Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)=O.[Cl:5]([O-:9])(=[O:8])(=[O:7])=[O:6].CS[C:12]1[S:16][CH:15]=[CH:14][S+:13]=1.C(OCC)C.[CH2:22]([O:24][C:25](=[O:33])[C@H:26]([CH2:29][CH2:30][S:31][CH3:32])[NH:27][CH3:28])[CH3:23]>C(OCC)(=O)C>[Cl:5]([O-:9])(=[O:8])(=[O:7])=[O:6].[S:16]1[CH:15]=[CH:14][S:13][C:12]1=[N+:27]([CH3:28])[CH:26]([C:25]([O:24][CH2:22][CH3:23])=[O:33])[CH2:29][CH2:30][S:31][CH3:32]
Reactant: CSc1scc[s+]1
Reactant: CCOC(=O)[C@H](CCSC)NC
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(CCSC)[N+](C)=c1sccs1
Temperature: 25 °C
Yield: 222.1 %

Procedure:
To 100 ml of acetone, 2.0 g of 2-methylthio-1,3-dithiolium perchlorate was dissolved, and 50 ml of an ethyl ether solution containing 2.3 g of N-methyl methionine ethyl ester was gradually added thereto under stirring at room temperature. The mixture was stirred at room temperature for 6 hours, and then the solvent was distilled off. The residue was washed with ethyl acetate, whereby 7 g (yield: 54%) of N-(1,3-dithiol-2-ylidene)-N-methyl-N-(3-methylthio-1-ethoxycarbonylpropyl)ammonium perchlorate (Compound No. 6) was obtained as oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(Cl)(Cl)Cl.[Br:20]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>CCCCCCC>[Br:20][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
A 1-L single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1 (10.6 g, 54.1 mmol), carbon tetrachloride (120 mL), N-bromosuccinimide (10.7 g, 59.9 mmol) and azobisisobutylonitrile (275 mg, 1.67 mmol), and the reaction mixture was heated at reflux for 18 h. After this time the reaction was cooled to room temperature and poured into heptane (120 mL). The resulting suspension was filtered and the filter cake washed with heptane (40 mL). The filtrate was concentrated under reduced pressure and the resulting residue was subjected to flash chromatography to afford 2 in 72% yield (10.7 g) as a clear oil: 1H NMR (500 MHz, CDCl3) δ 8.23 (d, 2H, J=9 Hz), 7.74 (d, 2H, J=9.0 Hz), 5.40 (s, 1H), 3.82 (s, 3H); MS (ESI−) m/z 272 (M−H). Reference: Tetrahedron 2002, 58, 10113.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][NH2:13]>C1COCC1>[CH3:12][NH:13][S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:10])=[O:9]
Reactant: CN
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cccc(Br)c1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 0° C. was added methylamine (2.0M in THF; 28 mL, 56 mmol). The resulting solution was allowed to warm to room temp. and was stirred at room temp. overnight. The resulting mixture was separated between EtOAc (25 mL) and a 1M HCl solution (25 mL). The aqueous phase was back-extracted with EtOAc (2×25 mL). The combined organic phases were sequentially washed with water (2×25 mL) and a saturated NaCl solution (25 mL), dried (MgSO4) and concentrated under reduced pressure to give N-methyl-3-bromobenzenesulfonamide as a white solid (2.8 g, 99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH2:24])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[S:43](Cl)(=[O:45])=[O:44])[CH:36]=[CH:35][CH:34]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH:24][S:43]([C:41]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:42]=1[N:33]=[CH:34][CH:35]=[CH:36]2)(=[O:44])=[O:45])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2cccc3cccnc23)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.123 g (0.35 mmol) of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dimethylformamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.159 g (0.7 mmol) of 8-quinolinesulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1). Yield 67 mg. MS (ES+): m/e=542.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:19]=O)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][NH:25][C@H:26]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:28][O:29][CH3:30]>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19][N:25]([CH3:24])[C@H:26]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:28][O:29][CH3:30])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@@H](CCOC)C(N)=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Product: COCC[C@@H](C(N)=O)N(C)Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC

