Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([F:13])[C:5]=1[CH2:14][CH2:15][NH:16][C:17](OC)=O.[H-].[Na+].CI.[Cl-].[NH4+]>C1COCC1>[F:13][C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]2[C:5]=1[CH2:14][CH2:15][N:16]([CH3:17])[C:3]2=[O:2]
Reactant: COC(=O)NCCc1c(F)ccc([N+](=O)[O-])c1C(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1CCc2c(F)ccc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
To a solution of 3-fluoro-2-(2-methoxycarbonylamino-ethyl)-6-nitro-benzoic acid methyl ester (20.4 g, 68 mmol) in THF (200 mL), sodium hydride (5.44 g, 136 mmol) was added at 0° C. and the mixture was stirred at rt for 2.0 hrs. To the reaction mixture was added methyl iodide (12.7 mL, 204 mmol) at 0° C. and the mixture was stirred at rt for 1.5 hours. To the mixture was added saturated ammonium chloride solution at 0° C., and the mixture was extracted three times with ethyl acetate. The organic layer was washed twice with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/ethyl acetate/hexane: from 99/1/50 to 99/2/50) to give 5-fluoro-2-methyl-8-nitro-3,4-dihydro-2H-isoquinolin-1-one (10.9 g) as yellow solid in 71% yield.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:17][C@H:18]1[CH2:22][NH:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19]1>O>[OH:17][CH:18]1[CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:20]([C:23]([OH:25])=[O:24])[CH2:19]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)C1CC(O)CN1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
10 g (70.9 mmol) of 4-fluoronitrobenzene, 11.75 g (85 mmol) of potassium carbonate and 9.3 g (70.8 mmol) of trans-4-hydroxyproline were stirred in 100 ml of distilled water. The mixture was refluxed for 16 hours and was then cooled to room temperature. The product was extracted with ethyl acetate. The organic phases were washed with a saturated solution, dried over sodium sulphate and concentrated under reduced pressure. The oil obtained was crystallized from an ethyl acetate/heptane mixture. A yellow powder was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:16][CH:17]([O:23][CH2:24][CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=1[OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38]OS(C)(=O)=O)=[CH:33][CH:32]=1)(=[O:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:16][CH:17]([O:23][CH2:24][CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=1[O:15][CH2:38][CH2:37][C:34]1[CH:33]=[CH:32][C:31]([O:30][S:27]([CH3:26])(=[O:28])=[O:29])=[CH:36][CH:35]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)OCCc1ccc(OS(C)(=O)=O)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c(NC(=O)OC(C)(C)C)c1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)c(NC(=O)OC(C)(C)C)c1)OCC
Yield: 21.4 %

