Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].Cl[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][Cl:21])=[O:15]>C(Cl)(Cl)Cl.OS([O-])(=O)=O.[K+]>[C:14](=[O:15])([O:8][C:7]1[C:2]([F:1])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9])[O:16][CH2:17][CH2:18][CH2:19][CH2:20][Cl:21]
Reactant: O=C(Cl)OCCCCCl
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(OCCCCCl)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of pentafluorophenol (1 g, 5.43 mmol) and TEA (0.91 ml, 6.52 mmol) in CHCl3 (8 ml), cooled to 0° C. and under nitrogen, a solution of 4-chlorobutyl chloroformate (0.76 ml, 5.43 mmol) in CHCl3 (1 ml) was dropped into. The mixture was allowed to warm to room temperature and stirred for 480 minutes. Then it was diluted with aqueous KHSO4 (2%), the two phases were separated and the organic phase was dried and evaporated yielding 4-chlorobutyl pentafluorophenyl carbonate (1.69 g, 98%) as a colorless oil that was used without further purification.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:17][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].Cl.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:17][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 24 h

Procedure:
102.2 g (442 mmoles) Boc-Leu-OH, 98.1 g (485 mmoles) Gly-OBzl.HCl and 55.9 g (478 mmoles HONSu were dissolved in 760 ml dichloromethane added 54 ml N-methylmorpholine. Cooling to 4° C. and addition of a cold solution (4° C.) of 100.1 g (485 mmoles) DCC in 190 ml dichloromethane. The stirring was kept for one day at 4° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]2[S:10][C:11]([C:13]([OH:15])=O)=[CH:12][C:7]2=[N:6][CH:5]=1)[CH3:2].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:49][C:50]1[CH:51]=[C:52]([NH:57][C:58](=[O:70])[C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([C:68]#[N:69])([CH3:67])[CH3:66])[CH:60]=2)[CH:53]=[CH:54][C:55]=1[CH3:56]>CN(C=O)C>[C:68]([C:65]([C:61]1[CH:60]=[C:59]([CH:64]=[CH:63][CH:62]=1)[C:58]([NH:57][C:52]1[CH:53]=[CH:54][C:55]([CH3:56])=[C:50]([NH:49][C:13]([C:11]2[S:10][C:8]3=[N:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][N:6]=[C:7]3[CH:12]=2)=[O:15])[CH:51]=1)=[O:70])([CH3:67])[CH3:66])#[N:69]
Reactant: CCOc1cnc2cc(C(=O)O)sc2n1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Temperature: 80 °C
Yield: 7.1 %

Procedure:
A solution of 97 (0.085 mmol, 18.29 mg), N,N-diisopropylethylamine (0.426 mmol, 0.070 ml, 55.1 mg) and HATU (0.128 mmol, 48.6 mg) in DMF (1 mL) was stirred for 5 min. N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 5 (0.085 mmol, 25 mg) was added and stirred at 80° C. over the weekend. The reaction mixture was quenched in citric acid solution and extracted with ethyl acetate (2×). Organic layer was washed with brine, dried and concentrated under reduced pressure. The crude compound was purified with HPLC to give the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-ethoxythieno[2,3-b]pyrazine-6-carboxamide 98 (3 mg, 7%). NMR (400 MHz, CDCl3) 1.48 (t, 3H), 1.78 (s, 6H), 2.36 (s, 3H), 4.51 (q, J=7.0 Hz, 2H), 7.24 (m, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.72 (t, J=7.8 Hz, 2H), 7.79 (m, 2H), 7.91 (s, 1H), 7.98 (m, 2H), 8.16 (d, J=2 Hz, 1H), 8.32 (s, 1H). (m/z)=501 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:23][CH2:22][N:21](C#N)[CH2:20][CH2:19]3)=[N:10]2)=[CH:5][CH:4]=1.OS(O)(=O)=O.[OH-].[Na+]>O>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: N#CN1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)c1ccc(-n2nc(C3CCNCC3)c3ccccc32)cc1
Yield: 91.8 %

