Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([CH:15]2[CH2:17][CH2:16]2)=[C:4]([CH:12]2[CH2:14][CH2:13]2)[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:18][CH2:19][CH3:20].[Na+].O>C(O)C>[CH:15]1([C:3]2[C:2]([O:18][CH2:19][CH3:20])=[N:7][N:6]3[C:8]([NH2:11])=[N:9][N:10]=[C:5]3[C:4]=2[CH:12]2[CH2:14][CH2:13]2)[CH2:17][CH2:16]1
Reactant: Nc1nnc2c(C3CC3)c(C3CC3)c(Cl)nn12
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1nn2c(N)nnc2c(C2CC2)c1C1CC1
Reaction time: 1 h
Yield: 96.3 %

Procedure:
6-Chloro-7,8-dicyclopropyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.016, 0.1 g) was dissolved in ethanol (20 ml) while stirring and under argon. Thereafter, the reaction mixture was admixed with sodium ethoxide (110 mg) and stirred at RT for 1 h, then at 55° C. for 1 h. Subsequently, the mixture was left to stand overnight and then heated to reflux for 7.5 h. After standing over the weekend, the solvent was drawn off, and the residue was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 100 mg of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:40])[CH2:9][CH2:10][N:11]([CH3:39])[C:12](=[O:38])[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=2)[C:16]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:15]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:41]([NH:48][S:49]([CH2:52][CH2:53][CH2:54][Cl:55])(=[O:51])=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:41]([N:48]([S:49]([CH2:52][CH2:53][CH2:54][Cl:55])(=[O:51])=[O:50])[C:23]([C:20]1[CH:21]=[C:22]2[C:17]([C:16]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:15]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:14]2[CH2:13][C:12]([N:11]([CH3:39])[CH2:10][CH2:9][N:8]([CH3:40])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:38])=[CH:18][CH:19]=1)=[O:24])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=S(=O)(CCCCl)NCc1ccccc1
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)C(=O)Cn1c(-c2ccccc2)c(C2CCCCC2)c2ccc(C(=O)O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(CCN(C)C(=O)OC(C)(C)C)C(=O)Cn1c(-c2ccccc2)c(C2CCCCC2)c2ccc(C(=O)N(Cc3ccccc3)S(=O)(=O)CCCCl)cc21
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of the crude 1-{2-[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}(methyl)amino]-2-oxoethyl}-3-cyclohexyl-2-phenyl-1H-indole-6-carboxylic acid in DCM (0.04 M) was treated with DMAP (2.5 eq), N-benzyl-3-chloropropane-1-sulfonamide (1.5 eq) and EDAC.HCl (1.5 eq). The reaction was left stirring at 40° C. overnight. Further DMAP (2.5 eq), N-benzyl-3-chloropropane-1-sulfonamide (1.5 eq) and EDAC.HCl (1.5 eq) were added and the reaction left to stir at 40° C. for another night. The mixture was diluted with DCM and washed with an aqueous solution of HCl (1N), a saturated aqueous solution of NaHCO3 and brine before being dried over Na2SO4, filtered and concentrated in vacuo. The crude was then used in the next step without any further purification. (ES+) m/z 777 (M+H)+
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22](=[O:37])(=[O:36])[N:23]([CH2:32][CH2:33][O:34][CH3:35])[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[CH:5]1)([CH3:3])[CH3:2].C([Li])CCC.CN([CH:46]=[O:47])C.O>C1COCC1>[CH:46]([C:5]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([S:22](=[O:36])(=[O:37])[N:23]([CH2:32][CH2:33][O:34][CH3:35])[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])=[CH:20][CH:21]=3)[N:10]=2)=[CH:7][N:6]=1)=[O:47]
Reactant: COCCN(COCC[Si](C)(C)C)S(=O)(=O)c1ccc(Nc2nccc(-c3cncn3C(C)C)n2)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCCN(COCC[Si](C)(C)C)S(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C=O)n3C(C)C)n2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
