Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Si:8]([O:15][C@@H:16]([CH3:37])[C@@H:17]([OH:36])[CH2:18][CH2:19][C:20]1[C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[O:28][C:24]=2[CH:23]=[CH:22][CH:21]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:38][S:39]([O:36][C@H:17]([C@@H:16]([O:15][Si:8]([C:11]([CH3:14])([CH3:12])[CH3:13])([CH3:10])[CH3:9])[CH3:37])[CH2:18][CH2:19][C:20]1[C:25]2[N:26]=[C:27]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[O:28][C:24]=2[CH:23]=[CH:22][CH:21]=1)(=[O:41])=[O:40]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)CCc1cccc2oc(-c3ccc(Cl)cc3)nc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CCc1cccc2oc(-c3ccc(Cl)cc3)nc12)OS(C)(=O)=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (0.248 ml) was added to an ice-cooled solution of (3S,4S)-4-(tert-butyldimethylsilyloxy)-1-[2-(4-chlorophenyl)-4-benzoxazolyl]-pentan-3-ol (P0006; 0.40 g) and methanesulfonyl chloride (0.139 ml) in dichloromethane (13 ml) and the mixture was stirred at 5° C. for 30 min. The mixture was washed with water, dried and evaporated. The residual oil (494 mg) was chromatographed over silica gel (15 g) eluting with a mixture of hexane and dichloromethane (2:1) to dichloromethane to give a colorless oil of (3S,4S)4-(tert-butyldimethylsilyloxy)-1-[2-(4-chlorophenyl)-4-benzoxazolyl]-3-pentyl methanesulfonate (P0007; 372 mg).
Reaction SMILES: [CH3:1][NH2:2].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2([C:14]([S:16]C)=S)[CH2:13][CH2:12][CH2:11][S:10]2)[CH:4]=1.C>C(O)C>[CH3:1][NH:2][C:14]([C:9]1([C:5]2[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=2)[CH2:13][CH2:12][CH2:11][S:10]1)=[S:16]
Reactant: CSC(=S)C1(c2cccnc2)CCCS1
Reactant: CN
Solvent: CCO
Product: CNC(=S)C1(c2cccnc2)CCCS1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A 33% (weight/volume) solution of methylamine in ethanol (11 cc) is added dropwise, in the course of 5 minutes, to a solution of methyl 2-(pyrid-3-yl)-tetrahydrothiophen-2-carbodithioate (14.3 g) in ethanol (50 cc), kept at a temperature of about 20° C. The solution is subsequently stirred for 5 hours at the same temperature and then cooled to 0° C. The resulting crystals are filtered off, washed with ethanol (8 cc) and then twice with diisopropyl ether (20 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. The product thus obtained (7.2 g) is dissolved in boiling ethanol (35 cc); decolourising charcoal (0.4 g) is added to the solution, which is filtered hot, and the filtrate is then cooled for 1 hour at a temperature of about 5° C. The resulting crystals are filtered off, washed with ethanol (5 cc) and then twice with diisopropyl ether (14 cc in total) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 40° C. N-Methyl-2-(pyrid-3-yl)-tetrahydrothiophen-2-carbothioamide (5.8 g), melting at 133° C., is thus obtained.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1>>[Cl:1][S:2]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:7]=1[F:6])[C:11]([OH:13])=[O:12])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccc(F)cc1
Product: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Temperature: 150 °C

