Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:22](=O)[NH2:23])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH2:22][NH2:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C(N)=O)c2ccccc2Cl)CC1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2Cl)CC1
Yield: 41.7 %

Procedure:
To 4-[Carbamoyl-(2-chloro-phenyl)-methyl]-piperazine-1-carboxylic acid tert-butyl ester 462(0.45 g, 1.27 mmol) in THF (10 mL) at 0° C. was added 1.0M BH3 in THF (5.1 mL). The reaction was allowed to stir at reflux for 18 h. MeOH (5.0 mL) was added to the reaction mixture and mixture was then concentrated to dryness. The resulting residue was taken up in MeOH (10 mL) and allowed to reflux for 1 h. The reaction mixture was concentrated to dryness and the resulting residue was taken up in EtOAc (30 mL) and washed with sat. NaHCO3 (30 mL) and brine (30 mL). The organic phase was concentrated to dryness yielding 0.18 g (43%) product.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9](O)=[O:10])=[O:5].CC(C)C([SiH2][O:35][NH2:36])(C)C>>[Cl:1][C:2]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([NH:36][OH:35])=[O:10])=[O:5]
Reactant: CC(C)C(C)(C)[SiH2]ON
Reactant: Cc1ccc(C(=O)O)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Product: Cc1ccc(C(=O)NO)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
Compound 424 (202 mg, 0.50 mmol) and O-[(dimethyl-t-butyl)silyl]-hydroxylamine (148 mg, 1.01 mmol) were treated as described for compound 337. Flash chromatography (ethyl acetate/petroleum ether: graduated from 67/33 to 100/0) provided the title compound. 13C NMR (DMSO-d6) δ 194.6, 162.9, 158.8 (dd), 155.8 (dd), 149.4, 139.5, 139.1, 133.6, 131.1, 130.3, 128.7, 127.0, 126.5 (m), 126.4, 124.1 (dd), 114.8, 111.9 (dd), 111.8, 105.0 (dd), 19.6
Reaction SMILES: CN(C)C=O.N(OC(C)(C)C)=O.Cl.N[C:15]1[CH:16]=[C:17]([CH:40]=[CH:41][C:42]=1[N:43]1[CH:47]=[N:46][CH:45]=[N:44]1)[C:18]([NH:20][C:21]1[C:26]([CH3:27])=[CH:25][C:24]([C:28]([F:37])([C:33]([F:36])([F:35])[F:34])[C:29]([F:32])([F:31])[F:30])=[CH:23][C:22]=1[CH2:38][CH3:39])=[O:19]>O>[CH2:38]([C:22]1[CH:23]=[C:24]([C:28]([F:37])([C:33]([F:34])([F:35])[F:36])[C:29]([F:31])([F:32])[F:30])[CH:25]=[C:26]([CH3:27])[C:21]=1[NH:20][C:18](=[O:19])[C:17]1[CH:40]=[CH:41][C:42]([N:43]2[CH:47]=[N:46][CH:45]=[N:44]2)=[CH:15][CH:16]=1)[CH3:39]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(-n2cncn2)c(N)c1
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(-n2cncn2)cc1
Temperature: 65 °C
Yield: 64 %

Procedure:
N,N-dimethylformamide (3 ml) was heated to 65° C. and added with tert-butyl nitrite (0.15 g). To the solution, an N,N-dimethylformamide solution (2 ml) in which 3-amino-N-[2-ethyl-4-(1,1,1,2,3, 3,3-heptafluoropropan-2-yl)-6-methylphenyl]-4-(1H-1,2,4-triazol-1-yl) benzamide (0.5 g) has been dissolved was slowly added dropwise, while maintaining the temperature of 65° C. After confirming that no more gas is generated, the mixture was adjusted to room temperature and added with a mixture including 2N hydrochloric acid and a small amount of ice. The mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with 2N hydrochloric acid, and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-4-(1H-1,2,4-triazol-1-yl)benzamide (0.31 g, yield 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([CH3:25])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N=C=NN=NN=C=NCC)C.S(=O)(=O)(O)O.[OH-].[Na+].CC1(C)[O:70][CH2:69][CH:68]([CH2:71]O)[CH2:67][O:66]1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:71][CH:68]([CH2:69][OH:70])[CH2:67][OH:66])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([CH3:25])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Reactant: CC1(C)OCC(CO)CO1
Agent: CCN=C=NN=NN=C=NCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCC(CO)CO
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.8 %