Procedure:
Ethyl 3-{3-[(tert-butoxycarbonyl)amino]-4-hydroxyphenyl}-2-ethoxypropanoate (0.16 g, 0.44 mmole) and 4-{2-[(methylsulfonyl)oxy]ethyl}phenyl methanesulfonate (0.26 g, 0.88 mmole) were dissolved in 2-butanone (10 ml). Polyethyleneglycol 400 (0.05 g) and anhydrous potassium carbonate (0.092 g, 0.66 mmole) were added the mixture. After stirring at reflux for 16 hours it was checked with using HPLC whether all the starting material was consumed. The mixture was washed with water dried with magnesium sulfate and evaporated. Purification of the crude product with preparative HPLC (Kromasil C8, 7 μm, 50×250 mm) using actonitrile(60-80%) in ammonium acetate buffer (pH 7) as mobile phase gave 0.052 g (21% yield) of the desired product
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:28])[C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21](OS(C)(=O)=O)[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:29]([O-:32])(=[S:31])[CH3:30].[K+]>CN(C)C=O>[C:29]([S:31][CH:21]1[CH2:20][N:19]([C:16]2[S:17][CH:18]=[C:14]([C:12](=[O:13])[N:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:28])[N:15]=2)[CH2:22]1)(=[O:32])[CH3:30]
Reactant: CC([O-])=S
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N(C)CCO[Si](C)(C)C(C)(C)C)cs2)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
To a solution of 1-(4-{N-[2-(t-butyldimethylsilyloxy)ethyl]-N-methyl-carbamoyl}-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (516 mg, 1.14 mmol) (obtained as described in Reference Example 40(5)) in dimethylformamide (15 ml) was added potassium thioacetate (815 mg, 7.14 mmol) at room temperature. The mixture was stirred in an oil bath (90° C.) for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:2) as the eluant to afford 3-acetylthio-1-(4-{N-[2-(t-butyldimethylsilyloxy)ethyl]-N-methyl-carbamoyl}-1,3-thiazol-2-yl)azetidine (279 mg, yield 57%) as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:17])(=O)=O>C(O)(=O)C>[Cl:17][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[NH:10][C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)NC(=O)CC2
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc2c(cc1Cl)CCC(=O)N2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
35.4 Grams of 7-methoxy-3,4-dihydrocarbostyril are dissolved in 300 ml of acetic acid. This solution is stirred under ice-cooling conditions, and 100 ml of acetic acid solution containing 27 g of sulfuryl chloride are added dropwise and allowed to stand overnight. The reaction mixture is poured into 1 liter of ice-water and the precipitate thus formed is separated by filtration, washed with water and dried. Recrystallization from methanol obtains 30 g of 6-chloro-7-methoxy-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 212° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])=[O:4].C(Cl)(=O)C([Cl:17])=O.CN(C)C=O>ClCCl>[Cl:17][C:8]([C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)Cl)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To 3-(methoxycarbonyl)benzoic acid (6.2 g, 34.44 mmol, 1.00 equiv) in dichloromethane (50 mL) was added oxalyl dichloride (8.74 g, 69.37 mmol, 2.00 equiv) and N,N-dimethylformamide (cat.) and the resulting solution was stirred for 1 h at 40° C. in an oil bath. The mixture was concentrated under vacuum to yield 6.6 g (87%) of methyl 3-(chlorocarbonyl)benzoate as brown oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]3[CH2:18][CH2:17]C[C@H:15]3[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:27])[C:3]1=[O:28].O(C[C@@H]1CCN1S(C1C=C2C(=CC=1)NC(=O)C2=O)(=O)=O)C1C=CC=CC=1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]3[CH2:18][CH2:17][C@H:15]3[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:12])=[O:13])=[CH:8][CH:9]=2)[C:4](=[O:27])[C:3]1=[O:28]
Reactant: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Agent: O=C1Nc2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc2C1=O
Product: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)ccc21
Yield: 48 %