4-(1-Isopropylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(2-trimethylsilylethoxymethyl)sulphamoyl]anilino}pyrimidine (Method 106; 1.22 g, 2.33 mmol), was dissolved in anhydrous THF (70 ml), under nitrogen. The solution was cooled to −78° C. and n-butyl lithium (3.48 ml of a 1.6 N solution in hexanes, 5.57 mmol), was added slowly, maintaining the temperature at less than −65° C. The reaction mixture was then stirred at −78° C. for 30 minutes, then DMF (345 μl, 4.46 mmol), was added and mixture allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was then poured into water (100 ml), and extracted with EtOAc (2×50 ml). The organic extracts were combined, washed with water (50 ml), brine (50 ml), and dried. The volatiles were removed and the residue was purified by chromatography on silica gel eluting with 3% MeOH in DCM, to give the title product, (307 mg, 24%), as a pale yellow foam. NMR: 0.02 (s, 9H), 0.83 (dd, 2H), 1.63 (d, 6H), 3.28 (s, 3H), 3.37 (t, 2H), 3.42 (dd, 2H), 3.52 (t, 2H), 4.78 (s, 2H), 5.71 (m, 1H), 7.40 (d, 1H), 7.82 (d, 2H), 7.92 (s, 1H), 8.01 (d, 2H), 8.78 (d, 1H), 9.91 (s, 1H); m/z: 573 [MH]−.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:19](/B(O)O)=[CH:20]\[CH2:21][CH2:22][CH2:23][CH3:24]>>[CH:19](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:20]\[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Brc1cnc2ccc(NCc3ccncc3)nn12
Reactant: CCCC/C=C/B(O)O
Product: CCCC/C=C/c1cnc2ccc(NCc3ccncc3)nn12
Yield: 53 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2 providing the title compound (47 mg, 53%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 8.46-8.44 (m, 2H), 7.61 (d, J=9.1 Hz, 1H), 7.46 (d, J=7.1 Hz, 2H), 7.38 (s, 1H), 6.75 (d, J=9.7 Hz, 1H), 6.56-6.37 (m, 2H), 4.62 (s, 2H), 2.18-2.11 (q, J=6.5 Hz, 2H), 1.39-1.28 (m, 4H), 0.92 (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 154.8, 152.0, 150.0, 138.0, 133.1, 129.4, 128.6, 125.9, 123.9, 116.6, 113.0, 45.5, 34.3, 32.7, 23.3, 14.3; HPLC tR=10.9 min (Luna), 97.4%; ES-MS: (M+H)=308 m/z.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([CH2:12][C:13]([O:15]CC)=[O:14])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.[NH2:21]O.CO.C([O-])(=O)C>O>[CH3:1][S:2]([NH:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]2[CH2:12][C:13](=[O:14])[O:15][N:21]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)CC(=O)c1ccc(NS(C)(=O)=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C2=NOC(=O)C2)cc1

Procedure:
To a mixture 23.0 g of ethyl 4-methanesulfonamidobenzoylacetate, 5.8 g of hydroxylamine hydrochloride, and 35 ml of methanol, 8.2 g of pottasium acetate was added, and the mixture was refluxed for 30 minutes while being heated. The reaction mixture was poured into 210 ml of water, and the precipitated crystals were collected by filtering and dried, thereby obtaining 1.39 of 3-(4-methanesulfonamidophenyl)isoxazolin-5-one.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]([OH:19])=[C:6]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:7]=1.[C:21]1(C)C=C(C)C=C(C)C=1Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[OH:20])[O:19][CH:21]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])[C:8]2=[O:18]
Reactant: Cc1cc(C)c(Cl)c(C)c1
Reactant: COc1ccccc1CC(=O)c1cc(Cl)c(O)cc1O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1coc2cc(O)c(Cl)cc2c1=O
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
BF3—OEt2 complex (7 ml, 56 mmol) was gradually added to a solution of 1-(5-chloro-2,4-dihydroxy-phenyl)-2-(2-methoxy-phenyl)-ethanone (4.1 gm, 14 mmol) in DMF at 0° C. The resulting solution was stirred for 30 min. Mesityl chloride (1.5 ml, 42 mmol) was then gradually added to it at 50° C. The solution was then heated up to 110° C. for 5 hours. The mixture was then concentrated. The residue was treated with ice and the solid obtained was purified with silica gel column chromatography using hexane-chloroform as the eluent to give 6-chloro-7-hydroxy-3-(2-methoxy-phenyl)-chromen-4-one (2.5 gm, 60%) as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]=[C:6]([NH2:11])[CH2:7][CH:8]1[CH2:10][CH2:9]1)[CH3:2].[F:13][C:14]([F:32])([F:31])/[C:15](/O)=[CH:16]/[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)=O>C(#N)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[C:15]([C:14]([F:13])([F:32])[F:31])=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:21][CH:20]=2)=[N:11][C:6]=1[CH2:7][CH:8]1[CH2:9][CH2:10]1)[CH3:2]
