Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]([OH:16])[CH2:14][NH2:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:24](Cl)(=[O:28])[C:25]([CH3:27])=[CH2:26]>C(Cl)Cl>[OH:16][CH:13]([CH2:12][O:11][CH2:10][CH2:9][CH2:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:14][NH:15][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26]
Reactant: CC(C)(C)[Si](C)(C)CCCOCC(O)CN
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NCC(O)COCCC[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-(3-(t-Butyldimethylsilyl)propyloxy)-2-hydroxypropylamine (19.0 g, 0.077 mol), triethylamine (7.8 g, 10.8 mL, 0.08 mol), and methylene chloride (57 mL) were mixed in a 250 mL one-neck flask which was placed in an ice bath. To the above mixture, methacryloyl chloride (8.3 g, 7.73 mL, 077 mol) was added dropwise through an additional funnel at 0° C. After the completion of the addition of methacryloyl chloride, the whole mixture was allowed to warm up to room temperature and stirred at ambient temperature for two days. The reaction suspension was diluted with 100 mL of methylene chloride and washed with deionized water, 0.5 N sodium hydroxide aqueous solution, 5% sodium chloride solution in water twice and saturated sodium chloride aqueous solution in sequence. The organic phase was dried over sodium sulfate. After the removal of sodium sulfate by filtration, the solvent was evaporated by using a rotary evaporator under vacuum. N-[2-Hydroxy-3-(3-(t-butyldimethylsilyl)propyloxy)propyl]-2-methyl acrylamide was obtained as a white solid after purification by silica gel column chromatography.
Reaction SMILES: [CH2:1]([OH:9])[CH:2]([OH:8])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH3:10][C:11]([CH3:13])=O>>[CH3:10][C:11]1([CH3:13])[O:8][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][OH:7])[CH2:1][O:9]1
Reactant: CC(C)=O
Reactant: OCCCCC(O)CO
Product: CC1(C)OCC(CCCCO)O1

Procedure:
15 g (112 mmol) of 1,2,6-hexanetriol were dissolved together with 0.5 g of FeCl3 in 1 l of acetone and boiled under reflux for 7 h. The mixture was filtered, and excess acetone was removed by distillation, resulting in the product in pure form.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(OCC)(=O)C>C1COCC1>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][C:12]([F:11])([F:21])[F:22])=[CH:15][CH:16]=2)[N:3]=[CH:4][N:5]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1c(Cl)ncnc1Nc1ccc(OC(F)(F)F)cc1
Reaction time: 2 h

Procedure:
To a solution of 4,6-Dichloro-pyrimidine-5-carbaldehyde (3.06 g, 17.5 mmol) in THF (15 mL) was added 4-trifluoromethoxyaniline (3.09 g, 17.45 mmol) at 0° C. The mixture was stirred for 2 h and ethyl acetate (100 mL) was added. The organic layer was separated from brine, dried (Na2SO4) and concentrated to yield crude title compound as yellow solids. The compound was then purified by silica gel column chromatography to give the title compound as yellow crystals. (2.9 g, 55%). MS m/z 318.2 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:22])=[C:4]([CH:9]=[C:10](B2OC(C)(C)C(C)(C)O2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:31]1([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][C:10]3[C:11]([CH3:12])=[C:2]([F:1])[C:3]([OH:22])=[C:4]([CH:9]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:26][CH:27]=2)[CH:35]=[CH:34][CH:33]=[N:32]1
Reactant: ClCc1ccc(-n2cccn2)cc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(F)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)c(F)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (2.52 g) was added to a mixture of methyl 3-fluoro-2-hydroxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (13.5 g), 1-(4-(chloromethyl)phenyl)-1H-pyrazole (8.39 g), sodium carbonate (9.23 g), DME (195 mL) and water (65.0 mL) under argon atmosphere, and the mixture was stirred overnight at 80° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with a mixed solvent of diisopropyl ether-ethyl acetate to give a crude product. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol). The obtained crude products are combined, and washed with diisopropyl ether-ethyl acetate to give the title compound (12.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16][CH2:17][C:18]([OH:20])=[O:19])[CH3:15])=[CH:10][CH:9]=1.[OH:21]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:17][C:18]([OH:20])=[O:19])=[O:21])[CH3:15])=[CH:10][CH:9]=1
Reactant: CC(SCC(=O)O)c1ccc(-c2ccccc2Cl)cc1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: CC(c1ccc(-c2ccccc2Cl)cc1)S(=O)CC(=O)O
Reaction time: 8 h

