Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH2:12][CH:11]([CH2:13][O:14][C:15]2[C:24]([CH:25]3[CH2:27][CH2:26]3)=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([F:28])[CH:16]=2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[C:1]([N:9]1[CH2:10][CH:11]([CH2:13][O:14][C:15]2[C:24]([CH:25]3[CH2:26][CH2:27]3)=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([F:28])[CH:16]=2)[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C2CC2)c(OCC2CN(C(=O)c3ccccc3)C2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(C2CC2)c(OCC2CN(C(=O)c3ccccc3)C2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
A mixture of methyl 4-((1-benzoylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate (70 mg, 0.18 mmol) and lithium hydroxide (22 mg, 0.91 mmol) in THF (5 mL) and H2O (10 ml) was stirred at room temperature for 18 h. The mixture was quenched with HCl (1N, 2 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to get the target compound (50 mg, 74%) as a yellow solid. LCMS (ESI) m/z: 370.1 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:22][CH3:23])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=3)=[CH:4][CH:3]=1.Cl[CH2:25][C:26]([N:28]=[C:29]=[O:30])=[O:27].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[O:30]=[C:29]1[NH:28][C:26](=[O:27])[CH2:25][N:1]1[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:22][CH3:23])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=3)=[CH:6][CH:7]=1
Reactant: CCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(CC)c2c1
Reactant: O=C=NC(=O)CCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CCOc1ccc2c(C#N)c(-c3ccc(N4CC(=O)NC4=O)cc3)n(CC)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
A solution of 2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (319 mg, 1.04 mmol) in 1,4-dioxane (3 mL) is treated with chloroacetyl isocyanate (0.10 mL, 1.17 mmol), and the resulting solution is warmed to 60° C. overnight. The solution is cooled, and DBU (0.20 mL, 1.31 mmol) is added. This mixture is stirred at ambient temperature overnight, and then is partitioned between water and ethyl acetate (50 mL each). The organic layer is washed with saturated brine, and then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is triturated with ether, and the resulting solid is collected by filtration and dried under high vacuum to afford the title product (319 mg, 0.821 mmol, 79%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][N:32]2[CH:31]=[CH:30][N:29]=[C:28]2[CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][C:10]2[CH:18]=[C:17]([CH3:19])[C:16]3[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=3)[CH:11]=2)=[CH:37][CH:36]=1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2ccc(F)cc2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (34.4 mg, 0.073 mmol), 4-fluorobenzyl bromide (10.5 μL, 0.084 mmol, 1.05 equiv), and potassium carbonate (25.0 mg, 0.18 mmol) were combined in dimethylformamide (1.0 mL). After stirring at room temperature for 16 h, the solvents were removed and the residue purified by column chromatography to afford 28.8 mg (68%). Mass spec.: 580.42 (MH)+.
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])C=C[CH:4]=[CH:3][CH:2]=1.C(S)CCC.CC[O-].[Na+].BrCC(OCC)=O>C(O)C>[CH2:1]([S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CSc1ccccc1
Agent: CCOC(=O)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCCCS
Solvent: CCO
Product: CCCCSCC(=O)OCC

Procedure:
The procedure is as in Example 2 for the preparation of ethyl (phenylthio)acetate, starting with n-butylmercaptan (10.7 cc), a 2M ethanolic solution of sodium ethylate (50 cc) and ethyl bromoacetate (16.7 g) in ethanol (100 cc). Ethyl (n-butylthio)acetate (15.4 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[N:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:5]1.FC(F)(F)CN1C(=O)C=NC(C2C=CC=CC=2)=N1.[CH2:38]([SH:41])[CH2:39][CH3:40]>C(OCC)(=O)C>[F:19][C:2]([F:1])([F:18])[CH2:3][N:4]1[C:9](=[O:10])[CH:8]([S:41][CH2:38][CH2:39][CH3:40])[NH:7][C:6]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[N:5]1
Reactant: O=c1cnc(-c2ccc(Cl)cc2)nn1CC(F)(F)F
Reactant: CCCS
Agent: O=c1cnc(-c2ccccc2)nn1CC(F)(F)F
Solvent: CCOC(C)=O
Product: CCCSC1NC(c2ccc(Cl)cc2)=NN(CC(F)(F)F)C1=O
Reaction time: 1 h
Yield: 55 %

