Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:22]=2)[C:8]2[C:13]3[S:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:42]1([CH3:48])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:46]1[C:47]2[NH:7][C:1]3[C:48](=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:42]=2[CH:43]=[C:44]([C:24]2[CH:23]=[CH:22][C:21]([N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[C:13]4[S:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=5[C:12]=4[CH:11]=[CH:10][CH:9]=3)=[CH:26][CH:25]=2)[CH:45]=1
Reactant: Cc1ccccc1
Reactant: CC1(C)OB(c2ccc(N(c3ccccc3)c3cccc4c3sc3ccccc34)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: c1ccc(N(c2ccc(-c3ccc4[nH]c5ccccc5c4c3)cc2)c2cccc3c2sc2ccccc23)cc1
Yield: 91 %

Procedure:
To a solution of N-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)dibenzo[b,d]thiophen-4-amine (5.9 g, 12.4 mmol), 3-bromocabazole (3.5 g, 14.2 mmol), K2CO3 (16.6 g, 120.0 mmol) in toluene (150 mL), water (50 mL) and EtOH (50 mL) was bubbled for 30 min. Pd(PPh3)4 (0.4 g, 0.4 mmol) was added. The mixture was bubbled for 15 min. The resultant mixture was refluxed for 12 h. After cooling, the reaction mixture was extracted by CH2Cl2 and dried by MgSO4. The solvent was removed in vacuo and the residue was purified by flash chromatography using 25-50% CH2Cl2/hexane to afford N-(4-(9H-carbazol-3-yl)phenyl)-N-phenyldibenzo[b,d]thiophen-4-amine (5.8 g, 91% yield) as a white solid.
Reaction SMILES: [S:1]=[C:2]1[N:6]([CH2:7][C:8]#N)[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1.S(=O)(=O)(O)[OH:15].[OH2:19]>>[S:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:15])=[O:19])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1
Reactant: O=S(=O)(O)O
Reactant: N#CCn1c(=S)sc2ccccc21
Reactant: O
Product: O=C(O)Cn1c(=S)sc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A stirred slurry containing 10.3 g (0.05 mol) of 2-thioxo-3-benzothiazolineacetonitrile and 150 ml of 30% sulfuric acid (by volume) was heated at reflux for 2 hours. After cooling to 25° C., 800 ml of water was added and stirring was continued for 30 minutes at 25°-30° C. The solid was collected by filtration, washed with water until neutral to litmus, and air-dried at 25°-30° C. The product, 2-thioxo-3(2H)-benzothiazoleacetic acid was obtained in 90% yield , m.p. 187°-189° C. After recrystallization from 1,2-dichloroethane the crystals melted at 192°-193° C.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][C:20](=[O:24])[NH:21]2)=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C.[Cl-].[F:35][C:36]1[C:45]([F:46])=[C:44]2[C:39]([C@H:40]([NH3+:49])[CH2:41][C:42]([CH3:48])([CH3:47])[O:43]2)=[CH:38][CH:37]=1>C1COCC1.C([O-])(O)=O.[Na+]>[F:35][C:36]1[C:45]([F:46])=[C:44]2[C:39]([C@H:40]([NH:49][C:2]([NH:13][C:14]3[CH:23]=[C:22]4[C:17]([CH2:18][CH2:19][C:20](=[O:24])[NH:21]4)=[CH:16][CH:15]=3)=[O:4])[CH2:41][C:42]([CH3:47])([CH3:48])[O:43]2)=[CH:38][CH:37]=1
Reactant: Nc1ccc2c(c1)NC(=O)CC2
Reactant: CC1(C)C[C@@H]([NH3+])c2ccc(F)c(F)c2O1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C[C@@H](NC(=O)Nc2ccc3c(c2)NC(=O)CC3)c2ccc(F)c(F)c2O1
Reaction time: 2 h
Yield: 255.3 %

