Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:22][CH:23]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH2:24]1.[C:38]([CH2:46][CH2:47][CH2:48][C:49](O)=[O:50])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl.C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:23]([NH:22][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][C:38](=[O:45])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:24]2)=[CH:36][CH:35]=1
Reactant: NC1CCCCN(Cc2ccc(Cl)cc2)C1
Reactant: O=C(O)CCCC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCCC(=O)c1ccccc1)NC1CCCCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
EDCI (23 mg), HOBt (16.2 mg) and triethylamine (15.2 μL) were added to a chloroform (1 mL) solution of 3-amino-1-(4-chlorobenzyl)homopiperidine (24 mg, 0.10 mmol) and 4-benzoylbutyric acid (1.2 equivalents), and the resulting mixture was stirred at 25° C. for 16 hours. The reaction mixture was diluted with dichloromethane (0.5 mL), filtered through a PTFE membrane and concentrated to provide 1-(4-chlorobenzyl)-3-[(4-benzoylbutyryl)amino]homopiperidine (Compd. No. 994) (43 mg, 99%). The purity was determined by RPLC/MS (98%). ESI/MS m/e 413 (M++H, C24H29ClN2O2).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12](O)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:27][C:2]1([CH3:1])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: CS(N)(=O)=O
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(N2CCOCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1ccc(N2CCOCC2)cc1
Temperature: 65 °C
Yield: 40.3 %

Procedure:
A mixture of 3,3-dimethyl-2-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (70 mg, 0.19 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (55 mg, 0.29 mmol), 4-dimethylaminopyridine (35 mg, 0.29 mmol), methane sulfonamide (54 mg, 0.57 mmol) in dichloromethane (10 mL) was heated for at 65° C. for 12 hours. Removal of the solvent to afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[3,3-dimethyl-2-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (34 mg, 40%) as a light yellow solid: LC/MS m/e calcd for C23H29N3O4S (M+H)+: 444.6, observed: 444.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].N1C=CC=CC=1.[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20]>C(Cl)Cl.O>[CH3:17][N:18]([CH3:22])[C:19](=[O:20])[O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: CN(C)C(=O)Cl
Reactant: O=Cc1ccc(O)c(F)c1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CN(C)C(=O)Oc1ccc(C=O)cc1F
Yield: 96.1 %

Procedure:
To a 250 mL dry round bottom flask were added 3-fluoro-4-hydroxybenzaldehyde (4.90 g, 35.0 mmol), anhydrous CH2Cl2 (20 mL) and pyridine (3.68 mL, 45.5 mmol). The mixture was stirred in an ice-water bath, then dimethylcarbamic chloride (3.54 mL, 38.5 mmol) was added. The mixture was stirred at room temperature for 62 hours. Water (80 mL) and CH2Cl2 (50 mL) were added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (50 mL×3). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 2-fluoro-4-formylphenyl dimethylcarbamate (7.10 g) as white solid. Yield: 96%. 1H NMR (CDCl3, 300 MHz): δ=9.92 (d, J=1.8 Hz, 1H), 7.69-7.64 (m, 2H), 7.40 (t, J=7.5 Hz, 1H), 3.13 (s, 3H), 3.03 (s, 3H). 13C NMR (CDCl3, 75.5 MHz): δ=190.0, 156.5, 153.0 (d, J=17.1 Hz), 144.2 (d, J=12.8 Hz), 134.7 (d, J=5.5 Hz), 126.6 (d, J=3.6 Hz), 124.8, 116.5, 116.2, 36.8, 36.5. 19F NMR (CDCl3, 282.3 MHz): δ=−127.5.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:22][C@@H:23]([CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C=O)C>[CH3:22][C@@H:23]([CH2:32][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=3)[CH2:14][CH2:13]2)=[CH:16][CH:17]=1)[CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26]
Reactant: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)CC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](COc1ccc(N2CCN(c3ccncc3)CC2)cc1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 42.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.44 g) was added to a stirred suspension of 4-[4-(4-pyridyl)piperazin-1-yl]phenol (15.5 g) in dry DMF (120 ml) and the mixture was stirred for 45 minutes at room temperature. tert-Butyl (3R)-3-methyl-4-(p-toluene-sulphonyloxy)butyrate (20 g) was added and the mixture was stirred at room temperature for 20 hours. The mixture was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with water, filtered through phase separating paper (Whatman IPS) and evaporated. The residue was triturated under diethyl ether. The solid so obtained was recrystallised from ethyl acetate to give tert-butyl (3R)-3-methyl-4-[4-[4-(4-pyridyl)piperazin-1-yl]phenoxy]butyrate (10.6 g), m.p. 112°-113° C.; [alpha]D =-5.5° (conc.=1g/100 ml of methanol; 20° C.); NMR (CDCl3) δ 8.3(2H,d), 6.89(4H,m), 6.7(2H,m), 3.79(2H,d), 3.46(4H,m), 3.28(4H,m), 2.31-2.53(2H,m), 2.08-2.21(1H,m), 1.44(9H,s), 1.07(3H,d).
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[NH:8][C:9](=[O:15])OC(C)(C)C)=O.C(OCC)(=O)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].N1CCCCC1>CCO>[O:15]=[C:9]1[NH:8][C:4]2[S:5][CH:6]=[CH:7][C:3]=2[CH:1]=[C:17]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)Nc1sccc1C=O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2ccsc2[nH]c1=O

