Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:10].Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1>CS(C)=O.C(OCC)(=O)C>[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][CH:22]=2)[CH:12]=1)=[O:10]
Reactant: Clc1ccnc2ccccc12
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cn(-c2ccnc3ccccc23)c2ccccc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 152.2 %

Procedure:
1.73 g (12.5 mmol) of potassium carbonate are added at 20° C. under an argon atmosphere to 0.876 g (5 mmol) of 3-methoxycarbonyl-1H-indole in 10 cm3 of dimethyl sulphoxide. After stirring at 20° C. for 1 hour, 0.654 cm3 (5 mmol) of 4-chloroquinoline is added. After stirring at 100° C. for 43 hours, the reaction mixture is cooled and diluted with 20 cm3 of ethyl acetate and then washed with 3 times 10 cm3 of water and 10 cm3 of saturated aqueous sodium chloride solution. After separating the phases by settling, the organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 2.30 g of a residue which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (7/3 by volume)]. After concentrating the fractions under reduced pressure, 1.07 g of 3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole are obtained in the form of a white solid melting at 142° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.[CH3:30][C:31]1[C:36]([N+:37]([O-])=O)=[CH:35][N:34]=[C:33]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH:32]=1>>[NH2:37][C:36]1[C:31]([CH3:30])=[CH:32][C:33]([N:40]([CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:18][CH2:19][N:20]([C:23]3[N:24]=[CH:25][C:26]([Cl:29])=[CH:27][N:28]=3)[CH2:21][CH2:22]2)[C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[N:34][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)ncc1[N+](=O)[O-]
Product: Cc1cc(N(CC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)C(=O)OC(C)(C)C)ncc1N

Procedure:
The title compound was synthesized by procedure analogous to Step 2 and 3 of Example 28 from 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate from Step 1 of Example 5 and tert-butyl (4-methyl-5-nitropyridin-2-yl)carbamate from Step 1 of this example.
Reaction SMILES: C([O:8][C:9]([C:11]1([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.[OH-].[Na+]>C1COCC1.O.C(OCC)(=O)C>[F:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:23]2[CH:24]=[CH:25][C:20]([S:17]([NH:16][C:11]3([C:9]([OH:10])=[O:8])[CH2:15][CH2:14][CH2:13][CH2:12]3)(=[O:18])=[O:19])=[CH:21][CH:22]=2)=[CH:28][CH:29]=1
Reactant: O=C(OCc1ccccc1)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
1-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-cyclopentanecarboxylic acid benzyl ester (15 g, 32 mmole) in 75 mL THF was combined with 75 mL (150 mmole) 2N aqueous sodium hydroxide and stirred at reflux for 1 hour. The reaction was cooled to ambient temperature and diluted with 100 mL water and 100 mL ethyl acetate. The pH of the aqueous phase was adjusted to pH 1.2 and the ethyl acetate layer separated. The ethyl acetate layer was washed with 100 mL water and dried over magnesium sulfate. The ethyl acetate was stripped in vacuo and replaced with 75 mL methyl tert-butyl ether. The product was filtered and dried to yield 11.16 g (92%) of 1-[4-(4-fluoro-phenoxy) benzenesulfonylamino]-cyclopentanecarboxylic acid. 1H NMR (CDCl3) □ 7.71-7.78 (m, 2H), 6.88-7.04 (m, 6H), 5.04 (s, 1H), 2.01-2.13 (m, 2H), 1.92-1.98 (m, 2H), 1.44-1.68 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]=[C:7]=[O:8])[CH3:2].[F:9][C:10]1[C:11](=[O:17])[NH:12][C:13](=[O:16])[NH:14][CH:15]=1>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7]([N:14]1[CH:15]=[C:10]([F:9])[C:11](=[O:17])[NH:12][C:13]1=[O:16])=[O:8])[CH3:2]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CCOCCN=C=O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOCCNC(=O)n1cc(F)c(=O)[nH]c1=O
Reaction time: 3 h

