Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.[I:17]N1C(=O)CCC1=O>O>[NH2:1][C:2]1[C:10]([I:17])=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(I)cc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.1 %

Procedure:
To a mixture of 1.5 g of 2-amino-5-chlorobenzoic acid and 100 ml of N,N-dimethylformamide was added 2.7 g of N-iodosuccinimide at room temperature, and the mixture was stirred at room temperature for 24 hours. After 30 ml of water was poured into the reaction mixture, the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.2 g of 2-amino-5-chloro-3-iodobenzoic acid of the formula:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH2:9][O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc(Br)c1
Product: Brc1cccc(OCc2ccccc2)c1

Procedure:
The title compound was synthesized (4.8 g, quant.) following Description 41 from 3-bromophenol (3 g, 17.3 mmol) and benzylbromide (2.1 ml); Rt (HPLC): 6.42 min.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1(C)C=CC=CC=1.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>[C:18]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH3:23])=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:22])[O:4][CH:2]([CH3:3])[CH3:1])[CH2:8][C@@H:9]1[CH3:21])(=[O:20])[CH3:19]
Reactant: Cc1ccccc1B(O)O
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3ccccc3C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Yield: 93 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (25 mg, 0.068 mmol), (2-methylphenyl)boronic acid (11.97 mg, 0.088 mmol), potassium carbonate (28.1 mg, 0.203 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.91 mg, 3.39 μmol) in ethanol (1 mL) and toluene (1 mL) was degassed under house vacuum and quenched several times with nitrogen, and then was heated at 100° C. for 30 min before being cooled to room temperature. The mixture was filtered through celite and the insoluble washed with EtOH. Most of the solvent was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 30 to 60% AcOEt in hexanes) gave 1-methylethyl [(2S,4R)-1-acetyl-2-methyl-6-(2-methylphenyl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (24 mg, 0.063 mmol, 93%) as a colourless solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[C:18]([O:22][C:23]([NH:25][C@@H:26]1[CH2:30][CH2:29][C@:28]([CH:34]([CH3:36])[CH3:35])([C:31](O)=[O:32])[CH2:27]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[C:18]([O:22][C:23](=[O:24])[NH:25][C@@H:26]1[CH2:30][CH2:29][C@:28]([CH:34]([CH3:35])[CH3:36])([C:31]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[CH:5]=[C:4]([C:14]([F:17])([F:15])[F:16])[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH2:9][CH2:10]2)=[O:32])[CH2:27]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: Cc1cc(C(F)(F)F)cc(N2CCNCC2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)cc(N2CCN(C(=O)[C@@]3(C(C)C)CC[C@@H](NC(=O)OC(C)(C)C)C3)CC2)n1
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a solution of 1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]piperazine (280 mg, 1.1 mmol), (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (460 mg, 1.7 mmol) in methylene chloride (30 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.60 g, 1.4 mmol), and triethylamine (0.20 g, 2.0 mmol). After being stirred overnight, the reaction mixture was diluted with methylene chloride, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography to provide the desired product (200 mg, 35.1%). LCMS calculated for C25H37F3N4O3: (M+H) 499.3; found 499.2.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:8])[CH2:5][CH2:6]Br.[CH:9]([CH:11]=[CH2:12])=[O:10]>>[CH3:8][CH:4]([CH2:5][CH2:6][CH:9]([OH:10])[CH:11]=[CH2:12])[CH2:3][CH2:2][CH:9]([OH:10])[CH:11]=[CH2:12]
Reactant: C=CC=O
Reactant: CC(CCBr)CCBr
Product: C=CC(O)CCC(C)CCC(O)C=C
Yield: 77.9 %

