Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([C:27]2[C:28]([CH:33]=O)=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:33][C:28]2[C:27]([S:24]([C:21]3[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=3)(=[O:25])=[O:26])=[CH:32][CH:31]=[CH:30][N:29]=2)=[C:6]1[CH3:15]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1ncccc1S(=O)(=O)c1ccc(F)cc1
Product: COC(=O)Cn1c(C)c(Cc2ncccc2S(=O)(=O)c2ccc(F)cc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and 3-(4-fluorobenzenesulfonyl)pyridine-2-carbaldehyde.
Reaction SMILES: [CH2:1](O)[CH2:2][CH:3]([OH:5])[CH3:4].[S:7](Cl)([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8]>C(Cl)Cl>[S:7]([CH2:1][CH2:2][CH:3]([OH:5])[CH3:4])([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)CCO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCC(C)O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
To a mixture of 1,3-butandiol (1.0 g, 11.1 mmol), Et3 3N (1.6 mL, 11.5 mmol) in CH2Cl2 (10 mL) at 0° C. was added dropwise a solution of TsCl(2.12 g, 11.1 mmol) in CH2Cl3 (5 mL). The resulting mixture was stirred at 0° C. and warmed gradually to room temperature, then kept at room temperature for overnight. It was transferred into a separatory funnel and washed with H2O (3×20 mL). The organic layer was dried (MgSO4), filtered. The filtrate was concentrated in vacuo. The residue was purified on column chromatography (silical gel, 30% ethyl acetate/hexane), thereby affording a colorless oil (1.3 g, 48%). 1H NMR (CDCl3) d 1.07 (d, J=6.0 Hz, 3 H, CH3), 1.52-1.76 (m, 2 H, CH2), 2.33 (s, 3 H, CH3), 3.84 (br s, 1 H, OH), 4.08-4.20 (m, 2 H, CH2), 7.25 (d, J=8.4 Hz, 2 H, aromatic), 7.77 (d, J=8.1 Hz, 2 H, 5 aromatic). 13C NMR (CDCl3) d 21.60 (q, CH3), 23.58 (q, CH3), 37.86 (t, CH2), 64.10 (d, CH), 67.79 (t, CH2OTs), 127.85 (d, aromatic) 129.84 (d, aromatic), 144.78 (s, aromatic), 152.23 (s, aromatic).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]C(O)=O)=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3]1.C([N:31](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.Cl>C(#N)C.O>[NH2:31][CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]3[CH2:7][C:2]([CH3:1])([CH3:28])[NH:3][C:4]([CH3:26])([CH3:27])[CH2:5]3)[N:14]=2)=[CH:20][CH:19]=1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(CCC(=O)O)cc3)n2)CC(C)(C)N1
Reactant: CCN(CC)CC
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: O
Product: CC1(C)CC(Nc2nccc(-c3ccc(CCN)cc3)n2)CC(C)(C)N1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A suspension of 3-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-propionic acid (100 mg, 0.26 mmol) (Step A of Example 185), triethylamine (37 μl, 0.26 mmol) and diphenylphosphoryl azide (57 μl, 0.26 mmol) in 3 ml acetonitrile was heated for 18 hours at 70° C. Then, 1.2 ml 0.4N-HCl was added and the mixture was stirred for 1 hour at ambient temperature. The solution was diluted with water, extracted with ether and the aqueous phase was made basic with 2N-NaOH. Extraction with EtOAc and purification with preparative HPLC gave the title compound. Yield: 24 mg (26%).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[C:37]([CH3:38])=[CH:36][C:35]([CH:39]4[CH2:41][CH2:40]4)=[CH:34][N:33]=3)[CH2:28][CH2:27]2)=[O:25])=[C:20]([F:42])[CH:19]=1>>[CH:39]1([C:35]2[CH:36]=[C:37]([CH3:38])[C:32]([N:29]3[CH2:28][CH2:27][N:26]([C:24]([C:21]4[CH:22]=[CH:23][C:18]([N:11]5[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]5(=[O:15])=[O:16])=[CH:19][C:20]=4[F:42])=[O:25])[CH2:31][CH2:30]3)=[N:33][CH:34]=2)[CH2:40][CH2:41]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3[C@H](CO)CCS3(=O)=O)cc2F)CC1