Procedure:
Triphosgene (0.281 g, 0.948 mmol) (Sigma-Aldrich) in THF (5 mL) was added to a to a solution of 7-amino-3,4-dihydroquinolin-2(1H)-one (0.4659 g, 2.87 mmol) (Astatech, Inc) and DIEA (2.01 mL, 11.5 mmol) (Aldrich) in THF (28 mL) at room temperature. After 10 minutes (R)-7,8-difluoro-2,2-dimethylchroman-4-aminium chloride (0.717 g, 2.87 mmol) (B-8; WO2010/04401) was added and the mixture was stirred for an additional 2 hours. The mixture was diluted with saturated aqueous NaHCO3 (30 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with 1 N aqueous HCl (30 mL) and concentrated. The residue was purified by silica gel chromatography (5% MeOH/CH2Cl2) to afford the title compound (0.970 g, 2.42 mmol, 84% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.50 (s, 1H), 7.14-6.84 (m, 5H), 6.44 (d, J=8.6 Hz, 1H), 4.95 (dd, J=15.7, 9.7 Hz, 1H), 2.78 (t, J=7.5 Hz, 2H), 2.41 (dd, J=8.4, 6.5 Hz, 2H), 2.16 (dd, J=13.4, 6.1 Hz, 1H), 1.80 (dd, J=13.2, 11.3 Hz, 1H), 1.45 (s, 3H), 1.32 (s, 3H); MS (ESI+) m/z 402 (M+H)+, 400 (M−H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:29][C:30]1[C:37]([OH:38])=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:37]([OH:38])[C:30]=3[OH:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(O)c1O
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Oc1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1O

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2,3-dihydroxybenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 501; MS (ESI) m/z 499.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][N:33]1[CH2:38][CH2:37][CH:36](O)[CH2:35][CH2:34]1.N(C(OCC)=O)=NC(OCC)=O>CO.C1C=CC=CC=1>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH:36]2[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]2)[CH:3]=1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: CN1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(F)cc1OC1CCN(C)CC1
Temperature: 0 °C
Yield: 57.5 %

Procedure:
A mixture of methyl 4-fluoro-2-hydroxybenzoate (12 g, 70.5 mmol), triphenyl-phosphine (22.2 g, 84.6 mmol), N-methyl-4-hydroxypiperidine (8.1 g, 70.3 mmol) and benzene (25 mL) was heated until all the solids dissolved. The solution was cooled to 0° C., then sonicated while adding diethyl azodicarboxylate (14.7 g, 84.6 mmol) dropwise. After the addition was complete, the reaction was sonicated for an additional 60 minutes, and then purified by flash chromatography, eluting sequentially with 50% EtOAc in hexanes followed by 1%, 2%, 5% then 10% MeOH in CHCl3, to yield 10.8 g (40.4 mmol, 57%) of an oil.
Reaction SMILES: CS(C)=O.[CH:5]1([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16](=[O:32])[C:17]([CH2:27][CH2:28][CH2:29][CH2:30][OH:31])=[CH:18][N:19]3[CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][C:13]=2[F:33])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.Cl>O>[CH:5]1([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16](=[O:32])[C:17]([CH2:27][CH2:28][CH2:29][CH:30]=[O:31])=[CH:18][N:19]3[CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][C:13]=2[F:33])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=c1c(CCCCO)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCCCc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a 4 ml DMSO solution of 310 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(4-hydroxybutyl)quinolin-4(1H)-one was added 0.7 ml of triethylamine and 620 mg of a sulfur trioxide pyridine complex, followed by stirring at room temperature for 24 hours. By adding 1 M hydrochloric acid and water, the insoluble materials were collected by filtration to obtain 290 mg of 4-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]butanal.
Reaction SMILES: O=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C[Si](C)(C)[C:16]([F:19])([F:18])[F:17].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1C[O:43]CC1>Cl>[C:3]1([C:8]([OH:43])([C:16]([F:19])([F:18])[F:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: CCOC(=O)CC1C=CC=CC1=O
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Product: CCOC(=O)C(O)(c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To stirred ethyl 2-oxo-phenylacetate (1.0 g, 5.6 mmol) under nitrogen atmosphere at ambient temperature was added trimethyl(trifluoromethyl)silane (1.0 mL, 6.73 mmol) and 1.0 TBAF in THF (6.2 mL, 6.2 mmol). This mixture was stirred at ambient temperature for 72 h. To the reaction was added 5N HCl solution (10 mL) and the mixture was stirred at ambient temperature for 18 h. The mixture was partitioned between Et2O and water. The Et2O layer was separated, dried over anhydrous Na2SO4, and filtered. Crude ethyl 2-phenyl-2-hydroxy-3,3,3-trifluoropropanoate was obtained as a yellow oil (0.9 g; HPLC RT=3.30 min, method A; 1H NMR, 400 MHz, CDCl3, 8.2 ppm (d, 1H), 7.78 ppm (m, 1H), 7.4 ppm (m, 3H), 4.4 ppm (m, 2H), 1.35 ppm (t, 3H)).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.Cl[Sn](Cl)(Cl)Cl.[CH3:15][O:16]C(Cl)Cl.CCOC(C)=O>C(Cl)Cl.CCCCC>[O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:15]=[O:16])[C:2]1=2
Reactant: c1ccc2c(c1)CCO2
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=Cc1cccc2c1OCC2
Temperature: 0 °C
Yield: 0.6 %

