Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11](O)[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.S([Cl:34])(C)(=O)=O>C(Cl)Cl>[Cl:34][CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(O)C(=O)OCc2ccccc2)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(Cl)C(=O)OCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To 6D (450 mg, 1.5 mmol) in CH2Cl2 (5 mL) at 0° C. was added triethylamine (0.42 mL, 3.0 mmol) followed by mesyl chloride (0.14 mL, 1.8 mmol). After stirring at rt overnight, the reaction was concentrated and purified via silica gel chromatography (0-25% ethyl acetate/hexanes) to provide 6E (268 mg, 56%). 1H NMR (400 MHz, CD3OD) δ ppm 3.81 (s, 3H) 3.87 (s, 3H) 5.19 (m, 2H) 5.36 (s, 1H) 6.81 (d, J=8.35 Hz, 1H) 6.93-7.07 (m, 2H) 7.20-7.42 (m, 5H).
Reaction SMILES: [CH2:1]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:28]N1C(=O)CCC1=O>O1CCOCC1>[CH2:1]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[C:17]([OH:20])[C:18]([Cl:28])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2cc(O)ccc2C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2cc(O)c(Cl)cc2C1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
A solution of N-benzyl-N-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (166 mg) and N-chlorosuccinimide (66.4 mg) in 1,4-dioxane (2 ml) was refluxed for 28 hours, cooled to room temperature, and partitioned between ethyl acetate and brine. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (toluene -ethyl acetate) over silica gel (3.6 g) to afford N-benzyl-N-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (139 mg) as a colorless gum.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].Br[CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25]>C(O)C>[C:1]([NH:4][C:5]([CH:21]=[CH:22][CH2:23][CH2:24][CH3:25])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: C=CCCCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCC=CC(NC(C)=O)(C(=O)OCC)C(=O)OCC

Procedure:
Diethyl acetamidomalonate (6.0 g) was dissolved in 50 ml of dehydrated ethanol and 2.26 g of sodium ethoxide and 5.22 g of 5-bromo-1-pentene were added thereto. The mixture was refluxed under a nitrogen atmosphere overnight. The reaction mixture was neutralized and concentrated. The concentrate was purified by silica gel column chromatography using hexane-ethyl acetate (5:1→2:1) as an eluent to give 4.871 g of colorless, oily diethyl 2-acetamido-2-pentenylmalonate.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]([NH:12][C:13]2[CH:25]=[CH:24][C:16]3[S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:15]=3[CH:14]=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:28]O>C(O)(=O)C>[O:28]=[S:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:15]2[CH:14]=[C:13]([NH:12][C:10]([O:9][CH2:8][C:7]3[CH:26]=[CH:27][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:11])[CH:25]=[CH:24][C:16]1=2
Reactant: O=C(Nc1ccc2sc3ccccc3c2c1)OCc1ccc([N+](=O)[O-])cc1
Reactant: OO
Solvent: CC(=O)O
Product: O=C(Nc1ccc2c(c1)-c1ccccc1S2=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C

