Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]3[CH3:23])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C=O.[BH3-][C:27]#N.[Na+].O>CO.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:27])[CH2:19][C@H:18]3[CH3:23])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: [BH3-]C#N
Reactant: C[C@@H]1CNCCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1CN(C)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.7 %

Procedure:
A mixture of 115d (500 mg, 1.3 mmol) and 30% formaldehyde (650 mg, 6.5 mmol) in methanol/acetic acid (30 mL/3 mL) was stirred at room temperature for 5 minutes, followed by the addition of NaBH3CN (120 mg, 1.9 mmol). The mixture was stirred at room temperature for 4 h. water (20 mL) was added and the resulting mixture was concentrated under reduced pressure. The residue was extracted with dichloromethane (3×30 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 115e as a yellow solid (473 mg, 92%). MS-ESI: [M+H]+ 392.
Reaction SMILES: I[CH2:2][CH3:3].[Br:4][C:5]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([F:18])[C:8]([OH:19])=[C:7]([CH:20]=[O:21])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:4][C:5]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([F:18])[C:8]([O:19][CH2:2][CH3:3])=[C:7]([CH:20]=[O:21])[CH:6]=1
Reactant: CCI
Reactant: O=Cc1cc(Br)c(-c2ccc(F)cc2)c(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(C=O)cc(Br)c(-c2ccc(F)cc2)c1F
Temperature: 60 °C
Reaction time: 5 h
Yield: 95.8 %

Procedure:
Iodoethane (2.54 g) was added to a mixture of 6-Bromo-2,4′-difluoro-3-hydroxybiphenyl-4-carbaldehyde (3.40 g) and potassium carbonate (3.00 g) in DMF (35 mL) at room temperature. The mixture was stirred at 60° C. under nitrogen atmosphere for 5 hours. The mixture was quenched with water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.55 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23](O)=[O:24])[CH2:19][CH2:18]2)[N:4]=1.C(O)(C(F)(F)F)=O.[F:33][C:34]([F:44])([F:43])[C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([NH:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[C:34]([F:33])([F:43])[F:44])=[O:24])[CH2:19][CH2:18]2)[N:4]=1
Reactant: CNc1nc(N[C@H]2CC[C@H](C(=O)O)CC2)nc(N2CCN(C)CC2)n1
Reactant: NCc1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1nc(N[C@H]2CC[C@H](C(=O)NCc3ccccc3C(F)(F)F)CC2)nc(N2CCN(C)CC2)n1