Procedure:
Preparation ofthe di-Grignard reagent from 1,5-dibromo-3-methylpentane (46 g, 189 mmole) and treatment with acrolein (23.3 g, 415 mmole), as described in Example 6 (Step 2/Method A), gave 6-methylundeca-1,10-diene-3,9-diol (29.2 g, 78% yield). C12H22O2 (198.31 g/mole). bp: 115° C., 0.4 mm Hg. 1HNMR (500 MHz, CDCl3): 0.86 (d, 3H), 1.08-1.58 (m, 9H), 1.95 (bs, 2H), 4.02 (m, 2H), 5.06 (d, 2H), 5.18 (m, 2H), 5.79-5.87 (m, 2H) ppm. 13CNMR (125 MHz, CDCl3): 19.66, 32.38, 32.66, 32.77, 34.47, 73.50, 73.67, 114.62, 114.70, 141.32, 141.38. IR (νmax(cm−1)): 3360(bs), 3080(w), 2925(s), 2860(s), 1645(w), 1430(w), 995(s), 920(s). MS (m/z): 165(M-33), 151, 147, 109, 95, 81, 67, 57, 41.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:12]=1)=[O:6].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.O>CN1CCCC1=O>[C:14]1([CH3:21])[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[C:11]1[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:22]=[CH:23][N:24]=[C:2]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[CH:3]=2)[S:9][CH:10]=1
Reactant: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(Cl)c3)n2)c(C)c1
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(N4CCN(C)CC4)c3)n2)c(C)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
A mixture of 2-chloro-N-(4-mesitylthiazol-2-yl)isonicotinamide (300.0 mg, 0.8 mmol, 1.0 equiv) and 1-methylpiperazine (1.12 mL, 10.1 mmol, 12 equiv) in methylpyrrolidone (9.0 mL) was stirred at 150° C. for 16 h. The mixture was poured into icy H2O (15.0 mL) and the resultant solids were filtered to provide N-(4-mesitylthiazol-2-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide (95.6 mg, 0.20 mmol) as yellow solids in 27% yield: 1H NMR (CDCl3, 500 MHz) δ 8.27 (d, J=5.1 Hz, 1 H), 7.12 (s, 1 H), 6.83-6.86 (m, 3 H), 6.78 (s, 1 H), 3.63-3.65 (m, 4 H), 2.35 (s, 3 H), 2.27 (s, 3 H), 2.04 (s, 6 H); ESI-MS: m/z 422.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18]CN=C=NCCCN(C)C.CO>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:18][O:16][C:15](=[O:17])[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CC(=O)O)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
[4-(tert-Butoxycarbonyl)phenyl]acetic acid (2.94 g, 12.4 mmol) and DMAP (152 mg, 1.24 mmol) were dissolved in CH2Cl2 (50 mL) and cooled to 0° C. EDCI (3.10 g, 16.2 mmol) and MeOH (660 μL, 16.2 mmol) were added. After stirring for 30 min at 0° C., the reaction was allowed to warm to room temperature and stirred 2 h. The mixture was then diluted with CH2Cl2, washed (sat. NaHCO3, brine), dried (MgSO4), and concentrated. Flash chromatography on silica gel (0-10% EtOAc/hexanes) afforded tert-butyl 4-(2-methoxy-2-oxoethyl)benzoate as a colorless oil. 1H NMR (CDCl3) δ 7.93 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 3.68 (s, 3H), 3.66 (s, 2H), 1.57 (s, 9H). MS (ESI) calcd [M+Na]+ 273.1, found 273.1.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6](O)[CH:7]=[CH:8][CH:9]=1)=[N+:2]=[N-:3].NC1C=CC([OH:18])=CC=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:18])=[CH:8][CH:9]=1)=[N+:2]=[N-:3]
Reactant: Nc1ccc(O)cc1
Reactant: [N-]=[N+]=Nc1cccc(O)c1
Product: [N-]=[N+]=Nc1ccc(O)cc1

Procedure:
4-Azidophenol was prepared similarly to 3-azidophenol, using 4-aminophenol (5.0 g) instead of 3-aminophenol. This gave 5.27 g (85% yield) of a dark red oil. 1H NMR (acetone-d6, 300 MHz, ppm): 8.48 (s, 1H, Ar—OH), 6.94 (m, 4H, Ar—H). 13C NMR (MeOD-d4, 75 MHz, ppm): 156.4, 132.4, 121.1, 117.7. FT-IR (cm−1): 3372, 2113, 2072.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Br:12][CH2:13][C:14](C1C=CC(C)=CN=1)=[O:15]>>[Br:12][CH2:13][C:14]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1)=[O:15]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1ccc(C(=O)CBr)nc1
Product: O=C(CBr)c1ccc(C(F)(F)F)cn1

