Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[C:13]2[NH:14][CH:15]=[C:16](COCC[Si](C)(C)C)[N:17]=2)=[CH:5][C:4]=1[CH3:26].Cl.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[NH:14]1[CH:15]=[CH:16][N:17]=[C:13]1[C:10]1[C:11]2[C:6](=[CH:5][C:4]([CH3:26])=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][CH:9]=1
Reactant: COc1cc2c(cc1C)CCC=C2c1nc(COCC[Si](C)(C)C)c[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Product: COc1cc2c(cc1C)CCC=C2c1ncc[nH]1
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A stirred solution of 3.0 grams (0.0081 mole) of 1-{[2-(7-methoxy-6-methyl(3,4-dihydronaphthyl))imidazolyl]methoxy}-3,3-dimethyl-3-silabutane (xii), 5 mL of aqueous 3N hydrochloric acid, and 25 mL (0.025 mole) of tetrabutylammonium fluoride (1.0M in THF) was warmed to 50° C. where it stirred for about two hours. After this time, analysis of the reaction mixture using thin layer chromatography indicated that the reaction had not gone to completion. The reaction mixture was concentrated under reduced pressure to a residue and 15 mL of concentrated hydrochloric acid was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature during an 18 hour period. After this time, the reaction mixture was poured into a mixture of aqueous 50% sodium hydroxide and ice. The mixture was stirred until the ice melted, and a solid was collected by filtration. The solid was washed with ethyl acetate and dried, yielding 1.2 grams of the subject compound, mp 197-229° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([C:20]4[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=4)=[N:14][N:15]([CH2:17][CH:18]=O)[CH:16]=3)=[CH:11][C:6]=2[N:5]([CH2:27][CH3:28])[C:4]1=[O:29])[CH3:2].[CH3:30][O:31][CH2:32][CH2:33][NH2:34]>C1C=CC=CC=1>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([C:20]4[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=4)=[N:14][N:15]([CH2:17][CH2:18][NH:34][CH2:33][CH2:32][O:31][CH3:30])[CH:16]=3)=[CH:11][C:6]=2[N:5]([CH2:27][CH3:28])[C:4]1=[O:29])[CH3:2]
Reactant: CCn1c(=O)n(CC)c2cc(-c3cn(CC=O)nc3-c3cccc(C)c3)ccc21
Reactant: COCCN
Solvent: c1ccccc1
Product: CCn1c(=O)n(CC)c2cc(-c3cn(CCNCCOC)nc3-c3cccc(C)c3)ccc21
Reaction time: 1 h

Procedure:
To a benzene (3 mL) solution of [4-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3-m-tolyl-pyrazol-1-yl]-acetaldehyde (0.034 g) was added methoxyethylamine (0.03 mL) and 4 Å molecular sieves. The reaction was allowed to stand at 23° C. for 1 hour then was filtered and concentrated. The resulting oil was diluted with methanol (2 mL), 4 Å molecular sieves were added and the mixture was treated with sodium cyanoborohydride (0.02 g). After stirring for 18 hours the mixture was poured onto ethyl acetate/saturated sodium bicarbonate and extracted. The organic layer was dried over sodium sulfate and concentrated. Preparative thin layer chromatography gave 1,3-Diethyl-5-{1-[2-(2-methoxy-ethylamino)-ethyl]-3-m-tolyl-1H-pyrazol-4-yl}-1,3-dihydro-benzoimidazol-2-one (0.014 g). Subsequent treatment with 1M hydrochloric acid in ether gave the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[F:15][C:16]([F:31])([F:30])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:27][C:26]([CH:28]=O)=[CH:25][CH:24]=1>>[F:31][C:16]([F:15])([F:30])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:27][C:26]([CH:28]=[N:1][C:2]2[CH:3]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[OH:8])=[CH:25][CH:24]=1
Reactant: Nc1cc(-c2ccccc2)ccc1O
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)o1
Product: Oc1ccc(-c2ccccc2)cc1N=Cc1ccc(-c2ccccc2C(F)(F)F)o1

Procedure:
Using 3-aminobiphenyl-4-ol and 5-(2-(trifluoromethyl)phenyl)furan-2-carbaldehyde, 1.64 g of 3-{[5-(2-(trifluoromethyl)phenyl)furan-2-yl]methyleneamino}biphenyl-4-ol was obtained as an orange powder (yield 34%).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([Br:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[OH:24])[CH2:4][CH3:5])[CH3:2].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[Br:22][C:18]1[CH:19]=[C:20]([CH3:21])[C:15]([O:14][C:9]2[C:8]3[O:24][C:26](=[O:28])[N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]=3[CH:12]=[C:11]([CH3:13])[N:10]=2)=[C:16]([CH3:23])[CH:17]=1
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(CC)n1c(=O)oc2c(Oc3c(C)cc(Br)cc3C)nc(C)cc21
Reaction time: 8 h
Yield: 177.2 %

