Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([C:10]2[C:14]([S:15][CH3:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:12]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:40])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:5]1[S:6][C:7]([C:10]2[C:14]([S:15]([CH3:16])=[O:40])=[C:13]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:12]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1c(-c2nnc(C(C)(C)C)s2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1c(-c2nnc(C(C)(C)C)s2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a solution of 2-tert-Butyl-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-(methylthio)-1H-pyrazol-3-yl)-1,3,4-thiadiazole (Ia-2) (190 mg, 0.37 mmol) in CH2Cl2 (10 mL) was added m-CPBA (77% Max, 91 mg, 0.41 mmol). The reaction mixture was stirred for 1 hr at room temperature. Saturated NaHCO3 was added to the reaction mixture, then the organic extract was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was subjected to silica gel column chromatography (eluent: hexane/EtOAc=½) to obtain 148 mg (76%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](=O)[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]1([CH3:18])[C:8]2[NH:9][C:4]3[C:5]([C:7]=2[CH2:10][CH2:11][O:12]1)=[CH:6][CH:1]=[CH:2][CH:3]=3
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CC(=O)CCCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(CCCCl)OCCc2c1[nH]c1ccccc21
Reaction time: 1 h

Procedure:
To a solution of tryptophol (15 g, 0.09 M) in 150 ml of benzene, 5-chloro-2-pentanone (12 g, 0.10 M) is added. The mixture is heated in the presence of 200 mg of p-toluenesulfonic acid and hydrated alkali-aluminum silicate (Molecular Sieves No. 4). After 1 hr. of refluxing, 400 mg more of acid is added. After a total of 2 hr. the reaction is cooled, filtered and washed with 5% sodium bicarbonate, water and dried over sodium sulfate. Evaporation under reduced pressure affords an oil. This oil is purified by chromatography on silica gel. Elution with benzene and concentration of the eluent gives 1-(3-chloropropyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, nmr (CDCl3) δ1.33 (3H); 1.93 (4H), 2.75 (2H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[F:9][C:10]([F:19])([F:18])[C:11]1[CH:12]=[C:13](Cl)[CH:14]=[CH:15][CH:16]=1>[Cu]>[F:9][C:10]([F:19])([F:18])[C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: Oc1ccc(O)cc1
Reactant: FC(F)(F)c1cccc(Cl)c1
Agent: [Cu]
Product: Oc1ccc(Oc2cccc(C(F)(F)F)c2)cc1

Procedure:
In an analogous manner to that described in the preceding paragraph, hydroquinone and 3-trifluoromethyl-chlorobenzene in the presence of a catalytic amount of copper powder yield p-(α,α,α-trifluoro-m-tolyloxy)-phenol which distils in the bulb-tube at 140° C./0.05 Torr; nD20 =1.5370.
Reaction SMILES: CN([CH:4]=[CH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=O)C.[NH:15]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[C:16]([NH2:18])=[NH:17].CN1C(=O)CCC1>O>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:18]=[C:16]([NH:15][C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:26])=[O:27])=[CH:21][CH:20]=3)[N:17]=2)=[CH:9][CH:10]=1
Reactant: CN(C)C=CC(=O)c1ccc(Br)cc1
Reactant: N=C(N)Nc1ccc(S(N)(=O)=O)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: NS(=O)(=O)c1ccc(Nc2nccc(-c3ccc(Br)cc3)n2)cc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
A flask is charged with the 1-(4-bromo-phenyl)-3-dimethylamino-propenone (1.05 g, 4.10 mmol), 4-guanidino-benzenesulfonamide (1.33 g, 6.20 mmol), and NMP (30 ml). The reaction mixture is stirred at 120° C. for 20 h. The reaction mixture is cooled to room temperature, diluted with water, and filtered. The solid residue is washed with water and dried to yield 1.66 g of a white solid. MS (ESI) m/z 405.1; HRMS: calcd for C16H13BrN4O2S+H+, 405.00153; found (ESI-FTMS, [M+H]1+), 405.00158.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[CH3:13][NH:14][C:15]1[C:16]([NH2:21])=[N:17][CH:18]=[CH:19][CH:20]=1.[Cl-].[Cl-].[Ca+2]>C1COCC1>[CH3:13][N:14]1[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:21][C:6]1=[O:7]
Reactant: CNc1cccnc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2ncccc21
Yield: 79.7 %

Procedure:
CDI (2.251 g) was added to a solution of N3-methylpyridine-2,3-diamine (1.14 g) in THF (dry) (50 ml) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) over weekend. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give 1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.1 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:23])C(=O)C1>CC(O)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:23][C:5]1[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][N:9]=2)=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Cc1cnc(-c2cccc(Cl)n2)c(C)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1cnc(-c2nc(Cl)ccc2Cl)c(C)c1
Temperature: 120 °C
Reaction time: 20 h
Yield: 69.2 %

