Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[S:13][CH:12]=[CH:11][C:7]=3[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=[N:2]1.C(N(CC)CC)C.[F:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:40])=[C:26]([CH:39]=1)[C:27]([NH:29][C:30]1[N:35]=[CH:34][C:33]([C:36](Cl)=[O:37])=[CH:32][CH:31]=1)=[O:28].[OH-].[Na+]>ClCCl>[NH:1]1[C:5]2[C:6]3[S:13][CH:12]=[CH:11][C:7]=3[N:8]([C:36]([C:33]3[CH:32]=[CH:31][C:30]([NH:29][C:27](=[O:28])[C:26]4[CH:39]=[C:22]([F:21])[CH:23]=[CH:24][C:25]=4[CH3:40])=[N:35][CH:34]=3)=[O:37])[CH2:9][CH2:10][C:4]=2[CH:3]=[N:2]1
Reactant: c1cc2c(s1)-c1[nH]ncc1CCN2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3sccc32)cn1
Reaction time: 8 h

Procedure:
To a solution of 2 mmol of 1,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepine and 10 mmol of triethylamine in 25 ml of dichloromethane is added 4.2 mmol of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride. After stirring overnight, the mixture is worked-up as described for Example 1, and the initial solid treated with 1N NaOH as described for Example 1 to give the product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.CN1CCOCC1.C(OC(Cl)=O)C.[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][CH:29]=1)([O-:27])=[O:26].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[C:4]([C:5](=[O:7])[CH2:35][C:34]([C:31]2[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:33][CH:32]=2)=[O:36])=[CH:8][CH:9]=[CH:10][N:11]=1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ncccc1C(=O)O
Agent: CCOC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ncccc1C(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
To a stirred solution of 2-methoxynicotinic acid (2.3 g, 15 mmol) in 75 mL anhydrous THF was added N-methyl morpholine (1.52 g, 15 mmol). The reaction mixture was cooled to −10° C. Ethylchloroformate (1.63 g, 15 mmol) was added dropwise at −10° C. The reaction mixture was stirred at −10° C. for 15 min. and then at rt for 10 h. Water (50 mL) was added, and the solution was extracted with ethyl acetate. The organic layer was separated, dried (Na2SO4), and concentrated to give a colorless liquid in 97% yield (3.29 g). To a solution of this colorless liquid (3.28 g, 14.57 mmol) and 4′-nitroacetophenone (2.477 g, 15 mmol) in anhydrous THF (75 mL) was added lithium bis(trimethylsilyl)amide 1.0M solution in THF (18 mL) at −30° C. over a period of 45 min. Stirring continued at −30° C. for 30 min. The reaction mixture was allowed to warm to rt. The stirring was continued for another 15 h at rt, and the reaction mixture was then diluted with ethyl acetate (200 mL). Saturated NH4Cl solution (50 mL) was added. The organic layer was separated and dried over anhydrous Na2SO4. Removal of solvent gave the crude product which was triturated with ether to give 1-(2-methoxy pyridine-3-yl)-3-(4-nitrophenyl)propane-1,3-dione as yellow solid in 62% yield (2.79 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:24])[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1>O1CCOCC1.O>[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:24])[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:10]([CH3:12])[CH3:11])[CH2:5][CH2:6]2)=[CH:35][CH:34]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCCCOC(C(=O)NC1CCNCC1)(c1ccccc1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCCCOC(C(=O)NC1CCN(Cc2ccc(OC)cc2)CC1)(c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-(4-Piperidinyl)-2-butoxy-3-methyl-2-phenylbutanamide (invention compound, Compound No. 27) (4.5 g) was dissolved in dioxane (25 ml) and water (25 ml). To the resulting solution, potassium carbonate (0.7 g) and 4-methoxybenzyl chloride (0.8 g) were added, followed by stirring at room temperature for 2 days. To the reaction mixture, was added water (40 ml). The resulting mixture was extracted with an ethyl acetate. The extract was then dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by a silica gel column to obtain the invention compound (Compound No. 29, 0.60 g, 26.4%) as a colorless oil.
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]([C:25]2[N:35]=[CH:34][CH:33]=[CH:32][C:26]=2[C:27]([O:29]CC)=[O:28])[CH2:21][CH2:22][O:23][CH3:24])=[CH:15][CH:14]=1)([C:3]([O:5]C)=[O:4])=[O:2].[OH-].[Na+]>O1CCOCC1>[CH3:24][O:23][CH2:22][CH2:21][N:20]([C:25]1[N:35]=[CH:34][CH:33]=[CH:32][C:26]=1[C:27]([OH:29])=[O:28])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:1]([C:3]([OH:5])=[O:4])=[O:2])=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cccnc1N(CCOC)Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCN(Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1)c1ncccc1C(=O)O
Temperature: 50 °C
Reaction time: 19 h
Yield: 62.7 %

