Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C1COCC1>[CH:2]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C1CNCCN1
Reactant: ClC(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: c1ccc(C(c2ccccc2)N2CCNCC2)cc1

Procedure:
Synthesized according to General Procedure A: chlorodiphenylmethane (4{23}, 5 mL, 28.1 mmol, 1 equiv.), piperazine (14.5 g, 168.7 mmol, 6 equiv.), THF (61.4 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{23} (5.12 g, 72%) as a light yellow solid. 1H-NMR (500 MHz, CDCl3): δ 7.43 (d, 4H, J=7.0 Hz), 7.28 (t, 4H, J=7.5 Hz), 7.18 (t, 2H, J=7.5 Hz), 4.22 (s, 1H), 2.88 (t, 4H, J=5.0 Hz), 2.36 (br s, 4H), 1.46 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 142.6, 128.3, 127.9, 126.7, 76.7, 53.3, 46.3.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([NH2:24])=[O:23]>>[C:22]([CH2:21][C:20]([NH:19][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:26])[CH3:25])(=[O:23])[NH2:24]
Reactant: CC(C)(N)CC(N)=O
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CC(C)(CC(N)=O)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 50 mg, 0.21 mmol) and 3-amino-3-methyl-butanamide hydrochloride (1:1) (CAN 173336-86-2, 35.8 mg, 0.235 mmol) as starting materials and isolated (56 mg, 79%) as light yellow solid; LC-MS (UV peak area, ESI) 100%, 333.1926 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[I:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:33]([C:30]2[CH:31]=[CH:32][C:27]([I:26])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(I)cc1
Yield: 52.3 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3-chloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (92) (150 mg, 0.53 mmol), pyridine (Aldrich, 0.21 mL, 2.63 mmol) and 4-iodobenzenesulfonyl chloride (Acros, 175 mg, 0.58 mmol) in THF. 153 mg (53%) of 100 was obtained as a pale yellow solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:11])[CH2:7][CH2:6][CH:5]([C:8](O)=[O:9])[CH2:4][CH2:3]1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH2:23]([O:25][C:26]#[CH:27])[CH3:24]>C(Cl)Cl.C1COCC1.C(N(CC)CC)C>[CH2:26]([O:25][C:23]1[C:5]2([CH2:6][CH2:7][S:2](=[O:11])(=[O:1])[CH2:3][CH2:4]2)[C:8](=[O:9])[CH:24]=1)[CH3:27]
Reactant: O=C(O)C1CCS(=O)(=O)CC1
Reactant: C#COCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC1=CC(=O)C12CCS(=O)(=O)CC2
Reaction time: 72 h
Yield: 67 %

Procedure:
A solution of 1,1-dioxo-hexahydro-1λ6-thiopyran-4-carboxylic acid (10.2 g, 57.3 mmol) [prepared according to the procedure of Org. Prep. Proc. Int. 1977, 94] and DMF (0.3 ml) in DCM (120 ml) at rt, was treated dropwise with oxalyl chloride and the resulting slurry stirred for 3 d. The crude reaction was then concentrated in vacuo to give an oil which was re-dissolved in THF (100 ml), treated with ethoxyacetylene (10 ml, 50% w/w) and triethylamine (10 ml) and the resulting slurry stirred for 10 d at rt. Filtration and concentration of the filtrate in vacuo gave a crude oil which was purified by chromatography (SiO2, 30% EtOAc:hexanes) to give the title compound as a yellow oil (8.9 g, 38.6 mmol, 67%). δH (CDCl3, 300K) 4.88 (1H, s), 4.27 (2H, q, 47.1 Hz), 3.44-3.37 (2H, m), 3.13-3.05 (2H, m), 2.47-2.40 (2H, m), 2.35-2.29 (2H, m), 1.48 (3H, t, J 7.1 Hz); m/z (ES+, 70V) 230.9 (MH+).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:16](=[O:17])[NH:15][C:13]1=[O:14])=[O:5])C.C(N1C(=O)C(CCCCCCCC)N(CCCCCCC(OCC)=O)C1=O)CCC>>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:16](=[O:17])[NH:15][C:13]1=[O:14])([OH:5])=[O:3]
Reactant: CCCCCCCCC1C(=O)NC(=O)N1CCCCCCC(=O)OCC
Agent: CCCCCCCCC1C(=O)N(CCCC)C(=O)N1CCCCCCC(=O)OCC
Product: CCCCCCCCC1C(=O)NC(=O)N1CCCCCCC(=O)O

