Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[C:6]([NH:9][CH:10]3[CH2:12][CH2:11]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH:15]1([NH:18][C:19](=[O:37])[C:20]2[CH:25]=[C:24](B3OC(C)(C)C(C)(C)O3)[C:23]([CH3:35])=[C:22]([F:36])[CH:21]=2)[CH2:17][CH2:16]1.C(=O)([O-])O.[Na+]>C(O)(C)C>[CH:15]1([NH:18][C:19](=[O:37])[C:20]2[CH:21]=[C:22]([F:36])[C:23]([CH3:35])=[C:24]([C:2]3[CH:14]=[CH:13][C:5]4[C:6]([NH:9][CH:10]5[CH2:12][CH2:11]5)=[N:7][O:8][C:4]=4[CH:3]=3)[CH:25]=2)[CH2:16][CH2:17]1
Reactant: Brc1ccc2c(NC3CC3)noc2c1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(NC3CC3)noc2c1
Yield: 43.7 %

Procedure:
A mixture of 6-bromo-N-cyclopropyl-1,2-benzisoxazol-3-amine (Intermediate 53) (0.02 g) N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 62) (0.02 g) saturated aqueous sodium hydrogen carbonate (0.5 ml) and tetrakis(triphenykphosphine)palladium(0) in isopropanol (2 ml) was heated in a microwave at 150° for 10 min. The residue was absorbed onto silica Merck 7734) and applied to a Varian Bond Elut SPE cartridge (silica, 5 g) elutin with cyclohexane:ethyl acetate (75:25 to 0:100) to give the title compound (10 mg).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:12]=[CH:11][C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=1.C(=O)([O-])O.[Na+].[C:18](Cl)([CH:20]=[CH2:21])=[O:19]>O>[C:18]([NH:3][C:4]1[CH:12]=[CH:11][C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=1)(=[O:19])[CH:20]=[CH2:21]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc2[nH]nnc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=CC(=O)Nc1ccc2[nH]nnc2c1
Reaction time: 1 h
Yield: 58.5 %

Procedure:
20.7 g of 5-aminobenzotriazole dihydrochloride and 30 g of sodium hydrogen carbonate were dissolved in 300 ml of water, and 10 g of acryl chloride was added dropwise at a temperature of lower than 10° C. over 20 minutes. After being stirred for 1 hour, the formed white precipitate was filtered off. Yield: 13.8 g. It was dissolved in 100 ml of DMF, and 500 ml of hot water at about 70° C. was added. It was immediately filtered under atmospheric pressure. The filtrate was allowed to cool, and the separated crystals were filtered out, washed with water and dried to obtain 11 g of the desired product which melted at 248°-253° C. The structure was confirmed by IR, NMR and elementary analysis.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[NH2:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH3:43][N:44]([CH3:59])[C:45]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:46]=1[CH:47]=[CH:48][CH:49]=[C:50]2[S:55](Cl)(=[O:57])=[O:56]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[NH:34][S:55]([C:50]1[C:51]2[C:46](=[C:45]([N:44]([CH3:59])[CH3:43])[CH:54]=[CH:53][CH:52]=2)[CH:47]=[CH:48][CH:49]=1)(=[O:57])=[O:56])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Cl)ccc1N
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
To a stirring solution of (S)-2(2-amino-5-chloro-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)propionic acid methyl ester (100 mg, 0.2 mmol) prepared above dissolved in DCM containing pyridine (31.6 mg, 0.4 mmol), was added 5-Dimethylamino-naphthalene-1-sulfonyl chloride (59.1 mg, 0.0.22 mmol) at 0° C. The reaction mixture was stirred at rt for 3 h, extracted with DCM, washed with 1M HCl and brine evaporation followed by column chromatography purification (silica, CH2Cl2) giving (2S)-[5-chloro-2-(5-dimethylamino-naphthalene-1-sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (100 mg) as a light yellow solid which was hydrolyzed according to Procedure C yielding the title compound (93 mg) as a light yellow solid. LC/MS (m/z): 720 (M+1)+.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:23][CH:22]=1.CCOC(C)=O>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:25][CH:26]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(NC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Temperature: 120 °C
Yield: 46.7 %