Procedure:
2,3-Dihydrobenzo[b]furan (Maybridge Chemicals) (25 g, 0.21 mole) was taken up in DCM (500 ml) and stirred under nitrogen at 0° C. SnCl4 (36.5 ml, 0.3 mole) was added in one portion to produce a pale yellow solution. Dichloromethyl methyl ether (18.8 ml, 0.21 mole) was then added and the solution stirred for 30 min, after which time the cooling bath was removed and the reaction poured onto ice-water (1000 ml). The organic layer was separated, washed with water (2×100 ml), 2N HCl (100 ml) and brine (50 ml), and then charcoal (30 g) and Na2SO4 were added to the solution. Filtration through Celite and evaporation gave a black oil, which was subjected to flash chromatography using 7-10% EtOAc in pentane to give the title product (190 mg, 0.01%); 1HNMR (400 MHz, CDCl3) δ: 3.24 (t, 2H), 4.75 (t, 2H), 6.93 (t, 1H), 7.40 (d, 1H), 7.59 (d, 1H), 10.2 (s, 1H); LRMS: (M+H) 149, TS+. Anal. Found: C, 72.98; H, 5.46%. C9H8O2 requires C, 72.96; H, 5.44%.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[N:6]([CH3:9])[CH:7]=[N:8][C:4]=2[CH:3]=1.[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1>>[CH3:9][N:6]1[C:5]2[CH:10]=[C:11]([C:19]3([OH:22])[CH2:20][CH2:21][C:16]4([O:15][CH2:14][CH2:13][O:12]4)[CH2:17][CH2:18]3)[CH:2]=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: Cn1cnc2cc(Br)ccc21
Reactant: O=C1CCC2(CC1)OCCO2
Product: Cn1cnc2ccc(C3(O)CCC4(CC3)OCCO4)cc21

Procedure:
The title compound was prepared as a white solid from 5-bromo-1-methyl-1H-benzoimidazole (prepared by methylation of 5-bromo-1H-benzoimidazole) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: C1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10](F)=[C:11](N4C[C@H](C)N[C@H](C)C4)[CH:12]=3)[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)CC1.N>>[O:24]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][CH:5]=[C:6]1[C:25]([OH:27])=[O:26]
Reactant: C[C@@H]1CN(c2cc3c(c(F)c2F)c(=O)c(C(=O)O)cn3C2CC2)C[C@H](C)N1
Agent: N
Product: O=C(O)c1c[nH]c2ccccc2c1=O