Procedure:
4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazoline-6-carbaldehyde was coupled with N2,O-dimethyl-L-homoserinamide analogously as for the equivalent step in Example 1 to give N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2,O-dimethyl-L-homoserinamide; 1H NMR spectrum: (DMSO d6) 1.91 (m, 2H), 2.25 (s, 3H), 3.23 (s, 3H), 3.27 (t, 1H), 3.39 (m, 1H), 3.48 (m, 1H), 3.66 (d, 1H), 3.81 (d, 1H), 3.96 (s, 3H), 7.07 (brs, 1H), 7.20 (s, 1H), 7.29 (t, 1H), 7.38 (brs, 1H), 7.49 (t, 1H), 7.55 (t, 1H), 8.35 (s, 1H), 8.43 (s, 1H), 9.77 (s, 1H); Mass Spectrum: (M+H)+ 462.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=2[CH2:7][O:6][C:5]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:4]1=2.CC1(C)C(C)(C)OB([C:28]2[CH:37]=[CH:36][C:31]3[NH:32][C:33](=[O:35])[NH:34][C:30]=3[CH:29]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[F:19][C:16]1[CH:17]=[CH:18][C:4]2[C:3](=[CH:2][C:28]3[CH:37]=[CH:36][C:31]4[NH:32][C:33](=[O:35])[NH:34][C:30]=4[CH:29]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=3[CH2:7][O:6][C:5]=2[CH:15]=1
Reactant: Fc1ccc2c(c1)OCc1c(F)cccc1C2=CBr
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)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: [Na+]
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(C=C3c4ccc(F)cc4OCc4c(F)cccc43)cc2[nH]1
Yield: 74.4 %

Procedure:
Following procedures essentially as described in Example 219, mix 11-bromomethylene-3,7-difluoro-6,11-dihydro-dibenzo[b,e]oxepine (E-isomer, 68 mg, 0.21 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (52 mg, 0.20 mmol), Na2CO3 (2M in water, 251 μL, 0.503 mmol), dioxane (2 mL), and Pd(PPh3)4 (12 mg, 0.010 mmol). Purify on silica gel (12 g) eluting with THF to afford a brown solid. Triturate with acetone to afford 56 mg (74%) of the title compound as a white solid. HPLC (ISO80-10) t=2.42 min, 96%; MS [ES] 375 (M−H); 1H-NMR (DMSO-d6) δ 10.58 (s, 1H), 10.46 (s, 1H), 7.57 (dd, 1H, J=8.8, 7.0 Hz), 7.24 (m, 2H), 7.00 (s, 1H), 6.81 (m, 2H), 6.72 (m, 2H), 6.64 (dd, 1H, J=10.6, 2.6 Hz), 6.59 (s, 1H), 5.55-5.19 (br d, 2H).
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[C:6]([N:8]([C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[CH:21]=2)[CH2:16][CH2:15]1)[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7]>O.CO.C1COCC1>[Cl:3][C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[C:6]([N:8]([C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=2)[CH2:16][CH2:15]1)[CH2:9][C:10]([F:12])([F:11])[F:13])=[O:7]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N(CC(F)(F)F)C(=O)c1ccccc1Cl)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(c1)[C@H](N(CC(F)(F)F)C(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
A solution of LiOH (153 mg, 3.64 mmol, 1.5 eq.) in water (8 ml) was added to a cooled (0° C.) solution of (R)-methyl 3-(2-chloro-N-(2,2,2-trifluoroethyl)benzamido)-2,3-dihydro-1H-indene-5-carboxylate (B-41) (1.0 g, 2.43 mmol, 1.0 eq.) in MeOH:THF (1:1, 16 ml) and the reaction mixture was then stirred at RT for 5 h. After completion of the reaction (monitored by TLC), the mixture was evaporated to dryness and diluted with water (15 ml). The aqueous layer was acidified to pH ˜3 using 1N HCl and then extracted with ethyl acetate (2×30 ml). The organic layer was washed with brine (20 ml), dried over anhydrous Na2SO4 and evaporated to afford the desired product as a white solid. Yield: 88% (850 mg, 2.14 mmol).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]1N2CN3CN(C2)CN1C3.[OH2:26]>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:16]=[O:26])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