Procedure:
(S)-1-Methyl-5-(2-phenoxymethyl-azetidine-1-sulfonyl)-1H-indole-2,3-dione (18a) was prepared according to the same procedure for compound 11a, except using compound 17, and purified with ether to afford 46 mg (48%) of 18a as an orange solid, mp 173.5-174.9° C. 1H NMR (300 MHz, CDCl3) δ 8.04 (m, 2H), 7.24 (m, 2H), 6.94 (m, 2H), 6.79 (m, 2H), 4.46 (m, 1H), 4.10 (m, 2H), 3.86 (m, 2H), 3.25 (m, 3H), 2.30 (m, 2H). Anal. Calcd for C19.N2O5S: C, 59.06, H, 4.70, N, 7.25. Found: C, 58.98, H, 4.75; N, 7.19.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:36]=[CH:35][C:29]([CH2:30][S:31](Cl)(=[O:33])=[O:32])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][S:31]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)(=[O:33])=[O:32])=[CH:35][CH:36]=1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)Cc3ccc(Cl)cc3)cc2)c2ccc3ccccc3c2N1
Yield: 56 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 4-chlorobenzylsulfonyl chloride, the title compound (yield 56%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(F)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenol: ESMS m/e: 505.2 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:42])=[C:30]([NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[O:18]=[C:16]1[NH:15][C:14](=[O:19])[CH:13]([CH2:12][C:11]2[CH:20]=[CH:21][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][C@@H:24]([C:26]4[CH:27]=[CH:28][C:29]([OH:42])=[C:30]([NH:32][S:33]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)(=[O:35])=[O:34])[CH:31]=4)[OH:25])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[S:17]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: NC[C@H](O)c1ccc(O)c(NS(=O)(=O)c2ccccc2)c1
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(=O)(=O)c5ccccc5)c4)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidine-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and N-[5-((R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-phenylsulfonamide (which was obtained in Example 32) according to the procedure of Example 73 as a white solid; mp >150° C. (decomposed); 1H NMR (300 MHz, DMSO- d6) δ 1.39 (m, 4H), 1.85 (m, 4H), 2.64 (m, 2H), 2.89 (s, 3H), 4.48 (m, 1H), 6.67 (d, J=6 Hz, 1H), 6.86 (m, 2H), 7.02 (m, 2H), 7.48 (m, 2H), 7.72 (d, J=6 Hz, 1H); MS (ES) m/z: 597.0 (MH+, 100%); HRMS Calcd. for C29H32N4O6S2 (MH+): 597.1836. Found: 597.1827.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>CO>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(O)c1c(Cl)cccc1Br
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1c(Cl)cccc1Br
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-bromo-6-chlorobenzoic acid (17.7 g, 75.2 mmol) in methanol (200 mL) at 0° C. was added (trimethylsilyl)diazomethane (2M in hexanes, 100 mL, 0.200 mol). The solution was stirred at 0° C. for 1.5 hours, then warmed to room temperature and washed with aqueous sodium bicarbonate and brine, dried over Na2SO4, filtered and concentrated. The residue was subjected to silica gel chromatography eluted with 0-5% ethyl acetate in hexanes to provide methyl 2-bromo-6-chlorobenzoate as a pale yellow oil that gave proton NMR spectra consistent with theory.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Br:8])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:10]1([C@@H:16]2[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+].C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Cl:1][C:2]1[C:7]([Br:8])=[C:6]([NH:22][C@H:19]2[CH2:18][CH2:17][C@@H:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:21][CH2:20]2)[CH:5]=[CH:4][N:3]=1
Reactant: N[C@H]1CC[C@@H](c2ccccc2)CC1
Reactant: Clc1ccnc(Cl)c1Br
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: Clc1nccc(N[C@H]2CC[C@@H](c3ccccc3)CC2)c1Br

Procedure:
2.27 g (10 mmol) of 2,4-dichloro-3-bromopyridine, 2.6 g (15 mmol) of cis-4-phenylcyclohexylamine and 0.1 g of ammonium chloride are heated at 120° C. for 10 hours in 10 ml of N-methylpyrrolidone. After cooling, saturated sodium hydrogencarbonate solution is added and the reaction product is extracted with ethyl acetate. Purification is carried out by column chromatography. Yield: 1.9 g (52%); m.p. 105° C.
Reaction SMILES: [C:1]([C:9]1[CH:40]=[CH:39][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:38]=[CH:37][C:23]([CH2:24][CH:25]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:41][O:42][NH2:43]>>[CH2:30]([CH:25]([CH2:24][C:23]1[CH:37]=[CH:38][C:20]([O:19][CH2:18][CH2:17][N:13]2[C:12]3[CH:39]=[CH:40][C:9]([C:1](=[N:43][O:42][CH3:41])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]=3[S:15][C:14]2=[O:16])=[CH:21][CH:22]=1)[C:26]([O:28][CH3:29])=[O:27])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)C(Cc1ccccc1)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Reactant: CON
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(Cc2ccccc2)C(=O)OC)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([Cl:21])=[CH:11][C:12]([Cl:20])=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]1CCOCC1>O>[CH2:1]([O:8][C:9]1[C:10]([Cl:21])=[CH:11][C:12]([Cl:20])=[C:13]2[C:18]=1[N:17]=[C:16]([CH:19]=[O:22])[CH:15]=[N:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cnc2c(Cl)cc(Cl)c(OCc3ccccc3)c2n1
Reactant: C1COCCO1
Solvent: O
Product: O=Cc1cnc2c(Cl)cc(Cl)c(OCc3ccccc3)c2n1
Yield: 59 %

