Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8]CN2CCN(C3C(OC)=CC=CN=3)CC2C)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:40][O:41][C:42]1[C:43]([N:48]2[CH2:53][CH2:52][NH:51][CH:50]([CH3:54])[CH2:49]2)=[N:44][CH:45]=[CH:46][CH:47]=1>>[ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8][N:51]2[CH2:52][CH2:53][N:48]([C:43]3[C:42]([O:41][CH3:40])=[CH:47][CH:46]=[CH:45][N:44]=3)[CH2:49][CH:50]2[CH3:54])[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2
Reactant: COc1cccnc1N1CCN(CCCc2csc3ccccc23)C(C)C1
Reactant: COc1cccnc1N1CCNC(C)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Product: COc1cccnc1N1CCN(CCc2csc3ccccc23)C(C)C1

Procedure:
The title compound was prepared (1.39 g, 85%, mp 197°-200° C.) in a manner analogous to the preparation of 1-[3-(benzo[b]thien-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)-2-methylpiperazine hydrochloride (Example 41) by the reaction of 3-benzo[b]thieneethanol tosylate (Example 47) with 1-(3-methoxy-2-pyridinyl)-3-methylpiperazine.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[Br:22].C(OCC)(=O)C.[H][H]>[C].[Ru].C(O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:12]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][C:13]=1[Br:22]
Reactant: Brc1ccc2ccccc2c1-c1c(Br)ccc2ccccc12
Reactant: [H][H]
Agent: [Ru]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Brc1ccc2c(c1-c1c(Br)ccc3c1CCCC3)CCCC2
Temperature: 30 °C
Reaction time: 20 h

Procedure:
A 500 ml capacity stainless steel autoclave was charged with 35 g (0.085 mol) of 2,2'-dibromo-1,1'-binaphthyl, 5.25 g of 5%-ruthenium-carbon (manufactured by NECHEMCAT), 130 ml of ethyl acetate and 130 ml of 95% ethanol. After carrying out 20 hours of hydrogenation at a temperature of 100° C. under a hydrogen pressure of 50 kg/cm2, absorption of 4 mols of hydrogen per mol substrate was confirmed. The reaction mixture was cooled to 30° C. to remove the catalyst by filtration, the resulting filtrate was allowed to stand overnight at room temperature and then 30.6 g of the thus precipitated crystals were collected by filtration (yield, 85.7%).
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=4)[O:14][C:13]3=[O:26])[C:8]([C:27]3[CH:28]=[C:29]([CH2:35][CH2:36][C:37]([OH:39])=O)[CH:30]=[CH:31][C:32]=3[O:33][CH3:34])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:47].C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=4)[O:14][C:13]3=[O:26])[C:8]([C:27]3[CH:28]=[C:29]([CH2:35][CH2:36][C:37]([NH2:47])=[O:39])[CH:30]=[CH:31][C:32]=3[O:33][CH3:34])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: COc1ccc(CCC(=O)O)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C)cc(C)c2)[C@@H]1C
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CCC(N)=O)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C)cc(C)c2)[C@@H]1C
Reaction time: 0.5 h

Procedure:
To a solution of 3-[3-(6-azetidin-1-yl-2-{[(4S,5R)-5-(3,5-dimethylphenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}pyridin-3-yl)-4-methoxyphenyl]propanoic acid (EXAMPLE 228) (8 mg, 0.014 mmol) in DCM (2 ml) was added oxalyl chloride (2M in DCM) (100 μl, 0.200 mmol) and a drop of DMF. The solution was stirred for 30 minutes, concentrated, dissolved in THF (2 ml), added ammonium hydroxide (50 μl, 0.360 mmol) and stirred overnight. The mixture was acidified with 50 μl of TFA, concentrated, dissolved in MeOH, filtered, and purified by RP HPLC to afford the title compound. Mass spectrum (ESI) 529.5. 1H NMR (500 MHz, CD3OD): δ 7.31 (d, J=8.3 Hz, 1H); 7.20 (dd, J=8.4, 2.3 Hz, 1H); 7.02 (s, 1H); 6.96 (s, 2H); 6.83 (s, 2H); 6.35 (d, J=8.4 Hz, 1H); 5.40 (d, J=8.5 Hz, 1H); 4.80-4.48 (m, 1H); 4.24-3.64 (m, 2H); 4.05 (t, J=7.4 Hz, 4H); 3.75 (s, 3H); 2.88 (m, 2H); 2.48 (m, 3H); 2.41 (m, 2H); 2.28 (s, 6H); 0.59 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=O.[OH-].[K+].C(O)C>O>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])/[CH:10]=[CH:11]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CC(=O)c1cccc(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(/C=C/c1cccc(F)c1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
A mixture of 3-fluorobenzaldehyde (7.63 mL, 72.4 mmol), 3-fluoroacetophenone (10 g, 72.4 mmol), potassium hydroxide (5.18 g, 92.6 mmol), ethanol (23 mL) and water (47 mL) was stirred overnight at room temperature. After the reaction solution was diluted with water, the solid was collected by filtration and washed with ethanol and diethyl ether, to give the title compound (16.4 g, 93%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:10][C:9](=[O:11])[C:6]2([CH2:8][CH2:7]2)[CH2:5]1.[BH4-].[Na+]>CO>[OH:1][CH2:2][CH2:3][N:4]1[CH2:10][CH:9]([OH:11])[C:6]2([CH2:7][CH2:8]2)[CH2:5]1
Reactant: O=C1CN(CCO)CC12CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCCN1CC(O)C2(CC2)C1
Temperature: 25 °C