Procedure:
By the method of Example 92, 1-(6-ethoxycarbonylhexyl)-5-octylhydantoin was converted into 3-butyl-1-(6-ethoxycarbonylhexyl)-5-octylhydantoin, which was hydrolysed to give 3-butyl-1-(6-carboxyhexyl-5-octylhydantoin as a colourless oil.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[CH2:13]([O:20][C:21]([NH:23][CH2:24][C:25]([CH3:30])([CH3:29])[C:26](O)=[O:27])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH4+].[OH-]>O1CCCC1.O>[CH2:13]([O:20][C:21]([NH:23][CH2:24][C:25]([CH3:30])([CH3:29])[C:26]([NH2:3])=[O:27])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(CNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CNC(=O)OCc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
11.6 g of sodium periodate (54.2 mmol) and 0.2 g of ruthenium trichloride (0.96 mmol) were added to a solution of 4.6 g of 3-benzyloxycarbonylamino-2,2-di(methyl)propanol obtained in Reference Example (2a) (19.4 mmol) in a mixed solvent of carbon tetrachloride (40 ml), acetonitrile and water (40 ml), and the mixture was stirred at room temperature for 16 hours. 11.6 g of sodium periodate (54.2 mmol) and 0.2 g of ruthenium trichloride (0.96 mmol) were added to the reaction mixture, and the mixture was further stirred at room temperature for three days. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was dried over magnesium sulfate. After filtration, 300 ml of a saturated potassium carbonate aqueous solution was added to the residue, followed by washing with ethyl acetate. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 3.16 g of crude 3-benzyloxycarbonylamino-2,2-di(methyl)propionic acid. 3.0 g of 1,1′-carbonylbis-1H-imidazole (18.5 mmol) was added to a solution of 3.1 g of the crude 3-benzyloxycarbonylamino-2,2-di(methyl)propionic acid obtained above (12.3 mmol) in tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for one hour. 20 ml of a 28% ammonia aqueous solution (914 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for one hour. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was washed with a 1 M hydrochloric acid aqueous solution and brine and dried over magnesium sulfate. After filtration, 300 ml of a saturated potassium carbonate aqueous solution was added to the residue, followed by washing with ethyl acetate. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:ethyl acetate/n-hexane=2/1-3/1) to obtain 2.54 g of the title compound (yield: 54%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:11]=[C:12]([C:13]([O:15]CC)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].C(O)C.[OH-].[Na+]>C1COCC1>[CH3:3][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=3)[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:1]
Reactant: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)nc2c1cnn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)n1ncc2c(C(=O)O)cc(-c3ccc(S(C)(=O)=O)cc3)nc21

Procedure:
The title compound was prepared in the same manner as described for intermediate 58 using ethyl 1-(1-methylethyl)-6-[4-(methylsulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (260 mg, 0.671 mmol), Ethanol (4 mL), THF (1 mL) and sodium hydroxide (2N, 1.118 mL, 3.36 mmol). The final product was collected as 231 mg (96%). LCMS E-S (M+H)=360.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (d, J=6.8 Hz, 6H), 3.30 (s, 3H), 5.34-5.49 (m, 1H), 8.11 (d, J=8.6 Hz, 2H), 8.30 (s, 1H), 8.44 (s, 1H), 8.51 (d, J=8.6 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].F[C:9](F)(F)[C:10](O)=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:45]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39].C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:10]([N:42]1[CH2:43][CH2:44][C@@H:40]([C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:45]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:39])[CH2:41]1)(=[O:11])[CH3:9]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)[C@@H]1CCNC1
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CC[C@@H](C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 43 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using (3R)—N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide bis(trifluoroacetate) and acetyl chloride as starting materials in 43% yield. LCMS for C25H26ClN6O2 (M+H)+: m/z=477.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:13]2[C:21]3[C:16](=[C:17]([N+:22]([O-])=O)[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pt]>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[CH:15]=[CH:14][N:13]2[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c([N+](=O)[O-])cccc21
Agent: [Pt]
Solvent: CCOC(C)=O
Product: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Reaction time: 3 h

