Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=2)[CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:46][C:45]5[CH:44]=[CH:43][C:42]([CH2:41][N:38]6[CH2:37][CH2:36][N:35]([CH3:34])[CH2:40][CH2:39]6)=[CH:48][CH:47]=5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2ccc(CN3CCN(C)CC3)cc2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
In a dry round bottom flask, 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (89.4 mg, 0.2 mmol), 4-((4-methylpiperazin-1-yl)methyl)aniline hydrochloride (66.7 mg, 0.24 mmol) were dissolved in dry N,N-dimethylformamide (3.0 mL). Then added diisopropylethylamine (107 μL, 0.6 mmol) and finally HATU (114 mg, 0.3 mmol) to the reaction, continued at room temperature for 2 hours. After completion, purified the product using reverse phase HPLC using water-acetonitrile solvent system. Pure fractions were mixed and evaporated to a minimal amount then basified with sat.NaHCO3 solution and extracted into EtOAc ((2×100 mL), combined organic layer was washed with sat. brine solution, dried over Na2SO4 and evaporated to get the pure product 72 mg (57% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.80 (m, 6H) 1.97 (br. s., 2H) 2.15 (s, 3H) 2.34 (br. s., 8H) 3.42 (s, 2H) 3.93 (s, 3H) 4.07 (t, J=12 Hz, 2H) 4.80 (t, J=8.21 Hz, 1H) 7.26 (d, J=8.59 Hz, 2H) 7.51-7.67 (m, 2H) 7.70 (m, J=8.59 Hz, 2H) 8.05 (s, 1H) 8.29 (s, 1H) 8.37 (d, J=8.34 Hz, 1H) 10.09 (s, 1H). [M+H] calc'd for C33H40F2N8O3, 635. found 635.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH:5]=1)[CH3:2].C([N-]C(C)C)(C)C.[Li+].CN(C)P(N(C)C)(N(C)C)=O.Br[CH2:31][CH2:32][CH:33]=[CH2:34].O>O1CCCC1>[CH2:34]([CH:7]1[C:6](=[O:10])[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH2:9][CH2:8]1)[CH2:33][CH:32]=[CH2:31]
Reactant: CCOC1=CC(=O)CCC1
Reactant: C=CCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: C=CCCC1CCC(OCC)=CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
A solution of 25 g. (0.178 mole) of 3-ethoxy-2-cyclohexen-one in 25 ml. of tetrahydrofuran was added dropwise over a 30 minute period to a -78° C. solution of 0.196 mole of lithium diisopropylamide (from 27.4 ml., 0.196 mole, of diisopropylamine and 85 ml., 0.187 moles of 2.2M n-butyllithium in hexane) in 125 ml. of tetrahydrofuran. The reaction was then stirred for 30 minutes and 65 ml. (0.374 mole) of hexamethylphosphoramide added followed by 38.9 ml. (0.383 mole) of 4-bromo-l-butene. The reaction was then allowed to warm to room temperature, stirred for 1.5 hours and then quenched by addition of 5 ml. (0.277 mole) of water. Most of the solvent was removed on a rotovapor and the residue diluted with 1000 ml. ice water and 500 ml. ether. The ether phase was separated, washed with two 300 ml. portions of water, dried over magnesium sulfate and evaporated on a rotovapor. Distillation of the resulting crude oil gave 10.1 g. (29%) of the title product.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[C:12]3[C:32](Cl)=[CH:33][CH:34]=[N:35][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([SH:51])=[CH:47][CH:46]=1>CN(C=O)C.CCOC(C)=O>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[C:12]3[C:32]([S:51][C:48]4[CH:49]=[CH:50][C:45]([O:44][CH3:43])=[CH:46][CH:47]=4)=[CH:33][CH:34]=[N:35][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(S)cc1
Reactant: CN1CCN(c2ccc(-c3ccc4c(c3)c3c(Cl)ccnc3n4S(=O)(=O)c3ccccc3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Sc2ccnc3c2c2cc(-c4ccc(N5CCN(C)CC5)cc4)ccc2n3S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a suspension of 9-Benzenesulfonyl-4-chloro-6-[4-(4-methyl-piperazin-1-yl)-phenyl]-9H-pyrido[2,3-b]indole (Building block A) (60 mg) in DMF (1.2 mL), under Argon, K2CO3 (56 mg, 3.5 equiv.) and 4-methoxythiophenol (0.029 mL, 2 equiv.) were added. After stirring for 0.5 h at r.t., the reaction mixture was diluted with AcOEt (20 mL), washed with sat. aqueous NH4Cl (20 mL) and brine (20 mL) The organic layer was dried over MgSO4, filtered and evaporated to dryness. The trituration procedure afforded the desired compound in 72% yield as a beige solid. 1H-NMR (300 MHz, CDCl3) δ=8.55 (d, J=8.8 Hz, 1H), 8.48 (d, J=1.6 Hz, 1H), 8.21 (d, J=5.4 Hz, 1H), 8.18-8.09 (m, 2H), 7.77 (dd, J=8.8, 1.9 Hz, 1H), 7.65 (d, J=8.7 Hz, 2H), 7.57-7.48 (m, 3H), 7.45-7.35 (m, 2H), 7.04 (d, J=7.8 Hz, 2H), 7.01 (d, J=8.7 Hz, 2H), 6.53 (d, J=5.5 Hz, 1H), 3.88 (s, 3H), 3.47-3.33 (m, 4H), 2.90-2.74 (m, 4H), 2.51 (s, 3H). 13C-NMR (75 MHz, CDCl3) δ=161.4 (C), 150.7 (C), 150.6 (C), 147.7 (C), 146.0 (CH), 138.8 (C), 137.7 (2 CH), 137.1 (C), 136.0 (C), 134.0 (CH), 131.9 (C), 129.0 (2 CH), 128.0 (2 CH), 127.6 (2 CH), 126.5 (CH), 123.8 (C), 121.5 (CH), 118.2 (C), 116.3 (2 CH), 115.8 (2 CH), 115.1 (CH), 114.8 (CH), 114.6 (C), 55.5 (CH3), 55.1 (2 CH2), 48.8 (2 CH2), 46.2 (CH3). ESI-MS: m/z 621.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[CH2:10]([NH:7][C:5](=[O:6])[CH:4]1[CH2:8][CH2:9][NH:1][CH2:2][CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)C1CCNCC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1ccccc1)C1CCNCC1
Yield: 51.7 %

