Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(CN)C=NC=1.[N:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=1.[CH2:18]([N:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23]1=[O:36])[CH:19]([CH3:21])[CH3:20]>>[CH2:18]([N:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]([C:33]([NH:17][CH2:16][C:13]3[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=3)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23]1=[O:36])[CH:19]([CH3:21])[CH3:20]
Reactant: NCc1ccncc1
Reactant: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)O
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)NCc1ccncc1
Yield: 48 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with pyridin-4-ylmethanamine to react with 2-(3-isobutyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 48% yield: mp 185-187° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CD3OD) δ 8.49-8.47 (m, 2H), 7.40-7.38 (d, J=7.4 Hz, 1H), 4.55 (s, 2H), 4.14-4.07 (m, 2H), 3.68-3.63 (m, 2H), 3.12 (d, J=7.5 Hz, 2H), 2.55 (s, 3H), 2.02-1.93 (m, 1H), 0.95 (d, J=6.6 Hz, 6H); MS (ES+) m/z 373.8 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][OH:5].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([O:17][CH3:18])=[O:16])=[CH:7]1.N12CCN(CC1)CC2.ClN1C(=O)CCC1=O.CS(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[CH3:18][O:17][C:15]([C:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[N:6]2[CH2:2][CH2:3][CH2:4][O:5][C:7]=12)=[O:16]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: OCCCCl
Agent: C1CN2CCN1CC2
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c2n(c3ccccc13)CCCO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 54.3 %

Procedure:
Method A A solution of 3-chloropropanol (14.74 kg, 98.4% pure, 153.4 mole) in dichloromethane (67 L) was cooled to -17° C. In a second vessel dichloromethane (68 L), methyl indole-3-carboxylate (13.5 kg, 99.8% pure, 76.9 mole) and 1,4-diazabicyclo[2.2.2]octane (4.75 kg, assumed 100% pure, 42.3 mole) were cooled to 0° C. N-Clorosuccinimide (11.3 kg, 99.5% pure, 84.2 mole) was added to the second vessel and stirred at 0° C. for 10 minutes. In the meantime methane sulphonic acid (0.59 L, 99.7% pure, 6.14 mole) was added to the first vessel. The solution in the second vessel was added to the first vessel over 49 minutes at -15 to 3° C. and the resulting mixture stirred for a further 31 minutes at -5 to 0° C. 10% Sodium carbonate solution (147 L), made from sodium carbonate (42.2 kg, 398 mole) and process water (422 L), was added over 14 minutes and stirred. The organic layer was separated and washed twice with 10% sodium carbonate solution (147 L each wash). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure below 30° C. The concentrate was dissolved in acetone (101 L) at about 18° C. and potassium carbonate (14.9 kg) added. The mixture was stirred at 18 to 28° C. for 18 hours. Analysis of the reaction showed it to be complete. The inorganic salts were filtered off, the filtrate concentrated under reduced pressure below 30° C. and dissolved in dichloromethane (101 L). The dichloromethane solution was washed twice with 5% sodium bicarbonate solution (85 L each wash), made from sodium bicarbonate (8.3 kg) and water (167 L) and dried over anhydrous sodium sulfate. After filtration the filtrate was concentrated under reduced pressure to a base temperature of about 95° C. and diluted with toluene (12 L). The toluene solution was cooled, causing the product to crystallise and cooling continued to about 0° C. overnight. The product was collected by filtration, washed on the filter with cold (0° C.) toluene (7 L) and dried in vacuo at 30° C. for 21 hours to give the title compound (9.654 kg, 98.9% pure, 53.7%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[NH:15][CH2:14][CH2:13][N:12]=2)[CH:2]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].N1C=CC=CC=1.C(OCC)(=O)C>C(Cl)Cl>[C:22]([N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:11]([C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[N:12][CH2:13][CH2:14]1)(=[O:24])[CH3:23]
Reactant: c1ccc2c(c1)NCCN=C2c1cnc2ccccc2c1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCN=C(c2cnc3ccccc3c2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
2,3-Dihydro-5-(3-quinolinyl)-1H-1,4-benzodiazepine (0.20 g, 0.73 mmol) was dissolved in 10 mL of methylene chloride, and acetic anhydride (0.1 mL, 1.1 mmol), pyridine (0.18 mL, 2.2 mmol) were added to the resulting solution, followed by stirring at room temperature for 2 hours. Then the resulting solution was distilled off under redused pressure for 14 hours. The resulting reaction solution was cooled to room temperature and added with ethyl acetate. Then the solution was washed with 0.5N citric acid solution, brine and saturated bicarbonate water, followed by drying with magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=9:1) to obtain the target compound (0.17 g, yield: 15%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][C:25]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:28][C:26]=3[CH:27]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[S:24][C:25]5[CH:31]=[CH:30][C:29]([C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=6)=[CH:28][C:26]=5[CH:27]=4)[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2cc3cc(-c4ccccc4)ccc3s2)n1
Product: c1ccc(-c2ccc3sc(-c4nc(COc5ccc(CCCn6ccnc6)cc5)co4)cc3c2)cc1
Yield: 67 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(5-phenyl-2-benzothienyl)oxazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-phenyl-2-benzothienyl)oxazole. The yield was 67%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 168-169° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[H][H]>CC(O)=O.[Pd]>[OH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH2:5][CH2:4][NH:3][C:2]2=[O:1]
Reactant: Oc1cccc2c(O)nccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1NCCc2c(O)cccc21
Yield: 86.4 %

