Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8][C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[CH2:12][CH2:13][N:14]([CH2:22][CH2:23]Cl)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[H-].[Na+]>CS(C)=O.ClCCl>[Br:1][C:2]1[C:3]([C:8]2([C:9]#[N:10])[CH2:23][CH2:22][N:14]([C:15]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:21])[CH2:13][CH2:12]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1ncccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ncccc2Br)CC1
Temperature: 18 °C
Reaction time: 18 h

Procedure:
The (3-bromopyridin-2-yl)acetonitrile (2.00 g, 10.2 mmol) and tert-butyl bis(2-chloroethyl)carbamate (2.46 g, 10.2 mmol) were dissolved in 102 mL of DMSO. The reaction was purged with a stream of nitrogen and cooled to 18° C. To this reaction was added sodium hydride (0.564 g, 22.3 mmol), which was then warmed to 50° C. and stirred for 18 hours. The mixture was diluted with dichloromethane (150 mL), washed with water (3×150 mL), and partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate, filtered, concentrated, and subjected to silica gel chromatography eluting with 5-30% EtOAc in hexanes to yield tert-butyl 4-(3-bromopyridin-2-yl)-4-cyanopiperidine-1-carboxylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)(=[O:9])=[O:8].C(=O)(O)[O-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)(=[O:8])=[O:9]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2ccccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)c2ccccn2)cc1
Temperature: 0 °C
Yield: 88.8 %

Procedure:
A stirred solution of 4-nitrophenyl 2-pyridyl sulfone (6.50 g, 24.6 mmol) and stannous chloride dehydrate (27.72 g, 123.0 mmol) in absolute ethanol (200 mL) was heated at reflux for 25 min. The reaction mixture was poured into ice water, and the aqueous solution basified with sodium bicarbonate (pH=8-9) and extracted with ethyl acetate (2×400 mL). The organics were combined, dried (MgSO4), filtered, and the solvent distilled to yield the title benzenamine (5.12 g, 89%) as a white solid; mp 158°-160° C. 1H--NMR (300 MHz, d6 --DMSO): 6.27 (broad s, 2H, NH2), 6.66 (d, 2H, J=8.7 Hz, aromatic), 7.61 (m, 3H, aromatic), 8.08 (d, 2H, J=4.9 Hz, aromatic), 8.68 (d, 1H, J=4.9, aromatic). MS (CI, CH4): 235(M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[S:13][CH:12]=[N:11][CH:10]=2)[CH:3]=1.Cl[C:15]1[N:16]=[CH:17][C:18]2[CH:23]=[C:22]([C:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH:29]=3)[NH:21][C:19]=2[N:20]=1>C(O)CCC>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17]2[C:18]3[CH:23]=[C:22]([C:24]4[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH:29]=4)[NH:21][C:19]=3[N:20]=[CH:15][N:16]=2)=[CH:3][C:4]=1[C:9]1[S:13][CH:12]=[N:11][CH:10]=1
Reactant: Nc1ccc(O)c(-c2cncs2)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3cnc(Cl)nc3[nH]2)CC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccc(O)c(-c5cncs5)c4)ncnc3[nH]2)CC1
Temperature: 120 °C
Reaction time: 14 h

Procedure:
4-Amino-2-thiazol-5-ylphenol (70.0 mg, 0.364 mmol) was added to a solution of tert-butyl 4-(chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (192 mg, 0.546 mol) in n-butanol (2.0 mL). The reaction was stirred at 120° C. for 14 h. The solvent was removed and the residue was dissolved in DMF. The DMF solution was filtered and purified by HPLC to give the title compound. 1H-NMR (DMSO-d6, 400 MHz): δ=1.43 (s, 9H), 2.46 (m, 2H), 3.56 (t, J=5.6 Hz, 2H), 4.04 (s, 2H), 6.38 (s, br, 1H), 6.70 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 7.70 (dd, J=2.4, 8.8 Hz, 1H), 8.07 (d, J=2.4 Hz, 1H), 8.22 (s, 1H), 8.32 (s, 1H), 9.05 (s, 1H), 9.23 (s, 1H), 10.25 (s, br, 1H), 11.88 (s, 1H). MS (ES+): m/z 490.94 (MH+). HPLC: tR=2.51 min (ZQ2000, polar—5 min).
Reaction SMILES: [OH:1][C:2]1[CH:3]([CH3:14])[NH:4][C:5]([CH3:13])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1>C(Cl)Cl.CCOC(C)=O.CCCC(C)C.[O-2].[O-2].[Mn+4]>[OH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([CH3:13])=[N:4][C:3]=1[CH3:14]
Reactant: CCOC(=O)C1=C(C)NC(C)C(O)=N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCC(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(O)c(C)nc1C
Temperature: 35 °C
Reaction time: 0.17 h
Yield: 72.6 %