Procedure:
50 gm (0.163 mol) of [1-(2'-chloro-4-biphenylyl)-ethylthio]-acetic acid were suspended in 163 ml of glacial acetic acid and 16.0 gm (0.171 mol) of 36.3% hydrogen peroxide were added dropwise to the suspension at 10° C. while vigorously stirring. Afterwards, the mixture was allowed to stand overnight at room temperature, during which time the starting compound dissolved. Subsequently, 500 ml of water were added, the reaction product was extracted with ethyl acetate, and the organic solvent was removed from the extract in vacuo, leaving 45.1 gm (85% of theory) of the title compound, m.p. 144°-147° C. (from ethyl acetate).
Reaction SMILES: O=[C:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[N:6]2[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]2[CH2:4][NH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[S:29]=[C:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[N:6]2[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]2[CH2:4][NH:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1ncn2c1CNC(=O)c1sccc1-2
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncn2c1CNC(=S)c1sccc1-2
Yield: 132.1 %

Procedure:
4. 24.07 g of ethyl 5,6-dihydro-6-oxo-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylate are suspended in 260 ml of toluene and treated with 22.73 g of Lawesson reagent. The mixture is heated to reflux temperature for 1.25 h., then cooled and filtered. The filter cake is dried. 21.78 g of ethyl 5,6-dihydro-6-thioxo-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylate are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH3:10])[CH:5]=[C:4]([CH3:12])[C:3]=1[OH:13].Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1.O>C(O)(C)C>[OH:13][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([C:8]2[NH:23][C:20]3[C:21]([C:9]=2[CH3:10])=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc(NN)cc1
Reactant: CCC(=O)c1cc(C)c(O)c(C)c1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: COc1ccc2[nH]c(-c3cc(C)c(O)c(C)c3)c(C)c2c1
Yield: 72 %

Procedure:
5.1 g of 2,6-dimethyl-4-propionylphenol and 5.0 g of 4-methoxyphenylhydrazine hydrochloride were dispersed in 30 ml of isopropanol, and the dispersion was refluxed for 20 hours in a nitrogen stream. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration. The crystals were dissolved in ethyl acetate, and washed with a 5% aqueous sodium hydroxide solution, water, 2N hydrochloric acid and water. The organic layer was dried, and the solvent was evaporated. Recrystallization of the resulting crude crystals from ethanol-hexane gave 5.8 g of 2-(4-hydroxy-3,5-dimethylphenyl)-5-methoxy-3-methylindole.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:8]=[C:9]([N:14]2[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[NH:15]2)[CH:10]=[CH:11][C:12]=1[CH3:13].O.CN(C)[CH:24]=[O:25]>>[CH3:6][C:7]1[CH:8]=[C:9]([N:14]2[C:18]([OH:19])=[C:17]([CH:24]=[O:25])[C:16]([CH3:20])=[N:15]2)[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: CN(C)C=O
Reactant: Cc1cc(=O)n(-c2ccc(C)c(C)c2)[nH]1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc(-n2nc(C)c(C=O)c2O)cc1C
Temperature: 100 °C
Yield: 79 %

Procedure:
Phosphorus oxychloride (4.82 mL, 51.6 mmol) was added dropwise to an ice-cooled, stirred suspension of 1-(3,4-dimethylphenyl)-3-methyl-3-pyrazolin-5-one (8.70 g, 43.0 mmol) in dimethylformamide (18.0 mL) at such a rate as to maintain the temperature below 20° C. After the addition, the mixture was heated at 100° C. for 2 h, then cooled, poured into iced water (200 mL). The resulting mixture was stirred for 18 h, then filtered. The solid was washed with water and dried to give the title compound (7.83 g, 79%) as a cream-coloured powder. MS (ES) m/e 231 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3](=[O:18])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)([CH3:6])[CH3:5].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH2:2][C:3](=[O:18])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)([CH3:6])[CH3:5])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C(=O)CBr)c1ccc(S(N)(=O)=O)c(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C(=O)CN=[N+]=[N-])c1ccc(S(N)(=O)=O)c(Cl)c1
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a solution of 4-(4-bromo-2-methyl-3-oxobutan-2-yl)-2-chlorobenzenesulfonamide (11.3 g, 31.8 mmol) in DMF (50 mL) was added NaN3 (3.1 g, 47.8 mmol, 1.5 eq) at 0° C. After stirring 2 h, the residue was diluted with water and extracted with EtOAc. The combined extracts were washed with 1M HCl and water successively, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography (Hex/EtOAc=4:1 to 2:1) to give 4-(4-azido-2-methyl-3-oxobutan-2-yl)-2-chlorobenzenesulfonamide (8.0 g, 79% yield) as yellow sticky oil. 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.29 (d, J=2.2 Hz, 1H), 5.12 (s, 2H), 4.11 (s, 2H), 1.58 (s, 6H).
Reaction SMILES: N=C=N.[CH3:4][N:5]([C:9]1[S:13][CH:12]=[N:11][CH:10]=1)[CH2:6][CH2:7][NH2:8].[Cl:14][C:15]1[CH:16]=[C:17]([C:21]#[C:22][C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[C:17]([C:21]#[C:22][C:23]([NH:8][CH2:7][CH2:6][N:5]([CH3:4])[C:9]2[S:13][CH:12]=[N:11][CH:10]=2)=[O:24])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)C#Cc1cccc(Cl)c1
Reactant: CN(CCN)c1cncs1
Agent: N=C=N
Solvent: ClCCl
Product: CN(CCNC(=O)C#Cc1cccc(Cl)c1)c1cncs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.5 %

