Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[Br-].[In+3].[Br-].[Br-].C(Cl)Cl.[Br:14][C:15]1[CH:16]=[C:17]2[C:23]([CH:24]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[C:28]([F:33])[C:27]=3[Cl:34])O)=[CH:22][NH:21][C:18]2=[N:19][CH:20]=1>>[Br:14][C:15]1[CH:16]=[C:17]2[C:23]([CH:24]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[C:28]([F:33])[C:27]=3[Cl:34])[C:5]#[N:6])=[CH:22][NH:21][C:18]2=[N:19][CH:20]=1
Reactant: C[Si](C)(C)C#N
Reactant: OC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Agent: [Br-]
Agent: [In+3]
Solvent: ClCCl
Product: N#CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of trimethylsilyl cyanide (0.51 mL, 3.8 mmol) and indium(III) bromide (34.1 mg, 0.0961 mmol) in DCM (5.00 mL, 78.0 mmol) was added (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2,6-dichloro-3-fluorophenyl)methanol (150.0 mg, 0.3846 mmol). The resulting mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (DCM/Hexane 1:1 as eluent). 1H NMR (400 MHz, CD3OD): δ=6.52 (s, 1H), 7.39 (d, J=1.0 Hz, 1H), 7.45 (t, J=8.7 Hz, 1H), 7.63 (dd, J=9.1, 4.8 Hz, 1H), 8.02 (d, J=2.0 Hz, 1H), 8.31 (d, J=2.3 Hz, 1H). MS (ES+): m/z 397.85, 399.88, 401.85 [MH+]. HPLC: tR=4.19 min (OpenLynx, polar—5 min).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:6]=2[CH:24]=1.[NH:25]1[CH:29]=[N:28][CH:27]=[N:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.O.[Cu]I>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:7]2[CH2:8][C@@H:9]([CH3:16])[C:10]3=[N:14][N:13]=[C:12]([CH3:15])[N:11]3[C:5]3[CH:4]=[CH:3][C:2]([N:25]4[CH:29]=[N:28][CH:27]=[N:26]4)=[CH:24][C:6]2=3)=[CH:18][CH:19]=1
Reactant: c1nc[nH]n1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cc1)C[C@H]2C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nnc2n1-c1ccc(-n3cncn3)cc1N(c1ccc(Cl)cc1)C[C@H]2C
Temperature: 150 °C
Reaction time: 16 h
Yield: 25.5 %

Procedure:
A mixture of (R)-8-bromo-6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (40.2 mg, 0.1 mmol), 1H-1,2,4-triazole (13.8 mg, 0.2 mmol), copper(I) iodide (3.8 mg, 0.02 mmol), and cesium carbonate (59 mg, 0.18 mmol) in N-methyl-2-pyrrolidone (3 mL) was stirred at 150° C. for 16 hours. The mixture was diluted with water (10 mL), extracted with ethyl acetate (3*20 mL). The combined organic layer was washed with water (3*20 mL) and brine (3*20 mL) in turns, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-TLC (silica-gel, dichloromethane/methanol=15:1) to give (R)-6-(4-chlorophenyl)-1,4-dimethyl-8-(1H-1,2,4-triazol-1-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine as a white solid (10 mg, 25.7%).
