Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:17])[CH3:16])[CH:10]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>CN(C=O)C>[CH3:22][N:23]([CH3:25])[CH:24]=[CH:16][C:15]([C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:18])([F:19])[F:1])[CH:14]=[CH:13][CH:12]=1)=[O:17]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccc(-c2ccccc2C(F)(F)F)c1
Solvent: CN(C)C=O
Product: CN(C)C=CC(=O)c1cccc(-c2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
To a solution of 1-(2′-trifluoromethyl-1,1′-biphenyl-3-yl)ethanone (0.325 g, 1.3 mmol) in DMF (1.45 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (0.18 mL, 1.43 mL), and the solution was heated in a Smith Creator™ microwave reactor (commercially available from Personal Chemistry, Inc.) at 165° C. for 1200 seconds. The mixture was cooled to room temperature, partitioned between EtOAc and water, washed with brine, dried over sodium sulfate filtered and concentrated to give 0.395 g of the crude product (95%) (which was used as such for the subsequent step.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([NH:9][CH2:10][C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:12]=2)=[O:8])=[CH:5][N:6]=1.[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[C:11]([CH2:10][NH:9][C:7]([C:4]3[S:3][C:2]([N:33]4[CH2:34][CH2:35][CH:30]([OH:29])[CH2:31][CH2:32]4)=[N:6][CH:5]=3)=[O:8])=[CH:12][N:13]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1
Reactant: OC1CCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(Br)s1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(N2CCC(O)CC2)s1

Procedure:
2-(4-Hydroxypiperidin-1-yl)-thiazole-5-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate F and 4-hydroxypiperidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (t, J=5.54 Hz, 1H) 8.25 (d, J=8.66 Hz, 1H) 7.91 (s, 1H) 7.78 (s, 1H) 7.59-7.71 (m, 3H) 7.54-7.59 (m, 1H) 7.43 (dd, J=8.66, 2.01 Hz, 1H) 6.88 (d, J=1.81 Hz, 1H) 4.79 (d, J=4.03 Hz, 1H) 4.26 (d, J=5.44 Hz, 2H) 3.69 (dd, J=12.59, 4.53 Hz, 3H) 3.20 (ddd, J=13.09, 9.37, 3.53 Hz, 2H) 1.70-1.81 (m, 2H) 1.39 (td, J=8.66, 4.23 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][C:3]=1[CH:8]=[O:9].[OH:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:7][C:6]1[C:2]([C:14]2[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=2)=[C:3]([CH:8]=[O:9])[S:4][CH:5]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: O=Cc1scc(Br)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1scc(Br)c1-c1ccc(O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
A mixture of 3,4-dibromothiophene-2-carbaldehyde (see Intermediate 1 (see Example 15 for Intermediate synthesis)) (2.0 g, 7.5 mmol), 4-hydroxyphenylboronic acid (Scheme II, 8A, X1=4-hydroxyphenyl) (1.0 g, 7.5 mmol), Na2CO3 (1.6 g, 15 mmol), and Pd(PPh3)4 (431 mg, 0.37 mmol) in toluene/EtOH/H2O (30 mL, 5:3:2) was heated to 80° C. and stirred overnight under nitrogen. When TLC indicated that the starting material was consumed, the mixture was diluted with water, neutralized to pH=4-5 with HCl (1M), extracted with EtOAc, concentrated, and purified by column chromatography (PE:EtOAc=20:1) to give 4-bromo-3-(4-hydroxyphenyl)thiophene-2-carbaldehyde (Scheme II, 8, X1=4-hydroxyphenyl) (350 mg, yield 17%) as a white solid. 1H NMR (DMSO-d6 400 MHz): δ9.90 (s, 1H), 9.53 (s, 1H), 8.33 (s, 1H), 7.33 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H).
Reaction SMILES: C([O:5][C:6](=[O:27])/[CH:7]=[CH:8]/[C:9]1[CH:26]=[N:25][C:12]2[NH:13][C:14](=[O:24])[N:15]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:16][C:11]=2[CH:10]=1)(C)(C)C.C(OC(=O)/C=C/C1C=NC2NC(=O)N(CCN(C)C)CC=2C=1)(C)(C)C>>[CH2:22]([O:21][C:19]([CH2:18][CH2:17][N:15]1[CH2:16][C:11]2[CH:10]=[C:9](/[CH:8]=[CH:7]/[C:6]([OH:27])=[O:5])[CH:26]=[N:25][C:12]=2[NH:13][C:14]1=[O:24])=[O:20])[CH3:23]
Reactant: CCOC(=O)CCN1Cc2cc(/C=C/C(=O)OC(C)(C)C)cnc2NC1=O
Agent: CN(C)CCN1Cc2cc(/C=C/C(=O)OC(C)(C)C)cnc2NC1=O
Product: CCOC(=O)CCN1Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Yield: 44 %

