Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1C=CC(B2OC(C)(C)C(C)(C)O2)=C(NC(=O)OC(C)(C)C)C=1.[CH:25]1[C:34]2[C:29](=[C:30]([NH2:39])[N:31]=[C:32]3[CH:38]=[CH:37][CH:36]=[CH:35][C:33]3=2)[N:28]=[CH:27][CH:26]=1.[C:40](=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO>[CH3:40][C:37]1[CH:36]=[CH:35][C:33]2=[C:34]3[C:29](=[C:30]([NH2:39])[N:31]=[C:32]2[CH:38]=1)[N:28]=[CH:27][C:26]([CH:1]=[CH2:2])=[CH:25]3
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Reactant: Nc1nc2ccccc2c2cccnc12
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCO
Product: C=Cc1cnc2c(N)nc3cc(C)ccc3c2c1
Temperature: 25 °C

Procedure:
A solution of tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from Example 5/step 2) (1.0 eq.) and 3-chloro-5-vinylpicolinonitrile (from Example 29/Step 1) (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.03 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction content was diluted with methanol. The insoluble solids were filtered off, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 8-methyl-2-vinylbenzo[f][1,7]naphthyridin-5-amine as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH3:12])[CH2:5][C:6]2=[O:11].[Cu][C:14]#[N:15]>CN(C=O)C.O.Cl.C1(C)C=CC=CC=1.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[C:14]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH3:12])[CH2:5][C:6]2=[O:11])#[N:15]
Reactant: CC1CC(=O)c2cccc(Br)c21
Reactant: N#C[Cu]
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1CC(=O)c2cccc(C#N)c21
Reaction time: 6 h

Procedure:
A mixture of 2.6 g (11.5 mmol) of 4-bromo-3-methyl-1-indanone [J. Org. Chem. 22, 1019 (1957)] and 1.14 g (12.7 mmol) of copper(I) cyanide in 2.5 ml of DMF is stirred for 6 hours at 170°. The reaction mixture is then cooled to 100°, and 50 ml of toluene and a solution of 4.5 g (16.5 mmol) of iron(III) chloride hexahydrate in 7 ml of water and 1.7 ml of concentrated hydrochloric acid are added in succession thereto. The reaction mixture is stirred for 20 minutes at 70°, cooled and diluted with toluene and water. The organic phase is separated off, washed with water, a semi-saturated sodium hydrogen carbonate solution and again with water, dried and concentrated by evaporation. The residue is distilled at 100°-120°/0.05 mbar in a bulb tube still and corresponds to starting compound (a), m.p. 109°-111°; IR (CH2Cl2): 2220, 1710 cm-1 ; 1H-NMR (CDCl3): δ=7.92 (m,2H); 7.52 (t,1H); 3.73 (m,1H); 3.03 (q,1H); 2.40 (q,1H); 1.55 (d,3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH:4]=[CH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=4)=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.[H][H]>CO.ClCCl.[Pd]>[CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=4)=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1
Reactant: COC(=O)C=Cc1ccc2c(-c3c(-c4cccc(C)n4)nn4ccccc34)ccnc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCc1ccc2c(-c3c(-c4cccc(C)n4)nn4ccccc34)ccnc2c1
Reaction time: 0.25 h
Yield: 58.1 %

Procedure:
Add Pd/C (10%, 0.46 g) to a solution of 3-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-acrylic acid methyl ester (0.462 g, 1.1 mmol) in MeOH (10 mL) and dichloromethane (10 mL). Bubble nitrogen for 15 minutes. Connect the hydrogen balloon to the reaction flask and stir overnight. Filter through celite and wash the celite pad with dichloromethane (50 mL). Remove the solvent. Chromatograph the residue (elute with 2% MeOH in dichloromethane) to give the desired product as a pale yellow solid 0.27 g (59%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])(=O)=O)=CC=1.O.[NH2:20][NH2:21].[CH3:22][C:23]([CH3:30])([CH3:29])[C:24](=O)[CH2:25][C:26]#[N:27]>CCO>[C:23]([C:24]1[CH:25]=[C:26]([NH2:27])[N:21]([CH2:12][CH2:13][CH2:14][C:15]([F:16])([F:17])[F:18])[N:20]=1)([CH3:30])([CH3:29])[CH3:22]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Cc1ccc(S(=O)(=O)OCCCC(F)(F)F)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(CCCC(F)(F)F)n1
Temperature: 85 °C
Reaction time: 20 h
Yield: 45.8 %

