Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]([CH:7]1[CH2:10][C:9](=[C:11]([C:22]([O:24][CH3:25])=[O:23])[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8]1)=[O:6]>O1CCCC1>[CH3:3][O:4][C:5]([C@@H:7]1[CH2:10][C@H:9]([CH:11]([C:22]([O:24][CH3:25])=[O:23])[C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:8]1)=[O:6]
Reactant: COC(=O)C(C(=O)OCc1ccccc1)=C1CC(C(=O)OC)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OCc1ccccc1)[C@H]1C[C@@H](C(=O)OC)C1
Temperature: 0 °C

Procedure:
Sodium borohydride (4.28 g, 0.11 mol) was added portionwise to a stirred solution of benzyl methyl 3-methoxycarbonylcyclobutylidenemalonate (30 g, 0.09 mol) in dry tetrahydrofuran (200 ml) cooled to 0° C. The cooling bath was then removed and after 20 minutes water (300 ml) was added. The mixture was extracted with diethyl ether (3×200 ml) and the combined extracts washed with brine solution. The organic phase was dried, filtered and evaporated to a colourless oil (27.0 g). Chromatography on flash silica eluting with hexane-ether (9:1 then 8:2 then 7:3) gave the title compound as a colourless oil).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)CCC.[Cl-].[Li+]>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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[CH2:11][N:6]1[C:7]2[C:3](=[C:2]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[C:5]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1cc2c(Br)cccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Product: CCOC(=O)c1cc2c(-c3ccccn3)cccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 105 °C
Yield: 53.6 %

Procedure:
Ethyl 4-bromo-N-(3,4-dichlorobenzyl)indole-2-carboxylate (0.15 g), 2-(tri-n-butylstannyl)pyridine (0.155 g), lithium chloride (30 mg) and tetrakis triphenylphosphine-palladium(0) (15 mg) were dissolved in anhydrous degassed toluene under argon and warmed at 105° C. for 16 hours. The reaction was then cooled to room temperature and partitioned between water and dichloromethane. Combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography using i-hexane-30% ethyl acetate as eluent to give the desired end product as a white solid (0.08 g, 54%); M/z (+) 425 (M+).
Reaction SMILES: [I-].[I:2][C:3]1[CH:4]=[C:5]([I:15])[C:6]2[O:10]C(=[N+](C)C)[S:8][C:7]=2[CH:14]=1.[OH-].[Na+]>CO>[I:15][C:5]1[CH:4]=[C:3]([I:2])[CH:14]=[C:7]([SH:8])[C:6]=1[OH:10]
Reactant: C[N+](C)=c1oc2c(I)cc(I)cc2s1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1c(S)cc(I)cc1I
Yield: 69.4 %

Procedure:
An amount of 13 g (23.3 m mol) of N-(5,7-diiodo-1,3-benzoxathiol-2-ylidene)-N-methylmethanaminium iodide was heated at reflux for 4 hours in a mixture of 200 ml of methanol and 50 ml of aqueous 10 percent sodium hydroxide. The reaction mixture was filtered, added to 400 ml of water and acidified with hydrochloric acid. The mixture was extracted with methylene chloride. After drying over anhydrous sodium sulfate, the methylene chloride extract was condensed in vacuo to give 6.1 g (69.4 percent yield) of 2,4-diiodo-6-mercaptophenol: M.P. 177.5°-179.5° C; nmr (DMSO-d6) δ 7.96 (doublet), 7.57 (doublet), and 3.42 (broad singlet).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:34])([CH3:33])[CH:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:13])(=[O:7])=[O:6].[N-:35]=[N+:36]=[N-:37].[Na+]>CS(C)=O>[N:35]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:34])([CH3:33])[CH:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:13])(=[O:7])=[O:6])=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(COC(C(=O)OCCN2CCOCC2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(COC(C(=O)OCCN2CCOCC2)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-])cc1

Procedure:
Following the general procedure for the preparation of azides of Description 16, 2-morpholin-4-ylethyl (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoate (27a) (0.22 g, 0.42 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 68 mg (1.0 mmol) of sodium azide (NaN3). After work-up, the crude material (27b) was used in the next step without further purification. MS (ESI) m/z 523.07 (M+H)+.
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15](=O)[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl.[CH3:22][O:23][NH2:24].N1C=CC=CC=1>C(O)C>[CH3:22][O:23][N:24]=[C:15]([C:13]1[S:14][C:10]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)=[CH:11][CH:12]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCC(=O)c1ccc(-n2cnc3ccccc32)s1
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCC(=NOC)c1ccc(-n2cnc3ccccc32)s1

