Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[H-].[Na+].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>CN(C=O)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8])[CH3:19]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Br)cc1C=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
This compound was prepared according to a literature procedure (Yoo et al., Bioorg. Med. Chem. 5:445, 1997). 5-Bromo-2-hydroxybenzaldehyde (10.0 g, 49.7 mmol) was dissolved in 90 mL anhyd. DMF and the mixture was cooled to 0° C. NaH (60% dispersion in mineral oil, 2.38 g, 59.6 mmol) was added in portions and the reaction was stirred at 0° C. for 1 hour. Ethyl bromoacetate (9.95 g, 59.6 mmol) was then added dropwise over 10 minutes and the reaction was stirred at rt overnight (18 hours). After this time, 30 mL of 1 N HCl was added to adjust the pH to acidity, and the reaction mixture was transferred to a separatory funnel and extracted with EtOAc (3×60 mL). The combined organics rinsed with water (2×40 mL), dried over MgSO4, filtered, and concentrated in vacuo to provide a thick oil. Purification by flash chromatography (10% EtOAc/hexanes) provided the product as a clear oil (14.0 g, 98%). 1H-NMR (CD2Cl2, δ): 1.29 (t, 3H), 4.26 (q, 2H), 4.78 (s, 2H), 6.83 (d, 1H), 7.65 (dd, 1H), 7.94 (s, 1H), 10.47 (s, 1H); LRMS (GC/MS/EI) 286 [M]+.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([OH:16])[CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:17][C:18]([C:20]1[CH:25]=[CH:24][C:23](F)=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=1)=[O:19].O>CS(C)=O.ClCCl>[C:6]([O:5][C:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([O:16][C:23]2[CH:24]=[CH:25][C:20]([C:18](=[O:19])[CH3:17])=[CH:21][C:22]=2[C:27]([F:28])([F:29])[F:30])[CH2:11]1)=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)c1ccc(OC2CCCN(C(=O)OC(C)(C)C)C2)c(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a suspension of sodium hydride (408 mg, 10.2 mmol) in DMSO (15 ml) was added 1-boc-3-hydroxypiperidine (2.00 g, 10.2 mmol) at 0° C. Stirring was continued for 30 min at 10° C. and 4-fluoro-3-(trifluormethyl)acetophenone (1.40 g, 6.79 mmol) was added dropwise. The reaction mixture was stirred at RT for 1 h and then transferred into water (200 ml) at 0° C. Dichloromethane (300 ml) was added. The organic phase was washed with water (200 ml) and dried over sodium sulfate. Evaporation and purification of the crude product by silica gel chromatography using ethyl acetate/heptane=1:1 gave the desired product (1.80 g, 68%).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[S:40][C:39]([CH3:41])=[N:38][C:37]=1[CH3:42])(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[S:40][C:39]([CH3:41])=[N:38][C:37]=4[CH3:42])(=[O:35])=[O:34])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: Cc1nc(C)c(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)s1
Agent: Cl
Product: Cc1nc(C)c(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4[nH]cnc34)c2F)s1
Reaction time: 2 h
Yield: 91 %

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-2,4-dimethylthiazole-5-sulfonamide (20 mg, 0.033 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 15 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-2,4-dimethylthiazole-5-sulfonamide (percentage yield: 91%), was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[CH2:19][O:20][C:21](=[O:22])[C:14]=34)=[CH:11][N:10]([CH3:23])[N:9]=2)=[CH:4][CH:3]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)(=O)C>[CH2:24]([N:31]1[C:21](=[O:22])[C:14]2[C:15](=[N:16][CH:17]=[CH:18][C:13]=2[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][N:10]([CH3:23])[CH:11]=2)[C:19]1=[O:20])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cn1cc(-c2ccnc3c2C(=O)OC3)c(-c2ccc(F)cc2)n1
Reactant: NCc1ccccc1
Solvent: CC(=O)O
Product: Cn1cc(-c2ccnc3c2C(=O)N(Cc2ccccc2)C3=O)c(-c2ccc(F)cc2)n1
Reaction time: 0.17 h