Procedure:
A solution of 535 mg of ethyl 2-{N-[(2'-methoxalylbiphenyl-4-yl)methyl]-N-(2-methoxyethyl)amino}nicotinate [prepared as described in step (a) above] dissolved in 4.5 ml of dioxane and a 1N aqueous solution of sodium hydroxide were mixed, and the resulting mixture was stirred at 50° C. for 19 hours. At the end of this time, the dioxane was removed by distillation under reduced pressure, and 4.5 ml of 1N aqueous hydrochloric acid was added to the residual aqueous solution. The crystals thus precipitated were collected by filtration, to give 306 mg of the title compound, melting at 173° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([CH3:11])[CH:3]=1.[O:12]=[S:13]1(=[O:30])[CH2:18][CH2:17][N:16]2[CH2:19][CH2:20][CH2:21][C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:15]2=[N:14]1.N1C=CC=CC=1>CC#N.C(O[Cu]OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:29][C:26]2[CH:25]=[CH:24][C:23]([C@H:22]3[C:15]4=[N:14][S:13](=[O:30])(=[O:12])[CH2:18][CH2:17][N:16]4[CH2:19][CH2:20][CH2:21]3)=[CH:28][CH:27]=2)=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1B(O)O
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1cc(Cl)ccc1Oc1ccc([C@@H]2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.1 %

Procedure:
A mixture of (4-chloro-2-methylphenyl)boronic acid (912 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (500 mg), pyridine (3.60 mL) cesium carbonate (581 mg), diacetoxycopper (648 mg) and powdered 4A MS (5.00 g) in MeCN (18 ml) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (37.0 mg) as a white solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C(N(CC)C(C)C)(C)C.[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][CH2:24][CH2:25]Br)([CH3:19])([CH3:18])[CH3:17].[C:28]([C:30]1[CH:60]=[CH:59][C:33]([O:34][C:35]2[N:49]=[C:48]([O:50][C:51]3[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[CH:53][CH:52]=3)[CH:47]=[CH:46][C:36]=2[C:37]([NH:39][CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:38])=[CH:32][CH:31]=1)#[N:29]>CN(C=O)C>[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][CH2:24][CH2:25][N:43]1[CH2:44][CH2:45][CH:40]([NH:39][C:37]([C:36]2[C:35]([O:34][C:33]3[CH:32]=[CH:31][C:30]([C:28]#[N:29])=[CH:60][CH:59]=3)=[N:49][C:48]([O:50][C:51]3[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)=[O:38])[CH2:41][CH2:42]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: N#Cc1ccc(Oc2ccc(C(=O)NC3CCNCC3)c(Oc3ccc(C#N)cc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCN1CCC(NC(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Temperature: 45 °C
Yield: 88.7 %

Procedure:
0.117 g (0.85 mmol) of K2CO3 and N,N-diisopropylethylamine 0.072 g (0.56 mmol) followed by 0.201 g (0.85 mmol) of (3-bromo-propyl)-carbamic acid tert-butyl ester, dissolved in 5 ml of DMF, were added to a stirred solution of 0.373 g (0.85 mmol) of 2,6-bis-(4-cyano phenoxy)-N-piperidine-4-yl nicotinamide, dissolved in 5 ml of DMF over a period of 15 min at 20° C. Reaction mixture was allowed to attain RT and heated to 45° C. for 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was partitioned between water (150 ml) and ethyl acetate (150 ml). The organic phase was washed with 1 M Na2CO3 and saturated brine solution, and dried over sodium sulphate. The solution was concentrated and the oily residue was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 0.45 g of the required product. Percentage purity (LCMS): 72.5%, (M+1)=596.2+1.
Reaction SMILES: C([Si:3](OC)(OC)OC)=C.[CH2:10]([O:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH2:11][CH2:12][CH3:13]>>[SiH4:3].[CH2:10]([O:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH2:11][CH2:12][CH3:13]
Reactant: C=C[Si](OC)(OC)OC
Agent: C=CC(=O)OCCCC
Product: [SiH4]

