Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:14](OCC)=O)[N:8]2[CH2:11][C:12]#[N:13])=[CH:4][C:3]=1[CH3:19].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Na].[K].C(OCC)(=O)C>CCOCC>[Cl:1][C:2]1[C:3]([CH3:19])=[CH:4][C:5]2[CH:6]=[C:7]3[CH2:14][NH:13][CH2:12][CH2:11][N:8]3[C:9]=2[CH:10]=1
Reactant: CCOC(=O)c1cc2cc(C)c(Cl)cc2n1CC#N
Agent: [Al+3]
Agent: [H-]
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1cc2cc3n(c2cc1Cl)CCNC3
Temperature: 25 °C
Reaction time: 70 h
Yield: 19 %

Procedure:
Ethyl 6chloro-1-(cyanomethyl)-5-methylindole-2-carboxylate (1.75 g, 6.3 mmol) was added portionwise over 2 min to a stirred solution of lithium aluminium hydride (0.61 g, 16 mmol) in ether (50 mL) at room temperature under Ar. The reaction was then heated to reflux and stirred for 70 h. The mixture was cooled to room temperature, a further portion of lithium aluminium hydride (0.61 g) was added and the reaction was heated to reflux and stirred for 18 h. The mixture was allowed to cool and then poured into aqueous potassium sodium tare solution (200 mL) and ethyl acetate (150 mL). The mixture was filtered through celite and the aqueous and organic layers were separated. The aqueous was extracted with ethyl acetate (2×100 mL) and the combined organic extracts were washed with brine (1×100 mL) dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave a crude oil. The oil was purified by flash column chromatography [SiO2; ethyl acetate-methanol, (100:0)→(9:1)] to give the product as a yellow solid (027 g, 19%). IR νmax (Nujol)/cm−1 3351, 3190, 2922, 2731, 1734, 1647, 1615, 1562, 1543, 1457, 1416, 1378, 1350, 1316, 1304, 1261, 1246, 1223, 1182, 1157, 1134, 1116, 1028, 983, 972, 962, 902, 883, 835, 800, 782, 732, 700, 666, 632, 617, 558, 510 and 496; NMR δH (400 MHz; CDCl3) 7.35 (1H, s), 725 (1H, s), 6.06 (1H, m), 4.16 (2H, s), 3.91 (2H, t, J 5.5 Hz), 3.31 (2H, t, J 5.5 Hz), 2.42 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:24]O>>[CH3:24][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CO
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCCCNC(=O)OCc1ccccc1
Yield: 58 %

Procedure:
To a solution of 6-benzyloxycarbonylamino-hexanoic acid (10 g, 38 mmol) in methanol (200 mL) at room temperature was added thionyl chloride (11 g, 95 mmol). The reaction mixture was then refluxed for 16 h. The solvent was concentrated in vacuo, the residue was dissolved in ethyl acetate (200 mL) and washed with brine (3×150 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was- purified by flash column chromatography (silica, 14% ethyl acetate in hexane) to afford the titled compound (6.2 g, 58%), a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[C:8]1([CH2:14][CH2:15][C:16](Cl)=[N:17][OH:18])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[N+](C)([O-])=O>[NH2:7][C:4]1[N:5]([C:16](=[N:17][OH:18])[CH2:15][CH2:14][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:6]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: ON=C(Cl)CCc1ccccc1
Solvent: C[N+](=O)[O-]
Product: Cc1cc(N)n(C(CCc2ccccc2)=NO)n1
Yield: 57.9 %

Procedure:
Analogous to example 1, synthesis step 1, using 5.65 g (0.058 mol) of 3(5)-amino-5(3)-methyl-pyrazole and 10.6 g (0.058 mol) of 3-phenyl-propanehydroximoyl chloride. The oil obtained as raw product is dissolved in nitromethane in the cold and made to crystallise by scratching the side of the container. 8.2 g (57%) of 5-amino-3-methyl-1-(3-phenyl-propanehydroximoyl)-pyrazole with a m. pt. of 138°-140° C. are obtained.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.COC1C=C(NC=C(C(OCC)=O)C(OCC)=O)C=CC=1.COC1C=C2C(C=C(C(OCC)=O)C=N2)=CC=1.C(Cl)(=O)C([Cl:85])=O.S(Cl)(Cl)=O.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl.C(Cl)Cl.CN(C=O)C>[Cl:85][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1O
Agent: CCOC(=O)C(=CNc1cccc(OC)c1)C(=O)OCC
Agent: CCOC(=O)c1cnc2cc(OC)ccc2c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2cc(OC)ccc2c1Cl
Reaction time: 2.5 h

