Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:13][C@H:12]2[C@H:14]3[C@H:23]([CH2:24][CH2:25][C@:5]2([CH2:6][O:7][C:8](=[O:11])[CH2:9]Br)[CH2:4]1)[C@@H:22]1[C:17](=[CH:18][C:19](=[O:26])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)[CH3:2].[C:27]([O-:32])(=[O:31])[CH:28]([CH3:30])[CH3:29].[K+]>CC(C)=O.O>[CH2:1]([C@H:3]1[CH2:13][C@H:12]2[C@H:14]3[C@H:23]([CH2:24][CH2:25][C@:5]2([CH3:4])[C@H:6]1[O:7][C:8](=[O:11])[CH2:9][O:32][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[C@@H:22]1[C:17](=[CH:18][C:19](=[O:26])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)[CH3:2]
Reactant: CC(C)C(=O)[O-]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(COC(=O)CBr)C1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)C(C)C
Yield: 70.8 %

Procedure:
In a mixture of 50 ml of acetone and 10 ml of water are dissolved 1.5 g of 16β-ethyl-bromoacetoxy-4-estren-3-one and 0.8 g of potassium isobutyrate and the solution is refluxed for 6 hours. The acetone is distilled off under reduced pressure and the residue is extracted with 200 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 100 ml of diisopropyl ether, elution is carried out with 300 ml of ethyl ether. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.08 g of the above-identified compound as a viscous oil.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:20]=[C:19]([C:21](=[O:36])[CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH:18]=[C:17]2[C:12]=1[CH2:13][N:14]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1)[C:15](=[O:45])[N:16]2[C:37]1[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:44]>C(Cl)Cl>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:20]=[C:19]([C:21]([OH:36])([CH3:1])[CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH:18]=[C:17]2[C:12]=1[CH2:13][N:14]([CH2:46][C:47]1[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=1)[C:15](=[O:45])[N:16]2[C:37]1[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:44]
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(C(=O)CN4CCN(C(=O)OC(C)(C)C)CC4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(C(C)(O)CN4CCN(C(=O)OC(C)(C)C)CC4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methylmagnesium bromide (68 μL, 1.4M) in CH2Cl2 (0.2 mL) at 0° C. was added tert-butyl 4-{2-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]-2-oxoethyl}piperazine-1-carboxylate (EXAMPLE ABA4, Step A) (35.6 mg, 0.047 mmol) dissolved in CH2Cl2 (0.3 mL) slowly. The reaction mixture was stirred for 2 h while warming up to rt. It was quenched with saturated aqueous solution of NH4Cl, and extracted with CH2Cl2. The combined organic layers were washed with brine and dried over Na2SO4. After removal of the solvent, the crude product was purified by preparative thin layer chromatography eluting with 1:3 acetone:hexane to obtain the title compound. Mass spectrum (ESI): 765.2 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]([OH:39])[CH2:33][C:34]4[N:35]=[N:36][NH:37][N:38]=4)=[CH:28][CH:27]=3)[C:14]([NH:16][C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49].N12CCCN=C1CCCCC2>C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([N:13]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([CH:32]([O:39][S:48]([CH3:47])(=[O:50])=[O:49])[CH2:33][C:34]4[N:35]=[N:36][NH:37][N:38]=4)=[CH:30][CH:31]=3)[C:14]([NH:16][C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)=[O:15])=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(Nc1cc(Cl)cc(Cl)c1)N(Cc1ccc(C(O)Cc2nn[nH]n2)cc1)c1ccc(C2=CCCCC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(Cc1nn[nH]n1)c1ccc(CN(C(=O)Nc2cc(Cl)cc(Cl)c2)c2ccc(C3=CCCCC3)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)-1-{4-[1-hydroxy-2-(2H-tetrazol-5-yl)ethyl]benzyl}urea (100 mg, 0.17 mmol) was dissolved in DCM (1 ml) and triethyl amine (27 μl, 0.195 mmol) was added. The mixture was cooled to 0° C. and methansulphonyl chloride (15 μl, 0.195 mmol) was added followed by 1,8-diazabicyclo[5,4,0]-undec-7-ene (29 μl, 0.195 mmol). The mixture was stirred at 0° C. for 2 hours, and at room temperature overnight, then diluted with DCM (20 ml) and washed with brine (20 ml). The organic solution was dried with anhydrous sodium sulphate and evaporated to dryness, to give pure title material as a white powder. Yield: 113 mg (100%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][C@@H:5]([NH:7][C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:4][N:3]1C(OC(C)(C)C)=O.Cl>CO.O1CCOCC1>[CH3:1][C@@H:2]1[NH:3][CH2:4][C@H:5]([NH:7][C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[CH2:6]1
Reactant: C[C@H]1C[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H]1C[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 121.5 %