Procedure:
According to the procedure of Preparation 130(e), except substituting (E)-3-[3-(2-ethoxycarbonyl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid tert-butyl ester for the (E)-3-[3-(2-dimethylamino-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid tert-butyl ester, the title compound (0.16 g, 44%) was prepared as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 8.30 (d, J=1.5 Hz, 1H), 8.16 (s, 1H), 7.70-7.60 (m, 1H), 6.60-6.50 (m, 1H), 4.70 (s, 2H), 4.13 (q, J=7.0 Hz, 2H), 3.74-3.68 (t, J=6.5 Hz, 2H), 2.74-2.66 (t, J=6.5 Hz, 2H), 1.25 (t, J=5.5 Hz, 3H); MS (ESI) m/e 320 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:48][C:49]1[C:54]([NH2:55])=[CH:53][CH:52]=[C:51]([CH3:56])[N:50]=1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([NH:55][C:54]4[C:49]([CH3:48])=[N:50][C:51]([CH3:56])=[CH:52][CH:53]=4)=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:3])([CH3:5])[CH3:4]
Reactant: Cc1ccc(N)c(C)n1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)Nc2ccc(C)nc2C)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2,6-dimethyl-pyridin-3-ylamine (Alfa) to give the title compound. HR-MS (ES, m/z) calculated for C42H50Cl2N7O3 [(M+H)+] 770.3347, observed 770.3351.
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:26][S:27]([CH:20]1[NH:19][CH2:18][C:16]2=[C:15]3[C:11](=[C:10]([C:22]([F:25])([F:24])[F:23])[C:9]([CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:17]2)[CH:12]=[CH:13][N:14]3[CH2:21]1)(=[O:29])=[O:28]
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1

Procedure:
A solution of 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (prepared as described in Example 2 above, 53 mg, 0.14 mmol), methanesulfonyl chloride (16 mg, 0.14 mmol) and diisopropylethylamine (0.072 mL, 0.42 mmol) in CH2Cl2 (3 mL) was stirred overnight. The solvent was evaporated under reduced pressure and the resulting residue purified by trituration from methanol-diethyl ether to 2-(methylsulfonyl)-6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (43 mg).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.C[O-].[Na+].[C:14](OCC)(=[O:16])C>[Cu]Br.O>[CH3:14][O:16][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: CCOC(C)=O
Reactant: Brc1ccc2sccc2c1
Agent: [Cu]Br
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2sccc2c1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
To a solution of 4-bromobenzenethiol (24.7 g) in acetone (100 ml) was added potassium carbonate (18.5 g), then 2-bromo-1,1-diethoxyethane (19.5 ml) was added dropwise thereto, the solution was stirred overnight at room temperature, then acetone was added thereto. The solution was filtered, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system). To a solution of the resulting 1-bromo-4-(2,2-diethoxyethylsulfanyl)benzene (32.5 g) in chlorobenzene (350 ml) was added polyphosphoric acid (60 ml), and then the solution was stirred for 2 hours at 140° C. The reaction mixture was poured into an ice, extracted with ethyl acetate, then sequentially washed with aqueous ammonia, water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo, the resulting residue was purified by silica gel column chromatography (hexane) to provide 5-bromobenzo[b]thiophene (13.7 g). By referring to the synthetic method of Tetrahedron Lett., 1993, 34, 1007, to 5-bromobenzo[b]thiophene (13.7 g) was added sodium methoxide (28% solution in methanol) (200 ml). Copper(I) bromide (13.5 g) and ethyl acetate (40 ml) were sequencially added thereto followed by stirring for 4.5 hours at 80° C. Ethyl acetate and water were sequentially added thereto, the solution was stirred, then filtered through celite pad, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (9.2 g).
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH:10]1([CH:15]([C:21]([CH3:23])=O)[C:16](OCC)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]1.Cl>C(O)C>[CH:10]1([C:15]2[C:16](=[O:17])[O:2][C:1]3[CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[C:3]=3[C:21]=2[CH3:23])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C(C(C)=O)C1CCCC1
Reactant: Oc1cc(O)cc(O)c1
Agent: Cl
Solvent: CCO
Product: Cc1c(C2CCCC2)c(=O)oc2cc(O)cc(O)c12