Procedure:
A mixture of 10.0 g (62.0 mmol) of 1,5-dihydroxyisoquinoline in 500 ml of HOAc and 2 g of 20% Pd-C was hydrogenated at room temperature until the required amount of hydrogen was absorbed. The solution was filtered and concentrated. The resulting solid was recrystallized from water (200 ml) to give 8.74 g (86%) of product; mp 195°-198°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([C:26]([N:28]3[CH2:33][CH2:32][CH2:31][CH:30]([CH2:34]OS(C)(=O)=O)[CH2:29]3)=[O:27])[CH2:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.O1C2C=CC(OCC3CCCN(C(C4(C5C=CC(Cl)=CC=5)CCC4)=O)C3)=CC=2OC1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([C:26]([N:28]3[CH2:33][CH2:32][CH2:31][CH:30]([CH2:34][O:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:29]3)=[O:27])[CH2:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Reactant: Oc1ccc(F)cc1
Agent: O=C(N1CCCC(COc2ccc3c(c2)OCO3)C1)C1(c2ccc(Cl)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(N1CCCC(COc2ccc(F)cc2)C1)C1(c2ccc(Cl)cc2)CCC1
Yield: 57.4 %

Procedure:
Compound 84 was synthesized from 4-fluorophenol (0.29 g, 2.60 mmol), cesium carbonate (1.27 g, 3.89 mmol) and compound 43 (1.0 g, 2.60 mmol), using the method described for the synthesis of compound 44 to give 0.60 g of the desired product 84. C23H25ClFNO2, LRMS (m/z)=402 (MH+).
Reaction SMILES: [OH-].[Na+].C([N:6]1[CH2:11][CH2:10][C:9]2[S:12][C:13]([C:16]([O:18]C)=[O:17])=[C:14]([NH2:15])[C:8]=2[CH2:7]1)(=O)C.Cl>O>[NH2:15][C:14]1[C:8]2[CH2:7][NH:6][CH2:11][CH2:10][C:9]=2[S:12][C:13]=1[C:16]([OH:18])=[O:17]
Reactant: COC(=O)c1sc2c(c1N)CN(C(C)=O)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(C(=O)O)sc2c1CNCC2
Yield: 37.6 %

Procedure:
An aqueous solution obtained by dissolving 9.1 g of sodium hydroxide in 90 ml of water was added to 5.8 g (46%) of methyl 5-acetyl-3-amino-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2carboxylate (Compound No. 16) obtained in Example 1 and the resultant mixture was heated under reflux for 2 hours. After cooling followed by neutralization with concentrated hydro-chloric acid, the solvent was distilled off. Methanol was added to the residue and the crystals thus formed were taken by filtration and thoroughly washed with water to obtain 1.7 g of 3-amino-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid. Yield: 38%.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([CH:34]=[CH:35][C:36]=1[F:37])[C:10]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:15]([N:22]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:23](=[O:25])[CH3:24])[CH2:14][C@@H:13]1[CH3:33])=[O:11])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>ClCCl>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([N:22]([C@H:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]([C:10](=[O:11])[C:9]3[CH:34]=[CH:35][C:36]([F:37])=[C:7]([OH:6])[CH:8]=3)[C@@H:13]([CH3:33])[CH2:14]2)[C:23](=[O:25])[CH3:24])=[CH:31][CH:30]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)c(O[Si](C)(C)C(C)(C)C)c2)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)c(O)c2)c2ccccc21
Temperature: 25 °C
Yield: 110.9 %