Procedure:
To the above solution of 2-ethoxyethyl isocyanate was added a solution of 5-fluorouracil (2.60 g.) in N,N-dimethylacetamide (20 ml.) at 80° and stirred for further 3 hours at the same temperature. The resultant mixture was diluted with ethyl acetate (200 ml.), washed with saturated sodium chloride aqueous solution (each 30 ml., 2 times), dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 1-[N-(2-ethoxyethyl)carbamoyl]-5-fluorouracil (1.82 g.).
Reaction SMILES: N(=[C:3]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][N:22]=1)[C:4]1[C:9](=[O:10])[N:8]2[C:11]3([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:12][C:13](=[O:14])[C:7]2=[C:6]([CH3:20])[CH:5]=1)N.CC(C)([O-])C.[K+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.ClCCl>[CH3:20][C:6]1[CH:5]=[C:4]([CH2:3][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][N:22]=2)[C:9](=[O:10])[N:8]2[C:11]3([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:12][C:13](=[O:14])[C:7]=12
Reactant: Cc1cc(C(=NN)c2ccncn2)c(=O)n2c1C(=O)NC21CCCCC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc(Cc2ccncn2)c(=O)n2c1C(=O)NC21CCCCC1
Temperature: 25 °C

Procedure:
To a solution of 6′-(hydrazono(pyrimidin-4-yl)methyl)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (4, 100 mg, 0.28 mmol) in toluene (4 mL) is added potassium tert-butoxide (94 mg, 0.84 mmol). The reaction is refluxed overnight. The resulting mixture is cooled to room temperature, diluted with dichloromethane and is hed with 1 M ammonium chloride solution. The organic layer is dried over magnesium sulfate, filtered and concentrated. The crude is purified via HPLC to afford 8′-methyl-6′-(pyrimidin-4-ylmethyl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (Cpd. No. 212).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][O:12][CH2:13][CH2:14][N:7]3[C@H:6]3[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][C@@H:5]23)[CH:10]=1.[F:26][C:27]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.C(O)(=O)C>[F:26][C:27]1[C:34]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:1][C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][O:12][CH2:13][CH2:14][N:7]3[C@H:6]3[CH2:15][CH2:16][NH:17][CH2:18][C@@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Reactant: O=Cc1cccc(C(F)(F)F)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: Fc1c(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B (35 mg, 0.10 mmol) in 5 mL of acetonitrile was added 2-fluoro-3-(trifluoromethyl)benzaldehyde (38 mg, 0.20 mmol) and three drops of glacial acetic acid. The reaction was stirred at ambient temperature for 1 h and then there was added sodium triacetoxyborohydride (64 mg, 0.30 mmol). The reaction was stirred at ambient temperature for 3 h and then was quenched by the addition of aq ammonium hydroxide. The mixture was extracted with methylene chloride, washed with brine, dried (K2CO3) and concentrated. The residue was taken up in 10 mL of methylene chloride and then there was added 5 mL of trifluoroacetic acid. The reaction was allowed to stir at ambient temperature for 3 h and then was concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and the product containing fractions were concentrated, free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to afford the title compound of EXAMPLE 126. 1H NMR(CDCl3) δ: 7.55-7.40 (m, 2H), 7.12 (t, 1H, J=7.7 Hz), 6.31 (d, 1H, J=2.0 Hz), 6.15 (d, 1H, J=1.9 Hz), 4.48 (ABq, 2H, JAB=14.3 Hz), 4.32 (s, 2H), 4.12 (app d, 1H), 3.63 (app t, 1H), 3.30-3.20 (m, 2H), 3.18-2.98 (m, 4H), 2.56 (app t, 1H), 2.43 (app t, 1H), 2.05-1.92 (m, 2H). LRMS (ES)+: 422.3 (M+H)+.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8](Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:16]([CH2:19][C@H:20]1[O:25][CH:24]=[CH:23][C@@H:22]([OH:26])[C@@H:21]1[OH:27])=[N+:17]=[N-:18]>C(O)C>[N:16]([CH2:19][C@H:20]1[O:25][CH:24]=[CH:23][C@@H:22]([O:26][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:21]1[O:27][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=NC[C@H]1OC=C[C@@H](O)[C@@H]1O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: [N-]=[N+]=NC[C@H]1OC=C[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Suspend 5.16 gm. of sodium hydride in 50 ml. of ahydrous dimethylformamide. Maintain the temperature at 0°C. and add 12.4 ml. of benzyl chloride, then 4.65 gm. of 6-azido-6-deoxy-D-glucal in 17 ml. of dimethylformamide. Stir for 4 hours and then add 15 ml. of ethanol, after a further 10 minutes, pour the reaction mixture on ice and then extract wth chloroform. Wash the extracts with water, then dry over MgSO4 and then reduce in vacuo. Chromatograph the residue on silica gel using 25% ethyl acetate in benzene as the eluant to obtain 6-azido-6-deoxy-3,4-di-O-benzyl-D-glucal, [α]26 D + 34.3° (EtOH); pmr (CDCl3)δ 3.52 (2H, m, -CH2N3), 4.6 (4H, m, Ar-CH2 -), 6.38 (1H, dd, J=1.5, 6-Hz, H-1); ν max (CHCl3) 2100, 1640 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10](Cl)=[O:11])[CH:5]=[N:6][CH:7]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].N1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([N:15]([O:16][CH3:17])[CH3:14])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(Cl)C=Cc1cncc(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)C=Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 3-(5-bromo-pyridin-3-yl)-acryloyl chloride in the form of unpurified dark brown liquid, N,O-dimethylhydroxylamine hydrochloride (11.6 g, 119.3 mmol), and pyridine (20.4 mL, 252.4 mmol) were added at 0° C. to dichloromethane (150.0 mL). The reaction mixture was stirred at room temperature for 3 hours, quenched with distilled water, and then extracted with dichloromethane. The extract was washed with a 1N hydrochloric acid solution and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was recrystallized from diethyl ether and n-hexane to give 8.2 g of the titled compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1.[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH3:25])[CH2:21][CH2:22][CH2:23][NH2:24]>COCCOC>[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH3:25])[CH2:21][CH2:22][CH2:23][NH:24][C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1
Reactant: COCCN(C)CCCN
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Solvent: COCCOC
Product: COCCN(C)CCCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Yield: 76.9 %

