Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[C:13]([F:38])=[C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:36][CH3:37])=[C:26]([O:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:15]=[CH:16][CH:17]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:11][C:12]1[C:13]([F:38])=[C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:36][CH3:37])=[C:26]([O:29][CH:30]4[CH2:31][CH2:32][N:33]([C:2]([O:4][C:5]5[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=5)=[O:3])[CH2:34][CH2:35]4)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
Phenyl chloroformate (43 mg, 0.25 mmol) was added dropwise to a mixture of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine (100 mg, 0.25 mmol) [prepared as described in Example 1] and diisopropylethylamine (50 μl, 0.30 mmol) in dichloromethane (2 ml). The mixture was stirred at room temperature for 18 hours. After evaporation of the solvents under vacuum, the residue was diluted in DMF (1 ml) and purified on an HPLC column (C18, 5 microns, 19 mm diameter, 100 mm length) of a preparative HPLC-MS system eluting with a mixture of water and acetonitrile containing 2 g/l of ammonium formate (gradient) to give the title compound as a solid (76 mg, 57%). NMR spectrum (DMSO-d6) 1.81 (m, 2H), 2.11 (m, 2H), 3.39 (m, 1H), 3.58 (m, 1H), 3.79 (m, 1H), 3.90 (m, 1H), 3.96 (s, 3H), 4.78 (m, 1H), 7.15 (d, 2H), 7.23 (m, 2H), 7.30 (m, 1H), 7.39 (m, 2H), 7.50 (m, 2H), 7.91 (s, 1H), 8.38 (s, 1H); Mass spectrum: MH+ 523.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH:9]1[C:14]([OH:15])=[CH:13][CH:12]=[C:11]([CH3:16])[CH:10]=1.[OH-].[K+]>[Cu]>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([O:15][C:14]2[CH:9]=[CH:10][C:11]([CH3:16])=[CH:12][CH:13]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(O)cc1
Reactant: Cc1ccc(Br)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(Oc2ccc(C)cc2)cc1
Temperature: 190 °C
Reaction time: 1 h

Procedure:
p-Bromotoluene (51g), p-cresol (33g) and potassium hydroxide (18.5 g) were mechanically stirred on a steam bath for 30 min., then heated at 190° C. for 1 hr. Copper bronze (2.0g) was added and the heating continued for a further 1 hr. at 190° C., then 220° to 230° C. for 2.5 hr. After cooling, the residue was extracted into chloroform, filtered, and the extract washed with water, dried, evaporated and crystallised from ethanol to yield 4,4'-dimethyldiphenyl ether, m.p. 49°-50° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CCOC(=O)Cc1ccc(C)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(C)c(O)c1
Temperature: -78 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
To a solution of 4c (2.2 g; 8.0 mmol) and 250 mL CH2Cl2 cooled to −78° C. was added dropwise via syringe BBr3 (9.8 mL; 0.104 mol). After 1 h at −78° C. the reaction was stirred for 4 h in an ice-water bath. The reaction mixture was recooled to −78° C. and the reaction quenched aqueous NaHCO3 then warmed to rt and the organic phase washed with water, saturated NaHCO3 and brine. The organic phase was dried (MgSO4) and the solvent evaporated to afford 1.4 g of ethyl 3-hydroxy-4-methylphenylacetate (5a).
Reaction SMILES: [NH2:1][C@H:2]([CH3:5])[CH2:3][OH:4].C([O:14][C@@H:15]1[C@H:19]([O:20]C(=O)C2C=CC=CC=2)[C@@H:18]([CH2:29][O:30]C(=O)C2C=CC=CC=2)[O:17][C@H:16]1[N:39]1[CH:47]=[N:46][C:45]2[C:40]1=[N:41][C:42]([Cl:49])=[N:43][C:44]=2Cl)(=O)C1C=CC=CC=1.C(N(CC)CC)C>O1CCOCC1>[Cl:49][C:42]1[N:43]=[C:44]([NH:1][C@H:2]([CH3:5])[CH2:3][OH:4])[C:45]2[N:46]=[CH:47][N:39]([C:40]=2[N:41]=1)[C@@H:16]1[O:17][C@H:18]([CH2:29][OH:30])[C@@H:19]([OH:20])[C@H:15]1[OH:14]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: C[C@@H](N)CO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@H](CO)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 200 h
Yield: 51.5 %

