Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.O[CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:19][CH2:20][NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OCCNC(=O)OC(C)(C)C)ccc2c1
Yield: 82.4 %

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 7.60 g, 33.0 mmol), tert-butyl N-(2-hydroxyethyl)carbamate (5.30 g, 32.9 mmol), N,N-dimethylaminopyridine (DMAP, 0.35 g, 2.86 mmol) and 1,3-dicyclohexylcarbodiimide (6.80 g, 33.0 mmol) in CH2Cl2 (200 mL) was stirred at ambient temperature overnight. The byproduct, dicyclohexyl urea, was removed by filtration. The filtrate was concentrated, dissolved in EtOAc (50 mL) and then cooled in a dry-ice bath to precipitate the remaining dicyclohexyl urea and then filtered. The filtrate was concentrated, dissolved in CH2Cl2 (15 mL) and hexane (200 mL) and then stirred until the product precipitated. The solid was dried under vacuum to give the title compound (10.12 g, 82% yield). Mp 82-84° C. 1H NMR (300 MHz, CDCl3) δ 7.72-7.65 (m, 3H), 7.42-7.38 (m, 1H), 7.16-7.11 (m, 2H), 5.05 (br, 1H), 4.13 (t, J=5.3 Hz, 2H), 3.91 (s, 3H), 3.87 (q, J=7.1 Hz, 1H), 3.30 (br. q, 2H), 1.58 (d, J=7.1 Hz, 3H), 1.45 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 174.4, 157.6, 155.6, 135.4, 133.6, 129.2, 128.8, 127.1, 126.0, 125.8, 119.0, 105.5, 79.3, 63.7, 55.2, 45.2, 39.5, 28.2, 18.3. Mass spectrum (API-TIS) m/z 374 (MH)+. Anal. calcd. for C21H27NO5: C, 67.54; H, 7.29; N, 3.75. Found: C, 67.43; H, 7.16; N, 3.66.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:11]1([C:7]2[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH:8]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNCC1
Reactant: CC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N1CC=C(N2CCCCC2)CC1
Temperature: 25 °C

Procedure:
A flask equipped with a Dean-Stark trap and a reflux condenser was charged with 1-acetyl-piperdin-4-one (100 g, 0.71 mol) and toluene (1 L). Piperidine (63.4 g, 0.75 mol) and p-toluenesulfonic acid monohydrate (0.27 g, 1.4 mmol, 0.2 mol %) were added, and the resulting solution was heated at reflux for 8 h. The mixture was cooled to rt and concentrated to give a crude product which was used directly in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:5]2.[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1)[CH3:25]>>[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]([NH:15][CH2:14][CH2:13][CH2:12][N:7]2[CH:6]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)=[O:35])[CH:30]=[CH:31][CH:32]=1)[CH3:25]
Reactant: NCCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1
Reactant: CCOc1cccc(N=C=O)c1
Product: CCOc1cccc(NC(=O)NCCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 238-b) as a starting material, and using 3-ethoxyphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].C([O-])([O-])=O.[K+].[K+].[Br:19][CH2:20][C:21](Br)=[O:22]>ClCCl.C(OCC)(=O)C>[CH2:7]([C:6]1[CH:5]=[CH:4][C:2]([O:3][C:21](=[O:22])[CH2:20][Br:19])=[C:1]([O:11][CH3:12])[CH:10]=1)[CH:8]=[CH2:9]
Reactant: C=CCc1ccc(O)c(OC)c1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCc1ccc(OC(=O)CBr)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a solution of eugenol (500 mg, 3.03 mmol) in dichloromethane (5 mL) were added K2CO3 (1.0 g, 7.57 mmol) followed by bromo acetyl bromide (931 mg, 4.54 mmol) at 0° C. The mixture was allowed to stir at room temperature (25° C.) over a period of 1 hr. The resulting mixture was diluted with ethyl acetate (200 mL), washed with water (2×200 mL) and dried over sodium sulphate. The crude product obtained up on evaporation of the solvent was further purified by silica gel column chromatography to obtain bromo-acetic acid 4-allyl-2-methoxy-phenylester as viscous oil (550 mg, 63%).
Reaction SMILES: [C:1]1(=[O:23])[N:5]([CH:6]=[CH:7][C:8]2[C:9](=[O:17])[NH:10][C:11]([CH3:16])=[C:12]([CH2:14][CH3:15])[CH:13]=2)[C:4](=[O:18])[C:3]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:2]12>CO.O1CCCC1.[Pd]>[C:4]1(=[O:18])[N:5]([CH2:6][CH2:7][C:8]2[C:9](=[O:17])[NH:10][C:11]([CH3:16])=[C:12]([CH2:14][CH3:15])[CH:13]=2)[C:1](=[O:23])[C:2]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:3]12
Reactant: CCc1cc(C=CN2C(=O)c3ccccc3C2=O)c(=O)[nH]c1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(CCN2C(=O)c3ccccc3C2=O)c(=O)[nH]c1C
Reaction time: 15 h