Procedure:
Chlorosulphonic acid (100 ml, 1.5 mol) was gradually added to 4-fluorobenzoic acid (43 g, 0.307 mol) with stirring. The clear dark yellow mixture was heated to 150° C. for 24 hours. The yellow solution was cooled back to room temperature and poured onto ice with vigorous stirring. The white precipitate was filtered and pressed dry. The solid was dried overnight in a desiccator under vacuum and over activated silica (54.65 g, 75%). Mp: 116–117° C.; m/z (LC-MS, ESP), RT=4.03 min, (M−−1)=237–239 (ratio 1:3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([C:32]([O:34]CC)=[O:33])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:18]([Cl:37])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH3:31])[C:32]([OH:34])=[O:33])=[C:18]([Cl:37])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)(CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)C(=O)O
Temperature: 50 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
The compound of Example 152 (2.74 g) was dissolved in ethanol (10 mL). To this solution, potassium hydroxide (330 mg) was added and the mixture was stirred at 50° C. overnight. Subsequently, the reaction mixture was diluted with water. 2 mol/L hydrochloric acid was then added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and the organic phase was dried over anhydrous magnesium sulfate and was concentrated. The residue was purified on a silica gel column chromatography (hexane:ethyl acetate=10:1 shifted to 2:1) to give the desired product as a yellow oil (2.38 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([O:36][C:37]([NH:39][C:40]1[C:41]([CH3:47])=[C:42]([OH:46])[CH:43]=[CH:44][CH:45]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[C:48]([C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57]O)=[CH:52][CH:51]=1)#[N:49]>C1COCC1.O>[C:32]([O:36][C:37]([NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH2:57][CH2:56][C:53]2[CH:54]=[CH:55][C:50]([C:48]#[N:49])=[CH:51][CH:52]=2)[C:41]=1[CH3:47])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: N#Cc1ccc(CCO)cc1
Reactant: Cc1c(O)cccc1NC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(NC(=O)OC(C)(C)C)cccc1OCCc1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
Triphenylphosphine (1.31 g, 13.5 mmol) and diethylazodicarboxylate (1.7 mL) were dissolved in THF (20 mL) under nitrogen. After 15 minutes 3-t-butoxycarbonylamino-2-methylphenol (2.48 g; 11.1 mmol; from step (i) above) dissolved in THF (20 mL) and 2-(4-cyanophenyl)ethanol (1.9 g, 13 mmol) were added. After 5 days at room temperature water was added and the stirring continued for 30 minutes. The mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and the solvent removed in vacuo. Purification by flash chromatography afforded 2.98 g (77%) of the sub-title compound.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[Br-].[Na+].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>O1CCCC1.O>[F:22][C:23]1[CH:24]=[C:25]([CH2:26][CH2:14][C:13]2[C:8]([C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Fc1cccc(CBr)c1
Reactant: Cc1cccnc1C(=O)NC(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ncccc1CCc1cccc(F)c1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (125 mL) and N-(1,1-dimethylethyl)-3-methyl-2-pyridine carboxamide (1 equivalent) are charged and cooled to -40° C. under nitrogen. Two equivalents of n-butyllithium are then added over 40 minutes. When half the n-butyllithium is added the mixture turns purple. Sodium bromide (1.3 g) is added and then 3-fluoro-benzyl bromide (1.05 equivalents) is added dropwise (1:1 solution in tetrahydrofuran) over 40-50 minutes while the temperature is maintained at -40° C. After 30 minutes at -40° C., the mixture is diluted with water (250 mL) and the organic phase separated. This phase is dried over sodium sulphate and the solvent removed yielding an oil from which solid product, 3-[2-(3-fluorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine carboxamide, may crystallize.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([CH3:13])([CH3:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:4].[NH3:14]>O.C(O)C>[NH2:14][CH2:2][C:3]([NH:5][C:6]([CH3:13])([CH3:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:4]
Reactant: N
Reactant: CCCCCC(C)(C)NC(=O)CCl
Solvent: O
Solvent: CCO
Product: CCCCCC(C)(C)NC(=O)CN
Reaction time: 0.5 h

