Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1.[Cl:12]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CO>[Cl:12][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1ccc2cc[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc2c(Cl)c[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.6 %

Procedure:
To a solution of 6-indole carbonitrile (1.0 g) in methanol (10 mL) was added N-chlorosuccinimide (1.2 g) at room temperature, and then the reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (1.3 g) as a white solid.
Reaction SMILES: Br.[CH2:2]([O:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:18])[CH3:17])[NH:8]C(OC(C)(C)C)=O)[CH:3]=[CH2:4]>C(Cl)(Cl)Cl>[CH2:2]([O:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:17])[CH3:18])[NH2:8])[CH:3]=[CH2:4]
Reactant: C=CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: Br
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)[C@@H](N)C(C)C
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
A solution of 100 mL CHCl3 /10% MeOH saturated at -20° C. with HBr gas was cooled to -78° C. To this solution was added N-(tert-Butyloxycarbonyl)-L-valine allyl ester (5.10 g, 19.8 mmol) dissolved in 10 mL CHCl3. The mixture was warmed to -20° C., stirred 15 min then poured into ice cold saturated NaHCO3 (300 mL). The organic phase was separated. The aqueous phase was washed with 50 mL of CHCl3. The organic phases were combined, dried over Na2 SO4, concentrated to afford 3.10 g (99%) of the title compound which was used without further purification.
Reaction SMILES: C([S:4][CH:5]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:6]([NH:8][CH:9]1[C:15](=[O:16])[N:14]([CH2:17][C:18]([OH:20])=[O:19])[C:13]([CH3:22])([CH3:21])[CH2:12][CH2:11][CH2:10]1)=[O:7])(=O)C.SCC(C(CS)O)O.[OH-].[Na+].C(O)(=O)C>>[SH:4][CH:5]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:6]([NH:8][CH:9]1[C:15](=[O:16])[N:14]([CH2:17][C:18]([OH:20])=[O:19])[C:13]([CH3:21])([CH3:22])[CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: CC(=O)SC(Cc1ccccc1)C(=O)NC1CCCC(C)(C)N(CC(=O)O)C1=O
Agent: OC(CS)C(O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC1(C)CCCC(NC(=O)C(S)Cc2ccccc2)C(=O)N1CC(=O)O
Temperature: 1 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A three necked flask was charged with [S-(R*,R*)]-6-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]hexahydro-2,2-dimethyl-7-oxo-1H-azepine-1-acetic acid (10 g, 23.78 mmoles) and D,L-dithiothreitol (390 mg, 2.5 mmoles). The flask was flushed with nitrogen. Deoxygenated water (20 ml) was added to the flask and the mixture was cooled to 1° C. Cold (1° C.) deoxygenated sodium hydroxide solution (1.22 N, total 70 ml, 84 mmoles) was added slowly while maintaining the temperature of the reaction mixture between 1° C. and 4° C. After addition of the initial 10 v/v % of the sodium hydroxide solution, the remainder of the solution was added, maintaining the reaction temperature between −2° to 3° C. After stirring the reaction mixture at −2° to 6° C. for 30 minutes, the reaction mixture was allowed to warm to room temperature. The reaction mixture was polish filtered into a crystallization flask and heated to 45° C. Deoxygenated acetic acid solution (1.06 N, 90 ml, 95 mmoles) was added while maintaining the reaction temperature between 410 and 46° C. The crystal slurry was stirred at 41° to 46° C. for 20 minutes and then allowed to cool to room temperature. After stirring at room temperature for 30 minutes, the product was filtered and washed with water (100 ml) and dried in a vacuum oven at 51° C./4.1 inch Hg to afford 8.45 g of title product having laboratory HPLC of 99.75 area percent.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@@H:13]3[OH:14])[C:6]=2[N:7]=1.[OH-:22].[Na+].Cl>>[NH2:1][C:2]1[NH:3][C:4](=[O:22])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c2nc(N)nc(Cl)c12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c2nc(N)[nH]c(=O)c12
Reaction time: 1 h