Procedure:
A partial suspension of 3-(2-phthalimidoethenyl)-5-ethyl-6-methylpyridin-2(1H)-one (145 mg, 0.47 mmol) in methanol (20 mL) and tetrahydrofuran (20 mL) containing 5% palladium/carbon (117 mg) was hydrogenated at atmospheric pressure for 10-20 hours. The catalyst was filtered off and the solvents evaporated to give product. This material was recrystallized from methanol to yield 110 mg (75%), m.p. 232°-233° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH2:19][NH:20][CH3:21].C(N(CC)CC)C>O1CCOCC1>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH2:19][N:20]([CH3:21])[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CNCc1ccc(Cl)cc1Cl
Reactant: O=C(CBr)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(CC(=O)c1ccccc1)Cc1ccc(Cl)cc1Cl
Temperature: 20 °C
Yield: 89.9 %

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-bromo-1-phenylethanone (1 g, 5.05 mmol, 1.00 equiv) in 1,4-dioxane (20 mL) and (2,4-dichlorophenyl)-N-methylmethanamine (1.1 g, 5.82 mmol, 1.15 equiv). Triethylamine (2 g, 19.80 mmol, 3.92 equiv) was added dropwise with stirring at 20° C. The resulting solution was stirred for 1 h at 20° C. in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 1.4 g (90%) of the title compound as a yellow oil.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:34][C:35]1[N:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]2)[C:42]2[C:37](=[CH:38][C:39]([C:52]([OH:54])=O)=[CH:40][CH:41]=2)[N:36]=1.[NH2:55][CH:56]([CH2:62][C:63]1[CH:64]=[N:65][C:66]([C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[C:70]=2[F:76])=[CH:67][CH:68]=1)[C:57]([N:59]([CH3:61])[CH3:60])=[O:58]>CN(C)C=O>[NH2:34][C:35]1[N:44]=[C:43]([N:45]2[CH2:46][CH2:47][N:48]([CH3:51])[CH2:49][CH2:50]2)[C:42]2[C:37](=[CH:38][C:39]([C:52]([NH:55][CH:56]([CH2:62][C:63]3[CH:64]=[N:65][C:66]([C:69]4[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[C:70]=4[F:76])=[CH:67][CH:68]=3)[C:57]([N:59]([CH3:61])[CH3:60])=[O:58])=[O:54])=[CH:40][CH:41]=2)[N:36]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: CN(C)C(=O)C(N)Cc1ccc(-c2cccc(F)c2F)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2nc(N)nc3cc(C(=O)NC(Cc4ccc(-c5cccc(F)c5F)nc4)C(=O)N(C)C)ccc23)CC1
Reaction time: 2 h
Yield: 17.4 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (20 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 uL, 0.07 mmol) were added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 0.03 mmol) and 2-amino-3-[6-(2,3-difluorophenyl)pyridin-3yl]-N,N-dimethylpropanamide (20 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL) at r.t. The reaction was stirred for 2 h. and the product was purified with out workup by RP-HPLC (pH=2) to afford the desired compound (0.003 g, 10%) as an amorphous white solid TFA salt. Analytical LCMS (M+H)+: m/z=575.0.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:23])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=2)[CH2:7]1.ClCl>ClCCl>[Cl:1][C:15]1[CH:16]=[C:17]([C:20](=[O:22])[CH3:21])[CH:18]=[CH:19][C:14]=1[CH:8]1[CH2:7][C:6]([CH3:23])([CH3:5])[CH2:11][C:10]([CH3:12])([CH3:13])[CH2:9]1
Reactant: CC(=O)c1ccc(C2CC(C)(C)CC(C)(C)C2)cc1
Reactant: [Cl-]
Agent: ClCl
Agent: [Al+3]
Solvent: ClCCl
Product: CC(=O)c1ccc(C2CC(C)(C)CC(C)(C)C2)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
40.25 g of aluminium chloride are added at 0° C., under an inert atmosphere, to 350 ml of dichloromethane, followed by addition of 5 g of 1-[4-(3,3,5,5-tetramethylcyclohexyl)phenyl]ethanone (compound V.1) dissolved in dichloromethane. After stirring for 2 hours at 0° C., 17.1 ml of chlorine gas (d=1.565, measured in the liquid state at −78° C.) are bubbled through the reaction. After warming to room temperature, a water/ice mixture is added to the reaction mixture. The resulting mixture is extracted with dichloromethane, the phases are separated after settling has taken place, and the organic phase is dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified on a column of silica gel, eluting with a 7/3 (v/v) cyclohexane/dichloromethane mixture; yield=74%; m.p.=64° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:10])=[S:9].Cl[CH2:12][CH:13]=O.NC(N)=O>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:12]=[CH:13][N:10]=1
Reactant: O=CCCl
Reactant: NC(=S)Nc1ccccn1
Agent: NC(N)=O
Solvent: CCO
Product: c1ccc(Nc2nccs2)nc1
Reaction time: 3 h