Procedure:
4-[3-(4-Fluorophenyl)-1-methyl-1H-pyrazol-4-yl]furo[3,4-b]pyridin-5(7H)-one (Example 1, step 5, 472 mg, 1.46 mmol) and benzyl amine (0.167 mL, 1.53 mmol) in acetic acid (4.7 mL) were heated at reflux for 18 hr, cooled and then concentrated to a brown solid. This material was stirred with diethyl ether (20 mL) for 10 min and then filtered to yield 450 mg (75%) of Ex 5-Step 1 product as a tan colored solid: LCMS m/z 413.5 (M+1); 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J=5.2, 1H), 8.15 (s, 1H), 7.26-7.42 (m, 7H), 7.13 (d, J=5.3, 1H), 7.01 (dd, J=8.6, 8.6, 2H), 4.87 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:12][C@H:11]1[C:13]([O:15]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:17].[OH-]>CO.C(Cl)(Cl)Cl>[CH2:1]([O:8][CH2:9][C@H:10]1[O:12][C@H:11]1[C:13]([NH2:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COC(=O)[C@@H]1O[C@@H]1COCc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC(=O)[C@@H]1O[C@@H]1COCc1ccccc1
Reaction time: 48 h

Procedure:
To a solution of 50 mg of methyl (2R-cis)-3-(benzyloxymethyl)oxirane carboxylate in 3 ml of MeOH was added 1 ml of concentrated NH4OH with rapid stirring. The mixture was allowed to stir for two days. The reaction was then diluted with 20 ml of CHCl3 and the organic layer separated and washed three times with 10 ml of 0.1N HCl. The combined organic layers were dried over MgSO4, filtered and evaporated to yield a pale yellow residue. Flash chromatography (7 mm column, 5% MeOH: CHCl3) afforded 24.2 mg of a clear oil which solidified upon standing. 1H NMR (CDCl3) 7.4-7.2 (m, 5), 6.08 (br, 1), 5.64 (br, 1), 4.58 (dd, 2, J=12, 15 Hz), 3.8 (m, 1), 3.5-3.4 (m, 3). Mass Spectra: EI: M-41 (--CONH2) Calc. 163.0758, Found 163.0745.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.[CH3:22][CH:23]([SH:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=3[N:3]=[C:2]2[S:25][CH:23]([CH3:24])[CH3:22])=[CH:13][CH:14]=1
Reactant: CC(C)S
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Sc1nc2c(c(=O)[nH]c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 80 °C
Yield: 101.5 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.2 g, 0.54 mmol, intermediate 8) in DMF (5 mL) was added propane-2-thiol (0.2 g, 2.7 mmol) and potassium carbonate (0.38 g, 2.7 mmol). The reaction was heated at 80° C. overnight. The mixture was cooled and partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated to give a crude product (0.2 g) which was used without purification. LCMS retention time 1.015 min; LCMS MH+ 365.
Reaction SMILES: B.C1COCC1.C1COCC1.[CH3:12][S:13][CH2:14][CH2:15][N:16]([C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35])[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1>C1COCC1>[CH3:12][S:13][CH2:14][CH2:15][N:16]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35])[C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:21][CH:22]=1
Reactant: COc1ccccc1C(=O)N(CCSC)c1ccc(S(N)(=O)=O)cc1
Agent: B
Solvent: C1CCOC1
Product: COc1ccccc1CN(CCSC)c1ccc(S(N)(=O)=O)cc1
Reaction time: 18 h
Yield: 77.4 %

Procedure:
A solution of 1 M BH3.THF/THF (6.8 mL, 6.8 mmol) was added to a solution of 4-[(2-methylthio-ethyl)-(2-methoxy-benzoyl)-amino]-benzenesulfonamide (0.51 g, 1.34 mmol) in THF (5 mL). After 18 h, the excess BH3 was quenched by addition of 0.1 M HCl; followed by partitioning the mixture between CH2Cl2 and NaHCO3. The organic layer was dried (Na2SO4), filtered, evaporated in vacuo, and the residue was purified by MPLC (CH2Cl2 to 70:30 CH2Cl2/EtOAc) to afford 0.38 g (77%) of 4-[(2-methylthio-ethyl)-(2-methoxy-benzyl)-amino]-benzenesulfonamide as a clear glass.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:19]=[C:18]2[CH:20]=[C:5]([C:6](=[O:29])[NH:7][CH:8]([CH:22]3[CH2:26][CH:25]([CH3:27])[C:24](=[O:28])[O:23]3)[CH2:9][CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17]2)[CH:4]=1>C(N)CCC>[CH2:6]([NH:7][C:24](=[O:28])[CH:25]([CH3:27])[CH2:26][CH:22]([OH:23])[CH:8]1[NH:7][C:6](=[O:29])[C:5]2=[CH:20][C:18](=[N:19][C:3]([O:2][CH3:1])=[CH:4]2)[NH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]([CH3:21])[CH2:9]1)[CH2:5][CH2:4][CH3:3]
Reactant: COc1cc2cc(n1)NCCCCCCC(C)CC(C1CC(C)C(=O)O1)NC2=O
Solvent: CCCCN
Product: CCCCNC(=O)C(C)CC(O)C1C[C@H](C)CCCCCCNc2cc(cc(OC)n2)C(=O)N1