A mixture of 10.42 g (50 mmol) of 2,4-di-tert-butylphenol and 21.03 g 150 mmol) of hexamethylenetetramine (HMT) in 50 mL of glacial acetic acid was heated at 130° C. with stirring for 2 hours. Twenty-five mL of water was then added and the resulting mixture was refluxed for 0.5 h. After cooling and workup as in Example 1, 5.5 g of 3,5-di-tert-butylsalicylaldehyde was obtained (46.9% yield).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].CS(O[CH2:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[CH3:48][O:47][CH2:46][CH2:45][CH2:44][CH2:43][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14]1)=[O:11]
Reactant: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution of tert-butyl (3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (200 mg), 4-methoxybutyl methanesulfonate (107 mg) and cesium carbonate (254 mg) in N,N-dimethylacetamide (5 ml) was stirred at 60° C. for 15 hr. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (10 ml×2). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-3:7) was concentrated under reduced pressure to give the object product (190 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][CH2:17][N:16]([S:20]([C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=4[O:30][CH3:31])(=[O:22])=[O:21])[C:15]=3[CH:32]=2)=[O:10])=[CH:4][C:3]=1[C:33]#[N:34].C(N([CH2:40][CH3:41])CC)C.[C:42]([O:45][CH2:46]C)(=[O:44])C>C(O)CC>[CH2:46]([O:45][C:42](=[O:44])[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][CH2:17][N:16]([S:20]([C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=4[O:30][CH3:31])(=[O:21])=[O:22])[C:15]=3[CH:32]=2)=[O:10])=[CH:4][C:3]=1[C:33]#[N:34])[CH2:40][CH3:41]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(Br)c(C#N)c3)cc21
Reactant: CCN(CC)CC
Reactant: CCOC(C)=O
Solvent: CCCO
Product: CCCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)cc1C#N
Yield: 42 %

Procedure:
A solution of 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo-[1,4]oxazine-6-carboxylic acid (4-bromo-3-cyano-phenyl)-amide (109 mg, 0.194 mmol), triethylamine (49 mg, 0.48 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane complex (20 mg, 25 μmol) in ethyl acetate (1.5 mL) and 1-propanol (1.5 mL) was heated at 110° C. under a carbon monoxide atmosphere for 16 h, then volatile material was removed by distillation. Chromatography of the residue (SiO2; heptane-ethyl acetate gradient, then dichloromethane/methanol 9:1) followed by trituration in dichloromethane produced 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-cyano-benzoic acid propyl ester (46 mg, 42%). White solid, MS (ISP)=568.2 (M−H)−.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][C@@H:13]1[NH:18][CH2:17][C@@H:16]([CH2:19][N:20]([CH3:22])[CH3:21])[O:15][CH2:14]1.C(N(CC)CC)C.CN1CCCC1=O>C(Cl)Cl>[NH2:7][C:6]1[CH:8]=[C:2]([N:18]2[C@@H:13]([CH3:12])[CH2:14][O:15][C@H:16]([CH2:19][N:20]([CH3:21])[CH3:22])[CH2:17]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: C[C@H]1CO[C@H](CN(C)C)CN1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CO[C@H](CN(C)C)CN1c1ccc([N+](=O)[O-])c(N)c1
Temperature: 140 °C

Procedure:
A mixture of 5-fluoro-2-nitroaniline (1.1 equivalents), [((2S,5S)-5-methylmorpholin-2-yl)methyl]dimethylamine (1 equivalent), triethylamine (3 equivalents), and N-methylpyrrolidinone was heated at 140° C. for 48 hours in a sealed high pressure vessel. The reaction mixture was then cooled to 25° C. and dissolved in CH2Cl2. The solution was washed with water (×2) and dried over Na2SO4. Purification via chromatography on silica gel (10% MeOH in dichloromethane) afforded the desired product as a dark yellow foam. LC/MS (m/z) 295.2 (MH+) Rt 1.55 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].ClCCl.