Procedure:
The intermediate of step F (0.6 g, 1.4 mmol) was dissolved in MeOH (3 mL) and a solution of 4 N HCl in dioxane (3 mL). After being stirred at room temperature for 4 hours, the solution was concentrated to give 0.56 g of the title compound. MS calculated (M+H)+ 330, found 330.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:10]=1[CH3:11])[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:17]O>>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:10]=1[CH3:11])[C:7]([O:9][CH3:17])=[O:8]
Reactant: Cc1c(N)cncc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cncc(N)c1C
Temperature: 70 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
To a stirred solution of 5-amino-4-methylnicotinic acid (5.0 g, 32 mmol) in methanol (75 mL), was added conc. H2SO4 (5 mL) slowly at room temperature. The mixture was stirred at 70° C. for 12 h. On completion, the solvent was removed under reduced pressure and the residue was neutralized with saturated NaHCO3 solution. Extraction was carried out using EtOAc; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound (4.1 g, 75%) which used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=1)[C:13]([O:15]C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)c1cccc(OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NC(C(=O)O)c1cccc(OCc2ccccc2)c1)OCc1ccccc1
Yield: 67.2 %

Procedure:
A solution of methyl 2-(benzyloxycarbonylamino)-2-(3-benzyloxyphenyl)acetate (640 mg, 1.75 mmol) and aqueous lithium hydroxide (1 N, 3.50 mL, 3.50 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was stirred at room temperature for one hour. The mixture was concentrated in vacuo and the residue diluted with dichloromethane (30 mL) and acidified to pH 0.5 with 2 N HCl. The aqueous phase was re-extracted with dichloromethane (2×50 mL). The combined organic fractions were dried over a hydrophobic frit and the solvent was removed in vacuo to give the title compound as a light brown oil (460 mg, 67%). This was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1Cl.[Na].[CH3:14][O:15][CH2:16][CH2:17][OH:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[O:18][CH2:17][CH2:16][O:15][CH3:14]
Reactant: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: COCCO
Agent: [Na]
Product: COCCOc1cc(C)c([N+](=O)[O-])cc1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
1,2-Dichloro-4-methyl-5-nitrobenzene (R.J. De Lang, et al. Tetrahedron (1998), 54(12), 2953-2966.) (860 mg; 4.17 mmol) was added to solution of sodium (115 mg; 5.01 mmol) dissolved in 2-methoxyethanol (15 ml). The brown reaction mixture was stirred at 100° C. for 1 h, poured on brine (50 ml) and extracted with TBME three times. The combined organic phases were evaporated and purified via chromatography (SiO2 acetone/hexanes 1/9) to yield the title compound as orange crystals (640 mg; 63%)
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:15]1[N:19]2[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:26])[F:25])=[N:23][C:18]2=[N:17][CH:16]=1)CCC>>[F:26][C:24]([F:25])([F:27])[C:22]1[CH:21]=[CH:20][N:19]2[C:15]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=3)=[CH:16][N:17]=[C:18]2[N:23]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: N#Cc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)nc1
Yield: 35.1 %

Procedure:
6-Chloronicotinonitrile (295 mg, 2.13 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol) by the method of Example 1 to give 6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)nicotinonitrile (142 mg) as a white solid: δH (400 MHz, DMSO) 7.79 (1H, d, J 7), 8.35 (1H, m), 8.43 (1H, m), 9.06 (1H, s), 9.14 (1H, s), 10.41 (1H, d, J 7); m/z (ES+) 290 (M++H).
Reaction SMILES: FC1C=CC(N2C(C(O)=O)=CN=C2SCC2C(F)=CC=C(F)C=2F)=CC=1.[Cl:27][C:28]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:29]=1[CH2:30][CH2:31][S:32]([C:35]1[N:36]([C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)[C:37]([C:40]([O:42]CC)=[O:41])=[CH:38][N:39]=1)(=[O:34])=[O:33].[Li+].[OH-]>C1COCC1.CO>[Cl:27][C:28]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:29]=1[CH2:30][CH2:31][S:32]([C:35]1[N:36]([C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)[C:37]([C:40]([OH:42])=[O:41])=[CH:38][N:39]=1)(=[O:34])=[O:33]
Reactant: CCOC(=O)c1cnc(S(=O)(=O)CCc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Agent: O=C(O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(S(=O)(=O)CCc2c(F)cccc2Cl)n1-c1ccc(F)cc1