Procedure:
A solution of 1-(2,2,2-trifluoroethyl)-3-(4-chlorophenyl)-1,2,4-triazin-6-one (0.40 g, 1.4 mmol), prepared in a similar manner to Compound 7 in 5 mL of ethyl acetate was treated with excess propanethiol at room temperature. The reaction mixture was stirred for 1 hour, then more ethyl acetate was added. The reaction mixture was washed with aqueous potassium carbonate (twice), water and brine, dried over magnesium sulfate, filtered and stripped. The resultant solid was recrystallized from methylene chloride/hexane to give 0.28 g of pale yellow crystals (55% yield), mp 99-100° C.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:4][NH:3]1.CS(C1C=CC(N2C=CC(OC3CCN(C(OC(C)(C)C)=O)CC3)=CC2=O)=CC=1)(=O)=O>>[NH:12]1[CH2:13][CH2:14][CH:9]([O:8][C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:1])[CH:7]=2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc[nH]c(=O)c2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Product: O=c1cc(OC2CCNCC2)cc[nH]1

Procedure:
4-(Piperidin-4-yloxy)pyridin-2(1H)-one was prepared according to procedures described in Example 106 Step A substituting tert-butyl 4-(2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate for tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate. MS (ESI) 195 (M+H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Si]([O:32][CH2:33][CH2:34][C:35]1[C:36]([F:53])=[C:37]([CH:50]=[CH:51][CH:52]=1)[CH2:38][N:39]1[CH2:49][CH2:48][C:42]2([O:47][CH2:46][CH2:45][NH:44][CH2:43]2)[CH2:41][CH2:40]1)(C(C)(C)C)(C)C.[CH:54]([C:57]1[N:62]=[C:61]([C:63](O)=[O:64])[CH:60]=[CH:59][CH:58]=1)([CH3:56])[CH3:55].C(N(CC)CC)C>CN(C=O)C>[F:53][C:36]1[C:35]([CH2:34][CH2:33][OH:32])=[CH:52][CH:51]=[CH:50][C:37]=1[CH2:38][N:39]1[CH2:40][CH2:41][C:42]2([O:47][CH2:46][CH2:45][N:44]([C:63]([C:61]3[CH:60]=[CH:59][CH:58]=[C:57]([CH:54]([CH3:56])[CH3:55])[N:62]=3)=[O:64])[CH2:43]2)[CH2:48][CH2:49]1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reactant: CC(C)c1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.20 g) was added to a solution of 9-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-1-oxa-4,9-diazaspiro[5.5]undecane (example 78, step d) (0.17 g), 6-isopropylpicolinic acid (example 85, step d) (0.07 g) and triethylamine (0.22 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL). The organic phase was separated, washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The residue was dissolved in THF (10 mL) and a solution of TBAF in THF (1M, 0.8 mL) was added. The resulting mixture was stirred for 2 h and the solvent evaporated. Purification was by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (50 mL) was added and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.2 g.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[CH:10]=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[CH2:13]=[CH:14][CH:15]=[CH2:16]>>[CH2:13]1[C:10]2[C:11](=[O:12])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7](=[O:8])[C:9]=2[CH2:16][CH2:15][CH2:14]1
Reactant: C=CC=C
Reactant: O=C1C=CC(=O)c2ccccc21
Product: O=C1C2=C(CCCC2)C(=O)c2ccccc21

Procedure:
A process has now been found for the isolation of purified anthraquinone from the crude anthraquinone which has been obtained by oxidation of naphthalene to give naphthoquinone, reaction of the oxidation product with butadiene to give tetrahydroanthraquinone, oxy-dehydrogenation of this reaction product with molecular oxygen to give a crude anthraquinone and optionally removal of naphthalene, phthalic anhydride and low-boiling substances from this crude anthraquinone, which is characterised in that the crude anthraquinone is treated with an oxygen compound of the elements of the first and/or second main group of the periodic system at an elevated temperature, optionally in the presence of a solvent, and purified anthraquinone is then isolated by subliming the anthraquinone present at a temperature of about 190° to about 290° C. and a pressure of about 1 to about 90 mm Hg and then desubliming it under the same pressure, or by vaporising the pretreated anthraquinone at a temperature of about 290° to about 380° C. and a pressure of about 90 to about 760 mm Hg and condensing the vapour under a pressure of about 90 to about 760 mm Hg.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][N:30]=[N+]=[N-])[O:26][C:25]3=[O:33])=[CH:20][C:19]=2[F:34])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][NH2:30])[O:26][C:25]3=[O:33])=[CH:20][C:19]=2[F:34])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(NC3CCN(C(=O)OCc4ccccc4)CC3)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@H]1CN(c2ccc(NC3CCN(C(=O)OCc4ccccc4)CC3)c(F)c2)C(=O)O1

