Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([NH2:36])[CH2:35][CH2:34][CH2:33]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:44][N:45]([CH3:49])[C:46](Cl)=[O:47]>O1CCCC1.O>[Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([NH:36][C:46](=[O:47])[N:45]([CH3:49])[CH3:44])[CH2:33][CH2:34][CH2:35]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(-c4cnc(C5(N)CCC5)s4)c(Cl)cnc32)cc1
Reactant: CN(C)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(-c4cnc(C5(NC(=O)N(C)C)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 70 °C

Procedure:
A mixture of 1-(5-(5-chloro-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanamine (40 mg, 0.074 mmol) (Example 121A) in anhydrous tetrahydrofuran (1 mL) was treated with triethylamine (0.014 ml, 0.104 mmol) and dimethylcarbamoyl chloride (8.18 μl, 0.089 mmol), and the reaction mixture was heated to 70° C. for 16 hours. Additional dimethylcarbamoyl chloride (4.09 μl, 0.044 mmol) and triethylamine (0.007 ml, 0.052 mmol) were added, and reaction solution heated for another 16 hours at 70° C. The reaction was cooled, diluted with water, and extracted with dichloromethane. The extracts were combined and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 2 to 5% methanol in dichloromethane, to provide the title compound. MS ESI(+) m/z 610.3 [M+H]+.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:10]=1.CC1(C)C(C)(C)OB([C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[N:40][CH:39]=2)O1.C(=O)([O-])O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:11]2[CH:10]=[C:9]([C:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:41]=[N:40][CH:39]=3)[CH:21]=[CH:20][C:12]=2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: CC1(C)OB(c2cncc3ccccc23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2cncc3ccccc23)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
To a mixed solution of toluene 4.0 mL, ethanol 1.2 mL and water 0.6 mL of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.20 g were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline 0.17 g, sodium hydrogen carbonate 0.12 g and tetrakis(triphenylphosphine)palladium(0) 35 mg, and it was heated and refluxed under nitrogen atmosphere for 4 hours. After the reaction mixture was cooled to room temperature, tetrakis(triphenylphosphine)palladium(0) 35 mg was added to it, and it was heated and refluxed under nitrogen atmosphere for 4 hours. After the reaction mixture was cooled to room temperature, and water was added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=2:1] to give tert-butyl 2-(4-fluoroanilino)-4-(isoquinolin-4-yl)benzoate 0.11 g of pale red solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]2[CH2:16][C:13]3([CH2:15][CH2:14]3)[CH2:12][CH:11]2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.Cl.[NH2:21][CH2:22][C:23]#[N:24].F[P-](F)(F)(F)(F)F.N1([PH+](N2CCCC2)N2CCCC2)CCCC1.C(N(CC)CC)C>CN(C)C=O>[C:22]([CH2:23][NH:24][C:17]([CH:11]1[CH:10]([CH2:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:16][C:13]2([CH2:14][CH2:15]2)[CH2:12]1)=[O:19])#[N:21]
Reactant: O=C(O)C1CC2(CC2)CC1CSc1ccc(F)cc1
Reactant: N#CCN
Agent: C1CCN([PH+](N2CCCC2)N2CCCC2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCNC(=O)C1CC2(CC2)CC1CSc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 11 h

Procedure:
To (5R/S,6R/S)-6-{[(4-fluorophenyl)sulfanyl]methyl}spiro[2.4]heptane-5-carboxylic acid (59 mg, 0.21 mmol) was added aminoacetonitrile hydrochloride (30 mg, 0.32 mmol) and benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (120 mg, 0.23 mmol) and dimethylformamide (0.70 mL). The reaction mixture was cooled to 0° C. and triethylamine (90 PL, 0.65 mmol) was added. After stirring for 11 h, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. Chromatography of the residue on silica gel with 35:65 ethyl acetate:hexanes provided the title compound as a of a colorless, waxy solid. 1H NMR (500 MHz, acetone-d6): δ=7.76 (1H, br s), 7.40 (2H, dd), 7.08 (2H, t), 4.22 (2H, d), 3.15 (1H, dd), 2.93 (1H, dd), 2.75 (1H, dd), 2.66 (1H, m), 1.90 (1H, dd), 1.86 (1H, dd), 1.50 (1H, dd), 0.45 (4H, m). MS [APCI, (M−H)−] m/z=317.0 amu.
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][NH:5]1)#[N:2].[H-].[Na+].Cl[CH2:12][C:13]#[C:14][CH2:15][NH:16][C:17](=[O:32])[C:18]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CS(C)=O>[C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][N:5]1[CH2:12][C:13]#[C:14][CH2:15][NH:16][C:17](=[O:32])[C:18]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)([OH:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)#[N:2]
Reactant: N#CN=C1NCCN1
Reactant: O=C(NCC#CCCl)C(O)(c1ccccc1)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CN=C1NCCN1CC#CCNC(=O)C(O)(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 75.2 %