Procedure:
2-(4-Nitrobenzoxycarbonylamino)dibenzothiophene (Example 1; 364 mg, 1.0 mmol) was suspended in a mixture of glacial acetic acid (5.0 ml) and 30% hydrogen peroxide (565 mg, 5 mmol) and the mixture was warmed at 60° C. for 2 hours. The suspension of the title compound was filtered and air dried. TLC: (2:1; EtOAc:isohexane) Rf=0.30.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=2)([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:31]I>CN(C=O)C.CCOC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=2)([CH2:16][N:17]([CH3:31])[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)C(F)(F)F)(c2ccc(I)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CC1(c2ccc(I)cc2)CCN(C(=O)OC(C)(C)C)CC1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a flask containing sodium hydride (0.07 g, 2.9 mmol, 5 eq.) under Ar at 0° C. was added a solution of 4-(4-iodo-phenyl)-4-[(2,2,2-trifluoro-acetylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (0.298 g, 0.58 mmol) in DMF (5 mL). The resulting mixture was warmed to room temperature and stirred for 2 h, heated to 35° C. for 0.5 h and CH3I (0.36 mL, 5.8 mmol, 10 eq.) was added. The mixture heated at 35° C. for a further 2 h. The reaction was diluted with EtOAc (25 mL) and washed with saturated NaHCO3 (25 mL) and saturated brine (25 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation. The crude product was purified by flash column chromatography by eluting with 30% EtOAc/hexanes to give 4-(4-iodo-phenyl)-4-{[methyl-(2,2,2-trifluoro-acetyl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (0.022 g, 0.42 mmol, 72%). 1H NMR (CDCl3): δ 7.83 (d, 2H), 7.20 (d, 2H), 3.93 (m, 2H), 3.78 (m, 1H), 3.53 (m, 1H), 3.07 (m, 2H), 2.60 (m, 3H), 2.24 (m, 2H), 1.93 (m, 2H), 1.54 (s, 9H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:35])=[C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=1.[K+].[Br-]>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:32]3[CH2:31][CH2:30][N:29]([C:27]4[CH:28]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]=4[CH3:35])[CH2:34][CH2:33]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: Cc1ccc(Cl)cc1N1CCNCC1
Agent: [Br-]
Agent: [K+]
Product: Cc1ccc(Cl)cc1N1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(5-chloro-2-methyl-phenyl)-piperazine The crude product was converted to the free base, yield 26%. White crystals; HPLC-MS:m/z=492(M+H) at Rt=5.5 min.; IR (KBr): ν 1722 (C═O) cm−1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:30])[CH3:2].[N:32]1([CH2:38][CH2:39][CH2:40]O)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:40][CH2:39][CH2:38][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:17]=[C:16]([C:21]#[C:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:30])[CH3:2]
Reactant: OCCCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#Cc3ccc(Cl)cc3)c2)cc1Cl
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(Cl)cc3)cc(OCCCN3CCOCC3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (293 mg; 0.62 mmol) was dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. 3-morpholin-4-yl-propan-1-ol (75 mg; 0.52 mmol) and tributylphosphine (0.23 mL; 0.93 mmol) was added followed by 1,1′-(Azodicarbonyl)dipiperidine (0.38 g; 1.5 mmol) dissolved in THF (10 mL). The reaction mixture was stirred at room temperature for 16 h, filtered and evaporated in vacuo. The crude product was purified by prep. HPLC (method B). Yield: 200 mg. HPLC-MS: m/z: 600.4 (M+); Rt: 2.2 min.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br-].[F:12][C:13]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:14]=1[CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:42](=O)[CH3:43].O>O1CCOCC1>[F:12][C:13]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:14]=1[CH:15]=[CH:42][CH3:43]
Reactant: CC=O
Reactant: O=[N+]([O-])c1ccc(F)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC=Cc1cc([N+](=O)[O-])ccc1F
Reaction time: 1 h

Procedure:
At 10° C., 5.99 g (32.7 mmol) sodium bis(trimethylsilyl)amide are added dropwise to a solution of 13.5 g (27.3 mmol) of the compound from Example 47A in 145 ml of dioxane. The mixture is stirred at this temperature for 1 h. A solution of 2.40 g (54.5 mmol) of acetaldehyde in 5 ml of dioxane is then added, and the reaction is stirred at RT for 1 h. 400 ml of water are then added, the mixture is extracted three times with dichloromethane and the combined organic phases are washed twice with saturated aqueous sodium chloride solution. After drying over sodium sulphate and subsequent filtration, the solvent is removed under reduced pressure. The product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate=40:1). This gives 5.2 g (100% of theory) of the desired product as an E/Z isomer mixture.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:21][C:22](=[O:24])[CH3:23]>>[CH2:21]([N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18])[C:22]([CH3:23])=[O:24]
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: CC(=O)CCl
Product: CCc1c(Oc2cc(C)cc(C)c2)n(CC(C)=O)c(=O)[nH]c1=O
Yield: 54 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and chloroacetone were reacted by the same way with the example 1 to obtain the titled compound (172 mg, yield: 54%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)[C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3oc2=O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=c1oc2cc(O)ccc2cc1-c1ccc(O)cc1
Reaction time: 1 h
Yield: 99.8 %