Procedure:
A solution of chloride 21 (2.0 g, 9.03 mmol) and N1-(2-methoxyethyl)-N1-methylpropane-1,3-diamine (297) (2.0 g, 13.6 mmol) in DME (140 mL) was stirred at 20° C. for 18 h, the solvent evaporated and the residue purified by column chromatography, eluting with a gradient (2-15%) of MeOH/DCM, to give 1-oxide 52 (2.3 g, 79%) as a yellow solid: mp 59-61° C.; 1H NMR [(CH3)2SO] δ 7.94 (s, 1H, H-9), 7.68 (br s, 1H, NH), 7.38 (s, 1H, H-5), 3.24-3.44 (m, 6H, CH2), 3.23 (s, 3H, OCH3), 2.92-2.99 (m, 4H, H-6, H-8), 2.56 (br t, J=5.8 Hz, 2H, CH2N), 2.24 (s, 3H, NCH3), 2.03-2.07 (m, 2H, H-7), 1.70-1.74 (m, 2H, CH2); HRMS (FAB+): calcd for C17H26N5O2 (MH+) m/z 332.2087, found, 332.2089.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:9]=1.[NH2:34][C:35]1[C:40]([CH:41]([OH:47])[C:42]([N:44]([CH3:46])[CH3:45])=[O:43])=[CH:39][C:38](Br)=[CH:37][N:36]=1.C(=O)(O)[O-].[Na+]>C(#N)C.O1CCCC1>[NH2:34][C:35]1[C:40]([CH:41]([OH:47])[C:42]([N:44]([CH3:45])[CH3:46])=[O:43])=[CH:39][C:38]([C:14]2[CH:15]=[C:16]3[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[CH:9][N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:11]3=[N:12][CH:13]=2)=[CH:37][N:36]=1
Reactant: CC1(C)OB(c2cnc3c(c2)c(-c2ccccc2F)cn3COCC[Si](C)(C)C)OC1(C)C
Reactant: CN(C)C(=O)C(O)c1cc(Br)cnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CN(C)C(=O)C(O)c1cc(-c2cnc3c(c2)c(-c2ccccc2F)cn3COCC[Si](C)(C)C)cnc1N
Temperature: 80 °C
Yield: 39.3 %

