Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.I[C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=1)[C:15]([OH:17])=[O:16]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH3:24][O:23][C:21]([C:19]1[CH:18]=[C:14]([CH:13]=[C:12]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:20]=1)[C:15]([OH:17])=[O:16])=[O:22]
Reactant: c1cocn1
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C. stirred solution of oxazole (432 mg, 6.3 mmol) in tetrahydrofuran (10 mL) is added n-butyllithium (2.5 M in hexanes, 2.75 mL, 6.9 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 18.75 mL, 18.75 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is added a solution of 3-iodo-5-(methoxycarbonyl)benzoic acid prepared by the method in Example SP-281, step 1 (1.8 g, 6 mmol) in anhydrous tetrahydrofuran (10 mL) followed by palladium(0)tetrakis(triphenylphosphine) (291 mg, 0.25 mmol). The reaction mixture is heated at reflux for 15 h. The reaction mixture is cooled, filtered through diatomaceous earth, diluted with ethyl acetate (50 mL), washed with water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 5% methanol/methylene chloride) provides the title compound in pure form. ESI MS m/z 246.1 [M−H]−.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:15]([O-])=O)[CH:11]=2)[N:6]=1)([CH3:3])[CH3:2]>ClCCl.CO>[CH:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:15])[CH:11]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccc2cc([N+](=O)[O-])ccc2n1
Solvent: ClCCl
Solvent: CO
Product: CC(C)Nc1ccc2cc(N)ccc2n1

Procedure:
Prepared analogously to Example 3.1.b. from isopropyl-(6-nitroquinolin-2-yl)amine. Yield: 0.51 g (78.1% of theory); C12H15N3 (M=201.27); calc.: molecular ion peak (M+H)+: 202; found: molecular ion peak (M+H)+: 202; Rf value: 0.25 (silica gel, dichloromethane/methanol (19:1)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[N:26]1[CH2:29][CH:28]([C:30](O)=[O:31])[CH2:27]1.[CH3:33][N:34](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:35].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CNC>CN(C=O)C.C1COCC1>[CH3:33][N:34]([CH3:35])[C:30]([CH:28]1[CH2:27][N:26]([C:3]2[CH:4]=[CH:5][C:6]([C:8]3[CH2:12][C:11]([C:17]4[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=4)([C:13]([F:16])([F:14])[F:15])[O:10][N:9]=3)=[CH:7][C:2]=2[Cl:1])[CH2:29]1)=[O:31]
Reactant: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-{2-Chloro-4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid (Preparation 14, 0.1 g, 0.189 mmol) in dry DMF (1 mL) was added HATU (0.108 g, 0.284 mmol) HOBt (0.028 g, 0.207 mmol), DIPEA (0.048 g, 0.378 mmol) and saturated solution of dimethyl amine in THF (2 mL) at 0° C. and stirred at 0° C. for 2 hours and at room temperature for 18 hours. After complete consumption of starting material, reaction mixture was quenched with water (15 mL), extracted with EtOAc (10 mL). Organic layer was washed with saturated solution of lithium chloride (2×20 mL), water (2×20 mL), dried over sodium sulphate and evaporated in vacuo to get crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Further purification by preparative TLC using 5% MeOH in DCM afforded white solid (0.020 g, 19%). 1H-NMR (400 MHz, CDCl3) δ: 2.95 (s, 3H), 2.97 (s, 3H), 3.59 (d, 1H, J=17.08 Hz), 3.67-3.71 (m, 1H), 4.00 (d, 1H, J=17.04 Hz), 4.29-4.38 (m, 4H), 6.48 (d, 1H, J=8.6 Hz), 7.40 (dd, 1H, J1=8.48 Hz, J2=2 Hz), 7.45 (d, 1H, J=1.92 Hz), 7.62 (s, 2H); LC-MS (m/z): [M+H] 554.10.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:25]([NH2:27])=[O:26])=[N:10][N:11]([C:13]4[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:15][CH:14]=4)[C:12]=3[C:4]=2[CH:3]=1.[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34].C(O)C(N)(CO)CO.CCOC(C)=O>N1C=CC=CC=1>[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH:1][C:2]1[CH:29]=[CH:28][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:25]([NH2:27])=[O:26])=[N:10][N:11]([C:13]4[CH:14]=[CH:15][C:16]([S:19]([N:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])=[CH:17][CH:18]=4)[C:12]=3[C:4]=2[CH:3]=1)=[O:34]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CN(C)S(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(N)ccc2CC3)cc1
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Reaction time: 14 h
Yield: 44.1 %