Procedure:
Manganese dioxide (150 g) was added to a suspension of ethyl 6-hydroxy-3,5-dimethyl-4,5-dihydropyrazine-2-carboxylate (121 g, 610.44 mmol) in DCM (1.8 L) at ambient temperature giving rise to a 2° C. exotherm. The reaction was stirred for 10 minutes then warmed to 35° C. for 1 hour. The reaction was incomplete so an additional 115 g of Manganese dioxide was added and the reaction stirred for 1 hour at 35° C. then stirred to cool to ambient temperature. The reaction was filtered through a short bed of silica and washed through with 2 L of 1:1 EtOAc/iso-hexane and finally 2×2 L EtOAc. The fractions were then combined and reduce in-vacuo to give an orange solid, which was slurried in 300 mL of 1:1 EtOAc/iso-hexane, filtered and washed with iso-hexane to afford the title compound (87 g, 72.6%) as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[OH:37][CH:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:39]#[N:40].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:37][CH:38]([C:39]#[N:40])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: N#CC(O)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C#N)c4ccccc4)c(C)c3C)c2cc1OC
Yield: 40.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-hydroxy-2-phenylacetonitrile (31 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (30 mg, yield 39%).
Reaction SMILES: [Br-].[CH2:2]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4].CC(C)([O-])C.[K+].[CH:37]([CH:39]1[CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH2:40]1)=O.O>C1COCC1>[CH2:2]([C:5]1[CH:30]=[CH:29][C:8]([CH:9]=[CH:37][CH:39]2[CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH2:40]2)=[CH:7][CH:6]=1)[CH2:3][CH3:4]
Reactant: CCCc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=CC1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc(C=CC2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
Suspension of 114 g of 4-n-propylbenzyltriphenyl phosphonium bromide in 500 ml of THF was stirred under nitrogen gas stream and 32.3 g of potassium-t-butoxide was added thereto at room temperature. After stirred at room temperature for 1 hour, a solution of 31.2 g of 4-formylcyclohexanone in 200 ml of THF was added dropwise to the suspension. After stirred at room temperature for 2 hours, 1 l of water was added thereto and then it was extracted with 1 l of ethyl acetate. Organic layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off under a reduced pressure, and then 500 ml of heptane was added thereto. Precipitate thus separated was filtered off and purified by a column chromatography over a silica gel by using ethyl acetate/heptane (1/5) as an eluent, and the solvent was distilled off under a reduced pressure to obtain 42 g of 4-(2-(4-n-propylphenyl)ethenyl)cyclohexanone.
Reaction SMILES: C([O:5][C:6](=[O:28])[C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[Cl:21])=[C:11]([Cl:22])[C:10]([NH:23][CH2:24][C:25](=O)[CH3:26])=[N:9][CH:8]=1)(C)(C)C.OS(O)(=O)=O.O.[OH-].[Na+]>CCOC(C)=O>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:12]2[C:7]([C:6]([OH:5])=[O:28])=[CH:8][N:9]3[C:25]([CH3:26])=[CH:24][N:23]=[C:10]3[C:11]=2[Cl:22])=[C:15]([Cl:21])[CH:16]=1
Reactant: CC(=O)CNc1ncc(C(=O)OC(C)(C)C)c(Nc2ccc(Br)cc2Cl)c1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cnc2c(Cl)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cn12

Procedure:
4-(4-Bromo-2-chlorophenylamino)-5-chloro-6-(2-oxopropylamino)-nicotinic acid tert-butyl ester (0.075 g, 0.15 mmol) was dissolved into concentrated H2SO4 (0.50 mL). After ten minutes, ice and water were and the mixture was stirred for ten minutes. The mixture was diluted with EtOAc, neutralized with 1 M NaOH, washed with brine, dried over Na2SO4 and concentrated to provide the desired product as an off-white solid. MS APCI (+) m/z 416, 418 (M+, Cl, Br pattern) detected.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)[C@H:10]([CH3:24])[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:24][C@@H:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][N:15]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)CCN1c1ccc(C(F)(F)F)cn1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CNCCN1c1ccc(C(F)(F)F)cn1
Yield: 91.4 %