Procedure:
In a sealed tube, 1-cyclopropyl-5,6-difluoro-7-(cis-3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 28% aqueous ammonia were heated at 100° C. for 48 hours. The reaction mixture was concentrated under reduced pressure. A 1N aqueous solution of sodium hydroxide was added to the residue, and the insoluble matter was removed by filtration. A 10% aqueous solution of acetic acid was added to the filtrate to adjust its pH to 8, and it was then extracted with chloroform. The extract was dried and concentrated. Acetonitrile was added to the residue, and the mixture was cooled with ice. The crystals were collected by filtration and recrystallized from aqueous ammonia to give 5-amino-1-cyclopropyl-6-fluoro-7-(cis-3,5-dimethyl-1-piperazinyl)-)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid m p. 253°-254° C.
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O.[I-].[Na+]>[CH2:1]1[CH:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][N:2]1[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNCC21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CCOC(=O)CN1CCN2c3ccccc3Cc3ccccc3C2C1
Yield: 82 %

Procedure:
0.546 g of 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine, 0.437 g of ethyl bromoacetate; 0.692 g of sodium carbonate and 0.016 g of sodium iodide were added to 20 ml of 4-methyl-2-pentanone, and the mixture was heated under reflux for 16 hours. At the end of this time, the mixture was diluted with water and then extracted with ethyl acetate. The solvent was then removed by evaporation under reduced pressure. The resulting residue was then subjected to column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to afford 0.602 g (yield 82%) of the title compound as a pale yellow oil. The hydrochloride of this compound, melting at 187°-190° C., may be prepared by similar means to Those described in Example 17.
Reaction SMILES: [C:1]([O:6][CH3:7])(=O)[C@H:2]([CH3:4])O.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.N1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1C.C([SH:37])CCCCC>CC#N>[CH3:7][O:6][C:1](=[S:37])[C@@H:2]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:4]
Reactant: COC(=O)[C@H](C)O
Reactant: Cc1cccc(C)n1
Reactant: CCCCCCS
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: CCCCCC[C@@H](C)C(=S)OC
Yield: 86.5 %

Procedure:
(S)-Methyl lactate (0.571 g, 5.27 mmol) was carried through the reaction sequence of Example 5 with triflic anhydride (1.02 ml, 6.05 mmol) and 2,6-lutidine (0.71 ml, 6.05 mmol) in 11 ml of CH3CN. Hexanethiol (1.02 ml, 6.84 mmol) and TEA (1.91 ml, 13.7 mmol) were added and the workup described in Example 5 followed by purification by silica gel chromatography using 25 to 1 hexane to ethyl acetate as eluent gave (R)-methyl-2-hexylthiopropionate as a clear yellow oil (0.933 g, 4.56 mmol, 86%). [α]D =+130.0° (c=1, MeOH). Anal. Calcd. for C10H20O2S: C, 58.78; H, 9.87: Found: D, 58.76; H, 9.99%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]=[C:16](SC)[N:15]=[C:14]([O:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[O:28][S:29]([O-:31])=O.[K+].[CH3:33]O.O>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]=[C:16]([S:29]([CH3:33])(=[O:31])=[O:28])[N:15]=[C:14]([O:20][C:21](=[O:26])[C:22]([F:23])([F:25])[F:24])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: CSc1nc(CCCOCc2ccccc2)cc(OC(=O)C(F)(F)F)n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1nc(CCCOCc2ccccc2)cc(OC(=O)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of trifluoro-acetic acid 6-(3-benzyloxy-propyl)-2-methylsulfanyl-pyrimidin-4-yl ester (494 mg) and Oxone (419 mg) in methanol/water (8/2 mL) was stirred at room temperature overnight. Methanol was evaporated under reduced pressure, and the resultant suspension was extracted with ethyl acetate (2×20 mL). The organic fraction was dried over sodium sulphate and evaporated under reduced pressure to afford trifluoro-acetic acid 6-(3-benzyloxy-propyl)-2-methanesulfonyl-pyrimidin-4-yl ester (135 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]2)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([O:19][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][Br:20])[CH2:15][CH2:14]2)[CH3:12])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: BrCCCCCCBr
Reactant: CN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(Br)cc1
Product: CN([C@H]1CC[C@H](OCCCCCCBr)CC1)S(=O)(=O)c1ccc(Br)cc1