Procedure:
To a solution of Example 135A (5 g, 17.7 mmol) in EtOH (50 mL) was added hydrazine hydrate (1.1 mL, 23.0 mmol). The mixture was warmed to reflux (85° C.) and was allowed to stir for 20 hours. The mixture was cooled to ambient temperature then 4,4-dimethyl-3-oxopentanenitrile (2.9 g, 23.0 mmol) was added and the mixture was again warmed to reflux (85° C.) and stirred for 6 hours. After cooling to ambient temperature, the mixture was concentrated under reduced pressure and the residue was dissolved in CH2Cl2 (100 mL) and saturated aqueous NaHCO3 (50 mL) was added slowly. The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 50% hexanes in EtOAc to 100% EtOAc to 9:1:0.1 EtOAc:MeOH:Et3N) afforded the title compound (2.0 g, 8.1 mmol, 46% yield). MS (ESI+) m/z 250 (M+H)+.
Reaction SMILES: CC1N=CC=CC=1C(N)=O.[C:11]([C:15]1[N:20]=[C:19]([CH3:21])[C:18]([CH:22]([NH2:24])[CH3:23])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[F:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[CH:32][N:31]([CH2:34][C:35](O)=[O:36])[C:30]=2[C:38]=1[F:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[C:11]([C:15]1[N:20]=[C:19]([CH3:21])[C:18]([CH:22]([NH:24][C:35](=[O:36])[CH2:34][N:31]2[C:30]3[C:38]([F:39])=[C:26]([F:25])[CH:27]=[CH:28][C:29]=3[N:33]=[CH:32]2)[CH3:23])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: Cc1nc(C(C)(C)C)ccc1C(C)N
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ncccc1C(N)=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(C)(C)C)ccc1C(C)NC(=O)Cn1cnc2ccc(F)c(F)c21

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of 2-methylnicotinamide, starting from [1-(6-tert-butyl-2-methylpyridin-3-yl)ethyl]amine (intermediate 32) (31.5 mg, 0.16 mmol), 6,7-diflurobenzimidazole-1-acetic acid (35 mg 0.16 mmol) HATU (38 mg, 0.18 mmol) and DIPEA (71 μl, 0.41 mmol). Water was added and the reaction concentrated. The mixture was partitioned between ethyl acetate and water, and extracted 3 more times with ethyl acetate. The product was then purified by silica gel flash chromatography with acetone/hexanes (Yield 25 mg, 40%). 1H NMR (400 MHz, CD3OD-D4) d ppm 1.32 (s, 9 H), 1.47 (d, J=7.03 Hz, 3 H), 2.53-2.57 (m, 3 H), 5.04-5.15 (m, 2 H), 5.15-5.22 (m, 1 H), 7.16 (ddd, J=11.43, 8.79, 7.52 Hz, 1 H), 7.28 (d, J=8.20 Hz, 1 H), 7.41 (dd, J=8.89, 3.61 Hz, 1 H), 7.68 (d, J=8.20 Hz, 1 H), 8.11 (s, 1 H) MS [MH+] calc. 387.1996 found 387.3.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][CH:13]([C:18]2[CH:23]=[CH:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH:19]=2)[C:14]([O:16]C)=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:33][C:34]1[CH:35]=[N:36][C:37](I)=[N:38][CH:39]=1.C([O-])(O)=O.[Na+].CC(O)=O>C1COCC1.CC#N>[Br:33][C:34]1[CH:35]=[N:36][C:37]([C:21]2[CH:20]=[CH:19][C:18]([CH:13]([NH:12][C:10]([C:8]3[S:9][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=3)=[O:11])[C:14]([OH:16])=[O:15])=[CH:23][CH:22]=2)=[N:38][CH:39]=1
Reactant: COC(=O)C(NC(=O)c1ccc(C(C)(C)C)s1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1cnc(I)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)NC(C(=O)O)c2ccc(-c3ncc(Br)cn3)cc2)s1
Temperature: 120 °C
Yield: 47.5 %