Procedure:
To a suspension of isonipecotamide (12.3 g, 96 mmol) in 200 mL of dichloromethane, was added, benzaldehyde (10.6 g, 100 mmol) and sodium triacetoxyborohydride (29.7 gm, 140 mmol) and the mixture was stirred at room temperature for 5 days. The thick white mixture was diluted with 100 mL water and extracted with EtOAc (2×20 mL). The aqueous phase was basified with 1N NaOH to pH>12. The resulting white precipitate was collected by suction filtration. The white solid was subsequently taken up in 50 mL of EtOAc, and was washed with 20 mL of brine, then dried (MgSO4), filtered and concentrated to give 10.84 g (50%) of the desired product. 1H-NMR (400 MHz, CDCl3) δ7.85 (m, 5H), 5.45 (s, 1H), 5.34 (s, 1H), 3.5 (s, 2H), 2.93 (d, J=10.96 Hz, 2H), 2.16 (t, J=12.13 Hz, 1H), 2.01 (t, J=11.74 Hz, 2H), 1.87 (d, J=12.52 Hz, 2H), 1.76 (q, J=12.52 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][CH2:9][CH:10]([NH:20]C(=O)OC(C)(C)C)[CH2:11][N:12]2[CH:17]3[CH2:18][CH2:19][CH:13]2[CH2:14][NH:15][CH2:16]3)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[CH2:37]([N:41]=[C:42]=[O:43])[CH2:38][CH2:39][CH3:40]>CC#N>[NH2:20][CH:10]([CH2:9][CH2:8][O:7][C:6]1[CH:28]=[CH:29][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:11][N:12]1[CH:13]2[CH2:19][CH2:18][CH:17]1[CH2:16][N:15]([C:42]([NH:41][CH2:37][CH2:38][CH2:39][CH3:40])=[O:43])[CH2:14]2
Reactant: CCCCN=C=O
Reactant: CC(C)(C)OC(=O)NC(CCOc1ccc(C#N)cc1)CN1C2CCC1CNC2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCNC(=O)N1CC2CCC(C1)N2CC(N)CCOc1ccc(C#N)cc1
Reaction time: 96 h