Procedure:
1.5 g (≅1.8 mmol) PS carbodiimide was added to a solution of 146 mg (0.93 mmol) N1-methyl-N1-(thiazol-5-yl)ethane-1,2-diamine and 252 mg (1.39 mmol) 3-(3-chlorophenyl)propiolic acid in DCM (10 ml) and the reaction solution was shaken for 16 h at RT. The resin was subsequently filtered off, washed with DCM and ethanol and the filtrate concentrated in a vacuum. CC (DCE/EtOH 10:1) was performed with the residue, whereby 63 mg (0.20 mmol, 21%) 3-(3-chlorophenyl)-N-(2-(methyl(thiazol-5-yl)amino)ethyl)propiolamide was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:27][CH:28]3[CH2:30][CH2:29]3)[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CC2CC2)CC1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 121.3 %

Procedure:
Treat a solution of 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan (0.50 g, 1.58 mmol, Preparation 9) and dimethylformamide (10 mL) with sodium hydride (0.083 g, 2.08 mmol, 60% dispersion in oil) at room temperature. After 15 minutes, add (bromomethyl)cyclopropane (0.21 mL, 2.17 mmol, Aldrich Chemical Company) and heat two hours at 80° C. Cool the reaction and partition between dichloromethane (150 mL) and NaHCO3 solution (40 mL). Wash the organic phase with brine (40 mL), dry (MgSO4), filter and concentrate the filtrate to afford 4-(1-cyclopropylmethyl-1H-benzoimidazol-2-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.71 g, Rf=0.87, silica gel, 95:5:0.5 dichloromethane:methanol:ammonium hydroxide).
Reaction SMILES: [OH:1][C:2]1[C:3](C)=[C:4]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:8]([C:24]#[N:25])[CH:7]=[N:6][N:5]2[CH:26]=1.[C:28](O)(C(F)(F)F)=[O:29].O.C(O)(C(F)(F)F)=O.CC#N>>[OH:1][C:2]1[C:3]([O:29][CH3:28])=[C:4]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=3)=[C:8]([C:24]#[N:25])[CH:7]=[N:6][N:5]2[CH:26]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1c(O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Solvent: CC#N
Solvent: O
Product: COc1c(O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 0.13 h
Yield: 76 %

Procedure:
The title compound (26 mg, 76%) was prepared from Example 398 (38 mg, 0.092 mmol) by a route analogous to that used for the preparation of compound 397A. It has a retention time of 6.08 min. (Column: HTS, 5 u, 4.6×50 mm; Gradient: 5-100% B in 8.0 min; A=0.1% TFA/H2O; B=0.1% TFA/CH3CN; Run time 10 min; Det: 215 nM; FR: 1.2 ml/min); MS Found: (M+H)+=373.2
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][Si:7]([CH3:10])([CH3:9])[CH3:8])=[O:3].C([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:20]([O:31][CH2:32][C:33]2[CH:42]=[C:41]([O:43][CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)[CH2:19]1)C1C=CC=CC=1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH:21]2[CH2:22][CH2:23][N:18]([C:2]([O:4][CH2:5][CH2:6][Si:7]([CH3:10])([CH3:9])[CH3:8])=[O:3])[CH2:19][CH:20]2[O:31][CH2:32][C:33]2[CH:42]=[C:41]([O:43][CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)=[CH:25][CH:26]=1
Reactant: C[Si](C)(C)CCOCOc1cc(COC2CN(Cc3ccccc3)CCC2c2ccc(F)cc2)cc2ccccc12
Reactant: C[Si](C)(C)CCOC(=O)Cl
Product: C[Si](C)(C)CCOCOc1cc(COC2CN(C(=O)OCC[Si](C)(C)C)CCC2c2ccc(F)cc2)cc2ccccc12

