Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:2]1.C(=O)(O)[O-].[Na+].[CH2:19]([O:26][C:27]1[C:36]2[O:35][CH2:34][C@H:33]([CH2:37]OS(C)(=O)=O)[O:32][C:31]=2[CH:30]=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([O:26][C:27]1[C:36]2[O:35][CH2:34][C@H:33]([CH2:37][N:1]3[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]4[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=4)[CH2:2]3)[O:32][C:31]=2[CH:30]=[CH:29][CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)OC[C@H]1COc2c(OCc3ccccc3)cccc2O1
Reactant: Oc1cccc([C@H]2CCCNC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1cccc([C@H]2CCCN(C[C@H]3COc4c(OCc5ccccc5)cccc4O3)C2)c1
Yield: 33.4 %

Procedure:
A mixture of hydrochloride salt of (R*)-3-(piperidin-3-yl)-phenol (240 mg, 1.12 mmol) and sodium bicarbonate in N,N-dimethylformamide (3 ml) were stirred at +120° C. under nitrogen atmosphere. To this mixture, a mixture of methanesulfonic acid (R)-5-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester (390 mg, 1.11 mmol) in N,N-dimethylformamide (3 ml) was added, and stirred at +130° C. for 3.5 h. The reaction mixture was cooled down, water (20 ml) and ethyl acetate (15 ml) were added and the layers were separated. Organic phase was recovered and water layer was extracted twice with ethyl acetate. Organic phase and ethyl acetate extracts were combined and washed five times with water and saturated sodium chloride solution. The combined organic phase was dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified with flash chromatography using heptane and ethyl acetate as eluents to give 160 mg of the title compound.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:4].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23]Cl>CN(C=O)C>[CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:23][C:22]2[CH:25]=[CH:26][C:27]([Cl:28])=[C:20]([Cl:19])[CH:21]=2)[C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:4]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C=O
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C=O)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 57 %

Procedure:
Sodium hydride (488 mg, 60% in mineral oil) was added to a stirred solution of ethyl 3-formylindole-2-carboxylate (2.21 g) in DMF (100 ml) under argon, and reaction stirred at ambient temperature for 25 minutes. 3,4-Dichlorobenzyl chloride (1.71 ml) was then added and the reaction stirred overnight. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate (80 ml) and washed with water (2×80 ml), dried (MgSO4) and concentrated in vacuo to give a crude residue which was purified by column chromatography using ethyl acetate:iso-hexane as eluent (gradient 5/95-100/0), to give the product as a yellow solid (2.17 g, 57%); NMR d (CD3SOCD3) 1.25 (t, 3H), 4.40 (q, 2H), 5.80 (s, 2H), 7.00 (m, 1H), 7.30-7.50 (m, 3H), 7.55 (m, 1H), 7.65 (m, 1H), 8.35 (m, 1H), 10.48 (s, 1H); M/z (+) 376.4 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH:7]([CH3:9])[CH3:8])[CH3:2].[H][H]>C(O)C.[Pd]>[CH3:9][CH:7]([CH3:8])[CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:19]
Reactant: CCOC(=O)C=C(Cc1cccc(OC)c1)C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(Cc1cccc(OC)c1)C(C)C

