Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1[C:6](=[O:10])[N:7]=[CH:8][CH:9]=1>O1CCCC1>[C:1]([N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C1N=CC=N1
Solvent: C1CCOC1
Product: CC(=O)N1CCNC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
23.6 parts by weight of acetyl chloride in 100 parts by volume of tetrahydrofurane were added dropwise over the course of 60 minutes to a suspension of 25.8 parts by weight of imidazol-2-one in 350 parts by volume of dry tetrahydrofurane at 0° C. The mixture was stirred for 3 hours at room temperature, dry air was subsequently blown through the solution for some time, the solvent was then removed in vacuo and the residue was recrystallized from boiling nitromethane.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:16][C:17]1[C:18](I)=[CH:19][C:20](=[O:36])[N:21]([CH2:23][CH2:24][C@@:25]([CH3:35])([S:31]([CH3:34])(=[O:33])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=1.O>O1CCOCC1.[Pd]>[F:16][C:17]1[C:18]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:19][C:20](=[O:36])[N:21]([CH2:23][CH2:24][C@@:25]([CH3:35])([S:31]([CH3:34])(=[O:32])=[O:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(I)cc1=O)S(C)(=O)=O
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2ccccc2)cc1=O)S(C)(=O)=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Pd EnCat™ (95 mg, 0.037 mmol) was added to a mixture of potassium carbonate (312 mg, 2.26 mmoll), phenylboronic acid (131 mg, 1.07 mmol), and ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (319 mg, 0.716 mmol) in dioxane:water (10 ml, 4:1) in a 20 mL vial equipped with a stir bar. The reaction was heated to 90° C. and allowed to stir overnight at that temperature. The reaction was allowed to cool to RT, filtered and the catalyst was washed with methanol (10 ml) and dichloromethane (10 ml). The filtrate was concentrated to afford a crude solid. The crude was purified via flash chromatography using an Analogix SF15-12 column and an eluant of ethyl acetate in heptane (50-100%) and methanol in ethyl acetate (0-5%) to afford the title compound as a yellowish white solid (250 mg, 64.8%). LC-MS m/z 396.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (t, J=7.12 Hz, 3H) 1.62 (s, 3H) 2.15-2.32 (m, 1H) 2.53-2.66 (m, 1H) 3.16 (s, 3H) 3.89-4.06 (m, 2H) 4.07-4.26 (m, 2H) 6.50 (d, J=7.61 Hz, 0H) 7.20-8.12 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:9][C:10]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[S:11])=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26].IC.[C:30](=O)([O-])[O-].[K+].[K+]>CC(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:9][C:10]([S:11][CH3:30])=[N:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26]
Reactant: O=C([O-])[O-]
Reactant: COC(CNC(=S)NC(c1ccccc1)c1ccc(N)c([N+](=O)[O-])c1)OC
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(CN=C(NC(c1ccccc1)c1ccc(N)c([N+](=O)[O-])c1)SC)OC
Temperature: 25 °C
Yield: 100 %

Procedure:
(a-3) A mixture of 22.3 parts of (+)-N-[(4-amino-3-nitrophenyl)phenylmethyl]-N'-(2,2-dimethoxyethyl)thiourea, 10.2 parts of iodomethane, 11.8 parts of potassium carbonate and 240 parts of 2-propanone was stirred over weekend at room temperature. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the elunet was evaporated, yielding 23 parts (100%) of (+)-methyl N-[(4-amino-3-nitrophenyl)phenylmethyl]-N'-(2,2-dimethoxyethyl)carbamimidothioate as a residue (141).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([OH:26])/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25].O[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[N:37][N:38]=2)=[CH:30][CH:29]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:20]([O:26][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[S:35][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[N:37][N:38]=2)=[CH:32][CH:33]=1)/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25]
Reactant: CCCCCc1nnc(-c2ccc(O)cc2)s1
Reactant: CCC/C=C/CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC/C=C/COc1ccc(-c2nnc(CCCCC)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
Triphenylphosphine (0.95 g) is added in small portions to a solution of (E)-hex-2-en-1-ol (0.40 g), 2-(4-hydroxyphenyl)-5-pentyl-1,3,4-thiadiazole (0.71 g), diethylazodicarboxylate (0.63 g) in dry tetrahydrofuran (40 cm3) at 0° C. under an atmosphere of nitrogen. The reaction mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the crude product was purified by column chromatography on silica gel using a 4:1 petroleum (40-60° C.) ether/ethyl acetate mixture as eluent, followed by recrystallisation from ethanol to yield 0.19 g of 2-(4-[(E)-hex-2-enyloxy]phenyl)-5-pentyl-1,3,4-thiadiazole.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][N:21]=1>C(OCC)(=O)C>[Br:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[N:21]=1
Reactant: C1=COCCC1
Reactant: Brc1n[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1nn(C2CCCCO2)c2ccccc12
Yield: 98.1 %