Procedure:
A stirred mixture of 4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carbonitrile of Example 101 (15 g. 0.041 moles) and 25% H2SO4 (100 ml) was refluxed for 20 hours. The mixture was cooled, poured into H2O, and basified with 25% NaOH solution. The product was extracted (dichloromethane), dried (MgSO4), and concentrated to yield 13 g (93%) of 1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole as an oil. To a stirred mixture of the indazole (4.15 g. 0.012 moles) and triethylamine (3.35 ml. 0.024 moles) in toluene (50 ml) was added acetyl chloride (0.93 ml, 0.013 moles). The reaction was stirred at ambient temperature for 2 hours and then poured into H2O. The product was extracted (CHCl3), dried (MgSO4), and concentrated to yield 4.3 g of an oil. The product was triturated with hexane and then recrystallized from CCl4 -hexane twice to yield 2.80 g of product. The product was further purified using high pressure liquid chromatography (silica gel, ethyl acetate)) to yield 2.1 g (45%) of 1-acetyl-4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine, m.p. 148°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:29][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[C:12]([O:11][C:9]([N:5]1[CH2:6][C:7](=[O:29])[CH2:8][CH:4]1[C:3]([O:2][CH3:1])=[O:16])=[O:10])([CH3:13])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)C1CC(=O)CN1C(=O)OC(C)(C)C
Reaction time: 72 h
Yield: 57 %

Procedure:
To a stirred solution of N-Boc proline methyl ester (2 .0 g, 8.15 mmol) in CH2Cl2 were added 3 A molecular sieves (2 g) and PDC (4.60 g, 12.2 mmol). The mixture was stirred for 3 days. The mixture was filtered through a Celiete pad and the filtrate was evaporated. The residue was chromatographed on silica gel with CHCl3—MeOH (10:1) as eluent to give methyl 1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylate (1.13 g, 57%) as a colorless oil. 1H-NMR (CDCl3) δ1.46-1.48 (m, 9 H), 2.56-2.61 (m, 1 H), 2.88-3.00 (m, 1 H), 3.77 (s, 3 H), 3.82-3.88 (m, 2 H), 4.71-4.83 (m, 1 H).
Reaction SMILES: [CH2:1]([OH:6])[C:2]#[C:3][CH2:4][OH:5].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1>C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:5][CH2:4][C:3]#[C:2][CH2:1][OH:6]
Reactant: C1=COCCC1
Reactant: OCC#CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: OCC#CCOC1CCCCO1
Yield: 68.8 %

Procedure:
To a mixture of 5.0 g of 2-butyne-1,4-diol and 10 milligrams of p-toluenesulfonic acid and 150 ml of dry ether there was added dropwise with stirring at room temperature 4.9 g of 3,4-dihydro-2H-pyran. After stirring overnight at ambient temperature the ether was evaporated and the residue was poured into 200 ml of water. The aqueous solution was extracted with hexane (2×100 ml) and then re-extracted with ether (3×100 ml). The combined ether extracts were washed with 100 ml of brine, dried over magnesium sulfate and evaporated to yield 6.8 g of 4-tetrahydropyranoxy-2-butyn-1-ol.
Reaction SMILES: [Cl:1][C:2]([Cl:5])([Cl:4])[CH3:3].[C:6]([Cl:9])([Cl:8])=[CH2:7]>>[Cl:1][C:2]([Cl:5])([Cl:4])[CH2:3][C:6]([Cl:9])([Cl:8])[CH3:7]
Reactant: C=C(Cl)Cl
Reactant: CC(Cl)(Cl)Cl
Product: CC(Cl)(Cl)CC(Cl)(Cl)Cl

Procedure:
2,2,4,4,4-Pentafluorobutane is another undesirable by-product of the fluorination of 1,1,1-trichloroethane. I believe that it is formed by the reaction between 1,1,1-trichloroethane and vinylidene chloride, followed by the reaction of additional 1,1,1-trichloroethane with vinylidene chloride to give 1,1,1,3,3-pentachlorobutane. Grigor'ev et al., Izv. Akad. Nauk. SSSR. Ser. Khim., 6, 1333-6 (1980). Hydrofluorination of the latter produces 2,2,4,4,4-pentafluorobutane.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[SH:22]>>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[S:22][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Sc1c(Cl)cccc1Cl
Product: COC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cccc2Cl)s1