Procedure:
Terpolymer 1 was produced by high-pressure polymerisation with free radical initiation, wherein ethylene monomers were reacted with vinyl trimethoxysilane (VTMS) and butylacrylate (BA) co-monomers amounts so as to yield 1.8 wt % (0.36 mol %) silane content and 17 wt % (4.4 mol %) BA content in final terpolymer 1, under the action of a radical initiator in a reactor at a high pressure of about 120 to 350 MPa and an elevated temperature of between 150 to 350° C. When the reaction was completed, the temperature and the pressure were lowered, and the resulting unsaturated polymer recovered.
Reaction SMILES: O.[OH:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7](O)[C:8]([O-])=O)=[CH:5][CH:4]=1.[Na+].[C-]#[N:16].[Na+].C(=O)([O-])[O-].[K+].[K+].C(OC)=O>CO>[OH:2][C:3]1[CH:13]=[CH:12][C:6]([CH2:7][C:8]#[N:16])=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: O=C([O-])C(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: COC=O
Solvent: O
Solvent: CO
Product: N#CCc1ccc(O)cc1
Yield: 90.2 %

Procedure:
A mixture of sodium p-hydroxymandelate monohydrate (208 g.), sodium cyanide (49 g.), potassium carbonate (69 g.), methyl formate (80 ml.) and methanol (300 ml.) is heated under reflux for 8 hours, the temperature being maintained below 58° C. as methyl formate is consumed in the early stages of the reaction by the dropwise addition of further methyl formate (120 ml.). The mixture is cooled and acidified to pH 4 with concentrated aqueous hydrochloric acid (90 ml.), and water (300 ml.) is added dropwise whilst the mixture is distilled under reduced pressure, until the final volume of the two-layer mixture is 530 ml. The upper organic layer is collected and the lower aqueous layer is extracted twice with methyl isobutyl ketone (80 ml. each time). The extracts and organic layer are combined and the mixture is washed with saturated sodium chloride solution (100 ml.) and then with water (80 ml.). The methyl isobutyl ketone is removed by evaporation and there is thus obtained as residue p-hydroxybenzyl cyanide (120 g.) which is suitable for conversion to p-hydroxyphenylacetamide without further purification.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].COC(C1C(C2C=CC=CC=2Cl)C(C(OC)=O)=C(C)NC=1COCCN[C:56](=[O:73])[CH2:57][O:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]2[CH2:70][CH2:69][C:68](=[O:71])[NH:67][N:66]=2)=[CH:61][C:60]=1[Cl:72])=O>C(OCC)(=O)C>[CH3:22][O:21][C:19]([C:10]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[C:7]([CH2:24][O:25][CH2:26][CH2:27][NH:28][C:56](=[O:73])[CH2:57][O:58][C:59]2[CH:64]=[CH:63][C:62]([C:65]3[CH2:70][CH2:69][C:68](=[O:71])[NH:67][N:66]=3)=[CH:61][C:60]=2[Cl:72])[NH:8][C:9]=1[CH3:23])=[O:20]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: COC(=O)C1=C(C)NC(COCCNC(=O)COc2ccc(C3=NNC(=O)CC3)cc2Cl)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(COCCNC(=O)COc2ccc(C3=NNC(=O)CC3)cc2Cl)NC(C)=C(C(=O)OC)C1c1ccccc1Cl

