Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:28])[CH2:9][N:10]([CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.[CH:29]1([O:35][C:36]2[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][C:41]=2[C:42]([O:44][CH3:45])=[O:43])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C1(NC2CCCCC2)CCCCC1.C1(NC2CCCCC2)CCCCC1.C([O-])(=O)C>[C:13]([O:12][C:11]([N:10]([CH2:9][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:28])[CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:38]2[CH:39]=[CH:40][C:41]([C:42]([O:44][CH3:45])=[O:43])=[C:36]([O:35][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:37]=2)=[CH:23][CH:22]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(CCNc1ccc(I)cc1)C[C@H](O)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(B(O)O)cc1OC1CCCCC1
Agent: [Pd+2]
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(NCCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 53.9 %

Procedure:
To a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-[(4-iodophenyl)amino]ethyl]carbamate (200 mg), [3-(cyclohexyloxy)-4-(methoxycarbonyl)phenyl]-boronic acid (193 mg), potassium phosphate (246 mg) in ethanol (1.5 ml) was added bis(dicyclohexylamine) -palladium(II) acetate (32.9 mg) and the mixture was stirred at 60° C. for 3 hours under nitrogen atmosphere. After warming to 80° C., the mixture was stirred at the same temperature for 3 hours. To the reaction mixture were added [3-(cyclohexyloxy)-4-(methoxycarbonyl)phenyl]boronic acid (107 mg) and bis(dicyclohexylamine)palladium(II) acetate (10.9 mg) and the mixture was stirred at 80° C. for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through the celite cake. The filtrate was washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave the crude product which was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/6 to 1/2) to give methyl 4′-[[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-ethyl]amino]-3-(cyclohexyloxy)-4-biphenylcarboxylate (130 mg) as a white solid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:8][NH:7][N:6]=1)=[N+]=[N-].[H][H]>[Ni].C(O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]2[C:9]3[C:5](=[N:6][NH:7][N:8]=3)[CH2:4][N:1]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[CH:12]=1
Reactant: [N-]=[N+]=NCc1n[nH]nc1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1n[nH]nc1-2
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A mixture of 3 g (8.9 mmole) of 4-azidomethyl-5-[4-chloro-2-(benzoyl)phenyl]-2H-1,2,3-triazole and about 3 teaspoonsful of Raney nickel in 150 ml of ethanol was shaken in a Parr bottle with an initial hydrogen pressure of 5 p.s.i. for 1 hr. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to give 2 g of gummy solid. The residue was chromatographed over silica gel using a 1:1 mixture of ethyl acetate and methylene chloride as eluent. Evaporation of the solvent gave a gum which crystallized from a small amount of ethyl acetate to give white crystals. Recrystallization from a mixture of ethyl acetate and petroleum ether gave colorless prisms, mp 203°-205° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:3]=1.[C:26](OCC)(=O)[CH3:27]>CN(C=O)C.[F-].[K+].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:9][C:8]([F:11])([F:10])[C:6]1[N:5]=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:3]=[C:2]([CH:26]=[CH2:27])[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)nc(C(F)(F)F)n2)CC1
Reactant: CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(F)(F)F)n1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-{[6-chloro-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidine-1-carboxylate (0.742 g, 1.94 mmol) in DMF (8.7 mL) was added (2-ethenyl)tri-n-butyltin (0.682 mL, 2.33 mmol) and tetrakis(triphenylphosphine)palladium(0) (112 mg, 0.0972 mmol). The reaction solution was stirred at 65° C. overnight. The reaction solution was diluted with ethyl acetate and saturated KF solution. The aqueous layer was extracted with ethyl acetate three times. The combined organic solutions were dried over Na2SO4, filtered and concentrated. The residue was purified with silica gel column to give the desired product as light brown oil. LCMS (M+H)+: 374.2.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C@:7]([OH:50])([C@@H:11]([C:29](=[O:49])[NH:30][C@H:31]([CH2:44][O:45]C(=O)C)[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]#[C:42][CH3:43])=[CH:35][CH:34]=1)/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:8]([OH:10])=[O:9])(=O)C.CO.[Li+].[OH-]>O>[CH2:40]([O:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][C@H:31]([NH:30][C:29]([C@@H:11](/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C@@:7]([OH:50])([CH2:6][CH2:5][OH:4])[C:8]([OH:10])=[O:9])=[O:49])[CH2:44][OH:45])=[CH:38][CH:37]=1)[C:41]#[C:42][CH3:43]
Reactant: CC#CCOc1ccc(C[C@@H](COC(C)=O)NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC(C)=O)C(=O)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC#CCOc1ccc(C[C@@H](CO)NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)O)cc1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To a mixture of No. 5257015 , (E)-(2S,3S)-2-(2-acetoxy-ethyl)-3-[(S)-1-acetoxymethyl-2-(4-but-2-ynyloxy-phenyl)-ethylcarbamoyl]-2-hydroxy-12-oxo-nonadec-4-enoic acid (17 mg, 0.0244 mmol) and methanol (1.7 mL) were added water (49 μL) and LiOH (2.4 mg, 0.0983 mmol), and the mixture was stirred at room temperature. After confirming the consumption of the starting materials by LCMS, the reaction solution was purified directly by preparative HPLC, and freeze-dried to obtain the title compound (9 mg, 60% yield, yellow oil).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Cl:19][CH2:20][CH2:21][CH2:22][S:23](Cl)(=[O:25])=[O:24]>>[Cl:19][CH2:20][CH2:21][CH2:22][S:23]([NH:18][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17])(=[O:25])=[O:24]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: O=S(=O)(Cl)CCCCl
Product: O=S(=O)(CCCCl)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
According to the general procedure A, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with 3-chloropropane-1-sulfonyl chloride to obtain the desired product. 1H NMR (500 MHz, CDCl3): δ=7.39-7.38 (d, 1H), 7.35-7.34 (m, 1H), 7.27-7.26 (m, 1H), 7.10-7.0 (q, 1H), 6.63 (s, 1H, br), 6.15-6.11 (q, 1H), 5.60 (s, 1H, br), 3.60-3.56 (t, 2H), 3.22-3.20 (m, 2H), 2.22-2.16 (m, 2H).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.[CH2:13]([C:17]1([C:21](OC)=[O:22])[CH2:20][CH2:19][CH2:18]1)[CH2:14][CH2:15][CH3:16]>C1COCC1>[CH2:13]([C:17]1([C:21](=[O:22])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:20][CH2:19][CH2:18]1)[CH2:14][CH2:15][CH3:16]
Reactant: COP(C)(=O)OC
Reactant: CCCCC1(C(=O)OC)CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC1(C(=O)CP(=O)(OC)OC)CCC1
Reaction time: 0.25 h