Procedure:
In an analogous manner to that described in Example 1(d) by cleavage of the benzyl group by means of β-trimethylsilylethyl chloroformate from (3RS,4RS)-1-benzyl-4-(4-fluoro-phenyl)-3-[4-(2-trimethylsilyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine there was obtained β-trimethylsilylethyl (3RS,4RS)-4-(4-fluorophenyl)-3-[4-(2-trimethylsilyl-ethoxymethoxy)-naphthalen-2-yl-methoxy]-piperidine-1-carboxylate as a light yellow oil; MS: 626 (M+H)+.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[OH:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[O:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:24]=4[OH:23])[CH2:29]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: COc1cccc(-c2nc(C(=O)O)c3ccccc3n2)c1
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1cccc(-c2nc(C(=O)N3CCc4c(ccc(OC)c4O)C3)c3ccccc3n2)c1
Yield: 17 %

Procedure:
Reaction of 2-(3-methoxylphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 47 (17% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.67 and 2.90 (2t, 2H), 3.50 and 4.04 (2t, 2H), 3.74-3.88 (4s, 6H), 4.39 and 4.92 (2s, 2H), 6.32 and 6.77 (2d, 1H), 6.70 and 6.91 (2d, 1H), 7.15-7.18 (m, 1H), 7.46-7.53 (m, 1H), 7.77-8.19 (m, 6H), 8.68-8.72 (2s, 1H); MS (ESI) m/z 442 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH3:12])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:25]([C:32]([NH:34][OH:35])=O)C1C=CC=CC=1>C1COCC1>[OH:35][NH:34][C:32]([N:22]1[CH2:21][CH2:20][CH:19]([N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH3:12])[CH2:24][CH2:23]1)=[O:25]
Reactant: O=C(NO)Oc1ccccc1
Reactant: Cc1cnc(CN(C2CCNCC2)C(C)c2ccccn2)c(C)c1
Solvent: C1CCOC1
Product: Cc1cnc(CN(C2CCN(C(=O)NO)CC2)C(C)c2ccccn2)c(C)c1
Temperature: 25 °C
Yield: 38 %