Procedure:
To a flask was added 2-pyridyl thiourea (5-1) (3.48 g, 22.7 mmol), 3 mL ethanol, and 50% by weight chloroacetaldehyde (14.4 mL, 113.5 mol). The flask was then heated to reflux. As the mixture was heated, the urea slowly dissolved in solution. After 3 hours, the ethanol was removed under reduced pressure. Saturated aqueous NaHCO3 was then added to the flask and a white precipitate formed after vigorous bubbling. The precipitate was filtered and washed with water. The white solid was then dried under vacuum overnight with P2O5 drying agent. 1H NMR (CDCl3): δ 10.95 (bs, 1H), 8.37 (d, 1H, J=4.2 Hz), 7.61 (t, 1H, J=7.0 Hz), 7.49 (d, 1H, J=3.5 Hz), 6.94 (d, 1H, J=8.3 Hz), 6.88 (t, 1H, J=7.1 Hz), 6.85 (d, 1H, J=3.7 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[C:29]([BH3-])#N.[Na+].C=O.C(O)(=O)C>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:24][N:25]([CH3:29])[CH2:26]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (chiral intermediate from Example 261) (50 mg, 0.13 mmol) in methanol (3 mL) was treated with sodium cyanoborohydride (20 mg, 0.31 mmol) followed by formaldehyde (37% in water) (37 μL, 0.50 mmol) and stirred at room temperature for 20 min. The reaction mixture was quenched with acetic acid (170 μL, 2.9 mmol), diluted with methanol, and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (30 mg, 58%). The product was isolated as a single enantiomer. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.46 (s, 1H), 7.37 (br s, 2H), 6.23 (q, J=7.0 Hz, 1H), 4.10-3.96 (m, 1H), 3.95-3.85 (m, 2H), 3.63 (s, 3H), 3.05-2.94 (m, 2H), 2.55 (s, 3H), 2.18 (s, 3H), 1.72 (d, J=7.1 Hz, 3H). LCMS for C20H23ClN7O (M+H)+: m/z=412.2; Found: 412.1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([S:11][C:12](=S)OCC)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O:17]([C:24]1[CH:25]=[C:26]([CH:39]=[CH:40][CH:41]=1)COS(C1C=CC(C)=CC=1)(=O)=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CO.CC(C)([O-])C.[K+]>O1CCCC1>[O:17]([C:24]1[CH:25]=[C:26]([CH:39]=[CH:40][CH:41]=1)[CH2:12][S:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OCc2cccc(Oc3ccccc3)c2)cc1
Reactant: CCOC(=S)Sc1ccc2ncccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc(Oc2cccc(CSc3ccc4ncccc4c3)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
To a solution of dithiocarbonic acid O-ethyl ester S-quinolin-6-yl ester described in Preparation Example W-1 (50 mg, 0.201 mmol), toluene-4-sulfonic acid 3-phenoxybenzyl ester (110 mg, 0.313 mmol) and methanol (1 ml) in tetrahydrofuran (5 ml) was added potassium tert-butoxide (135 mg, 1.20 mmol) under nitrogen atmosphere, which was then stirred at room temperature for 24 hours. This reaction solution was purified by thin layer silica gel chromatography (hexane:ethyl acetate=1:1), and the title compound (39 mg, 0.114 mmol, 57%) was obtained as a yellow oil.
Reaction SMILES: C(O)CCC.[ClH:6].[OH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[OH:17])[CH2:11][CH2:12][NH2:13].C(O[CH:21](OCC)[CH2:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)C>Cl.O>[ClH:6].[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([S:23][CH2:22][CH:21]2[C:14]3[C:10](=[CH:9][C:8]([OH:7])=[C:16]([OH:17])[CH:15]=3)[CH2:11][CH2:12][NH:13]2)=[CH:25][CH:26]=1
Reactant: CCOC(CSc1ccc(C)cc1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: Cc1ccc(SCC2NCCc3cc(O)c(O)cc32)cc1
Yield: 106.9 %