Procedure:
A solution of 1 (8.28 g, 24.0 mmol) in ethyl acetate (240 mL) was degassed, at which point platinum on carbon (1.41 g of a 10% wt/wt mixture, 0.721 mmol) was added, and the resulting suspension was stirred under a hydrogen atmosphere (balloon). After 3 h, the reaction mixture was filtered through a short column of CELITE® eluting with EtOAc. The combined organics were concentrated in vacuo to afford the title compound 2a. m/z (ES) 315 (MH)+.
Reaction SMILES: C([NH:8][CH2:9][C:10]([N:12]1[CH2:21][CH:20]([O:22][CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)=[O:11])(OC(C)(C)C)=O>Cl.CCOC(C)=O>[NH2:8][CH2:9][C:10]([N:12]1[CH2:21][CH:20]([O:22][CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)=[O:11]
Reactant: COC1CN(C(=O)CNC(=O)OC(C)(C)C)Cc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COC1CN(C(=O)CN)Cc2ccccc21
Yield: 80.3 %

Procedure:
A solution of N-(N'-Boc-glycyl)4-methoxy-1,2,3,4-tetrahydroisoquinoline (4.97 g, 16 mmol) in 30 mL of 3 N HCl and 30 mL of EtOAc was heated to reflux for 0.5 hour. The resulting solution was basified to pH 9 and extracted with EtOAc. The aqueous layer was then extracted with 10% iPrOH- CH2Cl2. Drying over MgSO4 of the iPrOH-CH2Cl2 solution and removal of the solvent gave 2.83 g (89%) of N-glycyl4-methoxy-1,2,3,4tetrahydroisoquinoline.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[C@H:13]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:12][CH2:11][O:10][CH2:9]1)(C)(C)C.[ClH:20]>O1CCOCC1>[ClH:20].[ClH:20].[N:14]1([CH:13]2[CH2:12][CH2:11][O:10][CH2:9][CH:8]2[NH2:7])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1COCC[C@H]1N1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1COCCC1N1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
trans-(4-Pyrrolidin-1-yl-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester (intermediate H, 345 mg, 1.28 mmol) was dissolved in 6.4 mL dioxane. Hydrochloric acid (4N in dioxan, 3.2 mL, 13 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated off. The crude material, light brown solid (378 mg, >100%), MS: m/e=171.2 [(M+H)+] was used without further purification.
Reaction SMILES: [H][H].[C:3]1([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH:15]([OH:20])[CH2:16][N:17]=[N+]=[N-])=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Pd].C(O)C>[C:3]1([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH:15]([OH:20])[CH2:16][NH2:17])=[CH:11][CH:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=NCC(O)COc1ccc(-c2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NCC(O)COc1ccc(-c2ccccc2)cc1
Yield: 106.9 %

Procedure:
Hydrogen was introduced into a mixture of 2.94 g of 3-(4-phenylphenoxy)-2-hydroxypropylazide (prepared as described in Preparation 83), 0.3 g of 10% w/w palladium-on-carbon and 60 ml of ethanol for 3 hours. At the end of this time, insolubles were removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure, to give 2.84 g of the title compound, melting at 137.7° to 146.8° C.
Reaction SMILES: [OH:1][C:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:30]([F:33])([F:32])[F:31])[C:3]([N:5]1[CH2:29][CH2:28][CH2:27][C@H:6]1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][NH:19]C(OC(C)(C)C)=O)=[O:8])=[O:4]>CCOC(C)=O>[OH:1][C:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:30]([F:32])([F:33])[F:31])[C:3]([N:5]1[CH2:29][CH2:28][CH2:27][C@H:6]1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][NH2:19])=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)C(O)(c1ccccc1)C(F)(F)F
Solvent: CCOC(C)=O
Product: NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)C(O)(c1ccccc1)C(F)(F)F
Temperature: 0 °C