Procedure:
(R)-2-Amino-1-propanol (0.23 g, 3.0 mmol), 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.7 g, 2.7 mmol) and triethylamine (0.30 g, 3.0 mmol) were dissolved in dioxan (20 ml) and stirred for 200 h at room temperature. Following purification by column chromatography, the resultant 2',3',5'-tri- O-benzoyl-2-chloro- N-[(R)-1-hydroxy-2-propyl]adenosine was deprotected using methanolic ammonia to provide the title 2-chloro- N-[(R)-1-hydroxy-2-propyl]adenosine as an amorphous foam (0.5 g, 54%), 1H NMR (DMSO-d6)δ 1.17 (3H, d, --CH3), 3.35-3.72 (4H, m, H-5'a, H-5'b and --CH2 --), 3.96 (1H, q, H-4'), 4.14 (1H, m, H-3'), 4.52 (1H, dd, H-2'), 5.08 (1H, t, 5'-OH), 5.22, 5.49 (2H, 2d, 2' and 3'-OH), 5.83 (1H, d, H-1'), 8.0 (1H, d, N--H) 8.40 (1H, s, H-8).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([N:22]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:31]4[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=4)[CH:28]=3)[C:23]2=[O:37])[CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[Br:38]N1C(=O)CCC1=O>O1CCCC1>[Br:38][C:32]1[CH:33]=[N:34][N:35]([CH3:36])[C:31]=1[C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:37])[N:22]([C@@H:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:10][N:11]1[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]1=[O:21])[CH2:30]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1nccc1-c1ccc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1ccc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 2-{(2S)-3-(3-fluorophenyl)-2-[5-(1-methyl-1H-pyrazol-5-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]propyl}-1H-isoindole-1,3(2H)-dione (200.0 mg, 0.4044 mmol) [prepared in Example 1] in tetrahydrofuran (5 mL) was added N-bromosuccinimide (72.0 mg, 0.404 mmol). The solution was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was purified by combi-flash chromatography eluted with EtOAc/hexane (50-100%). The purification afforded 231 mg (99.6% yield) of the desired product as white solid. LC/MS found: 573.0 (M+1)+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:22]O>>[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([O:14][CH3:22])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(-c2ccncc2)cc1

Procedure:
4-(4-Pyridyl)benzoic acid hydrochloride (12.4 g) was dissolved in methanol (200 ml), concentrated sulfuric acid (5 ml) was added at room temperature, and the mixture was heated under reflux for 3 hours. After completion of the reaction, the solvent was distilled off, and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue to extract it with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and hexane was added to the residue to solidify it, thereby obtaining the title compound (9.86 g) as colorless powder.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:10]=[N:11][N:12]=2)[CH:9]=1.CO.[NH4+:15]>>[NH2:15][CH2:3][C@@H:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:10]=[N:11][N:12]=2)[CH:9]=1)[OH:1]
Reactant: [NH4+]
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CO
Product: NC[C@H](O)c1ccc2nnnn2c1

Procedure:
The title compound was prepared from 6-[(2R)oxiranyl][1,2,3,4]tetraazolo[1,5-a]pyridine and saturated ammonium methanol in substantially the same manner, as described in Example 124. The product was obtained as an off-white solid; mp 153-154° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.60 (brs, 2H), 2.73-2.84 (m, 2H), 4.65-4.68 (m, 1H), 5.70 (brs, 1H), 7.83-7.87 (m, 1H), 8.14-8.16 (m, 1H), 9.08-9.09 (m, 1H); MS (ES) m/z: 180 (M+H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][C:9]2=[O:15].[CH3:22]I.Cl>CCCCCC.CS(C)=O>[OH:3][C:4]1[C:13]([O:14][CH3:22])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][C:9]2=[O:15]
Reactant: CI
Reactant: O=C1CC(c2ccccc2)Cc2c1ccc(O)c2O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: COc1ccc2c(c1O)CC(c1ccccc1)CC2=O
Yield: 43 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (0.39 g, 9.8 mmol) was washed with hexane and the hexane was decanted. DMSO (15 mL) was added to the sodium hydride and the resultant suspension was stirred vigorously. To the suspension was added a solution of 2.5 g (9.8 mmol) of 5,6-dihydroxy-3-phenyl-1,2,3,4-tetrahydro-1-naphthalenone, from Step 1, in 10 mL of DMSO. The mixture was stirred at ambient temperature for 80 min and 0.61 mL (9.8 mmol) of methyl iodide was added in one portion. The reaction mixture was stirred at ambient temperature overnight and then made acidic with 5% aqueous hydrochloric acid solution. The mixture was stirred for 30 min and then filtered. The filter cake was dissolved in 20% ethyl acetate in hexane and chromatographed on a silica gel column eluted with 20% ethyl acetate in hexane and 50% ethyl acetate in hexane to give a brown solid. The solid was crystallized from ethyl acetate to give 1.13 g (43% yield) of the title compound as white crystals.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:9][C:4]=2[CH2:3]1.[NH:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=O>N1CCCCC1.CC(O)C>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:9][C:4]=2/[C:3]/1=[CH:22]/[C:18]1[NH:17][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)c1cc2c(s1)NC(=O)C2
Reactant: O=Cc1ccc[nH]1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)c1cc2c(s1)NC(=O)/C2=C\c1ccc[nH]1
Temperature: 75 °C
Yield: 15.8 %