Procedure:
A mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.200 g, 0.667 mmol) and tert-butyl (4-aminophenyl)carbamate (0.278 g, 1.344 mmol) in DMF (2 ml) was heated in a microwave reactor at 120° C. for 30 mins. EtOAc was added, and the mixture was washed with brine and evaporated. The residue was triturated in MeOH, the solvent was decanted and the residue was purified by silica gel column chromatography using 15-65% EtOAc in petroleum ether 40-60° C. as eluent, to give the title compound (0.147 g, 47%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 9.18 (s, 1H), 9.16 (s, 1H), 7.22 (dt, 1H), 7.18 (dt, 2H), 7.08-7.00 (m, 4H), 6.64 (d, 2H), 1.65 (s, 9H), 1.44 (s, 9H); 13C NMR (d6-DMSO): δ 160.3, 153.0, 136.8, 132.3, 131.9, 129.6, 129.3, 128.6, 125.9, 123.2, 117.9, 109.2, 79.8, 61.4, 28.8, 27.9; Mass Spectrum: M−H+ 470.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([Li])CCC.C([Li])(CC)C.[C:19]1(=[O:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Cl>C1COCC1.C1(C)C=CC=CC=1.O>[OH:25][C:19]1([C:2]2[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C1CCCCC1
Reactant: Oc1ccc(Br)nc1
Agent: Cl
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Oc1ccc(C2(O)CCCCC2)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.4 %

Procedure:
To a solution of 6-bromo-pyridin-3-ol (5.0 g, 28.7 mmol) in anhydrous THF (75 mL) and anhydrous toluene (40 mL) at −78° C. was added n-butyllithium (2.5 M in hexane, 28.73 mmol). The mixture was stirred for 20 min. A solution of sec-butyllithium (1.4 M in cyclohexane, 43.1 mmol) was added dropwise and the mixture stirred at −78° C. for 1 hour. To the mixture was added cyclohexanone (4.23 g, 43.1 mmol) in THF (25 mL) at −78° C. and the mixture stirred at −78° C. for 1 hour. Saturated NaH2PO4 solution (10 mL) was slowly added to the mixture and the mixture then warmed to room temperature. Water (300 mL) was added. The reaction mixture was neutralized with hydrochloric acid (2N), and the mixture extracted three times with EtOAc. The organic layer was washed with brine and dried (Na2SO4). Silica gel chromatography (EtOAc/heptane) provided 2.63 g of the title compound. C11H15NO2 (193.11), LCMS (ESI): 194.09 (M++H).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[CH2:32]([C:34]1[C:35]([NH:42][C@H:43]2[C@@H:47]([OH:48])[CH2:46][N:45]([C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[O:50])[CH2:44]2)=[N:36][C:37]([CH2:40][CH3:41])=[CH:38][N:39]=1)[CH3:33].[F:59][CH2:60][CH2:61]Br>>[CH2:32]([C:34]1[C:35]([NH:42][C@H:43]2[C@@H:47]([O:48][CH2:61][CH2:60][F:59])[CH2:46][N:45]([C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[O:50])[CH2:44]2)=[N:36][C:37]([CH2:40][CH3:41])=[CH:38][N:39]=1)[CH3:33]
Reactant: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2O)n1
Reactant: FCCBr
Agent: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2OCCF)n1

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate and 2-fluoro-1-bromo ethane, and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, DMSO-d6) δ) 7.61, 7.38-7.36, 5.85, 5.08, 4.52, 4.50, 4.38, 4.22, 3.75-3.40, 2.60, 2.53, 1.19-1.13; IR (liq.) 2970 (s), 2937 (s), 2340 (w), 2068 (w), 1996 (w), 1954 (w), 1705 (s), 1546 (s), 1499 (s), 1448 (s), 1422 (s), 1395 (s), 1351 (s), 1136 (s), 1107 (s), cm−1; HRMS (FAB) calcd for C22H29FN4O3+H 417.2302, found 417.2299.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[CH2:45]([N:47]([C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH3:57])[CH:52]=1)[CH2:48][CH2:49][NH2:50])[CH3:46]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:50][CH2:49][CH2:48][N:47]([CH2:45][CH3:46])[C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([CH3:57])[CH:52]=2)=[O:43])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: CCN(CCN)c1cccc(C)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1[N+](=O)[O-])c1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-nitroaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (131 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1-ethyl-N1-(3-methylphenyl)-1,2-ethanediamine (78 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (101 mg, yield 64%).
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)[C:2]#[CH:3].[CH2:20]=O.[CH:22]1([CH2:28][NH:29][CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.Cl>>[CH:22]1([CH2:28][NH:29][CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][N:32]2[CH2:20][C:3]#[C:2][CH2:1][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: C1CCC(CNCC2CCCCN2)CC1
Reactant: C=O
Reactant: C#CCN1c2ccccc2C(=O)Nc2cccnc21
Agent: Cl
Product: O=C1Nc2cccnc2N(CC#CCN2CCCCC2CNCC2CCCCC2)c2ccccc21
Yield: 34 %