Procedure:
According to Scheme A, ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (VIII) is obtained in four steps from commercially available synthetically accessible m-anisidine (II). m-Anisidine is combined with diethyl ethoxymethylenemalonate at temperatures ranging from 100° C. to about 125° C., preferably 125° C. for a period of 1 to 5 h, preferably about 3 h to provide diethyl 2-(((3-methoxyphenyl)amino)methylene)malonate. Ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (III) is obtained by heating Dowtherm™ at a temperature of 257° C. and diethyl 2-(((3-methoxyphenyl)amino)methylene)malonate for a period of 15 minutes to 2 h. Compound (IV) ethyl 7-methoxyquinoline-3-carboxylate is commercially available or synthetically accessible from ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (III) in two steps. Chlorination of compound (III) under conditions known to one skilled in the art, for example, but not limited to, oxalyl chloride, thionyl chloride, or phosphorus oxychloride, with or without a catalytic amount of DMF, in the presence or absence of a solvent such as DCM or CHCl3, at temperatures ranging from 50° C. to about 70° C., for a period ranging from 2 to 4 h, preferably 2.5 h, provides ethyl 4-chloro-7-methoxyquinoline-3-carboxylate. Subsequent reduction of ethyl 4-chloro-7-methoxyquinoline-3-carboxylate, employing Pd/C under hydrogenation conditions, in a solvent such as MeOH or EtOH, in the presence or absence of an acid such as acetic or formic acid, provides ethyl 7-methoxyquinoline-3-carboxylate (IV). Commercially available or synthetically accessible ethyl 7-methoxyquinoline-3-carboxylate (IV) is reacted under demethylation conditions, for example, HBr in H2O or HOAc, at temperatures ranging from 80° C. to about 110° C., preferably 105° C. for a period of 0.5 h to 24 h, preferably about 2 h, to provide 7-hydroxyquinoline-3-carboxylic acid. Ethyl 7-hydroxyquinoline-3-carboxylate (V), where R3 is H, is obtained by esterification of 7-hydroxyquinoline-3-carboxylic acid, employing methods known to one skilled in the art, for example, but not limited to, reaction of 7-hydroxyquinoline-3-carboxylic acid with an acid such as H2SO4, and the like, in a solvent such as EtOH, at temperatures ranging from 60° C. to about 80° C., preferably 75° C. for a period of about 12 to 24 h, preferably 20 h.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([C:14]1([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:17][CH2:16][CH2:15]1)[NH:7][CH2:6][CH2:5]2.[C:25]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:14]2([CH:8]3[C:9]4[C:4](=[CH:3][C:2]([N:35]5[CH2:34][CH2:33][N:32]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:37][CH2:36]5)=[C:11]([O:12][CH3:13])[CH:10]=4)[CH2:5][CH2:6][NH:7]3)[CH2:15][CH2:16][CH2:17]2)=[CH:23][CH:22]=1
Reactant: COc1cc2c(cc1Br)CCNC2C1(c2ccc(Cl)cc2)CCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCN(C(=O)OC(C)(C)C)CC1)CCNC2C1(c2ccc(Cl)cc2)CCC1

Procedure:
A solution of 6-bromo-1-[1-(4-chlorophenyl)cyclobutyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline (203 mg, 0.5 mmol), Boc-piperazine (93 mg, 0.5 mmol), tris(benzylideaceton)dipalladium (18 mg, 0.02 mmol), sodium-tert-butylate (48 mg, 0.5 mmol) and 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine 815.7 mg, 0.04 mmol) under nitrogen in toluene (5 ml) was heated in the microwave to 120° C. for 10 minutes. The solvent was removed, the residue dissolved in methylenehloride and extracted with water. The methylenehloride was evaporated and the remaining solid purified by chromatography. Yield: 56 mg (0.1 mmol, 20%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[C:9]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:8]=1>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[C:9]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:8]=1
Reactant: COC(=O)c1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1-c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C)c(Cc2ccc(C(=O)O)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.4 %