Procedure:
A solution of 4-benzyl-2-(R)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine (175 mg, 0.522 mmol) and 10% Pd/C (cat) in ethanol (5 mL) was stirred under a hydrogen atmosphere (50 psi) for 3d. The reaction mixture was then filtered through Celite and purified by silica gel column chromatography (gradient eluent: 0-20% MeOH in dichloromethane) to provide the desired product (117 mg, 99%). 1H NMR (400 MHz, MeOH-D4) δ 8.39 (s, 1H), 7.60 (dd, 1H), 7.39-7.28 (m, 5H), 6.58 (d, 1H), 4.49 (br s, 1H), 4.10 (br d, 1H), 3.62 (br d, 1H), 3.47 (br d, 1H), 3.24 (br t, 1H), 2.95 (br d, 1H), 2.77 (br d, 1H), 2.35-2.15 (m, 2H), 1.25 (d, 3H); LCMS: 246.1 (M+1)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(OCC)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(C(=O)c2ccc(N3CCOCC3)cc2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 3.73 g of 1-acetyl-4-(4-fluorobenzoyl)piperidine and 2.6 ml of morpholine was stirred at 100° C. for 24 hours and the reaction mixture was then dissolved in 100 ml of ethyl acetate. The solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order and the organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed and the residual oil was purified by silica gel column chromatography (eluent: methanol:dichloromethane=1:19, v/v) to give 2.4 g of the title compound as oil.
Reaction SMILES: C[NH:2][NH:3][C:4]([NH:6][C:7](=O)[CH2:8][NH:9][C:10]1[C:15]([CH2:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:18][CH3:19])=[S:5].[OH-].[K+].[CH2:23](O)C>O>[CH2:16]([C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:18][CH3:19])[C:10]=1[NH:9][CH2:8][C:7]1[N:6]([CH3:23])[C:4](=[S:5])[NH:3][N:2]=1)[CH3:17]
Reactant: CCO
Reactant: CCc1cccc(CC)c1NCC(=O)NC(=S)NNC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCc1cccc(CC)c1NCc1n[nH]c(=S)n1C
Yield: 97 %

Procedure:
29.6 g (0.1 mole) of 1-methyl-4-[(2,6-diethylanilino)-acetyl]-thiosemicarbazide were suspended in 150 ml of ethanol and, after added 7 g of potassium hydroxide in 20 ml of water, the mixture was heated under reflux for 1 hour. Thereafter, most of the solvent was distilled off and 250 ml of water were added to the residue. After acidifying the mixture to pH 5 with glacial acetic acid, the precipitate which formed was filtered off and washed thoroughly with water. After drying, 27 g (97% of theory) of 2,6-diethyl-N-[(1-methyl-2-thiono-1,3,4-triazol-5-yl)-methyl]-aniline of melting point 117° to 121° C. were obtained. ##STR83##
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:7]1)=[O:5])C.I[CH3:23]>C1COCC1>[CH2:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C:6]([CH3:23])([C:4]([OH:3])=[O:5])[CH2:7]1)=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CI
Reactant: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a −78° C. solution of the product of Example 45A (6.0 g, 20.6 mmoles) in THF (50 mL) was added a solution of lithium bis(trimethlylsilyl)amide (1.0 M in THF, 22.7 mmoles). After 35 min, iodomethane (1.4 mL, 22.7 mmoles) was added and the reaction was slowly warmed to room temperature and stirred overnight. The reaction was quenched with aqueous sat. ammonium chloride and extracted with Et2O. The organic layer was then rinsed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane→65:35 hexane:EtOAc). The resulting ester was hydrolyzed overnight at room temperature in THF (15 mL), H2O (10 mL), and EtOH (15 mL) with NaOH (2.5 g). The solution was concentrated under vacuum; the residue was dissolved in saturated ammonium chloride; and, the solution was extracted with ethyl acetate (3×). The combined ethyl acetate extracts were dried over sodium sulfate, filtered, and concentrated under vacuum to yield the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C@:18]([OH:25])([CH2:23][OH:24])[C:19]([F:22])([F:21])[F:20])=[O:15].N1C=CC=CC=1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>ClCCl>[CH3:42][C:32]1[CH:37]=[CH:36][C:35]([S:38]([O:24][CH2:23][C@:18]([CH2:17][NH:16][C:14]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=3)[C:2]=2[NH2:1])=[O:15])([OH:25])[C:19]([F:22])([F:21])[F:20])(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: Nc1c(C(=O)NC[C@](O)(CO)C(F)(F)F)cnn1-c1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@](O)(CNC(=O)c2cnn(-c3ccc(F)cc3)c2N)C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
(S)-5-Amino-1-(4-fluorophenyl)-N-[3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)propyl]-1H-pyrazole-4-carboxamide (90 mg) was dissolved in dry dichloromethane (3 ml) and dry pyridine (3 ml) and cooled in an ice bath under nitrogen. p-Toluenesulphonyl chloride (62 mg) was added and the reaction was stirred at ice bath temperature for 1 hour and then at room temperature for 24 hours. p-Toluenesulphonyl chloride (25 mg) was added and the reaction was stirred at room temperature, under nitrogen over the weekend. p-Toluenesulphonyl chloride (25 mg) was added and the reaction was stirred at room temperature under nitrogen for 2 hours and heated at 50° C. for 2 hours and left stirring at room temperature overnight. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with 1M hydrochloric acid, water, sodium bicarbonate and brine, dried using a hydrophobic frit and evaporated to give a beige foam (94 mg). This was dissolved in dichloromethane and applied to a 10 g SPE cartridge and purified on the Flashmaster eluting with a 0-50% ethyl acetate in cyclohexane over a 20 minute gradient. The appropriate fraction was evaporated to give the title compound as a colourless oil (83 mg).
Reaction SMILES: [Cl:1][C:2]1[C:14]([N:15]2[C:19](=[O:20])[N:18]([CH:21]([F:23])[F:22])[C:17]([CH3:24])=[N:16]2)=[CH:13][C:5]([O:6][CH:7]([CH3:12])[C:8]([O:10]C)=[O:9])=[C:4]([CH3:25])[CH:3]=1.[OH-].[K+]>C(O)C.O>[Cl:1][C:2]1[C:14]([N:15]2[C:19](=[O:20])[N:18]([CH:21]([F:22])[F:23])[C:17]([CH3:24])=[N:16]2)=[CH:13][C:5]([O:6][CH:7]([CH3:12])[C:8]([OH:10])=[O:9])=[C:4]([CH3:25])[CH:3]=1
Reactant: COC(=O)C(C)Oc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(Cl)c(-n2nc(C)n(C(F)F)c2=O)cc1OC(C)C(=O)O
Yield: 84.8 %

