Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].OC=[C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:6]([C:16]3[CH2:15][CH2:14][CH2:13][C:12](=[O:17])[C:11]=3[NH:5]2)=[CH:7][CH:8]=1
Reactant: O=C1CCCCC1=CO
Reactant: Nc1cccc(Br)c1
Product: O=C1CCCc2c1[nH]c1cc(Br)ccc21

Procedure:
7-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one was prepared 3-bromoaniline (7.6 g, 44 mmol) and 2-(hydroxymethylene)cyclohexanone (4.3 g, 34 mmol) in a similar manner as described above and recrystallization from methanol to isolate 7-bromo isomer to give 280 mg (1%). of a light brown solid. 1H-NMR (DMSO-d6): δ 8.94 (s, 1H), 7.60 (d, 1H), 7.52 (d, 1H), 7.27-7.25 (m, 1H), 3.01-2.98 (m, 2H), 2.68-2.65 (m, 2H), 2.31-2.24 (m, 2H); MS m/z 263, 265 (M+1).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([C:18]#[C:19][C:20]([C:22]3[N:23](C(OC(C)(C)C)=O)[CH:24]=[C:25]([CH3:28])[C:26]=3[CH3:27])=[O:21])[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:36]C(OC(C)(C)C)=O)=O)(C)(C)C.[I-:44].[Na+].C(O)(C(F)(F)F)=O>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[F:17][C:13]1[C:12]([C:18]([I:44])=[CH:19][C:20](=[O:21])[C:22]2[NH:23][CH:24]=[C:25]([CH3:28])[C:26]=2[CH3:27])=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][C:9](=[O:36])[CH2:10]2
Reactant: Cc1cn(C(=O)OC(C)(C)C)c(C(=O)C#Cc2c(F)ccc3c2cc(OC(=O)OC(C)(C)C)n3C(=O)OC(C)(C)C)c1C
Reactant: [I-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c[nH]c(C(=O)C=C(I)c2c(F)ccc3c2CC(=O)N3)c1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-3,4-dimethyl-1H-pyrrol-2-yl)-3-oxo-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester (from Example 47 above) (0.79 g, 1.33 mmol) and sodium iodide (Aldrich, 0.50 g, 3.33 mmol) was slowly added TFA (Aldrich, 15 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours, and then diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. After separation, the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was triturated with ethyl acetate, filtered, and dried to give 5-fluoro-4-[1-iodo-3-oxo-3-(3,4-dimethyl-1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one as a brown solid which was used in the next step without further purification. (Yield 0.40 g, 71.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C@:12]12[CH2:17][C@H:16]1[CH2:15][NH:14][CH2:13]2.Br[CH2:19][CH2:20][CH2:21][Cl:22]>O1CCCC1.C(N(C(C)C)CC)(C)C>[Cl:22][CH2:21][CH2:20][CH2:19][N:14]1[CH2:15][C@H:16]2[C@:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[F:1])([CH2:17]2)[CH2:13]1
Reactant: ClCCCBr
Reactant: Fc1cc(C(F)(F)F)ccc1[C@@]12CNC[C@@H]1C2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(C(F)(F)F)ccc1[C@]12C[C@H]1CN(CCCCl)C2

Procedure:
To a solution of (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (300 mg) in dry tetrahydrofuran (3 mL), diisopropylethylamine (0.65 mL) and 1-bromo-3-chloropropane (1.01 mL) were added and the resulting mixture was refluxed for 3 hours.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[C:3]1=[CH2:13].[OH:14][C:15]1[CH:27]=[C:26]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:18]2[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:17]=2[C:16]=1[N:34]=O>CO>[CH3:1][N:2]1[C:3]2([CH2:13][NH:34][C:16]3[C:17]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[O:19][C:18]=4[C:26]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:27][C:15]=3[O:14]2)[C:4]([CH3:11])([CH3:12])[C:5]2[C:10]1=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=Nc1c(O)cc(N2CCCCC2)c2oc3ccccc3c12
Reactant: C=C1N(C)c2ccccc2C1(C)C
Solvent: CO
Product: CN1c2ccccc2C(C)(C)C12CNc1c(cc(N3CCCCC3)c3oc4ccccc4c13)O2
Reaction time: 41 h