Procedure:
* 2-Bromoacetyl-5-(trifluoromethyl)pyridine was prepared from 2-chloro-5-(trifluoromethyl)pyridine according to the procedure for preparing 2-bromoacetyl-5-methylpyridine described in step 1 of Example 32.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[H-].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: Fc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(-n2ccnc2)cc1
Temperature: 130 °C

Procedure:
1-Chloro-4-fluorobenzene (16.3 g, 124 mmol) and imidazole (5.0 g, 73.4 mmol) are dissolved in N,N-dimethylformamide (30 ml) and admixed while stirring with sodium hydride (60% strength in mineral oil; 3.82 g, 95.4 mmol) and then heated at 130° C. for 5 hours. After cooling, the reaction mixture is slowly poured into water. The precipitate formed is subsequently filtered off, washed with petroleum ether and subsequently dried under reduced pressure. This gives 10.3 g of 1-(4-chlorophenyl)imidazole.
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1(O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@@H:2]([O:1][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: Oc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.9 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), phenol (4.70 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.1 mg, 36.0% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.40-7.15 (m, 10H), 6.97 (d, 1H, J=7.6 Hz), 6.88-6.82 (m, 2H), 5.26 (m, 1H), 3.18 (m, 2H), 2.75 (m, 2H), 2.53 (m, 2H), 2.40-2.10 (m, 4H), 2.10-1.80 (m, 4H), 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 457.4 (M+H)+.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:17]I>CN(C)C=O.CCOCC.[Ag]=O>[C:1]([N:11]1[CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(OCc1ccccc1)N1CCC(O)C1
Reactant: CI
Agent: O=[Ag]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 35.6 ml of benzylchloroformate in 200 ml of dichloromethane was added dropwise to a mixture of 10 g of (racemic)-3-pyrrolidinol, 48.3 ml of triethylamine and 725 ml of dichloromethane which was cooled to 0° C. The mixture was stirred for 48 hours at room temperature. The dichloromethane solution was extracted with 5% hydrochloric acid and 5% aqueous sodium bicarbonate. The acid and bicarbonate washes were combined, salted with sodium chloride and extracted with 2×750 ml of ethyl acetate. The combined organic extracts were dried and concentrated, giving 22.7 g of (racemic)-N-carbobenzyloxy-3-pyrrolidinol. A mixture of 2.5 g of (racemic)-N-carbobenzyloxy-3-pyrrolidinol, 2.0 ml of methyl iodide and 5.1 g of silver oxide in 50 ml of dimethylformamide was stirred at room temperature for 2 days. The mixture was diluted with ether and then filtered. The filtrate was concentrated to a small volume. The ether solution was washed with water, dried and concentrated to dryness in vacuo. The residue was purified by chromatography (silica gel) to give 2.4 g of (racemic)-N-carbobenzyloxy-3-methoxypyrrolidine as a pale yellow oil.
Reaction SMILES: C(O[C:4]([N:6]=[C:7]=[S:8])=[O:5])C.C(OC([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][C:24]2[CH:28]=[CH:27][NH:26][C:25]=2C(OCC)=O)[CH2:18][CH2:17]1)=O)(C)(C)C.[Na].Cl>C(Cl)Cl>[NH:16]1[CH2:17][CH2:18][CH:19]([CH2:22][N:23]2[C:24]3[CH:28]=[CH:27][NH:26][C:25]=3[C:4](=[O:5])[NH:6][C:7]2=[S:8])[CH2:20][CH2:21]1
Reactant: CCOC(=O)N=C=S
Reactant: CCOC(=O)c1[nH]ccc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Product: O=c1[nH]c(=S)n(CC2CCNCC2)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.058 g, 0.44 mmol) was added to a stirred solution of 4-[(2-(ethoxycarbonyl)-1H-pyrrol-3-ylamino)-methyl]piperidine-1-carboxylic acid tert-butyl ester (0.156 g, 0.44 mmol) in CH2Cl2 (2 mL) and the mixture was stirred at r.t. for 1 h. The solvent was removed in vacuo and the residue was taken up in ethanol (1 mL) containing sodium (0.015 g, 0.66 mmol). The resulting mixture was heated in a microwave reactor at 120° C. for 10 minutes. 6M HCl (0.5 mL) was added and the reaction mixture was heated again in the microwave at 100° C. for 3 minutes. The pH was adjusted to neutral pH with 2M HCl and the solution was concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (0.038 g, 14%) as a white solid.
Reaction SMILES: [N:1]#[N:2].C([O:7][C:8](=[O:43])[CH2:9][N:10]([C:15](=[O:42])[C@H:16]([CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:41])[NH2:40])[NH:17][S:18]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[CH:27]=2)[CH:22]=1)(=[O:20])=[O:19])[CH2:11][CH2:12][CH2:13][CH3:14])(C)(C)C.Cl.C(OCC)(=O)C>C(Cl)(Cl)Cl>[N:1]#[N:2].[CH3:32][O:31][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:33][CH3:34])[CH:22]=[C:21]([S:18]([NH:17][C@H:16]([C:15]([N:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][C:8]([OH:43])=[O:7])=[O:42])[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:40])[NH2:41])(=[O:19])=[O:20])[CH:30]=[CH:29]2
Reactant: CCCCN(CC(=O)OC(C)(C)C)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Agent: Cl
Agent: N#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCN(CC(=O)O)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.6 %