Procedure:
A solution of trans-4-(4-(methylamino)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-ylamino)cyclohexanecarboxylic acid as TFA salt (18.4 mg, 0.04 mmol, 1 equivalent), 2-trifluoromethyl benzylamine (10.5 mg, 0.06 mmol, 1.5 equivalents) and DMAP (1.3 mg, 0.26 equivalents) in dichloromethane (1 ml) was cooled with stirring in an ice bath. EDCl (12.7 mg, 0.066 mmol, 1.65 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. The solution was diluted with dichloromethane (1 ml), which was further washed with saturated sodium bicarbonate and water. The solvent was removed to give the crude product, which was further purified by RP-HPLC (Luna 5μ, C8(2), 100×21 mm, 5-40% CH3CN/H2O, 0.1% TFA, 25 min) to give the final product (5.33 mg, 21.5%). MS (ES+): m/e 507.21 [M+H]+.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8]O)=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:17][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:2][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1ccc(-c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
4-Biphenylethanol (see Kawasaki et al., Tetrahedron: Asymmetry 2001, 12, 585-596) (1.47 g, 7.41 mmol) and CBr4 (1.12 equiv) were dissolved in CH2Cl2 (25 mL), the mixture was cooled to 0° C. and triphenylphosphine (1.1 equiv) was added in small portions. The reaction mixture was warmed at room temperature and stirred for 1 h before the solvent was removed in vacuo. Flash chromatography (0-5% EtOAc-hexanes) yielded 4-(2-bromoethyl)biphenyl (1.59 g, 82%). The title compound was prepared from S7 (55 mg, 0.27 mmol) and 4-(2-bromoethyl)biphenyl (280 mg, 1.07 mmol) by using general procedure D. Flash chromatography (SiO2, 1.5×18 cm, 50-100% EtOAc-hexanes) afforded the title compound (38 mg, 40%) as a white solid: 1H NMR (CDCl3, 500 MHz) δ 8.84 (dd, 1H, J=0.7, 4.7 Hz), 8.29 (d, 1H, J=7.9 Hz), 7.92 (dt, 1H, J=1.7, 7.8 Hz), 7.57 (m, 2H), 7.53 (m, 3H), 7.42 (t, 2H, J=7.7 Hz), 7.33 (m, 3H), 3.60 (t, 2H, J=7.5 Hz), 3.19 (t, 2H, J=7.5 Hz); 13C NMR (CDCl3, 150 MHz) δ 186.2, 165.3, 161.3, 150.9, 142.7, 141.0, 139.6, 139.0, 137.5, 129.0, 128.9, 127.5, 127.3, 127.2, 126.9, 124.2, 41.7, 29.1; HRMS-ESI-TOF m/z 356.1392 ([M+H]+, C22H17N3O2 requires 356.1393).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=O)[N:14]=[C:7]3[C:6]=2[CH:18]=1.CO[C:21](OC)([N:23](C)C)[CH3:22].C1(C)C=CC=CC=1.Cl.[CH:36]([NH:39]N)([CH3:38])[CH3:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:39]([CH:36]([CH3:38])[CH3:37])[N:23]=[C:21]([CH3:22])[N:17]=4)[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: CC(C)NN
Reactant: NC(=O)c1cn2c(n1)-c1cc(F)ccc1OCC2
Reactant: COC(C)(OC)N(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cn3c(n2)-c2cc(F)ccc2OCC3)n(C(C)C)n1
Temperature: 95 °C
Reaction time: 4 h
Yield: 25.5 %

Procedure:
10-Fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide from Example 90 (0.2 g, 0.81 mmol), dimethylacetamide-dimethylacetal (0.36 mL, 2.4 mmol), and toluene (10 mL, 90 mmol) were combined in a round bottom flask with a vigreux condensation column attached. Heated at 95° C. for more than 24 hours and concentrated in vacuo. The residue was dissolved in acetic acid and isopropylhydrazine hydrochloride (0.11 g, 0.97 mmol) was added and heated at 95° C. with a vigreux condensation column attached for four hours. Complete reaction by LCMS. Concentrated in vacuo and purified by HPLC to give 281 (67.7 mg, 26% yield, M+1 328.1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([C:21]2[CH:26]=[N:25][C:24]([N:27]3[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:23][N:22]=2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].C(N(CC)C(C)C)(C)C.Br[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46]>C(Cl)Cl.[Cl-].C[N+](CCCC)(CCCC)CCCC>[C:48]([O:47][C:45]([CH2:44][N:30]1[CH2:31][CH2:32][CH2:33][N:27]([C:24]2[N:25]=[CH:26][C:21]([C:19]([NH:18][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][C:6]=3[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=3)=[O:8])=[O:20])=[N:22][CH:23]=2)[CH2:28][CH2:29]1)=[O:46])([CH3:51])([CH3:50])[CH3:49]
Reactant: O=C(Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1)c1cnc(N2CCCNCC2)cn1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CN1CCCN(c2cnc(C(=O)Nc3ccc(F)cc3C(=O)Nc3ccc(Cl)cn3)cn2)CC1
Temperature: 25 °C