Procedure:
Prepared analogously to Example lb) from 5,11-dihydro-11-(prop-2-ynyl)-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, paraformaldehyde and 2-[[(cyclohexyl)methylamino]methyl]piperidine in a yield of 34% of theory. The monohydrochloride melted at 205° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C1C=CC(CC(NCN[C@H](C(O)=O)CC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1.[CH2:51]([NH2:57])[C:52]1[O:56][CH:55]=[CH:54][CH:53]=1>CS(C)=O.C(N(C(C)C)CC)(C)C.[Cl-].[Na+].O>[NH2:1][C:2]1[N:23]=[C:22]([NH:57][CH2:51][C:52]2[O:56][CH:55]=[CH:54][CH:53]=2)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Reactant: NCc1ccco1
Agent: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Nc1nc(NCc2ccco2)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 135 °C
Yield: 68 %

Procedure:
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (180 mg, 0.5 mmol) was dissolved in a mixture solution of dimethylsulfoxide (2 mL) and diisopropylethylamine (1 mL), furfurylamine (0.663 mL, 7.5 mmol) was added, and the solution was heated in a sealed tube for 13 hours 30 minutes (oil bath temperature: 135° C.). The reaction mixture was allowed to room temperature, poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then concentrated, the obtained residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=2:1), and the title compound (144 mg, 0.34 mmol, 68%) was obtained.
Reaction SMILES: C(N(CC)CC)C.[Br:8][CH2:9][CH2:10][N:11]([CH2:25][CH2:26][Br:27])[C:12]1[CH:17]=[CH:16][C:15]([NH:18]C(NCCBr)=O)=[CH:14][CH:13]=1>CCOCC>[Br:8][CH2:9][CH2:10][N:11]([CH2:25][CH2:26][Br:27])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1
Reactant: O=C(NCCBr)Nc1ccc(N(CCBr)CCBr)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Nc1ccc(N(CCBr)CCBr)cc1
Yield: 95 %

Procedure:
2HCl (2.93 g) was reacted with triethylamine (2.90 g) in ether (150 ml). The reaction mixture was filtered, and β-bromoethyl isocyanate (1.23 g) was added to the filtrate to give a white solid (3.32 g; melting point 103°-105° C.). The infrared absorption spectrum of the solid was as shown in FIG. 2. It was very similar to the infrared absorption spectrum of N-[p-bis(β-chloroethyl)aminophenyl]-N'-(β'-chloroethyl)urea obtained in Example 1, and showed a strong absorption based on the NH linkage at 3300 cm-1 and a strong absorption based on the carbonyl linkage of the ureido group at 1625 cm-1. The elemental analysis values were C 33.44%, H 3.47%, and N 8.84% which agreed with the calculated values for the composition formula C13H18N3OBr3 (472.04) which were C 33.908%, H 3.84%, N 8.90%. Its mass spectrum showed M⊕ at m/e=472 and peaks corresponding to [M⊕ -Br] at m/e=393 and 392. The foregoing results clearly show that the resulting white solid is N-[p-bis(β-bromoethyl)aminophenyl]-N'-(β'-bromoethyl)urea (designated as compound No. 1). The yield was 95.0%. ##STR13##
Reaction SMILES: S(=O)(=O)(O)O.[N+]([C:9]1[CH:10]=C(S(O)(=O)=O)C=C[CH:14]=1)([O-])=O.OCC(CO)O.[Br:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[O:33][CH3:34]>O>[Br:25][C:26]1[CH:32]=[C:31]2[C:29](=[CH:28][C:27]=1[O:33][CH3:34])[N:30]=[CH:10][CH:9]=[CH:14]2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Reactant: COc1cc(N)ccc1Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: OCC(O)CO
Product: COc1cc2ncccc2cc1Br
Temperature: 140 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
In a 100 mL round-bottom flask, a solution of concentrated sulfuric acid (2.1 mL, 39.6 mmol) in water (2.4 mL) was treated with 3-nitrobenzenesulfonic acid (2.06 g, 10.1 mmol) and glycerol (2.5 mL, 34.8 mmol) to give a thick grey suspension. The mixture was heated to 110° C. (oil bath) and 4-bromo-3-methoxyaniline (1.952 g, 9.66 mmol) was added portion-wise, resulting in an immobile slurry. Additional portions of water (3 mL), glycerol (3 mL), and concentrated sulfuric acid (3 mL) were added and the temperature increased to 140° C. After three hours the mixture had become a homogeneous dark brown solution, and LCMS analysis indicated reaction completion. The solution was cooled to RT, poured onto ice, and the pH was adjusted to 8 by addition of concentrated (30%) aqueous ammonium hydroxide. The mixture was partitioned between ethyl acetate and water, washed with water, brine, dried over magnesium sulfate and concentrated to a brown liquid. Purification by flash column chromatography (24 g silica gel, gradient of 0-20% ethyl acetate in dichloromethane over 25 column volumes) provided 6-bromo-7-methoxyquinoline (1.18 g, 46.2%) as a light brown fluffy solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 8.86 (dd, J=4.0, 1.5 Hz, 1H), 8.01-8.12 (m, 2H), 7.53 (s, 1H), 7.34 (dd, J=8.1, 4.5 Hz, 1H), 4.07 (s, 3H). NMR indicates the presence of about 10% 7-methyoxyquinoline. The mixture was taken on without further purification.
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][CH:14]=2)[CH2:8][O:7][C:6](=[O:9])[O:5][CH2:4]1)[CH3:2].[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:32]([OH:34])C>>[CH2:1]([C:3]([CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=1)([CH2:8][O:7][C:6]([O:5][CH2:4][CH3:21])=[O:9])[CH2:32][OH:34])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=Cc1ccc(COCC2(CC)COC(=O)OC2)cc1
Reactant: CCO
Product: C=Cc1ccc(COCC(CC)(CO)COC(=O)OCC)cc1