Procedure:
To a 0° C. solution of 4-(1-ethyl-propylamino)-6-methyl-2-(4-bromo-2,6-dimethyl-phenoxy)-pyridin-3-ol (40 mg, 0.101 mmol) was added triphosgene (10 mg, 0.035 mmol) and triethylamine (7 mg, 0.07 mmol) in 1 ml of dry THF. The resulting mixture was stirred overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified through silica gel column chromatography to give 26 mg (61%) of the title compound as a white solid. 1H NMR (CDCl3) δ 7.22(s,2H), 6.60(s,1H), 4.02(m,1H), 2.31(s,3H), 2.12(s,6H), 1.8–2.2(m,4H), 0.94(t,6H)ppm.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:6][C:7](O)=O)[C:3](O)=O.[NH2:11][CH2:12][CH2:13][OH:14]>>[CH3:1][C:2]1([CH3:10])[CH2:6][CH2:7][N:11]([CH2:12][CH2:13][OH:14])[CH2:3]1
Reactant: NCCO
Reactant: CC(C)(CC(=O)O)C(=O)O
Product: CC1(C)CCN(CCO)C1

Procedure:
The title compound was synthesized as described in Intermediate 21 using 2,2-dimethylsuccinic acid and 2-aminoethanol as starting materials. 1H NMR (CDCl3): δ 3.55 (t, 2H), 3.35 (br s, 1H), 2.60 (m, 4H), 2.33 (s, 2H), 1.55 (t, 2H), 1.43 (s, 6H).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(N(CC)CC)C.[C:18](Cl)(=O)[C:19]1[C:20]([O:25][CH3:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.Cl>C1COCC1>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[NH:10][C:1](=[O:9])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: NC(=O)c1ccccc1N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Temperature: 10 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a cooled (0-5° C.) mixture of anthranilamide (350 g, 2.57 mol) and triethylamine (286 g, 2.83 mol) in THF (2.5 L) was added dropwise o-anisoyl chloride (437 g, 2.57 mol) while maintaining the temperature between 0-20° C. The resulting suspension was stirred at room temperature overnight. The solvent was evaporated in vacuo, and the residue was washed several times with water. The wet residue was suspended in 2 M aq. NaOH (13 L), and the mixture was heated to reflux. After 20 minutes a clear solution was obtained. After 1 h of reflux the clear solution was cooled in an ice water bath and then acidified to pH 6 with conc. aq. HCl. The suspension was filtered, and the residue was washed thoroughly with water. The white solid was dried by azeotropic distillation with toluene. 2-(2-Methoxyphenyl)quinazolin-4(3H)-one (567 g) was obtained in 82%. 1H-NMR (200 MHz, Me2SO-d6): δ 3.90 (s, 3H), 7.20 (m, 2H), 7.60 (t, 2H), 7.85 (m, 3H), 8.20 (d, 1H), 12.20 (s, 1H).
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[Cl:18][C:19]1[CH:20]=[C:21]([O:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:22]=[N:23][CH:24]=1>>[C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][O:25][C:21]2[CH:22]=[N:23][CH:24]=[C:19]([Cl:18])[CH:20]=2)[CH2:29][CH2:30]1)#[N:2]
Reactant: Clc1cncc(OCCN2CCNCC2)c1
Reactant: CC(C)C(C#N)(CCCI)c1ccc(C#N)s1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cncc(Cl)c2)CC1)c1ccc(C#N)s1

Procedure:
The title compound was synthesized in accordance with Example 77 from 4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl iodide and 1-[2-(5-chloro-3-pyridyloxy)ethyl]piperazine. The physico-chemical data of the compound was as below.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1.[CH:13](O)([CH3:15])[CH3:14]>>[CH2:11]([C:4]1[CH:3]=[C:2]([Br:1])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH:13]([CH3:15])[CH3:14])=[O:7])[CH3:12]
Reactant: CCc1cc(Br)ccc1C(=O)O
Reactant: CC(C)O
Product: CCc1cc(Br)ccc1C(=O)OC(C)C

Procedure:
Using General Esterification Procedure A; 4-bromo-2-ethyl-benzoic acid (2.25 g, 9.9 mmols) was combined with isopropyl alcohol to give the title compound as a colorless oil after column chromatography (2% EtOAc-hexanes).
Reaction SMILES: C([O:3][C:4]([CH:6]=[N:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[C:18]([F:32])=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1)=[O:5])C.[Li+].[OH-].Cl>CO.O>[C:4]([CH:6]=[N:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[C:18]([F:32])=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C=Nc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C=Nc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1