Procedure:
3-(2-Fluoro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (289 mg, 0.617 mmol), 2-(2-amino-5-bromo-pyridin-3-yl)-2-hydroxy-N,N-dimethyl-acetamide (168.5 mg, 0.617 mmol) and dichloro[1,1′-bis(diphenyl-phosphino)ferrocene]palladium(II) dichloromethane adduct (25 mg, 0.031 mmol) were combined in 1:1 acetonitrile/tetrahydrofuran (4 mL) under nitrogen. Saturated sodium bicarbonate was added (4 mL), also under nitrogen, and the mixture was capped and heated for 18 h at 80° C. After cooling, the aqueous layer was removed and the organic layer was purified by silica gel chromatography using DCM and MeoH as eluent to afford 2-{2-Amino-5-[3-(2-fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-2-hydroxy-N,N-dimethyl-acetamide (130 mg, 39.3%). MS: m/z 536 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:20][C:21]1[CH:28]=[C:27](F)[C:24]([C:25]#[N:26])=[CH:23][N:22]=1>C1COCC1>[NH2:20][C:21]1[CH:28]=[C:27]([O:9][CH2:8][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:24]([C:25]#[N:26])=[CH:23][N:22]=1
Reactant: CN1CCC(CO)CC1
Reactant: N#Cc1cnc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCC(COc2cc(N)ncc2C#N)CC1
Reaction time: 0.03 h

Procedure:
(1-methylpiperidin-4-yl)methanol (283 mg, 2.19 mmol) was treated at room temperature with KHMDS (1 M in THF, 2.0 ml, 2.0 mmol). The reaction mixture was stirred for 2 min and then added to a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 100 mg, 0.729 mmol) in THF (1 ml). The resulting dark brown solution was stirred at room temperature for 1 h, quenched with sat. aq. NH4Cl and extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified twice by normal phase chromatography (4 g silica gel cartridge, DCM/(DCM/(1 M NH3 in MeOH) 9/1) 100:0 to 0:100) to give the title compound as a light brown resin. (UPLC-MS 3) tR 0.31 min, 0.33 min; ESI-MS 247.2, 247.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH:7]([CH2:9]O)[C:6]([NH:16][C:17]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[S:18])([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)[CH2:5]1)[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([N:4]1[CH2:8][CH:7]2[C:6]([C:11]3[S:15][CH:14]=[N:13][CH:12]=3)([N:16]=[C:17]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:18][CH2:9]2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CC(CO)C(NC(=S)NC(=O)c2ccccc2)(c2cncs2)C1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCN1CC2CSC(NC(=O)c3ccccc3)=NC2(c2cncs2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 0 %

Procedure:
To a solution of N-[[1-allyl-4-(hydroxymethyl)-3-thiazol-5-yl-pyrrolidin-3-yl]carbamothioyl]benzamide (60 mg, 150 moles) in tetrahydrofuran (1 mL) at 0° C. is added triphenylphosphine (80 mg, 30 μmoles) and di-t-butyl azodicarboxylate (88 mg, 30 μmoles). The mixture is stirred for 30 minutes at 0° C., warmed to room temperature and stirred for 1 hour. The mixture is concentrated and purified over silica gel eluting with methanol/dichloromethane (0-5%) to give the title product (26 mg, 70 μmoles, 45%). ES/MS (m/e): 385 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([C:15]1[S:16][C:17]([CH:21]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:25][CH:24]=3)[CH3:22])=[C:18](O)[N:19]=1)[CH3:14])[CH:7]=[CH:6]2.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([C:15]1[S:16][C:17]([CH:21]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:25][CH:24]=3)[CH3:22])=[C:18]([C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:19]=1)[CH3:14])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(C)c3nc(O)c(C(C)c4ccc(CC(C)C)cc4)s3)ccc2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc2cc(C(C)c3nc(C(=O)c4ccccc4)c(C(C)c4ccc(CC(C)C)cc4)s3)ccc2c1