Procedure:
6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (50 mg) and triphenylphosphine (158 mg) were dissolved in tetrahydrofuran (1 ml) to prepare a solution. A solution of diethylazocarbodiimide (105 mg) in (2,2-dimethyl[1,3]dioxan-5-yl)-methanol (27 mg) and tetrahydrofuran (0.2 ml) was added to the solution, and the mixture was stirred at room temperature for 5 hr. A 1 N aqueous sulfuric acid solution (1 ml) was then added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was made alkaline by the addition of 1 N sodium hydroxide, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (29 mg, yield 45%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[OH:13][CH2:14][CH:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[C:25]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:40])([F:39])[F:38])[NH:26][C:27]3=[O:30])=[CH:22][CH:21]=2)[C:16]1=[O:41].[Cl-].[NH4+]>ClCCl>[O:41]=[C:16]1[CH:15]([CH2:14][O:13][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:19][CH2:18][N:17]1[C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[C:25]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:38])[F:39])[NH:26][C:27]2=[O:30])=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1C(CO)CCN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C1=O
Temperature: -20 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
Methanesulfonyl chloride (0.023 ml, 0.299 mmol) and triethylamine (0.03 ml, 0.299 mmol) were added at −20° C. to a dichloromethane solution (2 ml) that contained the 7-(3-hydroxymethyl-2-oxopyrrolidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (80 mg, 199 mmol) obtained in Example 1-46. The obtained mixture was stirred at −20° C. for 2 hours. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=30:1->20:1), so as to obtain methanesulfonic acid 2-oxo-1-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]-pyrrolidin-3-ylmethyl ester (38 mg, 40%) in the form of a colorless oil substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[I:8].C([O-])(O)=O.[Na+].[Na+].[Br-].CC1(C)N([O])C(C)(C)CCC1.[O-]Cl.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O.CCCCCCC.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[I:8])[CH:9]=[O:10]
Reactant: OCc1ccc(I)c(Br)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=Cc1ccc(I)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
A solution of (3-bromo-4-iodophenyl)methanol (Preparation 24, 3.1 g, 9.9 mmol) in CH2Cl2/water (2:1, 225 mL) was treated with NaHCO3 (915 mg, 10.9 mmol), NaBr (1060 mg, 10.2 mmol) and TEMPO free radical (40 mg, 0.2 mmol). The resulting mixture was cooled to 0° C. and NaOCl solution (0.8 mL, 10% aqueous) was added dropwise. The reaction mixture was left to come to room temperature while stirring. TLC after 30 minutes showed approximately 50% conversion to less polar spot. Sequence repeated using same equivalent of reagents. TLC 25:75 EtOAc:heptane still showed unreacted starting material. The reaction mixture was separated and the organic phase was treated with 1.0× Dess-Martin periodinane (2.1 g, 4.9 mmol) while stirring. TLC after 10 minutes showed complete conversion to less polar spot. The organic phase was washed with sat NaHCO3, dried over Na2SO4, filtered and evaporated to give an orange solid. The crude material was chromatographed (80 g Redi-Sep column) eluting from 100% heptane to 50:50 EtOAc/heptane to give the intermediate (2.7 g, 87%) as a white solid. 1HNMR (CDCl3): 9.94 (1H), 8.10 (2H), 7.50 (1H).
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[N:11]=[CH:12][C:13]3[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:14]=3[N:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH:22]([CH2:24][CH3:25])[CH3:23]>CN(C)C=O>[CH:22]([N:16]1[C:14]2[N:15]=[C:10]([NH:9][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:11]=[CH:12][C:13]=2[CH:19]=[CH:18][C:17]1=[O:20])([CH2:24][CH3:25])[CH3:23]
Reactant: CCC(C)I
Reactant: O=c1ccc2cnc(Nc3ccccc3)nc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)n1c(=O)ccc2cnc(Nc3ccccc3)nc21
Temperature: 50 °C
Yield: 11.6 %