Reaction SMILES: O.C[O-].[Na+].[SH:5][CH:6]([C:10](=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]([CH3:9])[CH3:8].Cl[CH:17]([C:20](=[O:24])[CH2:21][CH2:22][CH3:23])[CH2:18][CH3:19]>CO>[CH:7]([CH:6]([S:5][CH:17]([CH2:18][CH3:19])[C:20]([CH2:21][CH2:22][CH3:23])=[O:24])[C:10]([CH2:11][CH:12]([CH3:14])[CH3:13])=[O:15])([CH3:9])[CH3:8]
Reactant: CCCC(=O)C(Cl)CC
Reactant: CC(C)CC(=O)C(S)C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCC(=O)C(CC)SC(C(=O)CC(C)C)C(C)C
Reaction time: 0.03 h

Procedure:
Into a 50 ml, round bottom, three-necked flask equipped with magnetic stirrer, pot thermometer, "Y" tube, nitrogen inlet tube, reflux condenser with cotton plug, and water bath is placed a solution of 0.65 grams (0.012 moles) of sodium methoxide dissolved in 10 ml anhydrous methanol. While maintaining the temperature of the reaction mass at 24°-27° C, a solution of 2.1 grams of 3-mercapto-2,6-dimethyl-4-heptanone dissolved in 12 ml anhydrous methanol is added to the sodium methoxide solution. 1.78 grams of 3-chloro-4-heptanone is then added to the reaction mass with stirring over a period of 2 minutes, the reaction mass temperature rising to 38° C. Two ml anhydrous methanol used as rinse is then added to the reaction mass, and with stirring the reaction mass temperature cools to 25° C. The reaction mass is continued to be stirred at 25° C for a period of 5 hours. At this point 25 ml distilled water is added, and the resulting solid dissolves. The oil phase is extracted with three 15 ml portions of methylene chloride, and the extracts are combined and washed with one 10 ml portion of water. The extracts are then dried over anhydrous sodium sulfate and gravity filtered and concentrated on a rotary evaporator using water aspirator vacuum to a weight of 3.20 grams (yellow oil). GLC analysis (8 feet × 1/4inch SE-30 column), NMR, IR and mass spectral analyses of GLC isolated material yield the information that the resulting product is 85% pure and has the structure: ##STR57##
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]=[CH:12][N:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:6][C:5]([CH2:16][NH:17][CH:18]2[CH2:23][CH:22]([CH3:24])[CH2:21][C:20]([CH3:26])([CH3:25])[CH2:19]2)=[CH:4][CH:3]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([S:8]([N:11]=[CH:12][N:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:6][C:5]([CH2:16][N:17]([CH:18]2[CH2:23][CH:22]([CH3:24])[CH2:21][C:20]([CH3:25])([CH3:26])[CH2:19]2)[S:28]([CH3:27])(=[O:30])=[O:29])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1CC(NCc2ccc(Cl)c(S(=O)(=O)N=CN(C)C)c2)CC(C)(C)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1CC(N(Cc2ccc(Cl)c(S(=O)(=O)N=CN(C)C)c2)S(C)(=O)=O)CC(C)(C)C1

Procedure:
This compound is obtained as an oil by reacting 6-chloro-N-dimethylaminomethylene-3-[(3,3,5-trimethylcyclohexylamino)methyl]benzenesulfonamide with methanesulfonyl chloride in methylene chloride in the presence of pyridine as auxiliary base and by purification by column chromatography (silica gel, methylene chloride:methanol=95:5).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:18])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([OH:15])[C:7]=1[CH:16]=[O:17])[CH:2]=[CH2:3].[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:4][C:5](=[O:18])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25])[C:7]=1[CH:16]=[O:17])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1c(C)c(OC)cc(O)c1C=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
To a solution of 15 g of 2-formyl-3-hydroxy-5-methoxy-6-methylbenzoic acid allyl ester in 0.12 l of N,N-dimethylformamide were added 13.8 g of tert-butyl-dimethylchlorosilane and 12.0 g of triethylamine. The mixture was stirred for 3 h at room temperature and then evaporated in vacuo. The residue was taken up in 0.4 l of ethyl acetate and the solution was washed successively with 1N hydrochloric acid, water and brine. The organic layer was dried over sodium sulfate. The solvent was evaporated in vacuo and the solid residue was recrystallized from hexane to give 20.5 g of 2-formyl-3-(tert-butyldimethylsilanyloxy)-5-methoxy-6-methylbenzoic acid allyl ester as white crystals of m.p. 94°-95° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH3:6][N:7]([CH2:9][C:10]1([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH3:8].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:5][CH2:4][CH2:3][CH2:2][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2([CH2:9][N:7]([CH3:8])[CH3:6])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:17][CH:18]=1