Procedure:
The oily mixture containing (65) was dissolved in ethanol (50 mL) and 10% Pd/C (200 mg) was added. The mixture was hydrogenated at room temperature using a hydrogen balloon overnight. Filtered through celite, the filtrate was concentrated to give 1.72 g of compound (66) (41% from the ketone) of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 0.89 (d, J=7.4 Hz, 3H), 0.91 (d, J=7.6 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H), 1.70-1.80 (m, 1H), 2.10-2.20 (m, 2H), 2.20-2.30 (m, 1H), 2.44 (dd, J1=13.6 Hz, J2=7.4 Hz, 1H), 2.64 (dd, J1=13.7 Hz, J2=6.2 Hz, 1H), 3.79 (s, 3H), 4.04 (q, J=7.2 Hz, 2H), 6.70-6.80 (m, 3H), 7.15-7.20 (m, 1H).
Reaction SMILES: ClC1C=CC(C2(CN3CCCC(C[C@@H](C4C=CC=CC=4)O)C3)CCC2)=CC=1.CC(C)([O-])C.[K+].CI.[OH-].[NH4+].[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2([CH2:49][N:50]3[CH2:55][CH2:54][CH2:53][CH:52]([CH2:56][CH:57]([O:64][CH3:65])[C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[CH2:51]3)[CH2:48][CH2:47][CH2:46]2)=[CH:41][CH:40]=1>C1COCC1.CCOC(C)=O.CCCCCC.CCOCC.O>[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2([CH2:49][N:50]3[CH2:55][CH2:54][CH2:53][C@@H:52]([CH2:56][CH:57]([O:64][CH3:65])[C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=4)[CH2:51]3)[CH2:48][CH2:47][CH2:46]2)=[CH:41][CH:40]=1
Reactant: COC(CC1CCCN(CC2(c3ccc(Cl)cc3)CCC2)C1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: O[C@@H](CC1CCCN(CC2(c3ccc(Cl)cc3)CCC2)C1)c1ccccc1
Agent: [K+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(C[C@@H]1CCCN(CC2(c3ccc(Cl)cc3)CCC2)C1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(S)-[2-{-[1-(4-Chloro-phenyl)-cyclobutylmethyl]-piperidin-3-yl}-1-phenyl-ethanol] (38 mg, 0.100 mmol) was dissolved in 1 mL of THF and cooled to 0° C. Potassium tert-butoxide was added (112 mg, 1.0 mmol) followed by methyl iodide in large excess (ca. 0.5 mL). After 30 minutes at 0° C., water (5 mL) and ether (5 mL) were added. Extractive workup gave, after concentration of the organic layers in vacuo and chromatography on silica gel using as eluent an EtOAc-hexane gradient with 1% ammonium hydroxide, the desired product 1-[1-(4-Chloro-phenyl)-cyclobutylmethyl]-3-(2-methoxy-2-phenyl-ethyl)-piperidine, 184, (28 mg, 70%). Data for this compound: MS 398 (M++1).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14](COCC[Si](C)(C)C)[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(OC(=O)[NH:37][CH2:38][CH:39]1[CH2:43][CH2:42][NH:41][CH2:40]1)(C)(C)C>>[NH2:37][CH2:38][CH:39]1[CH2:43][CH2:42][N:41]([C:2]2[CH:3]=[C:4]([C:8]3[N:9]=[C:10]4[C:16]([C:17](=[O:22])[C:18]([CH3:20])([CH3:21])[CH3:19])=[CH:15][NH:14][C:11]4=[N:12][CH:13]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:40]1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(I)c3)nc12
Reactant: CC(C)(C)OC(=O)NCC1CCNC1
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(N4CCC(CN)C4)c3)nc12

Procedure:
1-{2-[3-(3-Aminomethyl-pyrrolidin-1-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one was prepared starting from 1-[2-(3-iodo-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one and pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester following general procedures as described in these Examples. M+H=378.
Reaction SMILES: [Cl:1][C:2]1[CH:3]([OH:20])[CH:4]2[CH2:19][C:7]3([C:18]=1[C:17]1[CH:16]=[CH:15][C:14]4[NH:13][N:12]=[CH:11][C:10]=4[C:9]=1[CH2:8]3)[CH2:6][CH2:5]2>C(O)C.CO>[Cl:1][C:2]1[C@H:3]([OH:20])[C@H:4]2[CH2:19][C@@:7]3([C:18]=1[C:17]1[CH:16]=[CH:15][C:14]4[NH:13][N:12]=[CH:11][C:10]=4[C:9]=1[CH2:8]3)[CH2:6][CH2:5]2
Reactant: OC1C(Cl)=C2c3ccc4[nH]ncc4c3CC23CCC1C3
Solvent: CO
Solvent: CCO
Product: O[C@H]1C(Cl)=C2c3ccc4[nH]ncc4c3C[C@@]23CC[C@@H]1C3