Procedure:
A mixture of 1,3,3-trimethyl-2-methyleneindoline (0.435 g; 0.0025 mol) and 2-hydroxy-1-nitroso-4-piperidinodibenzofuran (0.675 g; 0.0025 mol) in methanol (25.0 ml) was heated under nitrogen and refluxed with stirring for 41 hours. The solution was evaporated to dryness and chromatographed over silica (eluent: dichloromethane) to yield 1,3,3-trimethyl-6'-piperidinospiro[2H-indole 2,3'-[3H]-[2H-[1,4]benzoxazino [6,5-b]benzofuran]] as an amber oil (0.35 g; 32%), which afforded a pale yellow solid upon trituration with diethyl ether, m.pt. 213.5°-216° C.; λmaxAbsorbance 570 nm (Polyurethane). ##STR13##
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][NH2:8])[CH2:3][CH2:2]1.[C:9]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=O)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C(O)C>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][C:19](=[N:8][O:7][CH:4]2[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]2)[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: NOC1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(=NOC2CCNCC2)CC1
Temperature: 70 °C

Procedure:
1.16 g (10 mmol) of crude 70b in 20 mL of ethanol was treated with boc-piperidinone (1.99 g, 10 mmol) and NaOAc.3H2O (2.04 g, 15 mmol). The reaction was heated up to 70° C. overnight. The ethanol was evaporated to 3 mL and the solution was diluted with water and a fine precipitate was filtered. The solid was dissolved in DCM, dried and concentrated to give 0.65 g of solid. The filtrate was extracted with ethyl acetate 3 times, dried and combined with the solid to give 1.1 g of crude 70c.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH2:24])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27].N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:34]([NH:24][CH2:23][C:22]([N:20]([C:15]1[C:14]([Cl:26])=[C:13]([C:18]([Cl:19])=[CH:17][CH:16]=1)[CH2:12][O:11][C:10]1[C:5]2[N:6]([C:2]([Br:1])=[C:3]([CH3:27])[N:4]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:21])=[O:25])(=[O:36])[CH3:35]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Reaction time: 1.5 h
Yield: 68 %

Procedure:
To a solution of 3-bromo-8-[2,6-dichloro-3-(N-glycyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (100 mg) in methylene chloride (2 ml) were added pyridine (17 mg), 4-dimethylaminopyridine (10 mg) and acetic anhydride (32 mg), and the mixture was stirred for 1.5 hours. The mixture was washed with water twice and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (methylene chloride:methanol=5:1, V/V) to give 8-[3-[N-(acetylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-3-bromo-2-methylimidazo[1,2-a]pyridine (74 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([OH:11])[CH:5]=1.[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[OH:11][C:6]1[CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:12])[CH:9]=[CH:8][C:7]=1[NH:10][C:20]([NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21]
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: O=C=Nc1ccccc1
Product: COC(=O)c1ccc(NC(=O)Nc2ccccc2)c(O)c1
Yield: 90.7 %

Procedure:
N-[2-Hydroxy-4-(methoxycarbonyl)phenyl]-N'-phenyl urea was prepared from methyl-4-amino-3-hydroxybenzoate (200 mg, 1.19 mmol) and phenyl isocyanate (1.19 mmol) according to the procedure noted above in General Method A. The product was purified by precipitation from toluene, and filtering, to afford the titled compound (309 mg, 90%). mp: 188.4°-188.8° C.; 1H NMR (CD3OD/CDCl3): δ8.15 (d, 1H, J=8.25 Hz), 7.70 (s, 1H), 7.51 (d, 1H, J=8.25 Hz), 7.43 (d, 2H, J=8.25 Hz), 7.30 (t, 2H, J=8.25 Hz), 7.01 (t, 1H, J=8.25 Hz), 3.87 (s, 3H); EI-MS m/z 286 (M+H)+ ; Anal. (C15H14N2O4) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=[O:9]
Reactant: Nc1ccccn1
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ccccn1)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 42 %