Procedure:
7-Methoxy-3-(4-methoxyphenyl)-chromen-2-one (21.8 g) was mixed with pyridine hydrochloride (80 g) and stirred for 1 hour at a temperature of 190° C. to 200° C. Water was added to the reaction mixture and the resulting precipitates were collected by filtration and dried under reduced pressure to give 7-hydroxy-3-(4-hydroxyphenyl)-chromen-2-one (19.6 g, Yield 100%). Diisopropylethylamine (35 ml)in dimethylformamide (70 ml) and methoxymethyl chloride (10.4 ml) were added to a solution of 7-hydroxy-3-(4-hydroxyphenyl)-chromen-2-one thus prepared (8.74 g) followed by stirring for 2 hours at 80° C. After cooling, water was added to the reaction mixture and the resulting precipitates were collected by filtration and dried under reduced pressure to give 7-methoxymethoxy-3-(4-methoxymethoxyphenyl)chromen-2-one (8.67 g, Yield 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]([F:27])([F:28])[F:26])[C:17]([OH:19])=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC(F)(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC(F)(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
65.0 mg (142 μmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4,4-trifluorobutanoate (racemate) in 1.6 ml of dichloromethane and 411 μl (5.34 mmol) of TFA were reacted according to General Method 6A. Yield: 53 mg (81% of theory)
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:29]2[C:28]3[C:23](=[CH:24][C:25]([OH:30])=[CH:26][CH:27]=3)[NH:22][C:21]=2[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][CH:18]=1>N1C=CC=CC=1.CCOC(C)=O>[N:1]1([C:7]([O:30][C:25]2[CH:26]=[CH:27][C:28]3[C:29]4[C:21](=[C:20]([C:31](=[O:32])[NH2:33])[CH:19]=[CH:18][C:17]=4[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[F:10])[NH:22][C:23]=3[CH:24]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(O)ccc12
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(OC(=O)N3CCOCC3)ccc12
Reaction time: 22 h
Yield: 31.4 %

Procedure:
Morpholine-4-carbonyl chloride (11.29 mg, 0.075 mmol) was added to a solution of 4-(2-fluorophenyl)-7-hydroxy-9H-carbazole-1-carboxamide (Example 40-1, 18.6 mg, 0.058 mmol) in pyridine (1 mL). After 22 h at rt, additional morpholine-4-carbonyl chloride (11.29 mg, 0.075 mmol) was added. After 15 h, the mixture was diluted with EtOAc (30 mL), washed with water (10 mL) and brine (5 mL), and dried and concentrated. The residue was purified by preparative HPLC to provide 8-carbamoyl-5-(2-fluorophenyl)-9H-carbazol-2-yl morpholine-4-carboxylate as a white solid (7.9 mg, 27%). 1H NMR (400 MHz, chloroform-d) δ 9.94 (1 H, br. s.), 7.41-7.65 (3 H, m), 7.33 (2 H, t, J=8.14 Hz), 7.20 (1 H, d, J=8.58 Hz), 6.92-7.15 (4 H, m), 6.73 (1 H, dd, J=8.58, 1.98 Hz), 3.80 (4 H, t, J=4.62 Hz), 3.67-3.76 (2 H, m), 3.62 (2H, br. s.). Mass spectrum m/z 434.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CC1C=CC(S(O[CH2:20][CH2:21][CH2:22][NH:23][C:24]2[C:25](=[O:41])[N:26]([C:37]([CH3:40])([CH3:39])[CH3:38])[S:27](=[O:36])(=[O:35])[C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=O)=O)=CC=1>>[C:37]([N:26]1[C:25](=[O:41])[C:24]([NH:23][CH2:22][CH2:21][CH2:20][O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[S:27]1(=[O:35])=[O:36])([CH3:38])([CH3:39])[CH3:40]
Reactant: Oc1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccccc2F)=C(c2ccccc2)S1(=O)=O
Yield: 62 %

Procedure:
The title compound was prepared as described for Example 12 from 2-fluorophenol and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate with a reaction time of 15 mins. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using 15% EtOAc in petroleum ether 40-60° C. as eluent then dissolved in EtOAc. The product containing fractions were evaporated and the residue was washed with aqueous K2CO3 (2M) and evaporated to give the title compound (0.063 g, 62%). 1H NMR (500 MHz CDCl3): δ 7.54-7.50 (m, 2H), 7.45-7.40 (m, 3H), 7.11-7.03 (m, 2H), 6.94-6.85 (m, 2H), 5.57 (t, 1H), 3.91 (t, 2H), 3.15-3.10 (m, 2H), 1.90-1.82 (m, 2H), 1.74 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.8, 153.9, 152.0, 146.8, 146.7, 135.3, 131.8, 129.8, 128.8, 125.2, 124.6, 124.5, 121.9, 121.8, 116.6, 116.5, 115.5, 107.4, 67.2, 61.7, 41.7, 29.2, 27.8. Mass Spectrum M+H+ 433.
Reaction SMILES: S(=Cl)=O.[F:4][C:5]1[CH:13]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].[CH2:18]([CH:20]([CH2:23][CH3:24])[CH2:21]O)[CH3:19]>N1C=CC=CC=1>[F:4][C:5]1[CH:13]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:21][CH:20]([CH2:23][CH3:24])[CH2:18][CH3:19])=[O:8]
Reactant: CCC(CC)CO
Reactant: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Solvent: c1ccncc1
Product: CCC(CC)COC(=O)c1ccc(OC(C)=O)cc1F