Procedure:
A suspension of 2-Chloro-N-(1,1-dimethylhexyl)acetamide (2.5 g, 12 m mol) in a mixture of water (50 ml) and ethanol (50 ml) was saturated in ammoniain the cold and held at room temperature for two days with the occasional passage of ammonia. The mixture was evaporated to a gum which was partially dried by azeotroping with ethanol then 40-60 petrol. The residuewas dissolved in chloroform (50 ml) and stirred with sodium carbonate (2 g)and water (10 ml) for 1/2 hour. The organic phase was then separated, driedover magnesium sulphate, evaporated to a yellow oil and distilled to give 2-amino-N-(1,1-dimethylhexyl)acetamide as a colourless oil, b.p. 109°-113° C. at 0.4 mm Hg.
Reaction SMILES: [CH3:1][C:2]([NH:14][C:15]1[C:16](=[O:41])[N:17]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH:19]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:3].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[CH3:3][C:2]([NH:14][CH:15]1[CH2:19][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)[N:17]([C:30]2[CH:31]=[CH:32][C:33]([O:36][C:37]([F:38])([F:40])[F:39])=[CH:34][CH:35]=2)[C:16]1=[O:41])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[N:5]=1)[CH3:1]
Reactant: CC(C)(NC1=CC(c2cccc(C(F)(F)F)c2)N(c2ccc(OC(F)(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(NC1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(OC(F)(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
Dissolve (±)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-1-(4-trifluoromethoxy-phenyl)-5-(3-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one (5.89 g, 10.0 mmol) in acetic acid (30 mL) and add sodium cyanoborohydride (1.26 g, 20.0 mmol). Stir for 30 min at ambient temperature. Pour reaction mixture into a mixture of saturated sodium bicarbonate solution and ethyl acetate. Extract the aqueous layer with additional ethyl acetate. Combine the organic extracts and wash with brine, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify by silica gel chromatography (45% EtOAc-hexane) to yield (±)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-1-(4-trifluoromethoxy-phenyl)-5-(3-trifluoromethyl-phenyl)-pyrrolidin-2-one (2.55 g, 43%) as a racemic mixture. LC-MS ESI m/z: 592.0 (M+H)+, Tr=2.63 min., method 2
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[CH:4][C:5]([C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)=O.N[C:14]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=C[NH:16][N:15]=1>C(O)(=O)C>[O:9]1[CH:10]=[CH:11][C:7]([C:5]2[N:16]3[N:15]=[CH:14][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]3[N:2]=[CH:3][CH:4]=2)=[CH:8]1
Reactant: CN(C)C=CC(=O)c1ccoc1
Reactant: CCOC(=O)c1c[nH]nc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3ccoc3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(3-furyl)-2-propen-1-one and 0.01 mole of ethyl 3-aminopyrazole-4-carboxylate in glacial acetic acid is heated at reflux temperature for 6 hours. The product is isolated as described for Example 1 to give the product of the example.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N:10]1[C:11](=[O:12])[C:6]2[C:7](=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:8]1=[O:9])[CH3:21]
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A mixture of 4-nitrophthalimide (82.54 g, 0.43 mol), ethyl bromoacetate (78.92 g, 0.47 mol) and potassium carbonate (130.6 g, 0.94 mol), and acetone (1.5 l) was refluxed for eighteen hours before it was cooled to room temperature, filtered and concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (107.39 g): MS: (+) m/z 279.25 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.C([BH3-])#[N:14].[Na+].C([O-])(=O)C.[NH4+]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[CH:7]([NH2:14])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)cc(F)c21
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(C)O
Product: NC1CCc2cc(Br)cc(F)c21

Procedure:
In analogy to the procedure described for the preparation of intermediates A-4 [A], 5-bromo-7-fluoro-indan-1-one was reacted with sodium cyanoborohydride and ammonium acetate in 2-propanol at reflux to yield the title compound as light yellow oil. MS: 228 (M−H−, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)=[O:4].[Br:16]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:15][CH2:14]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CC1CCc2ccccc2N1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC1CCc2cc(Br)ccc2N1
Reaction time: 2 h
Yield: 102.9 %

Procedure:
To a solution of 2-methoxycarbonylmethyltetrahydroquinoline (31.5 g, 0.153 mol) in DMF (750 mL) was added dropwise a solution of N-bromosuccinimide (27.41 g, 0.154 mol) in DMF (550 mL) at 0° C. The mixture was stirred for 2 h at the same temperature, poured into water (2 L), and extracted with a mixture of toluene and ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to give 44.72 g of the title compound (quant).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[CH3:10][O:9][C:4]1[CH:3]=[C:2]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: c1nc[nH]n1
Reactant: COc1cc(Br)ccc1N
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(-n2cncn2)ccc1N
Temperature: 110 °C
Yield: 47 %

