Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([O:16]CC)=O)[NH:2]1.O.[NH2:20][NH2:21]>CN(C)C=O>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([NH:20][NH2:21])=[O:16])[NH:2]1
Reactant: CCOC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: NNC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of ethyl (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (4.9 g), hydrazine hydrate (10 ml) and dimethylformamide (50 ml) is allowed to stand at room temperature overnight. The reaction mixture is is distilled under reduced pressure to remove the solvent. The residue is treated with ethyl acetate to give the title compound (3.40 g, 74%) as powder.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][C:7]([C:9]1[C:14]([NH2:15])=[N:13][C:12]([NH:16][CH:17]2[CH2:22][CH2:21][N:20](CC3C=CC=CC=3)[CH2:19][CH2:18]2)=[C:11](Cl)[N:10]=1)=[O:8]>C(O)C>[CH3:5][O:6][C:7]([C:9]1[C:14]([NH2:15])=[N:13][C:12]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:11][N:10]=1)=[O:8]
Reactant: COC(=O)c1nc(Cl)c(NC2CCN(Cc3ccccc3)CC2)nc1N
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1ncc(NC2CCNCC2)nc1N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 107.8 %

Procedure:
Ammonium formate (3.5 g, 48 mmol) was added to a solution of (37) (1.8 g, 4.8 mmol) in 60 mL of absolute ethanol. The mixture was purged with argon then palladium (0.5 g, 5% on activated carbon) was added. The resulting mixture was heated at 80° C. for with argon then palladium (0.5 g, 5% on activated carbon) was added. The resulting mixture was heated at 80° C. for 12 h then was cooled to 25° C. and filtered through celite. The filtrate was concentrated in vacuo and the residue was cooled to 0° C. Saturated Na2CO3 (100 mL) was added, and the resulting mixture was stirred for 30 min. The aqueous layer was extracted with EtOAc (3×50 mL) and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to give 1.3 g (quantitative yield) of the title compound: TLC (Rf =0.24; 10% MeOH/CH2Cl2); 1H NMR (DMSO) δ 7.86 (d, 1H, J=6.9), 7.28 (s, 1H), 7.10 (br s, 2H), 3.95 (m, 1H), 3.69 (s, 3H), 3.26 (d, 2H, J=12.8), 2.92 (t, 2H, J=9.8), 2.00 (d, 2H, J=12.0), 1.70 (m, 2H); 13C NMR (DMSO) δ 167.0, 156.4, 154.6, 122.8, 109.8, 50.9, 44.4, 41.8, 27.9; HRMS (FAB) m/z 252.1466 (M+H)+ (C11H17N5O2 requires 252.1461).
Reaction SMILES: [N+](C1C=CC(N)=C(N)C=1)([O-])=O.[CH:12]([C:15]1[NH:16][C:17]2[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:18]=2[N:19]=1)([CH3:14])[CH3:13].[N+](C1NC2C=CC=CC=2N=1)([O-])=O>C(O)(=O)C(C)C.CCOC(C)=O.[Pd]>[CH:12]([C:15]1[NH:16][C:17]2[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:18]=2[N:19]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1nc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Pd]
Agent: Nc1ccc([N+](=O)[O-])cc1N
Agent: O=[N+]([O-])c1nc2ccccc2[nH]1
Solvent: CCOC(C)=O
Solvent: CC(C)C(=O)O
Product: CC(C)c1nc2ccc(N)cc2[nH]1
Reaction time: 12 h
Yield: 92 %

Procedure:
A solution of 4-nitro-1,2-phenylenediamine (0.9 g, 5.9 mmol) in 5 ml of isobutyric acid was stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo to yield a dark brown residue, which was dissolved in 100 ml of EtOAc and washed with aqueous NaHCO3. Organic layer was dried over MgSO4 and concentrated in vacuo, yielding an oil which was characterized as 2-isopropyl-5-nitrobenzimidazole and subjected to a following reaction without further purification. The nitrobenzimidazole and 50 mg of 10% Pd—C were dissolved in 100 ml of MeOR and stirred for 12 h under H2. The reaction mixture was filtered and concentrated in vacuo, yielding 0.95 g (5.4 mmol, 92%) of the desired product.
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH2:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[CH:9]1[CH:8]=[CH:7][CH:6]=[C:3]2[C:2]=1[CH2:10][C@H:11]1[C@@H:4]2[O:5][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12]1
Reactant: C1=Cc2ccccc2C1
Reactant: OCc1ccccc1O
Product: c1ccc2c(c1)C[C@H]1Cc3ccccc3[C@H]1O2