Procedure:
Thionyl chlorine in an amount of 60 ml (milliliter) was added to 11.9 g (0.06 mol) of 2-fluoro-4-acetoxybenzoic acid, and the mixture was allowed to react under reflux for 7 hours. Then, excess thionyl chloride was distilled off, and then 10 ml of pyridine and 3.7 g (0.0402 mol) of 2-ethyl-1-butanol were dropwise added.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[C:11]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:10]=2)=[CH:4][CH:3]=1.[CH:27]([N:30]=[C:31]=[O:32])([CH3:29])[CH3:28].O>O1CCCC1>[CH2:20]([NH:19][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[NH:30][CH:27]([CH3:29])[CH3:28])=[CH:7][CH:6]=2)[N:14]=[CH:13][C:12]=1[CH2:15][C:16]([NH2:18])=[O:17])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NC(=O)Cc1cnc(Nc2ccc(N)cc2)cc1NCc1ccccc1
Reactant: CC(C)N=C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)NC(=O)Nc1ccc(Nc2cc(NCc3ccccc3)c(CC(N)=O)cn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 120.5 %

Procedure:
10 mg of 6-[(4-aminophenyl)amino]-4-(benzylamino) pyridine-3-carboxyamide (the compound of Example 65) was dissolved in 0.5 mL of tetrahydrofuran, and, under ice cooling, 7.6 mg of isopropyl isocyanate was added, and stirred at room temperature for 24 hours. To the reaction mixture, water was added, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was washed with methanol-ether to obtain 15 mg (80%) of the title compound as a light pink crystalline powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[CH:3][N:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([OH:14])=[O:13])=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)Cc1cncc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cc1cncc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of tert-butyl 2-(isoquinolin-4-yl)acetate (1.8 g, 7.4 mmol) in DCM (10 mL) was added TFA (10 mL) dropwise. The reaction was stirred at room temperature overnight. After the reaction completed, the solvent was evaporated and the residue was neutralized with aqueous ammonia to pH 3-4, then the precipitate was filtered, washed with water and ether, and the ether extract was collected to give the title compound (1.3 g, 93%) LC-MS (0.05% TFA): [M+1]+ 188.1. 1H-NMR (DMSO-d6, 400 MHz): δ 9.39 (s, 1H), 8.48 (s, 1H), 8.24 (d, 1H, J=6.4 Hz), 7.93 (t, 1H), 7.79 (m, 1H), 4.11 (s, 2H).
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][CH2:2]1.[C:11]1([S:21](Cl)(=[O:23])=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:11]1([S:21]([N:1]2[CH2:10][CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][CH2:2]2)(=[O:23])=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)C1CCN(S(=O)(=O)c2cccc3ccccc23)CC1
Reaction time: 8 h
Yield: 73.9 %

Procedure:
Methyl isonipecotate (1.0 g, 6.9 mmol), 1-naphthalenesulfonyl chloride (1.58 g, 6.9 mmol) and DMAP (0.17 g, 1.4 mmol) were dissolved in pyridine (10 mL). After stirring overnight, the reaction mixture was concentrated in vacuo, diluted with water (15 mL) and extracted into methylene chloride (3×10 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting yellow oil was purified by column chromatography on SiO2 eluted with hexanes/ethyl acetate (1:1) to yield 1.7 g (73%)of the title compound as a white foam. 1H NMR (400 MHz, Chloroform-d) δ, ppm: 1.67-1.77 (m, 2 H), 1.93 (dd, J=13.64, 3.79 Hz, 2 H), 2.25-2.34 (m, 1 H), 2.68-2.77 (m, 2 H), 3.63 (s, 3 H), 3.74 (ddd, J=12.51, 3.66, 3.54 Hz, 2 H), 7.56-7.66 (m, 3 H), 7.92 (d, J=9.35 Hz, 1 H), 8.07 (d, J=8.34 Hz, 1 H), 8.21 (d, J=7.33 Hz, 1 H), 8.71 (d, J=8.08 Hz, 1 H); ESI-MS: m/z 334.3 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH:12]1([CH3:22])[CH2:17][CH2:16][CH:15]([CH:18]([CH3:20])[CH3:19])[CH:14](O)[CH2:13]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.O>C1(C)C=CC=CC=1>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([O:5][CH:14]1[CH:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17][CH:12]([CH3:22])[CH2:13]1)=[O:4]
Reactant: O=C(O)C(O)c1ccccc1
Reactant: CC1CCC(C(C)C)C(O)C1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CCC(C(C)C)C(OC(=O)C(O)c2ccccc2)C1