Procedure:
To a mixture of n-butanol (10 ml), water (2.5 ml) and concentrated hydrochloric acid (1 drop) were added 3,4-dihydroxyphenethylamine hydrochloride (0.63 g) and (4-methylthiophenoxy)acetaldehyde diethyl acetal (1.0 g), and the mixture was refluxed for 5 hours. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The residue was crystallized by adding acetone, and the crystals were recrystallized from a mixture solvent of methanol and ether to give 1-(4-methylthiophenoxy)methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.2 g), mp 270° C. (dec.).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[OH:13][NH:14][C:15](=N)[CH2:16][CH2:17][CH3:18]>>[CH2:16]([C:15]1[N:12]=[C:11]([N:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)[O:13][N:14]=1)[CH2:17][CH3:18]
Reactant: N#CN1CCC2(CC1)OCCO2
Reactant: CCCC(=N)NO
Product: CCCc1noc(N2CCC3(CC2)OCCO3)n1

Procedure:
The title compound is prepared from 1,4-dioxa-8-aza-spiro[4.5]decane-8-carbonitrile and N-hydroxy-butyramidine following a procedure analogous to that described in Intermediate 2. LC (method 14): tR=1.16 min; Mass spectrum (ESI+): m/z=254 [M+H]+.
Reaction SMILES: [CH:1]1([CH:6]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(C(CC)(OP([CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])(O)=O)C)C.[Br-].[Li+].C(N(CC)CC)C>C1COCC1>[CH:1]1(/[CH:6]=[CH:16]/[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCC(C)(CC)OP(=O)(O)CC(=O)OCc1ccccc1
Reactant: O=CC1CCCC1
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(/C=C/C1CCCC1)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of cyclopentanecaboxaldehyde (0.069 g, 0.70 mmol), benzyl (diethylethyl phosphono)acetate (0.100 g, 0.35 mmol), lithium bromide (0.030 g, 0.35 mmol), and triethylamine (0.049 mL, 0.35 mmol) in THF (1 mL) at room temperature was stirred for 16 hours, quenched with water, stirred for 15 minutes, diluted with ethyl acetate, washed sequentially with pH 7 buffer and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI) m/e 231 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]2[C:8]3[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][CH2:12][C:6]2=[N:5][N:4]=1.[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH2:2][C:3]1[N:7]2[C:8]3[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][CH2:12][C:6]2=[N:5][N:4]=1)[CH3:25]
Reactant: ClCc1nnc2n1-c1ccccc1C(c1ccccc1)=NC2
Reactant: CNC
Product: CN(C)Cc1nnc2n1-c1ccccc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 1, 1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine was reacted with dimethylamine to give 1-[(dimethylamino)-methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 182°-183.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]([NH:18][C:19]2[CH:24]=[C:23]([NH:25][C:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH:29]=3)=[O:27])[CH:22]=[CH:21][C:20]=2[CH3:40])=[O:17])=[CH:12][CH:11]=1>O>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:10]1[N:15]=[CH:14][C:13]([C:16]([NH:18][C:19]2[CH:24]=[C:23]([NH:25][C:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)[CH:29]=3)=[O:27])[CH:22]=[CH:21][C:20]=2[CH3:40])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccc(Cl)nc1
Reactant: CN(C)CCCCN
Solvent: O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccc(NCCCCN(C)C)nc1
Temperature: 100 °C

Procedure:
A mixture of 4-dimethylaminobutylamine (5 ml) and 6-chloro-N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-3-carboxamide (0.181 g) was stirred and heated to 100° C. for 16 hours. The mixture was poured into water (50 ml) and stirred for 20 minutes. The resultant solid was isolated, washed with diethyl ether and under vacuum at 40° C. There was thus obtained the title compound (0.17 g); NMR Spectrum: (DMSOd6) 1.4-1.6 (m, 4H), 2.1 (s, 6H), 2.19 (s, 3H), 2.21 (m, 2H), 3.52 (m, 6H, 3.72 (m, 4H), 6.49 (d, 1H), 7.14 (m, 2H), 7.21 (m, 2H), 7.54 (d, 1H), 7.78 (s, 1H), 7.85 (d, 1H), 8.27 (d, 1H), 8.64 (s, 1H), 9.51 (s, 1H), 10.26 (s, 1H); Mass Spectrum M+H+ 532.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:27](Cl)=[O:28]>C(Cl)Cl>[N+:33]([C:32]1[CH:31]=[CH:30][C:26]([C:27]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:28])=[CH:25][C:24]=1[O:23][CH3:22])([O-:35])=[O:34]
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.2 %