Procedure:
tert-Butyl 3-(4-cyanophenoxy)-1-(3,8-diazabicyclo[3.2.1]oct-8-ylmethyl)propylcarbamate (100.1 mg, 0.25 mmol; see Preparation M) was dissolved in MeCN (2.5 mL) and triethylamine (37.9 mg, 0.38 mmol). Butylisocyanate (29.7 mg, 0.3 mmol) was added and the reaction mixture was stirred at r.t for 4 days. The solvent was evaporated and the resulting residue dissolved in ethyl acetate (0.5 mL). Ethyl acetate saturated with HCl (2 mL) was added and the mixture was stirred for 6 h. The solvent was evaporated and the residue dissolved in MeCN (2 mL). The solution was added to ion-exchange solid phase extraction plug. The plug was then eluted with DCM/MeCN (4×2 mL of 4:1) (fraction 1) followed by DCM:MeOH:Et3N (4×2 mL of 8:1:1)(fraction 2). Evaporation of fraction 2 gave the title compound in quantitative yield.
Reaction SMILES: Br[C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[N:4][N:5]([CH3:7])[CH:6]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.C(O[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)(C)C.CC1CCCO1>C1COCC1.O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[C:2]([B:26]3[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]3)=[CH:6][N:5]([CH3:7])[N:4]=2)=[CH:9][CH:10]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cn1cc(Br)c(-c2ccc(F)cc2)n1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CC1CCCO1
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc(F)cc2)n1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazole (700 g, 2.74 mol) in THF (1.4 L) was cooled to 15° C. and isopropylmagnesium chloride lithium chloride complex (1.3M in THF, 3.8 L, 4.94 mol) was added slowly while maintaining the reaction temperature below 25° C. The mixture was stirred for 3 hr at 20° C. and a 10° C. solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (610 g, 3.28 mol) in THF (1.4 L) was added dropwise while maintaining an internal temperature below 20° C. The resulting green/brown hazy solution as stirred for 1 hr between 10° C. and 20° C. after which time it was cooled to 10° C. Water (5.6 L) cooled to 10° C. was added slowly to the reaction mixture so that the reaction temperature stayed below 25° C. Celite (1.4 kg) was added followed by 2-methyltetrahydrofuran (7 L) and the mixture was stirred for 15 min at 20° C. The mixture was filtered through Celite and the filter pad was rinsed with 2-methyltetrahydrofuran (8 L). The organic phase was separated and washed with brine (5.6 L) then concentrated under vacuum to a low stir volume. The material was diluted with EtOH (3 L) and reconcentrated. This material was re-dissolved in EtOH (3.5 L) and water (4.2 L) was added over 30 min with strong stirring. The resulting slurry was stirred at 15° C. for 1 hr, filtered and washed with 4 volumes of water. The resulting cake was blown dry then further dried in a vacuum oven at 40° C. to yield 0.4 kg (48%) of Ex 1-Step 1 product as a white solid: APCI MS m/z 303.2 (M+1); 1H NMR (400 MHz, CDCl3) δ 7.91 (dd, J=8.9, 5.6, 2H), 7.70 (s, 1H), 7.03 (dd, J=8.8, 8.8, 2H), 3.90 (s, 3H), 1.29 (s, 12H).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[NH:29]1[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]1>>[CH3:28][N:2]([CH3:1])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:29]4[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Reactant: OC1CCNCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(CN4CCC(O)CC4)cn3)nc2n1C1CCCC1

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.2 g, 0.529 mmol) and piperidin-4-ol (56 mg, 0.556 mmol) gave 7-cyclopentyl-2-[5-(4-hydroxy-piperidin-1-ylmethyl)pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide is obtained as a white solid (25 mg, 10%) [following purification by preparative LCMS and further purification by SiO2 chromatography, eluting with 0-7% (2N NH3 in MeOH/EtOAc). MS (ESI) m/z 464.3 (M+H)+ (method B).
Reaction SMILES: C([N:4](CC)[CH:5]([CH3:7])[CH3:6])(C)C.[F:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:21]3[N:22]=[C:23]4[C:29]([C:30]([OH:32])=O)=[CH:28][N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:24]4=[N:25][CH:26]=3)=[N:16][N:17]2[CH3:20])=[CH:13][CH:12]=1.CN(C(O[N:49]1N=N[C:51]2[CH:52]=[CH:53]C=N[C:50]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>FC(F)(F)C(O)=O.N[C@@H]1CC[C@H](CC#N)C1.CN(C=O)C>[C:50]([CH2:51][C@@H:52]1[CH2:53][CH2:6][C@H:5]([NH:4][C:30]([C:29]2[C:23]3[C:24](=[N:25][CH:26]=[C:21]([C:15]4[C:14]5[C:18](=[CH:19][C:11]([F:10])=[CH:12][CH:13]=5)[N:17]([CH3:20])[N:16]=4)[N:22]=3)[N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:39])[CH3:40])[CH:28]=2)=[O:32])[CH2:7]1)#[N:49]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CC[C@H]1CC[C@@H](N)C1
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CC[C@@H](CC#N)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.5 %

