Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Cl:8].[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Cl:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:17])=[O:16]
Reactant: Cc1noc(N)c1Cl
Reactant: O=S(=O)(Cl)c1ccccc1
Product: Cc1noc(NS(=O)(=O)c2ccccc2)c1Cl
Yield: 84 %

Procedure:
N-(4-Chloro-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared according to the method in Example 1b from 5-amino-4-chloro-3-methylisoxazole and benzenesuIfonyl chloride in 84% yield. The crude product was purified by recrystallization using hexanes/ethyl acetate, m.p. 140°-143° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:8][CH:7]=1.I.[NH2:20][C:21]1[C:22]([C:29]([NH:31][C:32](=[NH:35])SC)=[O:30])=[N:23][C:24]([Cl:28])=[C:25]([NH2:27])[N:26]=1>C(O)C>[NH2:20][C:21]1[C:22]([C:29]([N:31]=[C:32]([NH2:35])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([N:14]([CH3:15])[CH3:16])=[O:13])=[CH:8][CH:7]=2)=[O:30])=[N:23][C:24]([Cl:28])=[C:25]([NH2:27])[N:26]=1
Reactant: CN(C)C(=O)COc1ccc(CCCCN)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCO
Product: CN(C)C(=O)COc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
A solution of 2-[4-(4-aminobutyl)phenoxy]-N,N-dimethylacetamide 29 (67 mg, 0.27 mmol) in absolute ethanol (1 mL) was stirred at 65° C. for 30 min, after which 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (110 mg, 0.29 mmol) was added in one portion. The reaction mixture was stirred at that temperature for 3 h and then cooled to room temperature. The reaction mixture was concentrated by rotary evaporation. The crude residue was triturated with water and filtered. The filter cake was purified by flash silica gel column chromatography eluting with dichloromethane/methanol/concentrated ammonium hydroxide (200:10:0, 200:10:1, v/v) to give 2-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}-phenoxy)-N,N-dimethylacetamide as a yellow solid (35 mg, 28% yield). This solid was dissolved in methanol (2 mL) and added to 4 N aqueous HCl (4 drops). Concentration in vacuo gave 2-(4-{4-[NA-(3,5-diamino-6-chloropyrazine-2-carbonyl)-guanidino]butyl}phenoxy)-N,N-dimethylacetamide hydrochloride (30, PSA 16313). mp 130-132° C. (decomposed). 1H NMR (300 MHz, CD3OD) δ 1.69 (m, 4H), 2.60 (m, 2H), 2.95 (s, 3H), 3.10 (s, 3H), 3.35 (m, 2H), 4.75 (s, 2H), 6.80 (d, 2H), 7.10 (d, 2H). m/z (ESI): 463 [C20H27ClN8O3+H]+.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1.[Na].[N-:13]=[N+:14]=[N-:15]>CN(C)C=O>[N:13]([CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)=[N+:14]=[N-:15]
Reactant: ClCCOCc1c[nH]cn1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCc1c[nH]cn1
Reaction time: 8 h
Yield: 57.7 %

Procedure:
A stirred suspension of 4-(2-chloroethoxymethyl)imidazole hydrochloride (14.7 g.) and sodium size azide (9.8 g.) in dry dimethylformamide (103 ml.) was maintained at 95° for 5 hours and then set aside overnight at room temperature. Following dilution with water and filtration, the filtrate was concentrated and the residue purified by chromatography on a dry column of alumina using ethanol. The product was basified with potassium carbonate (6.5 g.) in water (3 ml.) and the anhydrous residue was extracted with isopropyl alcohol (3×50 ml.). Concentration of the extracts afforded 4-(2-azidoethoxymethyl)imidazole (7.2 g.). Hydrogenation of the azido compound (7.2 g.) in isopropyl alcohol (142 ml.) over platinum oxide catalyst (3.0 g.) gave 4-(2-aminoethoxymethyl)imidazole (6.48 g.). A sample of the monopiocrate monohydrochloide had m.p. 139°-140° (from nitromethane). (Found: c, 35.4; H, 3.8; N, 20.5; Cl, 8.8. C12H15ClN6O8 requires: C, 35.4; H, 3.7; N, 20.7; Cl, 8.7).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:44])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:18])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:44])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[CH:33]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(N4CCOCC4)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(N4CCOCC4)c3)c1)=N2

