Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=1)=[C:2]=[S:3].[H-].[Na+].[NH2:18]/[C:19](/[N:26]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=1[O:47][CH3:48])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])=[CH:20]\[C:21](OCC)=[O:22].Cl>CN(C)C=O>[CH3:48][O:47][C:40]1[CH:41]=[C:42]([O:45][CH3:46])[CH:43]=[CH:44][C:39]=1[CH2:38][N:26]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[C:19]1[NH:18][C:2](=[S:3])[N:1]([C:4]2[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([F:13])([F:15])[F:14])=[CH:8][CH:9]=2)[C:21](=[O:22])[CH:20]=1
Reactant: CCOC(=O)/C=C(\N)N(Cc1ccc(OC)cc1OC)Cc1ccc(OC)cc1OC
Reactant: FC(F)(F)COc1ccc(N=C=S)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2OC)c2cc(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(=S)[nH]2)c(OC)c1
Reaction time: 0.08 h
Yield: 26.7 %

Procedure:
To a solution of 1-isothiocyanato-4-(2,2,2-trifluoroethoxy)benzene (3.96 g) in N,N-dimethylformamide (120 mL) was added sodium hydride (60% in oil, 0.68 g) under ice-cooling. The reaction mixture was stirred for 5 min under ice-cooling, ethyl (2E)-3-amino-3-[bis(2,4-dimethoxybenzyl)amino]prop-2-enoate (7.3 g) was added thereto, and the mixture was stirred for 30 min under ice-cooling. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (120 mL), sodium ethoxide (20% ethanol solution, 14.5 mL) was added thereto, and the mixture was stirred for 1 hr. To the reaction mixture was added 1M hydrochloric acid, and the precipitated solid was collected by filtration to give the title compound (2.8 g).
Reaction SMILES: [F:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:10][S:11]([O:9][CH2:8][C:2]1([F:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(F)CCOCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(F)CCOCC1

Procedure:
A mixture of EXAMPLE 296C (1.4 g), methanesulfonyl chloride (1.054 mL), triethylamine (2.99 mL), and 4-(dimethylamino)pyridine (0.051 g) in CH2Cl2 (20 mL) was stirred at 0° C. for 2 hours, concentrated and chromatographed on silica gel with 30% ethyl acetate in hexanes as eluent to give the product.
Reaction SMILES: C[O:2][CH2:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH:7]=[CH:6][N:5]=1.B(Br)(Br)Br>ClCCl>[N:19]1([S:16]([N:13]2[CH2:12][CH2:11][N:10]([C:8]3[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][OH:2])[N:9]=3)[CH2:15][CH2:14]2)(=[O:18])=[O:17])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COCc1nccc(N2CCN(S(=O)(=O)N3CCCC3)CC2)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(N1CCCC1)N1CCN(c2ccnc(CO)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxymethyl-4-[4-(pyrrolidine-1-sulfonyl)-piperazin-1-yl]-pyrimidine (prepared according to the method of Example 121, Step A, 3.1 g, 9.4 mmol) in dichloromethane (47 mL) was added boron tribromide (1 M in dichloromethane, 19 mL, 18.7 mmol) at 0° C. then stirred at ambient temperature for 2 h. The mixture was washed twice with saturated aqueous sodium bicarbonate, and the organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give an oil which was crystallized from isopropyl ether to give the title compound as a white solid, 2.431 g (77%). 1H NMR (CDCl3, 300 MHz) δ 1.82 (m, 4H), 3.15 (m, 8H), 3.81 (m, 4H), 4.35 (d, 2H), 4.83 (t, 1H), 6.71 (d, 1H), 8.18 (d, 1H); mp: 128-131° C.; MS (CI) 328 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl.CCN(CC)CC>[CH3:31][S:32]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1)(=[O:34])=[O:33]
Reactant: O=C(NC1CCNCC1)c1cc2ccccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(NC(=O)c2cc3ccccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Reaction time: 16 h