Procedure:
Prepared using General Procedure 10. A mixture of methyl 2-(5-(tert-butyl)thiophene-2-carboxamido)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (320 mg, 0.71 mmol) and 5-bromo-2-iodopyrimidine (220 mg, 0.78 mmol) in THF (2 mL) and MeCN (2 mL) was treated with saturated aq. NaHCO3 (1600 μl, 1.40 mmol) and de-gassed (N2 bubbling). PdCl2dppf (26 mg, 0.04 mmol) was added and the mixture was heated at 120° C. for 30 min in a microwave reactor. The mixture was poured onto H2O (30 mL), acidified with AcOH and extracted with EA (3×15 mL). The combined organics were dried over MgSO4, evaporated, and purified by chromatography (EA/hexane with 1% AcOH) to provide 160 mg (46%) of 2-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)acetic acid as a white solid. LCMS-ESI (m/z) calculated for C21H20BrN3O3S: 473.0. found 474.0 [M+H]+, tR=2.68 min (Method 8).
Reaction SMILES: [Na+].[C:2]1([CH:8]([N:10]2[C:14]([C:15]([O-:17])=[O:16])=[CH:13][N:12]=[CH:11]2)[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CN(C)P(=O)(N(C)C)N(C)C>O>[C:2]1([CH:8]([N:10]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[CH:11]2)[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(c1ccccc1)n1cncc1C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CC(c1ccccc1)n1cncc1C(=O)O
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 14.3 parts of (-)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid sodium salt, 1.9 parts of a 61.8% suspension of sodium hydride in mineral oil and 60 parts of hexamethylphosphoric triamide is stirred for 20 hours at 100° C. under Argon atmosphere. The mixture is allowed to cool to room temperature and poured onto 150 parts of water. The whole is washed three times with 200 parts of dichloromethane. The aqueous phase is neutralized (pH 7) with acetic acid and the product is allowed to crystallize. The product is filtered off, dried and recrystallized from ethanol, yielding (±)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid; m.p. 188° C.
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([OH:37])[C:5]=2[N:4]=1.Br[CH2:40][CH2:41][CH2:42][OH:43].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:38][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH2:40][CH2:41][CH2:42][OH:43])[C:5]=2[N:4]=1
Reactant: OCCCBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(O)cccc43)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OCCCO)cccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A mixture of 0.60 g (1.1 mmol) of tert-butyl 4-[4-[2-(difluoromethyl)-4-hydroxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperazine-1-carboxylate, 0.47 g (3.3 mmol) of 3-bromo-1-propanol, and 0.80 g (5.5 mmol) of powdered K2CO3 in 20 mL dry DMF was stirred at room temperature for 8 hrs. Dilution with water gave 0.66 g, (99% yield) of tert-butyl 4-[4-[2-(difluoromethyl)-4-(3-hydroxypropoxy)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate: 1H NMR (CDCl3) δ 7.94 (dd, J=8.4. 0.7 Hz, 1H), 7.49 (t, JHF=53.4 Hz, 1H), 7.34 (t, J=8.1 Hz, 1H), 6.92 (dd, J=8.0, 0.6 Hz, 1H), 4.47 (t, J=5.9 Hz, 2H), 3.98 (t, J=5.4 Hz, 2H), 3.87 (m, 8H), 3.79 (m, 4H), 3.54 (m, 4H), 3.30 (m, exchangeable with D2O, 1H), 2.14 (pentet, J=5.8 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C=CC=CC=1.[Br:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[CH3:36].C1C(=O)N([Br:44])C(=O)C1>CCOC(C)=O>[Br:25][C:26]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:27]=1[CH2:36][Br:44]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(F)(F)F)cc1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: FC(F)(F)c1ccc(CBr)c(Br)c1