Procedure:
The title compound was prepared from (5-ethoxy-2-{3-[3-(2-morpholin-4-yl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M287) (249 mg, 0.397 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (162 mg, 80%).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:19]([C:26]1[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:19]([C:26]1[N:31]=[CH:30][C:29]([NH:32][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: Nc1ccc(Oc2ccccc2)nc1
Product: O=C(Nc1ccc(Oc2ccccc2)nc1)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 6-phenoxypyridine-3-amine as the starting materials.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]3)=[CH:44][CH:43]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:42]4[CH:43]=[CH:44][C:45]([N:48]5[CH2:49][CH2:50][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:52][CH2:53]5)=[CH:46][CH:47]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:9]=2)[CH:12]=[N:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 42.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of step-i of example-9) (200 mg, 0.53 mmol) was coupled with tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (intermediate 40) (251 mg, 0.64 mmol) in sodium carbonate (168 mg, 1.59 mmol) PdCl2 (dppf) (19 mg, 0.0265 mmol), 1,2-Dimethoxyethane/water (25/3 ml) to afford 160 mg (59.47% yield) of the titled compound. MS: m/z=707.1 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[C:11]3/[C:12](=[O:20])[NH:13][C:14]4[C:19]/3=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:8]=2)[CH:3]=[N:2]1.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23](C2C3C(=CC(C=O)=CC=3)NN=2)[CH:22]=1>>[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]([C:3]2[C:4]3[C:9](=[CH:8][C:7]([CH:10]=[C:11]4[C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[NH:13][C:12]4=[O:20])=[CH:6][CH:5]=3)[NH:1][N:2]=2)[CH:22]=1
Reactant: O=Cc1ccc2c(-c3cnc4ccccc4c3)n[nH]c2c1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2cn[nH]c2c1
Product: O=C1Nc2ccccc2C1=Cc1ccc2c(-c3cnc4ccccc4c3)n[nH]c2c1

Procedure:
According to the procedure for the synthesis of (E)-3-((1H-indazol-6-yl)methylene)-indolin-2-one, except substituting 3-(quinolin-3-yl)-1H-indazole-6-carbaldehyde (8 mg, 0.03 mol), the title compound was obtained as a yellow solid (4.3 mg, 38%). A mixture of (E)- and (Z)-isomers (94:6 by NMR) was obtained. 1H NMR (400 MHz, d6-DMSO) δ 13.75 (br s, 1H), 10.66 (br. s, 1H), 9.61 (d, J=2.0 Hz, 1H), 9.04 (d, J=2.3 Hz, 1H), 8.47 (d, J=8.8 Hz, 1H), 8.22 (d, J=7.8 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 8.01 (s, 1H), 7.83 (s, 1H), 7.80 (td, J=6.8, 1.3 Hz, 1H), 7.68 (t, J=7.8, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 6.86 (t, J=7.8 Hz, 1H); MS ESI 389.1 [M+H]+, calcd for [C25H16N4O+H]+ 389.13.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1>CC(N(C)C)=O>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH2:4][CH2:3]1
Reactant: CN1CCCNCC1
Reactant: COC(=O)c1ccc(F)cc1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(N2CCCN(C)CC2)cc1
Temperature: 100 °C
Reaction time: 40 h
Yield: 24.1 %

Procedure:
1-Methyl-1,4-diazepane (15.07 g, 132.00 mmol) was added to methyl 4-fluorobenzoate (7.76 mL, 60 mmol) in DMA (150 mL). The resulting solution was stirred at 100° C. for 40 h. The reaction mixture was evaporated and quenched with 2M sodium hydroxide (50 ml). This was extracted with DCM (3×50 ml). The combined organic extracts were washed with saturated brine (50 ml), dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford methyl 4-(4-methyl-1,4-diazepan-1-yl)benzoate (3.59 g, 24.10%) as a tan waxy solid.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:16]=1.[OH-].[K+]>CO>[C:22]([NH:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][CH2:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[C:3]([OH:25])=[O:2])(=[O:24])[CH3:23]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1COc1cccc(NC(C)=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1cccc(OCc2cc([N+](=O)[O-])ccc2C(=O)O)c1