Procedure:
A solution of 2.51 g (5.35 mmol) 4-[4-{(5R)-5-azidomethyl2-oxo-oxazolidin-3-yl}-2-fluoro-phenylamino]-piperidine-1-carboxylic acid benzyl ester, 1.54 g (5.88 mmol) triphenylphosphine and 964 μl (53.5 mmol) water in 30 ml THF was stirred at 50° C. for 16 h.
Reaction SMILES: Cl[C:2]1N=C2C(=CC=1OCC)C=C1N2C(C)CNC1.[C:19]([O:23][C:24]([N:26]1[CH2:38][C@@H:37]([CH3:39])[N:36]2[C@H:28]([CH2:29][C:30]3[C:35]2=[N:34][C:33]([C@@H:40]([O:42][CH3:43])[CH3:41])=[C:32]([CH2:44][OH:45])[CH:31]=3)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].[H-].[Na+].CI>>[C:19]([O:23][C:24]([N:26]1[CH2:38][C@@H:37]([CH3:39])[N:36]2[C@H:28]([CH2:29][C:30]3[C:35]2=[N:34][C:33]([C@@H:40]([O:42][CH3:43])[CH3:41])=[C:32]([CH2:44][O:45][CH3:2])[CH:31]=3)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOc1cc2cc3n(c2nc1Cl)C(C)CNC3
Reactant: CO[C@@H](C)c1nc2c(cc1CO)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COCc1cc2c(nc1[C@H](C)OC)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to example 1, intermediate d) from (4R,9aR)-7-hydroxymethyl-6-(1-(S)-methoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and methyl iodide.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:22])[C:16](=[O:21])C(O)(C)C)[NH:13][C:12]1=[O:23])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:25].[Na+].C(O)(=O)C>O1CCCC1>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:12](=[O:23])[NH:13][C@@H:14]1[C@@H:15]([CH3:22])[C:16]([OH:21])=[O:25])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(C)(C)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)O
Reaction time: 24 h

Procedure:
To a solution of (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-3-hydroxy-1,3-dimethyl-2-oxobutyl]-2-azetidinone (135 mg) in tetrahydrofuran (4 ml) was added 1M solution of sodium periodate buffered with acetic acid (mole ratio 1:1) (7.8 ml) at room temperature and the mixture was stirred for 1 day at the same temperature. The reaction mixture was evaporated, acidified, and extracted twice with dichloromethane. The organic layer was washed twice with brine, dried over magnesium sulfate and evaporated to give (2R)-2-[(2S,3S)-3-{(1R)-1-(t-butyldimethylsilyloxy)ethyl}-4-oxoazetidin-2-yl]propionic acid (85 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.FC(F)(F)C(O)=O.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=[C:4]([NH:35][CH:32]2[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]2)[N:3]=1
Reactant: Nc1nc(Cl)ccc1C(=O)c1ccc(F)cc1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2ccc(C(=O)c3ccc(F)cc3)c(N)n2)CC1