Procedure:
To a solution of 50 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid piperidin-4-ylamide in 2 ml DCM, 0.3 ml NEt3 and 20 mg Methanesulfonyl chloride were added at RT and stirred for 16 h. After removal of the solvent under reduced pressure the residue was directly purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:7](=O)[NH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.Cl[C:20]1C(C(F)(F)F)=CC([N+]([O-])=O)=[CH:22][N:21]=1.CNC>>[CH3:20][N:21]([CH3:22])[C:7]1[C:6]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Reactant: O=c1[nH]cc([N+](=O)[O-])cc1C(F)(F)F
Agent: CNC
Solvent: O=S(Cl)Cl
Product: CN(C)c1ncc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
5-Nitro-3-(trifluoromethyl)pyridin-2(1H)-one was treated with thionyl chloride and then the resulting 2-chloro-5-nitro-3-(trifluoromethyl)pyridine was treated with dimethylamine to obtain N,N-dimethyl-5-nitro-3-(trifluoromethyl)pyridin-2-amine.
Reaction SMILES: C(O[C:4]([CH2:6][CH:7]([CH3:21])[CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]2)=[O:5])C.CC[O-].[Na+].[CH3:26][NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[CH3:34]>C(O)C>[CH3:26][N:27]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[CH3:34])[C:4]([CH2:6][CH:7]([CH3:21])[CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]2)=[O:5]
Reactant: CNC1CCCCC1C
Reactant: CCOC(=O)CC(C)COc1ccc2[nH]c(=O)ccc2c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(COc1ccc2[nH]c(=O)ccc2c1)CC(=O)N(C)C1CCCCC1C

Procedure:
2.7 Grams of 6-(3-ethoxycarbonyl-2-methylpropoxy)carbostyril, 0.5 g of sodium ethylate and 5 ml of N-methyl-2-methylcyclohexylamine are added to 100 ml of ethanol, and the mixture is reacted in an autoclave under 110 atm. and at 140° to 150° C. for 6 hours. After cooling, the reaction solution is concentrated under reduced pressure and the residue is dissolved in 200 ml of chloroform, washed with a 1% aqueous K2CO3 solution, diluted hydrochloric acid and water in that order and then dried with anhydrous Na2SO4. The solvent is distilled off and the residue is refined by silica gel column chromatography (silica gel: Wakogel C-200; eluent: 20/1 (V/V) chloroform-methanol) and the obtained crude crystals are recrystallized from benzene-ligroin, resultantly obtaining 1.0 g of 6-{3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]-2-methylpropoxy}carbostyril in the form of colorless needle-like crystals with melting point of 146°-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.Cl.[NH2:14][OH:15].[OH-].[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][CH2:10][C:9]2=[N:14][OH:15])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCC1c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: ON=C1CCC1c1ccc(Cl)cc1

Procedure:
A solution of 2-(4-chlorophenyl)cyclobutanone (1.122 g, 6.09 mmol), hydroxylamine hydrochloride (3.541 g. 8.2 eq.) and 36 ml of 5% NaOH in 30 ml EtOH was heated at reflux for 2 h. The solution was cooled, adjusted to pH 6, and extracted with CHCl3. The organic extract was washed with brine and dried. Filtration and concentration yielded 2-(4-chlorophenyl)cyclobutanone oxime as an oil. 1 g (84%)
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[NH2:11][C:12]1[C:13]([C:29]2[O:33][C:32]([C:34]3[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=3)[C:37](OC)=[O:38])=[N:31][N:30]=2)=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:28])[N:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)=[CH:16][N:17]=1>ClCCl>[NH2:11][C:12]1[N:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([N:25]([CH3:27])[CH3:26])=[O:28])=[CH:22][CH:23]=2)=[N:14][C:13]=1[C:29]1[O:33][C:32]([C:34]2[CH:43]=[CH:42][CH:41]=[C:36]([CH2:37][OH:38])[CH:35]=2)=[N:31][N:30]=1
Reactant: COC(=O)c1cccc(-c2nnc(-c3nc(-c4ccc(C(=O)N(C)C)cc4)cnc3N)o2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4cccc(CO)c4)o3)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.1 %