Procedure:
Solid benzoyl peroxide (1.5 g, 6.3 mmol) was added to a benzene solution (200 mL) of 2-bromo-1-methyl-4-(trifluoromethyl)benzene (10.0 g, 41.8 mmol) and NBS (8.2 g, 46.0 mmol) and the resulting mixture was refluxed. After 16 h the resulting mixture was cooled, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]1[CH2:14][CH2:13][N:12]([C@H:15]2[CH2:32][C@@:31]3([CH3:33])[C@@H:18]([CH2:19][CH2:20][C@@H:21]4[C@@H:30]3[CH2:29][CH2:28][C@@:26]3([CH3:27])[C@H:22]4[CH2:23][C@H:24]([N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[C@@H:25]3[OH:34])[CH2:17][C@@H:16]2[OH:40])[CH2:11][CH2:10]1.[C:41](Cl)(=[O:43])[CH3:42].[OH2:45]>C(Cl)Cl>[C:41]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C@H:15]2[CH2:32][C@@:31]3([CH3:33])[C@@H:18]([CH2:19][CH2:20][C@@H:21]4[C@@H:30]3[CH2:29][CH2:28][C@@:26]3([CH3:27])[C@H:22]4[CH2:23][C@H:24]([N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[C@@H:25]3[OH:34])[CH2:17][C@@H:16]2[OH:40])[CH2:11][CH2:10]1)(=[O:43])[CH3:42].[CH3:42][C:41]([CH2:26][C:25]([OH:34])=[O:45])=[O:43]
Reactant: CC(=O)Cl
Reactant: O
Reactant: C[C@]12C[C@H](N3CCC(O)CC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)O
Product: CC(=O)OC1CCN([C@H]2C[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](O)[C@@H](N5CCCC5)C[C@@H]43)C[C@@H]2O)CC1
Temperature: 25 °C
Yield: 71.9 %

Procedure:
After adding 7.9 g of triethylamine to a solution containing 9 g of 2β-(4-hydroxy-1-piperidinyl)-16β-(1-pyrrolidinyl)-5α-androstane-3α,17β-diol in 80 ml of methylene chloride, 9 g of acetyl chloride are dropwise added to the solution at a temperature of 0° C. under cooling and stirring. After termination of the addition, the reaction mixture is maintained at room temperature for 24 hours. After completion of the reaction the excess of acetyl chloride is decomposed by water, the methylene chloride solution is washed with aqueous sodium hydroxide solution until it becomes acid-free, then washed with water several times until neutral. After drying the methylene chloride solution and evaporating, the residue is purified on a silica gel column to yield 8.3 g (71.9%) of the title compound, Rf1 =0.36.
Reaction SMILES: [CH3:1][C:2](/[CH:8]=[CH:9]\[CH2:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:3][C:4]([O:6]C)=[O:5].CO.[OH-].[Na+]>O>[CH3:1][C:2](/[CH:8]=[CH:9]\[CH2:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)C=C(C)/C=C\CC(C)CCCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=CC(=O)O)/C=C\CC(C)CCCC(C)C

Procedure:
A mixture of 1 g. of trans/cis methyl 3,7,11-trimethyldodeca-2,4-dienoate, 60 ml. of methanol, 0.5 g. of sodium hydroxide and 6 ml. of water is stirred at about 30° for about 56 hours. The mixture is then diluted with water, neutralized and extracted with ether. The organic phase is washed with water, dried over sodium sulfate and evaporated to yield trans/cis 3,7,11-trimethyldodeca-2,4-dienoic acid.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]2=[O:22])=[N:6][C:5]=1[CH3:23])(=O)[CH3:2].COC(OC)[N:27]([CH3:29])C.O.[NH2:33]N>CN(C)C=O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:9]([C:7]3[S:8][C:4]([C:1]4[CH:2]=[CH:29][NH:27][N:33]=4)=[C:5]([CH3:23])[N:6]=3)[C:10]2=[O:22])=[CH:16][CH:17]=1
Reactant: CC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C
Reactant: NN
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1-c1cc[nH]n1
Temperature: 110 °C
Yield: 61 %