Procedure:
N-[(2S,4R)-1-(3-{[tert-butyl-(dimethyl)silyl]oxy}-4-fluorobenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-(4-chlorophenyl)acetamide (543 mg, 0.95 mmol) was dissolved in dichloromethane and a solution of TBAF (1.0 M in THF, 5.0 mL) was added; the reaction mixture was stirred at room temperature for until no starting material remained. The reaction was washed with sat. NaHCO3 and brine carefully. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography using Hexanes-EtOAc system to give N-(4-chlorophenyl)-N-[(2S,4R)-1-(4-fluoro-3-hydroxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (477 mg, 100%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH2:14].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH2:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1c(OCCCl)cccc1[N+](=O)[O-]
Reactant: NCc1ccccc1
Product: Nc1c(OCCNCc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 600 °C
Yield: 89.3 %

Procedure:
A mixture of 2-(2-chloro-ethoxy)-6-nitro-phenylamine (1a, 3.0 g, 13.8 mmol) and benzylamine (9.0 g, 84.0 mmol) was heated neat at 100-1100° C. for 6 hr. The excess benzylamine was removed by distillation under vacuum (70-75° C./0.1 mm). The residue was poured into 1 N sodium hydroxide (300 mL) and extracted with ethyl acetate (2×, 300 mL). The combined organic layer was washed with water (2×, 300 mL) and brine (300 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to give 5.1 g of crude red oil. Purification by chromatography (500 g silica gel, ethyl acetate: 2 M NH3 in methanol, 20:1) afforded 3.54 g (89.3%) of a red semi-solid, mp 33-60° C.; MS EI m/e 287 (M+).
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>>[CH3:13][C:12]1[C:7]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:32])([F:33])[F:23])=[CH:30][CH:29]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccc(C(F)(F)F)cc2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using [4-(trifluoromethyl)phenyl]amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.10 (s, 3H), 2.37 (s, 3H), 4.72 (d, J=5.4 Hz, 2H), 6.07 (bs, 1H), 6.55 (bs, 1H), 7.18 (t, J=7.0 Hz, 1H), 7.34 (d, J=7.5 Hz, 1H), 7.48 (d, J=8.6 Hz, 2H), 7.58-7.65 (m 3H), 8.58 (d, J=3.2 Hz, 1H); MS (ESI) m/z 374.7 (M+1)+.
Reaction SMILES: C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:30][N:31]([CH3:36])[C:32](=[O:35])[CH:33]=[CH2:34].Br[C:38]1[CH:39]=[CH:40][C:41]2[C:42]3[N:50]([CH2:51][C:52]([CH3:55])([OH:54])[CH3:53])[C:49]([CH2:56][CH3:57])=[N:48][C:43]=3[CH:44]=[N:45][C:46]=2[CH:47]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)(Cl)Cl.CO.C(#N)C>[CH2:56]([C:49]1[N:50]([CH2:51][C:52]([OH:54])([CH3:55])[CH3:53])[C:42]2[C:41]3[CH:40]=[CH:39][C:38]([CH:34]=[CH:33][C:32]([N:31]([CH3:36])[CH3:30])=[O:35])=[CH:47][C:46]=3[N:45]=[CH:44][C:43]=2[N:48]=1)[CH3:57]
Reactant: C=CC(=O)N(C)C
Reactant: CCc1nc2cnc3cc(Br)ccc3c2n1CC(C)(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CCc1nc2cnc3cc(C=CC(=O)N(C)C)ccc3c2n1CC(C)(C)O
Temperature: 120 °C
Yield: 86.9 %

Procedure:
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II) acetate (50 mg, 0.22 mmol), acetonitrile (50 mL), triethylamine (1.80 mL, 13.0 mmol), tri-o-tolylphosphine (200 mg, 0.65 mmol), N,N-dimethylacrylamide (511 mg, 5.16 mmol) and 1-(7-bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (1.50 g, 4.30 mmol). The reaction mixture was purged with nitrogen and the tube was sealed and heated at 120° C. in an oil bath. The reaction was maintained at 120° C. for 18 hours and then cooled to ambient temperature. Upon cooling a precipitate formed that was dissolved by the addition of methanol and chloroform. The remaining insoluble material was removed by filtration through a 0.2 micron PTFE membrane filter. The filtrate was concentrated under reduced pressure and purified by chromatography using a HORIZON HPFC system (silica, eluting with a 0-25% gradient of CMA in chloroform). The resulting product was washed with 1% aqueous sodium carbonate and filtered to provide 1.37 g of 3-[2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N,N-dimethylprop-2-enamide as an off-white solid, mp 196-198° C.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(Cl)Cl>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(I)cc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(I)cc1
Reaction time: 2 h