Procedure:
In accordance with general method V, 1.30 g (3.78 mmol) of (3) are dissolved in 20 ml of methanol, and 0.70 g (12.50 mmol) of KOH are added. Yield 1.20 g (96.1%); melting point: 225.0° C.; C167H14N2O6 (Mr=330.30)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:37][CH3:38])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1>C(O)(C)C>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH:5][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:37][CH3:38])=[C:20]([O:23][CH:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: Nc1ccc(F)c(Cl)c1F
Reactant: COc1cc2ncnc(Cl)c2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1OC1CCNCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
3-Chloro-2,4-difluoroaniline (1.7 g, 10.1 mmol) and 5N hydrogen chloride in isopropanol (2 ml) were added to a suspension of tert-butyl 4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1-carboxylate (4 g, 10.1 mmol, PCT Int. Appl. WO2003082831, AstraZeneca) in isopropanol (50 ml). The mixture was stirred at 80° C. for 3 hours. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 5-10% 7N methanolic ammonia in dichloromethane) to give 4-(3-chloro-2,4-difluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline (3.63 g, 85%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[O:19][C:18](=[O:20])[C:17]3[CH:21]=[C:22]([Cl:26])[CH:23]=[C:24]([CH3:25])[C:16]=3[N:15]=2)[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.O.[NH2:28][NH2:29].O1CCCC1>O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:17]=2[C:18]([NH:28][NH2:29])=[O:20])=[O:19])[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)cn3-c3ncccc3Cl)nc12
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)cc(C(=O)NN)c1NC(=O)c1cc(Br)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
A mixture of 0.29 g of 2-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one, 0.10 g of hydrazine monohydrate and 10 ml of tetrahydrofuran was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.30 g of 4-bromo-N-[4-chloro-2-(hydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxamide of the formula:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[O:30]1[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:35][C@H:32]2[CH2:33][CH2:34][O:30][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:26])[CH3:27])[C:6]=2[N:7]=1
Reactant: O[C@H]1CCOC1
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(Cl)c34)cc2o1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(O[C@H]5CCOC5)c34)cc2o1
Temperature: 75 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of 6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), (S)-tetrahydrofuran-3-ol (1.1 equiv) in 1,4-dioxane (0.2 M) was added sodium tert-butoxide (1.1 equiv). The reaction was stirred at 75° C. for 5 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then washed with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (magnesium sulfate), filtered, and concentrated. The crude was purified by silica gel column chromatography (0-90%) ethyl acetate in hexane) to give the title compound (90% yield) as yellow solid; 1H NMR (400 MHz, DMSO-d6) δ ppm −0.07 (s, 9H) 0.84-0.90 (m, 2H) 1.99-2.10 (m, 1H) 2.26 (dtd, J=13.96, 8.25, 8.25, 6.25 Hz, 1H) 2.63 (s, 3H) 3.53-3.62 (m, 2H) 3.73-3.81 (m, 2H) 3.84 (d, J=10.54 Hz, 1H) 3.93 (dd, J=10.54, 4.30 Hz, 1H) 5.57 (s, 2H) 5.72-5.80 (m, 1H) 7.59-7.64 (m, 1H) 7.66 (d, J=8.59 Hz, 1H) 7.89 (s, 1H) 7.91 (d, J=0.78 Hz, 1H); MS (ESI) m/z 501.1 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][N:5]=[C:4](S(C)=O)[N:3]=1.[CH2:21]([N:28]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.CCOC(C)=O>O1CCOCC1.O>[CH2:21]([N:28]1[CH2:32][CH2:31][CH:30]([NH:33][C:4]2[N:3]=[C:2]([CH3:1])[C:7]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])=[CH:6][N:5]=2)[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1nc(S(C)=O)ncc1C(=O)OCc1ccccc1
Reactant: NC1CCN(Cc2ccccc2)C1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(NC2CCN(Cc3ccccc3)C2)ncc1C(=O)OCc1ccccc1
Yield: 86 %

Procedure:
A solution of benzyl 4-methyl-2-(methylsulfinyl)-5-pyrimidinecarboxylate (3.27 g), 1-benzyl-3-aminopyrrolidine (2.98 g) and N,N-diisopropylethylamine (1.75 g) in dioxane (15 ml) was stirred at 130° C. for 11 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on allumina eluting with AcOEt-n-hexane (5:5). The eluted fractions containing the desired product were collected and evaporated in vacuo to give benzyl 2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinecarboxylate (3.9 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35](Cl)=[N:34][C:33]([C:37]#[N:38])=[C:32]([C:39]#[N:40])[N:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O)(=O)C>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([O:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[N:34][C:33]([C:37]#[N:38])=[C:32]([C:39]#[N:40])[N:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: OCc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(C#N)c(C#N)nc2Cl)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(C#N)c(C#N)nc2OCc2ccncc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.8 %

