Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:62])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([O:42][CH:43]5[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]5)=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:50]([F:61])[C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=2)[CH2:4][CH2:3]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[F:62][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:37]=[CH:38][C:39]([O:42][CH:43]5[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]5)=[CH:40][N:41]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:50]([F:61])[C:51]2[CH:52]=[CH:53][C:54]([C:57]([F:58])([F:60])[F:59])=[CH:55][CH:56]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(OC6CCN(C)CC6)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CN1CCC(Oc2cnc(N3CCC(c4nc5c(c(C6CCC(F)(F)CC6)c4C(F)c4ccc(C(F)(F)F)cc4)C(O)CC(C)(C)C5)CC3)nc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 16.3 %

Procedure:
To a solution of 86 mg (99 μmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(1-{5-[(1-methylpiperidin-4-yl)oxy]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 29, in 1.0 ml of dichloromethane, 0.2 ml of anisole and 0.2 ml of trifluoroacetic acid were added, and the reaction solution was stirred at room temperature for 12 hours. After completion of the reaction, the solvent in the reaction solution and trifluoroacetic acid were distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [dichloromethane/methanol/28% ammonia water=100/0/0-90/9.5/0.5 (V/V/V)] and thin layer chromatography [dichloromethane/methanol/28% ammonia water=90/9.5/0.5 (V/V/V)] to provide 12 mg of the title compound as a white solid (yield: 17%).
Reaction SMILES: [C:1]([O-:15])(=O)[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7].[Ca+2].[C:17]([O-:31])(=O)[CH2:18][CH2:19][NH:20][C:21](=[O:29])[C@@H:22]([C:24]([CH2:27][OH:28])([CH3:26])[CH3:25])[OH:23].Cl.Cl.[NH2:34][CH2:35][CH2:36][S:37][S:38][CH2:39][CH2:40][NH2:41].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1.O>[CH3:26][C:24]([C@@H:22]([OH:23])[C:21]([NH:20][CH2:19][CH2:18][C:17]([NH:34][CH2:35][CH2:36][S:37][S:38][CH2:39][CH2:40][NH:41][C:1]([CH2:2][CH2:3][NH:4][C:5]([C@H:6]([OH:7])[C:8]([CH2:11][OH:12])([CH3:9])[CH3:10])=[O:13])=[O:15])=[O:31])=[O:29])([CH2:27][OH:28])[CH3:25]
Reactant: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)[O-]
Reactant: NCCSSCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)CO
Reaction time: 1 h
Yield: 69.2 %

Procedure:
11.9g. of calcium pantothenate, 6.8g. of cystamine dihydrochloride and 7.7g. of 1-hydroxylbenzotrizole were dissolved in 50ml. of pyridine and 10ml. of water, and thereafter pyridine (25ml.) solution of 10.5g. of dicyclohexylcarbodiimide was added thereto at a time, and the reaction was effected at a temperature below 10° C for 1 hour and then for 5 hours at a room temperature. Next the solvent was removed under a reduced pressure, the residue thereof was added with 50ml. of water, and the deposited crystals were removed by filtration. Pyridine left in the filtered mother liquor was completely removed azetropically with water. The residue thereof was added with 50ml. of water and after cooling, the deposited crystals were filtration removed and extracted with 20ml. of chloroform two times. The water layer was treated under a reduced pressure to remove the remaining chloroform, and thereafter like Example 1, passed through the ion exchange resin, and the flowed out liquid was concentrated under a reduced pressure and thereby colorless transparent viscous liquid of pantethine which was the objective compound was obtained. Drying was carried out by means of a vacuum dryer for one night and as a result 9.6g. of pantethine (yield rate 69.2%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][OH:12].N[C:14](N)=[O:15].[OH-].[Na+]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][CH2:11][OH:12])[C:14](=[O:15])[NH:1][C:2]=2[CH:7]=1
Reactant: NC(N)=O
Reactant: Nc1cc(Cl)ccc1NCCO
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2cc(Cl)ccc2n1CCO
Reaction time: 8 h

