Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:6]2[CH:7]=[C:8]([CH2:20][OH:21])[CH:9]=[C:10](B3OC(C)(C)C(C)(C)O3)[C:5]=2[O:4][CH2:3]1.Br[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=[O:28]>>[OH:21][CH2:20][C:8]1[CH:9]=[C:10]([C:30]2[CH:29]=[C:26]([CH:25]=[CH:24][C:31]=2[O:32][C:33]([F:34])([F:35])[F:36])[CH:27]=[O:28])[C:5]2[O:4][CH2:3][C:2]([CH3:1])([CH3:22])[C:6]=2[CH:7]=1
Reactant: O=Cc1ccc(OC(F)(F)F)c(Br)c1
Reactant: CC1(C)COc2c(B3OC(C)(C)C(C)(C)O3)cc(CO)cc21
Product: CC1(C)COc2c(-c3cc(C=O)ccc3OC(F)(F)F)cc(CO)cc21
Yield: 59 %

Procedure:
The intermediate 3-(5-hydroxymethyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzaldehyde was prepared in a similar manner to example 1a using [3,3-dimethyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-5-yl]-methanol and 3-bromo-4-trifluoromethoxy benzaldehyde. 59% yield. 1H-NMR (300 MHz, CDCl3): 1.39 (s, 6H), 1.71 (m, 1H), 4.26 (s, 2H), 4.68 (s, 2H), 7.14 (d, J=2.3 Hz, 1H), 7.21 (d, J=1.5 Hz, 1H), 7.49 (dd, J1=8.5 Hz, J2=1.5 Hz, 1H), 7.91 (dd, J1=8.5 Hz, J2=2.1 Hz, 1H), 8.01 (d, J=2.3 Hz, 1H), 10.03 (s, 1H).
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][CH:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[N:1]1([CH:6]2[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)NC1CCC(N2CCCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
tert-butyl N-(4-pyrrolidin-1-ylcyclohexyl)carbamate (Intermediate 238; 222 mg, 0.83 mmol) was taken up in DCM (1.5 mL) and TFA (1 mL). The reaction mixture was stirred at ambient temperature for 3 hours, poured directly onto an SCX-3 cartridge (2 g), pre-wet with DCM. The cartridge was washed through with DCM (10 mL), followed by methanol (30 mL) and then eluted with 2M ammonia in Methanol (25 mL). Evaporation to dryness of the ammoniacal solution yielded the title compound as an amber coloured oil (103 mg, 74%)
Reaction SMILES: [C:1]([C:3]1[C:4]([N:11]([CH3:15])[C:12](=[O:14])[CH3:13])=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[NH2:2][C:1]1[C:3]2[CH:8]=[N:7][C:6]([S:9][CH3:10])=[N:5][C:4]=2[N:11]([CH3:15])[C:12](=[O:14])[CH:13]=1
Reactant: CSc1ncc(C#N)c(N(C)C(C)=O)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ncc2c(N)cc(=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
To a solution of N-(5-cyano-2-methylsulfanyl-pyrimidin-4-yl)-N-methyl-acetamide (400 mg, 1.80 mmol) in THF (18 mL) was added a solution of lithium bis(trimethyl-silyl)amide (1.0 M in hexane, 7.2 mL, 7.20 mmol) at RT. The reaction mixture was stirred at RT for 1 h, then quenched with water (100 mL). The resulting mixture was extracted with EtOAc (100 mL); the organic layer dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography (from 10 to >100% EtOAc/hexane in 10 min.) to give 163 mg (41% yield) of 5-amino-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]-pyrimidin-7-one as a yellow solid.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[S:20][C:21]([CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[CH:22][N:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:42].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:42][C:17]([C:19]4[S:20][C:21]([CH:24]([OH:29])[C:25]([F:28])([F:26])[F:27])=[CH:22][N:23]=4)=[CH:16][CH:15]=3)[CH2:31][CH:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ncc(C(O)C(F)(F)F)s1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(C(O)C(F)(F)F)s3)[nH]2)cc1)C1CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
A mixture of 5-[4-(cyclopropylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)-1-[5-(2,2,2-trifluoro-1-hydroxyethyl)-1,3-thiazol-2-yl]hexane-1,4-dione (0.45 g), ammonium acetate (0.31 g) and acetic acid (6 mL) was stirred at 80° C. for 3 hr. The reaction mixture was neutralized with 8M sodium hydroxide, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (0.28, yield 65%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 541 (MH+).
Reaction SMILES: [C:1]([N:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:5]1[CH2:10][C:9]([CH:11]=O)=[N:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1=[O:20])(=[O:3])[CH3:2].[CH3:28][N:29]([CH3:31])[NH2:30].Cl>CCO>[C:1]([N:4]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[N:5]1[CH2:10][C:9](/[CH:11]=[N:30]/[N:29]([CH3:31])[CH3:28])=[N:8][N:7]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:6]1=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(=O)OC(C)(C)C)N1CC(C=O)=NN(C(=O)OC(C)(C)C)C1=O
Reactant: CN(C)N
Agent: Cl
Solvent: CCO
Product: CC(=O)N(C(=O)OC(C)(C)C)N1CC(/C=N/N(C)C)=NN(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl 4-[acetyl(tert-butoxycarbonyl)amino]-6-formyl-3-oxo-5H-1,2,4-triazine-2-carboxylate (461 mg, 1.20 mmol) in EtOH was added N,N-dimethylhydrazine (0.110 mL, 1.44 mmol), followed by addition of 1 droplet of conc. HCl. The mixture was stirred at room temperature for 20 h followed by evaporation of the volatiles to give the title compound as a viscous oil. LCMS (Method K) RT 0.99 min. [M+H]+ 427.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: COc1cccc(CN)c1
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1cccc(OC)c1
Yield: 85 %