Yield: 10 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (241 mg) described in Preparation Example 1 and (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (418 mg) described in Preparation Example 121 and by the reaction and treatment in the same manner as in Example 32, the title compound (49 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH2:25]([N:27]([CH2:35][CH3:36])[C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1)[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([N:27]([CH2:35][CH3:36])[CH2:25][CH3:26])[CH:29]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CCN(CC)c1cccc(O)c1
Product: CCN(CC)c1cccc(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 39.3 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-diethylamino phenol (44 mg, 0.26 mmol) to give the title compound (26 mg, 39%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [Na].[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8][SH:9].Br[CH2:11][CH2:12][CH2:13][C:14]#[N:15]>C(O)C>[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8][S:9][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: Cc1[nH]cnc1CS
Reactant: N#CCCCBr
Agent: [Na]
Solvent: CCO
Product: Cc1[nH]cnc1CSCCCC#N

Procedure:
Sodium (5.0 g) was dissolved in ethanol (300 ml) and 5-methyl-4-(mercaptomethyl)imidazole (17 g) added, followed by a solution of 4-bromobutyronitrile (16 g) in ethanol (50 ml). The mixture was stirred under reflux for 45 minutes, cooled, filtered and the filtrate evaporated to dryness. The residue was taken up in water and extracted with ethyl acetate. The extract was dried (MgSO4) and solvent removed. Recrystallisation of the product from ethanol-ether gave 4-(5-methyl-4-imidazolylmethylthio)butyronitrile as its hydrochloride salt (12 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10]C)[CH:9]=1)[C:5]#[N:6].[Li+].[I-]>N1C(C)=CC(C)=CC=1C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[C:5]#[N:6]
Reactant: COc1cc(Br)cc(C#N)c1
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: N#Cc1cc(O)cc(Br)c1
Temperature: 150 °C
Yield: 89.7 %

Procedure:
step 3—Anhydrous collidine (100 mL) was added to a dry flask containing 3-bromo-5-methoxy-benzonitrile (10.4 g, 49 mmol) and LiI (19.6 g, 3 equiv). The solution was heated under nitrogen to 150° C. overnight, cooled to RT, and poured into an ice cold 1 M HCl solution. The mixture was extracted with a 1:1 EtOAc/hexanes solution, washed with water, and dried (MgSO4). Concentration in vacuo afforded 8.7 g (89%) of 3-bromo-5-hydroxy-benzonitrile.
Reaction SMILES: [C:1]1([CH:7]2[S:18][CH:10]3[S:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:9]3[C:8]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[S:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:9]=[C:10]1[S:18][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C1C(c2ccccc2)SC2Sc3ccccc3N12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H]1CCCN1C(=O)C(Sc1nc2ccccc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
5.7 g (0.02 m) 2-phenylthiazolo[2,3-b]benzothiazol-3(2H)-one mesoionic didehydro derivative, 2.2 g (0.02 m)-L-(-)-proline and 2.0 g (0.02 m) triethylamine are suspended in methylene chloride and the mixture is stirred at room temperature overnight. The reaction mixture is extracted with a dilute hydrochloric acid solution and dried over anhydrous magnesium sulfate. After the solvent is removed, the residue is extracted with hot cyclohexane. The solid obtained from the cyclohexane solution is recrystallized from acetonitrile. In order to remove all traces of acetonitrile, the solid is ground, stirred in water for 3 days, collected and then dried in an oven at 90° C. There is thereby obtained 3.0 g (37% yield) of the title compound, which has a melting point of 174°-5° C. (dec).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:26][C:11]2[N:12]=[C:13]([S:24][CH3:25])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[CH:17]=3)[C:10]=2[C:9]=1[NH2:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([NH:5][C:6]([C:8]1[S:26][C:11]2[N:12]=[C:13]([S:24][CH3:25])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CSc1nc(-c2cccc(O)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