Procedure:
To a stirring solution of 5-chloro-2-nitrobenzoic acid (15 g, 74 mmol) in dichloromethane (300 mL) was added DMF (a few drops) followed by oxalyl chloride (11.3 g, 89 mmol). After stirring for 2 h, the solvent was removed in vacuo and the residue was redissolved in dichloromethane (300 mL). To this stirring solution was added pyridine (17.5 g, 222 mmol), followed by 2-aminopyridine (7 g, 74 mmol). After 24 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was separated and washed twice with 1 M citric acid, once with brine, twice with satd aq NaHCO3, and once with brine. The organic phase was then dried (MgSO4), filtered and concentrated in vacuo to a volume of about 25 mL, then diluted with diethyl ether, and sonicated. The resulting precipitate was filtered and dried in vacuo to give 8.63 g (42%) of an off-white solid.
Reaction SMILES: [C:1]([CH2:3][O:4][CH:5]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1)#[N:2]>CCO.[Pd]>[NH2:2][CH2:1][CH2:3][O:4][CH:5]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC(OCC#N)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(OCCN)C1
Yield: 86.6 %

Procedure:
A mixture of tert-butyl 3-(cyanomethoxy)azetidine-1-carboxylate (0.46 g, 2.19 mmol) and 10% Pd/C (10%) in EtOH was stirred under H2 gas at 3 atm. After 3 h the reaction mixture was filtered through celite and the filtrate evaporated to dryness to give the title compound (0.41 g, 87%) as an oil. 1H NMR (CDCl3): δ 4.27-4.20 (m, 1H), 4.08 (t, 2H), 3.84 (dd, 2H), 3.49 (t, 2H), 2.84 (t, 2H), 1.45 (s, 9H); 13C NMR (CDCl3): δ 156.6, 79.7, 68.3, 68.2, 56.7, 49.4, 28.6.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:14][CH:13]([O:15][CH3:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=O>C1COCC1>[NH2:1][CH2:2][CH2:3][N:5]1[CH2:14][CH:13]([O:15][CH3:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1
Reactant: COC1CN(C(=O)CN)Cc2ccccc21
Solvent: C1CCOC1
Product: COC1CN(CCN)Cc2ccccc21
Temperature: 55 °C
Yield: 28 %

Procedure:
A solution of N-glycyl-4-methoxy-1,2,3,4-tetrahydroisoquinoline in 25 mL of THF was cooled in an ice bath and 10 M solution of borane-methyl sulfide complex in THF (3.85 mL) was added dropwise. The resulting mixture was warmed to 55° C. and then to reflux for 4 hours. Excess borane was destroyed by addition of 6N HCl. The resulting mixture was heated to 100° C. for 1 hour. The resulting solution was first extracted with EtOAc and then with 10% iPrOH—CH2Cl2. The iPrOH—CH2Cl2 extract gave 880 mg (28%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:22])[CH2:4]1.[O:23]=[C:24]1[CH2:29][S:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:50].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CO.C(Cl)Cl.CCOCC>[ClH:50].[ClH:50].[F:21][C:18]1[CH:19]=[C:20]2[C:15]([CH:14]=[CH:13][C:12](=[O:22])[N:11]2[CH2:10][CH2:9][N:5]2[CH2:6][C@H:7]([OH:8])[C@H:3]([CH2:2][NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[S:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:4]2)=[CH:16][CH:17]=1
Reactant: NC[C@@H]1CN(CCn2c(=O)ccc3ccc(F)cc32)C[C@@H]1O
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: O=C1CSc2ccc(CNC[C@@H]3CN(CCn4c(=O)ccc5ccc(F)cc54)C[C@@H]3O)nc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-{2-[(3R,4R)-3-(aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-fluoro-2(1H)-quinolinone (90 mg; 0.3 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (for a synthesis, see WO2004058144, Example 7(d) (60 mg, 0.3 mmol) in methanol (2 mL), DCM (4 mL) was stirred at room temperature overnight. Sodium triacetoxyborohydride (0.127 g; 0.6 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was evaporated and chromatographed on silica gel, eluting with 0-15% methanol-DCM-1% NH4OH to give an oil. The oil was treated with 1M HCl in Et2O to give the title compound (40 mg) as the dihydrochloride salt.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(C)c1ccc(N)c([N+](=O)[O-])c1