Procedure:
The compound prepared in Example 3 was reacted with 3-methoxy-benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2.[C:24]([NH:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:26])[CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:31]3[CH:32]=[CH:33][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[CH:29][CH:30]=3)=[CH:17][C:9]1=2
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Product: CC(=O)Nc1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Yield: 42 %

Procedure:
1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (90 mg) was reacted with 4-acetamidophenylboronic acid as in General Procedure 4B to give the title compound as a light gray solid (42% yield). m.p.=244° C., LCMS: m/z=461.24 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.13 (3H, s), 3.49 (2H, m), 3.65 (2H, m), 3.82 (2H, s), 4.61 (2H, s), 6.58 (1H, s), 7.28 (2H, d, J=8.1 Hz), 7.36 (1H, d, J=7.3 Hz), 7.51 (3H, m), 7.60 (1H, s), 7.65 (1H, d, J=8.6 Hz).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[OH-].[NH4+:9]>CN1C(=O)CCC1>[C:1]([O-:6])(=[O:7])[CH2:2][CH2:3][C:4]([NH2:9])=[O:5].[NH4+:9]
Reactant: O=C1CCC(=O)O1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: NC(=O)CCC(=O)[O-]
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To demonstrate that the reactions involved above are, in fact, clean and very nearly quantitative as claimed, the experiments described below were carried out. Succinic anhydride (10 g.; 0.1 mole) was dissolved with magnetic stirring in NMP (100 ml.). Conc. ammonium hydroxide (15 ml; 0.225 mole) was added dropwise with stirring. After the addition, the stirring was continued for 3 hours, and the product precipitated during this period. The mixture was cooled, stirring was continued, and ether (100 ml.) was added dropwise. This was done to ensure complete precipitation of the product. The reaction was refrigerated overnight and on filtration yields 13.4 g (100% yield) of ammonium succinamate; m.p., 112°-120°. A sample recrystallized from methanol had m.p., 108°-118°. Anal: for ammonium succinate C4H10N2O3 : calc. N, 20.88%; found N, 20.38%, 20.30%.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[NH2:21][CH2:22][CH:23]1[CH:27]([CH3:28])[CH2:26][NH:25][CH2:24]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:21][CH2:22][CH:23]1[CH:27]([CH3:28])[CH2:26][N:25]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:24]1
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CC1CNCC1CN
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC1CN
Temperature: 25 °C
Reaction time: 7 h
Yield: 33 %

Procedure:
A mixture of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.6 g), anhydrous acetonitrile (5 ml), 3-aminomethyl-4-methylpyrrolidine (0.27 g) and 1,8-diazabicyclo[5,4,0]-7-undecene (DBU; 0.3 g) was refluxed for an hour and then stirred at room temperature for 7 hours. The resulting precipitate was collected by filtration and recrystallized from chloroform-methanol-concentrated aqueous ammonia (10:10:1) to give the title compound (0.26 g) as colorless prisms, mp 235°-238° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=1[O:21][CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=2[O:21][CH3:22])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(C=O)ccc1F
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1Oc1ccc(N)c([N+](=O)[O-])c1