Procedure:
Racemic (7R,8R,10aS)-6-chloro-3,7,8,9,10,11-hexahydro-8,10a-methanoazuleno-[2,1-e]indazol-7-ol (318 mg) was dissolved in 4/1 ethanol/methanol (25 mL) and resolved by chiral HPLC on a 2.0×25 cm Daicel Chiralcel OJ column (3-4 mL injections, elution with 35% EtOH:Heptane at 7.5 mL/min, fractions monitored at 254 nm). The fractions containing the first enantiomer to elute (enantiomer A) were combined and concentrated to a clear oil which had a negative rotation. The pure fractions containing the second enantiomer to elute (enantiomer B) were combined, concentrated, and lyophilized from benzene to give a white solid which had a positive rotation.
Reaction SMILES: [O:1]=[C:2]1[CH:11](C(OC(C)(C)C)=O)[C:10]2[N:9]=[CH:8][C:7]([C:19]([F:22])([F:21])[F:20])=[CH:6][C:5]=2[CH2:4][NH:3]1.FC(F)(F)C(O)=O>ClCCl>[F:21][C:19]([F:20])([F:22])[C:7]1[CH:8]=[N:9][C:10]2[CH2:11][C:2](=[O:1])[NH:3][CH2:4][C:5]=2[CH:6]=1
Reactant: CC(C)(C)OC(=O)C1C(=O)NCc2cc(C(F)(F)F)cnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2ncc(C(F)(F)F)cc2CN1

Procedure:
To a mixture of the product from Step F above (16 g, 51 mmol) in dichloromethane (60 mL) was added trifluoroacetic acid (30 mL) and the resultant solution was stirred at room temperature for 0.5 h. The solution was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The mixture was neutralized by the slow addition of a solution of saturated sodium bicarbonate and the organic layer was removed. The aqueous layer was extracted with four portions of dichloromethane and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 7.78 (s, 1H), 7.30 (s, 1H), 4.63 (s, 2H), 3.90 (s, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C(=O)C>[CH3:29][N:15]([CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([CH2:7][O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:9][CH2:10]1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: C1CCNC1
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COCCCCN2CCCC2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with pyrrolidine in N,N-dimethylacetamide at room temperature to yield trans-N-methyl-N-[4-(4-pyrrolidin-1-yl-butoxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide as yellow solid, MS: 491 (MH+).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([N:16]([C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15]
Reactant: CCCNCCC
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN(CCC)c1ccc([N+](=O)[O-])cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
2-Fluoro-5-nitrobenzaldehyde (48 mg, 0.28 mmol) was dissolved in N,N-dimethylformamide (2.4 mL), and di-n-propylamine (0.15 mL, 1.1 mmol) and potassium carbonate (0.16 g, 1.1 mmol) were added thereto, followed by stirring at 25° C. for 1 hour. After the conventional post-reaction treatment, the residue was purified by silica gel chromatography(eluted with chloroform), to obtain 2-(N,N-di-n-propylamino)-5-nitrobenzaldehyde (49 mg, 69%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](F)[C:22]=1[N+:28]([O-:30])=[O:29]>CS(C)=O.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[C:22]=2[N+:28]([O-:30])=[O:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(F)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (0.204 g, 1.1 mmol) in 1 mL dimethylsulfoxide was added potassium carbonate (0.303 g, 2.2 mmol) followed by 1,3-difluoro-2-nitro-benzene (0.159 g, 1 mmol). The solution was stirred 30 minutes at room temperature, and was then diluted with 50 mL ethyl ether. The organic phase was washed three times with 50 mL water and once with 50 mL brine, dried over sodium sulfated, and concentrated in vacuo to give 0.314 g (0.965 mmol, 96.5%) of 4-(3-fluoro-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as a yellow oil. MS: 226 (M−BOC+H)+.
Reaction SMILES: Cl.C([S:5][CH2:6][CH2:7][C:8]([N:10]1[C@H:14]([C:15]([NH:17][C@H:18]([C:21]([OH:23])=[O:22])[CH2:19][OH:20])=[O:16])[CH2:13][S:12][C@@H:11]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30])=[O:9])(=O)C>O.N>[OH:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C@@H:11]1[N:10]([C:8](=[O:9])[CH2:7][CH2:6][SH:5])[C@H:14]([C:15]([NH:17][C@H:18]([C:21]([OH:23])=[O:22])[CH2:19][OH:20])=[O:16])[CH2:13][S:12]1
Reactant: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)N[C@@H](CO)C(=O)O
Agent: Cl
Agent: N
Solvent: O
Product: O=C(O)[C@H](CO)NC(=O)[C@@H]1CS[C@H](c2ccccc2O)N1C(=O)CCS
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
In 10 ml of 28% ammonia water 0.5 g of (2S)-N-[(2R,4R)-[3-(S-acetyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinyl]carbonyl]serine is dissolved. The solution is stirred at room temperature for 30 minutes, and acidified with hydrochloric acid after removing excess ammonia. The separated oil is extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and ethyl acetate is removed to give 0.4 g (88%) of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[NH:4][N:3]=1.[C:14]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=2)[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:4][N:3]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[CH:24][C:23]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([NH:1][C:2]5[CH:6]=[C:5]([C:7]6[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=6)[NH:4][N:3]=5)=[O:22])=[CH:18][CH:19]=4)=[CH:28][CH:27]=3)=[O:31])[CH:6]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(-c2cc(N)n[nH]2)cc1
Reactant: O=C(O)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Product: Cc1ccc(-c2cc(NC(=O)c3ccc(-c4ccc(C(=O)Nc5cc(-c6ccc(C)cc6)[nH]n5)cc4)cc3)n[nH]2)cc1