Procedure:
To a stirred solution of 8-amino-1-{4-[(dimethylamino)sulfonyl]phenyl}-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (Example 46) (1.52 g, 3.70 mmol) in pyridine (25 mL) at RT was added 2-chlorobenzoic chloride (970 mg, 5.55 mmol). After 14 h, trisamine (1 g) was added and the mixture was stirred for 2 h. The mixture was filtered through a silica gel pad with EtOAc and concentrated. Column chromatography (silica gel, EtOAc) gave the title compound as a yellow solid (900 mg, 1.63 mmol, 44%). Its structure was confirmed by 1H NMR and MS (551, M+1). C27H24ClN5O4S, Calc.: C: 58.96; H: 4.40, N: 12.73; Found, C: 58.66; H: 4.65, N: 12.58.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]=[C:10]([C:13]#N)[C:9](=[O:15])[C:8]=2[CH:16]=1)([CH3:3])=[CH2:2].[NH:17]1CCCCC1.[C:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24]>C(O)C>[NH2:24][C:23]1[N:17]=[C:11]2[O:12][C:7]3[CH:6]=[CH:5][C:4]([C:1]([CH3:3])=[CH2:2])=[CH:16][C:8]=3[C:9](=[O:15])[C:10]2=[CH:13][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: C=C(C)c1ccc2occ(C#N)c(=O)c2c1
Reactant: C1CCNCC1
Reactant: CCOC(=O)CC#N
Solvent: CCO
Product: C=C(C)c1ccc2oc3nc(N)c(C(=O)OCC)cc3c(=O)c2c1
Reaction time: 8 h

Procedure:
A mixture of 6-isopropenyl-4-oxo-4H-1-benzopyran-3-carbonitrile (800 mg), ethanol (40 ml), piperidine (0.6 ml) and ethyl cyanoacetate (0.7 ml) was subjected to reflux for three hours, which was then left standing at room temperature overnight. Precipitating crystals were collected by filtration, which were recrystallized from ethanol to afford colorless crystals (1.09 g) of ethyl 2-amino-7-isopropenyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylate, m.p. 227°-230° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([CH3:11])([CH3:1])[CH2:6][C:5]=2[CH:7]=1)=[O:18]
Reactant: O=C(Cl)CCCCCl
Reactant: CC1(C)Cc2ccccc2O1
Product: CC1(C)Cc2cc(C(=O)CCCCCl)ccc2O1

Procedure:
Using 2,2-dimethyl-2,3-dihydro-1-benzofuran (3.0 g) and 5-chlorovaleryl chloride (3.4 g) according to the same method as that of Reference Example 1, the title compound was obtained as a fine yellow oil (3.6 g).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([N:11]=[C:12]=[O:13])([CH3:10])[CH3:9].[CH3:14][C:15]1[NH:19][N:18]=[C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[CH:16]=1.Cl>C(OCC)(=O)C>[CH:8]([NH:11][C:12]([N:19]1[C:15]([CH3:14])=[CH:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[N:18]1)=[O:13])([CH3:10])[CH3:9]
Reactant: CC(C)N=C=O
Reactant: Cc1cc(Oc2cccc(C(F)(F)F)c2)n[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2cccc(C(F)(F)F)c2)nn1C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.6 %