Procedure:
A mixture of 4-bromo-2-methoxyaniline (208 mg, 1.03 mmol), 1,2,4-triazole (80 mg, 1.13 mmol), Cs2CO3 (0.67 g, 2.06 mmol) and CuI (20 mg, 0.103 mmol) in DMF was heated at 110° C. for 20 h. Further portions of 1,2,4-triazole (0.1 g, 1.44 mmol), Cs2CO3 (0.67 g, 2.06 mmol) and CuI (0.1 g, 0.52 mmol) were added and the mixture was heated a further 72 h at 110° C. The mixture was cooled, diluted with ethyl acetate (20 mL) and washed with water (2×20 mL). The combined aqueous washes were re-extracted with ethyl acetate (20 mL). The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% ethyl acetate/isohexane) gave 2-methoxy-4-(1H-1,2,4-triazol-1-yl)aniline as a light red solid (92 mg, 47%). 1H NMR (400 MHz, CDCl3): δ 8.41 (s, 1H); 8.05 (s, 1H); 7.11 (d, J=2.3, 1H); 6.99 (dd, J=8.3, 2.3, 1H); 6.74 (d, J=8.3, 1H); 3.97 (s, 2H); 3.92 (s, 3H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[CH3:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(C)cccc4C)c3O2)cc1
Product: CNCC1Cc2cc(F)cc(-c3c(C)cccc3C)c2O1

Procedure:
The title compound was prepared (0.148 g, 65%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.3 g, 0.70 mmol) and methylamine (0.22 g, 7.0 mmol). mp 175-178° C.
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=[O:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>C(O)(=O)C>[Br:20][C:10]1[C:11](=[O:13])[NH:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(-c2ccccc2)nc(-c2ccccc2)[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccccc2)nc(-c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 60 h
Yield: 48.3 %

Procedure:
To a suspension of 13.37 g (56 mmol) of 2,6-diphenyl-4(3H)-pyrimidinone and 200 mL glacial acetic acid was added 15.1 g (84.8 mmol) of N-bromosuccinimide and the mixture was left to stir at room temperature for 60 h. The reaction was poured onto 100 g crushed ice and vacuum filtered, washing well with water, then air dried to yield 8.85 g (48%) 5-bromo-2,6-diphenyl-4(3H)-pyrimidinone, as a white solid. 1H-NMR (d6DMSO) δ 7.55(6H,m); 7.75(2H,m); 8.15(2H,m).
Reaction SMILES: Cl.C([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=[O:23])[NH:13][C:14]2[S:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][N:18]=2)[CH:7]=1)(=O)C>O1CCCC1>[OH:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[C:12]([NH:13][C:14]1[S:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][N:18]=1)=[O:23]
Reactant: CC(=O)Oc1cccc(C(=O)Nc2ncc(S(C)(=O)=O)s2)c1
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cnc(NC(=O)c2cccc(O)c2)s1
Temperature: 25 °C
Yield: 56 %

Procedure:
2 M hydrochloric acid (40.0 mL) was added to a suspension of 79 (0.370 g, 1.09 mmol) in tetrahydrofuran (17.0 mL), and the reaction was warmed to reflux. The reaction became homogeneous upon heating. After refluxing for 4 hours, the reaction was allowed to cool to room temperature, and concentrated in vacuo. The residue was suspended in water and filtered. The filter pad was washed with water, air dried, and then re-dissolved in a minimum amount of warm THF. Water was added to the warm THF solution until the solution turned turbid, and the resulting mixture was allowed to cool to room temperature. Additional water was added, and a white solid formed on standing. The crystalline product was filtered, and the filter pad was washed with water, and dried in vacuo at 70° C. to give 81 (0.182 g, 56%) as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[CH:10]=O)=[CH:5][CH:4]=1.[C:14](Br)(Br)([Br:16])[Br:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:12][C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:13])[CH:10]=[C:14]([Br:16])[Br:15]
Reactant: COc1ccc(C(C)(C)C=O)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(C(C)(C)C=C(Br)Br)cc1
Reaction time: 1.5 h
Yield: 44 %