Procedure:
The reaction of N2-(3-ethoxycarbonylmethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (0.1 g) and LiOH (10 equivalents) in MeOH:water (1:1, v/v) for 1 h at room temperature followed by treatment with aqueous HCl gave the solid. The resulting solid was filtered, washed with water and dried to give N2-(3-carboxymethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 18.23 min.; purity: 87.6%; MS (m/e): 412.01 (Mg).
Reaction SMILES: [C:1]([N:8]([CH3:10])[OH:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][O:18][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[C:32]([Si:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:18][CH2:17][CH2:16][CH2:15][CH2:14][O:9][N:8]([CH3:10])[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])([CH3:33])([CH3:34])[CH3:35]
Reactant: CC(C)(C)[Si](OCCCCBr)(c1ccccc1)c1ccccc1
Reactant: CN(O)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(OCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Boc-N-methylhydroxylamine (a) (0.74 g, 5 mmol) was dissolved in 10 ml DMF, treated with NaH (200 mg, 60% dispersion in mineral oil, 4.75 mmol), and stirred for 1 h under an argon atmosphere. The mixture was cooled to 0° C., treated with a solution of 4-bromo-butoxy)-tert-butyl-diphenyl-silane (b) (1.56 g, 4 mmol) in DMF (10 mL) and stirred at 0° C. for an additional 3 hours. The solvents were removed under reduced pressure, and the residue was dissolved in EtOAc (150 mL) and poured into a separatory funnel. The organic layer was washed with 0.1 M NaOH (5×50 mL), H2O (50 ml), 0.1 M KHSO4, and brine (50 ml) and the dried with MgSO4. After removal of the solvent, the residue was chromatographed on silicagel(Hexane:EtOAc 10:1) to yield 0.588 g (24%). The product was identified by electrospray mass spectrometry (ESI-MS)(MFE calculated 457.26; found 457.8)
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[O:17][CH2:18][CH2:19][CH2:20][OH:21])[CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:34]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][C:35]=1[C:36]#[N:37].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[O:17][CH2:18][CH2:19][CH2:20][OH:21])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:34]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][C:35]=1[C:36]#[N:37]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
Reactant: Cc1cccc(OCCCO)c1N(C)C(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
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: C1COCCO1
Solvent: O
Product: Cc1cccc(OCCCO)c1N(C)C(=O)c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2C#N)c1
Temperature: 95 °C
Yield: 79.5 %

Procedure:
A mixture of 4-chloro-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (206 mg, 0.45 mmol), 2-bromo-5-(trifluoromethyl)-benzonitrile (75 mg, 0.3 mmol), Pd(PPh3)4 (34.7 mg, 0.03 mmol), Na2CO3 (190.8 mg, 1.8 mmol) in dioxane/water (9/1, 1.5 mL), was heated at 95° C. for approximately 16 hrs after degassing of the solvent with a stream of nitrogen. The reaction was allowed to cool to room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was further washed with brine and dried with MgSO4. The filtrate was evaporated and the residue purified by preparative TLC [eluent: 40% acetone in hexane] to afford 4-chloro-3-(2-cyano-4-trifluoromethyl-phenyl)-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N-methyl-benzamide 10-1 (120 mg). MS [M+H]+: 502.9; tR=8.15 min. (method 2)
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:26]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:26])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=3)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nccc1Nc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cc(S(C)(=O)=O)ccc3nc21
Temperature: 110 °C

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-5-(methylsulfonyl) anthranilic acid of example 37(b) and POCl3 (50 ml) is heated at 110° C. for 16 hours. The reaction mixture is poured into ice water, neutralized with NH4OH and extracted with CH2Cl2. The CH2Cl2 layer is evaporated, and the residue is purified by column chromatography on silica gel eluting with 50% ether/H2Cl2 to afford 1.1 g of 1-ethyl-4-chloro-6-(methylsulfonyl)-1H-pyrazolo[3,4-b]quinoline, m.p. 158°-160° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.S(Cl)([Cl:14])=O>>[CH3:1][N:2]=[C:3]([Cl:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: CNC(=O)c1ccc(C)cc1
Product: CN=C(Cl)c1ccc(C)cc1
Yield: 79.9 %