Procedure:
To a solution of 4-Iodo-aniline (15 g, 69 mmol) in dry CH2Cl2 (100 ml) was added acetic anhydride(14.09 g, 138 mmol) at room temperature, the reaction mixture was then stirred for 2 hr. The gray color precipitate formed during the reaction was filtered, washed with ether and collected, the mother solution was concentrated to dryness and AcOEt was added, the resulting precipitate was filtered, washed with ether and combined with the previous solid as the desired product (15.95 g, 88.7%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.II.[C:18]1([C:26]([CH2:28][C:29]2[CH:36]=[CH:35][C:32]([O:33][CH3:34])=[CH:31][CH:30]=2)=O)[CH:25]=[CH:24][C:21]([O:22][CH3:23])=[CH:20][CH:19]=1.OS(O)(=O)=O>C1COCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]([C:29]2[CH:36]=[CH:35][C:32]([O:33][CH3:34])=[CH:31][CH:30]=2)=[CH:26][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[CH:24][CH:25]=2)=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COc1ccc(C=C(c2ccc(OC)cc2)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
Benzyl 4-bromophenyl ether (13.155 g; 50 mmol), prepared in Example 2, in 20 mL THF was added to Mg turnings (1.17 g; 48 mg-atom) in 20 mL THF. Grignard reagent formation was facilitated by addition of a few drops of EtBr2, one crystal of I2, and heat. This mixture was stirred and heated to reflux for 2 h. 11.54 g (45 mmol) desoxyanisoin was added under reflux as a slurry in 60 mL THF. The resulting mixture was stirred at reflux for 18 h, cooled to room temperature, poured onto 200 g 2N H2SO4 and ice (1:1), and stirred at room temperature until the ice melted. The resulting mixture was placed in a separatory funnel and extracted with 200 mL Et2O. The organic layer was washed with aqueous Na2SO5 (100 mL), and brine (2×100 mL). The combined aqueous layers were extracted with Et2O (50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to give 19 g of a wine colored oil, which was dissolved in Et2O and refrigerated to precipitate any unreacted deoxyanisoin. After filtration and concentration of the solution, the resulting oil was purified on 60 g flash SiO2 (7:3 petroleum ether-CH2Cl2) to yield 12.4 g (65%) of 1-(4-Benzyloxyphenyl)-2,2-bis(4-methoxyphenyl)ethene as a yellow oil. NMR δ7.41 (s, 5H, O-benzyl C6H5), 7.35 to 6.57 (m, 13H, ArH and C=CH), 5.07 (s, 2H, PhCH2O), 3.78 (s, 1.5H, geminal ring OCH3), 3.77 (s, 1.5H, central ring OCH3), 3.72 (s, 3H, vicinal ring OCH3).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][C:12]([NH2:15])=[N:13][CH:14]=2)O1.Cl[C:18]1[N:19]=[C:20]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[C:21]2[N:27]=[C:26]([CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([C:35]([OH:38])([CH3:37])[CH3:36])[CH2:31][CH2:30]3)[CH:25]=[CH:24][C:22]=2[N:23]=1>>[NH2:15][C:12]1[N:13]=[CH:14][C:9]([C:18]2[N:19]=[C:20]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[C:21]3[N:27]=[C:26]([CH2:28][N:29]4[CH2:34][CH2:33][CH:32]([C:35]([OH:38])([CH3:37])[CH3:36])[CH2:31][CH2:30]4)[CH:25]=[CH:24][C:22]=3[N:23]=2)=[CH:10][N:11]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3n2)CC1

Procedure:
Following General Procedure A, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine and 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 were reacted to give 107. LCMS (MH+)=465.3. 1H-NMR (DMSO-d6): δ 8.29 (s, 1H), 8.09 (d, 1H), 7.80 (d, 1H), 7.09 (s, 2H), 4.50 (s, 4H), 4.01 (s, 1H), 3.81 (m, 4H), 3.68 (s, 2H), 2.91 (m, 2H), 1.97 (m, 2H), 1.65 (m, 2H), 1.29 (m, 2H), 1.17 (m, 1H), 1.03 (s, 6H)
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[N:12]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:12][C:3]1[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[N:7]([CH3:8])[C:2]=1[NH2:1]
Reactant: Cn1c(N)c(N=O)c(=O)n(C)c1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Cn1c(N)c(N)c(=O)n(C)c1=O
Temperature: 80 °C