Procedure:
Prepared according to the procedure described for step A of example 18 from methyl 5-chloro-4-nitrothiophene-2-carboxylate (5 g, 22.7 mmol) and 2,6-dichlorothiophenol (4.4 g, 24.8 mmol), The titled product was obtained as an off-white solid (5.5 g, 67% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.17 (1H, s), 7.83 (2H, m), 7.62 (1H, m), 3.77 (3H, s). MS m/z: 363.92, 365.93 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[S:22][C:12]=2[N:13]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCc1ccccc1
Product: FC(F)(F)c1cc2c(NCc3ccccc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyrazin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-y)-4-benzylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1.S(Cl)([Cl:46])=O>ClC(Cl)C>[Cl:46][CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1
Reactant: O=S(Cl)Cl
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CC(Cl)Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCCl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 60 °C
Yield: 90 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-hydroxyethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (1400 mg, 2.381 mmol) and thionyl chloride (1.738 mL, 23.81 mmol) in dichloroethane (15 mL) was heated up at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to provide the desired product as brown solid (1.3 g, 90%). LCMS: m/e 606.48 (M+H)+, 2.46 min (method 11).
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:7]([O:9]CC)=O)(=[O:5])[CH:2]([CH3:4])[CH3:3]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:1]([C:6]1[C:7](=[O:9])[C:19]2[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(=CNc1ccccc1OC)C(=O)C(C)C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cccc2c(=O)c(C(=O)C(C)C)c[nH]c12
Yield: 52.2 %

Procedure:
Ethyl 2-isobutyryl-3-(2-methoxyphenylamino)acrylate (18.8 g, 0.065 mol) was added in portions to boiling diphenyl ether (150 ml). The mixture was heated under reflux for 30 minutes, cooled, and diluted with petroleum ether (500 ml). Filtration of the mixture gave 3-isobutyryl-8-methoxy-4(1H)-quinolone as a light brown solid (8.32 g, 52.2%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:40]5[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][CH:39]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccc(OC)cc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 4-methoxyphenylboronic acid.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[N:7][CH:8]=1.C(N(CC)CC)C.CS([Cl:45])(=O)=O>CN(C=O)C>[Cl:45][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[N:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cn2)C(OCc2ccc3ccccc3c2)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCl)cn2)C(OCc2ccc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
A solution of 70 mg (0.156 mmol) of tert-butyl (3'RS,4'RS)-5-hydroxymethyl-3'-(naphthalen-2-ylmethoxy)-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridine-1'-carboxylate in 2 ml of absolute DMF was cooled to -10° C. and treated with 26 μl (19 mg,0.187 mmol) of triethylamine. 13 μl (20 mg, 0.172 mmol) of methanesulphonyl chloride and 2 mg of N,N-dimethylaminopyridine (DMAP) were added at -10 to -15° C. and subsequently the mixture was stirred at 0° C. for 1 hour. For the working-up, the mixture was partitioned between 25 ml of ethyl acetate and 25 ml of aqueous 5% ammonium chloride solution and the organic phase was separated. The aqueous phase was extracted three times with 10 ml of ethyl acetate each time. The combined ethyl acetate phases were dried over magnesium sulphate and finally evaporated under reduced pressure. The crude product was purified by chromatography on silica gel with a 1:1 mixture of ethyl acetate and hexane as the eluent. There were obtained 22 mg (35% of theory) of tert-butyl (3'RS,4'RS)-5-chloromethyl-3'-(naphthalen-2-ylmethoxy)-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridine-1'-carboxylate as a light yellow oil; MS: 467, 469 (M+H)+.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29]>CCOCC>[C:26]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: CCCC(=O)Cl
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCCOC(=O)CCC
Yield: 34.2 %

Procedure:
Oleyl alcohol (40 g, Eastman) and anhydrous pyridine (10 ml) were added to a 100 ml round-bottom flask equipped with a magnetic stirrer. The mixture was stirred and cooled in an ice bath for five minutes. Butyryl chloride (15.0 g, 0.14 mol, Eastman) was added dropwise via an addition funnel. The reaction mixture was stirred for 15 minutes at 5° and at room temperature for an hour. It was then diluted with ether and filtered. The filtrate was dried over sodium sulfate. Volatiles were removed under vacuum. Distillation of the residual oil (163°-168°, 0.26-0.28 torr) gave 16.2 g (34%) of 3. NMR: δ 0.9 (m, 6 H, CH3), 1.1-2.4 (m, 32 H, CH2), 3.95 (t, J=6 Hz, CH2O), 5.3 (t, J=4.5 Hz, 2 H vinyl). IR: 3005 (olefinic-CH), 1740 (C=O), 1175 cm-1 (C--O--C)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13]>O.C(O)(C)(C)C>[CH3:13][C:12]([CH3:15])([O:16][C:17]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:18])[CH3:14]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 103.8 %