Procedure:
A mixture of 9 parts of 2-[(2-amino-4-chlorophenyl)amino]-ethanol and 9 parts of urea is stirred and heated for 2 hours at 180°-190° C. After cooling the reaction mixture is treated with concentrated sodium hydroxide solution. The obtained solution is filtered from some unsoluble matter. It is then treated with activated charcoal and filtered again. The filtrate is acidified with concentrated hydrochloric acid. After keeping overnight at room temperature, the precipitated solid is filtered off, washed and dried, to yield 5 parts of 5-chloro-1-(2-hydroxyethyl)-1,3-dihydro-2H-benzimidazol-2-one; mp. 176°-178.2° C; pale-brown, amorphous powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[F:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>ClCCl>[NH2:1][CH2:2][CH2:3][CH2:4][NH:5][S:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:22]=[CH:23][C:7]([F:6])=[CH:8][CH:9]=2)=[CH:13][CH:14]=1)(=[O:19])=[O:20]
Reactant: NCCCN
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(F)cc2)cc1
Solvent: ClCCl
Product: NCCCNS(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1,3-diaminopropane (6.7 mL) in 100 mL of dichloromethane at -10° C. was slowly added over a 2 hour period a solution of 4-(4-fluorophenoxy)benzenesulfonyl chloride (5.7 g, 20 mmol) in 50 mL of dichloromethane. The reaction was stirred for 15 minutes after the addition was complete, and then partitioned between ethyl acetate and water. The resulting emulsion was cleared by addition of dichloromethane, and the organic layer was separated. The aqueous layer was extracted with dichloromethane and the combined organic layers were extracted with 0.5 N aq. sodium bisulfate. The aqueous phase was brought to pH 8 with sodium bicarbonate and then extracted with dichloromethane (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated to a volume of about 50 mL. Addition of hexane resulting in formation of a precipitate, which was collected by filtration to provide N-(3-aminopropyl)-4-(4-fluorophenoxy)benzenesulfonamide (4.27 g) as a white solid: mp 184° C. (softens), 237° C. (melts) 1H NMR (300 MHz, DMSO-d6): δ7.84 (d, J=9 Hz, 2H), 7.38-7.21 (m, 4H), 7.12 (d, J=9 Hz, 2H), 3.6-3.2 (br s, 3H), 2.80 (dd, J=7, 7 Hz, 2H), 2.77 (dd, J=7, 7 Hz, 2H), 1.72-1.60 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH:20]([CH3:22])[O:19][CH:18]([CH3:23])[CH2:17]2)[N:3]=1.O.[NH2:25][NH2:26].Cl>>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][C:4]([N:16]3[CH2:21][CH:20]([CH3:22])[O:19][CH:18]([CH3:23])[CH2:17]3)=[CH:5][C:6]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:26][N:25]=1
Reactant: CC1CN(c2cc(-c3ccccc3)c(C#N)c(Cl)n2)CC(C)O1
Reactant: NN
Agent: Cl
Solvent: O
Product: CC1CN(c2cc(-c3ccccc3)c3c(N)n[nH]c3n2)CC(C)O1

Procedure:
3-Amino-6-(2,6-dimethyl-morpholino)-4-phenyl-1H-pyrazolo[3,4-b]-pyridine was prepared analogous to Example 1 from 2-chloro-6-(2,6-dimethyl-morpholino)-4-phenyl-3-cyano-pyridine (m.p. 165°-178° C.; mixture of isomers) and hydrazine hydrate. M.p. of the hydrochloride: 235°-238° C. (decomp.).
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])[CH2:5]2.[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[O:32][C:31]([C:33](=O)[CH3:34])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[O:21])[CH2:15][CH2:14]1.N1CCCCC1>C1(C)C=CC=CC=1>[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=[C:33]([C:31]1[O:32][C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:20]([N:16]3[CH2:17][CH2:18][CH2:19][N:13]([CH3:12])[CH2:14][CH2:15]3)=[O:21])=[CH:27][CH:26]=2)=[CH:29][CH:30]=1)[CH3:34]
Reactant: CC(=O)c1ccc(-c2ccc(C(=O)N3CCCN(C)CC3)cc2)o1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(=C1C(=O)Nc2ccc(Cl)cc21)c1ccc(-c2ccc(C(=O)N3CCCN(C)CC3)cc2)o1
Yield: 19.4 %

