and 6-chloro-pyrazin-2-yl-thiourea.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([S:18]([CH3:21])(=[O:20])=[O:19])[C:10]=1F.O.[OH-].[Li+].O>CN(C)C=O>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([S:18]([CH3:21])(=[O:20])=[O:19])[C:10]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)c1c(C(=O)O)ccc(Cl)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1c(C(=O)O)ccc(Cl)c1Oc1ccccc1
Temperature: 100 °C
Yield: 70.4 %

Procedure:
Phenol (2.26 g) was added to a mixture of 4-chloro-3-fluoro-2-methylsulphonylbenzoic acid (4.46 g) and lithium hydroxide monohydrate (1.65 g) in N,N-dimethylformamide and the mixture was stirred and heated at 100° C. overnight. It was cooled, poured into water and acidified to pH 1, extracted with ethyl acetate and the organic phase extracted into aqueous sodium bicarbonate solution. The aqueous layer was acidified to pH 1 and extracted with ethyl acetate, washed with water, dried (magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 4-chloro-2-methylsulphonyl-3-phenoxybenzoic acid (4.06 g) as an off-white solid m.p. 231°-235° C.