Procedure:
A solution of 16-methoxy-9-methyl-11-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-2,12,17-triaza-bicyclo[12.3.1]octadeca-1(17),14(18),15-trien-13-one (49 mg, 0.12 mmol) in 1.2 ml butylamine is stirred at 50° for 3 h. Excess butylamine is evaporated and the residue purified by chromatography on silica gel to afford the title compound (mixture of diastereomers) as a slightly yellow powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([C:28](=[O:30])[CH3:29])[CH:25]=[CH:26][CH:27]=1>CC(O)C>[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:2]2[N:7]=[C:6]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:30])[CH3:29]
Reactant: NC(=O)Cc1ccccc1CCc1nc(Cl)ncc1Cl
Reactant: CC(=O)c1cccc(N)c1
Solvent: CC(C)O
Product: CC(=O)c1cccc(Nc2ncc(Cl)c(CCc3ccccc3CC(N)=O)n2)c1
Temperature: 150 °C
Yield: 60.1 %

Procedure:
A solution of 2-(2-(2-(2,5-dichloropyrimidin-4-yl) ethyl)phenyl)acetamide (A139) (0.158 g, 0.509 mmol) in 2-propanol (2 mL) containing 1-(3-aminophenyl)ethanone (0.138 g, 1.01 mmol) was heated under microwave irradiation at 150° C. for 2 hours. The reaction mixture was adsorbed onto silica gel and the product was purified using silica gel column chromatography (CombiFlash Rf, 12 g SiO2 Cartridge, 10-65% EtOAc in cyclohexane) to give the title compound (A141) as a white solid (0.125 g, 60%). LCMS-B: rt 6.804 min; m/z 409 [M+H]+.
Reaction SMILES: [N:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])=O.[NH4+].C(=O)([O-])[O-].[K+].[K+].Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1>CO.CN(C)C=O>[N:23]1[CH:24]=[CH:25][CH:26]=[N:27][C:22]=1[NH:10][S:7]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:9])=[O:8]
Reactant: NS(=O)(=O)N1CCCCC1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: O=C[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(Nc1ncccn1)N1CCCCC1
Reaction time: 1 h
Yield: 68 %

Procedure:
To a slurry of the piperidine sulfonamide from part F (6.3 g, 12.0 mmol) in methanol (25 mL) was added ammonium formate (2.2 g, 34.5 mmol). The system was purged with nitrogen for 10 minutes. The nitrogen stream was removed and palladium on carbon (1.2 g of 10 weight % on activated carbon, 50% water) was added. The reaction was refluxed for forty five minutes, cooled, filtered through Celite under nitrogen, and concentrated in vacuo. The residue (6.21 g, 13.8 mmol) was dissolved in dry dimethylformamide (28 mL) and potassium carbonate (5.7 g, 41.4 mmol) and 2-chloropyrimidine (3.16 g, 27.6 mmol) were added The reaction was stirred at eighty five degrees Celsius for one hour and then concentrated in vacuo. The residue was taken up in ethyl acetate and filtered through Celite. The filtrate washed with water two times, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo. The product was recrystallized (methanol) to give the N-pyrimidinyl piperidine sulfonamide as a white solid (4.94 g, 68%).
Reaction SMILES: [C:1]([NH:4][N:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>CN(C=O)C>[C:1]([N:4]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[N:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCBr
Reactant: CC(=O)NN=Cc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCN(N=Cc1ccc(OCc2ccccc2)cc1)C(C)=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of 5×10-3 moles of 4-(benzyloxy)benzaldehyde acetylhydrazone (1.34 g) in 5 ml of anhydrous DMF is added to 5×10-3 moles of sodium hydride (0.12 g) in suspension in 10 ml of anhydrous DMF. The reaction mixture is heated slowly on a water bath at 80° C. for 30 minutes. After cooling, a solution containing 0.85 g (5.1×10-3 moles) of methyl 3-bromopropionate in 5 ml of DMF is slowly added to the mixture. The latter is stirred for one hour at room temperature, then it is poured into 100 ml of ice-cold water. A product precipitates. After standing for 30 minutes, it is filtered, subjected to draining, at the end of which it is chromatographed on a MACHEREY-NAGEL silica gel 60 (0.04-0.063 ml) using a mixture of ethyl acetate and dichloromethane (1/9) as eluent. The oil obtained precipitates. The compound (I-a5) is slowly recrystallized from ether. Its melting point is 170° C. The reaction yield is 11%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N=C=NC(C)C)(C)C.[Cl:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[C:35]([NH:40][CH2:41][CH2:42]O)[N:34]=[C:33]2[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[C:50]([OH:53])(=[S:52])[CH3:51].C(=O)(O)[O-].[Na+]>C1COCC1.C1(C)C=CC=CC=1.O>[C:50]([S:52][CH2:42][CH2:41][NH:40][C:35]1[N:34]=[C:33]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:32]2[C:37](=[CH:38][CH:39]=[C:30]([Cl:29])[CH:31]=2)[N:36]=1)(=[O:53])[CH3:51]
Reactant: CC(O)=S
Reactant: OCCNc1nc(-c2ccccc2)c2cc(Cl)ccc2n1
Agent: CC(C)N=C=NC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)SCCNc1nc(-c2ccccc2)c2cc(Cl)ccc2n1
Reaction time: 0.33 h
Yield: 85.3 %