Procedure:
tert-Butyl 5,6-dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxylate (32 mg, 0.2 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (1 ml). Pyrrole-2-carboxaldehyde (0.39 mmol, 37 mg) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (6 ml) and the precipitated solid was collected by filtration and washed with water to give 10 mg of tert-butyl (Z)-5,6-dihydro-5-oxo-4-[(1H-pyrrol-2-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carboxylate as a yellow solid. MS(ES): m/e 317 [M+H].
Reaction SMILES: [N:1](CC1C=CC=CC=1)=[N+:2]=[N-:3].[C:11]([OH:17])(=[O:16])[CH2:12][CH2:13][C:14]#[CH:15]>>[NH:1]1[CH:15]=[C:14]([CH2:13][CH2:12][C:11]([OH:17])=[O:16])[N:3]=[N:2]1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#CCCC(=O)O
Product: O=C(O)CCc1c[nH]nn1

Procedure:
The title compound was prepared from (azidomethyl)benzene and pent-4-ynoic acid analogously to Example 17, steps 3 and 4;
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:21][C:15]3[N:16]=[CH:17][NH:18][C:19](=[O:20])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH:23]1([NH2:27])[CH2:26][CH2:25][CH2:24]1>CS(C)=O>[CH:23]1([NH:27][C:2]2[C:3]([CH3:22])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:21][C:15]4[N:16]=[CH:17][NH:18][C:19](=[O:20])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:26][CH2:25][CH2:24]1
Reactant: Cc1nc2cccc(-c3cc4c(=O)[nH]cnc4[nH]3)c2nc1F
Reactant: NC1CCC1
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c(=O)[nH]cnc4[nH]3)c2nc1NC1CCC1
Temperature: 50 °C
Yield: 21.2 %

Procedure:
A glass microwave reaction vessel was charged with 6-(3-fluoro-2-methylquinoxalin-5-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (Example 264; 60 mg, 0.203 mmol) and cyclobutylamine (0.173 mL, 2.032 mmol) in DMSO (0.6 mL). The reaction was heated in an oil bath at 50° C. for 15 min. The mixture was purified by rpHPLC (Phenomenex Gemini C18 column (100×50 mm, 10 μm), 90 mL/min, 5-40% ACN in water with 0.1% TFA). Product-containing fractions were combined and ACN was removed in vacuo. The residual mixture was neutralized with saturated aq. NaHCO3, and the suspension was filtered and dried to give 6-(3-(cyclobutylamino)-2-methylquinoxalin-5-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (15 mg, 0.043 mmol, 21% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 347.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 12.69 (brs, 1H), 11.97 (brs, 1H), 8.10 (1H, d, J=7.2 Hz), 7.90 (1H, br. s.), 7.66 (1H, d, J=7.0 Hz), 7.47 (1H, br. s.), 7.37 (2H, br. s.), 4.50 (1H, br. s.), 2.58 (3H, br. s.), 2.16-2.28 (2H, m), 1.83-1.97 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1sc(CCc2ccc(CO)cc2)nc1-c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Product: Cc1sc(CCc2ccc(C=O)cc2)nc1-c1ccccc1

Procedure:
4-[2-(5-Methyl-4-phenyl-2-thiazolyl)ethyl]benzyl alcohol was oxidized with manganese dioxide in the same manner as in Reference Example 15 to yield 4-[2-(5-methyl-4-phenyl-2-thiazolyl)ethyl]benzaldehyde, which was then recrystallized from hexane to yield colorless prisms having a melting point of 66°-67° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]2[CH:13]=[N:14][N:15]=[C:11]2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[O:16]1CCOCC1.[OH-].[Na+].Cl>CC(C)=O>[N:12]1[CH:13]=[N:14][N:15]2[C:11]=1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:4][C:3](=[O:16])[CH2:2]2
Reactant: ClCc1nc2ccccc2c2nncn12
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C1Cn2ncnc2-c2ccccc2N1
Temperature: 5 °C
Reaction time: 17 h