Procedure:
To a solution of 2-(cyanoimino)imidazolidine (0.28 g) in dimethyl sulfoxide (10 ml}was added 60% sodium hydride dispersed in mineral oil (0.1 g) and the mixture was stirred at room temperature for 25 minutes. After an addition of N-(4-chloro-2-butynyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide (0.40 g), the mixture was stirred at the same temperature for further 45 minutes and then quenched with cold water (50 ml). The mixture was extracted with ethyl acetate (50 ml×3). The combined extracts were washed with sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol (20:1) as an eluent to give N-[4-{2-(cyanoimino)-1-imidazolidinyl}-2-butynyl]-2-cyclohexyl-2-hydroxy-2-phenylacetamide (0.37 g).
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:50]([NH:57][CH2:58][CH2:59][NH2:60])([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:12](=[O:14])[NH:60][CH2:59][CH2:58][NH:57][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:15][CH2:16]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 97.4 %

Procedure:
General procedure A was followed using N-Boc-isonipecotic acid (0.20 g, 0.86 mmol), HATU (0.43 g, 1.1 mmol), DIPEA (0.76 mL, 4.4 mmol), N-Boc-ethylenediamine (0.18 g, 1.1 mmol) and DMF (4 mL) to furnish the title compound as a beige solid (311 mg, 96%), m.p. 172-174° C.; umax (CHCl3)/cm−1 3022, 2981, 1684, 1671, 1507, 1367, 1241, 1165; m/z (ESI) C18H33N3NaO5 requires 394.2312, found [M+Na]+ 394.2310.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11](Cl)=[O:12].[CH2:14]([O:16][CH:17]([O:30][CH2:31][CH3:32])[CH2:18][CH2:19][CH2:20][NH:21]C(C1CCCCC1)=O)[CH3:15]>>[CH2:31]([O:30][CH:17]([O:16][CH2:14][CH3:15])[CH2:18][CH2:19][CH2:20][NH:21][C:11]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:12])[CH3:32]
Reactant: CCOC(CCCNC(=O)C1CCCCC1)OCC
Reactant: O=C(Cl)N1CCc2ccccc2C1
Product: CCOC(CCCNC(=O)N1CCc2ccccc2C1)OCC

Procedure:
3,4-Dihydro-1H-isoquinoline-2-carboxylic acid (4,4-diethoxy-butyl)-amide (24B) is prepared from 24A as described for 20A.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:10](=[O:11])[CH2:9][CH:8]([C:12]([OH:14])=[O:13])[CH2:7]1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[O:11]=[C:10]1[NH:6][CH2:7][CH:8]([C:12]([OH:14])=[O:13])[CH2:9]1
Reactant: COc1ccc(CN2CC(C(=O)O)CC2=O)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(C(=O)O)CN1
Temperature: 80 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
To an optically active compound of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (14.3 g) were added anisole (8.4 ml) and trifluoroacetic acid (100 ml), and the mixture was stirred at 80° C. for 5 hours. This reaction solution was cooled to room temperature, and concentrated under reduced pressure. To the resulting residue was added diisopropyl ether (100 ml), and the mixture was stirred at room temperature. The insoluble substance was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to give the titled compound (4.96 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1(C)C=CC(S(O[CH2:17][CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([F:26])[C:20]=2[F:27])(=O)=O)=CC=1.O.[OH-].[Na+]>C(OCC)C>[F:27][C:20]1[C:21]([F:26])=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[CH2:18][CH3:17]
Reactant: Cc1ccc(S(=O)(=O)OCCc2c(F)ccc(F)c2F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCc1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.9 %