Procedure:
1-(2-Hydroxy-2-phenyl-3,3,3-trifluoropropanoyl)-N-(2-tert-butyloxycarbonylaminomethyl-5-chlorobenzyl)-L-prolinamide from step 3 (more polar isomer, 8.5 mg, 0.015 mmol) was dissolved in EtOAc (20 mL) and cooled with stirring to 0° C. Into this solution was bubbled in HCl gas for 5 min. The resulting solution was stirred at 0° C. for 30 min. The hydrochloride salt of the title compound was obtained as a white crystalline solid after concentrating the reaction in vacuo (HPLC RT=2.78 min, method A; LC-MS m/z=470.1; 1H NMR, 400 MHz, CD3OD, 7.54 ppm (m, 3H), 7.44 ppm (d, 1H), 7.42 ppm (m, 1H), 4.5 ppm (d, 1H), 4.4 ppm (m, 2H), 4.3 ppm (m, 2H), 3.75 ppm (m, 1H), 2.7 pm (m, 1H), 2.1 ppm (m, 1H), 1.7 ppm (m, 3H)).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[Br:16][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCCCCCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: BrCCCCCCCc1ccccc1
Reaction time: 0.01 h
Yield: 147.6 %

Procedure:
To a solution of 7-phenyl-1-heptanol (29.1 g, 151.3 mmol) in 800 mL CH2Cl2 at room temperature was added CBr4 (60.2 g, 181.6 mmol) then triphenylphosphine (47.6 g, 181.6 mmol). After 30 s, the reaction had turned a light green color. TLC indicated that the reaction was complete at this point. The solvent was removed in vacuo to give a greenish-white semisolid. To this material was added 10% EtOAc:90% Hexanes and the resulting suspension was filtered through a pad of silica gel washing well with the same solvent system. There yielded 57 g of a colorless oil as the desired bromide and triphenylphosphine oxide. This oil was then flash chromatographed (Hexanes) to yield 38.6 g, 100% of the bromide as a colorless oil. 1H NMR (CDCl3) δ 1.30-1.49 (m, 6H); 1.60 (quintet, J=8.18 Hz, 2H); 2.60 (t, J=8.18 Hz, 2H); 3.39 (t, J=8.18 Hz, 2H); 7.13-7.20 (m, 3H); 7.21-7.31 (m, 2H).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[C:32]1([SH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O>[C:32]1([S:38][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Sc1ccccc1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3Sc3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.40 g of potassium carbonate and 2 ml of DMF, a mixture of 0.17 g of thiophenol and 0.5 ml of DMF was added. The reaction mixture was stirred at room temperature for one hour. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.30 g of 2-[3-(phenylthio)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 49”).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]([CH:29]1[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)[CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].O1CCOCC1.[ClH:44]>C(OCC)C>[ClH:44].[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]([CH:29]1[CH2:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:37]1)[CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Yield: 84.6 %