Procedure:
A mixture of 6′-chloro-3,5-dimethyl-2,2′-bipyridine (300 mg, 1.37 mmol), NCS (202 mg, 1.51 mmol), and Pd(OAc)2 (31.4 mg, 0.137 mmol) in AcOH (9.15 mL) was heated to 120° C. in a sealed microwave vial using an oil bath. After 20 h, the reaction was removed from heat and concentrated. Took up the residue in EtOAc, filtered off the solid through a glass fiber filter, and washed with 1:1 EtOAc/heptane. The filtrate was concentrated and purified on Biotage 25S column, eluting with 0-25% EtOAc/heptane to get 240 mg (69%) of the title compound as an off-white solid. m/z (APCI+) for C12H10N2Cl2 253.00 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (s, 1 H) 8.16 (d, J=8.59 Hz, 1 H) 7.66 (d, J=8.59 Hz, 1 H) 7.61 (s, 1 H) 2.34 (s, 3 H) 2.08 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:19]1[CH2:27][C:26]2[C:21](=[C:22]([NH2:28])[CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>C1COCC1>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:19]1[CH2:27][C:26]2[C:21](=[C:22]([NH:28][C:34]([CH:31]3[CH2:33][CH2:32]3)=[O:35])[CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1
Reactant: CCOc1cc(C(CC(=O)OC)N2Cc3cccc(N)c3C2=O)ccc1OC(F)F
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)OC)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To the THF solution of 3-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid methyl ester (2.8 g, 7 mmol) was added cyclopropanyl carbonyl chloride (0.72 ml, 8 mmol) dropwise. The reaction mixture was then heated to reflux for 1 hour. The solvent was removed under vacuo. The mixture was dissolved in EtOAc (50 ml) and washed with water (50 ml×2). The organic layer was dried over Na2SO4 and concentrated under vacuo. The resulted solid was stirred with ether (20 ml) for 1 hour and filtered to give a total of 2.5 g (77% yield) white solid which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24]([O:26]C)=O.Cl.[OH-].[NH4+:30]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:30]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1F
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1F
Yield: 65 %

Procedure:
A solution of the 9-[(2,3-difluorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (514 mg, 1.4 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was stirred at room temperature for 94 hours. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 320 mg (65%) of the 9-[(2,3-difluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a yellow solid. 1H NMR (DMSO-d6) δ10.45 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (d, 1H, J=8 Hz), 7.5-7.2 (m, 4H), 7.05 (d, 1H, J=8 Hz), 6.95 (m, 1H), 6.6 (d, 1H, J=8 Hz), 6.35 (t, 1H, J=8 Hz), and 5.9 (s, 2H). IR (KBr, cm−1) 3350, 3125, 1628, 1598, and 1583. MS (ES) m/e 351, 353.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([C:22]([F:25])([F:24])[F:23])=[C:10]2[C:26](O)=[O:27])=[C:5]([O:29][CH3:30])[CH:4]=1)#[N:2].C(N1C=CN=C1)([N:33]1C=CN=C1)=O.N>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([C:22]([F:23])([F:24])[F:25])=[C:10]2[C:26]([NH2:33])=[O:27])=[C:5]([O:29][CH3:30])[CH:4]=1)#[N:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1nccc2c1C(c1ccc(C#N)cc1OC)C(C(=O)O)=C(C(F)(F)F)N2
Agent: N
Solvent: CCOC(C)=O
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC)C(C(N)=O)=C(C(F)(F)F)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
180 mg (0.429 mmol) of the compound from Example 38A are introduced into 5 ml of ethyl acetate and, after addition of 87.0 mg (0.537 mmol) of 1,1′-carbonyldiimidazole, stirred at room temperature for two hours. Complete conversion is established by a TLC check. The volatile components are removed in a rotary evaporator, and the residue is taken up in 4 ml of DMF. Then 597 μl of ammonia (28% by weight solution in water, 4.29 mmol) are added, and the reaction mixture is heated at 100° C. in a closed vessel for three hours. After cooling, the solvent is removed under reduced pressure, and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 10 mg (5% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15]C4(CCN(C)CC4)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1.Cl.Cl.[CH2:30]1[C:34]2(CNC[CH2:36][NH:35]2)[CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15][C:34]4([CH2:30][CH2:31][CH2:32][CH2:33]4)[NH:35][CH2:36][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Reactant: C1CCC2(C1)CNCCN2
Agent: Cl
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCNC4(CCCC4)C3)cc2n1