Procedure:
Lithium aluminum hydride (5.6 g) is suspended in dry diethyl ether (70 ml) and thereto is added dropwise with stirring a solution of 1-[2-(p-toluenesulfonyloxy)ethyl]-2,3,6-trifluorobenzene (23.3 g) in dry diethyl ether (170 ml) at below 10° C., and the mixture is stirred at room temperature for one hour. To the reaction mixture are added water (5.6 ml), 10% aqueous sodium hydroxide (10.0 ml) and water (5.6 ml) in this order, and the mixture is stirred at room temperature for 30 minutes. The resulting white precipitates are filtered off, and the filtrate is concentrated under atmospheric pressure to give 2,3,6-trifluoro-1-ethylbenzene (13.2 g), as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][C:9](=[O:22])[CH:10]=[CH:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][CH:17]([CH3:21])[O:18][C:19](=[O:20])[C:6]=2[C:5]([O:23]COCC)=[CH:4][C:3]=1[O:28]COCC.CC1(C)O[O:35]1>CC#N>[CH3:21][C@@H:17]1[O:18][C:19](=[O:20])[C:6]2[C:5]([OH:23])=[CH:4][C:3]([OH:28])=[C:2]([Cl:1])[C:7]=2[CH2:8][C:9](=[O:22])[CH:10]=[CH:11][CH2:12][CH2:13][C@H:14]2[O:35][C@@H:15]2[CH2:16]1
Reactant: CC1(C)OO1
Reactant: CCOCOc1cc(OCOCC)c2c(c1Cl)CC(=O)C=CCCC=CCC(C)OC2=O
Agent: C[C@H]1C[C@H]2O[C@@H]2CC/C=C/C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: CC#N
Product: C[C@H]1C[C@H]2O[C@@H]2CCC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reaction time: 1.5 h

Procedure:
To a solution of compound 2-112 (50 mg, 0.11 mmol) in CH3CN (5 mL) at 0° C. was added freshly made DMDO (275 μL, 0.11 mmol, 0.04 M in acetone) and the mixture was stirred for 1.5 h. After evaporation of the solvents under reduced pressure, purification by flash chromatography (silica gel, 0-70% Et2O/hexane gradient) afforded compound 2-122 (41 mg, 79%) as a 1:1 mixture of two diastereoisomers. 1H NMR (400 MHz, CDCl3, 25° C.): δ=7.12 (s, 1H), 7.11 (s, 1H), 6.90-6.76 (m, 2H), 6.11 (d, J=15.6 Hz, 1H), 6.05 (d, J=15.8 Hz, 1H), 5.37-5.27 (m, 6H), 5.26-5.21 (m, 4H), 4.14 (d, J=16.9 Hz, 1H), 4.12 (d, J=17.4 Hz, 1H), 4.04 (d, J=17.2 Hz, 1H), 3.82-3.70 (m, 9H), 2.81-2.78 (m, 1H), 2.74-2.72 (m, 1H), 2.67-2.62 (m, 2H), 2.38-2.11 (m, 8H), 2.05-2.03 (m, 1H), 2.03-2.00 (m, 1H), 1.74-1.60 (m, 2H), 1.41 (d, J=7.2 Hz, 3H), 1.39 (d, J=6.2 Hz, 3H), 1.27-1.22 (m, 12H); 13C NMR (100 MHz, CDCl3, 25° C.): δ=195.1 (×2), 166.7, 166.3, 154.9, 154.8, 154.0, 153.5, 147.8, 147.4, 132.9, 132.4, 129.1, 129.0, 119.7 (×2), 118.0, 117.9, 102.9, 102.8, 93.9 (×2), 93.6 (×2), 71.1, 70.4, 64.8 (×2), 64.6 (×2), 58.4, 57.6, 56.9, 55.1, 43.4 (×2), 39.0, 37.9, 29.9, 29.7, 27.9 (×2), 18.4, 18.0, 15.0 (×4); HRMS (ESI-TOF): m/z: calculated for C24H32ClO8: 483.1780, found 483.1814 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:15][C:16]#[N:17]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[C:15](=[CH:6]/[C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)/[C:16]#[N:17])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc(F)cc1
Product: COc1ccc(/C(C#N)=C/c2ccc(F)cc2)cc1OC
Yield: 72.5 %