Procedure:
A solution of tert-butyl 3-formyl-2-thienylcarbamate (11-3, 1.90, 8.36 mmol, 1 equiv), diethyl malonate (2.54 mL, 16.7 mmol, 2.00 equiv), and piperidine (0.413 mL, 4.18 mmol, 0.500 equiv) in EtOH (100 mL) was heated at reflux for 6 h. The reaction mixture was concentrated, and the residue was purified by flash column chromatography (EtOAc, initally, then 10% MeOH in EtOAc) to give ethyl 6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (10-4). 1H NMR (400 MHz, CDCl3) δ 11.57 (brs, 1H), 8.60 (s, 1H), 7.33 (d, 1H, J=6.0 Hz), 7.21 (d, 1H, J=6.0 Hz), 4.49 (q, 2H, J=7.1 Hz), 1.46 (t, 3H, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.[C:33]([NH:40][CH2:41][C:42](O)=[O:43])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[C:36]([O:35][C:33]([NH:40][CH2:41][C:42]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:9]([CH2:8][O:7][C:6]3[CH:31]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:32])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:28])([CH3:29])[CH:12]=[C:11]3[CH3:30])=[C:20]([O:26][CH3:27])[CH:21]=1)=[O:43])=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC(=O)CNC(=O)OC(C)(C)C)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 5-1, 30.2 mg, 0.070 mmol) and Boc-glycine (15.1 mg, 0.086 mmol) were dissolved in N, N-dimethylformamide (1 mL), N, N-diisopropylethylamine (31.4 μL, 0.18 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (35.4 mg, 0.093 mmol) were added thereto, and then the mixture was stirred at room temperature overnight. Ethyl acetate (10 mL) was added to the reaction mixture, then the mixture was washed with water (10 mL) and saturated brine (10 mL) successively. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (35.3 mg) as a colorless amorphous product. (Yield 86%)
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[CH2:14][SH:15])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.O>O1CCCC1>[C:1]([S:15][CH2:14][C:13]1[CH:16]=[C:17]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:18]([OH:19])=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:12]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC(C)(C)c1cc(CS)cc(C(C)(C)C)c1O
Reactant: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)SCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
S-(3,5-di-tert.-butyl-4-hydroxybenzyl) thiomethacrylate was prepared as follows: Methacryloyl chloride (8.65 grams) was added dropwise over 1 hour at 24° to 28° C. to a solution of 16.7 grams of 3,5-di-tert.-butyl-4-hydroxybenzyl mercaptan and 13.4 grams of triethylamine in 75 milliliters of tetrahydrofuran. The reaction mixture was stirred for 3 hours at room temperature and was then poured into 400 milliliters of water. The yellow oil which precipitated was separated by extraction with hexane. Evaporation of the hexane left 19.9 grams of a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][C:11]2([F:14])[F:13])=[CH:6][C:5]([N+:15]([O-])=O)=[C:4]([F:18])[CH:3]=1.C.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][C:11]2([F:13])[F:14])=[CH:6][C:5]([NH2:15])=[C:4]([F:18])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(OCC2CC2(F)F)c(Cl)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(OCC2CC2(F)F)c(Cl)cc1F