Procedure:
A solution of 5-chlorooxindole (362 mg, 2.17 mmol), 1-(5-(4-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)ethanone (800 mg of oil) and piperidine (214 μL, 2.17 mmol) in toluene (10 mL) was heated at reflux with a Dean-Stark receiver for 16 hours. After evaporation of the solvent, purification by silica column chromatography (methanol gradient in dichloromethane, 0 to 5% vol) gave 5-chloro-3-(1-(5-(4-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)ethylidene)indolin-2-one (200 mg) as an E:Z mixture. LCMS (ES): m/z 476 [M+1]+.
Reaction SMILES: C[Si](C)(C)OC([NH:6][C@@H]1C(=O)N2C(C(O[Si](C)(C)C)=O)=C(COC(=O)C)CS[C@H]12)=O.[Si](I)(C)(C)C.C([O-])(=O)C.C[Si](C)(C)OC(N[C@@H:45]1[C:61](=[O:62])[N:47]2[C:48]([C:54]([O:56][Si:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])=[C:49]([CH2:52][I:53])[CH2:50][S:51][C@H:46]12)=O.C[C:66]([O:68][Si:69]([CH3:72])([CH3:71])[CH3:70])=[O:67]>ClCCl>[CH3:70][Si:69]([CH3:72])([CH3:71])[O:68][C:66]([C@H:45]1[C:61](=[O:62])[N:47]2[C:48]([C:54]([O:56][Si:57]([CH3:58])([CH3:59])[CH3:60])=[O:55])=[C:49]([CH2:52][I:53])[CH:50]([NH2:6])[S:51][C@H:46]12)=[O:67]
Reactant: CC(=O)O[Si](C)(C)C
Reactant: CC(=O)OCC1=C(C(=O)O[Si](C)(C)C)N2C(=O)[C@@H](NC(=O)O[Si](C)(C)C)[C@H]2SC1
Reactant: C[Si](C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)O[Si](C)(C)C)=C(CI)CS[C@H]12
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CI)C(N)S[C@@H]2[C@@H](C(=O)O[Si](C)(C)C)C(=O)N12

Procedure:
To a stirred solution of (6R, 7R)-trimethylsilyl 7-[((trimethylsilyl)oxy)carbonyl]amino-3-acetoxymethylceph-3-em-4-carboxylate in dichloromethane (prepared according to Method B of Example 2; 5.0 g input 7-ACA) was added 3.0 ml (21.1 mmoles, 1.15 equivalents) of TMSI in a slow stream at ambient temperature under a blanket of dry nitrogen. The progress of the reaction was monitored by 1H NMR (acetate region). After a total of 65 minutes, the 1H NMR spectrum of an aliquot of the dark solution shows >95% conversion to the desired (6R, 7R)-trimethylsilyl 7-[((trimethylsilyl)oxy)carbonyl]amino-3-iodomethylceph-3-em-4-carboxylate: NMR (CD2Cl2) δ0.27 (br s, 9H --NHCOOSi(CH3)3), overlapped with CH3COOSi(CH3)3), 0.37 (s, 9H, --COOSi(CH3)3), 3.57 (d, 1H, J=18.1 Hz, --SCH2), 3.80 (d, 1H, J=18.1 Hz, --SCH2), 4.34 (d, 1H, J=9.2 Hz, --CH2I), 4.51 (d, 1H, J=9.2 Hz, --CH2I), 5.00 (d, 1H, J=4.6 Hz, --COCH(N)CH(N)SCH2 --); the remainder of the spectrum was obliterated by protonic dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:17]=1.[C:18](=O)([O-])[O-].[Cs+].[Cs+].IC.O>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:18])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:17]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCN(C2CCC2)c2nc(Cl)ncc2N1
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCN(C2CCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.127 g (0.0005 mole) of 2-chloro-9-cyclobutyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-23), 0.442 g (0.0014 mole) of cesium carbonate and 0.13 g (0.0009 mole) of iodomethane in 1 mL of dimethylformamide was stirred overnight at ambient temperature and then 2 mL of water was added and the mixture stirred for an additional 10 minutes. A solid formed, which was collected by filtration, to give 2-chloro-9-cyclobutyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-23), which was used directly in the next step.
Reaction SMILES: [O:1]=[C:2]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[C:4]([NH:11][C@@H:12]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:35])[C:27]3[C:32]([Cl:33])=[CH:31][N:30]=[CH:29][C:28]=3[Cl:34])=[CH:21][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:3]1.C(N(CC)CC)C.[Br:43]Br.CCOC(C)=O>C1COCC1>[Br:43][C:3]1[C:2](=[O:1])[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[C:4]=1[NH:11][C@@H:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:35])[C:27]2[C:28]([Cl:34])=[CH:29][N:30]=[CH:31][C:32]=2[Cl:33])=[CH:21][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: BrBr
Reactant: CCOC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)NC1=CC(=O)C12CCCCC2
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)NC1=C(Br)C(=O)C12CCCCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.7 %