Procedure:
The desired compound is prepared by treatment of the product of example 45 with benzoyl chloride and pyridine.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:13]1[N:17]([CH3:18])[N:16]=[N:15][N:14]=1)[C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[N:7]([CH3:9])[CH3:8].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].[Br:27][C:28]1[S:29][CH:30]=[C:31]([CH2:33]Br)[N:32]=1>C(#N)C>[Br:27][C:28]1[S:29][CH:30]=[C:31]([CH2:33][O:1][N:2]=[C:3]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][N:14]=2)[C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:9])[CH3:8])[N:32]=1
Reactant: CN(C)c1cccc(C(=NO)c2nnnn2C)c1
Reactant: BrCc1csc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CN(C)c1cccc(C(=NOCc2csc(Br)n2)c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a stirred solution of 3-[(hydroxyimino)(1-methyl-1H-tetrazol-5-yl)methyl]-N,N-dimethylaniline (1.25 g, 5.07 mmol) in acetonitrile (50 mL), were added cesium carbonate (3.47 g, 10.6 mmol), potassium iodide (421 mg, 2.53 mmol) and 2-bromo-4-bromomethyl-thiazole (1.44 g, 5.58 mmol). The resulting suspension was stirred at 25° C. for 4 h and 30 minutes. After cooling, the suspension was filtered, the filtrate was diluted with ethyl acetate (250 mL), washed with water (2×100 mL), dried over MgSO4 and concentrated in vacuo. Purification on silica gel afforded 3-[{[(2-bromo-1,3-thiazol-4-yl)methoxy]imino}(1-methyl-1H-tetrazol-5-yl)methyl]-N,N-dimethylaniline as an oil [1.83 g, yield 86%;
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[O:11]CC(C)(C)N=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24].Cl.[OH2:26]>>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[C:10]([OH:11])=[O:26])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24]
Reactant: O
Reactant: CC(C1=NC(C)(C)CO1)c1ccc(-c2ccc(F)cc2F)c(F)c1
Agent: Cl
Product: CC(C(=O)O)c1ccc(-c2ccc(F)cc2F)c(F)c1

Procedure:
2-[1-(2,2',4'-Trifluoro-4-biphenylyl)ethyl]-4,4-dimethyl-2-oxazoline (0.53 g.) was stirred and refluxed with hydrochloric acid (5 ml. of 2N) for 5 hrs. The mixture was diluted with water, extracted with ether and the latter extracted with 2.5% potassium carbonate solution. The aqueous extracts were acidified with dilute hydrochloric acid and the precipitate isolated in ether, washed with water, dried and evaporated. The residue was recrystallized from light petroleum (b.p. 80°-100° C.) to give 2-(2,2',4'-trifluoro-4-biphenylyl)propionic acid, m.p. 107°-108.5° C.
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]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=N1.CNCC1C=CC=CC=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[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]([N:32]2[CH2:33][CH2:38][CH2:37][CH2:36]2)=[O:23])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CNCc1ccccc1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCCC4)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), methylbenzylamine (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: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=O.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[N+:8]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[O:1][C:19]([C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([C:15]([F:14])([F:25])[F:26])[CH:17]=1)=[CH:12][C:11]2=[O:13])([O-:10])=[O:9]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1O
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: O=c1cc(-c2cccc(C(F)(F)F)c2)oc2c([N+](=O)[O-])cccc12
Temperature: 80 °C
Reaction time: 18 h
Yield: 13.5 %

Procedure:
1-(2-Hydroxy-3-nitrophenyl)ethanone 1 (1.2 g, 6.61 mmol) was taken up in 20 mL of pyridine along with 3-trifluoromethylbenzoyl chloride 48 (1.2 mL, 7.9 mmol) and DBU (2.9 mL, 14.5 mmol). The reaction mixture was stirred at 80° C. for 18 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with EtOAc and washed with dilute 1 N HCl. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (1:1 pentane/EtOAc) afforded 300 mg of 2. MS (ESI) calcd for C16H8F3NO4: 335.04. found: 336 [M+H].
Reaction SMILES: O1CCOCC1.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:10][CH:9]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(N(CC)CC)C>[C:21]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:12][CH:13]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(C2SC(=O)NC2=O)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1NC(=O)C(c2ccc(NC(=O)c3ccccc3)cc2)S1
Temperature: 0 °C
Yield: 93.3 %

Procedure:
Into 20 ml of dioxane were dissolved 0.5 g of 5-(4-aminophenyl) thiazolidine-2,4-dione, and, after added 0.34 g of benzoyl chloride and further added dropwise 0.24 g of triethylamine, the mixture was refluxed for 1 hour. After cooling by standing, the reaction mixture was poured into 150 ml of ice water and the crystals deposited were collected by filtration, washed with water and dried. These were recrystallized from chloroform to obtain 0.70 g of title compound.