Procedure:
36.9 g 4-Chloro-2-fluoro-5-(2,2-difluorocyclopropylmethoxy)nitrobenzene in 600 ml ethanol was hydrogenated by the addition of 5 g of 10% palladium metal on activated charcoal at room temperature and normal pressure. After the uptake of hydrogen is complete the catalyst is filtered off, the solvent evaporated to give 29.3 g(=89% of theory) of an oil, whose nmr spectrum is as follows: δ=1.1-2.2 ppm (m) 3H, δ=4.0 ppm (d 10 Hz wide) 2H, δ=5 ppm (s wide) 2H, δ=6.5 ppm (d 7 Hz) 1H, δ=7.0 ppm (d 10 Hz) 1H.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[CH2:26]([O:25][C:23](=[O:24])[C:22]([NH:13][C:12]1[C:7]([NH:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:28])[CH3:27]
Reactant: Nc1cccnc1NC1CCCC1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1cccnc1NC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
To a solution of N2-cyclopentylpyridine-2,3-diamine (C5) (1.78 g, 10.0 mmol) and triethylamine (1.52 g, 15.0 mmol) in dichloromethane (100 mL) was added ethyl chloro(oxo)acetate (1.49 g, 10.9 mmol), and the reaction mixture was stirred at room temperature for 18 hours. Removal of volatiles in vacuo afforded the crude product (2 g) as a brown solid, which was used in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[CH:5]([CH3:7])[CH3:6].F[B-](F)(F)F.[NH:14]=[C:15](SC)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH3:6][CH:5]([C:4]1[NH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:2][CH:3]=1)[CH3:7]
Reactant: CC(C)C(=O)CN
Reactant: CCOC(=O)C(=N)SC
Agent: Cl
Agent: F[B-](F)(F)F
Product: CCOC(=O)c1ncc(C(C)C)[nH]1
Yield: 57 %

Procedure:
The same operation as in Example (1b) was performed using 1-amino-3-methylbutan-2-one hydrochloride obtained in Example (35c) (about 17.6 mmol) and ethyl imino(methylthio)acetate tetrafluoroborate obtained according to a method known in the literature (J. Med. Chem., 38, 1995, 2196-2201) (about 22 mmol), to obtain 1.83 g of the title compound as a yellow solid (57%).
Reaction SMILES: [NH2:1][CH:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=1)[CH:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][CH:9]=1)[OH:4].[C:30]1([C:41](O)=[O:42])[CH:31]=[CH:32][CH:33]=[C:34]2[CH2:40][CH2:39][CH2:38][CH:37]=[CH:36][C:35]=12.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C.C(OCC)(=O)C>[OH:4][CH:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][CH:9]=1)[CH:2]([NH:1][C:41]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[CH2:40][CH2:39][CH2:38][CH:37]=[CH:36][C:35]=12)=[O:42])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1csc(-c2ccccc2)n1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1csc(-c2ccccc2)n1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.1 %

Procedure:
To a solution of (1RS,2RS)-2-amino-1-(2-phenyl-1,3-thiazol-4-yl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-1-propanol (310 mg, 0.73 mmol) in acetonitrile (10 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (132 mg, 0.70 mmol) and 1-hydroxybenzotriazole monohydrate (112 mg, 0.73 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg, 0.73 mmol) was finally added. The mixture was stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1, 2:1) and recrystallization (hexane-ethyl acetate) to give N-{(1RS,2RS)-2-hydroxy-2-(2-phenyl-1,3-thiazol-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide (247 mg, 59%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[N:12]=[C:13]=[S:14].[CH3:15][CH:16]([NH2:19])[CH2:17][CH3:18].Cl[CH2:21][C:22](O)=[O:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[N:12]=[C:13]1[N:19]([CH:16]([CH2:17][CH3:18])[CH3:15])[C:22](=[O:23])[CH2:21][S:14]1
Reactant: O=C(O)CCl
Reactant: CCC(C)N
Reactant: O=[N+]([O-])c1cc(Cl)c(N=C=S)c(Cl)c1
Product: CCC(C)N1C(=O)CSC1=Nc1c(Cl)cc([N+](=O)[O-])cc1Cl