Procedure:
A solution of phloroglucinol (2.00 g) and ethyl 2-cyclopentylaceto-acetate (3.14 g) in ethanol (40 ml) was treated with dry HCl at 0° C. for 2.5 hours and the solution kept at that temperature overnight. Solvent was evaporated and the precipitate purified with flash chromatography eluting with toluene-EtOAc-AcOH (8: 1:1). Yield 1.22 g (29%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2cc(F)ccc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc2cc(CBr)ccc2c1

Procedure:
6-Fluoro-2-methylnaphthalene (20.5 g, 128 mmol, prepared by adaptation of the method of Wolinska-Mocydlarz et al2) and NBS (22.8 g, 128 mmol) were heated at reflux for 16 hr in CCl4 (210 mL) during which time, benzoyl peroxide (2.5 g) was added portionwise. The cooled solution was filtered and evaporated and the residue was extracted thoroughly with hexane (4×250 mL). The extracts were decanted from tarry material, combined and evaporated to give the product as a yellow solid, 29.8 g (97%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:21][C:22]4[NH:27][C:26](=[N:28][NH:29][C:30](OCC)=[O:31])[CH2:25][O:24][C:23]=4[N:35]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CN(C=O)C.ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:21][C:22]4[N:27]5[C:30](=[O:31])[NH:29][N:28]=[C:26]5[CH2:25][O:24][C:23]=4[N:35]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)NN=C1COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(n[nH]c3=O)CO4)cc2)CCC1
Yield: 34.2 %

Procedure:
A solution of Ethyl 2-(6-(4-(1-(tert-butoxycarbonylamino)cyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-ylidene)hydrazinecarboxylate (24 mg, 0.04 mmol) in dry DMF (1 mL) was heated at 200° C. for 10 min under microwave irradiation. The reaction mixture was diluted with dichloromethane, filtered on celite and concentrated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC (method G, gradient 5 to 95% 0.1% FA/ACN in 0.1% FA/H2O) to give the title compound (7 mg, 32%). 1H NMR (500 MHz, CDCl3): 9.18 (1H, br s), 8.54 (1H, s), 7.32 (2H, d), 7.28-7.26 (5H,m), 7.22-7.20 (2H,m), 5.32 (2H, s), 5.07 (1H, br s), 2.55-2.25 (4H, m), 2.10-2.03 (1H, m), 1.86-1.78 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17]([OH:19])=O)(=[O:11])=[O:10].ClC(OCC)=O.[CH2:29]([N:31]1[CH2:35][CH:34]([NH2:36])[CH2:33][N:32]1[CH2:37][CH3:38])[CH3:30]>C(Cl)Cl>[CH2:29]([N:31]1[CH2:35][CH:34]([NH:36][C:17](=[O:19])[C:16]2[CH:20]=[C:12]([S:9]([CH3:8])(=[O:10])=[O:11])[CH:13]=[CH:14][C:15]=2[O:21][CH3:22])[CH2:33][N:32]1[CH2:37][CH3:38])[CH3:30]
Reactant: CCN1CC(N)CN1CC
Reactant: COc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(NC(=O)c2cc(S(C)(=O)=O)ccc2OC)CN1CC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 109.7 %