Procedure:
To a solution of (3,5-Dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-(1-pyridin-2-yl-ethyl)-amine (0.124 g, 0.38 mmol) in dry THF (4 mL) was added N-(phenoxycarbonyl)hydroxylamine (Stewart, A. O. et al. J. Org. Chem. 1992, 57, 5020-5023) (0.116 g, 0.76 mmol) and the resultant solution was stirred at 60° C. overnight. The mixture was cooled to room temperature and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 15:1:1 CH2Cl2-MeOH—NH4OH) provided 59 mg (38%) of COMPOUND 261 as a white solid. 1H NMR (CDCl3) δ 0.97-1.02 (m, 1H), 1.39-1.47 (m, 3H), 1.61-1.67 (m, 3H), 1.83-1.86 (m, 1H), 2.27 (s, 3H), 2.28 (s, 3H), 2.53-2.61 (m, 1H), 2.71-2.80 (m, 1H), 2.92-3.00 (m, 1H), 3.79-3.99 (m, 4H), 6.48-6.85 (m, 2H), 7.11-7.15 (m, 1H), 7.23 (br s, 1H), 7.34-7.40 (m, 1H), 7.58-7.63 (m, 1H), 8.19 (br s, 1H), 8.51 (d, 1H, J=3.9 Hz); 13C NMR (CDCl3) δ 16.42, 18.31, 18.68, 30.14, 30.52, 44.12, 44.18, 51.88, 55.29, 58.52, 122.25, 123.99, 132.19, 133.15, 136.48, 139.60, 146.63, 148.84, 155.08, 161.12, 162.90; ES-MS m/z 384 (M+H). Anal. Calcd. For C21H29N5O2.0.1CH2Cl2.1.0H2O: C, 61.81; H, 7.67; N, 17.08. Found: C, 62.17; H, 7.33; N, 16.74.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.C(O)=O.[NH2:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][C:17]2[N:22]=[C:21]([Cl:23])[C:20]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:19]([N:29]([CH3:31])[CH3:30])[N:18]=2)=[CH:14][CH:13]=1>C1COCC1>[Cl:23][C:21]1[C:20]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:19]([N:29]([CH3:30])[CH3:31])[N:18]=[C:17]([CH2:16][C:15]2[CH:14]=[CH:13][C:12]([NH:11][CH3:1])=[CH:33][CH:32]=2)[N:22]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(N)cc2)nc1N(C)C
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: CNc1ccc(Cc2nc(Cl)c(CC(=O)OC)c(N(C)C)n2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
To acetic anhydride (0.48 mL, 5.13 mmol) at 0° C. under Ar atmosphere was added formic acid (0.24 mL, 6.31 mmol) dropwise followed by heating of the mixture at 60° C. for 2 hours. After cooling to room temperature, THF (1 mL) was added followed by a solution of methyl [2-(4-aminobenzyl)-4-chloro-6-(dimethylamino)pyrimidin-5-yl]acetate (0.660 g, 1.97 mmol) in THF (1 ml). This was then stirred for 3 hours and concentrated to dryness. The remaining residue was dissolved in THF and cooled to 0° C. followed by the dropwise addition of borane dimethyl sulfide complex until the vigorous effervescence ceased. The mixture was gently refluxed for 14 hours and then cooled to 0° C. Methanol was added and the mixture was stirred at room temperature for 1 hour followed by the addition of concentrated HCl to pH ˜5 and stirring was continued for another 30 minutes. The solvent was evaporated in vacuo, the remaining residue basified with water and 1N NaOH, and the aqueous layer was extracted with Et2O. The combined organic extracts was dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the crude product which was chromatographed onver silica gel eluting with 5% acetone in CH2Cl2 to give methyl {4-chloro-6-(dimethylamino)-2-[4-(methylamino)benzyl]pyrimidin-5-yl}acetate (0.260 g, 38% yield) as a pale yellow oil.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.CCN(CC)CC.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C>[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][N:22]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:3][CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CN(S(C)(=O)=O)C2
Temperature: 20 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a stirring solution of (S)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (Example 149) (115 mg, 0.279 mmol) and NEt3 (43 μL, 0.307 mmol) in DMF (2 ml) was added methanesulfonyl chloride (24 μL, 0.307 mmol). Reation mixture was stirred at room temperature (20° C.) overnight before being concentrated in vacuo and purified by prep. HPLC at high pH to afford a white solid (75 mg, 55%).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:16]=[CH:17][C:18]([C:20]3[N:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:19][C:4]=2[CH2:3]1.[C:26]([OH:35])(=[O:34])[C@@H:27]([C@H:29]([C:31]([OH:33])=[O:32])[OH:30])[OH:28].O>CO>[C:31]([CH:29]([CH:27]([C:26]([OH:35])=[O:34])[OH:28])[OH:30])([OH:33])=[O:32].[CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5]2[CH:16]=[CH:17][C:18]([C:20]3[N:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:19][C:4]=2[CH2:3]1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CN1CCC(Oc2ccccc2)c2ccc(-c3cccnn3)cc2C1
Solvent: O
Solvent: CO
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
To a solution of the aryloxybenzazepine (52 mg, 0.16 mmol) from Step B above in methanol (1 mL) was added L-tartaric acid (23.5 mg, 0.16 mmol) followed by slow addition of water (5 mL). The resultant solution was lyophilized overnight to give (−)-2-methyl-5-phenoxy-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine, tartrate salt (70 mg, 93%, AUC HPLC>99%) as a white solid: mp 98-100° C.; 1H NMR (CD3OD, 500 MHz) δ 9.17 (d, J=5.0 Hz, 1H), 8.21-8.18 (m, 2H), 8.08 (d, J=8.0 Hz, 1H), 7.82-7.79 (m, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.28-7.25 (m, 2H), 7.06 (d, J=7.9 Hz, 2H), 6.95 (t, J=7.4 Hz, 1H), 5.75 (d, J=8.0 Hz, 1H), 4.92-4.84 (m, 1H), 4.51-4.48 (m, 1H), 4.41 (s, 2H), 3.95-3.85 (m, 1H), 3.57-3.55 (m, 1H), 2.88 (s, 3H), 2.46-2.38 (m, 2H); ESI MS m/z 332 [M+H].
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-])=O>CO.[Pd]>[NH2:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[S:2][CH3:1])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(SC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(SC)c(N)c1
Yield: 59.1 %

Procedure:
A stirred solution of methyl 4-methylthio-3-nitrobenzoate (6.82 g) in methanol (350 mL) is hydrogenated using a 5% w/w palladium on charcoal catalyst (0.8 g) at room temperature for 48 hours. After filtration the solution is concentrated, to give methyl 3-amino-4-(methylthio)benzoate (3.5 g), in the form of a pale yellow solid m.p. 63-65° C.