Procedure:
2,6-Dichloro-4-nitrophenyl isothiocyanate was reacted with 2-butylamine followed by chloroacetic acid according to Method C8a to afford 2-(2,6-dichloro-4-nitrophenylimino)-3-(2-butyl)-1,3-thiazolidin-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[OH:11][C:12]1[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([CH:19]=1)[CH:17]=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([CH:17]=[O:18])[CH:19]=2)[CH:3]=1
Reactant: COc1ccc(O)cc1C=O
Reactant: N#Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2cc(Cl)ccc2C#N)cc1C=O
Yield: 90 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.60 g, 3.9 mmol), 5-hydroxy-2-methoxybenzaldehyde (0.59 g, 3.9 mmol) and cesium carbonate (1.26 g, 3.9 mmol) were heated with stirring in dry DMF (4 ml) at 50° C. for 17 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water, 10% aqueous sodium carbonate (2×), water (2×), brine and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(3-formyl-4-methoxy-phenoxy)-benzonitrile (1.01 g, 90%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH2:12])=[CH:7][C:6]=1[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[N:28]=[C:29]=[S:30]>C(#N)C>[NH2:12][C:8]1[C:9]([NH:11][C:29]([NH:28][C:22]2[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=2[Cl:20])=[S:30])=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:19])=[C:6]([O:13][CH2:14][C:15]([F:16])([F:18])[F:17])[CH:7]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1cc(N)c(N)cc1OCC(F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1cc(NC(=S)Nc2c(Cl)cccc2Cl)c(N)cc1OCC(F)(F)F

Procedure:
Prepared analogously to example 583h from ethyl-4,5-diamino-2-(2,2,2-trifluoro-ethoxy)-benzoate (synthesis described at example 575) and 2,6-dichloro-1-isothiocyanato-benzene in acetonitrile.
Reaction SMILES: [CH:1]1([C@@H:4]([NH:9][C:10]2[C:22]3[C:21]4[CH:20]=[CH:19][C:18](B5OC(C)(C)C(C)(C)O5)=[CH:17][C:16]=4[NH:15][C:14]=3[C:13]([C:32]([NH2:34])=[O:33])=[CH:12][N:11]=2)[C:5]([F:8])([F:7])[F:6])[CH2:3][CH2:2]1.CC1C=CC(S([N-]Cl)(=O)=O)=CC=1.O.O.O.[Na+].[I-:51].[Na+]>C1COCC1.O.CCOC(C)=O>[CH:1]1([C@@H:4]([NH:9][C:10]2[C:22]3[C:21]4[CH:20]=[CH:19][C:18]([I:51])=[CH:17][C:16]=4[NH:15][C:14]=3[C:13]([C:32]([NH2:34])=[O:33])=[CH:12][N:11]=2)[C:5]([F:8])([F:7])[F:6])[CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc3c(c2)[nH]c2c(C(N)=O)cnc(N[C@H](C4CC4)C(F)(F)F)c23)OC1(C)C
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cnc(N[C@H](C2CC2)C(F)(F)F)c2c1[nH]c1cc(I)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]amino}-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-pyrido[4,3-b]indole-4-carboxamide (0.17 g, 0.35 mmol) in THF (0.88 mL) and water (0.88 mL) were added chloramine T trihydrate (0.11 g, 0.39 mmol) and sodium iodide (0.079 g, 0.53 mmol). The reaction mixture was left to stir at room temperature for 2 h, diluted with EtOAc, and washed with water and brine. The organic layer was dried (sodium sulfate), concentrated, and purified by prep-HPLC to afford the title compound.
Reaction SMILES: [F:1][C:2]([S:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O)([F:4])[F:3].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O:20](S(C(F)(F)F)(=O)=O)[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22]>>[O-:23][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:22])=[O:20].[F:3][C:2]([F:1])([F:4])[S+:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=1
Reactant: Fc1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=S(c1ccccc1)C(F)(F)F
Product: Fc1ccc([S+](c2ccccc2)C(F)(F)F)cc1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 10 h