Procedure:
To a solution of 4-pyridylcarbinol (0.44 mmol, 45 mg) and anhydrous tetrahydrofuran (3 ml) cooled at 0° C. was added LDA (2M, 0.6 mmol, 300 ul). The mixture was stirred at 0° C. for 15 minutes. A solution of 3′-Chloro-5′,6′-dicyano-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (0.29 mmol, 100 mg) in THF (2 ml) was then added to the cold mixture and stirred at 0° C. for 1 hour. Reaction mixture was poured onto 0.5M acetic acid and extracted with ethyl acetate. The crude product was purified by column chromatograph on silica using 70% EtOAc/hexanes to yield product 5′,6′-Dicyano-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (100 mg).
Reaction SMILES: [CH3:1][O:2]C1C=C(C2C(N3CCNCC3)=C3C=CNC3=NC=2)C=CC=1.[C:24]([O:28][C:29]([N:31]([CH:44]([CH3:46])[CH3:45])C[C@H](C1C=CC(Cl)=CC=1)C(O)=O)=[O:30])([CH3:27])(C)C.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:2]=[CH:1][CH2:27][CH2:24][O:28][C:29](=[O:30])[NH:31][CH:44]([CH3:45])[CH3:46]
Reactant: COc1cccc(-c2cnc3[nH]ccc3c2N2CCNCC2)c1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)NC(=O)OCCC=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 213 %

Procedure:
5-(3-Methoxyphenyl)-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyri dine (0.045 g, 0.118 mmol, see Example 8) and (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0424 g, 0.124 mmol, see Example H) were placed in DCM (3 mL). HOBT-H2O (0.0253 g, 0.165 mmol), EDCI (0.0294 g, 0.153 mmol), and DIEA (d 0.742; 0.103 mL, 0.590 mmol) were then added, and the reaction was stirred at room temperature for 2 hours. The reaction was then quenched with saturated Na2CO3 and extracted with DCM. The product was dried, filtered, and concentrated to give the crude product. The crude product was purified (500:5 DCM:MeOH) to yield (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-(3-methoxyphenyl)-1H-pyrrolo[2, 3-1)]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.040 g, 53.6% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=S)[NH:11][NH2:12].Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:21]([CH3:23])[NH:12][N:11]=1
Reactant: NNC(=S)Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2c(Cl)cccc2Cl)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A slurry of 9.4 g (0.04 mole) of 4-(2,6-dichlorophenyl)-3-thiosemicarbazide in 75 mL of absolute ethanol was stirred under nitrogen atmosphere while 6.8 g (0.04 mole) of ethyl 2-chloroacetoacetate was added. The reaction mixture became yellow as it stirred for 1 hr at room temperature. Then 40 mL of 2N ethanolic hydrogen chloride was added and the reaction mixture heated at reflux for 3 hr. Insoluble sulfur was removed by filtration and the filtrate concentrated in vacuo to give an orange solid, which when triturated with hot acetone yielded 11.3 g of pale yellow crystals, mp: plastic 175°-191° C., degasses at 195° C. and forms a clear melt at 215° C. Recrystallization from acetonitrile gave 6.5 g of product, mp 180°-190° C. Additional material was obtained from the reaction mixture filtrate upon setting. The filtrate was then concentrated to a solid. All crude materials were combined and dissolved in 125 mL of benzene, treated with charcoal, filtered, and the volume reduced to 40 mL. The benzene solution was treated with 25 mL of ligroin and the product crystallized from the hot solution to give 9.7 g of crystalline product which had a pink color, mp 191°-192° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>>[CH:29]1([NH:32][C:6]2[C:5]3[C:10](=[CH:11][C:2]([F:1])=[C:3]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:4]=3)[N:9]=[C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)[N:7]=2)[CH2:31][CH2:30]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Reactant: NC1CC1
Product: O=C(O)c1cnn(-c2nc(NC3CC3)c3cc(N4CCCCC4)c(F)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropylamine in step E. MS (ESI): predicted mass calcd. for C20H21FN6O2, 396.2