Procedure:
Crude 6-amino-1,3-dimethyl-5-nitroso-1H-pyrimidine-2,4-dione (5 mmol) was suspended in water (7 mL) at 40° C. and treated with sodium dithionite (17.5 mmol). After 20 minutes at 40° C. the reaction mixture was warmed to 80° C. for 30 mins and then cooled in ice for 30 mins. The precipitate was isolated by filtration, washed with cold water and dried in vacuo to give crude 5,6-diamino-1,3-dimethyl-1H-pyrimidine-2,4-dione as a light beige solid which was of sufficient purity for subsequent use without additional purification (80%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:4](=[O:21])[C@H:5]2[CH2:20][C@@:8]3([C:19]=1[C:18]1[CH:17]=[CH:16][C:15]4[NH:14][N:13]=[CH:12][C:11]=4[C:10]=1[CH2:9]3)[CH2:7][CH2:6]2.[BH4-].[Na+].[Cl-].[NH4+]>CCO>[F:22][C:2]([F:1])([F:23])[C:3]1[C@H:4]([OH:21])[C@H:5]2[CH2:20][C@@:8]3([C:19]=1[C:18]1[CH:17]=[CH:16][C:15]4[NH:14][N:13]=[CH:12][C:11]=4[C:10]=1[CH2:9]3)[CH2:7][CH2:6]2
Reactant: O=C1C(C(F)(F)F)=C2c3ccc4[nH]ncc4c3C[C@@]23CC[C@@H]1C3
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O[C@H]1C(C(F)(F)F)=C2c3ccc4[nH]ncc4c3C[C@@]23CC[C@@H]1C3

Procedure:
To a stirring solution of (8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanoazuleno[2,1-e]indazol-7(8H)-one (14 mg, 0.044 mmol) in EtOH (1 mL) was added sodium borohydride (6.7 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 1 hour after which saturated aqueous ammonium chloride was added in portions until bubbling stopped. The reaction mixture was then diluted with dichloromethane, dried over magnesium sulfate and filtered through a small pad of silica gel washing with ethyl acetate. The filtrate was concentrated under vacuum and the residue was purified by preparative TLC on silica gel (elution with 1:1 EtOAc/hexane) to give (7R,8R,10aS)-6-(trifluoromethyl)-3,7,8,9,10,11-hexahydro-8,10a-methanoazuleno[2,1-e]indazol-7-ol.
Reaction SMILES: CNC(=S)NC1C=CC=CC=1.[CH2:12]([NH:14][C:15](=[S:23])[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:13]>>[CH2:12]([NH:14][C:15]1[S:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1)[CH3:13]
Reactant: CCNC(=S)Nc1ccccc1
Agent: CNC(=S)Nc1ccccc1
Product: CCNc1nc2ccccc2s1
Yield: 94.4 %

Procedure:
When operating as described in Example 53, using instead of N'-methyl-N-phenylthiourea an equimolar amount of N'-ethyl-N-phenylthiourea, 2-ethylamino-benzthiazole melting at 93° C. is obtained in a yield of 94.4% of the theory and with an equally good purity.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:11])[C:8](=[O:10])[CH3:9].[Br:13]Br>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:13][CH2:9][C:8](=[O:10])[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:12])=[O:11]
Reactant: CC(=O)C(=O)c1ccccc1C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1C(=O)C(=O)CBr
Temperature: 70 °C
Yield: 97.6 %

Procedure:
A mixture of 3 g (18.49 mmol) 1-o-Tolyl-propane-1,2-dione and 1.05 ml (20.34 mmol) bromine in 30 ml CHCl3 and 0.53 ml acetic acid was heated to 70° C. for 16 h. The mixture was evaporated under reduced pressure to yield 4.35 g (98%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH2:13][O:14][CH3:15])[C:5]2=[O:16].C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CC(C)=O>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[N:6]([CH2:12][CH2:13][O:14][CH3:15])[C:5]3=[O:16])=[CH:26][CH:25]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COCCN1C(=O)c2ccc(O)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCN1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O
Temperature: 25 °C
Yield: 66 %

Procedure:
A mixture of 5-hydroxy-2-(2-methoxy-ethyl)-isoindole-1,3-dione, from example 13a, (570 mg, 2.6 mmol), potassium carbonate (445 mg, 3.2 mmol) and 4-fluorobenzyl-bromide (526 mg, 2.8 mmol) in acetone (40 mL) was heated under reflux for 17 h. After cooling to room temperature, the mixture was filtered, evaporated and the residue was purified by crystallization from diethylether:heptane (1:2) to afford the title compound (560 mg, 66%) as a white solid. MS: m/e=330.4 (M+H+).