Procedure:
4-Fluorobenzaldehyde (620 mg) and 3,4-dimethoxybenzyl cyanide (880 mg) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (1.02 g, yield: 72%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>O>[O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[N:13][OH:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: ON=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 397.2 %

Procedure:
To a mixture of 1,4-dioxaspiro[4.5]decan-8-one (50.3 g, 322.1 mmol) and hydroxylamine hydrochloride (89.5 g, 100.3 mmol) in water (450 mL) was added portionwise sodium carbonate (102.4 g, 966.2 mmol). The reaction mixture was stirred for 40 minutes at room temperature then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 68.2 g of crude 1,4-dioxaspiro[4.5]decan-8-one oxime.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH:33]=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:28][CH2:29][CH:30]([CH2:33][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH3:13])[CH2:31][CH2:32]1)=[O:26])([CH3:21])([CH3:22])[CH3:23]
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Product: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)CC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Reaction between (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amine (described above) and 4-formyl-piperidine-1-carboxylic acid tert-butyl ester using standard reductive amination conditions yielded 4-{[(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester, which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A, followed by treatment with HCl to cleave the BOC group to yield 320. 400 MHz 1H NMR CDCl3: 9.21 (s, 2H); 7.18 (s, 1H); 5.18 (brs, NH2); 3.96 (t, 4H, J=4.7 Hz); 3.81 (t, 4H, J=4.7 Hz); 3.71 (s, 2H, CH2); 3.01 (d, 2H, J=12.2 Hz); 2.56-1.50 (m, 2H); 2.23 (m, 5H, CH2&Me); 1.73 (d, 2H, J=12.8 Hz); 1.65-1.50 (m, 1H); 1.07-0.97 (m, 2H). LC-MS (m+1)=455.34
Reaction SMILES: [CH3:1][S:2]([CH:5]=[CH2:6])(=[O:4])=[O:3].C(N(CC)CC)C.[C:14]([OH:17])(=[S:16])[CH3:15].CCCCCC>CO.C(OCC)(=O)C>[C:14]([S:16][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:17])[CH3:15]
Reactant: C=CS(C)(=O)=O
Reactant: CC(O)=S
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)SCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
To a stirred solution of 53.2 g (0.5 mole) methylvinylsulfone and 1 ml triethylamine in 50 ml methanol, 38.06 g [35.75 ml (0.5 mole)] thioacetic acid was added dropwise over 15 minutes. During the addition, the temperature was maintained between 30°-40° C. with an ice bath. The mixture was stirred overnight at room temperature; then the solvent was removed using a rotovap to give a yellow-red oil which solidified upon cooling. The residue was dissolved in 150 ml of hot ethyl acetate; then 100 ml hexane was added. With cooling of the solution in an ice bath, fine white needle crystals formed. The crystals were recovered by filtration, were washed with cold 1:1 ethyl acetate:hexane and air-dried to give 35.28 g of the above-identified product as a crystalline solid, melting point 57°-59° C. A second crop of 29.13 g crystals melting point 57°-60° C. was obtained to give a total of 64.41 g of the above-identified product.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([C@@H:16]3[CH2:18][C@H:17]3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[N:25]=1.[NH2:26][C:27]1[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[O:32])=[CH:29][C:28]=1[O:43][CH3:44].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)(C)C>[F:14][C:9]1([F:15])[CH2:8][N:7]([C@@H:16]2[CH2:18][C@H:17]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[N:25]=[C:2]([NH:26][C:27]3[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)=[O:32])=[CH:29][C:28]=3[O:43][CH3:44])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CN1C(=O)C(F)(F)CN([C@@H]2C[C@H]2c2ccccc2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N([C@@H]1C[C@H]1c1ccccc1)CC(F)(F)C(=O)N2C
Yield: 45.3 %