Procedure:
In a round-bottomed flask, (cis-3-amino-cyclopentyl)-acetonitrile trifluoroacetate (crude from Step 6) was dissolved in DMF (1.3 ml) and N,N-diisopropylethylamine (0.65 ml, 3.72 mmol) was added. Then, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (110 mg, 0.25 mmol) and HATU (104 mg, 0.27 mmol) were added. The yellow solution was stirred at room temperature for 48 h. Water and petroleum ether were added and the resulting suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum to afford 128 mg (94%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-3-cyanomethyl-cyclopentyl)-amide as an off-white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:12][C:13]1[N:18]=[C:17]([NH2:19])[CH:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=1.CN1CCOCC1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:19][C:17]2[CH:16]=[C:15]([C:20]([F:22])([F:21])[F:23])[CH:14]=[C:13]([CH3:12])[N:18]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: Cc1cc(C(F)(F)F)cc(N)n1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)cc(NC(=O)Cc2ccc(Br)cc2)n1
Yield: 62.3 %

Procedure:
Dissolve 4-bromo-phenylacetic acid (660 mg, 3.07 mmol) and 6-methyl-4-trifluoromethyl-pyridin-2-ylamine (500 mg, 2.84 mmol) in 10 mL dry THF. Add 4-methyl morpholine (345 mg, 0.375 mL, 3.4 mmol), stir a few minutes under nitrogen atmosphere, then add DMTMM (865 mg, 3.12 mmol) and stir the pale yellow slurry overnight. Dilute slurry with 90 mL EtOAc, wash twice each with saturated aqueous NaHCO3 and aqueous saturated sodium chloride, then dry the organic layer over MgSO4 and concentrate to give an ivory crystalline solid. Purify this solid on a 120 g silica cartridge with 0→5% EtOAc in dichloromethane to give 660 mg (62%) of the title compound as a white crystalline solid. LCMS (ES) m/z 373/375 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1)=[CH2:2].[K+].Cl[CH2:14][C:15]([O:17][CH3:18])=[O:16]>CS(C)=O>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])(=[O:11])=[O:10])=[CH:7][CH:8]=1)=[CH2:2]
Reactant: COC(=O)CCl
Reactant: C=Cc1ccc(S(=O)[O-])cc1
Agent: [K+]
Solvent: CS(C)=O
Product: C=Cc1ccc(S(=O)(=O)CC(=O)OC)cc1
Temperature: 50 °C

Procedure:
To 188 ml of dimethyl sulfoxide was added 54.2 g of potassium p-vinylbenzenesulfinate, and the resulting mixture was stirred while heating at 50° C. Then, 23.0 ml of methyl chloroacetate was added dropwise to the mixture over 1 hour while maintaining it at 50° C., and the resulting mixture was stirred for 1 hour while maintaining at 50° C. The reaction mixture was cooled to room temperature and extracted with ethyl acetate, and the ethyl acetate was distilled away at an outer temperature of not more than 40° C. to yield 60.1 g of oily methyl p-vinylbenzenesulfonylacetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[NH2:33][C:34]1[CH:56]=[CH:55][C:54]([N:57]2[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]2)=[CH:53][C:35]=1[C:36]([NH:38][C:39]1[N:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([CH3:52])[CH:46]=2)=[CH:41][N:40]=1)=[O:37]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:52][C:47]1[CH:46]=[C:45]([C:42]2[CH:41]=[N:40][C:39]([NH:38][C:36]([C:35]3[CH:53]=[C:54]([N:57]4[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]4)[CH:55]=[CH:56][C:34]=3[NH:33][C:14]([C:13]3[CH:12]=[C:11]([CH:19]=[CH:18][CH:17]=3)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])=[O:16])=[O:37])=[N:44][CH:43]=2)[CH:50]=[CH:49][C:48]=1[CH3:51]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3N)nc2)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)nc2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 200 %