Procedure:
A suspension of the 2-methyl product from Step B (93 mg, 0.291 mmol) and SeO2 (100 mg) in dioxane (4 mL) and H2O (0.4 mL) was heated under reflux for 3 h. The mixture was cooled, filtered (celite), and concentrated. Dichloromethane was added and the insoluble material was filtered off. The solvent was evaporated and the residue purified by SiO2-gel chromatography (dichloromethane) to yield the desired aldehyde as an off-white solid (57 mg, 59%).
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.FC(F)(F)C(O)=O.[NH:30]1[CH2:33][CH:32]([C:34]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[O:35])[CH2:31]1>>[CH3:43][O:42][C:39]1[CH:40]=[CH:41][C:36]([C:34]([CH:32]2[CH2:31][N:30]([C:13]3[N:14]4[C:18]([N:19]=[C:11]5[CH2:10][CH2:9][NH:8][CH2:22][CH2:21][C:12]=35)=[CH:17][CH:16]=[N:15]4)[CH2:33]2)=[O:35])=[CH:37][CH:38]=1
Reactant: COc1ccc(C(=O)C2CNC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)C2CN(c3c4c(nc5ccnn35)CCNCC4)C2)cc1

Procedure:
The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) azetidin-3-yl-(4-methoxy-phenyl)-methanone trifluoroacetate was used as the amine.
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]2[C:4](=[C:5]([C:22]#[N:23])[N:6]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N+:7]=2[O-])[CH:3]=1.P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]2[C:4](=[C:5]([C:22]#[N:23])[N:6]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[N:7]=2)[CH:3]=1
Reactant: N#Cc1c2cc(Br)c([N+](=O)[O-])cc2[n+]([O-])n1-c1ccc(F)cc1
Solvent: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1c2cc(Br)c([N+](=O)[O-])cc2nn1-c1ccc(F)cc1
Temperature: 60 °C

Procedure:
To a stirred solution of 5-bromo-3-cyano-2-(4-fluorophenyl)-6-nitro-2H-indazole 1-oxide (5.0 g, 0.013 mol) in chloroform (50 mL) was added phosphorus trichloride (5.0 mL, 0.057 mol) dropwise and the reaction mixture was heated to 60° C. for 1 h. Then the reaction mixture was poured into ice water and extracted into DCM (2×80 mL). The organic layer was concentrated, and ethanol was added to the residue. After filtration, 5-bromo-2-(4-fluorophenyl)-6-nitro-2H-indazole-3-carbonitrile was collected as solid (4.3 g, 91%). 1H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.25 (s, 1H), 7.89˜7.91 (m, 2H), 7.33˜7.37 (m, 2H). MS (M+H)+: 361/363.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][C@@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH2:23][C:24](=[O:27])[NH:25][N:26]=3)=[C:17]([F:28])[CH:16]=2)[CH2:10]1.C(N(CC)CC)C>CN(C=O)C>[F:28][C:17]1[CH:16]=[C:15]([N:11]2[CH2:10][C@H:9]([CH2:8][NH:7][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[O:13][C:12]2=[O:14])[CH:20]=[CH:19][C:18]=1[C:21]1[S:22][CH2:23][C:24](=[O:27])[NH:25][N:26]=1
Reactant: NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Reactant: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)CC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
Diketene (0.0590 ml, 0.648 mmol) is added dropwise to a solution of 2-[4-(5(S)-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluorophenyl]-4H-[1,3,4]thiadiazin-5-one (0.200 g, 0.617 mmol) and triethylamine (0.0946 ml, 0.679 mmol) in DMF (2 ml) and is stirred overnight at room temperature. The reaction mixture is evaporated to dryness and the residue is purified by PTLC (10% MeOH/DCM) to give a white solid (0.22 g, 89%); 1HNMR (300 MHz, DMSO-d6) δ 2.08 (s, 3H), 3.34 (s, 2H), 3.42-3.54 (m, 2H), 3.59 (s, 2H), 3.78 (dd, J=6.3, 9.1 Hz, 1H), 4.14 (t, J=9.1 Hz, 1H), 4.75-4.83 (m, 1H), 7.37 (dd, J=2.2, 8.5 Hz, 1H), 7.52 (dd, J=2.2, 14 Hz, 1H), 7.69 (t, J=8.8 Hz, 1H), 8.45 (t, J=5.8 Hz, 1H), 11.6 (s, 1H); mp 176-8; MS (m/z): [M+H]+=409.
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:14]=2)[C:6]1=[O:26].[F:31][C:32]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:33]=1[NH2:34].FC1C=C([N+]([O-])=O)C=CC=1N=CN(C)C>>[F:31][C:32]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:33]=1[NH:34][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:14]=2)[C:6]1=[O:26]
Reactant: CS(=O)c1ccc(N2C(=O)N(Cc3ccccc3Br)C(C)(C)C2=O)cc1C(F)(F)F
Reactant: Nc1ccc(F)cc1F
Agent: CN(C)C=Nc1ccc([N+](=O)[O-])cc1F
Product: CS(=O)c1ccc(N2C(=O)N(Cc3ccccc3Nc3ccc(F)cc3F)C(C)(C)C2=O)cc1C(F)(F)F