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using 6,9-diaza-spiro[4.5]decane dihydrochloride in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. The title compound was obtained as a white solid (76 mg, 53%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7]C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Br[CH2:16][CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[NH2:7][CH:4]1[CH2:3][CH2:2][N:1]([CH2:16][CH2:17][OH:18])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC1CCN(CCO)CC1
Temperature: 25 °C
Yield: 94 %

Procedure:
A solution of 0.5 g of tert-butyl 4-piperidinylcarbamate, 0.21 ml of 2-bromoethanol and 2.76 g of K2CO3 in 10 ml of acetonitrile was stirred for 5 hrs under reflux. The reaction mixture was cooled to a room temperature, filtered to remove solids, and concentrated. The concentrate was purified by silica gel column chromatography (mobile phase: 20 (v/v) % EA in hexane) to afford 0.58 g of the title compound (Yield: 94%). 1H NMR (CDCl3) δ 4.76 (d, 1H), 3.65 (t, 2H), 3.48 (m, 1H), 2.92 (m, 2H), 2.59 (t, 2H), 2.26 (m, 2H), 1.94 (m, 2H), 1.52 (m, 2H), 1.44 (s, 9H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[CH3:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][NH2:31])=[N:28][CH:29]=1>COCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([NH:31][CH2:30][C:27]2[CH:26]=[CH:25][C:24]([CH3:23])=[CH:29][N:28]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: Cc1ccc(CN)nc1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cc(N)nc1-c1ccco1
Solvent: COCCOC
Product: Cc1ccc(CNc2cc(N)nc(-c3ccco3)c2C#N)nc1

Procedure:
From trifluoromethanesulfonic acid 6-amino-3-cyano-2-furan-2-yl-pyridin-4-yl ester and C-(5-methyl-pyridin-2-yl)-methylamine in DME. ES-MS m/e (%): 328 (M+Na+, 30), 306 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4]O.[Br:13]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[Br:13][CH2:4][C:3]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=1[F:1]
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1ccc(F)c(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(F)c(CBr)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-fluoro-5-nitrobenzyl alcohol (1 g, 5.84 mmol) in 25 mL ether, was added tetrabromomethane (3.87 g, 11.7 mmol), followed by triphenylphosphine (3.39 g, 11.7 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was concentrated and the crude residue purified by column chromatography (silica, 10% EtOAc/hexane) to give pure 2-bromomethyl-1-fluoro-4-nitro-benzene.
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].C(N(CC)CC)C.[F:21][C:22]([F:29])([F:28])[C:23](OCC)=[O:24]>CO>[F:21][C:22]([F:29])([F:28])[C:23]([NH:5][C@@H:4]1[C@@H:6]([OH:7])[C@H:8]([OH:9])[C@@H:10]([CH2:12][OH:13])[O:11][CH:3]1[OH:2])=[O:24]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
160 g (0.742 mole) of D-(+)-glucosamine hydrochloride were dissolved in 2200 ml of methanol (99.6% purity), and 187.9 g (1.86 mole) of triethylamine were added to the resulting solution. 115.9 g of ethyl trifluoroacetate were then added dropwise to the resulting mixture, whilst ice-cooling, after which the mixture was stirred overnight at room temperature. At the end of this time, the mixture was concentrated by evaporation under reduced pressure, and then benzene (250 ml twice) and ethyl acetate (250 ml) were repeatedly added to the residue, which was then concentrated by evaporation under reduced pressure and then finally dried sufficiently in vacuo. The whole of the resulting crude trifluoroacetyl compound was used in the subsequent step (b) without purification.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11]
Reactant: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@H](N)Cc2ccc(OC)cc2)CC1
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
To 3.7 g (7.16 mmol) of ethyl 1-[(R)-2-tert-butoxycarbonylamino-3-(4-methoxy-phenyl)propionyl]-4-cyclohexylpiperidine-4-carboxylate dissolved in 30 ml of DCM immersed in a bath at 0° C. are added 10 ml of trifluoroacetic acid. After stirring for 1 hour 30 minutes, the solvents are evaporated off. The reaction medium is washed with aqueous 1N sodium hydroxide solution and extracted with DCM. The organic phase is then washed with water and then dried over MgSO4, filtered and concentrated. 2.74 g of ethyl 1-[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexylpiperidine-4-carboxylate in the form of a white powder are obtained in a yield of 92%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:22])[C:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)([OH:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[CH:23]1([CH:30]=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[CH:23]1([CH2:30][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:22])[C:9]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)([OH:16])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:5][CH2:6]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=CC1CCCCCC1
Reactant: O=C(NC1CCNCC1)C(O)(c1ccccc1)C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(NC1CCN(CC2CCCCCC2)CC1)C(O)(c1ccccc1)C1CCCC1
Reaction time: 17 h