Reactant: ClCCCBr
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CC1(c2ccc(OCCCCl)cc2)CCOCC1
Temperature: 45 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
1-Bromo-3-chloropropane (0.42 ml, 4.25 mmol) was added to a solution of 4-(4-dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (1.0 g, 4.25 mmol) and potassium carbonate (1.5 g, 10.8 mmol) in N,N-dimethylformamide (10 ml). The reaction mixture was stirred at 45° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic layer was separated, dried over sodium sulphate, filtered and concentrated in vacuo to provide the title compound (800 mg, 60%). LRMS APCI+ m/z 412 [MH]+.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[O:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[N:3]1.C1([O:24][C:25](=O)[NH:26][C:27]2[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([O:34][CH3:35])[N:28]=2)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[CH3:1][N:2]1[C:6](=[O:7])[O:5][C:4]([C:8]2[C:9]([S:14]([NH:17][C:25]([NH:26][C:27]3[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([O:34][CH3:35])[N:28]=3)=[O:24])(=[O:16])=[O:15])=[CH:10][CH2:11][CH2:12][CH:13]=2)=[N:3]1
Reactant: Cn1nc(-c2ccccc2S(N)(=O)=O)oc1=O
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)C2=CCCC=C2c2nn(C)c(=O)o2)n1
Yield: 45.2 %

Procedure:
By the procedure of Example 5, 0.4 g of the product of Example 4 was reacted with 0.41 g of phenyl(4-methyl-6-methoxy-1,3,5-triazin-2-yl)carbamate and 0.24 g of "DBU" in 10 ml of p-dioxane. The isolated crude solid was purified by slurry-washing with 10 ml of warm acetonitrile to yield 0.3 g of the subject compound; m.p. 198°-200° C.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[CH3:22][C:23]1[CH:24]=[C:25](B2OC(C)(C)C(C)(C)O2)[S:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>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>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:25]3[S:26][CH:27]=[C:23]([CH3:22])[CH:24]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: Cc1csc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1csc(C2=C(n3c4c(c5cc(C)ccc53)CN(C)CC4)CCC2)c1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed stirred solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 4-methylthiophene-2-boronic acid pinacol ester (129 mg, 0.578 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4 mL)-water (2 mL) was purged with nitrogen followed by addition of Pd(PPh3)4 (16 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(4-methylthiophen-2-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.3 (s, 1H), 7.0 (m, 3H), 6.78 (s, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.37 (s, 3H), 3.03 (m, 2H), 2.83 (m, 2H), 2.61 (m, 2H), 2.4 (s, 3H), 2.2 (m, 2H), 2.17 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]([F:23])([F:22])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O>>[F:10][C:11]([F:22])([F:23])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]#[N:9])=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1-c1ccc(OC(F)(F)F)cc1
Yield: 71 %

Procedure:
Prepared in 71% yield from 2-chloro-3-cyanopyridine and 2-trifluoromethoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 264.8 (M+H)+; 1H NMR (CDCl3) δ 7.41-7.48 (m, 3H), 7.54-7.60 (m, 2H), 8.09 (dd, J=7.8, 1.7 Hz, 1H), 8.91 (dd, J=5.1, 1.7 Hz, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH:25]3[CH2:27][CH2:26]3)[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:28][O:29][CH2:30][CH2:31]Cl>CN(C)C=O>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:31][CH2:30][O:29][CH3:28])[C:19](=[O:24])[N:18]([CH:25]3[CH2:26][CH2:27]3)[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=c1[nH]c(=O)n(C2CC2)c2ncn(Cc3ccccc3)c12