Procedure:
5-(2-Hydroxyethyl)-5-azaspiro[2.4]heptan-7-one (100 mg) was dissolved into Methanol (8 ml) and stirred at RT. NaBH4 (100 mg) was added to the reaction and stirred at RT for 30 minutes. The reaction was evaporated and purified by column chromatography to give title compound. Mass: (M+1), 158
Reaction SMILES: [OH-].[Na+].[S:3]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:20])[NH:14][CH2:15][C:16]([O:18]C)=[O:17])[S:4]1>CO>[S:3]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:20])[NH:14][CH2:15][C:16]([OH:18])=[O:17])[S:4]1
Reactant: COC(=O)CNC(=O)NCCCCC1CCSS1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CNC(=O)NCCCCC1CCSS1
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.8 %

Procedure:
2.1 ml of a 1N aqueous solution of sodium hydroxide were added dropwise to a solution of 218 mg of methyl {3-[4-(1,2-dithiolan-3-yl)butyl]ureido}acetate (prepared as described in Example 46) in 4 ml of methanol, and then the mixture was stirred at room temperature for 5 hours. The reaction mixture was then allowed to stand overnight at room temperature, after which the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. The resulting mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract to distillation under reduced pressure. The residue was recrystallized from a 3:1 by volume mixture of ethyl acetate and hexane, to give 64 mg of the title compound as a pale yellow powder, melting at 95 to 96° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[CH:6]=1.[CH:18](O)=O>>[C:16]([C:14]1[CH:13]=[CH:12][C:3]2[N:4]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[CH:6]=3)[CH:18]=[N:1][C:2]=2[CH:15]=1)#[N:17]
Reactant: N#Cc1ccc(Nc2cccc(I)c2)c(N)c1
Reactant: O=CO
Product: N#Cc1ccc2c(c1)ncn2-c1cccc(I)c1
Temperature: 90 °C

Procedure:
A suspension of (30) (1.8 g, 5.36 mmol) in formic acid (20 ml) is heated to 80-100° C. for 1.5 hours. The hot reaction mixture is filtered through a cotton pad into ice-water (100 ml). The precipitate is filtered off, washed with water and dried. This crude product is dissolved in dichloromethane and is brought to precipitation by addition of petroleum ether. The product is filtered off and dried. Yield: 1.38 g (75%) of the title compound. Mp. 177-179° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=3)[O:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.B1([C:27]2[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[O:11][N:10]=[C:9]([C:4]3[CH:3]=[C:2]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:7]=[C:6]([F:8])[CH:5]=3)[N:13]=2)=[N:15][CH:16]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Fc1ccc(-c2nc(-c3cc(F)cc(Br)c3)no2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: Fc1ccc(-c2nc(-c3cc(F)cc(-c4cccnc4)c3)no2)nc1
Yield: 17.6 %