Procedure:
The title compound was prepared from (2-amino-6-chloro-pyridin-3-yl)-(4-fluorophenyl)methanone (Example 37) and 1-methanesulfonyl-piperidin-4-ylamine (Step A, Example 6) using the procedure described in Step B. Example 6. HRMS, observed: 393.1391, Calcd for (M+H)+: 393.1391.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[F:22][C:23]([F:40])([F:39])[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33](O)=[O:34])=[CH:26][CH:25]=1>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:33](=[O:34])[C:32]4[CH:36]=[CH:37][CH:38]=[C:30]([C:27]5[CH:28]=[CH:29][C:24]([C:23]([F:22])([F:39])[F:40])=[CH:25][CH:26]=5)[CH:31]=4)[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (53 mg, 0.189 mmol) and 3-(4-trifluoromethylphenyl)benzoic acid (151 mg, 0.57 mmol) were mixed in THF (5 ml) and the mixture shaken in a varian tube for 15 min at room temperature. Carbodiimde resin (500 mg) was added and shaking continued for 18 h. The solution was filtered off and concentrated under vacuum. The residue was chromatographed on a silica gel flash column eluting with ethyl acetate/hexane (1:1) and the solvent evaporated under vacuum to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-(4-trifluoromethylphenyl)benzamide (67 mg, 67%). NMR; δH CDCl3 8.11,(1H, t), 7.87-7.85,(2H, m), 7.83,(2H, d), 7.77,(1H, m), 7.72,(4H, s), 7.63-7.57,(2H, m), 7.50,(1H, d), 7.41,(2H, d), 7.30,(1H, d), 6.25,(1H, t), 3.34,(2H, m), 2.24,(3H, s), 1.08,(1H, m), 0.57,(2H, m), 0.29,(2H, m). LCMS: retention time 4.01 min, MH+529.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:7])[CH:5]=[O:6].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:15]([N:20]1[CH2:25][CH2:24][CH:23]2[S:26][C:27](=[O:29])[CH:28]=[C:22]2[CH2:21]1)[C:16]([O:18][CH3:19])=[O:17].CN(C)C(Cl)=O>C(OCC)(=O)C.O>[CH3:3][N:4]([CH3:7])[C:5]([O:29][C:27]1[S:26][C:23]2[CH2:24][CH2:25][N:20]([C@@H:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[Cl:8])[C:16]([O:18][CH3:19])=[O:17])[CH2:21][C:22]=2[CH:28]=1)=[O:6]
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1CCC2SC(=O)C=C2C1
Reactant: CN(C)C=O
Agent: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sc(OC(=O)N(C)C)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
In an ice bath, sodium hydride (20 mg, 60%) were added to 6 ml of anhydrous N, N-dimethyl formamide, to which 169 mg of (2S)-methyl 2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3.2-c]pyridine-5(2H,4H,6H)-yl)-acetate (IV-1) was then added. The reaction was naturally warmed to room temperature, stirred for 1 hr, and then cooled to 0° C. 200 μl of N,N-dimethylcarbamoyl chloride was slowly added dropwise. The reaction was naturally warmed to room temperature, and stirred for 3 hrs, and at this time, TLC showed that the raw materials substantially disappeared. The reaction solution was poured into water (30 ml), the aqueous phase was extracted with ethyl acetate (50 ml×3), and the organic phase was dried to obtain a crude product, which was subjected to flash column chromatography (petroleum ether:ethyl acetate=40:3), to obtain (S)-methyl 2-(2-(N,N-dimethylcarbamoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate (I-18) (95 mg). Yield: 45%, mp 96-98° C., ee=93.5% (chiral HPLC analysis conditions were the same as those in Example 10), [α]D20=+34° (c 0.50, MeOH); 1H-NMR (500 MHz, CDCl3) δ 2.73-2.76 (m, 2H), 2.85-2.89 (m, 2H), 2.99 (s, 3H), 3.03 (s, 3H), 3.52 (d, 1H, J=14.3 Hz), 3.63 (d, 1H, J=14.3 Hz), 3.72 (s, 3H), 4.91 (s, 1H), 6.19 (s, 1H), 7.26-7.69 (m, 4H); 13C-NMR (75 MHz, CDCl3) δ 25.03, 36.37, 36.88, 48.18, 50.40, 52.12, 67.87, 111.48, 125.38, 127.12, 129.09, 129.37, 129.76, 129.95, 130.56, 133.80, 134.34, 134.68, 151.04, 171.27; ESI-MS m/z 409.2 [M+H]+; HRMS Calcd for C19H22N2O4SCl [M+H]+ m/z 409.0992. found 409.0989.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:9][C:10]([C:13]1[CH:14]=[C:15]([S:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[S:30][CH2:31][C:32](N(C)CCC2C=CC=CN=2)=[O:33])[CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)([CH3:12])[CH3:11]>>[CH3:22][C:19]([C:17]1[CH:16]=[C:15]([S:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[S:30][CH2:31][C:32]([NH:1][CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[O:33])[CH:14]=[C:13]([C:10]([CH3:9])([CH3:11])[CH3:12])[CH:18]=1)([CH3:20])[CH3:21]
Reactant: CN(CCc1ccccn1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Reactant: NCc1cccnc1
Product: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2SCC(=O)NCc2cccnc2)cc(C(C)(C)C)c1