Procedure:
Triethylamine (0.17 g, 1.7 mmol) and isopropyl isocyanate (0.14 g, 1.7 mmol) were added to a solution of 5-methyl-3-(3-trifluoromethylphenyloxy)pyrazole (0.36 g, 1.5 mmol) in ethyl acetate (5 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a colorless viscous substance of N-isopropyl-5-methyl-3-(3-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.15 g, yield: 30.6%). 1H-NMR (CDCl3, TMS, ppm): δ 1.25 (d, J=6.6 Hz, 6H), 2.60 (d, J=0.6 Hz, 3H), 4.05 (sep, J=6.6 and 6.6 Hz, 1H), 5.71 (q, J=0.6 Hz, 1H), 6.81 (br d, J=6.6 Hz, 1H), 7.30-7.35 (m, 1H), 7.40-7.52 (m, 3H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH2:23])[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][C:45]([NH:21][C:18]2[C:17]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH2:23])=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:46])=[CH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: C=C(c1ccccc1)c1nc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cnc1N
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: C=C(c1ccccc1)c1nc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cnc1NC(=O)Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 33.3 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(1-phenylvinyl)pyrazin-2-amine (7c) (543 mg, 1.35 mmol) and 4-(dimethylamino)pyridine (15.0 mg, 123 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C., and the mixture was heated with stirring at 50° C. for 16 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11c (292 mg, 448 μmol, 33.3%) as a yellow foamy solid. Rf=0.26 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.13 (s, 6H), 0.18 (s, 6H), 0.91 (s, 9H), 0.92 (s, 9H), 3.22 (s, 2H), 5.51 (s, 1H), 5.65 (s, 1H), 6.67-6.74 (AA′BB′, 2H), 6.90-6.97 (AA′BB′, 2H), 6.97-7.03 (AA′BB′, 2H), 7.19-7.26 (m, 2H), 7.26-7.31 (m, 3H), 7.91-7.98 (AA′BB′, 2H), 8.95 (s, 1H), 10.19 (s, 1H); 13C NMR (75.5 MHz, acetone-d6) δ −4.3 (4C), 18.6, 18.7, 26.0 (6C), 42.5, 118.8, 120.5 (2C), 121.1 (2C), 127.9 (2C), 128.4, 128.6, 128.78 (2C), 128.84 (2C), 130.1, 131,3 (2C), 138.4, 140.0, 144.2, 146.9, 148.7, 148.9, 155.1, 157.9, 169.7; IR (KBr, cm−1) 546, 696, 781, 806, 839, 914, 1007, 1082, 1169, 1261, 1362, 1420, 1435, 1472, 1508, 1605, 1670, 2857, 2886, 2930, 2955, 3030, 3055, 3231; HRMS (ESI+) m/z 652.3390 ([M+H]+, C38H50N3O3Si2+ requires 652.3385).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:6]=2[N:19]=1.I[CH3:21].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:6]=2[N:19]=1
Reactant: CI
Reactant: CC(C)CCN1CC(C)C(=O)Nc2cnc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCN1CC(C)C(=O)N(C)c2cnc(Cl)nc21
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
To a mixture of 0.61 g, (0.00216 mole) of (rac)-2-chloro-7-methyl-9-(3-methyl-butyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-27), 0.2 mL (0.00324 mole) of iodomethane and 7 mL of N,N-dimethyl-formamide at 0 degrees, was added 0.13 g (0.00324 mole) of sodium hydride, 60% dispersion in mineral oil. The mixture was stirred at 0 degree for 1.5 hours, and then partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-60:40), to give 0.61 g of (rac)-2-chloro-5,7-dimethyl-9-(3-methyl-butyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-27). HRMS (ES+) m/z Calcd for C14H21ClN4O+H [(M+H)+]: 297.1477. Found: 297.1476.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][N:7]=1)(=[O:4])=[O:3].[Cl:15][C:16]1[CH:17]=[N+:18]([O-:45])[CH:19]=[C:20]([Cl:44])[C:21]=1[CH2:22][C@@H:23]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[C:31]([O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[CH:30]=1)[O:24][C:25](=[O:28])[CH2:26]O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:44][C:20]1[CH:19]=[N+:18]([O-:45])[CH:17]=[C:16]([Cl:15])[C:21]=1[CH2:22][C@@H:23]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[C:31]([O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[CH:30]=1)[O:24][C:25](=[O:28])[CH2:26][O:13][C:12]([C:9]1[CH:8]=[N:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[N:11][CH:10]=1)=[O:14]
Reactant: O=C(CO)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CS(=O)(=O)Nc1ncc(C(=O)O)cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ncc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cn1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
To a suspension of 2-(methylsulfonamido)pyrimidine-5-carboxylic acid (0.130 g, 0.599 mmol) in dry DCM (5.44 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-hydroxyacetoxy)ethyl)pyridine 1-oxide (See Scheme 21, step 6-9) (0.260 g, 0.544 mmol), EDC (0.313 g, 1.632 mmol), and DMAP (0.665 g, 0.544 mmol) were sequentially added with stirring at room temperature under nitrogen, and the mixture was stirred for 20 hours. The solvent was removed, and the crude was purified by flash chromatography on silica gel column (DCM:MeOH=97:3 to 95:5) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(2-(methylsulfonamido)pyrimidine-5-carbonyloxy)acetoxy)ethyl)pyridine 1-oxide as a pale yellow spongy solid (0.168 g, 0.248 mmol, 45.6% yield, MS/ESI+ 677.1 [MH]+, [αD]=−47.48, c=0.5, MeOH).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH:6]=[CH:5][N:4]=1.[Mn]([O-])(=O)(=O)=O.[K+].[S:21](S([O-])=O)([O-:24])(=O)=[O:22].[Na+].[Na+].[C:30](O)(=O)C>O>[CH3:30][S:21]([C:3]1[N:8]=[C:7]([O:9][CH2:10][C:11]([F:14])([F:12])[F:13])[CH:6]=[CH:5][N:4]=1)(=[O:24])=[O:22]
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: CC(=O)O
Reactant: CSc1nccc(OCC(F)(F)F)n1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1nccc(OCC(F)(F)F)n1
Yield: 87 %