Procedure:
A mixture of 3-(3-bromo-5-fluorophenyl)-5-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole (80 mg, 0.236 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (80 mg, 0.49 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 40 mg, 0.0346 mmol), in a solution of ethylene glycol dimethyl ether (1.5 mL) and 2M sodium carbonate (1.5 mL) was heated in a sealed vial at 100° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using a gradient of 50% ethyl acetate in hexane, afforded 14 mg (17.7%) 5-(5-fluoro-pyrid-2-yl)-3-[3-fluoro-5-(3-pyridyl)-phenyl]-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 8.95 (s, 1H), 8.76 (d, 1H), 8.66 (d, 1H), 8.37 (dd, 2H), 8.25 (s, 1H), 7.95 (d, 2H), 7.43 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[CH3:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[N:32]=[N:33][C:29]([CH3:28])=[N:30]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: Cc1nnn[nH]1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCCl)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCCCn3nnc(C)n3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, pale yellow oil, MS: m/e=458.4 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 5-methyl-1H-tetrazole.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH3:8])[N:4]1[CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26](=[S:28])[NH2:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11].[CH2:29](N)[CH2:30][CH3:31].S>C(O)C>[ClH:1].[CH3:8][CH:5]1[CH2:6][CH2:7][CH:3]([CH3:2])[N:4]1[CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26](=[S:28])[NH:27][CH2:29][CH2:30][CH3:31])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11]
Reactant: CC(CN1C(C)CCC1C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: CCCN
Agent: Cl
Agent: S
Solvent: CCO
Product: CCCNC(=S)c1ccc2c(c1)N(C(C)CN1C(C)CCC1C)c1ccccc1S2
Temperature: 120 °C

Procedure:
A solution of 10-((2RS)-1-[(2RS,5RS)-2,5-dimethyl-1-pyrrolidinyl]-2-propyl}-2-phenothiazinecarbothioamide hydrochloride (0.9 g) and propylamine (2.9 cc) in absolute ethanol (20 cc) is saturated with hydrogen sulphide and heated for 12 hours to a temperature in the region of 120° C. After cooling, the solution obtained is purged with nitrogen and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is dissolved in ethyl acetate (100 cc) and I the solution is washed with distilled water (2×20 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (1.09 g) is purified by chromatography on a column (height: 30 cm; diameter: 1 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with methylene chloride (200 cc) and then with a mixture (95:5 by volume) (250 cc) of methylene chloride and methanol and collecting 50-cc fractions. The combined fractions 3 to 7 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (0.75 g) is dissolved in ethyl acetate (20 cc) and treated with stirring, with a 3N solution (0.6 cc) of hydrochloric acid in ethyl ether. The gum formed is separated by decanting the solvent, taken up in solution in 2-propanol (2 cc) and treated with ethyl ether (10 cc). The solid formed is drained, washed with ethyl ether (2×5 cc) and dried under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. 10-{(2RS)-1-[(2 RS,5RS)-2,5-Dimethyl-1-pyrrolidinyl]-2-propyl}-N-propyl-2-phenothiazinecarbothioamide hydrochloride (0.63 g) is thereby obtained in the form of a yellow solid, m.p. 138°-140° C. (melts forming a paste).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:13]2[CH2:15][CH2:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[C:16]([NH:19][NH2:20])(=O)[CH3:17]>C(O)CCC>[Br:1][C:2]1[C:3]([CH:13]2[CH2:15][CH2:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:16]([CH3:17])=[N:19][N:20]=[C:7]1[CH2:6][CH2:5]2
Reactant: CC(=O)NN
Reactant: S=C1CCc2c(ccc(Br)c2C2CC2)N1
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccc(Br)c(C3CC3)c1CC2
Temperature: 120 °C

Procedure:
To a stirred solution of 6-bromo-5-cyclopropyl-3,4-dihydroquinoline-2(1H)-thione (147-7; 0.6 g, 0.00212 mol) in n-butanol (10 mL) was added acetic hydrazide (0.3 g, 0.005 mol). Reaction mass was warmed at 120° C. for 16 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound. MS (M+1): 305.1.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:12][C:13]1[CH:14]=[C:15]([N:19]=[C:20]=[O:21])[CH:16]=[CH:17][CH:18]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:20]([NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Br:12])[CH:14]=1)=[O:21]
Reactant: O=C=Nc1cccc(Br)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1cccc(Br)c1)Nc1ccc([N+](=O)[O-])cc1O
Yield: 84.1 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-bromo phenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 3-bromo phenyl isocyanate (3.24 mmol)according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.96 g, 87%). EI-MS m/z 350(M-H)-
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[S:13][CH:12]=[C:11]([CH:14]([C:19]2([C:32]([F:35])([F:34])[F:33])[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:21](=O)O2)C[N+]([O-])=O)[CH:10]=1.CCCCCC.C(OCC)(=O)C>C(#N)C.Cl.ClCCCl>[Br:8][C:9]1[S:13][CH:12]=[C:11]([C:14]2[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[NH:23][C:19]=2[C:32]([F:35])([F:33])[F:34])[CH:10]=1
Reactant: O=C1OC(C(C[N+](=O)[O-])c2csc(Br)c2)(C(F)(F)F)N=C1c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: FC(F)(F)c1[nH]c(-c2ccc(Cl)cc2)cc1-c1csc(Br)c1
Temperature: 25 °C