Procedure:
To a solution of 5-fluoro-2-[5-(hexahydro-1,4-diazepin-1-yl)pyrazin-2-ylcarbonylamino]-N-(5-chloropyridin-2-yl)-benzamide (Example 1, 0.3 g, 0.64 mmol) in methylene chloride was added methyltributylammonium chloride (1 mL), N,N-diisopropylethylamine (2.2 mL) and tert-butyl bromoacetate (2.496 g). The mixture was stirred at room temperature until a clear solution was obtained (24–48 h), diluted with methylene chloride (50 mL), washed with water (2×10 mL) and brine, dried over sodium sulfate, evaporated, and dried. Yield=0.079 g.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.[Li][CH2:12]CCC.CC([O-])(C)C.[K+].CI>C(OCC)C>[CH2:1]([C:2]1[NH:3][C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[CH:10]=1)[CH3:12]
Reactant: Cc1cc2cccnc2[nH]1
Reactant: [Li]CCCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Product: CCc1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-methyl-7-azaindole (1.32 g, 10 mmol) in dry diethyl ether (60 ml) at room temperature under an inert atmosphere is added n-BuLi (18.8 ml of a 1.6 M solution in hexanes, 30 mmol) followed by t-BuOK (2.24 g, 20 mmol). The reaction mixture is stirred at room temperature for 40 minutes and then cooled to −70° C. whereupon methyl iodide (1.25 ml, 20 mmol) is added dropwise. Stirring continues for a further 2 hours after which time, the reaction mixture is quenched with water (2 ml) and is allowed to slowly warm to room temperature. The cooled solution is poured onto water (200 ml), neutralized with 1N HCl and then extracted with diethyl ether (80 ml). The organic portion is washed with water (2×60 ml), dried (Na2SO4) and concentrated in vacuo to yield the titled compound as orange crystals. [MH+CH3CN]+=188)
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[OH:20].Br[C:22]1C(O)=C(C)C=C2C=1C=CC(C)=N2>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[C:3]([OH:20])=[C:2]([CH3:22])[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([CH3:12])=[N:9]3)=[CH:14][CH:15]=1
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(O)c(Cl)cc2n1
Reactant: Cc1ccc2c(Br)c(O)c(C)cc2n1
Product: Cc1ccc2c(-c3ccc(Cl)cc3)c(O)c(C)cc2n1

Procedure:
Compound 2D was prepared following the procedure used to prepare compound 1E of Example 1, except that 5-bromo-2,7-dimethylquinolin-6-ol (2C) was used instead of compound 1D. LCMS-ESI+ (m/z): 284.2, 286.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:16][CH3:17])=[N:14][CH:15]=3)[O:9][C:5]=2[CH:4]=1.Cl>C(Cl)Cl.C(OCC)C>[CH3:17][NH:16][C:13]1[N:14]=[CH:15][C:10]([C:8]2[O:9][C:5]3[CH:4]=[C:3]([OH:2])[CH:19]=[CH:18][C:6]=3[N:7]=2)=[CH:11][CH:12]=1
Reactant: CNc1ccc(-c2nc3ccc(OC)cc3o2)cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CNc1ccc(-c2nc3ccc(O)cc3o2)cn1
Reaction time: 0.25 h
Yield: 22.8 %