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C2CC2)c1=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2.2 g (15.9 mmol) of potassium carbonate were added to a hot solution of 3 g (11.0 mmol) of 7-benzyl-3-cyclopropylxanthine from stage a) in dimethylformamide at 60° C. and the mixture was stirred at 60° C. for one hour. 1.51 g (15.9 mmol) of 2-methoxyethyl chloride were then added dropwise and the mixture was stirred at 80° C. for 6 hours. It was then allowed to cool to room temperature and concentrated under reduced pressure. The oily residue was taken up in dichloromethane and extracted using 1 N sodium hydroxide solution, washed with water until neutral, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was employed in stage c) without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6]1)=O.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:3]([C:5]2([C:8]([OH:10])=[O:9])[CH2:7][CH2:6]2)=[O:2])=[CH:14][CH:13]=1
Reactant: COC(=O)C1(C(=O)O)CC1
Reactant: Nc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
To a mixture of 1-(methoxycarbonyl)cyclopropanecarboxylic acid (4.2 g) and 4-fluoroaniline (3.3 g) in DCM (40 ml) was added EDC (7.4 g) and HOBt (4 g), the reaction was stirred at RT for 4 hours and washed with 1N HCl, NaHCO3 solution, water, brine and dried over Na2SO4. The solution was evaporated and the residue was mixed with NaOH (3.2 g) and MeOH/H2O (60 ml/6 ml). The mixture was refluxed for 30 minutes then was evaporated. The residue was acidified with 4N HCl and the precipitate was filtered. The filter cake was washed with water followed by cold EtOH to give the product as 1-(4-fluorophenylcarbamoyl)-cyclopropanecarboxylic acid 2.8 g. This product (1.8 g) was mixed with DCM (30 ml) and two drops of DMF. Oxalyl chloride (1.2 ml) was added into the solution and the reaction was refluxed for one hour. The solvent was removed followed by adding DCM (20 ml) and DIPEA (1.3 ml). To the above solution was added 4-methoxybenzyl 1-((4-(2-fluoro-4-aminophenoxy)-6-methoxyquinolin-7-yloxy)-methyl)cyclopropylcarbamate (1.5 g), the reaction was stirred at RT for 4 hours. Saturated NaHCO3 (30 ml) and DCM (80 ml) were added into the reaction, the solution was further extracted with DCM twice. The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was evaporated and purified with silica gel column to give the titled compound 2.1 gram. Mass: (M+1), 739
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][C@H:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[O:9][C:4]=2[CH:3]=1.O.P([O-])([O-])([O-])=O.[OH-].[Na+]>O1CCCC1>[CH2:13]([O:12][C:10]([CH:8]1[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][C:2]([OH:1])=[CH:3][C:4]=2[O:9]1)=[O:11])[CH3:14]
Reactant: CCOC(=O)[C@H]1CCc2ccc(O)cc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1CCc2ccc(O)cc2O1
Reaction time: 7 h

Procedure:
This ester was then resubmitted to enzymatic hydrolysis with Pseudomonas lipase (P-30, Amano International) to enhance its enantiomeric purity. A 3 L three-necked flask equipped as described above was charged with 775 mL of deionized water, 194 mL of 0.05M phosphate buffer (pH 7.0) and 28.4 g (0.128 mol) of the above ester in 96 mL of tetrahydrofuran. The pH was adjusted to 8 with adequate 1.0N aqueous sodium hydroxide solution and 2.6 g of Pseudomonas lipase enzyme (P-30 Amano) was added to the mixture. The hydrolysis was allowed to proceed to 70% conversion over a 7 hour period while stirring at a fast rate and maintaining the pH at 8. The tetrahydrofuran was removed from the reaction mixture at 40° C. (10 mm Hg) and the aqueous phase was extracted with 3×250 mL=750 mL of ethyl acetate. The combined organic layers were washed successively with 250 mL of saturated aqueous sodium bicarbonate solution and 250 mL of deionized water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated at 40° C. (10 mm Hg) to give 6.7 g of nearly racemic 3,4-dihydro-7-hydroxy-2H-benzopyran-2-carboxylic acid ethyl ester. The aqueous layers were acidified to pH=1 with 33 mL of concentrated hydrochloric acid and extracted with 3×250 mL=750 mL of ethyl acetate. The combined organic layers were washed with 250 mL of brine and dried over anhydrous sodium sulfate. After filtration, the solvent was removed at 40° C. (10 mm Hg) to give 20.4 g of (S)-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid, 95.5% e.e. This material was esterified as described above to give 21.6 g (76% yield) of (S)-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid, ethyl ester as a beige solid, m.p. 77°-79° C.; (α)D22 +19.1° C. (c 1.0, CHCl3); 95.5% e.e.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([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:5][CH:4]=1.Cl.[CH3:24][O:25][C:26]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][NH:30][CH2:31]2>>[CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:30]3[CH2:29][CH2:28][C:27]4[C:32](=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:26]=4[O:25][CH3:24])[CH2:31]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: COc1ccc2c(c1OC)CCNC2