Procedure:
4.1. 77 g of 5-(chloromethyl)-1,2,4-triazolo[4,3-c]quinazoline are suspended in 2.0 l of acetone (or dioxan) and cooled to 5° C. 410 ml of 1N sodium hydroxide solution are added in such a manner that the temperature rises to about 13° C. The mixture is stirred at room temperature for 17 h. The reaction mixture is then made slightly acidic (pH 6) with 3N hydrochloric acid and concentrated in a vacuum. The crystalline precipitate is filtered off, washed and dried. There are obtained 65 g of crude 5H-[1,2,4]triazolo[1,5-d][1,4]benzodiazepin-6(7H)-one. The filtrate is saturated with sodium chloride and extracted 3 times with 0.51 of dichloromethane each time. The organic phases are evaporated in a vacuum. 12 g of crude 5H-[1,2,4]triazolo[1,5-d][1,4]benzodiazepin-6(7H)-one are obtained. Both crude crystallizates (77 g) are dissolved together in 5 l of dichloromethane and 250 ml of ethanol at reflux temperature. A small insoluble constituent is separated by filtration, the filtrate is cooled to room temperature and filtered through a column of 1500 g of silica gel. The column is rinsed with a mixture of 5.7 l of dichloromethane and 0.3 l of ethanol. After concentrating all eluates, there are obtained 62 g of yellow crystals. These are stirred at reflux temperature as a suspension in 600 ml of ethyl acetate and then cooled to 0° C. The crystals are filtered off, washed with diethyl ether and dried. There are obtained 51 g of 5H-[1,2,4]triazolo[1,5-d][1,4]benzodiazepin-6(7H)-one of m.p. 223°-223° C.
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[CH3:11][Si:12](Br)([CH3:14])[CH3:13].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:11][Si:12]([CH3:14])([CH3:13])[NH:4][C:3]1[C:5]([Cl:10])=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=1[Cl:1]
Reactant: C[Si](C)(C)Br
Reactant: Cc1ccc(Cl)c(N)c1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1ccc(Cl)c(N[Si](C)(C)C)c1Cl
Yield: 73.6 %

Procedure:
A solution of 50 ml of benzene, 4.0 g (22.7 mmole) of 2,6-dichloro-3-methylaniline, 10.67 ml (80.8 mmole) of trimethylsilyl bromide, and 13.1 ml (94.0 mmole) of triethylamine was heated at reflux over 42 hours. The product was isolated as described in Example 1 to provide 4.14 g (16.7 mmole, 73.5 percent yield) of 98.0 percent pure N-trimethylsilyl-2,6-dichloro-3-methylaniline as a light yellow oil, b.p. 64°-68° C. at 0.03 mm.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]([C:17](O)=[O:18])[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][C:9]=2[O:20][CH3:21].C(Cl)(=O)C([Cl:25])=O.CN(C=O)C>ClCCl>[F:1][CH2:2][CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]([C:17]([Cl:25])=[O:18])[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][C:9]=2[O:20][CH3:21]
Reactant: COc1cccc2c1c1c(n2CCF)CCCC1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc2c1c1c(n2CCF)CCCC1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A solution of 9-(2-Fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid (17) (347 mg, 1.2 mmol) in dry dichloromethane (2 mL) was stirred under nitrogen. Oxalyl chloride (453 mg, 3.6 mmol, 300 μL) was added followed by a drop of DMF. The reaction mixture was stirred at RT under nitrogen for 2 h then evaporated in vacuo to give 371 mg (quantitative) of 9-(2-fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carbonyl chloride as a gum which was used in the next step without purification. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 20.2, 21.7, 26.4, 43.3 (d, JCF=23 Hz), 54.9, 80.5, 83.1, 100.2, 102.2, 105.8, 116.7, 122.4, 135.5, 137.4, 153.5, and 176.6.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:12])[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:12])[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)(=[O:15])[CH3:14]
Reactant: Nc1cc2cccnc2c(Br)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc2cccnc2c(Br)n1
Temperature: 0 °C