Procedure:
To a stirred solution of Compound 45 (3.0 g, 17 mmol) and CBr4 (11 g, 34 mmol) in CH2Cl2 (100 ml) was added PPh3 (18 g, 67 mmol) at r.t., and stirred for 1.5 h. The mixture was quenched by the addition of H2O, and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. This was purified by SiO2 chromatography to give Compound 53 (2.5 g, 45%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2]C(Cl)Cl.[Sn](Cl)(Cl)(Cl)Cl.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH3:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Ca+2].[Cl-]>ClCCCl.CCCCCC>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:1]=[O:2])=[CH:21][C:20]=1[CH2:25][CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCc1ccccc1OCc1ccccc1
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCCl
Product: CCc1cc(C=O)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In 25 g of 1,2-dichloroethane was dissolved 3.25 g (28 mmol) of dichloromethyl methyl ether, and the solution was chilled with ice-water. Here was added dropwise 7.36 g (28 mmol) of anhydrous tin (IV) chloride, and the mixture was stirred for 10 minutes. Here was added dropwise 5.00 g (23.55 mmol) of 1-benzyloxy-2-ethylbenzene obtained in Step 2 dissolved in 1,2-dichloroethane, and the mixture was stirred at ambient temperature for 5 hours. To the reaction mixture, aqueous solution of calcium chloride was added dropwise at 20° C. or below, 15 g of hexane was added, the organic layer was washed with water, and the solvent was evaporated. The residue was purified by column chromatography (ethyl acetate:hexane=1:10, SiO2) to yield the desired product, 4-benzyloxy-3-ethylbenzaldehyde, as yellow liquid (3.17 g, Yield: 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]#[N:12].Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][NH2:12]
Reactant: COc1ccc(Cl)c(CC#N)c1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(CCN)c1
Temperature: 95 °C

Procedure:
Sodium cyanide (10.4 g) was added portionwise to a stirred solution of the above benzyl bromide (25 g) in a 2:1 mixture of ethanol and water (250 ml). The mixture was stirred for one hour at 50° C., poured into water and extracted with ether. The extract gave 2-chloro-5-methoxy-phenylacetonitrile (m.p. 62°-65° C.). 10M Boranemethylsulphide complex (11.3 ml) was added dropwise under nitrogen to a refluxing solution of the above phenylacetonitrile (18.6 g) in tetrahydrofuran (150 ml). The mixture was heated under reflux for 2 hours and dilute hydrochloric acid was added dropwise and the acidified mixture heated at 95° C. for one hour. The cooled mixture was washed with ether, basified with dilute sodium hydroxide solution and extracted with ether. The extract yielded 2 -chloro-5-methoxyphenethylamine as a yellow oil.
Reaction SMILES: N1C=CC=CC=1.[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:28][CH2:27]4)[CH:25]=3)=[C:17]([NH2:20])[CH:18]=2)[N:13]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:12][C@@H:11]1[CH3:35])(=[O:9])[CH3:8].[CH3:36][S:37](Cl)(=[O:39])=[O:38]>O1CCOCC1>[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:28][CH2:27]4)[CH:25]=3)=[C:17]([NH:20][S:37]([CH3:36])(=[O:39])=[O:38])[CH:18]=2)[N:13]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:12][C@@H:11]1[CH3:35])(=[O:9])[CH3:8]
Reactant: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(=O)N1c2cc(NS(C)(=O)=O)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
Pyridine (4.07 μL, 0.050 mmol) was added to a solution of isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.010 g, 0.025 mmol) in 1,4-dioxane (200 μL). Methanesulfonyl chloride (1.96 μL, 0.025 mmol) was added, and the mixture stirred at rt for 18 h. The reaction mixture was concentrated and ethyl acetate was added. The solution was washed with 1 N aqueous HCl, and the organic phase was separated and concentrated to afford isopropyl (S)-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-6-(methylsulfonamido)-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.0087 g, 73% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.07-1.16 (m, 6 H), 1.18-1.36 (m, 8H), 2.30 (s, 3 H), 2.99 (s, 3 H), 3.58-3.80 (m, 2 H), 3.84-3.99 (m, 1 H), 4.99-5.08 (m, 1 H), 6.85 (br s, 1 H), 7.49-7.50 (m, 1 H), 7.71 (d, J=4.40 Hz, 2 H), 7.97 (br s, 1 H). MS (ESI, pos. ion) m/z 476 [M+H]+.