Procedure:
To a solution of 292 mg of triphenylphosphine in dehydrated THF (3 ml) was added dropwise 563 mg of a 40% solution of diisopropylcarbodiimide in toluene under ice cooling, followed by stirring for 20 minutes. To the resulting suspension was added dropwise a solution of 167 mg of 6-chloro-2-(2-hydroxyethylamino)-4-phenylquinazoline (compound No. Ic3-1) in dehydrated THF (2 ml) under ice cooling, and immediately 127 mg of thioacetic acid was added dropwise. The resulting yellow clear solution was stirred for 1 hour under ice cooling, stirred at room temperature for 1 hour, poured into a saturated solution of sodium bicarbonate in water, and then extracted with chloroform. The extract was concentrated. The resulting residue was purified by silica gel column chromatography (chloroform:ethyl acetate=10:1) to obtain 170 mg of the titled compound. Mp.128.9° C. 1H NMR (CDCl3): 2.34 (3H, s), 3.22 (2H, t, J=6.5 Hz), 3.73 (2H, q, J=6.5 Hz), 5.74 (1H, br. t, J=6.5 Hz), 7.53-7.62 (5H, m), 7.65-7.70 (2H, m), 7.77 (1H, s).
Reaction SMILES: S(=O)=O.C(O)(C(F)(F)F)=O.[Br:11]Br.[CH2:13]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.CCCCCC.CCOCC>[Br:11][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([OH:25])=[O:24])=[CH:20][CH:19]=1
Reactant: BrBr
Reactant: O=C(O)c1ccccc1CCc1ccccc1
Agent: O=S=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1CCc1ccc(Br)cc1
Temperature: -28 °C
Reaction time: 17 h

Procedure:
Sulfur dioxide (625 mL) was condensed into a large flask with a dry ice condenser to this flask was added TFA (10 mL) and bromine (2 equiv). When the solution temperature reached -50°, o-phenethylbenzoic acid was added. The reaction was stirred at -28° C. for 17 hours. The SO2 and excess bromine were evaporated off at room temperature over a 2 hour period leaving slightly yellow solid. A 30 g sample was dissolved in hot toluene-hexane (100 mL of 2:3) with a few mL of Et2O. The solution was cooled slowly to 10° C., and the product was isolated by filtration.
Reaction SMILES: [C:1]([C:3]([OH:10])([CH2:7][CH2:8][CH3:9])[CH2:4][CH2:5][CH3:6])#[CH:2].Br[C:12]1[CH:13]=[C:14]([S:18][CH2:19][CH2:20][NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH:15]=[CH:16][CH:17]=1>>[F:26][C:23]([F:24])([F:25])[C:22]([NH:21][CH2:20][CH2:19][S:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:2]#[C:1][C:3]([OH:10])([CH2:7][CH2:8][CH3:9])[CH2:4][CH2:5][CH3:6])[CH:13]=1)=[O:27]
Reactant: O=C(NCCSc1cccc(Br)c1)C(F)(F)F
Reactant: C#CC(O)(CCC)CCC
Product: CCCC(O)(C#Cc1cccc(SCCNC(=O)C(F)(F)F)c1)CCC