Procedure:
Methyl 4-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoate (70 mg, 0.1601 mmol) was dissolved in a mixed solution of a 1N aqueous solution of sodium hydroxide (5 ml) and 1,4-dioxane (5 ml) followed by stirring at room temperature for 16 hours. The reaction solution was diluted with water (20 ml), washed with ether, acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom to give the title compound (45 mg, 0.1063 mmol, 66%).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].C([Mg]Cl)(C)C.[CH2:20]([O:22][C:23]([C:25]1[C:29]([CH:30]=[O:31])=[C:28]([S:32][C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=2)[N:27]([CH:41]([CH3:43])[CH3:42])[N:26]=1)=[O:24])[CH3:21]>O1CCCC1.O>[CH2:20]([O:22][C:23]([C:25]1[C:29]([CH:30]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[OH:31])=[C:28]([S:32][C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=2)[N:27]([CH:41]([CH3:42])[CH3:43])[N:26]=1)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1C=O
Reactant: Brc1ccncc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1C(O)c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
582 mg of 4-Bromopyridine hydrochloride was treated with a 5% sodium carbonate solution then extracted three times with anhydrous diethyl ether. The combined extracts were then dried over anhydrous magnesium sulphate, filtered and evaporated to give a colourless oil. The colourless oil was dissolved in 3 ml of anhydrous terahydrofuran under nitrogen at room temperature and then treated with 1.5 ml of isopropylmagnesium chloride (2M solution in tetrahydrofuran). The mixture was stirred at room temperature for 1.5 h and then treated with a solution of 5-(3,5-dichlorophenylsulfanyl)-4-formyl-1-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester in 3 ml of anhydrous tetrahydrofuran. The mixture was then stirred for 1 h. The mixture was then treated with water and extracted with dichloromethane three times. The combined extracts were washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (1:1 to 2:1) for the elution to give 690 mg of 5-(3,5-dichlorophenylsulfanyl)-4-[(4-pyridyl)hydroxymethyl]-1-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester as a pale yellow oil. Mass spectrum (EST) m/z 466 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:13]2([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:13]2([C:19]([O:21][CH3:22])=[O:20])[CH2:14][CH2:15][N:16]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:17][CH2:18]2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1(N(Cc2ccccc2)S(=O)(=O)c2ccc(OC)cc2)CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(N(Cc2ccccc2)S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-[carbomethoxy]-piperidine (1.0 g, 2.39 mmol) in dimethylformamide (160 mL) is added sodium hydride (287.0 mg, 7.18 mmol, 60% in oil) at 0° C., followed by benzyl bromide (450.0 mg, 2.63 mmol). The reaction mixture is slowly warmed to room temperature and stirred overnight. The mixture is quenched with water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried (Na2SO4) and the solvent is evaporated to give 4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1- [benzyl]-4-[carbomethoxy]-piperidine.
Reaction SMILES: Cl[C:2]([F:8])([F:7])C(OC)=O.[O:9]=[CH:10][C:11]1[CH:19]=[CH:18][C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:7][CH:2]([F:8])[O:17][C:16]1[CH:18]=[CH:19][C:11]([CH:10]=[O:9])=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1cc(C=O)ccc1O
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OC(F)F
Temperature: 67.5 °C
Yield: 40.5 %