Procedure:
A solution of triethylamine (3.24 g, 32.1 mmol) in acetonitrile is added slowly to a solution of 2-[1-(5-bromo-3-thienyl)-2-nitroethyl]-4-(p-chlorophenyl)-2-(trifluoromethyl)-3-oxazolin-5-one (13.30 g, 26.8 mmol) in acetonitrile. The reaction mixture is stirred at room temperature for several minutes and diluted with dilute hydrochloric acid. The organic layer is separated, dried over MgSO4 and concentrated in vacuo to obtain a black residue. Column chromatography of the residue using silica gel and a (9:1) hexane/ethyl acetate solution gives several solids. One of the solids is stirred in cold 1,2-dichloroethane, filtered and dried to give 3-(5-bromo-3-thienyl)-5-(p-chlorophenyl)-2-(trifluoromethyl) pyrrole as a light tan solid, mp 112°-115° C. Another solid is diluted with hexane and the mixture is refluxed, cooled to room temperature and filtered to obtain 3-(5-bromo-3-thienyl)-5-(p-chlorophenyl)-4-nitro-2-(trifluoromethyl)pyrrole as a yellow solid, mp 174°-176° C.
Reaction SMILES: CC1C=CC(S(O[CH:12]([CH2:22][CH2:23][S:24](=[O:27])(=[O:26])[NH2:25])[CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].O.Cl>CN(C=O)C>[CH2:15]([O:14][CH2:13][CH:12]1[CH2:22][CH2:23][S:24](=[O:27])(=[O:26])[NH:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)OC(CCS(N)(=O)=O)COCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S1(=O)CCC(COCc2ccccc2)N1
Temperature: 25 °C
Yield: 105.2 %

Procedure:
Sulfonamide 6 (109 g, 0.26 mol) was dissolved in DMF (800 mL) and stirred at ambient temperature. To this was added K2CO3 (63 g, 0.46 mol) in one portion and the resultant mixture heated at reflux (oil bath 160° C.) for 3 hours. After this time the heating was ceased and the reaction allowed to cool with stirring overnight. The completed reaction was poured into water (1 L) and acidified with aqueous HCl (1 M, ˜500 mL) to pH 2. The resultant brown suspension was extracted with DCM (5×500 mL) and the combined organics washed with brine (1 L). A thick emulsion formed which was separated by the addition of iPrOAc until two distinct layers were visible. The organics were separated, dried (MgSO4) and evaporated to give an orange oil (66 g). This oil was purified by flash column chromatography (silica gel, 5% MeOH/DCM) to yield dioxide 7 as a yellow-orange oil (40 g, 64%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[Cl:14])C=C.C(N(CC)[C:18]1[CH:23]=CC=C[CH:19]=1)C.Cl>>[CH2:23]([C:10]1[CH:9]=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([Cl:14])[C:5]=1[OH:4])[CH:18]=[CH2:19]
Reactant: CCN(CC)c1ccccc1
Reactant: C=CCOc1ccc([N+](=O)[O-])cc1Cl
Agent: Cl
Product: C=CCc1cc([N+](=O)[O-])cc(Cl)c1O
Temperature: 210 °C
Reaction time: 6 h