Procedure:
In a manner similar to Example 2, Step H, the reaction of 3.3 g (0.0088 mole) of methyl 2-[4-chloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)-2-methylphenoxy]propionate with 1.5 g (0.27 mole) of potassium hydroxide in 50 mL of ethanol and 15 mL of water produced 2.7 g of 2-[4-chloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)-2-methylphenoxy]propionic acid as a solid (mp 56°-60° C.), Compound A3.
Reaction SMILES: [C:1]([O:4][CH:5]([C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)[CH2:6][CH2:7][C@H:8]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:15][CH:14]=2)[C@@H:9]1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]2([O:43][C:44](=[O:46])[CH3:45])[CH2:40][O:39]C(C)(C)[O:37][CH2:36]2)=[CH:29][CH:28]=1)(=[O:3])[CH3:2].[C:54](O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C1COCC1.O>[C:44]([O:43][C:35]([CH2:40][OH:39])([CH2:36][OH:37])[CH2:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([C@@H:9]2[C@@H:8]([CH2:7][CH2:6][C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C:47]3[CH:48]=[CH:49][C:50]([F:53])=[CH:51][CH:52]=3)[C:11](=[O:12])[N:10]2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][NH:22][S:23]([CH2:26][CH3:54])(=[O:24])=[O:25])=[CH:15][CH:14]=2)=[CH:28][CH:29]=1)(=[O:46])[CH3:45]
Reactant: CC(=O)OC(CC[C@H]1C(=O)N(c2ccc(CCCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(CCC2(OC(C)=O)COC(C)(C)OC2)cc1)c1ccc(F)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)NCCCc1ccc(N2C(=O)[C@H](CC[C@H](OC(C)=O)c3ccc(F)cc3)[C@H]2c2ccc(CCC(CO)(CO)OC(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the intermediate of step E (1.5 g, 2 mmol) in THF/water (16 mL/4 mL) was added TFA (1 mL). The reaction mixture was stirred at RT for 16 hr. To the reaction mixture was added 100 mL toluene and the water was removed under vacuum with water bath temperature of 40° C. The residue was treated twice with 100 mL toluene followed by azeotropic removal of water. The solvent was completely removed under vacuum. The crude product was purified by MPLC (silica column) with stepwise gradient elution (50-100% EtOAc/hexanes as eluent). Mixed fractions were also isolated and were further purified by prep TLC eluting with CH2Cl2/MeOH (95/5). The purified fractions were combined to afford the title compound. m/z (ES) 653 (M-OAc)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([NH:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C(Cl)(Cl)Cl>[NH:15]1[C:12]2=[N:13][CH:14]=[C:9]([C:20]3[N:25]=[C:24]([NH:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:23]=[N:22][CH:21]=3)[CH:10]=[C:11]2[CH:17]=[CH:16]1
Reactant: CN(C)CCNc1cncc(Cl)n1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CN(C)CCNc1cncc(-c2cnc3[nH]ccc3c2)n1
Temperature: 100 °C