Procedure:
To a solution of 1-(5-acetyl-4-methylthiazol-2-yl)-3-(4-fluorobenzyl)-imidazolidin-2-one (0.33 g, 1.00 mmol) in N,N-dimethylformamide (10 mL) was added N,N-dimethylformamide dimethyl acetal (0.25 mL, 1.88 mmol). The reaction mixture was heated for 7 hours at 110° C., followed by the addition of hydrazine monohydrate (0.30 mL, 6.18 mmol). The reaction mixture was heated for another 10 minutes at 110° C., and concentrated in vacuo. The residue was washed with water and triturated with ethyl acetate to afford the title compound in 61% yield (0.22 g): mp 239-242° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 12.90 (br s, 1H), 7.76 (br s, 1H), 7.35-7.31 (m, 2H), 7.19-7.13 (m, 2H), 6.42 (d, J=2.1 Hz, 1H), 4.39 (s, 2H), 3.98-3.93 (m, 2H), 3.44-3.38 (m, 2H), 2.36 (s, 3H), 2.24 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 163.6, 160.4, 155.7, 144.0, 142.5, 133.2, 130.4, 118.1, 116.0, 115.7, 103.2, 46.6, 42.4, 42.0, 16.9; MS (ES+) m/z 358.2 (M+1).
Reaction SMILES: O[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([O:10]CC)=[O:9].P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnn(C)c1O
Product: Cn1ncc(C(=O)O)c1Cl
Reaction time: 65 h

Procedure:
A mixture of 10 g of ethyl 5-hydroxy-1-methyl-4-pyrazole carboxylate and 50 ml of phosphorus oxychloride was stirred at 90° to 100° C. for 65 hours. Excessive phosphorus oxychloride was evaporated under reduced pressure, and the residue was poured into ice-water. The precipitated crystals were filtered and dried to obtain 4.5 g of 5-chloro-1-methyl-4-pyrazole carboxylic acid. The filtrate was neutralized with aqueous ammonia (28%) and extracted with ether. After drying of the extract, evaporation of the solvent gave 4.0 g of ethyl 5-chloro-1-methyl-4-pyrazole carboxylate. To 5-chloro-1-methyl-4-pyrazole carboxylic acid were added 30 ml of thionyl chloride and 0.2 ml of dimethylformamide, and the mixture was refluxed for 5 hours. Then, excessive thionyl chloride was evaporated and the residue was added to dry ethanol. After stirring at room temperature for 3 hours, the solvent was evaporated and ether was added to the residue. After washing with water, drying and evaporation of the solvent, there was obtained 4.5 g of ethyl 5-chloro-1-methyl-4-pyrazole carboxylate as an oil. Total of the title compound: 8.5 g.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[Br:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.CO>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[Br:10][C:11]1[CH:16]=[C:15]([N:1]2[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]2=[O:3])[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: OB(O)c1cccc(Br)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: O
Product: Cc1cn(-c2cccc(Br)c2)c(=O)[nH]c1=O
Reaction time: 48 h

Procedure:
A 500 mL round bottom flask was charged with thymine (0.314 g, 2.49 mmol), 3-bromophenylboronic acid (1.00 g, 4.98 mmol), tetramethylethyldiamine (0.75 mL, 4.98 mmol), copper(II) acetate monohydrate (0.497 g, 2.49 mmol), methanol (200 mL), and H2O (50 mL). The blue reaction mixture was stirred for 48 h, concentrated and purified by CombiFlash (0 to 8% MeOH/CH2Cl2) to give desired product. LCMS-ESI+: calc'd for C11H9BrN2O2: 281.0 (M+H+); Found: 281.1 (M+H+).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:14]=O.[C:16]1([CH:22]=[CH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.C(O)(=O)C>[C:1]1([N:7]2[CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:14][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: C=Cc1ccccc1
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(C2CCNN2c2ccccc2)cc1
Reaction time: 2 h
Yield: 60.6 %