Procedure:
2-((2-Chloro-6-fluorophenethyl)sulfonyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylic acid (55) was prepared in a similar manner as that described for the synthesis of compound 11 using ethyl 2-((2-chloro-6-fluorophenethyl)sulfonyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (54) (250 mg, 0.5495 mmol), 1N LiOH (5 mL) in THF (5 mL) and MeOH (5 mL).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:25][CH:26]([O:32][CH2:33][CH3:34])[C:27]([O:29]CC)=[O:28])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:25][CH:26]([O:32][CH2:33][CH3:34])[C:27]([OH:29])=[O:28])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][S:21]([CH3:24])(=[O:22])=[O:23])=[CH:16][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)c(C(C)(C)C)c1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)c(C(C)(C)C)c1)C(=O)O
Yield: 81.8 %

Procedure:
Ethyl 3-[3-tert-butyl-4-(2-{4-[(methylsulfonyl)oxy]phenyl}ethoxy)phenyl]-2-ethoxypropanoate (0.025 g; 0.050 mmole) was dissolved in THF and water (2:1), 0.1 M lithium hydroxide (2 ml) was added and the reaction mixture was stirred over night. Water was added and the THF evaporated. The remaining water was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate. Evaporation gave 0.019 g (80% yield) of the product.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5]1([NH:10]C(=O)OC(C)(C)C)[CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH3:2][O:3][CH2:4][C:5]1([NH2:10])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COCC1(NC(=O)OC(C)(C)C)CCCC1
Agent: Cl
Product: COCC1(N)CCCC1

Procedure:
This compound was prepared as HCl salt by using procedures analogous to those described for the synthesis of Example 55, Step 2 starting from tert-butyl 1-(methoxymethyl)cyclopentylcarbamate. Analytic LCMS (M+H)+: m/z=144.1.
Reaction SMILES: C(OC1N(CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)C2C(C(O)=O)=CC=CC=2N=1)C.[C:53]([N:59]([CH2:67][C:68]1[CH:73]=[CH:72][C:71]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=2[C:80]2[N:84](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:83]=[N:82][N:81]=2)=[CH:70][CH:69]=1)[C@H:60]([C:64]([OH:66])=[O:65])[CH:61]([CH3:63])[CH3:62])(=[O:58])[CH2:54][CH2:55][CH2:56][CH3:57].[CH3:104][O:105][C@@H:106]1[C@@H:110]([O:111][N+:112]([O-:114])=[O:113])[CH2:109][C@H:108]([C:115]([O:117][CH:118](Cl)[CH3:119])=[O:116])[CH2:107]1.CO[C@@H]1[C@@H](O[N+]([O-])=O)C[C@H](C(O[C@@H](Cl)C)=O)C1>>[C:53]([N:59]([CH2:67][C:68]1[CH:73]=[CH:72][C:71]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=2[C:80]2[NH:84][N:83]=[N:82][N:81]=2)=[CH:70][CH:69]=1)[C@H:60]([C:64]([O:66][C@@H:118]([O:117][C:115]([C@H:108]1[CH2:109][C@H:110]([O:111][N+:112]([O-:114])=[O:113])[C@@H:106]([O:105][CH3:104])[CH2:107]1)=[O:116])[CH3:119])=[O:65])[CH:61]([CH3:63])[CH3:62])(=[O:58])[CH2:54][CH2:55][CH2:56][CH3:57]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@H](C(=O)O)C(C)C
Reactant: CO[C@H]1C[C@@H](C(=O)OC(C)Cl)C[C@@H]1O[N+](=O)[O-]
Agent: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CO[C@H]1C[C@@H](C(=O)O[C@H](C)Cl)C[C@@H]1O[N+](=O)[O-]
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O[C@H](C)OC(=O)[C@@H]1C[C@H](OC)[C@@H](O[N+](=O)[O-])C1)C(C)C