Procedure:
2-Hydroxybenzyl alcohol (15.0 g) and indene (75 g.) were heated at 210° for 1.5 hr. The unchanged indene was distilled off under reduced pressure and the residue chromatographed on silica gel, eluting with toluene. The product thus obtained, was recrystallised from cyclohexane to yield cis-4b,10,10a,11-tetrahydrobenz(b)indeno(2,1-e)pyran, 2.54 g., m.pt. 59°-60°. The product was characterised by its 1H-n.m.r spectrum. Isomeric purity was established by 13C-n.m.r spectroscopy
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12]4[C:13](=[CH:18][CH:19]=[CH:20][C:11]=4[C:10]2=S)[CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=1.[N:22]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][N:24]=[CH:23]1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12]4[C:13](=[CH:18][CH:19]=[CH:20][C:11]=4[C:10]2=[N:30][CH2:29][CH2:28][CH2:27][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=1
Reactant: NCCCn1ccnc1
Reactant: Cc1ccc(CN2C(=S)c3cccc4cccc2c34)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(CN2C(=NCCCn3ccnc3)c3cccc4cccc2c34)cc1
Temperature: 25 °C

Procedure:
A mixture of 2.5 g of 1-[(4-methylphenyl)methyl]benz[cd]indole-2(1H)-thione (Ca) and 1.2 g of 1H-imidazole-1-propanamine in 200 ml of ethyl alcohol is stirred and heated. A 2.7 g portion of mercuric acetate is added, the mixture is stirred at reflux for 6 hours, cooled to room temperature and treated with 2N sodium hydroxide (pH 9). After filtering the solution through diatomaceous earth, the reaction is concentrated in vacuo. The resulting oil is dissolved in dichloromethane, washed neutral with water, dried over sodium sulfate and concentrated in vacuo. The crystalline residue is recrystallized from dichloromethane/hexane giving 2.2 g of the desired product, mp. 94°-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:21]([N:23]([CH2:34][CH3:35])[S:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Cl)(=[O:26])=[O:25])[CH3:22]>C(N(C(C)C)C(C)C)C>[CH2:34]([N:23]([CH2:21][CH3:22])[S:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:25])=[O:26])[CH3:35]
Reactant: CCN(CC)S(=O)(=O)CCCCCCCl
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)S(=O)(=O)CCCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 93.9 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and N,N-diethyl-6-chlorohexanesulfonamide (511.6 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (50:1), to give N,N-diethyl-6-[4-[(4-chlorophenyl)phenylmethyl]1-piperazinyl]hexanesulfonamide (951.0 mg) as a pale brown oil (yield: 94.0%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:25])[C:20](OCC)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12.[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH2:34])[CH2:28][CH2:27]1>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:25])[C:20]([NH:34][CH2:33][CH2:32][N:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12
Reactant: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reactant: NCCN1CCOCC1
Solvent: CCOCC
Product: O=C(NCCN1CCOCC1)C(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Yield: 38.2 %

Procedure:
Ethyl 2-(3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylamino)-2-oxoacetate (prepared in Example 2; 36 mg, 0.10 mmol) and 2-morpholinoethanamine (65 mg, 0.50 mmol) were heated to 60° C. for 18 hours. The mixture was diluted with diethyl ether (1 mL) and filtered. The white solid was washed with diethyl ether (3×2 mL). The solid was dried under high vacuum. The product was obtained as a white powder (17 mg, 38%). 1H NMR (400 MHz, CDCl3) δ 9.50 (s, 1H), 8.52 (d, J=6 Hz, 1H), 7.99 (m, 1H), 7.87 (m, 1H), 7.76 (d, J=6 Hz, 1H), 7.58 (d, J=6 Hz, 1H), 7.41 (m, 1H), 7.29 (m, 1H), 6.52 (d, J=6 Hz, 1H), 3.74 (m, 4H), 3.49 (m, 2H), 2.59 (m, 2H), 2.50 (m, 4H). LRMS (ESI pos) m/e 445 (M+1). HPLC: 100% purity (220 nm).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:39])[C@H:10]([CH:36]([CH3:38])[CH3:37])[NH:11][C:12](=[O:35])[C@@H:13]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH:14][C:15](=[O:30])[CH:16]([OH:29])[CH:17]1[CH2:21][CH2:20][CH2:19][N:18]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:40].O1CCOCC1>ClCCl>[ClH:40].[CH2:1]([O:8][C:9](=[O:39])[C@H:10]([CH:36]([CH3:38])[CH3:37])[NH:11][C:12](=[O:35])[C@@H:13]([CH2:31][CH:32]([CH3:33])[CH3:34])[NH:14][C:15](=[O:30])[CH:16]([OH:29])[CH:17]1[CH2:21][CH2:20][CH2:19][NH:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](NC(=O)C(O)C1CCCN1C(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)C[C@@H](NC(=O)C(O)C1CCCN1)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
[2-Hydroxy-2-(N-t-butyloxycarbonylpyrrolidin-2-yl)acetyl]-D-leucylvaline benzyl ester (100 mg) was dissolved in dichloromethane (1 ml) and 1 ml of a 4N hydrochloric acid/dioxane solution was added to the solution under cooling with ice to conduct a reaction at room temperature for 2 h. The reaction liquid was concentrated under reduced pressure and the residue was washed with n-hexane several times and concentrated to give [2-hydroxy-2-(pyrrolidin-2-yl)acetyl]-D-leucylvaline benzyl ester hydrochloride.
Reaction SMILES: [C:1]1([CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13](=O)[C:12]3=[CH:22][S:23][CH:24]=[C:11]23)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B#B.[ClH:27]>O1CCCC1>[ClH:27].[CH2:8]([N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][CH2:13][C:12]2=[CH:22][S:23][CH:24]=[C:11]12)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1Nc2ccccc2N(C(=O)Cc2ccccc2)c2cscc21
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Product: c1ccc(CCN2c3cscc3CNc3ccccc32)cc1
Temperature: 25 °C