Procedure:
20.0 G. (0.148 moles) of 4-isopropylaniline is added with stirring to 75 ml. of acetic anhydride at from 20° to 45° C. The reaction mixture is stirred at 35° C. for 1 hour. 11 Ml. of fuming nitric acid (specific gravity 1.5) is added at a temperature of from 25° to 35° C. over a period of 20 minutes and stirred for 3 hours. The acid mixture is added to a mixture of 180 ml. of water, 45 ml. of concentrated sulfuric acid and 142 ml. of ethanol with stirring. The reaction mixture is stirred overnight at room temperature, refluxed for 2 hours, neutralized with saturated sodium carbonate solution and extracted with chloroform. The chloroform layer is dried and evaporated in vacuo affording 35 g. of a dark orange oil which is used as is in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]Br)=[CH:7][CH:6]=[CH:5][C:4]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1.[C-:19]#[N:20].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[CH:5][CH:6]=[CH:7][C:8]=1[CH2:9][C:19]#[N:20]
Reactant: [C-]#N
Reactant: COc1c(CBr)cccc1Oc1cccc(Cl)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(CC#N)cccc1Oc1cccc(Cl)c1
Yield: 98.1 %

Procedure:
A solution of 3-chlorophenyl 2-methoxy-3-bromomethylphenyl ether (20 g) in dimethyl sulfoxide (50 ml) and powdered sodium cyanide (3 g) were treated in a similar manner to that of Example 5-(4) to give oily 2-[2-methoxy-3-(3-chlorophenoxy)phenyl]acetonitrile (16.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[C:16]4[C:17](=[CH:21][N:22](CC5C=CC(OC)=CC=5)[N:23]=4)[N:18]=[CH:19][CH:20]=3)[CH:11]=[CH:10][N:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[N:22][NH:23][C:16]=34)[CH:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cn2cc3nccc(Nc4ccnc(-c5cc(Cl)ccc5F)c4)c3n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(Cl)cc1-c1cc(Nc2ccnc3cn[nH]c23)ccn1
Temperature: 70 °C