tert-Butyl 5-amino-2-methylthio-4-(3-methoxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1e, 1.8 g) was dissolved in dry CH2Cl2 (30 ml) and the resulting solution was cooled down to 0° C. A solution of boron tribromide (1.28 ml) in dry CH2Cl2 (30 ml) was added dropwise and the mixture was stirred overnight at room temperature. Sat. aq. NaHCO3 was added dropwise to the reaction mixture until cessation of the exothermic reaction. Thereafter, CH2Cl2 was removed from the mixture by evaporation and a large amount of EtOAc was added. The organic layer was washed with sat. aq. NaHCO3, dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[CH:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([CH3:20])[CH3:19]>>[F:17][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([CH:18]([CH3:20])[CH3:19])=[CH:22][CH:23]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: CC(C)c1ccc(B(O)O)cc1
Product: Cc1c2n(c3c(-c4ccc(C(C)C)cc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (69 mg, 82%), MS (ISP) m/z=337.5 [(M+H)+], mp 177° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-isopropyl-phenylboronic acid (53.3 mg, 0.325 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[N:5]=[N:6][C:7]=1[NH2:8].Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C=O)C>[Br:1][C:2]1[C:7]2[N:6]([CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]=2)[N:5]=[C:4]([Cl:9])[CH:3]=1
Reactant: Nc1nnc(Cl)cc1Br
Reactant: CCOC(=O)C(=O)CBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2nc(Cl)cc(Br)c2n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 5-bromo-3-chloro-6-aminopyridazine (15.7 g, 75.3 mmol) in dry DMF (80 mL) was added ethyl bromopyruvate (21.0 mL, 151 mmol) via a syringe. The resulting mixture was stirred at rt for 20 h. The reaction mixture was poured into ice water (300 mL), and the precipitated solid was isolated by filtration, and washed with water (2×50 mL) and Et2O (3×50 mL). The residual solvents in the solid were removed under reduced pressure to give compound 5a as an off-white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.50 (s, 1H), 7.47 (s, 1H), 4.49 (q, J=7.1 Hz, 2H), 1.44 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([F:11])[C:4]=1[CH3:12])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[F:11][C:5]1[C:4]([CH3:12])=[C:3]([CH:1]2[CH2:2][O:21]2)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc(C#N)c(F)c1C
Solvent: ClCCl
Product: Cc1c(C2CO2)ccc(C#N)c1F
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 4-ethenyl-2-fluoro-3-methylbenzonitrile (4.60 g, 28.5 mmol) and mCPBA (85%, 12.3 g, 71.4 mmol) in 300 mL of DCM was stirred at room temperature for 120 hours. The reaction mixture was cooled to 0° C. and was washed subsequently with saturated NaHCO3 (50 mL), saturated Na2SO3 (50 mL), 5% NaOH (2×50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (petrol ether:EtOAc=20:1) to afford the title compound: 1H-NMR (400 MHz, CDCl3) δ ppm 7.36-7.39 (m, 1H), 7.04-7.06 (m, 1H), 3.92-3.94 (m, 1H), 3.15-3.17 (m, 1H), 2.57-2.59 (m, 1H), 2.30 (d, J=2.0 Hz, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[O:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.Cl[C:24]1[CH:25]=[C:26]2[N:33]([CH3:34])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>>[Cl:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:18]=1)[O:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14][O:15][C:24]2[CH:25]=[C:26]3[N:33]([CH3:34])[CH2:32][CH2:31][N:27]3[C:28](=[O:30])[N:29]=2)=[CH:10][CH:9]=1
Reactant: OCc1ccc(Oc2cc(Cl)cc(C(F)(F)F)c2)nc1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CN1CCn2c1cc(OCc1ccc(Oc3cc(Cl)cc(C(F)(F)F)c3)nc1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (4.85 mg, 0.121 mmol), (6-(3-chloro-5-(trifluoromethyl)phenoxy)pyridin-3-yl)methanol (60 mg, 0.198 mmol) in THEF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (36.7 mg, 0.198 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:13][CH3:14])([CH3:12])[CH2:8]2)=[C:4]([CH3:15])[CH:3]=1.[CH3:16][O:17]C(Cl)Cl>ClCCl.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:13][CH3:14])([CH3:12])[CH2:8]2)=[C:4]([CH3:15])[C:3]=1[CH:16]=[O:17]