Procedure:
The mixture of 0.08 g (0.22 mmole) of 2-chloro-7,7-difluoro-5-methyl-9-(trans-2-phenyl-cyclopropyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-287), 0.069 g (0.26 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.062 g (0.33 mmole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in a pressure tube at 140 degrees overnight. After cooling, dichloromethane and saturated sodium carbonate were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-65:35) gave 0.059 g of give 4-[7,7-difluoro-5-methyl-6-oxo-9-(trans-2-phenyl-cyclopropyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-288) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[C:18]1([C:24]2[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH:1][C:2]3[CH:3]=[C:4]4[C:12](=[CH:13][CH:14]=3)[NH:11][C:10]3[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]4=3)=[O:29])=[CH:31][CH:32]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(-c5ccccc5)cc4)cc3c2C1
Yield: 71.1 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 15 mg (0.051 mMol) 4-phenylbenzoyl chloride, 13.4 mg (71%) of the title compound were recovered as a brown solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Reactant: COc1cccc(-c2ocnc2C(=O)O)c1
Product: COc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)=O)s3)n2)c1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[O:11])[CH:10]=1)[C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[N:5]2[CH3:16].[I:17]I>C(#N)C>[I:17][C:10]1[C:9](=[O:11])[N:8]2[C:4]([N:5]([CH3:16])[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=32)=[N:3][C:2]=1[CH3:1]
Reactant: Cc1cc(=O)n2c3ccccc3n(C)c2n1
Reactant: II
Solvent: CC#N
Product: Cc1nc2n(C)c3ccccc3n2c(=O)c1I

Procedure:
To a solution of Step 2 intermediate (1.2 g, 5.620 mmol) in acetonitrile (15 ml) was added ceric ammonium nitrate (1.53 g, 2.812 mmol) followed by iodine (0.857 g, 3.325 mmol) and refluxed for 2.0 h. After completion of the reaction, the solvent was evaporated and the residue dissolved in ethyl acetate. Combined organic layer was washed with water, saturated NaHSO3 solution, brine and dried and purified to afford the desired compound: 1H NMR (300 MHz, DMSO-d6) δ 2.61 (s, 3H), 3.75 (s, 3H), 7.39-7.42 (s, 1H), 7.52-7.58 (m, 1H), 7.68-7.70 (m, 1H), 8.38-8.41 (s, 1H); ESI-MS (m/z) 340.48 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH2:21][CH2:22][C:23](O)=[O:24])[C:13]3=[O:26])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:39]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.N12CCCN=C1CCCCC2.Cl>C1COCC1.O>[CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH2:21][CH2:22][C:23]([NH:48][S:45]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)(=[O:47])=[O:46])=[O:24])[C:13]3=[O:26])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Cc1cccc2scc(Cn3c(=O)n(CCC(=O)O)c4ccccc43)c12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1cccc2scc(Cn3c(=O)n(CCC(=O)NS(=O)(=O)c4ccccc4)c4ccccc43)c12
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid (150 mg, 0.41 mmol) is dissolved in dry THF (3.0 mL) and 1,1′-carbonyl diimidazole (150 mg, 0.92 mmol) is added into it at room temperature. The mixture is stirred for 30 min and then it is heated at 55° C. for 1 hr. After the mixture is cooled down to room temperature, benzenesulfonamide (130 mg, 0.82 mmol) is added and after 10 min, 1,8-diazabicyclo[5,4,0]undec-7-ene (0.12 mL, 0.82 mmol) is added. The mixture is stirred for 5 hr at room temperature and then 1.0 M HCl (3 mL) is added followed by water (30 mL). The mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined, dried and concentrated to give crude product. Purification by preparative TLC using 75% EtOAc in Hexanes affords 123 mg (60%) of N-{3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionyl}-benzenesulfonamide. LCMS (ESMS): m/z 506.18 (M+H+).