Procedure:
To a solution of 2.00 g of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester in 20 ml of chloroform was added 50 ml of 15% HCl-ethyl acetate. The reaction mixture was stirred for 5 hours at room temperature. At the end of this period, the reaction mixture was evaporated to dryness. The residue was washed several times with dry diethyl ether and chromatographed on 80 ml of Daiaion® SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness to give 1.43 g (79 percent) of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine as an amorphous solid, I.R. (KBr): 3,360, 3,140, 1,622 cm-1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH2:16]([NH:18][C:19]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[S:20])[CH3:17]>C(OCC)C>[CH2:16]([N:18]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=2)([OH:4])[CH2:2][S:20][C:19]1=[N:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[CH3:17]
Reactant: CCNC(=S)NCc1ccccn1
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Solvent: CCOCC
Product: CCN1C(=NCc2ccccn2)SCC1(O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
4.7 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 3 g of 1-ethyl-3-(2-pyridylmethyl)-thiourea were reacted according to the prescription given in Example 23 and 150 ml of diethyl ether were added to the reaction mixture. The hygroscopic 3-ethyl-4-(4-chloro-3-sulfamoylphenyl)-2-(2-pyridylmethylimino)-1,3-thiazolidine-4-ol-hydrobromide which had separated as crystals was rapidly filtered off, dissolved in 50 ml of water and converted into the end product as described in Example 28. Colorless solid body, decomposition beginning at 135° C., γC=N 1615 cm-1.
Reaction SMILES: [CH:1]1([CH:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[CH:29][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:23][S:24][CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:43]OS([O-])=O.[K+]>CO.O>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:23][S:24]([CH3:25])=[O:43])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S([O-])OO
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(-c3ccc(C(F)(F)F)cc3)oc2CSC)C2CCCCC2)cc1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(-c3ccc(C(F)(F)F)cc3)oc2CS(C)=O)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
Ethyl 3-[({4-[(cyclohexyl{2-[(methylsulfanyl)methyl]-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methyl)amino]phenyl}carbonyl)amino]propanoate (482 mg) was dissolved in methanol (9 mL) and water (1 mL), OXONE (295 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 100% ethyl acetate/hexane) to give the title compound (232 mg, 47%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[CH2:14][CH2:15][CH2:16][CH:10]3[C:9]2=[O:17])=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:38])[C:20]([C:22]1[N:31]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:25]2[N:26]=[C:27](Cl)[N:28]=[CH:29][C:24]=2[CH:23]=1)=[O:21]>>[CH3:18][N:19]([CH3:38])[C:20]([C:22]1[N:31]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:25]2[N:26]=[C:27]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:13][CH2:12][N:11]5[CH2:14][CH2:15][CH2:16][CH:10]5[C:9]4=[O:17])=[CH:6][N:7]=3)[N:28]=[CH:29][C:24]=2[CH:23]=1)=[O:21]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCCC1
Reactant: Nc1ccc(N2CCN3CCCC3C2=O)cn1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN5CCCC5C4=O)cn3)nc2n1C1CCCCC1
Yield: 64.7 %