Procedure:
Triethylamine (1.01 g, 0.010 mole) was added to a stirred mixture of 5-methylsulfonyl-2-methoxybenzoic acid (2.30 g, 0.010 mole) in 50 ml of methylene chloride. The mixture was cooled to 0° C. for 20 minutes and maintained at this temperature while ethyl chloroformate (1.09 g, 0.010 mole) was added dropwise. After another 20 minutes of stirring at 0° C., a solution of 1,2-diethyl-4-aminopyrazolidine (2.43 g, 0.010 mole) in 10 l of methylene chloride was added dropwise. The reaction mixture was allowed to come to ambient temperature and was stirred for 18 hrs. The reaction mixture was then extracted with 10% sodium bicarbonate solution, the methylene chloride layer separated and dried over magnesium sulfate. The methylene chloride solution was concentrated to give 3.90 g of a tanbrown solid which was recrystallized from water. A sulfate salt was prepared which was converted back to the free base. The solid free base that formed was recrystallized from ethanol-isopropyl ether to give 1.03 g (29%) of title compound; m.p. 123°-124° C. The compound was vacuum dried at 110° C.; the melting point was unchanged.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[F:28][C:29]([F:41])([F:40])[O:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35]>C1(C)C=CC=CC=1>[F:28][C:29]([F:40])([F:41])[O:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:35]
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1cccc(OC(F)(F)F)c1
Temperature: 103 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.0 g) and triethylamine (0.6 ml), and a solution of 3-trifluoromethoxybenzoyl chloride (0.5 g) dissolved in toluene (10 ml) was gradually added thereto under cooling and the mixture was stirred at 103° C. for 3 hours.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]=[N+:6]([O-:20])[C:7]2[CH:16]=[C:15]3[C:11]([CH2:12][CH:13]([N:17]([CH3:19])[CH3:18])[CH2:14]3)=[CH:10][C:8]=2[N:9]=1)[CH3:2].ClC1N=[N+]([O-:35])C2C3CCCC=3C=CC=2N=1>>[CH2:1]([NH:3][C:4]1[N:5]=[N+:6]([O-:20])[C:7]2[CH:16]=[C:15]3[C:11]([CH2:12][CH:13]([N:17]([CH3:19])[CH3:18])[CH2:14]3)=[CH:10][C:8]=2[N+:9]=1[O-:35])[CH3:2]
Reactant: CCNc1nc2cc3c(cc2[n+]([O-])n1)CC(N(C)C)C3
Reactant: [O-][n+]1nc(Cl)nc2ccc3c(c21)CCC3
Product: CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CC(N(C)C)C3

Procedure:
H2O2 (70%, 0.35 mL, ca. 6.9 mmol) was added dropwise to a stirred solution of TFAA (1.0 mL, 6.9 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 113 (188 mg, 0.7 mmol) and TFA (0.26 mL, 3.4 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 113 (175 mg, 93%) and (ii) 1,4-dioxide 114 (8 mg, 4%) as a red gum: 1H NMR δ 8.11 (s, 1H, H-9), 8.08 (s, 1H, H-5), 6.98 (br s, 1H, NH), 3.63 (dq, J=7.2, 1.0 Hz, 2H, CH2N), 3.15-3.30 (m, 3H, CH, CH2), 2.95-3.07 (m, 2H, CH2), 2.33 [s, 6H, N(CH3)2], 1.36 (t, J=7.2 Hz, 3H, CH3); MS (FAB+) m/z 290 (MH+, 20%), 274 (5); HRMS (FAB+) calcd for C14H20N5O2 (MH+) m/z 290.1617, found 290.1607.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2N=N1.N1CCCCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:30]1([C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]2)=[O:11])=[CH:20][CH:19]=3)=[O:22])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:33][CH2:34]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C1CCCNCC1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCCCCC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), azepane (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C@@H:13]2[CH2:14][CH2:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COC(=O)[C@H]1CC[C@@H](N)CC1
Product: COC(=O)[C@H]1CC[C@@H](NS(=O)(=O)c2ccc(Br)cc2)CC1