Procedure:
Compound 476 was prepared from 3-amino-5-(4-methylphenyl)pyrazole and biphenyl-4,4′-dicarboxylic acid. [M+H]+ calcd for C34H29N6O2: 553.24; found: 553.06.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH:6]=1.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][C:28]=1[CH3:35].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.O.C(O)(=O)C>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:15]([CH2:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH2:14][CH2:13][CH2:12][O:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:2])=[O:25])[CH:10]=[CH:9][CH:8]=2)=[CH:29][C:28]=1[CH3:35]
Reactant: Cc1cc(C=O)ccc1F
Reactant: COC(=O)Cc1cccc(OCCCNC[C@H](C)c2ccccc2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1cc(CN(CCCOc2cccc(CC(=O)O)c2)C[C@H](C)c2ccccc2)ccc1F
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
To a solution of {3-[3-((R)-2-Phenyl-propylamino)-propoxy]-phenyl}-acetic acid methyl ester (100 mg, 293 mmol) in methanol (1 ml) was added acetic acid (10% by volume) followed by 4-Fluoro-3-methyl-benzaldehyde (121 mg, 879 mmol) and sodium cyanoborohydride (54.5 mg, 879 mmol). After the resulting mixture was stirred for 18 h at RT water was added to quench the reaction. The solution was made basic by the addition of sodium hydroxide and heated for 30 min. The sample concentrated in vacuo and purified by preparative HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: 0.1% trifluoroacetic acid in acetonitrile B: 0.1% aqueous trifluoroacetic acid, A: 10 to 90% during 10 min, UV detection at 254 nm) to give the title compound as a solid (71.6 mg, 54%). MS (ESI) 450.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][CH:10]([C:16]([CH3:18])=O)[C:11](OCC)=[O:12].[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[OH:8][C:7]1[C:2]2=[N:1][C:16]([CH3:18])=[C:10]([CH3:9])[C:11](=[O:12])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: Nc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nc2c(O)cccn2c(=O)c1C
Temperature: 100 °C
Reaction time: 4 h
Yield: 19.1 %