Procedure:
Methyl chlorodifluoroacetate (1.4 mL, 13 mmol) was added to a suspension of vanillin (1.0 g, 6.6 mmol) and potassium carbonate (2.0 g, 14 mol) in DMF (10 mL). The suspension was heated to 65-70° C. for 16 h and the suspension was diluted with water. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with saturated aqueous NaHCO3, water, brine, dried and concentrated. The residue was purified by column chromatography, eluting with 10% EtOAc/petrol to give 4-(difluoromethoxy)-3-methoxybenzaldehyde (0.54 g, 41%) as a colourless oil; δH (400 MHz, CDCl3) 3.95 (s, 3H, OCH3), 6.60 (t, J=74 Hz, 1H, OCHF2), 7.30 (d, J5,6=8.0 Hz, 1H, H5), 7.45 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 7.50 (d, J2,6=2.0 Hz, 1H, H2), 9.93 (s, 1H, CHO); δC (100 MHz, CDCl3) 56.2, 110.9, 115.5 (t, J=256 Hz), 121.5, 125.0, 134.5, 144.9, 151.5, 190.8.
Reaction SMILES: FC(F)(F)C1C=C(C2C(C(O)=O)=NC=C(C3C=CC=C(C(F)(F)F)C=3)C=2)C=CC=1.C[O:31][C:32]([C:34]1[C:39]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)=[CH:38][C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=2)=[CH:36][N:35]=1)=O.CC1C(C(O)=O)=NC=C(C2C=CC=C(C(F)(F)F)C=2)C=1.[N:80]1([CH:85]2[CH2:90][CH2:89][NH:88][CH2:87][CH2:86]2)[CH2:84][CH2:83][CH2:82][CH2:81]1>>[F:47][C:46]([F:49])([F:48])[C:42]1[CH:41]=[C:40]([C:39]2[C:34]([C:32]([N:88]3[CH2:89][CH2:90][CH:85]([N:80]4[CH2:84][CH2:83][CH2:82][CH2:81]4)[CH2:86][CH2:87]3)=[O:31])=[N:35][CH:36]=[C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:58])([F:59])[F:57])[CH:51]=3)[CH:38]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1-c1cccc(C(F)(F)F)c1
Agent: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)O
Agent: O=C(O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1-c1cccc(C(F)(F)F)c1
Product: O=C(c1ncc(-c2cccc(C(F)(F)F)c2)cc1-c1cccc(C(F)(F)F)c1)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 1, 3,5-bis-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid [prepared from 3,5-bis-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester (intermediate 8) by saponification in analogy to the procedure described for intermediate 1B] was reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as light yellow oil. MS: 548.3 (MH+).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:15]#[C:16]/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]([C:54]([O:56]C)=[O:55])[CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36](=[O:53])/[CH:37]=[CH:38]/[C:39]#[C:40][C:41]4[CH:46]=[C:45]([O:47][CH3:48])[C:44]([O:49][CH3:50])=[C:43]([O:51][CH3:52])[CH:42]=4)[CH2:32][CH2:31]3)[CH2:23][CH2:22]2)=[O:20])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12].Cl>CO>[CH3:52][O:51][C:43]1[CH:42]=[C:41]([C:40]#[C:39]/[CH:38]=[CH:37]/[C:36]([N:33]2[CH2:32][CH2:31][CH:30]([CH2:29][CH:28]([C:54]([OH:56])=[O:55])[CH2:27][CH:24]3[CH2:25][CH2:26][N:21]([C:19](=[O:20])/[CH:18]=[CH:17]/[C:16]#[C:15][C:7]4[CH:6]=[C:5]([O:4][CH3:3])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=4)[CH2:22][CH2:23]3)[CH2:35][CH2:34]2)=[O:53])[CH:46]=[C:45]([O:47][CH3:48])[C:44]=1[O:49][CH3:50]
Reactant: COC(=O)C(CC1CCN(C(=O)/C=C/C#Cc2cc(OC)c(OC)c(OC)c2)CC1)CC1CCN(C(=O)/C=C/C#Cc2cc(OC)c(OC)c(OC)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C#C/C=C/C(=O)N2CCC(CC(CC3CCN(C(=O)/C=C/C#Cc4cc(OC)c(OC)c(OC)c4)CC3)C(=O)O)CC2)cc(OC)c1OC
Reaction time: 1 h
Yield: 34.4 %

Procedure:
A 5N aqueous sodium hydroxide (2 ml; 10 mmol) was added to a solution in methanol (2 ml) of methyl 1,3-bis(1-[(E)-5-(3,4,5-trimethoxyphenyl)-2-penten-4-ynoyl]-4-piperidinyl]-2-propanecarboxylate (136 mg; 0.18 mmol) synthesized by the above process, and the mixture was stirred for 1 hour in a bath controlled at 65° C. The reaction mixture was made acidic by addition of 1N hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 46 mg (yield: 35%) of the title compound as a pale yellow amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][N:10]3[C:11]=2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=13.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][N:10]3[C:11]=2[C:3]=1[CH:4]1[CH:9]3[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CN1CCc2ccc(Cl)c3c4c(n(c23)CC1)CCCC4
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCc2ccc(Cl)c3c2N(CC1)C1CCCCC31
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of 8-chloro-3-methyl-2,3,4,5,9,10,11,12-octahydro-1H-[1,4]diazocino[7,8,1-jk]carbazole (0.25 g, 0.86 mmole) in acetic acid (50 mL) was added sodium cyanoborohydride (0.22 g, 3.32 mmole) and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was diluted with methylene chloride (200 mL) and washed with aqueous sodium hydroxide (1N, 150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, 1.5% methanol in methylene chloride) provided 80 mg of the title compound as a colorless oil. The oil was further treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 178-180° C. MS (ESI) m/z 291 ([M+H]+).
Reaction SMILES: CCCC[Sn]([O:14][Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])(CCCC)CCCC.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32]O.O>C1C=CC=CC=1>[CH2:24]([Sn:15]([O:14][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: CN(C)CCCO
Reactant: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Solvent: O
Solvent: c1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)OCCCN(C)C