[CH3:17][NH2:18]>O1CCCC1>[CH3:17][NH:18][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: CN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 2-nitrobenzenesulfonyl chloride (25 g, 0.113 mol) and dichloromethane (450 mL) at 4° C. was added dropwise 2M methylamine in tetrahydrofuran (68 mL). The mixture was stirred overnight allowing the ice bath to melt. More 2M methylamine in tetrahydrofuran (97 mL) was added and the reaction was stirred for 1 hour. The reaction mixture was concentrated in vacuo. The residue was dissolved in chloroform (500 mL) and was washed with saturated sodium bicarbonate (250 mL). The aqueous layer was extracted with chloroform (250 mL) and all the chloroform layers combined, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue purified by silica gel chromatography using 0-4% methanol in dichloromethane. 22.63 g of N-methyl-2-nitrobenzenesulfonamide was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].Cl.O.[NH:33]1[CH2:38][CH2:37][C:36](=[O:39])[CH2:35][CH2:34]1.C(=O)(O)[O-:41].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:33]4[CH2:38][CH2:37][C:36]([OH:41])([OH:39])[CH2:35][CH2:34]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C([O-])O
Reactant: O=C1CCNCC1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCC(O)(O)CC1

Procedure:
After the procedure of Example 117, 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide. (0.51 mmol.) was stirred in dimethylformamide with 4-piperidone monohydrate hydrochloride (470 mg., 3.06 mmol.), and sodium bicarbonate (386 mg., 4.59 mmol.), for 24 hours. The crude product was purified in the same manner as Example 117 and produced 192 mg. (72%) of the product as a yellow solid: mp 225-30° C.
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH:11]=[CH:12][O:13][C:9]=2[CH:8]=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].C1(O)C=CC=CC=1>C(O)(=O)C.[Pd].CCOCC>[C:1]([C:5]1[C:10]2[CH2:11][CH2:12][O:13][C:9]=2[CH:8]=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(O)ccc2occc12
Agent: [Pd]
Solvent: Oc1ccccc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)(C)c1c(O)ccc2c1CCO2

Procedure:
To a solution of 4-tert butyl-5-benzofuranol (0,660 g, 3.47 mmol) 41a in acetic acid (20 mL) is added 10% palladium on carbon (0.130 ) and the mixture hydrogenated overnight at 40 psi. The reaction mixture is taken up in ether (25 mL) and filtered through a bed of Celite to remove the catalyst. The filtrate and washing are diluted with water (100 mL) and ether (50 mL) and the layers separated. The aqueous layer is washed with an additional portion of ether (50 mL) and the combined extracts washed sequentially with 5% NaHCO3 (3×50 mL), water (50 mL), and 20% NaCl (50 mL) then dried (MgSO4) and concentrated. Purification by flash chromatography using 5% ethyl acetate in hexane as eluant gives 4-tert-butyl-2,3-dihydro-5-benzofuranol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10]O)=[C:7]([CH3:12])[C:6]=2[C:13]=1[O:14][CH3:15].P(Br)(Br)[Br:17]>ClCCl.N1C=CC=CC=1>[Br:17][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[C:13]([O:14][CH3:15])[C:6]=2[C:7]=1[CH3:12]
Reactant: BrP(Br)Br
Reactant: COc1c(Cl)ccc2oc(CO)c(C)c12
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(Cl)ccc2oc(CBr)c(C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a 0° C. solution of (5-chloro-4-methoxy-3-methyl benzofuran-2-yl)-methanol (0.29 g; 1.3 mmol) in dichloromethane (5 mL) was added neat phosphorus tribromide (0.18 mL; 0.52 g; 1.9 mmol; 1.5 eq) and pyridine (3 drops). The ice bath was removed and the reaction was allowed to warm to room temperature overnight. Additional phosphorus tribromide (0.09 mL; 0.26 g; 0.95 mmol; 0.75 eq) was added and stirring continued at room temperature. After two hours, the reaction was quenched with ice and extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated sodium bicarbonate, followed by drying over magnesium sulfate, filtration and concentration in vacuo to give essentially pure 2-bromomethyl-5-chloro-4-methoxy-3-methyl benzofuran (0.37 g; 99%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[O:12]1[CH:16]2[O:17][CH2:18][CH2:19][N:15]2[CH2:14][CH2:13]1>ClCCl>[Br-:1].[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N+:15]23[CH2:19][CH2:18][O:17][CH:16]2[O:12][CH2:13][CH2:14]3)=[CH:6][CH:7]=1