Procedure:
5-(6-Methoxy-1,3-benzoxazol-2-yl)-N-methylpyridin-2-amine (50 mg, 0.20 mmol) was dissolved in CH2Cl2 (10 mL) and made acidic with 2M HCl in diethylether. The solvent was removed in vacuo and hydrogen bromide (48% aq., 2 mL) was added. The reaction was run in a microwave reactor at 120° C. for 15 minutes. The mixture was then made basic with sodium bicarbonate and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by preparative HPLC, to give the title compound (11 mg) as a white solid. 1H NMR δ ppm 9.95 (br. s, 1H) 8.72 (d, 1H) 7.99 (dd, 1H) 7.46 (d, 1 H) 7.28 (d, 1 H) 7.03 (d, 1H) 6.79 (dd, 1H) 6.58 (d, 1H) 2.85 (d, 3H); MS m/z (M+H) 242, (M−H) 240.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].[C:8]1([CH2:18][CH2:19][CH2:20]I)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.Cl>O1CCCC1.O>[C:3]([CH:2]([CH2:20][CH2:19][CH2:18][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[C:1]#[N:5])#[N:4]
Reactant: ICCCc1cccc2ccccc12
Reactant: N#CCC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(C#N)CCCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
A solution of 0.7 gram (0.011 mole) of malononitrile in 50 mL of tetrahydrofuran was stirred, and 0.5 gram (0.011 mole) of sodium hydride (60% in mineral oil) was added portionwise during a ten minute period. Upon completion of addition, the reaction mixture was stirred for 30 minutes at ambient temperature. After this time a solution of 3.0 grams (0.010 mole) of 3-(naphth-1-yl)propyl iodide (prepared as in Example 9, Steps A-D) in about 5 mL of tetrahydrofuran was added in one portion. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 20 hours. The reaction mixture was acidified with aqueous 6N hydrochloric acid and then was further diluted with 100 mL of water. The mixture was extracted with two 100 mL portions of diethyl ether. The combined extracts were washed with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated to a residue which was subjected to column chromatography on silica gel. Elution was accomplished using 40% to 65% methylene chloride and petroleum ether. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.1 grams of 2-cyano-5-(naphth-1-yl)pentanenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([N:8]1[CH2:29][CH2:28][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>[OH-].[OH-].[Pd+2].CO>[F:27][C:24]([F:25])([F:26])[O:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:13][CH2:12][C:11]3([CH2:10][CH2:9][NH:8][CH2:29][CH2:28]3)[C:15]2=[O:16])=[CH:18][CH:19]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 8-benzyl-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (3.14 g, 0.007 mol), acetic acid (5 ml) and Pearlman's catalyst (0.43 mg) in MeOH (40 ml) was stirred at room temperature under an atmospheric pressure of H2 for 3 h. The catalyst was removed by filtration and the filtrate was evaporated to give a crude residue which was triturated with diethyl ether (50 ml) to give 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one; acetic acid salt as a white solid (1.43 g, 49%). MS (ESI): 315.1 (MH+).
Reaction SMILES: O=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1CCCCC1>[C:11]1([NH:10]/[C:2](/[CH2:8][CH3:9])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCC(=O)CC(=O)OC
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CC/C(=C/C(=O)OC)Nc1ccccc1
Yield: 72.2 %

Procedure:
A mixture of methyl 3-oxovalerate (5.21 g, 40.0 mmol), aniline (3.66 mL, 40.0 mmol), p-toluenesulfonic acid monohydrate (533 mg, 2.80 mmol) and cyclohexane (25 mL) was stirred with heating under reflux for 2 hr. The mixture was concentrated under reduced pressure, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate, hexane:ethyl acetate=98:2→94:6) to give the title compound (5.93 g, 72%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH2:11][OH:12])=[O:8])=[C:4]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH2:11][O:12][S:25]([CH3:24])(=[O:27])=[O:26])=[O:8])=[C:4]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1
Reactant: C[Si](C)(C)c1cc(Cl)sc1C(=O)NCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C[Si](C)(C)c1cc(Cl)sc1C(=O)NCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound of Example 263 (0.4 g) and 0.5 mL triethylamine in 10 mL CH2Cl2 at 0° C. was added methanesulfonyl chloride (0.2 mL) and the resulting reaction solution was stirred at RT for 2 h. Water was added and the two layers were separated. The organic solution was washed with brine, dried and concentrated. Purification by flash chromatography with 30% ethyl acetate-hexane gave 0.4 g of product as a white solid. m.p. 82-86° C.
Reaction SMILES: C(S([C:10]1[N:15]2[N:16]=[CH:17][C:18]([CH:19]=[C:20]3[NH:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[C:14]2[N:13]=[C:12]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[CH:11]=1)=O)C1C=CC=CC=1.[NH2:35][CH2:36][CH2:37][OH:38].O>CN1C(=O)CCC1>[Cl:34][C:30]1[CH:29]=[C:28]([NH:27][C:12]2[CH:11]=[C:10]([NH:35][CH2:36][CH2:37][OH:38])[N:15]3[N:16]=[CH:17][C:18]([CH:19]=[C:20]4[NH:24][C:23](=[O:25])[NH:22][C:21]4=[O:26])=[C:14]3[N:13]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: NCCO
Reactant: O=C1NC(=O)C(=Cc2cnn3c(S(=O)Cc4ccccc4)cc(Nc4cccc(Cl)c4)nc23)N1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1NC(=O)C(=Cc2cnn3c(NCCO)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 120 °C