Procedure:
To a solution of 2-methylthio-4-(2,2,2-trifluoroethoxy)pyrimidine (1.0 g) in glacial acetic acid (20 ml) at 15° C. was added a solution of potassium permanganate (2.4 g) in water (75 ml). When the addition was complete a solution of sodium metabisulphite (10% aqueous) was added until a clear solution was obtained. The reaction mixture was extracted with ether (3×70 ml), the combined extracts were washed with brine (3×), dried and concentrated to give 2-methanesulphonyl-4-(2,2,2-trifluorethoxy)-pyrimidine (1.0 g, 87% yield) as a clear oil; 1H NMR δ 3.35(3H,s); 4.91(2H,q); 7.11(1H.d); 8.69(1H,d) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][C:7]3([O:18][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:10][N:9](C)[CH2:8]3.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23].CCCCCC>ClCCl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][C:7]3([O:18][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:10][N:9]([C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23])[CH2:8]3
Reactant: CN1Cc2ccccc2C2(Cc3ccc(Cl)cc3O2)C1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(Oc1ccccc1)N1Cc2ccccc2C2(Cc3ccc(Cl)cc3O2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To an ice cold solution of 6-chloro-2'-methylspiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (5.0 g) in dichloromethane (150 ml) is slowly added dropwise phenyl chloroformate (3.7 g) in dichloromethane (20 ml). The mixture is stirred at ambient temperature overnight. Removal of the solvent in vacuo yields an orange oil which solidifies upon trituration with hexane. An analytical sample is twice recrystallized from hexane to yield product as a solid (6.6 g, 99%), mp 138°-140°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[C:16]([O:17]C)=[CH:15][C:14]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:13][C:12]=2[F:25])=[CH:4][CH:3]=1.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[C:16]([OH:17])=[CH:15][C:14]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:13][C:12]=2[F:25])=[CH:4][CH:3]=1
Reactant: COc1cc(N2CCOCC2)cc(F)c1C(=O)NCc1ccc(Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1c(O)cc(N2CCOCC2)cc1F
Temperature: 25 °C
Yield: 37.8 %

Procedure:
To a solution of N-[(4-chlorophenyl)-methyl]-2-fluoro-6-methoxy-4-morpholin-4-yl-benzamide (1.3 g, 3.44 mmol) in dichloromethane (40 ml) is added neat boron tribromide (0.82 ml, 8.6 mmol) at −78° C. The temperature is raised to room temperature over a period of 2 h. The reaction mixture is poured onto cold water, extracted with dichloromethane (3×50 ml). The combined organic layers are washed with brine (30 ml), dried over sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography (silica gel, 5% ethyl acetate/dichloromethane) to yield N-[(4-chlorophenyl)-methyl]-2-fluoro-6-hydroxy-4-morpholin-4-yl-benzamide (0.5 g, 1.3 mmol, 39%).
Reaction SMILES: O1CCCC1.[C:6]([C:10]1[C:20]([F:21])=[CH:19][C:13]([O:14][CH2:15][C:16]([OH:18])=O)=[CH:12][C:11]=1[F:22])([CH3:9])([CH3:8])[CH3:7].[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:33][C@@H:34]([C:36]1[CH:41]=[CH:40][C:39]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[C:38]([CH3:47])[CH:37]=1)[CH3:35]>C(N(CC)CC)C>[C:6]([C:10]1[C:11]([F:22])=[CH:12][C:13]([O:14][CH2:15][C:16]([NH:33][C@@H:34]([C:36]2[CH:41]=[CH:40][C:39]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[C:38]([CH3:47])[CH:37]=2)[CH3:35])=[O:18])=[CH:19][C:20]=1[F:21])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1c(F)cc(OCC(=O)O)cc1F
Reactant: Cc1cc([C@@H](C)N)ccc1NS(C)(=O)=O
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc([C@@H](C)NC(=O)COc2cc(F)c(C(C)(C)C)c(F)c2)ccc1NS(C)(=O)=O
Reaction time: 2 h
Yield: 5.2 %