Procedure:
Substituting 3-(aminomethyl)pyridine for the 2-(2-methylaminoethyl)pyridine of Example 16, and following the procedure described therein, gives trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl]thio]-N-(3-pyridinylmethyl)-acetamide.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH2:21][F:22])([CH2:19][F:20])[O:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][C:6]=12.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.N1C=CC=CC=1>C(O)C>[F:18][C:12]([F:17])([C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([CH2:19][F:20])([CH2:21][F:22])[C@@H:2]([OH:1])[C@H:7]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:6]=2[CH:8]=1)[C:13]([F:15])([F:16])[F:14]
Reactant: Oc1ccccn1
Reactant: FCC1(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc2C2OC21
Solvent: CCO
Solvent: c1ccncc1
Product: O[C@H]1[C@H](Oc2ccccn2)c2cc(C(F)(F)C(F)(F)F)ccc2OC1(CF)CF
Yield: 20.3 %

Procedure:
A mixture of 0.42 g of 3,4-epoxy-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-2H-1-benzopyran, 0.21 g of 2-hydroxypyridine, 0.11 g of pyridine and 4 ml of ethanol was refluxed for 3 hours and the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain from the first eluted fraction 0.11 g of oily trans-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-4-(2-pyridyloxy)-2H-1-benzopyran-3-ol represented by the following formula.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3](=O)[CH2:4][C:5]1([CH3:18])[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[O:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1([CH3:18])[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[O:6]1
Reactant: CN(C)C(=O)CC1(C)Oc2ccccc2-n2cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CN(C)CCC1(C)Oc2ccccc2-n2cccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the amide of formula 3, N,N,4-trimethyl-4H-pyrrolo-[2,1-c][1,4]benzoxazin-4-acetamide (5 g), described in Example 14, in 150 ml of ether is added dropwise to a suspension of lithium aluminum hydride (2.6 g) in anhydrous ether (350 ml). The reaction mixture is stirred at room temperature for 4 hr. Decomposition of the mixture with 11 ml of water gives a white precipitate, which is collected on a filter and washed with ether. The filtrate is extracted with 2% aqueous HCl. The extract is rendered basic with a 10% solution of NaOH and extracted with chloroform. The chloroform extract is dried (MgSO4), filtered and evaporated to give the title compound, nmr (CDCl3) δ 1.61 (s, b 3H), 2.18 (s, 6H), 2.25 (m, 4H), 5.98 (m, 1H), 6.30 (6, J = 3.5 Hz, 1H), 6.9 - 7.5 (m, 5H).
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15]Cl)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15][N:29]2[CH2:30][CH2:31][C:26]([OH:32])([CH2:25][C:24]3[CH:33]=[CH:34][C:21]([CH3:20])=[CH:22][CH:23]=3)[CH2:27][CH2:28]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)CCl)cc1
Product: Cc1ccc(CC2(O)CCN(CC(=O)Nc3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)cc1

Procedure:
The title compound, m.p. 136°-138° C. and MS: m/e=468 (M+), was prepared from N-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-2-chloro-acetamide and 4-(4-Methyl-benzyl)-piperidin-4-ol.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[C:3]=1[CH2:24][C:25]([O:27][CH3:28])=[O:26].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:39]1[CH2:43]OC[CH2:40]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[C:3]=1[CH:24]([CH2:40][CH2:39][CH3:43])[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cc2ccccc2o1)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1cc2ccccc2o1)CCCC3
Yield: 81.9 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(benzofuran-2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.335 g; 0.85 mmol), LHMDS 1N in THF (1.27 mL; 1.27 mmol), 1-iodopropane (0.166 mL; 1.7 mmol) in DMF (4.2 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-40%) in heptane furnished 0.302 g (82%) of the title compound as a yellow oil.