Procedure:
To the compound from Step B (157 mg, 0.50 mmol) was added NaOH (2M, aqueous) (2 mL). The resulting solution was stirred at relux for 1 h, cooled and neutralized by addition of HCl (2M, aqueous). The mixture was evaporated in vacuo and the crude product purified on silica using methanol/dichloromethane (2:8) as eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (53 mg) as a colorless powder.
Reaction SMILES: [CH2:1]([Zn]CC)C.ClCI.[OH:9][CH2:10][C:11](=[CH2:25])[CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].[NH4+].[Cl-]>C(Cl)Cl>[O:24]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[N:14]1[CH2:13][CH2:12][C:11]1([CH2:10][OH:9])[CH2:1][CH2:25]1
Reactant: C=C(CO)CCN1C(=O)c2ccccc2C1=O
Reactant: CC[Zn]CC
Agent: ClCI
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCC1(CO)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a cold (0° C.), stirred solution of diethyl zinc (1.0 M in hexanes, 4.0 mL, 4.0 mmol) in CH2Cl2 (10 mL) was added neat ClCH2I (0.59 mL, 8.10 mmol) drop wise by syringe. After 30 minutes, a solution of 2-(3-Hydroxymethyl-but-3-enyl)-isoindole-1,3-dione (0.456 g, 1.97 mmol) in CH2Cl2 (6 mL) was added by cannula. After 60 minutes, the reaction mixture was treated with saturated aqueous NH4Cl (20 mL), diluted with CH2Cl2 (20 mL), and warmed to room temperature. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated. The crude material was purified by column chromatography on silica gel (1:1 hexanes-ethyl acetate) and provided 0.31 g (64%) of 1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclopropane-methanol as a white solid. 1H NMR (CDCl3) δ 0.31-0.34 (m, 2H), 0.38-0.43 (m, 2H), 1.75 (t, 2H, J=6.9 Hz), 3.54 (s, 2H), 3.90(t, 2H, J=6.6 Hz), 7.70-7.73 (m, 2H), 7.81-7.85 (m, 2H);
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.CCCCCC.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:26]([NH:25][C:22]4[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=4)=[S:27])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Fc1ccc(NC(=S)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)cc1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (0.20 g, 0.8 mmol) and 4-fluorophenyl isothiocyanate (0.14 g, 0.9 mmol) in THF (10 mL) are reacted according to method C yielding the title product as a solid after column chromatography with hexane-EtOAc.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]([OH:49])[CH2:11][NH:12][C:13]2[CH2:17][N:16](S(C(F)(F)F)(=O)=O)[C:15](=[O:25])[C:14]=2[C:26]2[N:30](C(OC(C)(C)C)=O)[C:29]3[CH:38]=[C:39]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[CH:40]=[C:41]([CH3:42])[C:28]=3[N:27]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].ClC1C=C([C@H](O)CNC2CNC(=O)C=2C2NC3C=C(N4CCOCC4)C=C(C)C=3N=2)C=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]([OH:49])[CH2:11][NH:12][C:13]2[CH2:17][NH:16][C:15](=[O:25])[C:14]=2[C:26]2[NH:30][C:29]3[CH:38]=[C:39]([N:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)[CH:40]=[C:41]([CH3:42])[C:28]=3[N:27]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(O)CNC2=C(c3nc4c(C)cc(N5CCOCC5)cc4n3C(=O)OC(C)(C)C)C(=O)N(S(=O)(=O)C(F)(F)F)C2)cc1Br
Agent: Cc1cc(N2CCOCC2)cc2[nH]c(C3=C(NC[C@@H](O)c4cccc(Cl)c4)CNC3=O)nc12
Product: COc1ccc(C(O)CNC2=C(c3nc4c(C)cc(N5CCOCC5)cc4[nH]3)C(=O)NC2)cc1Br
Yield: 54.5 %

Procedure:
4-[2-(3-Bromo-4-methoxy-phenyl)-2-hydroxy-ethylamino]-3-(1-tert-butyloxycarbonyl-4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl)-1-trifluoromethanesulfonyl-1,5-dihydro-pyrrol-2-one (0.018 g, 0.023 mmol) was reacted according to the procedure used to synthesize (S)-4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl)-1,5-dihydro-pyrrol-2-one and afforded the title material (0.0068 g, 54%) as a beige solid. HPLC: 98% (220 nm), LCMS (+ESI, M+H+) m/z 542, 544, HRMS calcd for C25H28N5O4Br=541.1325, found: 541.1331; 1H NMR (400 MHz, methanol-d4) δ (ppm): 2.48 (3H, s), 3.11 (4H, br dd), 3.49 (1H, dd, J=13.8 and 6.7 Hz), 3.57 (1H, dd, J=13.8 and 4.3 Hz), 3.84–3.87 (7H, m), 4.13 (2H, 2d, JAB=18.0 Hz), 4.85–4.94 (1H, m), 6.75 (1H, s), 6.92 (1H, s), 6.99 (1H, d, J=8.6 Hz), 7.37 (1H, dd, J=8.6 and 2.0 Hz), 7.64 (1H, d, J=2.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[S:9][C:10](Br)=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Li+].CN(C=O)C.[CH2:22]1COC[CH2:23]1>>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[S:9][C:10]([CH:22]=[CH2:23])=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)s1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1cnc(NC(=O)OC(C)(C)C)s1