Procedure:
A mixture of 2-amino-3-hydroxypyridine (11 g), ethyl 2-methylacetoacetate (14.4 g), polyphosphoric acid (20 ml), and acetic acid (40 ml) was heated at 100° C. with stirring for 4 hours. The reaction mixture was poured in ice-water, adjusted to pH 4 with aqueous sodium hydroxide solution and then to pH 7 with potassium carbonate. The resulting precipitate was extracted with chloroform and the extract was washed with water, dried, and concentrated to provide the title compound (3.63 g) as brown solid. 1H-NMR (DMSO-d6) δ: 2.25(3H,s), 2.49(3H,s), 6.97(1H,dd,J=7.4,6.8Hz), 7.05(1H,dd,J=7.4,1.6Hz), 8.47(1H,dd,J=6.8,1.6Hz).
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH3:3]>O1CCOCC1.ClCCl>[NH:15]1[CH2:14][CH:13]=[C:12]([C:8]2[CH:7]=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[CH:11]=[CH:10][CH:9]=2)[CH2:17][CH2:16]1
Reactant: CC(=O)Nc1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(C2=CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4 M HCl in dioxane (10 mL) was added to tert-butyl 4-[3-(acetylamino)phenyl]-1,2,3,6-tetrahydro-1-pyridinecarboxylate (8.25 mmol) in dichloromethane (30 mL). The reaction mixture was stirred at room temperature overnight, concentrated in vacuo, giving the desired product as the hydrochloride salt (2.1 g): 1H NMR (CDCl3) δ 7.41–7.00 (m, 4H), 6.10 (br, 1H), 3.55 (m, 2H), 3.16 (t, 2H, J=5.7 Hz), 2.44 (m, 2H), 2.19 (s, 3H).
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:16]([C:18]1[S:19][C:20](=[NH:35])[N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[CH:27]=3)[C:22]=12)#[N:17]>O>[C:16]([C:18]1[S:19][C:20](=[N:35][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[CH:27]=3)[C:22]=12)#[N:17]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc2c(cc1OC)-c1c(C#N)sc(=N)n1CC2
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2c(cc1OC)-c1c(C#N)sc(=NC(=O)c3ccccc3)n1CC2

Procedure:
5 ml. of pyridine and 0.3 ml. of benzoyl chloride are added to 0.5 g. of 1-cyano-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline, and the mixture is refluxed for 0.5 hours. After cooling, the mixture is diluted with water. 0.6 g. of 1-cyano-3-benzoylimino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a] isoquinoline is obtained in crystalline state; m.p.: 274°-276°C (after recrystallization from a mixture of dimethylformamide and butanol).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH:10]([OH:12])[CH3:11])=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19]CC2C=CC=CC=2)[C:7]([CH:27]=[CH:28][CH2:29][CH2:30][CH3:31])=[C:6]([CH:32]([CH3:34])[CH3:33])[N:5]=1)([CH3:3])[CH3:2]>C(O)C.[Pd]>[CH:1]([C:4]1[C:9]([CH:10]([OH:12])[CH3:11])=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[C:7]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:6]([CH:32]([CH3:33])[CH3:34])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(C(C)O)c1-c1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(C(C)O)c1-c1ccccc1O
Reaction time: 8 h
Yield: 101.6 %