Procedure:
To a vial containing N-(2-(5-chloro-2-fluorophenyl)pyridin-4-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine was added 5 mL of neat TFA and the mixture was heated at 70° C. for 3 hours. Cooled to room temperature and concentrated to dryness. The residue was purified by preparative HPLC eluting with a gradient of 10-30% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column conditions to give, after drying in vacuo, the title compound as a TFA salt as an off-white solid. 1HNMR (400 MHz, DMSO-d6) δ ppm 7.31-7.60 (4H, m) 7.62 (1H, ddd, J=8.78, 4.11, 2.78 Hz) 7.86 (1H, br. s.) 8.01 (1H, dd, J=6.69, 2.65 Hz) 8.56 (2H, d, J=6.32 Hz) 8.75 (1H, d, J=5.81 Hz) 11.12 (1H, br. s.), MS [M+H] found 340.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:12][CH:11]=1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(F)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-(3-{1-[6-(4-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.22 (s, br, 1H), 7.74–6.70 (m, 12H) 5.05–4.94 (m, 1H), 3.66–3.52 (m, br, 2H), 3.02–2.83 (m, br, 2H), 2.81–2.58 (m, br, 4H), 2.58–2.36 (m, br, 2H), 2.02–1.66 (m, br, 6H), 1.66–1.46 (m, br, 1H), 1.46–1.35 (m, br, 3H), 1.26 (d, 6H, J=6.0 Hz); ESMS m/e: 535.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([O:13][CH3:14])[CH:5]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:39][NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][CH:46]([O:49][C:50](=[O:64])[NH:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH2:45][CH2:44]1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:40]([CH2:41][CH2:42][N:43]2[CH2:44][CH2:45][CH:46]([O:49][C:50](=[O:64])[NH:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH2:47][CH2:48]2)[CH3:39])=[O:10])=[C:6]([O:13][CH3:14])[CH:5]=1
Reactant: CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: COC(=O)c1ccc(C(=O)O)c(OC)c1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a stirred solution of 2-methoxyterephthalic acid 4-methyl ester (450 mg, 2.1 mmol; prepared as described in Preparation 18) in DMF (10 mL) was added EDC (630 mg, 3.3 mmol), HOAt (2.4 mL, 1.18 mmol, 0.5M in DMF) and DIPEA (1.3 mL, 7.05 mmol). When the mixture was homogenous, a solution of biphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester (830 mg, 2.4 mmol; prepared as described in Preparation 4) was added slowly. The reaction mixture was stirred at room temperature for 16 hours and then washed with water (100 mL), 1N HCl (100 mL), 1N NaOH (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated to afford the title intermediate in 89% yield (1.04 g, 1.9 mmol). MS m/z: [M+H+] calcd for C31H35N3O6, 545.6; found, 546.6.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH3:34][C@H:35]1[CH2:40][O:39][CH2:38][CH2:37][NH:36]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:30][C:28]([F:29])([F:31])[C:27]([C:24]1[CH:25]=[CH:26][C:21]([N:8]2[CH2:9][CH2:10][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:12][CH:7]2[CH2:6][N:36]2[CH2:37][CH2:38][O:39][CH2:40][C@@H:35]2[CH3:34])=[CH:22][CH:23]=1)([OH:33])[CH3:32]
Reactant: C[C@H]1COCCN1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1COCCN1CC1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 150 °C

Procedure:
A 20 mL vial was charged with (4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (75 mg, 0.142 mmol), (S)-3-methylmorpholine (28.7 mg, 0.284 mmol Sigma-Aldrich, St. Louis, Mo.), potassium carbonate (39.2 mg, 0.284 mmol), and acetonitrile (4 mL). The vial was sealed and heated at 150° C. for 90 min in a microwave reactor (Emrys Optimizer Automated Microwave Synthesizer, Uppsala, Sweden). After this time, the mixture was filtered and the filtrate was concentrated. The crude material was purified via preparatory silica gel TLC (5% MeOH in CH2Cl2) to give 1,1,1-trifluoro-2-(4-(2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of four isomers.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:6]1[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=[C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:7]=1
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1-c1ccccc1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: COC(=O)Cc1c(C)nc(-c2ccccc2)nc1-c1ccccc1
Yield: 92.1 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-phenylpyrimidin-5-yl)acetate (200 mg; 0.723 mmol), benzeneboronic acid (264 mg; 2.168 mmol), tetrakis(triphenylphosphine) palladium(0) (84 mg; 0.072 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (3 mL) and water (1 mL). N,N-Diisopropylethylamine (0.444 mL; 2.89 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 1 h. The reaction mixture was partitioned between brine and ethyl acetate, the phases were separated and the water layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (5-40%) in heptane to give 212 mg (91%) of methyl 2-(4-methyl-2,6-diphenylpyrimidin-5-yl)acetate as a white solid. ESI/APCI(+): 319 (M+H).