Procedure:
The title compound was prepared by following the procedure for example 2, except that the reagent 2-ethoxy-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid was replaced by N-pentanoyl-N-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-L-valine and 1-chloroethyl (1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylate (intermediate 2) was replaced by (1S)-1-chloroethyl (1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylate (intermediate 3). LC-MS: m/z 667.3 (M+H).
Reaction SMILES: [Cu][C:2]#N.C[Li].[Cl-].C([Al+]CC)C.[O:12]=[C:13]([C:21]1[CH:34]=[CH:33][C:24]2[N:25]=[C:26]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[O:27][C:23]=2[CH:22]=1)/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH3:2][CH:15]([CH2:14][C:13](=[O:12])[C:21]1[CH:34]=[CH:33][C:24]2[N:25]=[C:26]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[O:27][C:23]=2[CH:22]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)/C=C/C(=O)c1ccc2nc(-c3cccs3)oc2c1
Reactant: N#C[Cu]
Agent: CC[Al+]CC
Agent: [Cl-]
Agent: [Li]C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)CC(=O)c1ccc2nc(-c3cccs3)oc2c1
Temperature: -5 °C
Reaction time: 0.75 h

Procedure:
5 ml THF are added to 110 mg (1.23 mmol) copper-(I)-cyanide, the suspension is cooled to −5° C., then 770 μl (1.23 mmol) 1.6M methyl lithium dissolved in THF are added dropwise at a maximum temperature of 0° C., the mixture is stirred for 45 min, then cooled to −70° C. 1.23 ml (1.23 mmol) 1M diethyl aluminium chloride dissolved in hexane are then added dropwise to the reaction mixture, it is stirred for 25 min at −70° C., then are 100 mg (0.31 mmol) ethyl (E)-4-oxo-4-(2-thiophen-2-yl-benzoxazol-6-yl)-but-2-enoate dissolved in 5 ml THF are added dropwise. The reaction solution is then added to sat. ammonium chloride solution and extracted with diethyl ether. The org. phase is concentrated by rotary evaporation i. V. and the residue is purified by RP-HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19].[CH3:22]I.[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:22])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20]
Reactant: CC(C)C(=O)Oc1ccc2c(c1Cl)Sc1ccccc1N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(=O)Oc1ccc2c(c1Cl)Sc1ccccc1N2C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-chloro-3-isobutyryloxy-10H-phenothiazine (see Example 8) (202 mg) in DMF (5 ml) was added methyl iodide (0.2 ml) and sodium hydride (18 mg) at 0° C. The reaction mixture was stirred at ambient temperature for 12 hours. To the reaction mixture was added water and the resulting aqueous layer extracted with EtOAc. The organic layers were collected, dried and evaporated to give a residue which was purified by chromatography on silica gel (plates) to give 100 mg of 4-chloro-3-isobutyryloxy-10-methyl-10H-phenothiazine (m.p. 147° C.).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:30]([CH3:29])(=[O:32])=[O:31])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1cncc(CNc2ccc(OCC3CCCCC3)cc2)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)c1ccc(OCC2CCCCC2)cc1

Procedure:
A 3.5 g. portion of 3-(4-cyclohexylmethoxyphenylaminomethyl)pyridine was dissolved in 15 ml. of dichloromethane, and 2.76 g. of potassium carbonate and 1.55 ml. of methanesulfonyl chloride were added. The mixture was stirred with gentle heating for 20 hours, and was then extracted with aqueous sodium bicarbonate, dried over magnesium sulfate and evaporated under vacuum. The residue was dissolved in chloroform and chromatographed over silica gel, eluting with chloroform. The product-containing fractions were combined and evaporated, and the residue was triturated with diethyl ether, filtered and dried to obtain 2.33 g. of impure product, which was further washed with diethyl ether to obtain 1.88 g. of the desired product, m.p. 36°-140°.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9][C@@H:8]1[C:22]([O:24][CH3:25])=[O:23].ClCCl>CO.O>[OH:3][CH:4]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9][C@@H:8]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)[C@H]1CN(CCCc2ccccc2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)[C@H]1CN(CCCc2ccccc2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 1.25 h
Yield: 87.1 %