Procedure:
A 6.12 g. portion of 4,9-dihydro-4-phenylacetyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one is suspended in 100 ml. of tetrahydrofuran under argon and stirred with cooling in an ice bath. To this is added 90 ml. of 1 M diborane in tetrahydrofuran over a period of 10 minutes. The mixture is then stirred at room temperature until solution is complete, refluxed for 18 hours, cooled and 45 ml. of 6 N hydrochloric acid is added. The tetrahydrofuran is removed in vacuo and 75 ml. of 5 N sodium hydroxide is added giving the desired final product, mp. 195°-197° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][NH:3]1.Cl.[CH3:15]O>>[OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:15])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc2c(=O)[nH][nH]c2c1
Agent: Cl
Product: COC(=O)c1ccc2c(O)n[nH]c2c1
Yield: 100 %

Procedure:
3-Oxo-2,3-dihydro-1H-indazole-6-carboxylic acid (1.5 g, 8.4 mmol) was suspended in methanol (17 mL). Concentrated hydrochloric acid (3.1 mL, 101 mmol) was added and the reaction was heated to reflux for 24 hours. The reaction was concentrated to give the title compound (1.6 g, 100%). +ESI (M+H) 193.1; 1H NMR (400 MHz, DMSO-d6, δ): 11.98 (br. s., 1H), 7.89 (s, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.50 (dd, J=8.5, 1.3 Hz, 1H), 3.85 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:15]=[CH:14][C:13]=2[NH:22][CH2:23][C:24]2[C:25]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[N:26][CH:27]=[CH:28][CH:29]=2)=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[O-:35][C:36]#[N:37].[Na+]>C(O)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:12]3[C:13](=[CH:14][CH:15]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:17]=3)[N:22]([CH2:23][C:24]3[C:25]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[N:26][CH:27]=[CH:28][CH:29]=3)[C:36](=[O:35])[N:37]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: N#C[O-]
Reactant: C#CCOc1ccc(NCc2cccnc2OCCOC)c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: [Na+]
Solvent: CC(=O)O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccnc1OCCOC
Reaction time: 2 h

Procedure:
To a solution of 200 mg (0.436 mmol) (4-Isopropyl-phenyl)-(2-{[2-(2-methoxy-ethoxy)-pyridin-3-ylmethyl]-amino}-5-prop-2-ynyloxy-phenyl)-methanone in 1.5 ml acetic acid is added 28 mg (0.436 mmol) sodium cyanate. After stirring for 2 h the solvent is removed in vacuo and the residue is partitioned between CH2Cl2 and water. The organic layer is dried and evaporated. Purification of the crude product by flash-chromatography (CH2Cl2/ether 3:7) affords a yellow oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.O.[CH2:22](O)[CH3:23]>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:22][CH3:23])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CCO
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)CCc1cccc(C(F)(F)F)c1