Procedure:
3,4-Dihydro-2H-pyran (0.232 mL, 2.54 mmol) and p-toluenesulfonic acid monohydrate (0.024 g, 0.127 mmol) were added to a solution of 3-bromo-1H-indazole (0.250 g, 1.269 mmol) in ethyl acetate (12.0 ml), and the mixture was heated at reflux for 48 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column. gradient elution with 0-25% ethyl acetate-hexane) to afford 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.350 g, 98%) as a colorless oil. MS (ESI, pos. ion) m/z 281, 283 [M+H]+.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38]S(CC1C=CC=CC=1)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:49][C:50]1[CH:51]=[C:52]([S:57](Cl)(=[O:59])=[O:58])[CH:53]=[CH:54][C:55]=1[Cl:56]>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:57]([C:52]1[CH:53]=[CH:54][C:55]([Cl:56])=[C:50]([Cl:49])[CH:51]=1)(=[O:59])=[O:58])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 60 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added 3,4-dichlorobenzenesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 60% yield.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([CH2:33][C:34]#[N:35])[S:31][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>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>[NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10]([C:28]3[CH:29]=[C:30]([CH2:33][C:34]#[N:35])[S:31][CH:32]=3)[C:5]=2[NH:4][N:3]=1
Reactant: Nc1n[nH]c2c(Br)cn(-c3ccccc3Cl)c(=O)c12
Reactant: CC1(C)OB(c2csc(CC#N)c2)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: CN(C)C=O
Solvent: O
Product: N#CCc1cc(-c2cn(-c3ccccc3Cl)c(=O)c3c(N)n[nH]c23)cs1
Temperature: 120 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
A mixture of 3-amino-7-bromo-5-(2-chlorophenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step B of Example 18 (200 mg), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acetonitrile (220 mg), tetrakis(triphenylphosphine)palladium(0) (68.1 mg), aqueous sodium carbonate solution (2 M, 0.589 mL) and N,N-dimethylformamide (3.0 mL) was stirred overnight at 120° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, methanol/ethyl acetate) to give the title compound (83.6 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[N:13][NH:12][C:11](=O)[C:10]=2[C:17]2[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=2[F:25])=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:11]1[N:12]=[N:13][C:14]([CH3:15])=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]=1[C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=1[F:25]
Reactant: COc1ccc(-c2c(C)n[nH]c(=O)c2-c2c(F)cc(F)cc2F)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2c(C)nnc(Cl)c2-c2c(F)cc(F)cc2F)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
2.06 g of 5-(4-methoxyphenyl)-6-methyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 2.14 g of 3-chloro-5-(4-methoxyphenyl)-6-methyl-4-(2,4,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (xix) of the present invention).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:29][C:30]2[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=2)[C:10]([NH:13][C:14]2[S:18][N:17]=[C:16]([C@H:19]3[CH2:23][O:22]C4(CCCCC4)[O:20]3)[N:15]=2)=[N:11][CH:12]=1.[ClH:37].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(OCC)(=O)C>[ClH:37].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:29][C:30]2[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=2)[C:10]([NH:13][C:14]2[S:18][N:17]=[C:16]([C@H:19]([OH:20])[CH2:23][OH:22])[N:15]=2)=[N:11][CH:12]=1
Reactant: COCCCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCCSc1cnc(Nc2nc([C@H](O)CO)ns2)c(Oc2cccnc2C)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
(S)—N-(5-(3-methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (85 mg, 0.16 mmol) was dissolved in ethanol (5 ml) and 1M HCl (0.5 ml) was added. The mixture was heated to 70° C. and agitated 3 hours. Upon cooling, the reaction was diluted with ethyl acetate, basified with sodium carbonate solution and washed with water and brine, dried (MgSO4), filtered and evaporated. The resulting solid was dissolved in small amount of dichloromethane and treated with 1M HCl in ether. After evaporation, (S)-1-(5-(5-(3-methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol hydrochloride (65 mg, 90% yield) was obtained as white solid. Mass Spectrum (apci) m/z=450.1 (M+H−HCl).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[NH:12][C:13](=[O:22])[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:15][C:10]=3[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:25][N:26]1[C:30]([CH2:31]Cl)=[N:29][CH:28]=[N:27]1.O>CN(C=O)C>[C:1]1([N:7]2[C:11]3=[N:12][C:13]([O:22][CH2:31][C:30]4[N:26]([CH3:25])[N:27]=[CH:28][N:29]=4)=[C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=[C:10]3[N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c2c(cc1-c1ccccc1)nnn2-c1ccccc1
Reactant: Cn1ncnc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nc2c(cc1-c1ccccc1)nnn2-c1ccccc1
Temperature: 25 °C
Yield: 10.4 %