Procedure:
4-Amino-3-nitrophenol (2 g, 13 mmol), 4-fluoro-3-(methyloxy)benzaldehyde (2 g, 13 mmol) and Cs2CO3 (5.1 g, 15.6 mmol) were stirred in dimethylformamide at 100 degrees Centigrade for approximately 18 hours. The reaction was filtered through an Alltech 75 mL Extract-Clean™ filter column packed with glass wool and eluted with ethyl acetate. The eluent was stirred with 5 mL of water then passed through a Varian Chem Elute™ 1010 column which was rinsed with 4-6 mL of ethyl acetate (gravity filtration). The eluent was dried over MgSO4, concentrated onto basic alumina and purified by silica gel column chromatography (hexanes/ethyl acetate gradient) to give 4-[(4-amino-3-nitrophenyl)oxy]-3-(methyloxy)benzaldehyde. (M+1) 289.0, 2.26 min (LC/MS method A)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([O-:14])=[O:13].[K+]>Cl>[Cl:1][C:2]1[C:3]([C:4]([OH:6])=[O:5])=[C:7]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=1
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: [K+]
Product: Cc1c([N+](=O)[O-])ccc(Cl)c1C(=O)O
Reaction time: 0.08 h

Procedure:
2-Chloro-6-methylbenzoic acid (99 mg, 0.58 mmol) was dissolved in conc. hydrochloric acid (1 mL) and cooled in an ice bath. To this solution potassium nitrate in conc. hydrochloric acid (1 mL) was added drop wise. The reaction mixture was stirred for 5 min, then the ice bath was removed and stirring was continued for another 2 hours. The reaction mixture was poured onto ice (25 g) and extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to give a mixture of the desired 3-nitro (70%) and the 5-nitro (30%) derivatives (118.6 mg, 95%). No effort was made to separate the two isomers, and the mixture was used in the next step.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1.[CH:24]([NH:27][CH:28]([CH3:30])[CH3:29])([CH3:26])[CH3:25]>CN(C)C=O>[CH:24]([N:27]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1)[CH:28]([CH3:30])[CH3:29])([CH3:26])[CH3:25]
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Reactant: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)N(Cc1nc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)no1)C(C)C
Yield: 61.7 %

Procedure:
72 g (212 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at 80° for 16 hours in 150 ml (1.06 mol) of diisopropylamine and 300 ml of N,N-dimethylformamide. After evaporating the solvent the residue was dissolved in methylene chloride and the solution was extracted twice with 100 ml of 2N hydrochloric acid. The acidic phase was made alkaline with conc. sodium hydroxide solution and extracted with methylene chloride. The organic phase was dried over magnesium sulfate and evaporated. By chromatography of the residue on silica gel while eluting with ethyl acetate/methanol/acetic acid 95/3/2 and recrystallization from ethanol there were obtained 51.6 g (61%) of 3-(5-diisopropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 117°-119°.
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[CH2:3][C:4]#[N:5].[NH2:8][C:9]1[N:13]=[CH:12][NH:11][N:10]=1>C(O)(=O)C>[CH2:6]([C:2]1[CH:3]=[C:4]([NH2:5])[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]=1)[CH3:7]
Reactant: CCC(=O)CC#N
Reactant: Nc1nc[nH]n1
Solvent: CC(=O)O
Product: CCc1cc(N)n2ncnc2n1
Temperature: 150 °C
Yield: 11.9 %