Procedure:
A solution containing Intermediate 4 (500 mg, 0.97 mmol) and triethylamine (2 eq, 270 μl) in THF (10 ml) at 0° was treated dropwise with a solution of bromine (1.1 eq, 170 mg) in THF (5 ml). After 20 mins the reaction was allowed to warm to room temperature prior to dilution with EtOAc (100 ml). The crude reaction mixture was washed with saturated aqueous NaHCO3 (20 ml) and brine (20 ml), dried (MgSO4) filtered and concentrated in vacuo. The residual foam was chromatographed (SiO2; EtOAc) to give the title compound as a white powder (511 mg, 0.86 mmol, 95%). δH (CDCl3, 300K) 8.48 (2H, s), 8.05 (1H, s br), 7.52 (2H, d J 8.4 Hz), 7.04 (2H, d J 8.5 Hz), 5.81 (1H, d br, J 8.3 Hz), 4.98-4.91 (1H, m), 4.21 (2H, q, J 7.1 Hz), 3.21 (2H, d J 5.3 Hz), 1.70-1.66 (4H, m), 1.53-1.44 (4H, m), 1.28 (3H, t J 7.1 Hz), 1.20-1.16 (2H, m); m/z (ES+, 70V) 597.9 and 595.0 (MH+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][O:23][N:24]=[C:25]1[C:29]2([CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]2)[CH2:28][NH:27][CH2:26]1.C(#N)C.C(N(CC)CC)C>CN(C)C=O>[C:36]([O:35][C:33]([N:31]1[CH2:32][C:29]2([C:25](=[N:24][O:23][CH3:22])[CH2:26][N:27]([C:11]3[C:12]([F:14])=[C:13]4[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]4[CH:1]4[CH2:2][CH2:3]4)=[C:9]([NH2:17])[C:10]=3[F:16])[CH2:28]2)[CH2:30]1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON=C1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC12CN(C(=O)OC(C)(C)C)C2
Reaction time: 1 h
Yield: 30.9 %

Procedure:
1-cyclopropyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid, 1.05 g of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate and 4 g of AmberliteR IRA-420 were added to 20 ml of acetonitrile and thereto 2 ml of triethylamine was added by dropping. The mixture was refluxed for 5 days and then 2 ml of dimethylformamide was added thereto. The resulting mixture was stirred for 1 hour and thus precipitated solid was filtered off. The filtrate was concentrated under the reduced pressure and then to the resulting residue 10 ml of acetonitrile was added and stirred for 1 hour. The precipitated solid was filtered and dried to give 420 mg of the titled compound (yield: 30.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].N1C=CC=CC=1.Cl[C:34]([C:36]1[CH:37]=[C:38]([CH:50]=[CH:51][CH:52]=1)[CH2:39][S:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:35]>ClCCl>[Cl:26][C:23]1[CH:24]=[CH:25][C:2]([NH:1][C:34]([C:36]2[CH:37]=[C:38]([CH:50]=[CH:51][CH:52]=2)[CH2:39][S:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:47])[CH3:48])=[O:44])=[O:35])=[C:3]([C:4](=[O:5])[NH:6][C:7]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[N:8]=2)[CH:22]=1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 2-amino-5-chloro-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide (191 mg, 0.50 mmol, 1.00 equiv) in dichloromethane (5 mL), pyridine (120 mg, 1.50 mmol, 3.00 equiv), and tert-butyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (158 mg, 0.50 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was washed with 2×50 mL of water. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (20:1) to give 100 mg (30%) of product as yellow oil.
Reaction SMILES: [NH2:1][CH:2]([CH:10]([OH:27])[CH2:11][CH:12]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][C:29]=1[C:38](O)=[O:39].CN1CCOCC1>C(Cl)Cl>[C:21]1([S:18]([CH:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][CH:10]([OH:27])[CH:2]([NH:1][C:38]([C:29]2[CH:30]=[N:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]=2)=[O:39])[CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:20])=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1cnc2ccccc2n1
Reactant: CC(C)CCC(CC(O)C(N)Cc1ccccc1)S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of one equivalent of 2-amino-5-benzenesulfonyl-8-methyl-1-phenyl-nonan-3-ol in methylene chloride is added 1.05 equivalents each of 2-quinoxalinecarboxylic acid, N-methyl morpholine, and O-benzotriazol-1-yl-N,N,N′,N′-teteramethyluronium hexafluorophosphate. The reaction mixture is stirred at ambient temperature for 18 h. After standard aqueous work-up and extraction, followed by concentration and silica gel chromatography the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[Br:7][C:8]1[S:16][C:15]2[CH:14]=[CH:13][N:12]=[C:11](Cl)[C:10]=2[CH:9]=1.O>CN(C=O)C>[Br:7][C:8]1[S:16][C:15]2[CH:14]=[CH:13][N:12]=[C:11]([S:16][C:15]3[CH:14]=[CH:3][C:2]([CH3:5])=[CH:1][CH:10]=3)[C:10]=2[CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: Clc1nccc2sc(Br)cc12
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2nccc3sc(Br)cc23)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Para-thiocresol (500 mg, 4 mmol) in DMF (10 mL) was treated with potassium t-butoxide (451 mg, 4 mmol) at room temperature, after 15 minutes cooled to 0° C., treated with 2-bromo-4-chlorothieno[3,2-c]pyridine (prepared in 6 steps according to the method of F. Eloy and A. Deryckere (Bull. Soc. Chim. Belg. 1970, 79,301) (1.0 g, 4.0 mmol), stirred at 0° C. for 2 hours and at room temperature for 12 hours, poured into water and extracted with diethyl ether. The extract was washed with water, dried (Na2SO4), and concentrated under vacuum. The residue was purified by flash chromatography on silica gel with 1:20 ethyl acetate-hexane to provide the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[NH2:8][CH2:9][C@H:10]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C@H:11]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1.C(N(CC)CC)C.O>C1COCC1>[Cl:31][C:26]1[CH:25]=[C:24]([C@H:11]2[C@@H:10]([CH2:9][NH:8][S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH:29]=[CH:28][C:27]=1[Cl:30]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CN)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C=CS(=O)(=O)NC[C@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
2-Chloroethanesulfonyl chloride (390 mg) was added dropwise to a solution of tert-butyl (6R,7S)-7-(aminomethyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (600 mg) and triethylamine (0.67 mL) in THF (5 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (235 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.[Cl-].[NH4+]>O1CCCC1.O.[Zn]>[CH3:1][C:2]1([CH3:21])[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CC1(C)COc2cccc(Oc3ccc([N+](=O)[O-])cc3)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COc2cccc(Oc3ccc(N)cc3)c21
Temperature: 40 °C
Yield: 77.6 %