Procedure:
To tert-butyl N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl-N-(2-indanyl)glycinate (1.4 g, 2.75 mmoles) was added p-dioxane which had been saturated with anhydrous hydrogen chloride (35 ml). the resulting solution was stirred for two and a half hourst at room temperature and then solvent was evaporated to afford a colorless solid. Anhydrous diethyl ether was added to the residue and the product was filtered and washed with a small amount of ether to give N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl-N-(2-indanyl)glycine hydrochloride (1.1 g, 84.6%) as a colorless solid: m.p. 181°; [α]DETOH=+16.44°; mass spectra (CI): 435.6(m+1-H2O, 100%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C@H:10]2[C@H:15]([N:16]([CH3:33])[C:17](=[O:32])[C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)[CH2:14][CH2:13][NH:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].[C:34]([N:41]1[CH2:49][CH2:48][CH:44]([C:45](O)=[O:46])[CH2:43][CH2:42]1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O>[F:27][C:24]([F:25])([F:26])[C:22]1[CH:23]=[C:18]([C:17]([N:16]([CH3:33])[C@@H:15]2[CH2:14][CH2:13][N:12]([C:45]([CH:44]3[CH2:48][CH2:49][N:41]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:42][CH2:43]3)=[O:46])[CH2:11][C@H:10]2[C:5]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=2)=[O:32])[CH:19]=[C:20]([C:28]([F:31])([F:29])[F:30])[CH:21]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CCN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A mixture of N-[(3R*,4R*)-3-(3,4-dichlorophenyl)piperidin-4-yl]-N-methyl-3,5-bis(trifluoromethyl)benzamide monohydrochloride (0.90 g) obtained in Example 2, N-Boc-isonipecotic acid (1.52 g), WSC.HCl (0.82 mg) and HOBt (0.65 mg) was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 50→100% ethyl acetate/hexane, then 0→10% methanol/ethyl acetate) to give the title compound (1.19 g, 59%) as a white powder.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13]C(=O)C)=[CH:8][N:7]=1)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[H-]>O1CCCC1>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][N:7]=1
Reactant: CC(=O)OCc1ccc(COC(C)=O)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(CO)nc1
Reaction time: 1 h

Procedure:
2,5-Di(acetoxymethyl)pyridine (0.05 mole) is reduced with lithium aluminum hydride (0.025 mole) in tetrahydrofuran (50 ml.) at 0° C. with stirring. After one hour, water is added to decompose excess hydride, and the mixture is concentrated to dryness. The residue is extracted with hot isopropanol (2×60 ml.) and the extract is concentrated to dryness to give 2,5-di(hydroxymethyl) pyridine.
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][N:6]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=3)=[O:16])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.C(O[CH:31](N(C)C)[N:32]([CH3:34])[CH3:33])(C)(C)C>ClCCl>[N:1]1[N:10]2[C:4]([CH2:5][N:6]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23](=[O:25])[CH:24]=[CH:31][N:32]([CH3:34])[CH3:33])=[CH:21][CH:22]=3)=[O:16])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)c1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Solvent: ClCCl
Product: CN(C)C=CC(=O)c1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.4 %

Procedure:
A mixture of 1-[4-(4H,10H-pyrazolo[5,1-c][1,4]benzodiazepine-5-carbonyl) phenyl]ethanone (0.73 g), tert-butoxybis-[dimethylamino]methane (0.964 g) in dichloromethane (10 ml) was stirred at room temperature for 2 days. The mixture is concentrated in vacuo and the residue crystallized from dichloromethane-hexane to give 0.65 g of the title compound as yellow crystals, m.p. 225-230° C.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[N:18]=[CH:17][C:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[CH:15][CH:14]=2)[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[N:18]=[CH:17][C:16]([NH:19][S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:28]=3)(=[O:22])=[O:21])=[CH:15][CH:14]=2)[CH2:9]1
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2ccc(C3CCN(Cc4ccccc4)C3)nc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc(S(=O)(=O)Nc2ccc(C3CCNC3)nc2)cc1
Reaction time: 4 h

Procedure:
0.12 g of N-[6-(1-benzyl-pyrrolidin-3-yl)-pyridin-3-yl]-4-isopropyl-benzene-sulfonamide (0.28 mmol) were dissolved in 20 ml of methanol, a tip of a spatula 10% Pd/C was added, and the reaction mixture was hydrogenated for 2 h at room temperature and 4 h at 50° C. The catalyst was removed by filtration and the filtrate evaporated to dryness to yield 0.088 g of the desired debenzylated compound.