Procedure:
Diisobutylaluminium hydride (810.0 μL of 1 M, 0.8100 mmol) in dichloromethane was added dropwise to a solution of methyl 3-[5-[3-amino-6-[4-(dimethylcarbamoyl)phenyl]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]benzoate (120 mg, 0.2700 mmol) in CH2Cl2 (6 mL) at 0° C., the solution darkened upon addition. The resulting solution was stirred at 0° C. for 30 min and allowed to warm slowly to room temperature. The reaction mixture was stirred at room temperature for 4 h and then quenched by addition of 1M HCl (3 mL). The resulting mixture was filtered through a Celite pad and washed with dichloromethane (2×5 mL). The layers were separated and the aqueous layer extracted further with dichloromethane (2×10 mL) and combined organic extracts dried over MgSO4 and concentrated in vacuo. The residue was purified using by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were combined and lypholised to give the product as a yellow solid (20.3 mg, 18% yield); 1H NMR (400 MHz, DMSO) d 2.98 (m, 6H), 4.66 (s, 2H), 7.55 (m, 2H), 7.63 (m, 2H), 7.80 (br s, 2H), 8.04 (m, 1H), 8.16 (m, 3H) and 8.99 (s, 1H) ppm; MS (ES+) 417.23
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=2)[CH:12]=[CH:13][C:14]=1[CH3:15].[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][C:29]=1[C:38](Cl)=[O:39]>C(Cl)Cl>[CH3:25][N:24]([CH3:26])[C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([NH:8][C:38]([C:29]2[CH:30]=[N:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]=2)=[O:39])[CH:10]=1)=[O:27]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cnc2ccccc2n1
Yield: 41 %

Procedure:
Triethylamine (0.28 ml) was added to a stirred mixture of N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide (0.27 g), 2-quinoxalinylcarbonyl chloride (0.29 g) and methylene chloride (10 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The reaction mixture was partitioned between methylene chloride and water. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate and evaporated. The residue was triturated under ethyl acetate. There was thus obtained the title compound as a solid (0.175 g); NMR Spectrum: (DMSOd6) 2.31 (s, 3H), 2.95 (s, 6H), 3.31 (s, 3H), 6.91 (d, 1H) 7.27 (m, 4H), 7.59 (d, 1H), 8.01 (m, 2H), 8.24 (m, 3H), 9.56 (s, 1H), 10.15 (s, 1H), 10.42 (s, 1H); Mass Spectrum: M+H+426.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([I:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18]Cl.[H-].[Na+]>O1CCCC1>[CH2:1]([C:8]1[C:13]([O:14][CH2:16][O:17][CH3:18])=[CH:12][CH:11]=[C:10]([I:15])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: Oc1ccc(I)nc1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(I)nc1Cc1ccccc1

Procedure:
12 g of 2-benzyl-3-hydroxy-6-iodopyridine was dissolved in 50 ml of tetrahydrofuran, followed by adding 3.8 ml of chloromethyl methyl ether. 2 g of 60% oily sodium hydride was added little by little thereto to under stirring under ice-cooling. After adding sodium hydride, the cooling medium was removed and the mixture was stirred at room temperature for 2.5 hours. Then, ice water was added thereto little by little under cooling, followed by extracting with ethyl acetate. The organic phase was further washed brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 15% ethyl acetate/hexane as an eluent for separation and purification, to give 13 g of the target compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[S:11].[H-].[Na+].C(N=[N+]=[N-])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].Cl>C1COCC1>[C:15]([CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]1=[S:11])(=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN1C(=S)Cc2ccccc21
Reactant: [N-]=[N+]=NCC(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=S)C(C(=O)c2ccccc2)c2ccccc21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 1-methyl-2-indolinethione (0.50 g, 3.06 mmol) in dry THF (3 mL) was added dropwise at 20° C. under N2 to a stirred suspension of NaH (0.13 g of a 60% w/w suspension in mineral oil, 3.37 mmol) in THF (2 mL). After gas evolution had ceased (5 minutes), a solution of the above phenacyl azide in THF (2 mL) was added dropwise, and the mixture was stirred at 20° C. for 1 hour, then poured into 6N HCl and extracted with EtOAc. The residue from the organic layer was chromatographed on silica gel. Elution with CH2Cl2 /petroleum ether (3:7) gave foreruns, and elution with CH2Cl2 /petroleum ether (2:3) gave 3-benzoyl-1-methyl-2-indolinethione [XV: R1 =H, R3 =Me, R5 =C6H5] (24) (0.31 g, 38%); mp (trituration from MeOH) 132°-134° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([N:11]1[C:20]([CH3:21])=[C:19]([C:22](=[O:36])[NH:23][C@@H:24]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[C:18]2[C:13](=[C:14]([F:37])[CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:38])[CH2:8][CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[Br:40]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:39])[N:7]([N:11]1[C:20]([CH2:21][Br:40])=[C:19]([C:22](=[O:36])[NH:23][C@@H:24]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[C:18]2[C:13](=[C:14]([F:37])[CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:38])[CH2:8][CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(C(=O)OC(C)(C)C)n1c(C)c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCN(C(=O)OC(C)(C)C)n1c(CBr)c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c1=O