Procedure:
In analogy to example 11.11, trans-4-Bromo-N-(4-hydroxy-cyclohexyl)-N-methyl-benzenesulfonamide and 1,6-dibromohexane were reacted to yield trans-4-Bromo-N-[4-(6-bromo-hexyloxy)-cyclohexyl]-N-methyl-benzenesulfonamide as off-white solid, MS: 510 (MH+, 1Br).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[C:4]2[O:12][C:13]([CH3:17])([CH3:16])[O:14][CH2:15][C:3]=12.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.[Cl-].[NH4+]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[C:4]3[O:12][C:13]([CH3:17])([CH3:16])[O:14][CH2:15][C:3]=23)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COC(=O)c1ncc(N)c2c1OC(C)(C)OC2
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: COC(=O)c1ncc(NC(=O)c2ccc(F)cc2)c2c1OC(C)(C)OC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 5-amino-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate (23c) (70 mg, 0.25 mmol), 4-fluorobenzoyl chloride (35 μL, 0.27 mmol) and 4-dimethylaminopyridine in pyridine (1 mL) was stirred at room temperature overnight and a saturated solution of ammonium chloride was added. The reaction mixture was extracted with dichloromethane (3×25 mL) and the combined organic layers were dried (anh. Na2SO4), filtered and concentrated under reduced pressure to give methyl 5-(4-fluorobenzamido)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate (23d) as a white solid MS-ESI m/z 361 [MH]+.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:7]1)=[O:5].[Cl-].[CH2:23]1[CH2:27]OC[CH2:24]1>>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][CH:6]([C:4](=[O:5])[CH2:24][CH2:23][CH3:27])[CH2:7]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(CN2CCCC(C(=O)N(C)OC)C2)cc1
Reactant: C1CCOC1
Agent: [Cl-]
Product: CCCC(=O)C1CCCN(Cc2ccc(OC)cc2)C1
Yield: 94 %

Procedure:
Combine 1-(4-Methoxy-benzyl)-piperidine-3-carboxylic acid methoxy-methyl-amide (401.0 mg, 1.37 mmol) and THF (10 mL) at 0° C. under a Nitrogen atmosphere. By dropwise addition, add Propylmagesium chloride (4.0 mL, 8.22 mmol). Reflux the reaction for 5 hours then cool the reaction to room temperature and quench the reaction mixture with sat NH4Cl (aq) and extract product from the water using Ethyl acetate. Wash the organic layer with brine and then dry over Na2SO4. Concentrate under reduced pressure and add to an SCX (5 g) column pre-treated with 5% AcOH/MeOH. Wash with MeOH and elute product using 1N NH3 MeOH to give 356.0 mg (94% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 0.8 (3H, t), 1.3 (1H, qd), 1.4-1.5 (3H, m), 1.6-1.8 (1H, n), 1.9 (1H, dd), 2.0 (1H, td), 2.1 (1H, t), 2.4 (2H, t), 2.5-2.6 (1H, m), 2.7 (1H, d), 2.9 (1H, d), 3.4 (2H, dd), 3.8 (3H, s), 6.8 (2H, d), 7.2 (2H, d); TLC 4% 1N NH3 MeOH:CH2Cl2 Rf=0.42.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH3:22][C:23]1[CH:52]=[CH:51][C:26]2[N:27]=[C:28]([N:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH:31]3[CH2:43][O:44][C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)[O:29][C:25]=2[CH:24]=1>CO>[ClH:1].[CH3:22][C:23]1[CH:52]=[CH:51][C:26]2[N:27]=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH:31]3[CH2:43][O:44][C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)[O:29][C:25]=2[CH:24]=1
Reactant: Cc1ccc2nc(N3CCN(C(=O)OC(C)(C)C)CC3COc3cccnc3)oc2c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc2nc(N3CCNCC3COc3cccnc3)oc2c1
Reaction time: 2 h