Procedure:
Synthetic details: To a solution of phenyl trifluoromethyl sulfoxide (5) (582 mg, 3.0 mmol) in dry 1-fluorobenzene (8.4 mL, 30 mmol) was added (CF3SO2)2O (2.5 mL, 15 mmol) at 0° C. The reaction mixture was stirred for 10 h at 0° C., and then at rt for another 2 h. Removal of the solvent left a crude residue that was subjected to column chromatography on silica gel using CH3CN—CH2Cl2 (1:4) as eluent to give the product as white crystals (886 mg, 70%), mp 80-1 C (recrystallized from ethyl acetate/hexanes). IR (nujol): 3108 (m), 1719 (w), 1589 (m), 1494 (m), 1255 (s), 1171 (s), 640 (s) cm−1; 1H NMR (CDCl3): 8.35 (dd, J23=6.0 Hz, J2F=4.0 Hz, 2H), 8.19 (bd, J2′3′=6.0 Hz, 2H), 7.83 (m, 3H), 7.51 (dd, J32=6.0 Hz, J3F=9.0 Hz, 2H); 19F NMR (CDCl3): −50.7 (s, 3F), −78.7 (s, 3F), −95.5 (s, 1F); 13C NMR (CDCl3): 170 (d, J=261 Hz), 139, 137, 135, 135, 127 (q, J=265 Hz), 126 (q, J=263 Hz), 121, 116 ppm; FAB+-MS [m/e (species, intensity)]: 273 ((Cl3H9F4S)+, 100), 272 ((C13H8F4S)+, 14.2), 254 ((C13H9F3S)+, 5.9), 204 ((C13H9F4S)+-CF3, 98.0), 196 ((C13H9F4S)+-C6H5, 5.3), 178 ((C13H9F4S)+-C6H4F, 3.4), 127 ((C6H4FS)+, 13.0), 109 ((C6H5S)+, 20.1) ); Chemical analysis: Calculated for C14H9F7O3S2: C, 39.81; H, 2.15. Found: C, 39.45; H, 2.17.
Reaction SMILES: [F:1][C:2]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:19][CH:18](O)[CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:21][CH3:22])[N:7]=1.[CH2:28]([N:30](CC)[CH2:31][CH3:32])[CH3:29].CS(Cl)(=O)=[O:37]>C(Cl)Cl>[F:1][C:2]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:17][CH:18]([N:30]3[CH2:31][CH2:32][O:37][CH2:29][CH2:28]3)[CH2:19]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:21][CH3:22])[N:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: COc1cc(NS(=O)(=O)N2CC(O)C2)nc(SCc2cccc(F)c2F)n1
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)N2CC(N3CCOCC3)C2)nc(SCc2cccc(F)c2F)n1
Temperature: 50 °C

Procedure:
A solution of N-{2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}-3-hydroxyazetidine-1-sulfonamide (the product from example 109) (0.28 g) in DCM (10 ml) was treated with triethylamine (0.8 ml) and methanesulfonylchloride (0.9 ml) under nitrogen. After heating the mixture at 50° C. for 16 h the reaction mixture was partitioned between DCM and aqueous NaHCO3. The organic extracts were dried (MgSO4), filtered and the solvent evaporated under reduced pressure. To a solution of the resulting residue in MeOH (10 mL) and morpholine (8 ml) K2CO3 (0.19 g) was added and heated at 80° C. for 16 h. The reaction mixture was then partitioned between EtOAc and H2O. The organic extracts were washed with brine, dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The residue was purified by reverse phase HPLC (symmetry as the stationary phase and NH4OAc/acetonitrile as the mobile phase) then titurated with Et2O to give the title compound as a white solid.
Reaction SMILES: Cl[Si](C)(C)C.[O:6]=[C:7]1[N:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:9]2[CH2:20][S:21][CH2:22][C:8]1=2.ClN1C(=O)CCC1=O>N1C=CC=CC=1.O>[O:6]=[C:7]1[N:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:9]2=[CH:20][S:21][CH:22]=[C:8]12
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)CSC3
Agent: C[Si](C)(C)Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1ccc2nc3cscc3c(=O)n2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chlorotrimethylsilane (2.6 ml, 0.02 mol) is added to a cooled (icebath) solution of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid (5.0 g., 0.02 mol) in pyridine (40 ml) under nitrogen. The mixture is stirred at ice bath temperature for one hour and then allowed to warm to room temperature. N-Chlorosuccinimide (2.74 g., 0.02 mol) is added and the mixture is heated at 90°-95° C. for 20 minutes. The mixture is cooled, diluted with water (5 ml) and stirred for 15 minutes. The precipitate is filtered off, dried, washed with boiling acetone (3×100 ml) and recrystallized from dimethylformamide to give the product (3.9 g.), mp 320° C. (dec).