Procedure:
To the solution of compound (84) (0.703 mmoles) in Ethanol (10 ml) was added N-methoxy amine HCl (2.878 m.moles) and Pyridine (2.844 m.moles) at ambient temp. The reaction mass was heated to reflux for 2.0 hrs. After completion of reaction, distilled off the solvent completely, added Water (20 ml) and the product was extracted in ethyl acetate (2×100 ml), washed with 10% brine and dried over sodium sulphate. The solvent was distilled completely under reduced pressure to get the crude compound. This crude compound was purified by preparative HPLC to get the pure isomers (88 & 89).
Reaction SMILES: [OH-].[Na+].[C:3](Cl)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[CH:26]=[CH:27]/[C:28]2[N:42]=[C:31]3[CH:32]([CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH2:33][CH2:34][CH2:35][N:30]3[N:29]=2)[CH:17]=[CH:18][C:19]=1[N:20]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]1>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[CH:26]=[CH:27]/[C:28]2[N:42]=[C:31]3[CH:32]([CH:36]4[CH2:37][CH2:38][N:39]([C:4]5([CH:3]=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]5)[CH2:40][CH2:41]4)[CH2:33][CH2:34][CH2:35][N:30]3[N:29]=2)[CH:17]=[CH:18][C:19]=1[N:20]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCNCC2)ccc1-n1cnc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCN(C3(C=O)C=CC=CC3)CC2)ccc1-n1cnc(C)c1

Procedure:
A 1 N sodium hydroxide solution (0.5 ml) and benzoyl chloride (11 ul) were added to a solution of racemic 2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperidin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine obtained in Examples 118 and 119 (20 mg) in methylene chloride (1 ml), and the reaction solution was stirred under ice-cooling for four hours. Methylene chloride was added to the reaction solution, and the organic layer was separated. The aqueous layer was reextracted with methylene chloride. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 19 mg of racemic 1-[4-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)piperidin-1-yl]phenylmethanone. Then, the racemate was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: 50% ethanol-hexane) to obtain the title optically active compound with a retention time of 16 minutes and positive optical rotation (6.9 mg; 100% ee) and the title optically active compound with a retention time of 22 minutes and negative optical rotation (6.8 mg; >99% ee).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:34]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([C:16]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:35](=[O:36])[C:34]4[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:33]=4[CH3:32])=[CH:21][CH:22]=3)=[O:24])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1
Reactant: Cc1nc2c(s1)CCN(C(=O)c1ccc(N)cc1)c1ccccc1-2
Reactant: Cc1ccc(F)cc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2c(s1)CCN(C(=O)c1ccc(NC(=O)c3cc(F)ccc3C)cc1)c1ccccc1-2
Reaction time: 18 h