Procedure:
A mixture of 3-oxopentanenitrile (1.0 g, 10.3 mmol) and 3-amino-1,2,4-triazole (0.91 g, 10.8 mmol) in 10 mL of acetic acid was heated in a pressure tube at 150° C. for 24 h. The reaction mixture was allowed to cool to room temperature, and solvent was removed in vacuo. The solid was removed via filtration. The filtrate partially upon standing at room temperature, and the solid was collected via filtration to give the title compound (200 mg, 12% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:13])=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[I:14].[N+:15]([O-])([OH:17])=[O:16]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:13])=[C:7]([N+:15]([O-:17])=[O:16])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[I:14]
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(O)c2cc(I)c(Cl)cc2[nH]1
Product: O=c1[nH]c2cc(Cl)c(I)cc2c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
7-Chloro-4-hydroxy-6-iodo-2(1H)-quinolinone (Intermediate 142) (300 mg, 0.933 mmol) was dissolved in nitric acid (1 mL, 22.38 mmol) and the reaction mixture was stirred 15 min at room temperature and heated 30 min at 75° C. After cooling, the reaction mixture was poured into ice water and the precipitate was filtered and dried to give the title compound 7-chloro-4-hydroxy-6-iodo-3-nitro-2(1H)-quinolinone (280 mg, 0.764 mmol, 82% yield) as yellow solid. LCMS: (M+H)+=367; Rt=2.06 min.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:16][CH2:15][C:14]4[C:10](=[CH:11][N:12]([CH2:17][CH2:18][N:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)[N:13]=4)[C:9]=3[S:26][C:6]=2[N:5]=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[NH2:31].Cl.O1CCOCC1>C(O)(C)C>[Cl:27][C:28]1[CH:29]=[C:30]([NH:31][C:2]2[N:3]=[CH:4][N:5]=[C:6]3[S:26][C:9]4[C:10]5[C:14]([CH2:15][CH2:16][C:8]=4[C:7]=23)=[N:13][N:12]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH:11]=5)[CH:32]=[CH:33][C:34]=1[N:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1
Reactant: CN1CCN(CCn2cc3c(n2)CCc2c-3sc3ncnc(Cl)c23)CC1
Reactant: Nc1ccc(N2CCOCC2)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CN1CCN(CCn2cc3c(n2)CCc2c-3sc3ncnc(Nc4ccc(N5CCOCC5)c(Cl)c4)c23)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 6-chloro-2-[2-(4-methylpiperazin-1-yl)ethyl]-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazole (50 mg, 0.13 mmol) and 3-chloro-4-morpholinoaniline (82 mg, 0.39 mmol) in isopropanol (3 mL) was added HCl in dioxane (4M, 0.26 mL, 1.03 mmol). The reaction mixture was sealed in a microwave reaction vessel and it was placed in a microwave instrument at 160° C. for 10 min. After it was cooled to room temperature, solvents were evaporated and the residue was dissolved in water/DMF and purified by prep. HPLC. After drying, the TFA salt was neutralized with aq saturated NaHCO3 and extracted with a mixture of CHCl3:isopropanol (3:1). The organic phase was dried over Na2SO4 and concentrated to dryness. The desired product was obtained as a pale solid (40 mg, 55%). 1H-NMR (CD2Cl2) δ 8.43 (s, 1H), 7.84 (d, 1H), 7.53 (m, 2H), 7.08 (m, 2H), 4.20 (t, 2H), 3.86 (m, 4H), 3.37 (t, 2H), 3.11 (t, 2H), 3.04 (m, 4H), 2.80 (t, 2H), 2.53 (m, 4H), 2.43 (m, 4H), 2.26 (s, 3H); LCMS RT=2.29 min; [M+H]+=565.4.
Reaction SMILES: [O:1]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36](Br)[CH:37]=1)[C:33]#[N:34].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Br:29][C:30]1[CH:37]=[C:36]([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][O:1][Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:21][CH:22]=2)[CH:35]=[C:32]([C:33]#[N:34])[CH:31]=1
Reactant: CC(C)(C)[Si](OCc1ccc(B(O)O)cc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cc(Br)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)[Si](OCc1ccc(-c2cc(Br)cc(C#N)c2)cc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A mixture of 1.49 g (3.83 mmoles) of boronic acid derivative from Example 4, 2.0 g (7.67 mmoles) of 3,5-dibromobenzonitrile, and 133 mg (0.1 mmoles) of tetrakistriphenylphosphine in 16 mL toluene and 3.4 mL 95% ethanol with 3.47 mL (6.97 mmoles) of 2 N sodium carbonate was stirred vigorously at 80° C. under nitrogen for 3.5 hours.
Reaction SMILES: C1(C2[O:12][CH2:11][CH:10]([O:13][CH2:14][CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH2:9][O:8]2)C=CC=CC=1>[Pd].CCOC(C)=O>[O:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[O:16][CH2:15][CH2:14][O:13][CH:10]([CH2:11][OH:12])[CH2:9][OH:8]
Reactant: c1ccc(C2OCC(OCCOC3CCCCO3)CO2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: OCC(CO)OCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of 10% palladium on carbon (172 mg, 0.162 mmol) in a solution of 2-phenyl-5[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]-1,3-dioxane (498.9 mg, 1.618 mmol) in EtOAc (32.4 mL) was stirred under H2 at 25° C. for 3 days. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated in vacuo to afford 2-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]propane-1,3-diol. LCMS calc.=243.12; found=243.22 (M+Na)+.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:25][C:26]1[N:27]=[C:28]([CH3:31])[S:29][CH:30]=1.O>CN(C)C=O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:25][C:26]2[N:27]=[C:28]([CH3:31])[S:29][CH:30]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Reactant: Cc1nc(CCl)cs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1Cc1csc(C)n1
Reaction time: 0.25 h