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3ccc(N(C)C)cc3)nc3ccccc13)C2
Yield: 11 %

Procedure:
Reaction of 2-(4-(dimethylamino)phenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 34 (11% yield) as a brown solid, 1H NMR (300 MHz, DMSO-d6) δ 2.73 and 2.97 (2t, 2H), 3.03 (s, 6H), 3.47 and 4.02 (2t, 2H), 3.69-3.81 (4s, 6H), 4.40 and 4.92 (2s, 2H), 6.63 and 7.01 (2d, 1H), 6.80 and 7.07 (2d, 1H), 6.83-6.86 (m, 2H), 7.55-7.65 (m, 1H), 7.77-7.88 (2d, 1H), 7.96-8.02 (m, 2H), 8.32-8.38 (m, 2H); MS (ESI) m/z 469 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([CH:8]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[OH:9])[CH:7]=1.C1(C)C=CC=CC=1>ClCCl.[O-2].[Mn+4].[O-2]>[S:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH3:19])=[O:9]
Reactant: Cc1ccc(Br)cc1C(O)c1nc2ccccc2s1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(Br)cc1C(=O)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
To a solution of the above 5-bromo-2-methylphenyl-(benzothiazol-2-yl)methanol (2.60 g) in dichloromethane (30 ml)-toluene (10 ml) was added manganese(IV) oxide (3.42 g), and the mixture was stirred at room temperature for 3 hours. Insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure to give 5-bromo-2-methylphenyl benzothiazol-2-yl ketone (2.45 g) as colorless crystals. APCI-Mass m/Z 332/334 (M+H). (3) The above 5-bromo-2-methylphenyl benzothiazol-2-yl ketone was treated in a manner similar to Reference Example 14-(1) to give 1-(benzothiazol-2-ylmethyl)-5-bromo-2-methylbenzene as oil. APCI-Mass m/Z 318/320 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([CH:21]2[CH2:26][NH:25][CH:24]([C:27]([O:29]C)=[O:28])[CH2:23][CH2:22]2)[C:3]=1[Br:31].C1COCC1.[OH-].[Na+]>O>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([CH:21]2[CH2:26][NH:25][CH:24]([C:27]([OH:29])=[O:28])[CH2:23][CH2:22]2)[C:3]=1[Br:31]
Reactant: COC(=O)C1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(Br)c(C2CCC(C(=O)O)NC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.8 %

Procedure:
Methyl 5-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-2-carboxylate (11 mg, 0.023 mmol) in 2:1 THF:H2O (1.5 mL) was treated with 2N NaOH(aq) (0.25 mL). The resulting solution was stirred at room temperature for 18 hours. This solution is reduced in vacuo and purified by prep-LC to afford the title compound (8.9 mg): LC/MS RT=2.16 min. Mass calculated for, M+H 467.08, observed 467.08.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH3:11][O:12][C:13](=[O:46])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH:25]([C:32](=[O:41])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=3)[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:23]3[CH:42]=[CH:43][CH:44]=[CH:45][C:22]=3[N:21]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:11][O:12][C:13](=[O:46])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH:25]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[C:32](=[O:41])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH:1]=[O:3])[CH:35]=3)[C:23]3[CH:42]=[CH:43][CH:44]=[CH:45][C:22]=3[N:21]=2)=[CH:16][CH:15]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(-c2nc3ccccc3n2C(C(=O)Nc2cccc(N)c2)C2CCCCC2)cc1
Solvent: O=CO
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc3ccccc3n2C(C(=O)Nc2cccc(NC=O)c2)C2CCCCC2)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
A mixture of acetic anhydride (162 mg, 1.58 mmol, 2.2 equiv.) and formic acid (73 mg, 1.58 mmol, 2.2 equiv.) was heated to 60° C. for 15 minutes. The reaction was cooled to room temperature and a solution of 4-{1-[(3-amino-phenylcarbamoyl)-cyclohexyl-methyl]-1H-benzoimidazol-2-yl}-benzoic acid methyl ester (35 mg, 0.72 mmol, 1.0 equiv.) in dichloromethane (2 mL) was added and the reaction mixture stirred at room temperature for 16 hours. The reaction mixture was washed with 1 N HCl (2 mL) and the organic layer dried over magnesium sulphate. The reaction mixture was concentrated in vacuo to afford 4-{1-[cyclohexyl-(3-formylamino-phenylcarbamoyl)-methyl]-1H-benzoimidazol-2-yl}-benzoic acid methyl ester, 23 mg (62% yield) as a yellow solid, MS (ES+): 511 (M+H).