Procedure:
Suspended in 32 ml of pyridine was 4.84 g of 6-amino-8-bromo-1,7-naphthyridine, followed by an addition of 66 ml of acetic anhydride. The resultant mixture was stirred at room temperature for 4 hours. After the reaction, the reaction mixture was poured in 500 ml of ice water and crystals, which precipitated out, were collected by filtration and then washed thoroughly with water. They were recrystallized from methanol to obtain 5.37 g of 6-acetamido-8-bromo-1,7-naphthyridine as colorless needle-like crystals (yield: 93.4%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:17]1([NH2:26])[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[N:17]1([NH:26][C:14]([C:11]2[CH:10]=[N:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:13][CH:12]=2)=[O:15])[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1
Reactant: O=C(Cl)c1cnc(-c2cccc(F)c2)nc1
Reactant: Nn1ccc2ncccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nn1ccc2ncccc21)c1cnc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid chloride (0.45 mmol) in EtOAc (8 mL) is added to a stirred solution of pyrrolo[3,2-b]pyridin-1-ylamine (0.45 mmol) and K2CO3 (0.45 mmol) in EtOAc (4 mL) and H2O (8 mL) at rt, and the reaction mixture is stirred at rt for 30 min. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid pyrrolo[3,2-b]pyridin-1-ylamide (116 mg, 77%) as a solid. MS: 334 (M+H); 1H NMR (300 MHz, CDCl3): δ 6.60 (d, H) 7.15-7.60 (m, 4H), 8.01 (m, H), 8.10-8.41 (m, 3H), 9.27 (s, 2H), 12.45 (br, N—H). IC50=18 nM.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=12.C1C[O:21][CH2:20]C1>>[C:1]1([CH:20]=[O:21])[S:2][CH:3]=[C:4]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=12
Reactant: c1ccc2c(c1)c1ccccc1c1cscc21
Reactant: C1CCOC1
Product: O=Cc1scc2c3ccccc3c3ccccc3c12
Yield: 85.9 %

Procedure:
Phenanthro[9,10-c]thiophene (H. G. Pars Pharmaceutical Laboratories, Inc.) was formylated using the procedure of A. Rieche et al., Chem. Ber. 93, 88 (1960) to give a 85.9% yield of phenanthro[9,10-c]thiophene-1-carbaldehyde, mp 198°-199°, (C,H,S), (THF/95% EtOH).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH:14]1([CH2:19][NH:20][CH2:21][CH3:22])[CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[CH:14]1([CH2:19][N:20]([CH2:21][CH3:22])[C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: CCNCC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC1CCCC1)c1ccc(C(F)(F)F)cc1C=O
Temperature: 25 °C
Yield: 71.5 %

Procedure:
To a solution of 2-fluoro-5-(trifluoromethyl)benzaldehyde (3.00 g, 15.6 mmol) in toluene (60 mL) was added N-(cyclopentylmethyl)-N-ethylamine (2.70 g, 21.2 mmol) synthesized by the method described in International Patent Publication WO2006/073973 and potassium carbonate (6.50 g, 47.0 mmol), and the mixture was refluxed by heating for 68 hours. The reaction mixture was cooled to room temperature, then added with water, and extracted with chloroform. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 2-[(cyclopentylmethyl)(ethyl)amino]-5-(trifluoromethyl)benzaldehyde (3.34 g, 71%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[C:22]1([CH:28]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:29][CH2:30][C:31](O)=[O:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:34]1([CH:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:29][CH2:30][C:31]([N:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:2]3([CH3:1])[CH2:6][C:5]4[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=4[O:3]3)[CH2:17][CH2:18]2)=[O:32])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(O)CCC(c1ccccc1)c1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCN(C(=O)CCC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 29 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and 4,4-diphenylbutyric acid, the procedure of Example 10 was otherwise repeated to provide the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([CH:8]=[C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:21]O.OS(O)(=O)=O>C1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])=[CH:19][CH:20]=1)([O:3][CH3:21])=[O:2]
Reactant: O=C1Nc2ncccc2C1=Cc1ccc(C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(C=C2C(=O)Nc3ncccc32)cc1
Yield: 90 %

Procedure:
A solution of 3-(4-carboxybenzylidene)-7-azaoxindole (2.663 g, 10 mmol), methanol (3.2 g, 0.1 mol) and H2SO4 95% (1 g) in benzene (100 ml) was heated in a Soxhlet apparatus for 10 h. To dry the distillate continuously, the cap of the Soxhlet contained anhydrous MgSO4. After cooling, water was added, the organic phase repeatedly washed with water and then evaporated under vacuum. Thus almost pure title compound was obtained in about 90% yield.