Procedure:
(5-Bromo-thiazol-2-yl)-carbamic acid tert-butyl ester (0.200 g, 0.71 mmol), tetrakis(triphenylphospine)palladium (0.042 g, 0.036 mmol), lithium chloride (0.91 g, 2.14 mmol), and tributyl (vinyl)stannate (0.68 g, 2.14 mmol) were taken in 8 mL of THF and 8 mL of DMF and reflux for 2 hrs. After completion of reaction THF was removed under reduced pressure on ratavapour and the residue was partioned between ethyl acetate (20 mL) and water (20 mL). The layers were separated. Aq. Layer was extracted with ethyl acetate (2×20 mL). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure to get the crude product which was purified by preparative TLC to get the pure product (5-Vinyl-thiazol-2-yl)-carbamic acid tert-butyl ester (0.137 g).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[CH:15]=[C:14]([CH2:16][CH2:17][C@@:18]([CH3:33])([S:29]([CH3:32])(=[O:31])=[O:30])[C:19]([NH:21][O:22]C2CCCCO2)=[O:20])[O:13][N:12]=1>O1CCOCC1.ClCCl.O>[F:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[CH:15]=[C:14]([CH2:16][CH2:17][C@@:18]([CH3:33])([S:29]([CH3:32])(=[O:31])=[O:30])[C:19]([NH:21][OH:22])=[O:20])[O:13][N:12]=1
Reactant: COc1cccc(-c2cc(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)on2)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1cccc(-c2cc(CC[C@](C)(C(=O)NO)S(C)(=O)=O)on2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
Hydrochloric acid (4.0 M in 1,4-dioxane, 0.49 mL, 1.9 mmol, 4.0 equiv) was added to a solution of (2R)-4-[3-(2-fluoro-3-methoxyphenyl)isoxazol-5-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (0.23 g, 0.49 mmol, 1.0 equiv) in 1,4-dioxane-dichloromethane-water (2:2:1, 5 mL), and the reaction was allowed to stir at room temperature for 2 h. The solvent was removed under reduced pressure, and the resulting crude material was purified by flash chromatography (30 g C18 reverse phase column, 5-60% gradient acetonitrile in water) to provide (2R)-4-[3-(2-fluoro-3-methoxyphenyl)isoxazol-5-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide as a light brown solid (0.09 g, 48%). MS (LCMS) m/z 387.1 (M+1). 1H NMR (400 MHz, METHONAL-d4) δ1.67 (s, 3H) 2.20-2.38 (m, 1H) 2.80 (s, 2H) 2.95-3.09 (m, 1H) 3.10 (s, 3H) 3.94 (s, 3H) 6.68 (d, J=3.12 Hz, 1H) 7.22 (dd, J=5.95, 1.17 Hz, 2H) 7.33-7.51 (m, 1H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[C:32]5[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)c1ccc(F)cc1

Procedure:
The title compound, white solid (23.8 mg, 64.4%), MS (ISP) m/z=454.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 4-fluorobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][N:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH3:9])=[CH:5][S:4][C:3]=1[C:20]([OH:22])=O.[CH3:23][C:24]1[N:28]=[C:27]([CH2:29][NH:30][C:31]([CH:33]2[O:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[NH:35][CH2:34]2)=[O:32])[O:26][N:25]=1.C(N(CC)CC)C.CCOC(C)=O>S(Cl)(Cl)=O.ClCCl>[Cl:1][C:2]1[C:6]([CH2:7][N:8]([S:10]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)(=[O:11])=[O:12])[CH3:9])=[CH:5][S:4][C:3]=1[C:20]([N:35]1[C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[O:38][CH:33]([C:31]([NH:30][CH2:29][C:27]2[O:26][N:25]=[C:24]([CH3:23])[N:28]=2)=[O:32])[CH2:34]1)=[O:22]
Reactant: CN(Cc1csc(C(=O)O)c1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1noc(CNC(=O)C2CNc3ccccc3O2)n1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1noc(CNC(=O)C2CN(C(=O)c3scc(CN(C)S(=O)(=O)c4ccc(Cl)cc4)c3Cl)c3ccccc3O2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.5 %