Procedure:
To a tetrahydrofuran (THF) (3.0 ml) solution of (4-tert-butyl-3,5-difluorophenoxy)acetic acid (166 mg, 0.68 mmol) was added 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (110 mg, 0.68 mmol) at room temperature and the mixture was stirred for 2 hours, followed by the addition of triethylamine (0.5 ml) and N-{4-[(1R)-1-aminoethyl]-2-methylphenyl}methanesulfonamide hydrochloride (180 mg, 0.68 mmol) with stirring for 10 hours. The reaction was partitioned with water and dichloromethane and the organic layer was separated and dried over sodium sulfate. Then filtration and evaporation under reduced pressure gave the crude residue which was purified by silica gel column chromatography, eluting with dichloromethane/methanol from 5:1 to 5:2, to furnish 1 16mg (38%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1([C:9]2[N:10]=[C:11](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=3)[S:12][CH:13]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.O.O.[Sn](Cl)Cl>[OH-].[Na+]>[CH:1]1([C:9]2[N:10]=[C:11](/[CH:14]=[CH:15]/[C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)[S:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=[N+]([O-])c1cccc(/C=C/c2nc(C3CCCCCCC3)cs2)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cccc(/C=C/c2nc(C3CCCCCCC3)cs2)c1
Yield: 98.6 %

Procedure:
A mixture composed of 2.0 g of (E)-4-cyclooctyl-2-[2-(3-nitrophenyl)ethenyl]thiazole, 50 ml of ethyl alcohol and 4.6 g of tin(II) chloride dihydrate was heated to reflux for 1.2 hr. The cooled reaction mixture was then diluted with 200 ml of 1.5N sodium hydroxide and this mixture was extracted with ethyl ether. The combined extracts were washed with brine, dried (MgSO4) and condensed in vacuo and the residual materials were further purified by silica gel chromatography using ethyl acetate as the eluant to yield 1.8 g of (E)-3-[2-[4-(cyclooctyl)-2-thiazolyl]ethenyl]benzeneamine as an oil.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:15].[C:24]([OH:32])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH2:33]>CC(C)=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:15].[C:24]([O-:32])(=[O:31])[C:25]1[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=1)[OH:33]
Reactant: O=C(O)c1ccccc1
Reactant: O
Agent: CCCCCCCCCCCCC[N+](C)(C)Cc1ccccc1
Solvent: CC(C)=O
Product: O=C([O-])c1ccccc1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Benzalkonium saccharinate (0.01 mol) and benzoic acid (0.01 mol) were dissolved in 25 mL of hot acetone. The mixture was stirred at room temperature for 5 h. Distilled water was added. The organic phase was separated and washed with distilled water. Organic phase was evaporated and the product, benzalkonium salicylate, was dried under vacuum. 1H and 13C NMR (DMSO) were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:5]2=[N:6][CH:7]=1.[Li][C:19](C)(C)C.CCCCC.CI>CCOCC>[C:14]([Si:11]([CH3:13])([CH3:12])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([CH3:19])[CH:3]=[C:4]2[CH2:10][CH2:9]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cc(Br)cnc21
Reactant: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CI
Solvent: CCOCC
Product: Cc1cnc2c(c1)CCN2[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
To a stirred and cooled (−78° C.) solution of bromide 4 (0.20 g, 0.64 mmol) in Et2O (2.5 mL) was added dropwise a 1.5 M solution of tert-BuLi in pentane (0.89 mL, 1.34 mmol). After 38 min MeI (0.1 mL, 1.61 mmol) was added dropwise and the mixture allowed to gradually warm to r.t. After 12 h the mixture was partitioned between CHCl3 and saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CHCl3 (2×). The combined organic extracts were dried (MgSO4), and concentrated to afford 7 as a yellow oily residue, which was used directly in the next step without purification.