Procedure:
Analogous to Example 1, the title compound was synthesized using 13.8 g of 5-ethyl-5-(4-vinylbenzyloxy) methyl-2-oxo-1,3-dioxane, 4,6 g of ethanol and 0.2 g of p-toluenesulfonic acid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=O)=[N:4][N:3]=1.BrC1S[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][N:12]=1.[NH4+:21].[OH-]>C1COCC1>[Br:1][C:2]1[S:6][C:5]([C:7]2[N:9]=[N:12][N:13]([CH2:14][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:21]=2)=[N:4][N:3]=1
Reactant: CCOC(=O)c1nnc(Br)s1
Reactant: NC(=O)c1nnc(Br)s1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1nnc(-c2nnc(Br)s2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Bromo-1,3,4-thiadiazole-2-carboxamide To a solution of ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate in THF (1.1 M) at room temperature was added concentrated NH4OH (2.9 equiv). The mixture was stirred at room temperature overnight and a precipitate appeared in the aqueous layer. Then the volatile solvent was removed in vacuo. The resulting mixture was diluted with water and the precipitate was collected, washed with water and dried under vacuum to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[CH3:16])=[O:5].C1CCCCC=1.C(O)C>[Pd].O>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[F:1])=[C:8]([CH3:16])[CH:9]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)c1ccccc1F
Agent: [Pd]
Solvent: O
Solvent: C1=CCCCC1
Solvent: CCO
Product: Cc1cc(N)ccc1NC(=O)c1ccccc1F
Temperature: 4 °C

Procedure:
A mixture of 2-fluoro-N-(2-methyl-4-nitrophenyl)benzamide (4.55 g), cyclohexene (30 mL), ethanol (70 mL), water (30 mL) and 10% palladium on charcoal (3 g) is heated at reflux for 30 minutes. The mixture is filtered through diatomaceous earth and concentrated under reduced pressure. The resulting oil is dissolved in 50 mL of ethyl acetate and cooled at 4° C. for 12 hours. Filtration provides the product as a tan solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[O:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1>CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:19][C:18]2[CH:17]=[CH:16][C:15]([N:12]3[CH2:13][CH2:14][O:9][CH2:10][CH2:11]3)=[CH:21][CH:20]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CC(C)O
Product: Clc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Temperature: 84 °C
Yield: 46 %

Procedure:
100 mg of 4,6-dichloropyrimidine and 92 mg of p-morpholino aniline were dissolved in 5 mL of i-PrOH. The mixture obtained was refluxed at 84° C. for 6 hours under a nitrogen atmosphere. A colorless precipitate was formed which was collected by filtration. 6-Chloro-N-(4-morpholinophenyl)pyrimidin-4-amine was obtained in the form of a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[O:22])[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH-].[Na+]>C1COCC1.CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[O:22])[C:5]2[O:10][CH:9]([C:11]([F:13])([F:14])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(C=O)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Reaction time: 40 h
Yield: 61.5 %