Procedure:
A solution of 3-(3-trifluoromethylphenyl)propionic acid (13.6 g) in anhydrous ethanol (25 ml) containing concentrated sulphuric acid (1.5 ml) was heated at reflux for 24 hours and was then poured into water (100 ml). The mixture was extracted with diethyl ether and the ethereal extract was washed with water, with aqueous sodium carbonate solution (2 N), and with water, then dried over magnesium sulphate and evaporated. The resulting residue was distilled, to give ethyl 3-(3-trifluoromethylphenyl)propionate (11.5 g) in the form of a colourless oil, b.p. 133°-135° C./17 mm Hg. [elemental analysis: C, 58.6; H, 5.2%. C12H13F3O2 requires C, 58.5; H, 5.3%. νmax 1125, 1170, 1330 and 1740 cm-1 ].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.NC1C=NC=CN=1.[CH3:16][S-:17].[Na+]>>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([S:17][CH3:16])=[CH:4][N:3]=1
Reactant: Nc1cnc(Br)cn1
Reactant: C[S-]
Agent: Nc1cnccn1
Agent: [Na+]
Product: CSc1cnc(N)cn1

Procedure:
2-Amino-5-bromopyrazine can be prepared from aminopyrazine as described (Tetrahedron, Vol. 44, pp. 2977-2984 (1988)). Reaction of 2-amino-5-bromopyrazine with sodium methanethiolate proceeds to form 2-amino-5-methylthiopyrazine (J. Het. Chem., Vol. 28, pp. 1131-1137 (1991)). Oxidation of 2-amino-5-methylthiopyrazine with m-chloroperbenzoic acid produces 2-amino-5-methanesulfonylpyrazine. 2-Hydrazino-5-methanesulfonylpyrazine can be prepared by known procedures (J. Het. Chem., Vol. 27, pp. 2151-2163 (1990)). Subsequent reaction of 2-Hydrazino-5-methanesulfonylpyrazine with 4,4,4-trifluoro-1-(4-methoxyphenyl)-1,3-butanedione (made from 4-methoxyacetophenone and ethyl trifluoroacetate via Scheme 1) can then produce the title compound.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:1]([N:14]1[CH2:13][CH:12]=[C:11]([CH2:10][OH:9])[CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccncc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: OCC1=CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
10.7 ml (0.0901 mol) of benzyl bromide were added to a solution of 8.9 g (0.0815 mol) of 4-hydroxymethylpyridine in 30 ml of dimethylformamide and the mixture was stirred at 100° for 2 hours. Subsequently, the reaction mixture was cooled to room temperature, diluted with 111 ml of ethanol and treated portion-wise with 3.9 g (0.103 mol) of NaBH4. The mixture was boiled under reflux for 3 hours and stirred at room temperature for a further 18 hours. Then, the solvent was distilled off, the residue was partitioned between dichloromethane/water, extracted and dried. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:1 as the eluent. 9.26 g (56%) of (1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-methanol were obtained as yellow crystals; m.p. 57°-60°.
Reaction SMILES: [CH2:1]1[O:21][C:4]([CH3:20])([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([O:12]CC3C=CC=CC=3)=[CH:8][CH:7]=2)[O:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[CH2:2]1[O:3][C:4]([CH3:20])([CH2:5][C:6]2[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=2)[O:21][CH2:1]1
Reactant: [H][H]
Reactant: CC1(Cc2ccc(OCc3ccccc3)cc2)OCCO1
Agent: [Pd]
Solvent: CCO
Product: CC1(Cc2ccc(O)cc2)OCCO1

Procedure:
A solution of 1-(4-benzyloxyphenyl) propan-2-one ethylene ketal (6 g) in ethanol (100 ml) was hydrogenated at 45 psi and ambient temperature in the presence of 10% Pd/C until hydrogen uptake had ceased. The solution was filtered and evaporated to give a light coloured oil which crystallised on standing m.p. 61°-64°.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:47]=[CH:48][C:49]([N:51]3[CH2:56][CH2:55][CH2:54][N:53]([CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:52]3=[O:64])=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].CO>Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:24][N:25]=[N:26][N:27]=3)=[CH:15][CH:16]=2)[C:8]2[CH:47]=[CH:48][C:49]([N:51]3[CH2:56][CH2:55][CH2:54][N:53]([CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:52]3=[O:64])=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(N3CCCN(Cc4ccccc4)C3=O)ccc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: CCCCc1nc2cc(N3CCCN(Cc4ccccc4)C3=O)ccc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 55 from 4'-[[2-n-butyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanol in methanolic hydrochloric acid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](O)=[O:5]>C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[CH2:4][OH:5]
Reactant: Cc1cccc(C)c1C(=O)O
Solvent: C1CCOC1
Product: Cc1cccc(C)c1CO
Yield: 55.2 %