Procedure:
3-Dimethylamino-1-Propyl Tributylstannyl Ether is prepared from 59.6 gm (0.1 mole) bis(tributyltin) oxide and 20.6 gm (0.2 mole) 3-dimethylamino-1-propanol in 200 ml benzene. This is stirred and heated to reflux in a system that contains a Dean-Starke tube. After 30 minutes refluxing water began to collect in the Dean-Starke tube and after refluxing for 22 hours a total of 1.9 ml of water (theory 1.8 ml) had collected. The benzene is stripped off on a rotating evaporator to provide 77.1 gm of straw colored liquid. This is fractionated at reduced pressure, with 53.0 gm water-white liquid (Percent yield - 67.6) being collected at 135°-139° C. at 0.7 mm. Infrared spectral analysis shows this to be the desired ether.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH2:27][OH:28])[C:12]([NH:14][CH2:15][CH:16]([OH:26])[CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:13])C1C=CC=CC=1>C(O)C.[Pd]>[C:22]([O:21][C:19]([NH:18][CH2:17][CH:16]([OH:26])[CH2:15][NH:14][C:12](=[O:13])[C@H:11]([CH2:27][OH:28])[NH2:10])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCC(O)CNC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(O)CNC(=O)[C@@H](N)CO
Reaction time: 15 h

Procedure:
131 mg (0.318 mmol) of benzyl[(1S)-2-({3-[(tert-butoxycarbonyl)amino]-2-hydroxypropyl}amino)-1-(hydroxymethyl)-2-oxoethyl]carbamate (Example 100A) are dissolved in 20 ml of ethanol. 20 mg of palladium on activated carbon (10%) are added thereto, and the mixture is hydrogenated under atmospheric pressure for 15 h. The reaction mixture is filtered through prewashed kieselguhr, and the filtrate is concentrated in vacuo on a rotary evaporator. The crude product is reacted without further purification.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([N:18]1[CH:22]=CC=N1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[N:30]1([C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])[CH2:35]CN[CH2:32][CH2:31]1>CO>[CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:32][CH2:31][N:30]([C:36]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[CH2:35][CH2:22]1)=[N:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[O:7])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCN(C(=O)OCc2ccccc2)CC1
Yield: 50.3 %

Procedure:
Following the procedure described in Example 7, the reaction of N,N′-bis{[(2-methyl-2-propanyl)oxy]carbonyl}-1H-pyrazole-1-carboximidamide (0.25 g, 1.1 mmol), triethylamine (0.5 mL, 3.4 mmol) and benzyl piperazine-1-carboxylate (0.422 g, 1.36 mmol) in methanol (10 mL) gave the title compound (0.256 g, 50%) as a colorless liquid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][Si:9]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].C(N)CN>>[CH2:14]([O:13][Si:9]([CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)([O:16][CH2:17][CH3:18])[O:10][CH2:11][CH3:12])[CH3:15]
Reactant: CCO[Si](CCl)(OCC)OCC
Reactant: C1COCCN1
Solvent: NCCN
Product: CCO[Si](CN1CCOCC1)(OCC)OCC
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
82 g of dry morpholine (pKb 5.67) were heated to 120° C. in a 500 ml four-necked flask having a reflux condenser, KPG stirrer and thermometer and 80 g of chloromethyltriethoxysilane were added in the course of 180 min with stirring. After the end of the addition, the temperature was reduced to 105° C. and 56.6 g of ethylenediamine (pKb 4.07) were added to the mixture in the course of 10 min with stirring, phase separation occurring. At constant temperature, stirring was effected for a further 30 min and the heavier ethylenediamine hydrochloride phase was then separated off. The upper phase was subjected to fractional distillation. 68 g (yield 68%) of 4-(triethoxysilylmethyl)tetrahydro-1,4-oxazine were obtained, the purity of which was determined as 98.4% by gas chromatography.