Procedure:
A solution of 3-chloro-4-(N-(4-chlorobenzenesulphonyl)-N-methylaminomethyl)-thiophene-2-carboxylic acid (57 mg, 0.15 mmol) in thionyl chloride (2 ml) and dichloromethane (5 ml) was heated at reflux for 1 h. The mixture was cooled and reduced in vacuo. The residue was added to a solution of N-(3-methyl-1,2,4-oxadiazol-5-ylmethyl)benzomorpholine-2-carboxamide (40 mg, 0.15 mmol) and triethylamine (42 μl, 0.30 mmol) in dichloromethane (10 ml) and stirred at room temperature for 3 days. The mixture was reduced and chromatography (30% EtOAc/70% hexanes and 100% EtOAc) afforded 4-(3-chloro-4-(N-(4-chlorobenzenesulphonyl)-N-methylaminomethyl)thiophene-2-carbonyl)-N-(3-methyl-1,2,4-oxadiazol-5-ylmethyl)benzomorpholine-2-carboxamide as a colourless oil (31 mg, 33%).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=2)[N:43]=1>C(Cl)(Cl)Cl>[Cl:20][C:14]1[C:15]([F:19])=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[N:41]([C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=3)[N:43]=1)[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]2=[O:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Reactant: COc1ccc(CNc2nc(N)c(F)cc2F)cc1
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(NCc3ccc(OC)cc3)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To 18 ml of chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 2.52 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 2.65 g of 2-amino-3,5-difluoro-6-(p-methoxybenzylamino)pyridine. The solution was concentrated under reduced pressure, and to the residue were added 2.5 g of anhydrous potassium carbonate and 6 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 15 minutes and allowed to cool. The solution was separated by adding 50 ml of chloroform and 500 ml of distilled water, and the chloroform layer was washed twice with 500 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and allowed to stand. The precipitate was dispersed in ethanol, collected by filtration, and washed with ethanol to obtain 3.20 g of the title compound as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33]>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]#[N:23])[CH:3]=1)=[O:33]
Reactant: O=C=Nc1ccccc1Cl
Reactant: N#Cc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(N)c1
Product: N#Cc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(NC(=O)Nc2ccccc2Cl)c1

Procedure:
The title compound was prepared from 4-(3-aminophenyl)-8(trifluoromethyl)quinoline-3-carbonitrile and 2-chlorophenyl isocyanate according to the procedure of Example 65. MS (ES) m/z 464.8.
Reaction SMILES: [C:1]([O:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O.[C:23]1([CH3:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:10]([O:9][CH:1]1[CH2:2][CH:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[O:17][C:10](=[O:9])[CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:23][CH3:29])(=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccccc1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCCCCCCCCCCC1CC(OC(=O)c2ccccc2)C(CCCCCC)C(=O)O1
Yield: 103.4 %

Procedure:
177.3 g of the δ-lactone from c) were suspended in 1250 ml of toluene while stirring. After the addition of 138.6 g of benzoic anhydride the mixture was stirred for 10 minutes. Then, 2.5 ml of perchloric acid were added. The mixture was stirred for a further 2.5 hours. The reaction solution was extracted in toluene with 1N sodium hydroxide solution and then with water. The combined toluene phases were dried, the drying agent was filtered off under suction and washed with toluene. Evaporation of the solvent gave 237.2 g (103.4%) of rac-(2RS,3RS,5SR)-3-benzoyloxy-2-hexyl-5-undecyl-δ-valerolactone, which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:4]=1[CH2:5][NH:6][C:7]1[C:12]([NH2:13])=[CH:11][N:10]=[C:9]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[N:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:15]=2)[N:8]=1.[S:38](N)(N)(=[O:40])=[O:39].N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:4]=1[CH2:5][N:6]1[C:7]2[N:8]=[C:9]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=4)[N:16]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[N:15]=3)[N:10]=[CH:11][C:12]=2[NH:13][S:38]1(=[O:40])=[O:39]
Reactant: NS(N)(=O)=O
Reactant: COc1ccc(CNc2nc(-c3nn(Cc4ccccc4F)c4ncc(F)cc34)ncc2N)c(OC)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CN2c3nc(-c4nn(Cc5ccccc5F)c5ncc(F)cc45)ncc3NS2(=O)=O)c(OC)c1
Temperature: 160 °C