Procedure:
The starting material 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (70 mg, 0.286 mmol, 1 eq) and N1-(6-chloropyrazin-2-yl)-N2,N2-dimethylethane-1,2-diamine (66) (457 mg, 0.286 mmol, 1 eq) in 1,4-dioxane (5 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (150 mg, 0.614 mmol, 1.5 eq) followed by addition of Pd(dpp)Cl2 (6.2 mg, 0.0086 mmol, 0.03 eq) and degassing and purging under argon for additional 10 min. The reaction mixture was heated at 100° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through oCelite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1% MeOH/CHCl3 to obtain pale yellow solid compound N1-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)-N2,N2-dimethylethane-1,2-diamine 127 in 10 mg quantity. The compound 127 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 11.78 (s, 1H), 8.90 (d, J=1.82, 1H), 8.57 (s, 1H), 8.30 (s, 1H), 7.89 (s, 1H), 7.51 (m, J=151.58, 1H), 7.01 (m, J=201.21, 1H), 6.53 (m, J=191.45, 1H), 3.48 (m, J=5.85, 2H), 2.22 (s, 6-H); MS m/z 283 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:15]([O:22][C:23](=[O:34])[NH:24][CH2:25][CH2:26][C@H:27]1[CH2:32][CH2:31][C@@H:30]([NH2:33])[CH2:29][CH2:28]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CC(O)C>[CH2:15]([O:22][C:23](=[O:34])[NH:24][CH2:25][CH2:26][C@H:27]1[CH2:28][CH2:29][C@@H:30]([NH:33][C:2]2[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:31][CH2:32]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Reactant: N[C@H]1CC[C@@H](CCNC(=O)OCc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN(C)c1nc(N[C@H]2CC[C@@H](CCNC(=O)OCc3ccccc3)CC2)nc2ccccc12
Temperature: 170 °C

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (2.45 g, 10.2 mmol) and cis-[2-(4-amino-cyclohexyl)-ethyl]-carbamic acid benzyl ester (3.3 g, 10.2 mmol) and triethylamine (1.65 mL, 10.2 mmol) in 2-propanol (15 mL) was heated at 170° C. for 45 min using a Smith Microwave Synthesizer. The mixture was concentrated and the residue was purified by column chromatography (silica gel, CH2Cl2 to 10% 2 M NH3/MeOH in CH2Cl2) to give cis{2-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-ethyl}-carbamic acid benzyl ester (4.48 g, 85%) as a yellow oil.
Reaction SMILES: C1(S)C=CC=CC=1.C(N(CC)CC)C.[N:15]([CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:27])[CH:20]=1)=[N+]=[N-]>C(#N)C>[NH2:15][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:27])[CH:20]=1
Reactant: N#Cc1ccc(CN=[N+]=[N-])cc1F
Agent: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(CN)cc1F
Reaction time: 1.5 h
Yield: 72.5 %

Procedure:
To a suspension of stannous chloride dihydrate (0.45 g, 2.4 mmol) in 20 mL of acetonitrile under stirring was added thiophenol (1.07 g, 9.7 mmol) and triethylamine (0.726 g, 7.17 mmol). Thereafter was added a solution of 4azidomethyl-2-fluorobenzonitrile (0.279 g, 1.58 mmol; see step (iv) above) in a few mLs of acetonitrile. After 1.5 h, the azide was consumed and the solvent was evaporated. The residue was dissolved in methylene chloride and washed three times with 2M NaOH. The organic phase was extracted twice with 1M HCl. The combined acidic aqueous phase was washed with methylene chloride and then made alkaline with 2M NaOH and extracted three times with methylene chloride. The organic phase was dried (Na2SO4) and evaporated to give 0.172 g (72%) of the desired sub-title compound which could be used without purification.