Procedure:
To a stirred solution of 0.235 g of 5,6-dihydro-2-methyl-6-(4-aminobenzoyl)4H-thiazolo[5,4-d][1]-benzazepine in 6 ml of methylene chloride under argon is added 107 μl of triethylamine followed by the dropwise addition of 2-methyl-5-fluorobenzoyl chloride in 1 ml of methylene chloride. Stirring is continued at room temperature for 18 hours. The reaction mixture is washed with H2O, saturated NaHCO3 and brine. The organic layer is treated with activated carbon, filtered through MgSO4 and the filtrate evaporated in vacuo to a residue which is chromatographed on silica gel by elution with 15% ethyl acetate in methylene chloride to give 300 mg of the desired product as a white solid; Anal. Calc'd for C27 H22FN3O2S: C,68.8; H,4.7; N,8.9; F,4.0; S,6.8 Found: C,67.7; H,4.6; N,8.5; F,3.7; S,6.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[CH3:16][N:17]1[C@H:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[NH:19][C:18]1=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:16][N:17]1[CH:21]2[CH2:22][CH2:23][CH2:24][CH:20]2[N:19]([C:2]2[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][N:3]=2)[C:18]1=[O:25]
Reactant: Brc1ccc(C#Cc2ccccc2)cn1
Reactant: CN1C(=O)N[C@@H]2CCC[C@@H]21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN1C(=O)N(c2ccc(C#Cc3ccccc3)cn2)C2CCCC21
Temperature: 70 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a suspension of 2-bromo-5-(phenylethynyl)pyridine (Example 96, step 1) (55.0 mg, 0.213 mmol), (3aR,6aS)-1-methylhexahydrocyclopenta[d]imidazol-2(1H)-one (Example 106, step 3) (35.8 mg, 0.256 mmol, 1.2 equiv.), 139 mg cesium carbonate (139 mg, 0.426 mmol, 2 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) (5 mg, 0.008 mmol, 0.04 equiv.) in 1 ml of toluene was added under argon atmosphere tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (4 mg, 0.0046 mmol, 0.02 equiv.). The mixture was stirred overnight at 70° C. The mixture was directly loaded on a 20 g silicagel column and was eluted with a heptane to 33% ethylacetate in heptane gradient to yield the title compound (49 mg, 73%) as an amorphous light-yellow solid, MS: m/e=318.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].[C:19](OC(C)(C)C)(=[O:24])[CH2:20][C:21]([CH3:23])=[O:22]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:11])=[O:12])[CH2:7][N:6]1[C:19](=[O:24])[CH2:20][C:21](=[O:22])[CH3:23])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1C(=O)CC(C)=O

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-4-benzenesulfonyl-pyrrolidine-2-carboxylic acid methyl ester was reacted with tert-butyl acetoacetate to give the title compound as yellow solid.
Reaction SMILES: N1(C(=O)C(N2C=CN=C2)=O)C=CN=C1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:31]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([CH:43]=[N:44]O)[CH:28]=3)[C:23]2=[O:46])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.ClCCCl.C(OCC)(=O)C>[C:43]([C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:46])[N:22]([C:19]1[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=1)[C:31]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:30]2)#[N:44]
Reactant: CC(C)(C)OC(=O)CCCCc1cc2cc(C=NO)ccc2c(=O)n1-c1ccc(F)cc1
Agent: O=C(C(=O)n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CCCCc1cc2cc(C#N)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
1,2-di-(1H-imidazol-1-yl)ethane-1,2-dione (130 mg, 0.684 mmol) was added to a stirred, room temperature mixture of tert-butyl 5-(2-(4-fluorophenyl)-6-((hydroxyimino)methyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (200 mg, 0.456 mmol) in toluene (6.00 mL) and 1,2-dichloroethane (2 mL) and the mixture was stirred at 80° C. for 2 h. The mixture was cooled, diluted with ethyl acetate (20 mL), washed with aqueous sodium hydrogen carbonate (1 M, 1×15 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to give tert-butyl 5-(6-cyano-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (185 mg, 0.440 mmol) as a yellow gum.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:21])([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[CH2:22]([N:29]1[CH2:34][CH:33]=[C:32]([C:35]2[N:40]=[C:39](Cl)[CH:38]=[CH:37][N:36]=2)[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]1[CH2:30][CH:31]=[C:32]([C:35]2[N:36]=[C:37]([C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:11]([CH3:21])([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:12])=[N:10][C:5]4=[N:4][CH:3]=3)[CH:38]=[CH:39][N:40]=2)[CH2:33][CH2:34]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(Br)cnc2n1
Reactant: Clc1ccnc(C2=CCN(Cc3ccccc3)CC2)n1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(C4=CCN(Cc5ccccc5)CC4)n3)cnc2n1

Procedure:
3-Bromo-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (287 mg, 0.77 mmol) and 2-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-4-chloropyrimidine: (266 mg, 0.93 mmol) were reacted together as described in Example 39, Step 1. Purification by column chromatography on silica, using 4-7.5% MeOH/CH2Cl2, gave 3-[2-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine: m/z (ES+) 540 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1([N:29]([CH3:31])[CH3:30])[CH2:13][CH2:12][C:11]([C:14]2[NH:15][C:16]3[C:21]([C:22]=2[CH3:23])=[CH:20][C:19]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:18][CH:17]=3)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.C(O)C.[Pd]>[CH2:1]([C:8]1([N:29]([CH3:31])[CH3:30])[CH2:9][CH2:10][CH:11]([C:14]2[NH:15][C:16]3[C:21]([C:22]=2[CH3:23])=[CH:20][C:19]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:18][CH:17]=3)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C2=CCC(Cc3ccccc3)(N(C)C)CC2)[nH]c2ccc(OC(F)(F)F)cc12
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Cc1c(C2CCC(Cc3ccccc3)(N(C)C)CC2)[nH]c2ccc(OC(F)(F)F)cc12
Reaction time: 4 h