Procedure:
Phenylhydrazine (108.14 g, 1 mole) is added dropwise to a cooled (4°-8° C.) and stirred mixture of concentrated sulfuric acid (147 g, 1.5 moles), glacial acetic acid (200 ml) and water (25 ml). Paraformaldehyde (30.03 g, 1 mole) and phenylethylene (104.1 g, 1 mole) are added simultaneously during 1 hr at 25° C. and stirring is continued for 2 hr at 30° C. Water (500 ml) is added and the aqueous dark solution is washed with benzene. The aqueous layer is basified with 50% sodium hydroxide and extracted with benzene. The organic extracts are combined, dried over magnesium sulfate and evaporated. The residue is distilled at 170° C. 0.6 torr to give a distillate of the title compound (135.9 g). The title compound is dissolved in diethyl ether and dry hydrogen chloride is added. The precipitate is collected and crystallized from methanol-diethyl ether to obtain the hydrochloride salt of the title compound, mp 212°-214° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17].C(N(CC)CC)C>C(O)CCC>[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1
Reactant: NCCCCN
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: NCCCCNc1nc(Cl)nc2[nH]ccc12
Yield: 49.6 %

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.53 mmol), 1,4-diaminobutane (0.125 mL, 1.25 mmol) and triethylamine (0.150 mL, 1.08 mmol) in nBuOH (4 mL) was stirred at 70° C. for 4 h. It was then purified by HPLC to give N-(4-aminobutyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a solid (63 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][C:12]([F:22])=[C:13]([NH:18][CH:19]4[CH2:21][CH2:20]4)[CH:14]=3)[C:9]2=[O:23])=[CH:4][CH:3]=1.C([O:26][C:27](=O)[NH:28][S:29]([C:32]1[S:33][C:34]([Cl:37])=[CH:35][CH:36]=1)(=[O:31])=[O:30])C>C1(C)C=CC=CC=1>[Cl:37][C:34]1[S:33][C:32]([S:29]([NH:28][C:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][C:12]([F:22])=[C:13]([NH:18][CH:19]5[CH2:21][CH2:20]5)[CH:14]=4)[C:9]3=[O:23])=[CH:4][CH:3]=2)=[O:26])(=[O:31])=[O:30])=[CH:36][CH:35]=1
Reactant: Nc1ccc(-n2ccc3cc(NC4CC4)c(F)cc3c2=O)cc1
Reactant: CCOC(=O)NS(=O)(=O)c1ccc(Cl)s1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(-n2ccc3cc(NC4CC4)c(F)cc3c2=O)cc1)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 110 °C
Yield: 43.7 %

Procedure:
A mixture of 2-(4-Amino-phenyl)-6-cyclopropylamino-7-fluoro-2H-isoquinolin-1-one (Example 11) (23 mg, 0.073 mmol) and (5-Chloro-thiophene-2-sulfonyl)-carbamic acid ethyl ester (Example 12) (28 mg, 0.10 mmol, 1.35 eq) in dry toluene (1.5 mL) was heated at 110° C. for 2 hr. Upon cooling, the reaction was concentrated in vacuo and the crude residue was purified by HPLC (C-18) to give 17 mg (46%) of pure 5-chloro-N-[({4-[6-(cyclopropylamino)-7-fluoro-1-oxoisoquinolin-2(1H)-yl]phenyl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+=533, 535 (Cl).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][C:28]=1[Br:35])[C:9]1[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:10]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)(C)(C)C.[ClH:37].O1CCOCC1>C(#N)C>[ClH:37].[NH2:7][CH:8]([C:9]1[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:10]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=1)[C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][C:28]=1[Br:35]
Reactant: CC(C)(C)OC(=O)NC(C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O)c1ccc(C#N)cc1Br
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: N#Cc1ccc(C(N)C2=C(Nc3cccc(C(F)(F)F)c3)CCCC2=O)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
{(2-Bromo-4-cyano-phenyl)-[6-oxo-2-(3-trifluoromethyl-phenylamino)-cyclohex-1-enyl]-methyl}-carbamic acid tert-butyl ester (INTERMEDIATE 20, 20.8 g, 36.9 mmol) is suspended in acetonitrile (150 mL) and a solution of hydrogen chloride in 1,4-dioxane (4 M, 46.1 mL, 184.3 mmol) is added. The mixture is stirred at room temperature for 3 h. The product precipitates from the reaction mixture. The precipitate is filtered off, washed with acetonitrile and dried. Yield: 16.5 g ESI mass spectrum: [M+H]+=464 (bromine isotope pattern), Retention time HPLC: 0.56 min, (X012_S02).