Procedure:
2-(2-{2-[2-Chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-acetylamino}-ethoxymethyl)-4-(2-chloro-phenyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester (Compound 9) (12b) was synthesized from commercial amlodipine (5b, 1.73 g, 4.23 mmol) and 6-{4-[3-carboxymethoxy]-3-chlorophenyl}-4,5-dihydro-3(2H)-pyridazinone (11) using the same procedure as for Compound 8. Pure Compound 9 was obtained by re-crystallization from ethyl acetate (1.45 g, 51% yield, 99% pure by 10 min. LCMS (UV @ 215 nm: retention time=6.86 min., peak area=99%, TOF-ES+ with 25 eV cone voltage: m/z=673.30 (100%) & 675.30 (30%)). 1H NMR: (CDCl3, TMS internal standard, δ in ppm): 8.50 (1H, s), 7.85 (1H, d, J=2.20 Hz), 7.59 (1H, dd, J1=8.60 Hz, J2=2.20 Hz), 7.38 (1H, dd, J1=7.78 Hz, J2=1.65 Hz), 7.23 (1H, dd, J1=7.87 Hz, J2=1.28 Hz), 7.17 (1H, broad s), 7.13 (2H, td, J1=7.43 Hz, J2=1.28 Hz), 7.04 (1H, J=7.57 Hz, J2=1.71 Hz), 6.94 (1H, d, J=8.78 Hz), 5.40 (1H, s), 4.76 (1H, d, J=15.83 Hz), 4.68 (1H, d, J=15.83 Hz), 4.62 (2H, s), 4.04 (2H, m, J1=7.12 Hz), 3.77–3.63 (4H, m), 3.62 (3H, s), 2.94 (2H, t, J=8.32 Hz), 2.61 (2H, t, J=8.23 Hz), 2.35 (3H, s), 1.18 (3H, t, J=7.14)
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3]1=[O:26]>O1CCCC1>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][N:4]1[C:5]2[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=2[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[N:8]=[C:2]([NH:1][C:3]([NH:4][CH:5]([CH3:19])[CH3:6])=[O:26])[C:3]1=[O:26])[CH3:25]
Reactant: CCOC(=O)CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C(NC(=O)NC(C)C)=NC(c2ccccc2F)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-ethoxycarbonylmethyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one and isoproplylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 155°-157° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][C:14]1[S:18][C:17]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)=[O:21])=[N:16][CH:15]=1.NN>C(O)C>[NH2:3][CH2:12][CH2:13][C:14]1[S:18][C:17]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)=[O:21])=[N:16][CH:15]=1
Reactant: O=C(Nc1cccc(F)c1)Nc1ncc(CCN2C(=O)c3ccccc3C2=O)s1
Agent: NN
Solvent: CCO
Product: NCCc1cnc(NC(=O)Nc2cccc(F)c2)s1
Temperature: 65 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
To a suspension of compound 60.1 (2.6 g) in ethanol (64 mL) was added hydrazine (2.0 mL) and the reaction stirred at 65° C. for 4 hours. The solid that formed was filtered off and the filtrate was concentrated to give 1-[5-(2-amino-ethyl)-thiazol-2-yl]-3-(3-fluoro-phenyl)-urea (compound 60.2; 1.6 g) as a yellow solid.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][OH:12])[CH2:7][CH2:6]1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[CH2:13]([O:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC[C@H]1CC[C@H](CO)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC[C@H]1CC[C@H](COCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
In 10 ml of tetrahydrofuran was suspended 1.51 g of sodium hydride (55% content), and a solution of 5.0 g of trans-1,4-dihydroxymethylcyclohexane dissolved in 20 ml of tetrahydrofuran was added dropwise thereto with stirring under ice-cooling, and the reaction mixture was stirred at room temperature for 50 minutes. To the reaction mixture was added 3.79 ml of benzyl bromide with stirring under ice-cooling and the mixture was stirred under ice-cooling for 1 hour and further at room temperature overnight. The insolubles were separated by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed successively with an aqueous sodium chloride solution, 10% aqueous hydrochloric acid solution, an aqueous sodium chloride solution and an aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: cyclohexane/ethyl acetate=20/1-5/1) to obtain 1.75 g of the desired compound as a colorless oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[Br:22])(=[O:3])[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[S:24]([O:21][C@@H:8]1[C@H:7]([Br:22])[C@@H:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:10][C@H:9]1[N:11]1[C:20]2[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=2[N:13]=[CH:12]1)([CH3:23])(=[O:26])=[O:25]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1Br
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OS(C)(=O)=O)[C@@H]1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
After 1 g (2.7 mmols) of 5'-O-acetyl-3'-deoxy-3'-bromoadenosine was added to 10 ml of pyridine, 340 mg (1.1 eq.) of methanesulfonyl chloride was added to the mixture. The mixture was stirred at room temperature for 30 minutes and pyridine was distilled off under reduced pressure. The residue was added to 30 ml of water followed by extraction twice with 30 ml of chloroform. After the organic solvent was washed with water and then dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to give 1.09 g (yield, 90%) of 2'-O-mesyl-5'-O-acetyl-3'-deoxy-3'-bromoadenosine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[C:10](Br)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22]1[C:26](B(O)O)=[CH:25][CH:24]=[N:23]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[C:10]([C:26]2[N:22]([CH3:21])[N:23]=[CH:24][CH:25]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nccc1B(O)O
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)c(Br)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: COCCOC
Solvent: O
Product: Cn1nccc1-c1cc(NC(=O)OC(C)(C)C)ccc1OC(F)(F)F
Temperature: 80 °C
Yield: 36.5 %