Procedure:
N-Methyl 4-methylbenzamide (10.02 g, 67.2 mmole) was treated with thionyl chloride (31.7 g, 267 mmole) as in Example I. Gas evolution ceased after the reaction had been heated for 45 minutes. The product was isolated as in Example I to yield 9.0 g (80%) of the title compound as a clear colorless liquid, b.p. 57° C. (~0.1 mm Hg).
Reaction SMILES: Cl.[C:2](=[N:10][OH:11])(Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.I[C:13]([CH:15]1[CH2:17][CH2:16]1)=[CH2:14].C(N(CC)CC)C>C(O)C>[CH:15]1([C:13]2[O:11][N:10]=[C:2]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=3)[CH:14]=2)[CH2:17][CH2:16]1
Reactant: ON=C(Cl)c1cccnc1
Reactant: C=C(I)C1CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1cncc(-c2cc(C3CC3)on2)c1
Reaction time: 1 h

Procedure:
To a stirred mixture containing 1.35 g. of nicotinoyl chloride oxime hydrochloride and 2.6 g. of 1-iodovinylcyclopropane in 50 ml. of ethanol is added dropwise over a 1 hour period, a solution of 4.27 g. of triethylamine in 40 ml. of ethanol. The reaction is stirred for 1 hour and then the solvent is removed under reduced pressure. The residue is dissolved in water and ether and the ether layer is separated. The water layer is extracted twice with ether and then the combined ether layers are dried over sodium sulfate. Filtration and removal of the solvent under reduced pressure gives an orange-yellow solid. This material is recrystallized from isopropyl alcohol to give white crystals, melting point 74°-75°C., nmr spectrum δ6.82 (DMSO-d6, s, 4-isoxazolyl H).
Reaction SMILES: [CH3:1][C:2]([OH:16])([CH2:5][CH2:6][CH:7]=[C:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:3]#[CH:4]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCCCCC>[CH3:1][C:2]([OH:16])([CH2:5][CH2:6][CH:7]=[C:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])[CH:3]=[CH2:4]
Reactant: C#CC(C)(O)CCC=C(C)CCCC(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Product: C=CC(C)(O)CCC=C(C)CCCC(C)C
Yield: 99.1 %

Procedure:
An autoclave having an internal volume of 3 liters was charged with 630 g of the 3,7,11-trimethyl-6-dodecen-1-yn-3-ol thus obtained, 270 g of hexane and 0.22 g of a Lindlar catalyst (supported on calcium carbonate) to carry out the hydrogenation for 4 hours under hydrogen pressure of 5 to 8 kg/cm2 (gauge pressure) at a temperature of 25 to 43° C. Thereafter, the catalyst was filtered off, and the resultant filtrate was concentrated with a rotary evaporator to give 630 g of crude 3,7,11-trimethyl-1,6-dodecadien-3-ol. Analysis by gas chromatography (column: DC-550, available from Gasukuro Kogyo Inc.; column length: 3 m; column temperature: 160° C.; and column: PEG-20M, available from Gasukuro Kogyo Inc.; column length: 3 m; column temperature: 190° C.) revealed that the conversion of 3,7,11-trimethyl-6-dodecen-1-yn-3-ol was 95.5%, and the selectivity to 3,7,11-trimethyl-1,6-dodecadien-3-ol was 94.6%.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH:12]=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]3)=[N:23]2)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH:32]([NH:35][CH2:12][C:9]4[CH:10]=[CH:11][C:5]5[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:33][CH2:34]3)=[N:23]2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Product: COc1ccc2ncc(SCCN3CCC(NCc4ccc5c(c4)NC(=O)CS5)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow waxy solid (54 mg, 48% yield) following Scheme 3 and in analogy to Example 40 using 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (42 mg, 0.22 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70 mg, 0.22 mmol, 1.0 eq) as starting materials.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)[N:3]=1.Cl.[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33])(=[O:28])=[O:27].C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)[N:3]=1)(=[O:27])=[O:28]
Reactant: O=C1CCc2cc(Nc3ncc(C(F)(F)F)c(Cl)n3)ccc2N1
Reactant: CS(=O)(=O)c1cccc(CN)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1cccc(CNc2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2C(F)(F)F)c1
Temperature: 100 °C
Yield: 53.3 %