Procedure:
A mixture of 1-(allyloxy)-2-chloro-4-nitrobenzene (55.2 g) and N,N-diethylaniline (50.0 mL) was stirred at 210° C. for 6 hours, and then followed by stirring at 175° C. overnight. At room temperature, the pH of the reaction mixture was adjusted to 1 by the addition of concentrated hydrochloric acid, followed by extraction with ether. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, the insoluble materials were separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 88:12) to obtain 2-allyl-6-chloro-4-nitrophenol (30.1 g) as a yellow solid.
Reaction SMILES: CN(C)CCCN=C=NCC.O.[C:13]([NH:20][C@H:21]([C:26]([OH:28])=O)[CH2:22][CH:23]([CH3:25])[CH3:24])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.[CH2:48]([O:55][C:56]([N:58]1[CH2:64][CH:63]([OH:65])[CH:62]([NH2:66])[CH2:61][CH2:60][CH:59]1[CH3:67])=[O:57])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C=O)C.CCOC(C)=O>[CH2:48]([O:55][C:56]([N:58]1[CH2:64][C@H:63]([OH:65])[C@@H:62]([NH:66][C:26](=[O:28])[C@@H:21]([NH:20][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:22][CH:23]([CH3:24])[CH3:25])[CH2:61][CH2:60][C@H:59]1[CH3:67])=[O:57])[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CC1CCC(N)C(O)CN1C(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)N(C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.164 g, 0.22 mmol) was added to a solution of Boc-Leucine-hydrate (0.190 g, 0.76 mmol), diisopropylethylamine (0.164 g, 0.22 ml, 1.27 mmol), hydroxybenztriazole (0.114 g, 0.83 mmol), and racemic (2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester (0.27 g, 0.57 mmol) in DMF (3.2 ml). The reaction was stirred overnight at RT, then was diluted with EtOAc (100 ml), washed with H2O (3×50 ml), brine (50 ml), dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 50% EtOAc/hexanes) to yield the title compound (0.218 g, 72%): 1H NMR: 7.40-7.29 (m, 5H), 6.75 (1H, bd), 5.12 (2H, AB), 5.0 (1H, bs), 4.15-3.72 (m, 2H), 3.06 (1H, d), 1.60-1.30 (m, 2H), 1.60-1.30 (m, 5H), 1.12 (3H, d), 0.97-0.87(6H, dd); Electrospray mass spec: M+H+=492.0
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][C:23](=[O:26])[CH2:24][CH3:25])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][C:23](=[O:26])[CH2:24][CH3:25])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CCC(=O)N[C@@H](C)c1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCC(=O)N[C@@H](C)c1ccc(C2CCNCC2)cc1

Procedure:
9.58 g (27.5 mmol) ((S)—N-{1-[4-(1-Benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-ethyl}-propionamide (XXII.1) in 130 mL ethanol are hydrogenated (3 bar) for 7 h at 50° C. using 0.80 g Pd/C (10%). After that time, the catalyst is filtered off and the solvent is evaporated. The residue is purified by HPLC (column: Gemini Phenomenex, 10 μM; eluent A: water+0.30% NH4OH, eluent B: acetone) to yield the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@H:4]([OH:6])[CH3:5].C(N(CC)CC)C.[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.CCOC(C)=O>[Si:15]([O:6][C@H:4]([CH3:5])[C:3]([O:2][CH3:1])=[O:7])([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H](C)O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 12 h
Yield: 99.8 %

Procedure:
To the mixture of (R)-2-Hydroxy-propionic acid methyl ester (1.0 g, 9.6 mmol), triethyl amine (4.0 mL, 28.81 mmol) in tetrahydrofuran (12 mL), was added tert-butyldiphenylsilylchloride (3.68 mL, 14.4 mmol) at room temperature and allowed the reaction mixture to stir for 12 h. After completion of the reaction, the reaction mixture was diluted with EtOAc (80 mL) and washed with water (70 mL) and brine (70 mL). The EtOAc layer was dried over Na2SO4 and solvent was evaporated in vacuo to afford methyl (2R)-2-{[tert-butyl(diphenyl)silyl]oxy}propanoate (3.28 g). The above crude material was sufficiently pure for the next step and used without further purification. The crude material was diluted with THF-MeOH—H2O (1:1:1, 20 mL) and added LiOH. H2O (1.17 g, 28.0 mmol). The reaction mixture was stirred for over night at room temperature. The reaction mixture neutralized with conc.HCl and concentrated in vacuo. The residue was diluted with 75 mL water and extracted with EtOAc (3×50 mL), the combined EtOAc layers were dried over Na2SO4 and evaporated in vacuo. The crude carboxylic acid was purified by Isco silica gel flash column using EtOAc to obtain the carboxylic acid (0.6 g). 1H NMR (CDCl3) δ 7.70-7.60 (m, 4H), 7.50-7.38 (m, 6H), 4.32 (q, J=6.6 Hz, 1H), 1.30 (d, J=7.0 Hz, 9H); LC-MS [M−H]+ 327.2
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16]2[C:15](=[O:17])[N:13]([CH3:14])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[N:9]=[CH:8]1.[C-:20]#[N:21].[K+]>CN(C)C=O>[C:20]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16]2[C:15](=[O:17])[N:13]([CH3:14])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[N:9]=[CH:8]1)#[N:21]
Reactant: Cn1c(=O)c2c(ncn2CCCCCCl)n(C)c1=O
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2CCCCCC#N)n(C)c1=O
Yield: 76.5 %

Procedure:
10.0 g. of 1-chloro-5-(theophyllin-7-yl)-pentane, 2.44 g. of potassium cyanide and 40 cm3 of dimethylformamide are reacted according to Example 13c and 7.92 g. (76.5% yield) of 7-(5-cyano-pentan-1-yl)-theophylline are obtained, m.p.: 86°-88° C.