Procedure:
To a solution of 0.55 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 8 ml of methylene chloride is added 0.55 g of triethylamine followed by 0.97 g of 3-methoxy-4-nitrobenzoyl chloride. The reaction mixture is stirred at room temperature for 2 hours and then quenched with 10 ml of 1N NaOH. The methylene chloride layer is evaporated and the resulting suspension filtered. The precipitate is washed with 1N NaOH (2×5 ml), water (3×5 ml) and hexane (2×5 ml). The collected solid is dried in vacuo to give 1.13 g of off-white solid. MS(CI): 364(M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:1]([C:2]2[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=2)[S:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1cc(Br)cnc1Cl
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc(F)cc1)N(c1cc(Br)cnc1Cl)S(=O)(=O)c1ccc(F)cc1
Yield: 85.8 %

Procedure:
A solution of 3-amino-5-bromo-2-chloropyridine (0.94 g, 4.5 mmol) (Oakwood Products, Inc., West Columbia, S.C.) and 4-fluorobenzenesulfonyl chloride (Aldrich, St. Louis, Mo.) (1.73 g, 8.9 mmol) in pyridine (20 mL) was heated in a microwave tube at 100° C. for 15 minutes. The mixture was concentrated in vacuo and the residue was washed with EtOAc containing small amount of MeOH to give the desired product as a white solid (2.0 g).
Reaction SMILES: C([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:14][CH:13]=3)=O)(C)C.C(N(CC)CC)C.Cl[Si](C)(C)C>C1(C)C=CC=CC=1>[CH2:23]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][C:7]([CH:5]=[O:4])=[C:19]([CH2:20][O:21][CH3:22])[C:18]2=1)[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(CCc4ccccc4)cc3c12
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COCc1c(C=O)ncc2[nH]c3ccc(CCc4ccccc4)cc3c12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
1.2 g of 6-phenethyl-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester is mixed in 25 ml of dry toluene with 2.5 ml of triethylamine and 0.78 ml of chlorotrimethylsilane and heated for 1 hour to 50° C. solution temperature. After concentration by evaporation to about half it is cooled to -78° C. and 5 ml of a 1.2 molar diisobutylaluminium hydride solution is instilled. It is stirred for 30 minutes at -78° C., mixed with 1.2 ml of ethanol and allowed to come to room temperature. 10.2 ml of 0.5-N NaOH and 10.2 ml of ethanol are added to the batch and stirred for 2.5 hours at room temperature. The batch is added to 35 ml of glacial acetic acid and extracted three times from ethyl acetate. The organic phase is washed in succession with dilute ammonia and saturated common salt solution, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride:ethanol=1:1 and 720 mg of 6-phenethyl-4-methoxymethyl-β-carboline-3-carbaldehyde is obtained, that in 8 ml of dimethylformamide is mixed in succession with 322 mg of hydroxylaminehydrochloride, 1.6 ml of ethanol, 322 mg of powdered potassium hydroxide and refluxed for 3 hours. Suctioning off yields 740 mg of 6-phenylethyl-4-methoxymethyl-β-carboline-3-carbaldehyde aldoxime of a melting point of 197°-198° C. This oxime is dissolved in 26 ml of dimethylformamide and mixed with a solution of 381 mg of N-bromosuccinimide in 3.4 ml of dimethylformamide and stirred for 15 minutes at room temperature. 1.38 ml of triethylamine and 0.26 ml of methylpropargly ether is added to the batch and stirred for 7 hours at room temperature. After concentration by evaporation it is spread in ethyl acetate/water and the organic phase is dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with toluene:ethanol=9:1. After combining and concentrating by evaporation the corresponding fractions and recrystallization 251 mg (30% of theory) of 6-phenethyl-4-methoxymethyl-3-(5-methoxymethyl-isoxazol-3-yl)-β-carboline, of a melting point of 133°-135° C. (ethyl acetate) is obtained.