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(6-methylbenzo[d]oxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate di-TFA salt (91.1 mg, 0.140 mmol) in MeOH (1 mL). After 2 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were brought to pH 12 with 1 N NaOH, and brine (20 mL) was added. This was extracted with EtOAc (3 x). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure, yielding 33.0 mg of the free-base of the desired product. The material was dissolved in MeOH (1 mL) and 4 M HCl in 1,4-dioxane (0.025 mL) was added. The mixture was concentrated under reduced pressure to give 35.5 mg (70%) of the desired product as the hydrochloride salt. LC-MS: RT=4.40 min, [M+H]+=325.1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:14])[C:5]2[N:11]=[C:10]([CH2:12]Br)[CH:9]=[CH:8][C:6]=2[N:7]=1.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[K].CO>CC(N(C)C)=O.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([NH2:14])[C:5]2[N:11]=[C:10]([CH2:12][S:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Sc1ccccc1
Reactant: Nc1nc(N)c2nc(CBr)ccc2n1
Agent: [K]
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: ClC(Cl)Cl
Product: Nc1nc(N)c2nc(CSc3ccccc3)ccc2n1
Reaction time: 72 h
Yield: 0.7 %

Procedure:
To a suspension of 7 (~2.5 mmol) in anhydrous dimethylacetamide was added 1 mL thiophenol (5 mmol) and 690 mg anhydrous potassium (5 mmol). After the suspension was stirred for 3 days, the spot of 7 disappeared from TLC. The Rf value of one of new spots which is assigned as 9 is 0.35 (in 2:8 methanol:chloroform). The solvent DMAC was removed under diminished pressure. The solid residue was washed with methanol three times and filtered. The combined liquid was added silica gel and then the methanol was evaporated to dryness. A small amount of product was separated through a dry column. 1HNMR, the product. After crystallization, 5 mg of pure product was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:13][NH2:14].Cl.[C:16]1(NN)C=CC=CC=1.[CH:24]([NH:26][C:27](=O)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=O>>[Cl:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[N:13]1[C:27]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:16])=[N:26][CH:24]=[N:14]1
Reactant: NNc1ccccc1
Reactant: O=CNC(=O)Cc1ccccc1
Reactant: NNc1cccc(C(F)(F)F)c1Cl
Agent: Cl
Product: Cc1ccccc1Cc1ncnn1-c1cccc(C(F)(F)F)c1Cl

Procedure:
The title compound was prepared using the procedure as described in Example 80 substituting 2-chloro-3-trifluoromethylphenylhydrazine hydrochloride for phenylhydrazine hydrochloride and substituting Example 76A for N-formylphenylacetamide. The residue was purified by flash chromatography (20% ethyl acetate/hexanes) to provide the title compound. MS (ESI) m/e: 352 (M+H); 1H NMR (DMSO-d6) δ 2.05 (s, 3H), 4.05 (s, 2H), 6.7-6.75 (d, 1H), 6.85-6.96 (m, 1H), 7.04-7.1 (d, 2H), 7.7-7.75 (t, 1H), 7.89-7.97 (d, 1H), 8.05-8.1 (d, 1H), 8.18 (s, 1H); Anal. calcd. for C: 58.05, H: 3.73, N: 11.95. Found C, 58.10; H, 3.86; N, 11.68. The title compound (0.12 g, 0.34 mmol) in ethyl acetate (3 mL) was treated with 1 M HCl/diethyl ether (5 mL). After stirring for 1 hour, the mixture was diluted with diethyl ether, filtered, and the filter cake was dried under high vacuum to provide the title compound as a hydrochloride salt. MS (ESI) m/e: 352 (M+H)+; 1H NMR (DMSO-d6) δ 2.05 (s, 3H), 4.05 (s, 2H), 6.7-6.75 (d, 1H), 6.85-6.96 (m, 1H), 7.04-7.1 (d, 2H), 7.7-7.75 (t, 1H), 7.89-7.97 (d, 1H), 8.05-8.1 (d, 1H), 8.18 (s, 1H); Anal. calcd. for C, 52.60; H, 3.63; N, 10.82. Found C, 52.54; H, 3.42; N, 10.79.