Procedure:
6-Aminocaproic acid (14.4 g, 110 mmol, 1.1 eq.) was treated with sodium hydroxide (4.4 g, 110 mmol) dissolved in 11 mL of water. t-Butanol (22 mL) was added resulting in a suspension which was next treated with di-tertbutylcarbonate (21.8 g, 100 mmol) dissolved in t-butanol (22 mL). The reaction mixture, which remained a suspension, was stirred for 48 hours at room temperature, then treated with water (75 mL), giving a clear solution. The aqueous solution was then rinsed with two portions of petroleum ether (250 mL), then cooled in an ice-bath and acidified to pH 2 with solid potassium hydrogen sulfate. The acidified aqueous layer was extracted twice with portions of ethyl acetate (250 mL). The combined organic extract was rinsed with two 50 mL portions of water and brine, then dried over anhydrous magnesium sulfate and concentrated in vacuo. Trituration of the crude product (24 g) afforded 21.67 g of the title C compound, m.p. 39°-42° C.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@@:21]3([NH:25][CH:24]([C:26]([O:28]C)=O)[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[NH3:45]>>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@@:21]3([NH:25][CH:24]([C:26]([NH2:45])=[O:28])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:8]=1
Reactant: N
Reactant: COC(=O)C1CC[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)N1
Solvent: CO
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCC(C(N)=O)N2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 48 h
Yield: 84 %

Procedure:
A solution of Methyl (5R,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (diastereoisomer 2) (Intermediate 8, 18 mg, 0.030 mmol) in 7N Ammonia in MeOH (5 mL, 35.0 mmol) was stirred at 25° C. for 1 day and then it was left still for 2 days. The solvent was evaporated to dryness and the crude was purified by SCX and silica cartridges (from 1:0 to 97.5:2.5 DCM/0.5 M NH3 in MeOH) to give two batches of the title compound as colourless oil (total amount: 14.9 mg, 0.025 mmol, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.90-8.08 (m, 1H) 7.62-7.77 (m, 2H) 7.26-7.46 (m, 1H) 7.04-7.23 (m, 2H) 6.84-6.96 (m, 1H) 6.69-6.80 (m, 1H) 5.24-5.41 (m, 1H) 4.31-4.49 (m, 1H) 3.49-3.65 (m, 1H) 3.10-3.25 (m, 1H) 2.94-3.08 (m, 1H) 2.61-2.87 (m, 3H) 2.35 (s, 3H) 1.92-2.10 (m, 1H) 1.62-1.84 (m, 2H) 1.38-1.60 (m, 8H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[N:43]([CH2:44][CH2:45][CH3:46])[CH:42]=[N:41][N:40]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][C:39]5[N:43]([CH2:44][CH2:45][CH3:46])[CH:42]=[N:41][N:40]=5)=[O:56])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CCC)cc2)CCN3CCC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CCC)cc2)CCN3CCC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (843.7 mg) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.48 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:5→1:4), to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 141) (490.8 mg) as yellow amorphous.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH:4]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[O:22][CH3:23])[O:5][C:6]2=[O:13].[CH2:24]([SiH](CC)CC)C.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:24][C:10]1[CH:9]=[C:8]([O:11][CH3:12])[C:7]([C:6]([OH:5])=[O:13])=[C:3]([CH2:4][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[O:22][CH3:23])[CH:2]=1
Reactant: COc1ccc(OC)c(C2OC(=O)c3c(OC)ccc(C)c32)c1
Reactant: CC[SiH](CC)CC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(OC)c(Cc2cc(C)cc(OC)c2C(=O)O)c1
Temperature: 25 °C

Procedure:
4-Methyl-7-methoxy-3-(2',5'-dimethoxyphenyl)-1-(3H)-isobenzofuranone (17 g) and triethylsilane (15 g) were dissolved in dichloromethane (200 ml) and stirred at room temperature under nitrogen. Titanium tetrachloride (5N in CCl4, 25 ml) was added by syringe. The reaction mixture was stirred at room temperature for 4 hours. Water (10 ml) was added dropwise and the reaction mixture was concentrated down. The resulting slurry was dissolved (with heating) in 2N NaOH (aq) and filtered through celite. The filtrate was washed with diethyl ether (2×200 ml) and acidified with concentrated HCl (aq). The resulting precipitate was collected by filtration and dried to give 4-methyl-6-methoxy-2-(2',5'-dimethoxybenzyl)benzoic acid, m.p. 172°-174° C.