Procedure:
34 mg of N-(piperidin-4-yl)-2-cyclopentyl-2-hydroxy-2-phenylacetamide obtained in Step 2 of Example 27, 50 mg of cycloheptanecarbaldehyde and 10 mg of acetic acid were dissolved in tetrahydrofuran. 70 mg of sodium triacetoxyborohydride was added thereto and the resulting mixture was stirred for 17 hours. After the addition of a saturated aqueous solution of sodium bicarbonate, the reaction mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by preparative thin layer chromatography (Kieselgel™, 60F254, Art 5744 (manufactured by E. Merck; developing solvent: chloroform/methanol=10/1) to obtain the title compound.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].Cl.[CH3:15][O:16][C:17](=[O:23])[C@H:18]([CH:20]([CH3:22])[CH3:21])[NH2:19].CN1CCOCC1>C(Cl)Cl>[CH3:15][O:16][C:17](=[O:23])[C@H:18]([CH:20]([CH3:22])[CH3:21])[NH:19][C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 66.1 g (0.328 mol) of 4-nitrophenyl chloroformate in 1.2 liters of CH2Cl2 was cooled to 0° C. and treated with L-valine methyl ester hydrochloride. The resulting mixture was treated slowly, with stirring, with 68.9 ml (0.626 mol) of 4-methylmorpholine. The resulting solution was allowed to slowly warm to ambient temperature and was stirred overnight. After washing with 3 portions of 10% aqueous NaHCO3, the solution was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography by eluting with chloroform to provide the desired compound. 1H NMR (DMSO-d6) δ0.94 (d, J=7 Hz, 3H), 0.95 (d, J=7 Hz, 3H), 2.12 (octet, J=7 Hz, 1H), 3.69 (s, 3H), 4.01 (dd, J=8, 6 Hz, 1H), 7.41 (dt, J=9, 3 Hz, 2H), 8.27 (dt, J=9, 3 Hz, 2H), 8.53 (d, J=8 Hz, 1H). Mass spectrum: (M+NH4)+ =314.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[C@@H:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1>>[C@@H:13]1([NH:23][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
3-(Trifluoromethyl)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:47]1[CH:46]=[C:45]3[C:48]([CH2:55][C:56]4[CH:61]=[CH:60][C:59]([CH2:62][CH3:63])=[CH:58][CH:57]=4)=[C:49]([Si](C)(C)C)[S:50][C:44]3=[CH:43][C:42]=1[CH2:41][O:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:67])(=O)=O.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:47]1[CH:46]=[C:45]3[C:48]([CH2:55][C:56]4[CH:61]=[CH:60][C:59]([CH2:62][CH3:63])=[CH:58][CH:57]=4)=[C:49]([Cl:67])[S:50][C:44]3=[CH:43][C:42]=1[CH2:41][O:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(Cc2c([Si](C)(C)C)sc3cc4c(cc23)[C@]2(OC4)O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCc1ccc(Cc2c(Cl)sc3cc4c(cc23)[C@]2(OC4)O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 43.1 %

Procedure:
(3′R,4′S,5S,5′S,6′R)-3′,4′,5′-tris-benzyloxy-6′-benzyloxymethyl-3-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydro-2-trimethylsilyl-spiro[thieno[2,3,f]isobenzofuran-5(7H),2′-[2H]pyran] (0.122 g, 0.139 mmol) was dissolved in acetonitrile (0.93 mL). Sulfuryl chloride (20.6 mg, 0.153 mmol) was added to the resultant solution, and then the solution was stirred for 3.5 hours at room temperature. Saturated aqueous sodium hydrogen carbonate was added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography (developing solution=ethyl acetate:n-hexane (1:11.5)), to thereby obtain the titled compound (50.2 mg, 43%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19]([N:32]3[CH2:31][CH2:30][C:29]([C:26]4[CH:27]=[CH:28][C:23]([Br:22])=[CH:24][CH:25]=4)([OH:35])[CH2:34][CH2:33]3)=[O:21])=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Product: O=C(Nc1ccc(F)cc1)c1cnc(OCC(=O)N2CCC(O)(c3ccc(Br)cc3)CC2)nc1
Yield: 84 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 4-(4-bromophenyl)-piperidin-4-ol (56 mg, 0.22 mmol) as the coupling partner. Concentration (no chromatography) yielded 76 mg (84%) of the titled compound. ESI-MS m/z 530, 532 (MH+), 527, 529 (M−H−).