Procedure:
To 5-((7-(benzylsulfinyl)-5-(3-chlorophenylamino) pyrazolo[1,5-a]pyrimidin-3-yl) methylene) imidazolidine-2,4-dione (15 mg, 0.0304 mmol) in NMP was added 2-aminoethanol (14.6 μL, 0.242 mmol). The mixture was heated in the microwave at 120° C. for 20 minutes. Water was added to the reaction mixture and the precipitate was collected by filtration. The precipitate was washed with methanol to yield 5-((5-(3-chlorophenylamino)-7-(2-hydroxyethylamino) pyrazolo[1,5-a]pyrimidin-3-yl)methylene) imidazolidine-2,4-dione LCMS (M+1=414). Similar products (shown below) were also obtained as precipitates by addition of water while other reactions were purified by prep HPLC to yield corresponding products.
Reaction SMILES: C(OP([CH:9]([C:17]#[N:18])[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(=O)OCC)C.[O:19]1[CH2:24][CH2:23][CH2:22][O:21][CH:20]1[C:25]1[CH:26]=[C:27]([S:31][C:32]2[C:33]([F:43])=[CH:34][C:35]([N+:40]([O-:42])=[O:41])=[C:36]([CH:39]=2)[CH:37]=O)[CH:28]=[CH:29][CH:30]=1>C1COCC1.C(OCC)(=O)C>[O:19]1[CH2:24][CH2:23][CH2:22][O:21][CH:20]1[C:25]1[CH:26]=[C:27]([S:31][C:32]2[C:33]([F:43])=[CH:34][C:35]([N+:40]([O-:42])=[O:41])=[C:36]([CH:37]=[C:9]([CH2:10][CH:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[C:17]#[N:18])[CH:39]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: CCOP(=O)(OCC)C(C#N)CC1CCOCC1
Reactant: O=Cc1cc(Sc2cccc(C3OCCCO3)c2)c(F)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CC(=Cc1cc(Sc2cccc(C3OCCCO3)c2)c(F)cc1[N+](=O)[O-])CC1CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
[1-Cyano-2-(tetrahydro-pyran-4-yl)-ethyl]-phosphonic acid diethyl ester (0.614 g, 2.23 mmol), prepared as described in Example 1, Steps A and B, was dissolved in THF (75 mL) and the resulting mixture cooled to 0° C. Lithium (bistrimethylsilyl)amide (2.2 mL, 2.2 mmol, [1M]) was then added dropwise. The resulting mixture was stirred 15 min, and then 5-(3-[1,3]dioxan-2-yl-phenylsulfanyl)-4-fluoro-2-nitro-benzaldehyde (0.6 g, 1.65 mmol) was added. Stirring was continued at room temperature overnight. The resulting mixture was then diluted with ethyl acetate and washed with saturated aqueous NaHCO3. The organic phase was separated and dried with MgSO4, and filtered. The solvent was removed to yield an oil, which was used in the next step without further purification.
Reaction SMILES: [S:1]([O:5][CH2:6][CH:7]1[O:9][CH2:8]1)([CH3:4])(=[O:3])=[O:2].[ClH:10]>>[S:1]([O:5][CH2:6][CH:7]([OH:9])[CH2:8][Cl:10])([CH3:4])(=[O:3])=[O:2]
Reactant: Cl
Reactant: CS(=O)(=O)OCC1CO1
Product: CS(=O)(=O)OCC(O)CCl
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Concentrated HCl (20 ml) was added to 3-mesyloxy-1,2-epoxypropane (5.0 g, 0.033 m) over 15-20 minutes. After stirring for an additional 30 minutes, the water was removed through the addition and subsequent evaporation of ethanol. Finally, residual ethanol was removed at room temperature and 0.1 mm to give 3-mesyloxy-2-hydroxy-1-chloropropane (5.4 g, 85%).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1([CH2:24][C:25]2[S:29][C:28]([C:30](O)=[O:31])=[N:27][CH:26]=2)[CH:23]=[CH:22][N:21]=[CH:20]1>>[N:19]1([CH2:24][C:25]2[S:29][C:28]([C:30]([NH:1][C@@H:2]([CH3:18])[CH2:3][N:4]3[CH:8]=[CH:7][C:6]([C:9]4[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=4)=[N:5]3)=[O:31])=[N:27][CH:26]=2)[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1ncc(Cn2ccnc2)s1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ncc(Cn2ccnc2)s1
Yield: 4.8 %