Procedure:
550 mg (1.093 mmol) of the compound from example 92A were divided between 11 microwave vessels. 50 mg of the substance in each were admixed with 48 mg (0.496 mmol) of sulfamide and 2.5 ml of pyridine and then heated at 160° C. under microwave radiation for 30 min. Subsequently, all batches were combined and freed of the solvent under reduced pressure. The residue was taken up in dichloromethane and extracted three times with water. The phases were separated and the organic phase was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). This gave 0.130 g (12% of theory, purity 50%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH3:36])[C:29]#[N:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:38][C:39]([O:41]C(C)(C)C)=[O:40].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:38][C:39]([OH:41])=[O:40])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:25][C:26]1[CH:27]=[C:28]([C:29]#[N:30])[CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(O)cc3N2C)C(=O)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(OCC(=O)O)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 80 °C

Procedure:
To the product of Example 57 (158 mg, 0.31 mmol) in anhydrous DMF (5 mL) were added tert-butyl bromoacetate (460 μL, 10 equiv) and anhydrous K2CO3 (425 mg, 10 equiv). The suspension was heated at 80° C. under nitrogen for 16 h. After cooling, resulting solids were removed by filtration. The filtrate was concentrated to give a residue, which was purified by chromatography on silica gel, eluting with MeOH-DCM (5:95) to give the product, which was used in the next step without further purification.
Reaction SMILES: CC1(C)CC=C(C2SC=CN=2)C2C=C(C#CC3C=CC=CC=3C(O)=O)C=CC1=2.[CH3:29][C:30]1([CH3:58])[CH2:39][CH:38]=[C:37]([C:40]2[O:41][CH:42]=[CH:43][CH:44]=2)[C:36]2[CH:35]=[C:34]([C:45]#[C:46][C:47]3[CH:57]=[CH:56][C:50]([C:51]([O:53]CC)=[O:52])=[CH:49][CH:48]=3)[CH:33]=[CH:32][C:31]1=2>>[CH3:29][C:30]1([CH3:58])[CH2:39][CH:38]=[C:37]([C:40]2[O:41][CH:42]=[CH:43][CH:44]=2)[C:36]2[CH:35]=[C:34]([C:45]#[C:46][C:47]3[CH:48]=[CH:49][C:50]([C:51]([OH:53])=[O:52])=[CH:56][CH:57]=3)[CH:33]=[CH:32][C:31]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccco2)=CCC3(C)C)cc1
Agent: CC1(C)CC=C(c2nccs2)c2cc(C#Cc3ccccc3C(=O)O)ccc21
Product: CC1(C)CC=C(c2ccco2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(5,6-dihydro-5,5-dimethyl-8-(2- thiazolyl)-2-naphthalenyl)ethynyl]benzoic acid (Compound 30a), ethyl 4-[(5,6-dihydro-5,5-dimethyl-8- (2-furyl)-2-naphthalenyl)ethynyl]benzoate (Compound 66) was converted into the title compound (colorless solid) using 16.0 mg (0.38 mmol) of LiOH in H2O. PMR (d6 -DMSO): δ 1.26 (6H, s), 2.33 (2H, d, J=4.9 Hz), 6.41 (1H, t, J=4.9 Hz), 6.60 (2H, m), 7.45-7.53 (3H, m), 7.64 (2H, d, J=8.3 Hz), 7.75 (1H, d, J=1.6 Hz), 7.93 (2H, d, J=8.3 Hz).
Reaction SMILES: CO[C:3]([CH:5]1[C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:7][CH2:6]1)=[O:4].[C:16]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1)#[N:17].C(O)(=O)C(C)(C)C>>[O:4]=[C:3]1[N:24]([C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[CH:19][CH:20]=2)[NH:25][C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:7][CH2:6][C:5]1=2
Reactant: N#Cc1ccc(NN)cc1
Reactant: COC(=O)C1CSc2ccccc2C1=O
Agent: CC(C)(C)C(=O)O
Product: N#Cc1ccc(-n2[nH]c3c(c2=O)CSc2ccccc2-3)cc1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
4-Oxo-thiochroman-3-carboxylic acid methyl ester (0.200 g, 0.90 mmol), 4-cyanophenylhydrazine (0.132 g, 0.99 mmol) together with a small amount of pivalic acid was heated at 118° C. in an oil bath under N2. After 1 h the mixture was cooled to room temperature and then triturated with ether. The precipitate was filtered and dried to yield 4-(3-oxo-1,4-dihydro-3H-thiochromeno[4,3-c]pyrazol-2-yl)-benzonitrile (0.233 g): 1H NMR (400 MHz, DMSO-d6) δ 8.06 (2H, d), 7.92 (2H, d), 7.80-7.83 (1H, m), 7.30-7.33 (1H, m), 7.18-7.25 (2H, m), 3.91 (2H, s).