Procedure:
The reaction of 114.2 with 2,4-difluoroaniline under conditions as described for the preparation of compound 1 afforded 114. Molecular weight 551.13 (C26H22F5N3O3S); retention time Rt=2.06 min. [B]; MS (ESI): 552.17 (MH+).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccc(Cl)c(Cl)c3)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1ccc(Cl)c(Cl)c1

Procedure:
The 2-trifluoroacetamido-3-(3,4-dichlorophenyl)-6-benzoyl-imidazo[1,2-a]pyridine (9.91 g, 20.8 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 7.17 g. (90.4%). EA, MS(FD).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C@@H:6]1[C@@H:13]2[C@@H:9]([O:10]C(C)(C)[O:12]2)[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][C:19]([Cl:40])=[N:20][C:21]=3[NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:7]1)=[O:5])[CH3:2]>C(O)(C(F)(F)F)=O.O>[CH2:1]([NH:3][C:4]([C@@H:6]1[C@@H:13]([OH:12])[C@@H:9]([OH:10])[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][C:19]([Cl:40])=[N:20][C:21]=3[NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:7]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
A solution of (3aS,4S,6R,6aR)-6-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid ethylamide (Step D1) in TFA/water (2:1) is stirred at RT overnight. The reaction mixture is concentrated in vacuo to afford the titled compound.
Reaction SMILES: [C:1]([C:14]1[CH:20]=[CH:19][C:17]([OH:18])=[CH:16][C:15]=1[OH:21])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.O>C(O)(=O)C.C(Cl)(Cl)Cl.[Zn].[Hg](Cl)Cl>[CH2:1]([C:14]1[CH:20]=[CH:19][C:17]([OH:18])=[CH:16][C:15]=1[OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)c1ccc(O)cc1O
Agent: Cl
Agent: Cl[Hg]Cl
Agent: [Zn]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCCCc1ccc(O)cc1O

Procedure:
29.2 g of the product from (i) in 200 ml of acetic acid was added to 300 ml of 6 M hydrochloric acid to give a fine precipitate. To this was assed a zinc amalgam (made by intimately mixing 60 g of zinc, 6 g of mercury (II) chloride, 5 ml of conc. hydrochloric acid and 90 ml of water over 20 minutes. The mixture was heated at reflux for 5 hours; three further portions of 60 ml of conc. hydrochloric acid being added. After cooling, the filtered solids were taken up in chloroform, refiltered, and washed with 6 M hydrochloric acid, then water, dried and evaporated to give 26 g of the crude product. This was recrystallised from light petroleum (b.p. 60°-80° C.) to give 22.9 g of the product with a melting point of from 81°-82.5° C.