Procedure:
(4-{[(S)-Cyclobutyl-(3-fluoro-phenyl)-methyl]carbamoyl}-8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-yl)-propyl-carbamicacid tert-butyl ester (0.2 g, 0.4 mmol; prepared as described in example 8), carbon tetrachloride (50 mL), N-bromosuccinimide (0.072 g, 0.41 mmol) and benzoyl peroxide (10 mg, 0.04 mmol) are warmed at 80° C. for 2 hours. The reaction mixture was cooled and washed with 10 ml of water. The organic phase was dried over MgSO4 and was rotovaped to give 0.3 g. crude product. The product was chromatographed on silica gel with Etac:Hept, 30:70 as eluent to give 0.15 g. the title compound as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[N:16]=[C:15]([CH3:17])[N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2C1CCCCO1.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=1.Cl>C(O)C.C([O-])(O)=O.[Na+]>[CH3:32][O:31][C:28]1[N:29]=[CH:30][C:25]([NH:24][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][NH:12]3)=[CH:26][CH:27]=1
Reactant: COc1ccc(N)cn1
Reactant: Cc1nc(-c2cnccc2Cl)c2ncn(C3CCCCO3)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Nc2ccncc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 160 °C
Yield: 57.8 %

Procedure:
A glass microwave reaction vessel was charged with 6-(4-chloropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (36 mg, 0.109 mmol) and 5-amino-2-methoxypyridine (27.1 mg, 0.218 mmol, Aldrich) in ethanol (1 mL) and a drop of 5 N HCl. The reaction mixture was stirred and heated in a Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 160° C. for 30 min. The reaction mixture was diluted with NaHCO3 (5 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (3 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give a yellow solid. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column eluting with 10% MeOH/CH2Cl2 to provide 6-methoxy-N-(3-(2-methyl-9H-purin-6-yl)pyridin-4-yl)pyridin-3-amine (21 mg, 58% yield) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 9.98 (s, 1H); 8.42 (s, 1H); 8.07-8.24 (m, 2H); 7.72 (d, J=8.92 Hz, 1H); 6.85-7.00 (m, 2H); 3.96 (s, 3H); 2.83 (s, 3H). m/z (ESI, +ve ion) 334 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:13][C:12]([CH3:15])([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][CH:21]=[N:20][C:19]=3F)=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].Cl.Cl.[NH:28]1[C:32]2=[N:33][C:34]([CH2:37][NH2:38])=[CH:35][CH:36]=[C:31]2[CH:30]=[CH:29]1>>[C:1]([N:4]1[CH2:13][C:12]([CH3:15])([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][CH:21]=[N:20][C:19]=3[NH:38][CH2:37][C:34]3[N:33]=[C:32]4[NH:28][CH:29]=[CH:30][C:31]4=[CH:36][CH:35]=3)=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1Cc2cc(NC(=O)c3cccnc3F)ccc2C(C)(C)C1
Reactant: NCc1ccc2cc[nH]c2n1
Agent: Cl
Product: CC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3ccc4cc[nH]c4n3)ccc2C(C)(C)C1