Procedure:
To a stirred solution of the ester (Step 3)(0.284 g, 0.849 mmol) in THF:EtOH:H2O (7:2:1, 5 mL) was added aqueous NaOH solution (0.41 mL of 2.5 M, 1.02 mmol). After stirring 40 hours, the reaction was partially concentrated in vacuo to remove the organic solvents, diluted with H2O, washed with diethyl ether, sparged with nitrogen to remove trace diethyl ether, and acidified with concentrated HCl yielding a suspension. Vacuum filtration of the suspension yielded the title compound as a pale yellow powder (0.160 g, 23%) mp 243.3–252.4° C. 1H NMR (acetone-d6/300 MHz) 10.39 (s, 1H), 7.98 (s, 1H), 7.88 (d, 1H, J=2.6 Hz), 7.75 (d, 1H, J=2.6 Hz), 6.08 (q, 1H, J=6.9 Hz). FABLRMS m/z 307 (M+H). ESHRMS m/z 304.9839 (M−H, Calc'd 304.9828). Anal. Calc'd for C12H6Cl1F3O4: C, 47.01; H, 1.97. Found: C, 46.64; H,1.86.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2]2.S(=O)(=O)(O)O.[CH3:22][OH:23]>>[OH:23][C@H:22]1[C@H:1]([O:6][CH3:5])[CH2:2][N:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4]1
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Reactant: CO
Agent: O=S(=O)(O)O
Product: CO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Yield: 69.8 %

Procedure:
Benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (21.0 g, 96 mmol) was dissolved in MeOH (200 mL). Added sulfuric acid (3.64 g, 37.1 mmol) dropwise. After ˜3 hrs the reaction was concentrated and the residue was diluted with ethyl acetate and neutralized with 1N aq. NaOH. The organic extract was dried (Na2SO4) and concentrated. The reaction product was purified by silica gel column chromatography eluting with Hexane/Acetone mixtures to give (+/−)-Trans-benzyl 3-hydroxy-4-methoxypyrrolidine-1-carboxylate (16.8 g, 66.9 mmol, 69.8% yield) LCMS:M+1=252, Rt=1.42 min.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[O:14][C:13]([CH2:16][N:17]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:12][C:11]=3[CH:10]=[C:9]([Cl:28])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN.Cl>C(O)C.C(O)(C)C>[Cl:28][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[O:14][C:13]([CH2:16][NH2:17])=[CH:12][C:11]=2[CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc2cc(Cl)cc(-c3ccccc3)c2o1
Agent: CN
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: NCc1cc2cc(Cl)cc(-c3ccccc3)c2o1
Temperature: 70 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a suspension of 2-[(7-phenyl-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione (0.382 g, 0.985 minol) in ethanol (10 mL) was added the methylamine (33% in ethanol, 20 mL) and the reaction mixture was heated to 70° C. and allowed to stir for 1 h. The reaction mixture was allowed to cool to room temperature and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (50 mL) and washed with water (2×20 mL), saturated aqueous sodium bicarbonate (20 mL), saturated aqueous sodium chloride (20 mL), dried (magnesium sulfate), and the solvent removed in vacuo. Purification by flash column chromatography (silica, 10% ammonium hydroxide in methanol:ethyl acetate 1:9) provided a colorless oil that was dissolved in isopropanol (2 mL) and hydrogen chloride (1.0 N in diethyl ether, 5 mL) was added. The resulting precipitate was filtered, washed (diethylether), and dried to afford 0.165 g (57%) of [(5-chloro-7-phenyl-1-benzofuran-2-yl)methyl]amine as a white solid. mp>225° C.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[ClH:16]>C(#N)C>[Cl:16][CH:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cl
Reactant: Nc1ccccc1
Reactant: C=Cc1ccccc1
Solvent: CC#N
Product: ClC(Cc1ccccc1)c1ccccc1
Yield: 66.7 %

Procedure:
Following the general procedure of Example I, 236 mmols of distilled styrene were reacted with 25 mmols of distilled aniline in 30 mL of acetonitrile and in the presence of 38 mmols of concentrated HCl and 2.5 mmols of cuprous oxide. The process resulted in a 66.7% yield of 2-chloro-1,2-diphenylethane.