Procedure:
2.1 kg of hydroxyphenylacetic acid are esterified with 2.5 kg of (-)-menthol in 15 l of boiling toluene with the addition of 40 g of toluenesulphonic acid; the water of reaction is removed from circulation in a water separator. When water is no longer separated, the mixture is cooled, washed with 4 l of saturated NaHCO3 and twice with 4 l of water and concentrated to dryness in vacuo. The title compound is obtained as an oily residue.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])[CH:3]=1.Cl.[CH3:26][O:27][C:28](=[O:40])[C@@H:29]([NH2:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([I:38])[CH:32]=1>>[CH3:26][O:27][C:28](=[O:40])[C@@H:29]([NH:39][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][C:4]=1[NH:11][S:12]([C:15]1[C:16]2[N:17]=[CH:18][CH:19]=[N:20][C:21]=2[CH:22]=[CH:23][CH:24]=1)(=[O:14])=[O:13])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([I:38])[CH:32]=1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)c(I)c1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Cl)c(I)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
4-Iodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid was coupled to (S)-2-amino-3-(4-chloro-3-iodo-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C, to afford title compound. HPLC: RT=10.61 min. MS (ESI+): mass calcd. for C25H19ClI2N4O5S, 776.77; m/z found, 777/779 [M+H]+. 1H NMR (400 MHz, CDCl3): 11.09 (s, 1H), 9.01-8.98 (m, 1H), 8.95-8.92 (m, 1H), 8.58 (d, J=7.3, 1H), 8.34 (d, J=8.5, 1H), 8.11 (d, J=1.5, 1H), 7.94-7.88 (m, 1H), 7.57 (d, J=1.9, 1H), 7.36-7.26 (m, 2H), 7.00-6.94 (m, 2H), 6.42 (d, J=6.3, 1H), 4.95-4.88 (m, 1H), 3.81 (s, 3H), 3.20-3.07 (m, 2H).
Reaction SMILES: CO[C:3]1[C:4](=[O:10])[C:5](=[O:9])[C:6]=1[O:7][CH3:8].[NH2:11][C:12]1[C:13]([F:31])=[C:14]([CH:28]=[CH:29][CH:30]=1)[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])=[O:16]>CO>[F:31][C:13]1[C:12]([NH:11][C:3]2[C:4](=[O:10])[C:5](=[O:9])[C:6]=2[O:7][CH3:8])=[CH:30][CH:29]=[CH:28][C:14]=1[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])=[O:16]
Reactant: CC(C)OC(=O)[C@@H]1CCCN1C(=O)c1cccc(N)c1F
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CO
Product: COc1c(Nc2cccc(C(=O)N3CCC[C@H]3C(=O)OC(C)C)c2F)c(=O)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.6 %

Procedure:
1.80 g (0.01 mol; 2.0 eq) of 3,4-dimethoxy-3-cyclobutene-1,2-dione were added to a solution of 1.87 g (0.08 mol; 1.0 eq) of isopropyl (S)-1-(3-amino-2-fluorobenzoyl)pyrrolidine-2-carboxylate in 45 ml of methanol. The reaction medium was stirred at ambient temperature for 24 hours. The solvent was evaporated off and the residue was chromatographed on silica gel (200 g prepacked column, eluent 20/80 then 0/100 heptane/ethyl acetate). 1.32 g of isopropyl (S)-1-[2-fluoro-3-(2-methoxy-3,4-dioxocyclobut-1-enylamino)benzoyl]pyrrolidine-2-carboxylate were obtained in the form of a light yellow amorphous solid. Yield=51%.