Reactant: CCC1(C)Cc2c(C)cc(Cl)c(C)c2C1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC1(C)Cc2c(C)c(Cl)c(C=O)c(C)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 19 g of the 6-chloro-2-ethyl-2,4,7-trimethylindane in 100 ml of dry dichloromethane was continuously added 9.5 ml of α,α-dichloromethyl methyl ether and 11.5 ml of TiCl4 at 0° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with 100 ml of water, and separated the organic layer. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 20.85 g of the title compound as yellow solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:15]1([NH:20][S:2]([C:5]2[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=2)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Reactant: NC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)c1cc(S(=O)(=O)NC2CCCC2)ccc1F
Yield: 90 %

Procedure:
5-Chlorosulfonyl-2-fluoro-benzoic acid (A, 0.506 g, 0.0021 mol), cyclopentylamine (B, 0.1806 g, 0.00212 mol) and diisopropylethyl amine (DIEA, 1.1 mL, 0.00636 mol) in CH2Cl2 were stirred at room temperature overnight. The solvent was evaporated and the crude product was purified by silica gel chromatography (MeOH containing 10% AcOH)/CH2Cl2) to give 5-cyclopentylsulfamoyl-2-fluoro -benzoic acid (C, 0.55 g, 90%). After drying overnight under vacuum, C (0.48 g, 0.0016 mol) in SOCl2 (5 mL) was heated at 80° C. for 3 hours, after which the SOCl2 was evaporated and the residue was dried overnight. The residue was then dissolved in tetrahydrofuran (5 mL), 3,4-Difluoro-phenylamine (D, 0.216 g, 0.00167 mol) was added followed by diisopropylethyl amine (0.5 mL). The mixture was heated to 70° C. overnight. The solvent was evaporated, followed by ethyl acetate extraction. After purification by silica gel chromatography (ethyl acetate/hexane), 0.3 g (45%) of 5-cyclopentylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide (DVR-56) was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:19])=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10]2.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:19])=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10]2)(=[O:30])=[O:29]
Reactant: CCOC(=O)c1cc2c(C)ccc(OCCO)c2[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(C)ccc(OCCOS(C)(=O)=O)c2[nH]1
Temperature: -10 °C

Procedure:
A mixture of ethyl 7-(2-hydroxyethoxy)-4-methyl-1H-indole-2-carboxylate (1.10 g, 4.18 mmol), triethylamine (0.93 g, 9.19 mmol) and dichloromethane (30 ml) was cooled to -10° C., after which methanesulfonyl chloride (0.57 g, 5.01 mmol) was added dropwise with stirring at -10° C. After completion of the dropwise addition, the resulting mixture was stirred at -10° C. for another 2 hours and the reaction mixture was poured into ice water, followed by extraction with chloroform (three times). The extract solution was washed successively with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium hydrogencarbonate solution and a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain ethyl 7-(2-methanesulfonyloxyethoxy)-4-methyl-1H-indole-2-carboxylate. This compound was used in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([O:27]C)=O)[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[NH3:29].O1CCCC1>CO>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([NH2:29])=[O:27])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(Cc2c(-c3ccccc3)[nH]c3cc(OC)ccc23)n1
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(Cc3cccc(C(N)=O)n3)c(-c3ccccc3)[nH]c2c1

Procedure:
A mixture of methyl 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (500 mg), a solution (about 7 mol/L, 20.1 mL) of ammonia in methanol, and tetrahydrofuran (6.7 mL) was stirred at room temperature for 61 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (490 mg). 1H-NMR (CDCl3) δ ppm: 3.86 (3H, s), 4.42 (2H, s), 5.37-5.60 (1H, br), 6.77 (1H, dd, J=2.3, 8.8 Hz), 6.92 (1H, d, J=2.3 Hz), 7.24-7.29 (1H, m), 7.31-7.39 (2H, m), 7.40-7.49 (2H, m), 7.50-7.58 (2H, m), 7.69 (1H, t, J=7.8 Hz), 7.75-7.95 (1H, br), 7.97-8.03 (1H, m), 8.09 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:17])=[C:7]([CH3:16])[C:8]=2[N+:13]([O-])=O)[N:3]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:13][C:8]1[C:7]([CH3:16])=[C:6]([CH3:17])[CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([Cl:12])[C:2]([Cl:1])=[N:3]2
Reactant: Cc1cc2nc(Cl)c(Cl)nc2c([N+](=O)[O-])c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc2nc(Cl)c(Cl)nc2c(N)c1C
Yield: 83 %

Procedure:
A mixture of 2,3-dichloro-6,7-dimethyl-5-nitroquinoxaline (from step (b), 8.33 g, 30.6 mmol) and stannous chloride dihydrate (34.54 g, 153 mmol) in ethyl acetate (300 ml) was heated at reflux for 11 hours. A further portion of stannous chloride dihydrate (13.82 g, 61.2 mmol) was added and the mixture was heated for 2 hours, cooled and diluted with ethyl acetate (500 ml). The mixture was added to saturated aqueous sodium bicarbonate (200 ml) and filtered, washing the filter cake well with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium bicarbonate (3×100 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with methanol/dichloromethane) to afford 5-amino-2,3-dichloro-6,7-dimethylquinoxaline (6.15 g, 83%), as an orange solid, m.p. 178-180° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[OH:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH:8]=1
Reactant: COC(=O)CNCc1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2cc(CNCCO)ccn2)cc(OC)c1OC
Reaction time: 4 h

Procedure:
N-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-glycine methyl ester (6.54 g) was dissolved in THF (80 mL), and to the solution lithium aluminum hydride (717 mg) was gradually added portionwise at 0° C. under an argon atmosphere, and the mixture was stirred for 4 hours. A small amount of water was added to the reaction mixture. When bubbling ended, sodium sulfate was excessively added. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=20:1) to obtain the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:41])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH:38]3[CH2:40][CH2:39]3)[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:38]1([C:34]2[CH:33]=[C:32]([C:28]3[CH:27]=[C:26]([C:24]4[CH2:23][C:22](=[O:41])[NH:21][C:9]5[CH:10]=[C:11]([C:17]([F:19])([F:20])[F:18])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=5[N:7]=4)[CH:31]=[CH:30][CH:29]=3)[CH:37]=[CH:36][N:35]=2)[CH2:40][CH2:39]1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C4CC4)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C4CC4)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyclopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M268) (298 mg, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (179 mg, 75%).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14]C)=[O:13])[C:8]=2[CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)(=O)C>CO>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[C:8]=2[CH2:16][CH2:17][C:18]([F:20])([F:21])[F:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1noc(-c2ccccc2)c1CCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1noc(-c2ccccc2)c1CCC(F)(F)F
Yield: 20.9 %

Procedure:
A solution of methyl 5-phenyl-4-(3,3,3-trifluoropropyl)isoxazole-3-carboxylate (25 mg, 0.084 mmol) and 1N aqueous sodium hydroxide (125 μL, 0.125 mmol) in methanol (1 mL) was heated at 23° C. for 2 h. To the reaction mixture was added acetic acid until the pH was ˜5. The mixture was purified by preparative HPLC to afford 5-phenyl-4-(3,3,3-trifluoropropyl)isoxazole-3-carboxylic acid (5 mg). The compound had an HPLC ret. time=3.16 min.−Column. YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=286+.