Reactant: C1CN2CCOC2O1
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: ClCCl
Product: O=C(C[N+]12CCOC1OCC2)c1ccc(Br)cc1
Product: [Br-]
Yield: 96.7 %

Procedure:
A solution of 2.779 g (10 mmol) 2,4′-dibromoacetophenone and 1.152 g (10 mmol) tetrahydro[1,3]oxazolo[2,3-b][1,3]oxazole in 20 ml of dichloromethane was refluxed for 3 hours. The precipitate was filtered off, washed twice with dichloromethane and dried. 3.801 g (96.7%) of white amorphous product was obtained, which can be further purified by recrystallisation from rectified ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=S)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:18]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:15]([F:17])[F:16])[CH2:9][O:10][CH2:11][C:12]([NH2:18])=[N:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: FC(F)C1(c2cccc(Br)c2)COCC(=S)N1
Solvent: CO
Product: NC1=NC(c2cccc(Br)c2)(C(F)F)COC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-(3-Bromo-phenyl)-5-difluoromethyl-morpholine-3-thione (7.49 g, 23.25 mmol) was dissolved in 36 ml 7N NH3 in methanol and stirred at room temperature for 18 h. After completion, volatiles were removed under reduced pressure to yield the title compound. 1H-NMR (360 MHz, DMSO-d6): 7.80 (s, 1H), 7.52 (m, 2H), 7.33 (m, 1H), 6.25 (br, 2H, NH2), 6.04 (t, 1H, CHF2), 4.15-3.90 (m, 2H), 3.72 (d, 1H), 3.45 (d, 1H); MS: 305 [(M+H)+].
Reaction SMILES: [C:1]([O:9][CH:10]([C:14](=O)[CH3:15])[C:11](=O)[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][NH:18][NH2:19]>C(O)C>[C:1]([O:9][C:10]1[C:14]([CH3:15])=[N:19][N:18]([CH3:17])[C:11]=1[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNN
Reactant: CC(=O)C(OC(=O)c1ccccc1)C(C)=O
Solvent: CCO
Product: Cc1nn(C)c(C)c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
A flask was charged with 2,4-dioxopentan-3-yl benzoate (82.59 g, 375.0 mmol) and ethanol (1.5 L) was added. To this solution was added methylhydrazine (39.90 ml, 750.1 mmol) in ethanol (150 mL). The reaction was stirred at ambient temperature for 2 hours and concentrated in vacuo to afford 1,3,5-trimethyl-1H-pyrazol-4-yl benzoate (80 g, 92.6% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:5][C:4]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3]1.[CH3:27][I:28]>C(Cl)Cl>[I-:28].[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:4]1([NH:6][S:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:5][N+:2]([CH3:27])([CH3:1])[CH2:3]1)[CH3:26]
Reactant: CI
Reactant: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CN(C)C2)cc1
Solvent: ClCCl
Product: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)C[N+](C)(C)C2)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
Ethyl 2-(1-methyl-3-(4-pentylphenylsulfonamido)azetidin-3-yl)acetate (10 mg, 0.026 mmol) was dissolved into CH2Cl2 (2 mL). The solution was treated with methyl iodide (37 mg, 0.26 mmol). The mixture was stirred at room temperature overnight. Solvent was removed under vacuum to obtain the title compound as a yellow solid (10 mg, 77%) which was used in the next step without purification. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, 2H, J=8 Hz), 7.33 (d, 2H, J=8 Hz), 5.04 (m, 4H), 3.90 (q, 2H, J=7.2 Hz), 3.64 (s, 3H), 3.58 (m, 3H), 3.14 (s, 2H), 2.66 (t, 2H, J=8 Hz), 1.65-1.58 (m, 2H), 1.32 (br, 4H), 1.10 (t, 3H, J=7.2 Hz), 0.89 (m, 3H); MS ESI 397.2 [M]+, calcd for [C20H33N2O4S]+ 397.22.