Procedure:
Sonogashira coupling of alkynol 20 with N-(2-(3-bromophenylthio)ethyl)-2,2,2-trifluoroacetamide (128) according to the method used in Example 1 followed by flash chromatography (5-50% ethyl acetate/hexanes gradient) gave 2,2,2-trifluoro-N-(2-(3-(3-hydroxy-3-propylhex-1-ynyl)phenylthio)ethyl)acetamide (129) as an orange. Yield (0.22 g, 52%): 1H NMR (400 MHz, DMSO) δ 9.52-9.60 (m, 1H), 7.26-7.36 (m, 3H), 7.16-7.20 (m, 1H), 5.11 (s, 1H), 3.60 (ddd, J=6.4 Hz, 2H), 3.11 (t, J=7.2 Hz, 2H), 1.52-1.62 (m, 4H), 1.38-1.52 (m, 4H), 0.89 (t, J=7.2 Hz, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.C1N2CCN(CC2)C1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C1COCC1>[OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=2)(=[O:29])=[O:28])=[CH:6][CH:5]=1
Reactant: OCCc1ccc(CCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(CCO)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a stirred solution of the intermediate from Step A in THF (50 mL) was added DABCO (1.51 g, 13.5 mmol) and then p-toluenesulfonyl chloride (50 mL). The resulting mixture was stirred overnight at room temperature and then filtered to remove precipitated hydrochloride salts. The filtrate was concentrated under reduced pressure and DCM (50 mL) was added to the residue. The organic layer was then washed with water (1×100 mL), saturated NaCl (1×100 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The resulting material was purified by silica gel chromatography (70% EtOAc/hexane) to afford 1.25 g of the title intermediate (43% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH:5]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:5]2[CH:47]([OH:51])[C:48]([CH3:50])([CH3:49])[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)[NH:11][C:6]=2[C:7]([F:10])=[CH:8][CH:9]=1)=[O:20]
Reactant: CC(C)C=O
Reactant: COC(=O)c1ccc(F)c(N=Cc2cccc(Br)c2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(F)c2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To a stirred mixture solution of 3-[(3-bromo-benzylidene)-amino]-4-fluoro-benzoic acid methyl ester (51.7 g, 153.8 mmol) and ytterbium(III) triflate hydrate (14.3 g, 23.1 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (14 mL, 153.8 mmol) and water (2.8 mL, 153.8 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-8-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (63.0 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrFNO3 (M+H)+: 409.27, observed: 390.0 & 392.0.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=2[CH:18]=[C:19]([CH3:29])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4ccccc4F)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(C)cc(-c3ccccc3F)c2O1

Procedure:
The title compound was prepared (0.03 g, 28%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2-fluorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.14 g, 0.34 mmol) and methylamine (0.105 g, 3.4 mmol). mp 153-155° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:25]=[CH:24][C:23]5[CH2:22][NH:21][CH2:20][CH2:19][C:18]=5[N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:26]=[CH:27][N:28]=[CH:29][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:30][CH2:31][C:32](O)=[O:33].C(Cl)CCl.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:25]=[CH:24][C:23]5[CH2:22][N:21]([C:31](=[O:30])[CH2:32][OH:33])[CH2:20][CH2:19][C:18]=5[N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:26]=[CH:27][N:28]=[CH:29][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CO
Reactant: c1cc2c3cnc(Nc4ccc5c(n4)CCNC5)nc3n(C3CCCC3)c2cn1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CO)N1CCc2nc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)ccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
To a solution of 9-cyclopentyl-N-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-2-amine (21) (145 mg, 0.367 mmol) in DMF (10 mL) were added 2-hydroxyacetic acid (34.3 mg, 0.451 mmol), EDC (191.7 mg, 0.451 mmol), N-hydroxybenzotriazole (61 mg, 0.451 mmol), and N,N-diisopropylethylamine (157 uL, 0.903 mmol). The mixture thus obtained was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel eluting with 20% to 75% solvent A (DCM:MeOH:NH4OH, 100:10:1) to give the title compound as an off-white solid (117 mg, 70% yield). 1H NMR (500 MHz, DMSO-d6) δ 1.77-1.80 (2H, m), 2.07-2.10 (4H, m), 2.42-2.44 (2H, m), 2.82-2.91 (2H, m), 3.66-3.82 (2H, m), 4.18-4.20 (2H, m), 4.57-4.66 (2H, m), 5.36 (1H, m), 7.68 (1H, d, J=10.0 Hz), 8.06 (1H, d, J=5.0 Hz), 8.19 (1H, d, J=10.0 Hz), 8.48 (1H, d, J=5.0 Hz), 9.03 (1H, s), 9.31 (1H, s) 9.98 (1H, br. s) ppm; LCMS m/z: 444 (M+1).