Procedure:
6-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3,4-dihydro-1H-quinolin-2-one (50 mg, 0.145 mmol) was added to 0.5 ml NMP and 3-Methanesulfonyl-benzylamine mono hydrochloride salt (32 mg, 0.145 mmoles) and triethylamine (0.060 ml, 0.435 mmoles) were added the reaction was heated to 100° C. for one hour. The reaction was cooled to room temperature and 0.5 mL NMP was added. The reaction was then filtered and purify by preparative reverse phase HPLC 30×50 mm XTerra C18 prep column, fifteen minute gradient 15-60% (0.1% NH4OH in Acetonitrile) and (0.1% NH4OH in water)), flow rate 40 mL/min. The desired product eluted (retention time 8.41 minutes) and was concentrated to a solid (38 mg, 54% yield). 1H NMR (Methanol-d4, 400 MHz) δ 2.52 (m, 2H), 2.80 (m, 2H), 2.99 (s, 3H), 4.80 (s, 2H), 6.73 (d, J=9 Hz; 1H), 7.22 (d, J=9 Hz; 1H), 7.37 (s, 1H), 7.57 (t, J=8 Hz; 1H), 7.64 (d, J=8 Hz;1H), 7.80 (m, 1H), 7.90 (s, 1H), 8.12 (s, 1H). HPLC ret. time: 5.390, LRMS (M+) 492.12.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:12]2[CH2:14][O:13]2)=[CH:4][C:5]2[CH2:9][O:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[O:15]=[C:16]1[CH2:21][NH:20][CH2:19][CH2:18][N:17]1[CH:22]1[CH2:31][CH2:30][C:29]2[CH:28]=[C:27]([C:32]#[N:33])[CH:26]=[CH:25][C:24]=2[CH2:23]1>CCO>[OH:13][CH:12]([C:3]1[C:2]([CH3:1])=[CH:11][C:6]2[C:7](=[O:10])[O:8][CH2:9][C:5]=2[CH:4]=1)[CH2:14][N:20]1[CH2:19][CH2:18][N:17]([CH:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[C:27]([C:32]#[N:33])[CH:26]=[CH:25][C:24]=3[CH2:23]2)[C:16](=[O:15])[CH2:21]1
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Reactant: Cc1cc2c(cc1C1CO1)COC2=O
Solvent: CCO
Product: Cc1cc2c(cc1C(O)CN1CCN(C3CCc4cc(C#N)ccc4C3)C(=O)C1)COC2=O
Temperature: 140 °C

Procedure:
A mixture of 6-methyl-5-(oxiran-2-yl)-2-benzofuran-1 (3H)-one (22 mg, 0.12 mmol) and 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (30 mg, 0.12 mmol) in EtOH (2 mL) was heated to 140° C. for 1 hour. The reaction mixture was concentrated to dryness, and dissolved in MeOH, filtered and shot into Mass-directed HPLC for separation to give the title product. LC-MS (IE, m/z): 446 [M+1]+.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[NH:4]1)[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:22])([F:21])[F:20])[CH3:2].C=O.[BH3-][C:28]#N.[Na+]>C(O)(=O)C>[CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[N:4]1[CH3:28])[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:21])([F:22])[F:20])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC[C@@H]1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC[C@@H]1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1C
Yield: 89.8 %

Procedure:
This compound was prepared by General Method 5 (EXAMPLE 1) from (3R)-3-ethyl-3,4-dihydro-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (0.015 g, 0.044 mmol), paraformaldehyde (0.013 g, 0.44 mmol) and NaCNBH3 (0.014 g, 0.22 mmol) in 1 mL glacial acetic acid to afford 0.014 g (93%) of (3R)-3-ethyl-3,4-dihydro-8-isopropoxy-4-methyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, of sufficient purity as to be used directly in the next reaction. Rf0.5 (9:1 hexane:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.44 (d, 1H, J=9.0), 7.20 (d, 1H, J=9.0), 7.18 (s, 1H), 5.48 (septet, 1H, J=6.2), 4.29 (dd, ABX, 1H, J=10.7, 2.5), 4.02 (dd, ABX, 1H, J=10.7, 2.7), 3.21–3.16 (m, 1H), 3.03 (s, 3H), 1.74–1.56 (m, 2H), 1.39 (d, 3H, J=6.2), 1.37 (d, 3H, J=6.2), 0.99 (t, 3H, J=7.5).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](N)=[N:4][C:2]1=[O:3].S([O-])([O-])(=O)=O.[NH4+].[NH4+].[CH3:16][Si:17]([CH3:24])([CH3:23])[NH:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>>[CH3:16][Si:17]([N:18]([Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]1[CH:7]=[CH:5][NH:4][C:2](=[O:3])[N:1]=1)([CH3:24])[CH3:23]
Reactant: Nc1cc[nH]c(=O)n1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: C[Si](C)(C)N(c1cc[nH]c(=O)n1)[Si](C)(C)C

Procedure:
Cytosine (12.0 g), hexamethyldisilazane (60 ml) and ammonium sulfate (10 mg) were refluxed at 125° C. for 30 minutes to form a homogenous solution. The hexamethyldisilazane was removed by distillation to form the titled product.