Procedure:
A mixture of 3,6-diphenyl-5-oxo-4H-1,2,3-triazolo[4,5-b]pyridine (0.03 g, 0.10 mmol) and sodium hydride (55% in oil, 0.006 g, 0.12 mmol) in dry DMF (2 ml) was stirred at room temperature under nitrogen until all effervescence had ceased. A solution of 2-methyl-3-chloromethyl-1,2,4-triazole (0.025 g, 0.20 mmol) in dry DMF (0.5 ml) was added and the mixture was stirred for 4 days. Water (20 ml) was added and the aqueous solution was extracted with 10% methanol-dichloromethane (20 ml). The extract was dried (Na2SO4), filtered and concentrated. Preparative thin-layer chromatography on silica gel, eluting with 5% methanol-dichloromethane, gave the alkylation product which was recrystallised from ethyl acetate-hexane to give 3,6-diphenyl-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine (0.004 g, 10%) as a white, crystalline solid, m.p. 153-156° C. δH (360 MHz; CDCl3) 3.71 (3H, s), 5.69 (2H, s), 7.42-7.54 (6H, m), 7.63 (2H, dd, J=8 and 8), 7.86 (1H, s), 8.24 (2H, d, J=8) and 8.32 (1H, s); m/z (ES+) 383 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20].Cl>O.C(=S)=S>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:19](=[O:21])[CH3:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: COc1ccc(-c2ccccc2C(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The 4′-methoxybiphenyl (0.05 mol) and AlCl3 (0.06 mol) were dissolved in boiling CS2 (60 mL) with stirring. Acetyl chloride (0.1 mol) was added dropwise and reflux continued for 1 hour. The mixture was poured onto crushed ice (150 mL) containing water (50 mL) and HCl (50 mL). The organic phase was separated and the CS2 removed by distillation. The residue was recrystallised from aqueous isopropanol to give the title compound. δC (CDCl3, 62.9 MHz): 26.6, 55.4, 114.4, 126.6, 128.4, 129.0, 132.2, 135.3, 145.4, 159.9 and 198.0
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:12]1([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[N:28]=[C:27]([NH2:29])[CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)[CH2:14][CH2:13]1>N1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH:12]3[CH2:13][CH2:14]3)[CH2:21][CH2:20]2)[N:28]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: Nc1cccc(OC2CCN(CC3CC3)CC2)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cccc(OC2CCN(CC3CC3)CC2)n1)c1ccc(F)cc1Cl
Reaction time: 15 h
Yield: 79.4 %

Procedure:
Add 2-chloro-4-fluorobenzoyl chloride (149 mg, 0.58 mmol) to a solution of 6-(1-cyclopropylmethyl-piperidin-4-yloxy)-pyridin-2-ylamine (preparation 70, 130 mg, 0.53 mmol) in pyridine (7 mL) and beat at 55° C. for 15 hr. Remove pyridine in vacuo, dissolve the residue in CH2Cl2, wash with saturated NaHCO3 solution, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel, eluting with 5% 2M NH3-Methanol in CH2Cl2) provides 170 mg (79%) of the title compound: mass spectrum (ion spray): 404.1 (M+1); 1H NMR (CDCl3, ppm): 8.08 (s, 1H), 7.63 (m, 2H), 7.52 (t, 1H), 7.11 (m, 1H), 6.99 (m, 1H), 6.41 (d, 1H), 4.82 (m, 1H), 2.72 (m, 2H), 2.26 (m, 2H), 2.17 (d, 2H), 1.89 (m, 2H), 1.69 (m, 2H), 0.77 (m, 1H), 0.40 (m, 2H), 0.00 (m, 2H). Hydrochloride salt: Analytical calc. for C21H23ClFN3O2.HCl.0.5H2O: C, 56.13; H, 5.61; N, 9.35. Found: C, 56.12; H, 5.30; N, 9.35.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)cc4)CC3)nn2C(C)(C)C)cc1

Procedure:
82 mg (55%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-(4-chlorophenyl)piperazine (80 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[C:15]3[C:21]4[CH:22]=[CH:23][C:24]([C:26](O)=[O:27])=[CH:25][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:29]=2)=[N:11][CH:10]=[N:9]1.[CH3:30][S:31]([CH2:34][CH2:35][NH2:36])(=[O:33])=[O:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[C:15]3[C:21]4[CH:22]=[CH:23][C:24]([C:26]([NH:36][CH2:35][CH2:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:27])=[CH:25][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:29]=2)=[N:11][CH:10]=[N:9]1
Reactant: CS(=O)(=O)CCN
Reactant: O=C(O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccccc3Cl)nc1-2
Product: CS(=O)(=O)CCNC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccccc3Cl)nc1-2