Reactant: O=C(/C=C(\O)C(F)(F)F)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C=C(N)CC1CC1
Solvent: CC#N
Product: CCOC(=O)c1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1CC1CC1
Yield: 40 %

Procedure:
231 mg (1.4 mmol) 3-Amino-4-cyclopropyl-but-2-enoic acid ethyl ester were added to a solution of 819 mg (2.7 mmol) (Z)-4,4,4-trifluoro-3-hydroxy-1-(4-trifluoromethoxy-phenyl)-but-2-en-1-one in 2.7 ml acetonitrile. The mixture was heated under reflux conditions for 12 h, the solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, heptane/AcOEt) to give 242 mg (0.56 mmol, 41%) of the title compound as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[C:9]1[C:15]1[S:31][C:18]2[C:19]3[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][C:20]=3[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1.O=S(Cl)[Cl:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[C:9]1[C:15]1[S:31][C:18]2[C:19]3[CH:27]=[CH:26][C:25]([C:28]([Cl:34])=[O:30])=[CH:24][C:20]=3[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1nc(-c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)n(-c2ccccc2Cl)c1=O
Product: Cn1nc(-c2cc3c(s2)-c2ccc(C(=O)Cl)cc2OCC3)n(-c2ccccc2Cl)c1=O

Procedure:
A solution of 2-(4-(2-chlorophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid (300 mg, 0.66 mmol) in 10 mL of SOCl2 was heated at 80° C. for 3 h. Concentration gave the crude acid chloride, 2-(4-(2-chlorophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonyl chloride which was slowly added (ca. 312 mg, ca. 0.66 mmol in 10 mL of THF), to a solution of NH3 (saturated solution in THF) and pyridine (0.5 mL) in 5 mL of THF at 0° C. The mixture was stirred at room temperature overnight, Diluted with water, the solids were washed with water and dried in vacuum. The crude product was purified by HPLC separation, gave 160.1 mg of 363, isolated yield: 54%. ESI-MS: 453. 1H NMR (DMSO-d6, 400 MHz): δ 7.98-7.41 (m, 9H, ArH, NH2), 6.49 (s, 1H, ═CH), 4.20 (s, 2H, CH2), 3.49 (s, 3H, CH3), 2.99 (s, 2H, CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[C:28]([O:32][C:33]([NH:35][C@@H:36]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:43][CH:42]=1)[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:28]([O:32][C:33]([NH:35][C@@H:36]([CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:45][CH:46]=1)[C:37]([O:10][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[CH2:8][C:7]1[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=1[Cl:1])=[O:38])=[O:34])([CH3:30])([CH3:31])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OS(C)(=O)=O)cc1)C(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OS(C)(=O)=O)cc1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (100 mg, 0.24 mmol) and (S)-2-(tert-butoxycarbonyl-amino)-3-(4-(methylsulfonyloxy)phenyl)propanoic acid (172 mg, 0.48 mmol) were dissolved in DMF (3 ml). DMAP (35 mg, 0.29 mmol) and EDC (92 mg, 0.48 mmol) were added, and the mixture was stirred at RT for 3 hours, then was quenched with HCl 1N and extracted with EtOAc. The organic layer was washed with HCl 1N and NaHCO3 sat. sol., then was dried over Na2SO4 and evaporated under vacuum to give 155 mg (85%) of the title compound which was employed in the next step without any further purification. MS/ESI+ 761.14 [MH]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[N:12]1([CH2:18][CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:12]1([CH2:18][CH2:19][NH:20][C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: NCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(NCCN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 48 h