Procedure:
Following general N—C coupling procedure 1, 2-(6-amino-pyridin-3-yl)-hexahydro-pyrrolo[1,2-a]pyrazin-1-one (0.050 g, 0.215 mmol) was combined with 2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.066 g, 0.215 mmol, 1.0 eq), and gave 7-Cyclohexyl-2-[5-(1-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as a beige solid (75 mg, 0.139 mmol), in 65% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.23-1.52 (m, 4H) 1.72-1.90 (m, 2H) 1.90-2.00 (m, 6H) 2.00-2.18 (m, 2H) 2.21-2.39 (m, 1H) 2.52-2.82 (m, 3H) 2.95-3.14 (m, 3H) 3.15-3.27 (m, 8H) 3.42 (t, J=8.28 Hz, 1H) 3.66 (dt, J=11.54, 4.02 Hz, 1H) 3.95 (ddd, J=11.80, 9.29, 4.52 Hz, 1H) 4.27-4.41 (m, 1H) 6.45 (s, 1H) 7.69 (dd, J=9.03, 2.51 Hz, 1H) 8.11 (s, 1H) 8.25 (d, J=2.51 Hz, 1H) 8.65 (d, J=9.03 Hz, 1H) 8.73 (s, 1H); HRMS calc for m/z=503.2883 and found m/z=503.2892 (M+H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[C:34]([NH:37][C@@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)(=[O:36])[CH3:35]>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:40]5[CH2:41][CH2:42][CH:38]([NH:37][C:34](=[O:36])[CH3:35])[CH2:39]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)N[C@@H]1CCNC1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Agent: OC1CCNC1
Product: CC(=O)NC1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)C1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with (3R)-(+)-3-acetamidopyrrolidine. A yellow solid 123 was obtained (0.0397 g, 78%). 1H-NMR (CDCl3, 400 MHz) δ 2.03 (s, 3H), 2.25–2.31 (m, 1H), 2.34–2.42 (m, 1H), 3.80–3.90 (m, 3H), 4.02–4.11 (m, 1H), 4.28–4.34 (m, 4H), 4.63–4.68 (m, 1H), 6.78 (s, 1H), 6.93–6.97 (m, 2H), 7.05 (dd, J=2.2 Hz, 8.4 Hz, 1H), 7.09–7.13 (m, 2H), 7.18 (brs, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.83 (s, 1H), 8.07 (d, J=6.6 Hz, 1H); MS (APCI) m/z 516 (M+H)+.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.Cl.[CH3:14][O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.N1C=CC=CC=1>ClCCl>[CH3:14][O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:7]([Cl:10])=[O:6])[CH2:18][CH2:17]1
Reactant: COC1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC1CCN(C(=O)Cl)CC1

Procedure:
To a stirred solution of triphosgene (7.4 g, 0.025 mmol) in dichloromethane (200 ml) at ice bath was added dropwise a solution of 4-methoxy-piperidine hydrochloride salt (10 g, 0.066 mmol) and pyridine (10.9 g, 0.139 mmol) in dichloromethane (100 ml). The mixture was stirred over night and filtered through a silica pad, eluting with dichloromethane and evaporated. After trituration with diisopropyl ether, the mixture was used without purification.