Procedure:
(±)-N-[1-Benzyl-4-(3-methyl-5-trifluoromethoxy-1H-indol-2-yl)cyclohex-3-enyl]-N,N-dimethylamine (230 mg, 0.53 mmol) was dissolved in methanol (40 ml) and ethanol (10 ml), while heating, and Pd/C (5%, 100 mg) was added under argon. Hydrogenation was carried out at 40° C. under 3 bar for 4 h. The catalyst was then filtered off with suction over Celite and the filtrate was concentrated. The solid colourless residue (227 mg) was separated by chromatography [silica gel 60 (30 g); ethyl acetate/methanol (20:1; 400 ml); (4:1; 500 ml) (2:1; 300 ml)]. 1-Benzyl-N,N-dimethyl-4-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)cyclohexanamine (more polar diastereomer) was obtained in a yield of 175 mg (77%) as a colourless solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.Cl[Si](C)(C)C.[F:26][C:27]([F:37])([F:36])[C@H:28]([CH3:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].[Br:38]N1C(=O)CCC1=O>CCCCCC.O.C1COCC1>[Br:38][CH:29]([C@@H:28]([CH3:35])[C:27]([F:36])([F:37])[F:26])[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)C[C@@H](C)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Br)[C@@H](C)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
91.2 ml (228 mmol) of a 2.5 M solution of n-butyllithium solution in hexane were added to a solution, cooled to −40° C., of 32.0 ml (228 mmol) of diisopropylamine in 160 ml of abs. THF. The resulting LDA solution was stirred at −40° C. for 30 min and then cooled to −78° C., and 52.4 ml (413 mmol) of chlorotrimethylsilane were subsequently added dropwise. After 5 min, 40.0 g (217.2 mmol) of (+)-ethyl (3R)-4,4,4-trifluoro-3-methylbutanoate, dissolved in 40 ml of abs. THF, were added dropwise over a period of 1 h. At −78° C., in three portions a total of 40.59 g (228 mmol) of N-bromosuccinimide were added to the resulting suspension, and the mixture was then slowly warmed to RT overnight. Water was added carefully, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed successively with 1 N hydrochloric acid, sat. sodium bicarbonate solution and sat. sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure without heating. 130 ml of diethyl ether were added to the resulting suspension, and the mixture was kept at 4° C. overnight. The undissolved solid formed was then filtered off and discarded. The filtrate was concentrated under reduced pressure without heating and the residue was briefly dried under high vacuum. This gave 48.5 g of ethyl (3S)-2-bromo-4,4,4-trifluoro-3-methylbutanoate (diastereomer mixture) as a crude product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([CH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](CNC(=O)OC(C)(C)C)Cc1cc(Cl)ccc1OC
Solvent: CC#N
Product: COC(=O)C(CNC(=O)OC(C)(C)C)Cc1cc(Cl)ccc1OC
Yield: 91.3 %