Procedure:
The titled compound was prepared from N-(2-acetyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-fluoro-nicotinamide and C-(1H-pyrrolo[2,3-b]pyridin-6-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 469 (M+H). Calc'd. for C27H28N6O2—468.56.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:29]>CO>[C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)[C:7]([O:9][CH3:29])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
A solution of the crude 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid in Methanol (4 mL) was treated with TMS-diazomethane (1.481 mL, 2.96 mmol) and then resultant was allowed to stir at ambient temperature for 10 minutes. The mixture was concentrated and then purified on silica gel (0-10% MeOH/DCM) to give the desired product (67 mg, 41% yield over 2 two steps). 1H NMR (400 MHz, CHLOROFORM-d) d=9.71 (br. s., 1H), 7.47-7.32 (m, 3H), 7.31-7.23 (m, 1H), 7.19 (t, J=2.4 Hz, 1H), 6.10 (t, J=2.1 Hz, 1H), 5.39 (s, 1H), 3.82 (s, 3H), 3.72 (s, 3H), 2.44 (s, 3H), 0.94 (s, 9H); LC/MS (m/z) ES+=383 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][O:15][C:16](=[O:23])[C@@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18]>>[CH3:21][CH:20]([CH3:22])[CH2:19][C@@H:17]([NH:18][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)=[O:13])[C:16]([O:15][CH3:14])=[O:23]
Reactant: Cc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: COC(=O)[C@H](N)CC(C)C
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1cc2cc(C)ccc2[nH]1
Yield: 50 %

Procedure:
Prepared in a similar manner to example 4 using 5-Methyl-1H-indole-2-carboxylic acid and D-leucine methyl ester. Yield: 50%. 1H NMR (500 MHz, CDCl3): 0.98 (d, 3H, J=6.3 Hz), 1.00 (d, 3H, J=6.1 Hz), 2.44 (s, 3H), 3.784 (s, 3H), 4.87 (m, 1H), 6.56 (d, 1H, J=8.39 Hz), 6.85 (dd, 1H, J=1.94 Hz, J=0.68 Hz), 7.12 (dd, 1H, J=8.46 Hz, J=1.55 Hz), 7.31 (d, 1H, J=8.45 Hz), 7.42 (s, 1H). MS (MH+, 303).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=1)[C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[C:12]=1[CH3:13].O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[C:12]=1[CH3:13]
Reactant: COCCCCC(Nc1ccc(C(=O)OC)cc1)c1oc2ccc(OC)cc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCCCC(Nc1ccc(C(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Yield: 84.7 %

Procedure:
To a mixture of methyl 4-{[5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentyl]amino}benzoate (1.07 g) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10.0 mL), and the mixture was stirred with heating under reflux for 1 day, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (10.0 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (875 mg, 85%) as a brown solid.
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][N:26]=2)[C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[N:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Li+]>CO>[CH:1]1([CH:7]([NH:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=2)[C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=3)=[N:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2cnc(-c3ccc(C(F)(F)F)cc3)nc2)C2CCCCC2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(NC(c2cnc(-c3ccc(C(F)(F)F)cc3)nc2)C2CCCCC2)nc1
Temperature: 50 °C

Procedure:
A mixture of the (+/−)-methyl 6-[(cyclohexyl{2-[4-(trifluoromethyl)phenyl]pyrimidin-5-yl}methyl)amino]nicotinate (486 mg, 1.03 mmol) was dissolved in methanol (2.1 ml) and tetrahydrofuran (1.0 ml) and treated with aqueous lithium hydroxide (1.0 ml, 2.1 mmol, 2.0M). The reaction was heated to 50° C. for 12 hours. The mixture was concentrated in vacuo, and the residue was diluted with water and acidified with aqueous 1.0M hydrochloric acid. The mixture was then concentrated in vacuo a second time, and the crude residue was used directly for further transformations.