Procedure:
Using a method analogous to Method A with 4-bromophenylsulfonyl chloride and methyl cis-4-aminocyclohexanecarboxylate, the title compound was obtained as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[CH:14]=[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[C:12]([N+:28]([O-:30])=[O:29])=[CH:11][N:10]=1>C1COCC1>[CH:25]([NH:24][C:22]([C@H:19]1[CH2:20][CH2:21][C@@H:16]([NH:15][C:13]2[C:12]([N+:28]([O-:30])=[O:29])=[CH:11][N:10]=[C:9]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:14]=2)[CH2:17][CH2:18]1)=[O:23])([CH3:27])[CH3:26]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cc(N[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)c([N+](=O)[O-])cn1
Reaction time: 0.33 h

Procedure:
To an ice-bath cooled solution of 2-methoxyethanol (0.296 mL, 3.76 mmol) in THF (2.3 mL) was added sodium hydride (150 mg, 3.76 mmol), and the mixture was stirred for 20 minutes. To the mixture was added cis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (400 mg, 1.174 mmol), and the flask was removed from the ice bath and the reaction was stirred for 2 hours. The reaction was quenched with water and diluted with DCM, washed with water, saturated aqueous NaHCO3, and the organic layer dried over Na2SO4 and filtered through Celite® brand filter aid. The material was purified via flash chromatography using a linear gradient of 0% to 5% of 1% NH4OH in MeOH in CH2Cl2. The title compound was collected as a yellow solid (273 mg, 61% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:22]1[CH2:31][C@H:30]([OH:32])[CH2:29][C@H:23]1[C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[O:20][CH3:21].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[C:37]([O:45][C:46]([F:49])([F:48])[F:47])[CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:41]([C:38]1[CH:39]=[CH:40][C:35]([O:34][CH3:33])=[CH:36][C:37]=1[O:45][C:46]([F:47])([F:48])[F:49])(=[O:43])=[O:42])[C:6](=[O:11])[C:5]2([N:22]1[CH2:31][C@H:30]([OH:32])[CH2:29][C@H:23]1[C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[O:20][CH3:21]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccc(C2(N3C[C@H](O)C[C@H]3C(=O)N(C)C)C(=O)Nc3ccc(Cl)cc32)c(OC)c1
Product: COc1ccc(C2(N3C[C@H](O)C[C@H]3C(=O)N(C)C)C(=O)N(S(=O)(=O)c3ccc(OC)cc3OC(F)(F)F)c3ccc(Cl)cc32)c(OC)c1
Yield: 39.1 %

Procedure:
With 150 mg of (4R)-1-[5-chloro-3-(2,4-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-L-prolinamide (levorotatory compound), which is the compound described in Preparation 3.39 of brochure Publication No. WO01/055130 and 110 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 91 mg of the title compound (yellow amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:17]1([CH2:23][CH2:24][C:25](Cl)=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:11]([NH:16][C:25](=[O:26])[CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cc1cccnc1N)OCC
Reactant: O=C(Cl)CCc1ccccc1
Solvent: c1ccncc1
Product: CCOP(=O)(Cc1cccnc1NC(=O)CCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.2 %

Procedure:
To a solution of diethyl[(2-amino-3-pyridyl)methyl]phosphonate (9.65 g, 39.51 mmol) in pyridine (60 mL) was added 3-phenylpropionyl chloride (7.00 mL, 47.41 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 20 hrs. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-0/1, ethyl acetate/hexane=9/1) to give the title compound (13.56 g, yield 91%) as a brown oil.