Procedure:
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (157 mg, 0.60 mmol) was coupled with 5-((1H-imidazol-1-yl)methyl)thiazole-2-carboxylic acid (0.60 mmol) using the method of Example 34(d). Crude product was purified twice by CombiFlash (1st column: C-18, eluent: 0-100% MeCN in water; 2nd column: silica, eluent: 0-8% MeOH in DCM) to yield 13 mg (5%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.18 (d, 2H), 4.29-4.52 (m, 3H), 5.36 (s, 2H), 6.92 (s, 1H), 6.94 (dd, 1H), 7.22 (s, 1H), 7.71 (s, 1H), 7.75 (s, 1H), 7.83 (d, 1H), 7.90 (dd, 1H), 7.96 (d, 1H), 8.04 (d, 1H), 8.83 (d, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:14]([N:15]=1)[C:13](=[O:16])[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]=2.[OH-].[Na+].[CH2:19]([OH:21])[CH3:20]>O>[CH2:19]([O:21][C:2]1[CH:3]=[CH:4][C:5]2[N:14]([N:15]=1)[C:13](=[O:16])[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]=2)[CH3:20]
Reactant: CCO
Reactant: O=c1c2ccccc2nc2ccc(Cl)nn12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc2nc3ccccc3c(=O)n2n1
Reaction time: 2 h

Procedure:
To 1.2 g of 2-chloro-10H-pyridazino[3,2-b]quinazolin-10-one dissolved in ethanol, there was added a solution of sodium hydroxide (2.0 g) in water (8 ml), and stirring was continued at 40° C. for 2 hours. After completion of the reaction, the solvent was removed by distillation, followed by addition of an aqueous solution of acetic acid. The precipitates were collected by filtration and recrystallized from a mixture of methanol and water to give 1.0 g of 2-ethoxy-10H-pyridazino[3,2-b]quinazolin-10-one (Compound No. 2). M.P., 159.5°-160.5° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH3:28])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:29].[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)[CH2:33][CH2:32]1>C1COCC1>[CH3:30][N:31]1[CH2:32][CH2:33][N:34]([C:37]2[CH:42]=[CH:41][C:40]([NH:43][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([CH2:12][C:13]5[CH:14]=[C:15]([NH:19][C:20]([C:22]6[N:23]([CH3:28])[N:24]=[C:25]([CH3:27])[CH:26]=6)=[O:21])[CH:16]=[CH:17][CH:18]=5)=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:29])=[CH:39][CH:38]=2)[CH2:35][CH2:36]1
Reactant: Cc1cc(C(=O)Nc2cccc(Cc3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(Cc3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 34.9 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indol-6-ylmethyl)-phenyl]-amide (prepared below, 50 mg, 0.129 mmol) and THF (1 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (24.6 mg, 0.129 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in EtOAc. The resulting solution was diluted with Hexanes to initiate the precipitation of the product. The solid precipitate that formed was filtered then washed with ˜3 mL of i-prOH yielding 35% (25.3 mg, 0.045 mmol) of the title compound.