Procedure:
2-(1-(2-Chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (40 mg, 0.1 mmol) was reacted with 2-(methylsulfonyl)ethanamine to provide 2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-N-(2-(methylsulfonyl)ethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide 134. LC/MS (ESI+): m/z 514 (M+H). 1H NMR (400 MHz, DMSO) δ 8.72 (s, 1H), 8.56 (s, 0H), 8.20 (s, 1H), 7.94 (s, 1H), 7.73 (d, J=7.0, 1H), 7.71-7.52 (m, 3H), 7.43 (s, 1H), 7.36 (d, J=8.9, 1H), 4.48 (d, J=6.6, 3H), 3.73-3.58 (m, 2H), 3.02 (s, 3H)
Reaction SMILES: [Na].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([CH3:13])[C:7]=1[OH:14])([CH3:5])([CH3:4])[CH3:3].[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17].C(O)(=O)C>C1(C)C=CC=CC=1>[C:2]([C:6]1[C:7]([OH:14])=[C:8]([CH3:13])[C:9]([CH3:12])=[C:10]([CH2:17][CH2:16][C:15]([O:19][CH3:20])=[O:18])[CH:11]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1ccc(C(C)(C)C)c(O)c1C
Reactant: C=CC(=O)OC
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C)c1C
Reaction time: 2 h

Procedure:
1.53 grams of sodium metal was added in small pieces to 240.6 grams of 2-tert.-butyl-5,6-dimethylphenol warmed at 60°. The reaction mixture was then heated at 120° with stirring for 2 hours, during which time the sodium metal was completely reacted. 174 grams of methyl acrylate was then added gradually over a period of 1 hour so that the temperature was maintained at 120°. The reaction mixture was then heated at 120° to 130° for an additional four hours. 3.9 ml. of acetic acid was then added. The reaction mixture was diluted with 600 ml. of toluene and warmed to dissolve a precipitate. The toluene solution was washed successively with 2N sodium carbonate, saturated sodium chloride, water, dilute aqueous hydrochloric acid and finally with water until the water washings were almost neutral. After drying over sodium sulfate, the clear toluene solution was evaporated at 20 mm Hg. pressure and finally at 1 mm. Hg. pressure for two hours. The crude residual product was crystallized from a mixture of 450 ml. of isopropanol and 200 ml. water and kept at about 15° C overnight. The thick crystalline slurry was filtered, the filter cake being washed with a little cold isopropanol-water mixture. After drying and recrystallization, the desired product was obtained as white crystals melting at 74° to 76° C (Compound 1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])([CH3:16])[CH3:15])=[CH:9][CH:8]=[C:7]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:6]=2.NC1C=NC2C(C=1NCCCCNC(=O)OC(C)(C)C)=CC=[C:36]([O:54][CH2:55][C:56]1C=CC=CC=1)[CH:35]=2.C(OCC(Cl)=O)C.COCCC(Cl)=O>ClCCl>[CH2:23]([O:22][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][C:14]([NH:17][S:18]([CH3:21])(=[O:19])=[O:20])([CH3:16])[CH3:15])[C:35]([CH2:36][O:54][CH2:55][CH3:56])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reactant: CC(C)(CNc1c(N)cnc2cc(OCc3ccccc3)ccc12)NS(C)(=O)=O
Agent: CCOCC(=O)Cl
Agent: COCCC(=O)Cl
Solvent: ClCCl
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O

Procedure:
A modification of the general method described in Part C of Example 50 was followed using N-[2-(3-amino-7-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]methanesulfonamide (12.6 g, 30.4 mmol) in lieu of tert-butyl {4-[3-amino-7-(benzyloxy)quinolin-4-ylamino]butyl}carbamate and ethoxyacetyl chloride (3.33 mL, 30.4 mmol) in lieu of methoxypropionyl chloride. The crude product was dissolved in dichloromethane (300 mL), and the resulting solution was washed with water (2×100 mL) and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a brown oil. The oil was purified by column chromatography on silica gel (eluting with 97.5:2.5 chloroform:methanol) to provide 12.4 g of N-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a beige foam.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C:17]1([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:16][C:3]1([CH2:2][N:28]2[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:26][CH2:27]2)[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Reactant: c1ccc(CCN2CCNCC2)cc1
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCN(CCc3ccccc3)CC1)O2
Yield: 50 %

Procedure:
Using 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and 1-(2-phenylethyl)piperazine, the procedure of Example 1 was otherwise repeated to provide the title compound.