Procedure:
The diastereomeric mixture of intermediates from Step B (39 mg) was dissolved in absolute ethanol (1.5 mL) under argon, treated with 10% palladium on carbon (4 mg), then stirred under a hydrogen atmosphere for 8 hr. After purging the system with argon, the catalyst was removed by filtration through a pad of Celite. The solvent was removed and the product dried in vacuo to afford 32 mg of the title compound as a colorless solid. Preparative thin layer chromatography (“prep TLC”) using a 20% ethyl acetate-hexane mixture as the eluent provided the two diastereomers.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:18])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7]2.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[C:23]([Sn](C)(C)C)[CH:24]=[CH:25][CH:26]=1.C(OCC)(=O)C.O>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH3:18][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:32])([F:31])[F:19])[CH:26]=3)[CH:3]=1)[N:10]=[C:9]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7]2
Reactant: C[Sn](C)(C)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc(Br)c2nc(OCC(F)(F)F)ccc2c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c2nc(OCC(F)(F)F)ccc2c1
Reaction time: 3 h
Yield: 29.3 %

Procedure:
A mixture of 1.5 g (6.2 mmol) of 8-bromo-6-methyl-2-(2,2,2-trifluoroethoxy) quinoline, 2.3 g of crude 3-(trifluoromethyl) phenyltrimethylstannane (Example 1), and 0.2 g of tetrakis (triphenylphosphine)palladium(O) was heated in 30 ml of toluene at reflux with stirring for 3 hours. Ethyl acetate (200 ml) and excess water was added. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo to give an oil. Silica gel column chromatography (20:1 followed by 10:1 hexane/ethyl acetate) afforded 0.7 g of product, isolated as an oil. NMR(CDCl3): ppm 2.55 (s, 3H), 4.71 (q, 2H), 7.15 (d, 1), 7.5-8.15 (m, 7H).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[OH:11][C@@H:12]1[CH2:17][O:16][C:14](=[O:15])[CH2:13]1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>C1COCC1>[CH2:18]([C@H:13]1[C@H:12]([OH:11])[CH2:17][O:16][C:14]1=[O:15])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C1C[C@H](O)CO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OC[C@@H](O)[C@@H]1Cc1ccccc1
Temperature: -45 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
Lithium hexamethyldisilazide (25 ml, 25 mmol) was loaded under argon gas in a reaction vessel. (S)-3-Hydroxy-γ-butyrolactone (1.012 g, 9.913 mmol) in THF (20 ml) was added thereto under cooling to −45° C. After stirring for 30 minutes at the same temperature, benzyl bromide (1.9 ml, 11.89 mmol) in THF (20 ml) was dropped thereto. After stirring for 4 hours at the same temperature, an aqueous saturated ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and condensed in vacuo. The residue was purified by silica gel chromatography to give (2S,3S)-2-benzyl-3-hydroxy-γ-butyrolactone (0.762 g, yield 40%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:22])[CH2:14][C@@H:15]1[CH3:21])[CH2:10][CH2:9]3.[CH2:23](O)[CH2:24][OH:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:23]1[CH2:24][O:25][C:13]2([CH2:14][C@H:15]([CH3:21])[C@@:16]3([CH3:17])[C:11](=[CH:10][CH2:9][C@@H:8]4[C@@H:18]3[CH2:19][CH2:20][C@@:3]3([CH3:4])[C@H:5]4[CH2:6][CH2:7][C@@H:2]3[OH:1])[CH2:12]2)[O:22]1
Reactant: OCCO
Reactant: C[C@H]1CC(=O)C=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C[C@H]1CC2(CC3=CC[C@H]4[C@@H]5CC[C@H](O)[C@@]5(C)CC[C@@H]4[C@]31C)OCCO2
Yield: 25 %

Procedure:
A solution of 7.0 g of 17β-hydroxy-1α-methyl-4-androsten-3-one in 500 ml of benzene is combined with 80 ml of 1,2-ethanediol and 400 mg of p-toluenesulfonic acid and the evolving water is distilled off azeotropically within 20 hours. After cooling of the reaction mixture, the latter is combined with 5 ml of pyridine, washed with water, dried over sodium sulfate, and concentrated under vacuum. The residue is chromatographed on silica gel, thus obtaining with hexane-ethyl acetate gradients (25-30% ethyl acetate) 6.3 g of 3,3-ethylenedioxy-1α-methyl-5-androsten-17β-ol.