Procedure:
In a round bottom flask was placed a solution of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (88.6 mg, 0.30 mmol, 1.20 equiv) in dichloromethane (15 mL), EDC.HCl (143.2 mg, 0.75 mmol, 3.00 equiv), 4-dimethylaminopyridine (152.1 mg, 1.24 mmol, 5.00 equiv), and 2-amino-N-(5-(3,4-dimethylphenyl)pyrimidin-2-yl)-5-(piperidin-1-yl)benzamide (100 mg, 0.25 mmol, 1.00 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The resulting solution was diluted with 50 mL of dichloromethane. The resulting mixture was washed with 1×20 mL of diluted hydrochloric acid and 2×30 mL of brine. The mixture was dried over sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 340 mg of crude product as a brown syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:16]([O:20][C:21](=[O:46])[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([NH:32][S:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])=[CH:31][C:26]=2[N:25]=[C:24]1[CH2:43][CH2:44][CH3:45])([CH3:19])([CH3:18])[CH3:17]>CC#N.CCOC(C)=O.O>[C:16]([O:20][C:21](=[O:46])[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([N:32]([CH2:6][C:5]3[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=3)[S:33]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)(=[O:34])=[O:35])=[CH:31][C:26]=2[N:25]=[C:24]1[CH2:43][CH2:44][CH3:45])([CH3:19])([CH3:18])[CH3:17]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCCc1nc2cc(N(Cc3ccc(Cl)cc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Chlorobenzyl chloride (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:25][CH2:24]3)=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:32])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:25][CH2:24]3)=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)C2CC2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)C2CC2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(cyclopropylcarbonyl)piperazin-1-yl]quinolin-7-yl}ethanone (0.021 g, 0.059 mmol) and ammonium acetate (0.0452 g, 0.587 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.14 mL, 0.14 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C19H24ClN4O (M+H)+: m/z=359.2; Found: 359.1.
Reaction SMILES: C(O)(=O)CO.[Br:6][CH2:7][C:8]([OH:10])=[O:9].[O:11]1[CH:15]=[CH:14][CH2:13][CH2:12]1>>[O:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[O:9][C:8](=[O:10])[CH2:7][Br:6]
Reactant: O=C(O)CBr
Reactant: C1=COCC1
Agent: O=C(O)CO
Product: O=C(CBr)OC1CCCO1

Procedure:
The glycolic acid derivative is obtained by reacting 6.95 g (0.05 mol) of bromoacetic acid and 2.80 g (0.4 mol) of 2,3-dihydrofuran at room temperature in the absence of moisture, and stirring the mixture after 5 hours (bromoacetic acid is converted quantitatively). This reaction solution was employed in the following synthesis step, without isolation. The glycolic acid derivative has the formula: ##STR6##
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.CN(C)C=O.ClCCl.[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C>Cl>[NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:21])[CH:27]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(Br)cnc1N
Reactant: Nc1cccc(B(O)O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(-c2cccc(N)c2)cnc1N
Temperature: 87.5 °C
Yield: 54.3 %

Procedure:
To a solution of 3-amino-6-bromo-N-methyl-2-pyrazinecarboxamide (1.23 g, 5.30 mmol) in N,N-dimethylformamide (30 mmol) were added [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1, 433 mg, 0.53 mmol), 3-aminophenylboronic acid (1.15 g, 7.41 mmol), and triethylamine (1.07 g, 10.6mmol). The solution was degassed with nitrogen 3-5 min. The reaction was heated at 85-90° C. for 15 h with stirring. The reaction was allowed to cool to room temperature and diluted with ethyl acetate (400 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (50 mL), saturated aqueous sodium chloride (50 mL), dried over magnesium sulfate, filtered, and concentrated to give crude product. To the crude product was added 4.0 N hydrochloric acid (1,4-dioxane solution, 30 mL). The resulting solid was filtered and washed with diethyl ether/methanol (4:1). The solid was dissolved in methanol and neutralized with sufficient AG 1-X8 Resin (hydroxide form) that the pH of the solution became basic. The mixture was filtered, and the filtrate was concentrated on a rotary evaporator at reduced pressure to afford 3-Amino-6-(3-aminophenyl)-N-methylpyrazine-2-carboxamide (0.70 g, 54% yield) as dark green solid. 1H NMR (400 MHz, d6-DMSO): 8.70(br s, 1H), 8.62 (s, 1H), 7.60 (br s, 2H), 7.25 (m, 2H), 7.10 (t,. 1H), 6.15 (d, 1H), 5.06 (s, 2H), 2.8 (br s, 3H); MS (EID for C12H13N5O: 244 ).