Procedure:
A 25-mL round-bottom flask was charged with (3-bromo-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (230.0 mg, 0.65 mmol), 1-methyl pyrazole-5-boronic acid (392.9 mg, 1.93 mmol), sodium carbonate (137.8 mg, 1.3 mmol), DME (5 mL) and water (0.5 mL) under argon atmosphere. Tetrakis(triphenylphosphine)palladium (75.1 mg, 0.065 mmol) was added and reaction mixture purged with argon again. The reaction mixture was heated at 80° C. overnight then cooled to room temperature. Ethyl acetate (10 mL) was added then washed with brine and water. Organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue that was subjected to a purification by flash chromatography (SiO2, Hexanes/EtOAc gradient elution) to afford [3-(2-methyl-2H-pyrazol-3-yl)-4-trifluoromethoxy-phenyl]-carbamic acid tert-butyl ester as an off-white solid in 36.5% yield. LCMS m/z (%)=358 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 9.83 (bs, 1H), 7.77 (d, J=8.95 Hz, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.57 (d, J=8.84 Hz, 1H), 6.45 (s, 1H), 3.78 (s, 3H), 1.60 (s, 9H).
Reaction SMILES: CC[C@@H]1[C@@H]2[N:9]3[CH2:11][CH2:12][C:13]4[C:17]5[CH:18]=[C:19](OC)[CH:20]=[CH:21][C:16]=5N[C:14]=4[C@@H]2C[C@@H](C3)C1.[S:24]1C=CC2C=CC=CC1=2.[C-]#N>>[C:11]([CH2:12][C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:24][CH:14]=1)#[N:9]
Reactant: c1ccc2sccc2c1
Reactant: CC[C@H]1C[C@H]2C[C@H]3c4[nH]c5ccc(OC)cc5c4CCN(C2)[C@@H]13
Agent: [C-]#N
Product: N#CCc1csc2ccccc12

Procedure:
The synthesis of ibogaine analogs 7a-c is outlined in FIG. 2, wherein the benzo[b]thiophene is chloromethylated to yield 1, then reacted with cyanide ion to yield 3-cyanomethylbenzothiophene (2), which is reduced with LiAlH4 /AlCl3 to yield the corresponding primary amine 3. The latter was acetylated with acetic anhydride and the resulting amide was reduced with borane-tetrahydrofuran to yield 5. Refluxing of the 5 with a preselected styrene oxide in EtOH and subsequent cyclization of the corresponding secondary alcohol provided the compounds 7a, (R=H) 7b (R=NO2) and 7c (R=Br). The compounds were characterized by 1H NMR and purity was determined by combustion analysis. Cyclization was associated with a 0.1δ upfield shift in the methine proton signal. The hydrochlorides were prepared by passing HCl gas through a solution of the corresponding free bases in EtOH.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[NH:14][C:13]3[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:12]=3[N:11]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C)C=O>[Cl:3][C:4]1[C:9]([C:10]2[N:11]([CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:12]3[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:13]=3[N:14]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Fc1cc2nc(-c3cccnc3Cl)[nH]c2cc1F
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc2nc(-c3cccnc3Cl)n(CC3CCCCC3)c2cc1F
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a suspension of sodium hydride (0.40 g, 60%, 10 mmol) in dry N,N-dimethylformamide (10 ml) at 25° C. was slowly added a solution of 2-(2-chloro-pyridin-3-yl)-5,6-difluoro-1H-benzoimidazole (1.33 g, 5 mmol) in dry N,N-dimethylformamide (5 ml), and was allowed to stir for 0.5 h. A solution of bromomethyl-cyclohexane (1.06 g, 6 mmol; CAS Reg. No. 2550-36-9) in N,N-dimethylformamide (5 ml) was then added drop wise to the above solution, and further stirred for 16 h at 25° C. The reaction mixture was quenched with saturated aqueous solution of ammonium chloride. The solvents were removed under reduced pressure. The crude material was dissolved in ethyl acetate, washed with water, and then with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography over silica gel (20% ethyl acetate/n-hexane) to afford the title compound as a colorless solid (51%). MS (Turbo Spray): m/z=362.2 (M+H).