Procedure:
To a suspension of NaH (47 mg of a 60% suspension of NaH in mineral oil) in 6 mL of dimethylformamide was added 2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one (202 mg, 0.85 mmol). The reaction mixture was heated to 50° C. to 60° C. resulting in a yellow solution. The solution was cooled slightly, and 2-iodobutane (140 μL, 1.22 mmol) was added. The reaction was heated at 50° C. for 20 minutes, then cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography eluting with 2:1 ethyl acetate:hexane gave 29 mg (12%) of 8-sec-butyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one, mp 155-156° C.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[OH-].[Li+]>CN(C=O)C.O.C1COCC1>[N:16]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: C1COCCN1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A mixture of ethyl 4-fluoro-3-nitrobenzoate (Chontech 01072; 500 mg; 2.35 mmol; 1 eq.) and morpholine (Fluka 69880; 613.06 mg; 7.04 mmol; 3 eq.) in DMF (2 mL) was stirred at 50° C. for 3 hours. The reaction was then allowed to return to room temperature and diluted with water. Extraction with ethyl acetate, drying over sodium sulfate and concentration in vacuo gave a yellow oil. The latter was taken up in THF (15 mL) and lithium hydroxide (280.86 mg; 11.73 mmol; 5 eq.) was added followed by water (15 mL). The reaction mixture was stirred at room temperature for 5 hours. The THF was evaporated and the residue diluted with water. The aqueous phase was washed with Et2O and acidified to pH 5 with acetic acid. Extraction with Et2O followed by drying over magnesium sulfate and concentration in vacuo afforded the title compound (548 mg, 93%) as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of triethylamine (0.12 g, 1.15 mmol, 1.5 equiv.) in dichloromethane (3 mL) was added octanol (0.10 g, 0.77 mmol, 1.0 equiv.) at 0° C. followed by the addition of methanesulfonyl chloride (0.10 g, 0.85 mmol, 1.1 equiv.), over a period of 5 minutes. After 30 minutes at 0° C., the reaction mixture was diluted in dichloromethane (50 mL) and extracted with ice cold water (50 mL), ice cold 10% aqueous HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and with saturated aqueous NaCl (50 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford 17 (97%): 1H NMR (CDCl3, 400 MHz) δ 4.21 (t, J=6.5 Hz, 2H, CH2OSO2Me), 2.99 (s, 3H, CH3SO3), 1.77 (p, J=6.7 Hz, 2H), 1.35 (m, 10H), 0.87 (t, J=6.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][NH:18][CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:22])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:23](#N)C.C=O.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][N:18]([CH3:23])[CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:22])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1ccc(C2=CCCNC2)c(O)c1
Reactant: CC#N
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCCCC(C)(C)c1ccc(C2=CCCN(C)C2)c(O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 25° C. solution of 1.0 g. (3.32 mmoles) of 3-[4-(1,1-dimethyl-heptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine in 15 ml. of acetonitrile is added 1.32 ml. (17.6 mmoles) of 37% formaldehyde solution. After stirring for one hour the reaction is cooled to 0° C. and 332 mg. (5.3 mmole) of sodium cyanoborohydride added. The reaction mixture is allowed to warm to 25° C. over a one hour period while the pH is maintained at 7 by the addition of acetic acid. The reaction mixture is evaporated, made basic with 2 N potassium hydroxyide and extracted with 200 ml. of dichloromethane. The organic extract is dried over magnesium sulfate and evaporated. The residue is crystallized from ether-pentane to yield 350 mg. of the title compound.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].CCOCC.I[C:11]1[N:12]=[N+:13]([O-:24])[C:14]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][CH2:21]3)=[CH:17][C:15]=2[N:16]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:11]1[N:12]=[N+:13]([O-:24])[C:14]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][CH2:21]3)=[CH:17][C:15]=2[N:16]=1)[CH3:2]
Reactant: [O-][n+]1nc(I)nc2cc3c(cc21)CCC3
Reactant: CC[Mg+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
A solution of EtMgBr in Et2O (3 M, 15 mL, 45 mmol) was added to a stirred solution of ZnCl2-Et2O (45% in DCM, 15 mL, 42 mmol) in THF (100 mL) at 0° C. under N2 and the solution stirred at 0° C. for 10 min. Pd(PPh3)4 (578 mg, 0.5 mmol) and iodide 66 (3.15 g, 10.1 mmol) were added and the mixture stirred at 0° C. for 1 h. The mixture was poured into ice/water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 30% EtOAc, to give 1-oxide 67 (1.20 g, 56%) as a pale yellow solid: mp (MeOH) 80-81° C.; 1H NMR δ 8.26 (s, 1H, H-9), 7.26 (s, 1H, H-5), 3.11 (q, J=7.2 Hz, 4H, H-6, H-8), 3.02 (q, J=7.6 Hz, 2H, CH2), 2.21 (p, J=7.2 Hz, 2H, H-7), 1.43 (t, J=7.6 Hz, 3H, CH3); 13C NMR δ 167.0, 154.6, 148.7, 147.6, 132.3, 122.7, 114.3, 33.2, 32.8, 30.6, 25.8, 12.4. Anal. calcd for C12H13N3O.¼CH3OH: C, 65.9; H, 6.3; N, 18.8. Found: C, 66.0; H, 6.1; N, 18.5%.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](I)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[N:6]2[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].CN(C)C=O.[CH2:31]([C:33]1([OH:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[CH3:32]>[Cu]I.C(N(CC)CC)C>[NH2:1][C:2]1[N:10]=[C:9]([C:32]#[C:31][C:33]2([OH:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[N:6]2[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CCCn1c(-c2cccc(F)c2)nc2c(N)nc(I)nc21
Reactant: CCC1(O)CCCCC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCCn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC3(O)CCCCC3)nc21
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 89.6 %