Procedure:
To a solution of 3,3-dimethyl-4-[(4-nitrophenyl)oxy]-2,3-dihydro-1-benzofuran (Intermediate 54, 0.9 g) in tetrahydrofuran (20 ml, SCRC) and water (10 ml) were added ammonium chloride (1.687 g, 31.5 mmol, SCRC) and zinc powder (1.031 g, 15.77 mmol, SCRC). The mixture was heated at 40° C. for 2 hours and then filtered through a pad of celite. The filtrate was partitioned with water (20 ml) and ethyl acetate (50 ml, SCRC). The organic layer was dried, evaporated and purified by column chromatography on silica gel (EtOAc/PE=from 1/50 to 1/30) to afford the title compound as a yellow liquid (0.625 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>O.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[N:19][OH:20])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NO
Reactant: O=C(Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Yield: 66.2 %

Procedure:
A mixture of 1-(3,4-dichlorophenyl)-2-phenyl-ethan-1-one (Step 1) (12.5 g, 53.88 mmol), hydroxylamine hydrochloride (9.4 g, 135.4 mmol) and sodium acetate (268.5 mmol) in ethanol water (1:1, 250 mL) was heated at reflux for 4 hours, then was diluted with water (200 mL). The precipitate formed was filtered, dried and was recrystallized from hexane to afford 10 g (75%) of the desired product: mp 81°-82° C. 1H NMR (CDCl3) 7.50-7.06 (m, 9H), 4.18 (s, 2H). Found: Anal. Calc'd for C14H11NOCl2 :
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](O)([C:14]([F:17])([F:16])[Cl:15])[C:10]([F:13])([F:12])[Cl:11])=[CH:5][CH:4]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].Cl>N1C=CC=CC=1>[CH3:1][N:2]([S:20]([CH3:19])(=[O:22])=[O:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:14]([F:17])([F:16])[Cl:15])[C:10]([F:13])([F:12])[Cl:11])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNc1ccc(C(O)(C(F)(F)Cl)C(F)(F)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CN(c1ccc(C(C(F)(F)Cl)C(F)(F)Cl)cc1)S(C)(=O)=O
Reaction time: 1.5 h

Procedure:
To 6.1 g (20 mmole) N-methyl-4-(1,3-dichlorotetrafluoro-2-hydroxy-2-propyl)aniline in 30 ml pyridine add 3.4 g (30 mmole) methanesulfonyl chloride. Stir 1.5 hours, pour onto water, acidify with concentrated HCl and filter. Dissolve the solid in 1N NaOH, wash with Et2O, acidify and filter. Recrystallize the solid from Et2O-hexane to give the product; m.p. 140°-142° C.