Procedure:
To a solution of Example 74B (0.79 g, 2.43 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (Aldrich, 98 mg, 2.43 mmol) and the reaction mixture was stirred for 15 min and 4-(chloromethyl)-2-methylthiazole (0.36 g, 2.43 mmol) was added. The reaction mixture was stirred at room temperature for 18 hr, poured into water (75 mL) and then extracted with EtOAc (75 mL). The organic layer was washed with water (2×75 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to provide the title compound. MS, DCI, m/z 436 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([OH:19])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1.[H-].[Na+].O>CN(C=O)C>[CH:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[C:8]1[N:7]3[O:19][CH2:2][CH2:3][CH2:4][CH2:5][C:6]3=[N:18][C:9]=1[CH:10]=[N:11]2
Reactant: On1c(CCCCCl)nc2cnc3ccccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)ncc1nc3n(c12)OCCCC3
Yield: 106.2 %

Procedure:
A stirred solution of 2-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-1-ol (0.167 g, 0.606 mmol) in 6 mL of anhydrous DMF was treated with 60% NaH in mineral oil (0.032 g, 0.787 mmol). After 45 minutes the mixture was poured into 20 mL of water and washed with ethyl acetate. The organic portions were combined, washed successively with dilute aqueous K2CO3, H2O, and brine, dried over Na2SO4, and concentrated under reduced pressure to give 0.154 g of 8,9,10,11-tetrahydro[1,2]oxazepino[2′,3′:1,2]imidazo[4,5-c]quinoline as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:7]=[CH:6]2
Reactant: BrCc1ccccc1
Reactant: COc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(ccn2Cc2ccccc2)c1

Procedure:
5-Methoxy-1H-indole (5.6 g, 21.5 mmol) was reacted with 1.0 g (25 mmol) of 60% sodium hydride and then 3.0 mL (25 mmol) of benzyl bromide by the method described in Example 12, Part D to give crude 5-methoxy-1-(phenylmethyl)-1H-indole. This material was dissolved in 250 mL of methylene chloride, cooled to -5° C., 50 mL of 1M BBr3 /CH2Cl2 added, the cooling bath removed and the mixture stirred for 1.75 hours. Ice water was added and the mixture stirred. The organic layer was separated, washed with saturated NaCl, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted with 20% ether/hexane→ether to give 870 mg (19% overall yield) of crude 5-hydroxy-1-(phenylmethyl)-1H-indole.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].[C:16]([NH:19][NH2:20])(=O)[CH3:17]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[CH:6]=[C:7]([CH3:8])[C:2]3[N:3]([C:16]([CH3:17])=[N:19][N:20]=3)[N:4]=2)=[CH:10][CH:11]=1
Reactant: CC(=O)NN
Reactant: Cc1cc(-c2ccc(Cl)cc2)nnc1Cl
Solvent: CCCCO
Product: Cc1cc(-c2ccc(Cl)cc2)nn2c(C)nnc12

Procedure:
A mixture of 1.0 g. of 3-chloro-6-(p-chlorophenyl)-4-methylpyridazine, 0.62 g. of acetic acid hydrazide and 10 ml. of n-butanol is refluxed for 48 hours. The solvent is removed and the residue dissolved in dichloromethane and filtered through magnesol. The solid from the filtrate is recrystallized from dichloromethane-hexane to give 0.6 g. of solid, m.p. 209°-212° C. Recrystallization from dichloromethane-hexane gives the product of the example as light pink colored crystals, m.p. 215°-217° C.