Procedure:
2,6-Dimethylbenzyl alcohol was prepared according to Beaulieu et al. (2000, which is incorporated herein by reference), but was unsuccessful, so a different reducing agent was used. To a suspension of 2,6-dimethylbenzoic acid (1.00 g, 6.65 mmol) in anhydrous THF (10 mL) a solution of BH3(SMe2) in THF was cautiously added under nitrogen atmosphere. The mixture was heated at reflux for 16 hours, then quenched with saturated ammonium chloride (5 mL) and 2 M HCl (10 mL). (CAUTION: vigorous gas evolution!). Organic layer was separated; aqueous layer was extracted three times with ethyl acetate (45 mL each); combined extracts were washed twice with saturated sodium bicarbonate (20 mL each), dried over anhydrous Na2SO4, evaporated, and purified by silica gel chromatography to yield 2,6-dimethylbenzyl alcohol (0.50 g, 51%) as an white solid. 1H NMR (400 MHz, CDCl3): δ 7.08 (m, 3H, Ph-H), 4.70 (s, 2H, Ph-CH2), 4.05 (br s, 1H, OH), 2.40 (s, 6H, CH3).
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH:3]=[CH2:4].[OH-].[K+].Cl[CH2:15][C:16]([C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21]([OH:27])=[C:20]([CH:28]([CH3:30])[CH3:29])[CH:19]=1)=[O:17].Cl>CN1CCCC1=O>[CH3:1][C:2]([CH:3]=[CH2:4])([O:11][CH2:15][C:16]([C:18]1[CH:19]=[C:20]([CH:28]([CH3:30])[CH3:29])[C:21]([OH:27])=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:23]=1)=[O:17])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9]
Reactant: CC(C)c1cc(C(=O)CCl)cc(C(C)C)c1O
Reactant: C=CC(C)(O)CCC=C(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: C=CC(C)(CCC=C(C)C)OCC(=O)c1cc(C(C)C)c(O)c(C(C)C)c1
Reaction time: 16 h
Yield: 2.2 %

Procedure:
To a solution of 12.7 g (79 mmol) of 3,7-dimethyl-octa-1,6-dien-3-ol and 10.9 g (195 mmol) of potassium hydroxide in 80 ml of N-methylpyrrolidone a solution of 10.0 g (39 mmol) of 2-chloro-1-(4-hydroxy-3,5-di-isopropylphenyl)-ethanone in 120 ml of N-methylpyrrolidone is added dropwise at room temperature and under inert atmosphere. After the addition is completed stirring is continued for additional 16 hours. Then the reaction mixture is acidified with 1N HCl and extracted with ethyl acetate. The collected organic phases are washed with water and brine, dried and evaporated. Crystallization of the crude product from hexane gives 0.32 g of compound III, m.p. 71-72° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[N:14]=[CH:13][CH:12]=[C:11]([I:15])[C:7]=1[C:8](O)=[O:9].CO>ClCCl>[OH:5][C:6]1[N:14]=[CH:13][CH:12]=[C:11]([I:15])[C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(I)ccnc1O
Solvent: CO
Solvent: ClCCl
Product: O=C(Cl)c1c(I)ccnc1O
Temperature: 75 °C

Procedure:
Thionyl chloride (3.81 ml, 52.2 mmol) was added to a suspension of 2-hydroxy-4-iodonicotinic acid (3.46 g, 13.1 mmol) in dichloromethane (12 mL) in a pressure vessel at room temperature. The reaction mixture was then heated at 75° C. for 3 h. An aliquot was taken and hydrolyzed with methanol. LCMS analysis showed the derived methyl ester seen as major compound. The reaction mixture was cooled to room temperature and was concentrated in vacuo to give 2-hydroxy-4-iodonicotinoyl chloride. 2-hydroxy-4-iodonicotinoyl chloride in MeOH (100 mL) was stirred at room temperature for 2 h. Concentration in vacuo of the reaction mixture afforded methyl 2-hydroxy-4-iodonicotinate (3.64 g, 13.1 mmol, quantitative yield). MS (ESI pos. ion) m/z: 280 (MH+). Calc'd exact mass for C7H61NO3: 279.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[CH:20]=[C:21]([F:22])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:22][C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=2[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4cccc(F)c4)cc(F)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(-c3cccc(F)c3)cc(F)c2O1

Procedure:
The title compound was prepared (0.12 g, 88%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-fluoro-5-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.19 g, 0.45 mmol) and methylamine (0.28 g, 9.1 mmol). mp >250° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:26]1([CH2:32][C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:33](=[O:34])[CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)Cc2ccccc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.43 mmol) and triethylamine (88 μL, 0.64 mmol) in methylene chloride (20 mL) was added dropwise phenylacetyl chloride (70 mg, 0.45 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 10 min and then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 95 mg (61%) of the title compound as white crystals: mp 151-152° C.; [α]21D -4.3° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 363 (21, M+).