Procedure:
0.15 g of sodium borohydride was added portionwise at a temperature in the region of 20° C. and under an inert atmosphere to a stirred solution of 1.59 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine-3-carboxylate in 25 cm3 of methanol. The mixture was subsequently stirred for 75 minutes at a temperature in the region of 20° C. 15 cm3 of distilled water were then added while maintaining the same temperature. The mixture, with a milky appearance, was concentrated under reduced pressure (5 kPa) at a temperature in the region of 30° C. The residue obtained was taken up in 40 cm3 of distilled water to which have been added 80 cm3 of dichloromethane, stirred, and then separated by settling. The organic phase was withdrawn and then washed with one times 40 cm of water and dried over magnesium sulfate. After filtering through paper and then evaporating the solvent under reduced pressure (5 kPa) at a temperature in the region. of 40° C., 1.39 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine-3-carboxylate were obtained in the form of a sticky solid with a foamy appearance and an orange color.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26]#[N:27])[CH2:22][CH2:21]1)[CH3:9])(C)(C)C>CC(O)=O>[NH2:7][C@H:8]([C:10]1[N:19]([C@H:20]2[CH2:25][CH2:24][C@H:23]([C:26]#[N:27])[CH2:22][CH2:21]2)[C:13]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=2[N:11]=1)[CH3:9]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1N[C@H]1CC[C@H](C#N)CC1
Solvent: CC(=O)O
Product: C[C@H](N)c1nc2ccc(F)cc2n1[C@H]1CC[C@H](C#N)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of {(S)-1-[2-(trans-4-cyanocyclohexylamino)-4-fluorophenylcarbamoyl]ethyl}carbamic acid tert-butyl ester (195 mg, 0.48 mmol) in AcOH (2 mL) was heated at 80° C. under a nitrogen atmosphere for 1 h, then at 90° C. for 2 h and finally at 110° C. for 16 h. The volatiles were removed under reduced pressure and the resulting residue dissolved in 6N HCl (5 mL) and heated at reflux temperature for 2 h. The volatiles were removed in vacuo and the resulting residue dissolved in an aqueous solution of NaHCO3 and extracted with EtOAc (×3). The combined organic fractions were washed with water, dried and concentrated in vacuo to afford the title compound as a brown solid (100 mg, 72%). LCMS (Method C): RT 2.01 min [M+H]+ 287.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:17])([C:13]([F:16])([F:15])[F:14])[O:8][C:7](=[O:18])[CH2:6]2.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:17])([C:13]([F:14])([F:15])[F:16])[O:8][CH:7]([OH:18])[CH2:6]2
Reactant: COc1ccc2c(c1)CC(=O)OC2(C)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CC(O)OC2(C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution 6-methoxy-1-methyl-1-trifluoromethyl-isochroman-3-one (1.50 g, 5.76 mmol) in tetrahydrofuran (30 mL) at 0° C. was added sodium borohydride (0.240 g, 6.34 mmol) followed by boron trifluoride diethyl ether complex (0.992 g, 8.07 mmol). The reaction mixture was warmed to room temperature and was stirred overnight. The reaction mixture was added to water (75 mL) and extracted with methyl-tert-butyl ether (75 mL). The layers were separated and the organic layer was washed with 1N aqueous hydrochloric acid (50 mL), dried over magnesium sulfate, filtered, and concentrated to afford 6-methoxy-1-methyl-1-trifluoromethyl-isochroman-3-ol as an oil and a mixture of a and b anomers (1.19 g, 79%). Data reported for the major diastereoisomer. 1H NMR (400 MHz, CDCl3) δ1.74 (s, 3), 2.85 (dd, 1, J=15.7, 4.3), 2.88-2.99 (m, 1), 3.11 (dd, 1, J=15.7, 3.2), 3.80 (s, 3), 5.63 (t, 1, J=3.7), 6.69 (d, 1, J=2.7), 6.82 (dd, 1, J=8.7, 2.7), 7.22-7.27 (m, 1). 13C NMR (100 MHz, CDCl3, data reported for identifiable signals of the major diastereoisomer) δ24.52, 35.46, 55.16, 90.71, 113.11, 113.98, 125.22, 127.57, 132.98, 159.59. IR 3439, 2949,1735, 1613, 1506, 1166, 1141, 1070cm−1