Yield: 20.9 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), 2-(4-morpholinyl)-ethylamine (2.8 g, 20 mmol), and K2CO3 (3.0 g, 22 mmol) in DMF (20 mL) was stirred at 110° C. for 48 h. The reaction mixture was cooled to room temperature, poured into water (200 mL) and extracted with dichloromethane (CH2Cl2) (250 mL). The combined organic extracts were washed with water (200 mL) and brine (200 mL), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (silica gel, 4×15 cm, eluted with 90:10 EtOAc/MeOH) to yield the product as an orange solid (0.39 g, 20%).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].C([O:16][CH2:17][N:18]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1)[C:19](=[O:24])[CH2:20]S(C)=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.O>[OH:4][CH:20]1[O:16][CH2:17][N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=2)[C:19]1=[O:24]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOCN(C(=O)CS(C)=O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1C(O)OCN1c1cccc(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic anhydride (17.6 g) was added dropwise to a stirred solution of crude product of Step 3 in tetrahydrofuran (220 ml) with water bath cooling to 20° C. After 2 hours the mixture was left to stand for 20 hours. A solution of sodium hydrogen carbonate (14.1 g) in water (220 ml) was added during 5 minutes with stirring and cooling to 20° C. After 30 minutes the mixture was refluxed for 41/2 hours, cooled to 25° C., extracted with dichloromethane (3×300 ml), the extract dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a brown oil (21.4 g). The brown oil (20.09 g) was dissolved in 1,4-dioxane (500mi) and hydrogen chloride gas bubbled in for 31/4 hours, with stirring, at 23° C. The mixture was left in a stoppered flask for 20 hours, concentrated under reduced pressure, dissolved in dichloromethane (400 ml), neutralised with a minimum of saturated aqueous sodium hydrogen carbonate, dried over magnesium sulphate, filtered and concentrated under reduced pressure to a brown oil (21.9 g). The oil was subjected to column chromatography on silica gel, gradient eluting with dichloromethanet-butyl methylether mixtures to give the crude product as a yellow gum (4.7 g). The gum was crystallised from hexane solution to give a yellow solid. 1H NMR (CDCl3): δ 4.43(1 H,bs); 5.49(1 H,s); 5.68(2 H,m); 7.49-7.8(4 H,m).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[CH3:12][C:13]1([NH2:16])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[C:3]([S:9][CH3:10])=[N:4][C:5]([NH:16][C:13]2([CH3:12])[CH2:15][CH2:14]2)=[N:6][CH:7]=1
Reactant: CSc1nc(Cl)ncc1Br
Reactant: CC1(N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CSc1nc(NC2(C)CC2)ncc1Br
Temperature: 90 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a stirring suspension of 5-bromo-2-chloro-4-(methylthio)pyrimidine (1.0 g, 4.18 mmol) in ethanol (6.0 mL) was added 1-methylcyclopropanamine hydrochloride (0.674 g, 6.26 mmol) and DIEA (2.188 mL, 12.53 mmol). The mixture was stirred at 90° C. for 16 h. Upon completion of the reaction as indicated by LCMS and TLC the reaction mixture was concentrated and purified by silica gel chromatography using a gradient of 0%-20% ethyl acetate in hexanes. The product fractions were combined and concentrated to afford 5-bromo-N-(1-methylcyclopropyl)-4-(methylthio)pyrimidin-2-amine (0.665 g, 58% yield) as a white solid. MS (ESI) m/z 276.2 [M+1]+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1.[CH3:15]I>C1COCC1.CCOCC>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:14])([CH3:13])[CH2:11][O:12][CH3:15])[CH:5]=1
Reactant: CC(C)(CO)c1cccc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCC(C)(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
To a suspension of NaH (0.22 g, 9.00 mmol, 95%) in THF (30 mL) was added dropwise at ambient temperature the solution of 2-(3-bromo-phenyl)-2-methyl-propan-1-ol (1.7 g, 7.46 mmol) in THF (10 mL). After 10 min MeI (0.8 mL, 15 mmol) was added and the mixture stirred for 3 h at ambient temperature. The mixture was diluted with ether and washed twice with water. Organic layer was separated and concentrated to obtain the desired product (1.64 g, 91%) as a clear oil. NMR (DMSO-d6): 7.52 (m, 1H), 7.40 (m, 2H), 7.26 (m, 1H), 3.38 (s, 2H), 3.20 (s, 3H), 1.12 (s, 6H). MS (DCI): 260 (M+NH4).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.C(O)C.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>O>[OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=[N:21][OH:22])[C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 75 °C