Procedure:
To a solution of methyl (2R)-3-[(tert-butoxycarbonyl)amino]-2-(5-chloro-2-methoxybenzyl)propanoate (1.0 g, 98%ee) in acetonitrile (10 ml), 1,8-diazabicyclo[5.4.0]undecene-7 (510.5 mg) was added and the mixture was stirred under heating and refluxed for 5 hours. After the solvent was distilled off in vacuo, ethyl acetate was added to the obtained residue, and the organic layer was washed with 1N hydrochloric acid, and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, and the residue was purified by silica gel column chromatography to obtain the title compound (913 mg, 0%ee) as an oily substance. The 1H-NMR spectral data matches with those of Example 316.
Reaction SMILES: F[B-](F)(F)F.C[O+:7]([CH3:9])[CH3:8].[F:10][C:11]([F:52])([F:51])[C:12]1[CH:13]=[C:14]([C@H:22]([N:24]([CH3:50])[C:25]([N:27]2[CH2:41][CH2:40][C@:30]3([NH:34]C(=O)[CH:32]([C:36]([O:38][CH3:39])=[O:37])[CH2:31]3)[CH2:29][C@@H:28]2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[CH3:49])=[O:26])[CH3:23])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1>ClCCl>[F:52][C:11]([F:10])([F:51])[C:12]1[CH:13]=[C:14]([C@H:22]([N:24]([CH3:50])[C:25]([N:27]2[CH2:41][CH2:40][C@:30]3([N:34]=[C:8]([O:7][CH3:9])[CH:32]([C:36]([O:38][CH3:39])=[O:37])[CH2:31]3)[CH2:29][C@@H:28]2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[CH3:49])=[O:26])[CH3:23])[CH:15]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:17]=1
Reactant: C[O+](C)C
Reactant: COC(=O)C1C[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)NC1=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)C1C[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N=C1OC

Procedure:
A solution of Trimethyloxonium tetrafluoroborate (10.35 mg, 0.070 mmol) and methyl (5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-oxo-1,8-diazaspiro[4.5]decane-3-carboxylate (Intermediate 35, 36 mg) in Dichloromethane (DCM) (2 ml) was stirred at rt for 2 hrs. The mixture was washed with NaHCO3 saturated solution and the aqueous layer was extracted with DCM. The organic layers were combined, filtered through a phase separator tube and concentrated obtaining the intermediate methyl(5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methy)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-(methyloxy)-1,8-diazaspiro[4.5]dec-1-ene-3-carboxylate:
Reaction SMILES: [NH2:1][C:2]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.C(N1CCCCC1)C.[N+](C1C=CC([O:30][C:31](=O)[CH2:32][NH:33][C:34](=[O:48])[C@H:35]([CH3:47])[NH:36][C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])=CC=1)([O-])=O>CN(C)C=O>[CH2:40]([O:39][C:37]([NH:36][C@H:35]([C:34]([NH:33][CH2:32][C:31]([CH:3]1[CH2:4][CH2:5][CH2:6][C:2]1([NH2:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:30])=[O:48])[CH3:47])=[O:38])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C1(N)CCCC1
Agent: CCN1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C1(N)CCCC1C(=O)CNC(=O)[C@H](C)NC(=O)OCc1ccccc1
Reaction time: 12 h
Yield: 67 %

Procedure:
To a dimethylformamide (25 ml) solution of ethyl 1-amino-1-cyclopentanecarboxylate liberated from its hydrochloride (1.0 g, 5 mmoles) with N-ethylpiperidine (0.7 ml) there was portionwise added benzyloxycarbonylalanyl-glycine p-nitrophenyl ester (2.1 g, 5 mmoles). After 3 hours of stirring and 12 hours of standing at room temperature the solution was evaporated, the residue was taken into ethyl acetate and extracted successively with 1% ammonia and water, dried over anhydrous sodium sulfate and evaporated. The residue was crystallized from ethyl acetate-petroleum ether to give 1.4 g (67%) of the title product, m.p. 119° to 121° C. An analytical sample was crystallized similarly, m.p. 137° to 139° L C. [α]D20 -3.4°.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C@@H:17]1[CH2:21][S:20][C@@H:19]([CH2:22][SH:23])[CH2:18]1)=[O:16])=O)(C)(C)C.[ClH:24]>C(OCC)(=O)C>[ClH:24].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C@@H:17]1[CH2:21][S:20][C@@H:19]([CH2:22][SH:23])[CH2:18]1)=[O:16]
Reactant: CC(C)(C)OC(=O)NCCCCCNC(=O)[C@@H]1CS[C@@H](CS)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCCCCNC(=O)[C@@H]1CS[C@@H](CS)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
(2R,4R)-N-(5-tert-butoxycarbonylaminopentyl)-2-mercaptomethyl-4-tetrahydrothiophenecarboxamide (compound No. 20-4, 35 mg) was added to 2.3N ethyl acetate solution of hydrogen chloride (3 ml) and the mixture was stirred for 2 hours at room temperature. The mixture was concentrated in vacuo and the oily residue was purified by a silica gel column chromatography to give 11.3 mg (39%) of the titled compound (compound No. 21-1).