Procedure:
To 162 mg of methyl 4-[6-amino-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]butanoate were added 8 ml of N,N-dimethylformamide, 30 mg of copper(I) iodide, 30 mg of dichlorobis(triphenylphosphine)palladium(II)l, 80 mg of 1-ethylcyclohexanol and 74 μl of triethylamine and the mixutre was stirred in a nitrogen stream at 70° C. for 2.5 hours. After it was allowed to cool, the solvent was evaporated and the resulting reside was subjected to a silica gel column chromatography (25 g of silica gel; chloroform-methanol (100:0-100:1-50:1) to give 144 mg of the title compound. The yield was 90%.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH2:36]([C:29]1[CH:30]=[C:31]([OH:35])[C:32]([F:34])=[CH:33][C:28]=1[C:24]1[CH:23]=[C:22]2[C:27]([C:19]([C:17]3[NH:16][C:13]4[CH2:14][CH2:15][N:10]([C:8]([C:5]5[CH:4]=[N:3][C:2]([N:38]6[CH2:42][CH2:41][CH2:40][CH2:39]6)=[CH:7][N:6]=5)=[O:9])[CH2:11][C:12]=4[N:18]=3)=[N:20][NH:21]2)=[CH:26][CH:25]=1)[CH3:37]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Reactant: C1CCNC1
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(N5CCCC5)cn3)C4)n[nH]c2c1
Yield: 21.2 %

Procedure:
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (80 mg, 154 μmol) and pyrrolidine (22 mg, 308 μmol) using the method of Example 32. The crude material was purified by HPLC Method D to afford (18 mg, 19%) of the title compound as off-white solid.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=[O:2].[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C>[CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1[nH]c2ccccc2c1C=O
Temperature: 15 °C
Reaction time: 16 h

Procedure:
3-Formylindole (10.0 g, 69 mmoles) was dissolved in DMF (100 ml). Under N2 was a 60% suspension of NaH in mineral oil (3.0 g) added in portions with cooling (temp<15° C.). At <15° C. was a solution of ethyl bromoacetate (8.4 ml) in DMF (15 ml) added drop wise over 30 minutes. The resulting mixture was stirred at room temperature for 16 hours and evaporated in vacuo. The residue was added water (300 ml) and extracted with ethyl acetate (2×150 ml), the combined organic extracts were washed with satd. NH4Cl, dried (MgSO4) and concentrated to afford 15.9 g ethyl (3-formylindolyl)acetate.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([F:22])[CH:15]=2)=[CH:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:30]([S:33](Cl)(=O)=[O:34])([CH3:32])[CH3:31]>C(Cl)Cl>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:6]2[C:7]3[C:12](=[CH:11][C:10]([NH:13][S:33]([CH:30]([CH3:32])[CH3:31])=[O:34])=[CH:9][CH:8]=3)[N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)=[CH:15][C:16]=1[F:22])#[N:21]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)n1cc(-c2ccc(C#N)c(F)c2)c2ccc(N)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1cc(-c2ccc(C#N)c(F)c2)c2ccc(NS(=O)C(C)C)cc21
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
Cool a mixture of 1-Isopropyl-3-(4-cyano-3-fluoro-phenyl)-1H-indol-6-ylamine (0.442 g, 1.51 mmol) and triethylamine (0.306 g, 3.02 mmol) in methylene chloride (10 mL) in a brine/ice bath under argon and treated with a solution of isopropyl sulfonyl chloride (0.210 g, 1.66 mmol) in methylene chloride and the resulting mixture was stirred in the cooling bath for 30 min. After this time dilute the reaction with methylene chloride (40 mL); wash with a saturated aqueous sodium bicarbonate solution (50 mL), then water (50 mL), then brine (50 mL); and dry over sodium sulfate. Remove the solids by filtration; concentrate the filtrate under reduced pressure. Triturate the residue with boiling methylene chloride (×3) then boiling acetonitrile to afford the title compound (0.212 g, 37%) as a white solid: mp 173-175° C. dec;
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17](O)=[O:18].[CH:20]([NH:23][NH:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH2:34][O:35][CH3:36])([CH3:22])[CH3:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([N:23]([CH:20]([CH3:22])[CH3:21])[NH:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH2:34][O:35][CH3:36])=[O:18]
Reactant: COCCOc1ccccc1C(=O)NNC(C)C
Reactant: Cc1cccc(-c2ccccc2CCC(=O)O)c1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOc1ccccc1C(=O)NN(C(=O)CCc1ccccc1-c1cccc(C)c1C)C(C)C
Yield: 35.8 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-propionic acid (110 mg, 0.44 mmoles) and 2-(2-methoxy-ethoxy)-benzoic acid-N′-isopropyl hydrazide (100 mg, 0.40 mmoles) in DMF (3 mL) was treated with triethylamine (0.16 mL, 1.19 mmoles), HOBT (64 mg, 0.48 mmoles) and EDCI (91 mg, 0.48 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed successively with water, 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with 10% ethyl acetate/hexanes to afford the product (70 mg, 36%). LC-MS m/e 489.39 (M+H+)