Procedure:
4,4'-dihydroxybenzophenone (100.0 grams, 0.467 mole) is added to ethanol (300 milliliters) in a 1 liter Erlenmeyer flask and stirred. After dissolution of the 4,4'-dihydroxybenzophenone, a solution of hydroxylamine hydrochloride (48.6 grams, 0.699 mole) and sodium acetate (57.4 grams, 0.700 mole) in deionized water (70 milliliters) is added followed by an additional 100 milliliters of ethanol. This mixture is stirred and heated on a hot plate to a gentle reflux (75° C.). After heating for 4 hours, the solution is allowed to cool to room temperature (25° C.) with stirring and then filtered. The filter cake is washed with ethanol (100 milliliters); then the total filtrant obtained (600.4 grams) is concentrated to a weight of 219.2 grams by evaporation of the ethanol and water. The concentrated solution is placed into a 1 liter Erlenmeyer flask then stirred as 600 milliliters of deionized water is added. The addition of the deionized water induced formation of a white precipitate. After thirty minutes of stirring, the mixture is filtered. The solid 4,4'-dihydroxybenzophenone oxime thus obtained weighed 98.22 grams after drying. 4,4'-Dihydroxybenzophenone oxime (66.0 grams, 0.288 mole) and glacial acetic acid (330 milliliters) are added to a 500 milliliter round bottom flask equipped with a stirrer, water cooled condensor, nitrogen purge and heating mantle. A catalytic amount of p-toluenesulfonic acid (1.85 grams, 0.027 mole) is added and the reaction mixture then heated to 83° C. After heating for approximately two hours, a precipitate formed and the mixture is stirred for an additional two hours at 87° C. After this time, 25 milliliters of deionized water is added to the reactor and after thirty minutes, the contents of the reactor is transferred to a 1 liter Erlenmeyer flask and maintained therein with stirring. Immediately following the transfer, 400 milliliters of deionized water is added to the flask. The mixture is stirred for forty five minutes and then filtered. The filter cake thus obtained is washed with 800 milliliters of deionized water and then dried. The resultant light beige colored solid weighed 54.82 grams. Fourier transform infrared spectrophotometric analysis of a portion of the product confirmed the product structure as that of 4,4'-dihydroxybenzanilide. Differential scanning calorimetry demonstrated a sharp melting point endotherm at 273° C. for the 4,4'-dihydroxybenzanilide product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:23](=[O:25])[CH3:24])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(Sc2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Sc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2.19 g portion of this amine was dissolved in 50 ml of dichloromethane, cooled in an ice bath and treated with 1.52 g of triethylamine. The mixture was then treated dropwise with a solution of 1.18 g of acetyl chloride in 20 ml of dichloromethane over 20 minutes. This mixture was stirred at room temperature overnight, then the solution was washed successively with water, saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, filtered and concentrated to dryness. The residue was recrystallized from methanol-water, giving 2.26 g of the desired product as colorless crystals, mp 140°-141° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[C:8](=[O:15])[N:7]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH3:22])[CH2:6][CH2:5]2.C(O)(=O)C>C1COCC1.[Fe]>[NH2:12][C:11]1[CH:10]=[C:9]2[C:4]([CH2:5][CH2:6][N:7]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[CH3:22])[C:8]2=[O:15])=[CH:3][C:2]=1[F:1]
Reactant: Cc1ccncc1N1CCc2cc(F)c([N+](=O)[O-])cc2C1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccncc1N1CCc2cc(F)c(N)cc2C1=O
Yield: 96.2 %

Procedure:
6-Fluoro-7-nitro-2-(4-methyl-pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-84a: 150 mg, 0.498 mmol) was reduced with iron powder (139 mg, 2.4 mmol) and acetic acid (5 mL) in THF (5 mL) at 70° C. for 4 hours to afford 130 mg of the product (96.2% yield).