Procedure:
To a solution of dimethyl methylphosphonate (1.46 g, 11.8 mmol) in anhydrous THF (25 mL) at −78° C. was added n-BuLi (7.4 mL, 1.6 M, 11.8 mmol) dropwise under Ar. The reaction was stirred for 15 minutes. A solution of methyl 1-butylcyclobutanecarboxylate (1.00 g, 5.87 mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirred for 30 minutes at −78° C., after which it was allowed to warn to room temperature. The reaction was quenched with 5% HCl, extracted with CH2Cl2 (3×30 mL), the combined organic phase was washed with brine, dried (MgSO4). After concentration, flash chromatography (silica gel, 1:1 ethylacetate:hexanes), the title compound was obtained as a colorless oil. 1HNMR (CDCl3) δ 0.85˜0.89 (m, 3H), 1.05˜1.15 (m, 2H), 1.22˜1.35 (m, 2H), 1.65˜1.95 (m, 6H), 2.35˜2.50 (m, 2H), 3.00 (s, 1H0, 3.06 (s, 1H), 3.78 (s, 3H), 3.82 (s, 3H). MS (m/z) 285 (M+Na)
Reaction SMILES: C1([NH2:7])CCCCC1.C(S(C[C@@H:16]([CH2:20][C:21]1[C:30]2[C:25](=CC=CC=2)[CH:24]=[CH:23][CH:22]=1)C(O)=O)(=O)=O)(C)(C)C>>[C:21]1([C@H:20]([NH2:7])[CH3:16])[CH:30]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1cccc2ccccc12)C(=O)O
Reactant: NC1CCCCC1
Product: C[C@@H](N)c1ccccc1

Procedure:
3-Substituted 2-sulfonylmethylpropionic acids have been prepared in moderate e.e. (enantiomeric excess), i.e. up to around 80% e.e. in two steps, from the corresponding allyl sulfides, by sequential asymmetric hydrogenation and oxidation at sulfur (DE-A-4233100; Jendralla, Tetrahedron: Asymmetry (1994) 5:1183-1186; Beck et al, Tetrahedron (1994) 50:4691-4698; Jendrella, Proceedings of Chira Tech '97 (The Catalyst Group). The requisite allyl sulfides are normally prepared as E/Z mixtures by a Wittig olefination reaction; subsequent separation of geometric isomers is required to give optimum results in the asymmetric hydrogenation process. For example, (E)-2-tert-butylthiomethyl-3-(1-naphthyl)acrylic acid was hydrogenated in methanol using a catalyst prepared from (S)-(−)-BINAP, benzeneruthenium (II) chloride dimer and NaOAc at 150° C. and 13800 kPa (2000 psi), followed by peracid oxidation to give (S)-3-tert-butylsulfonyl-2-(1-naphthylmethyl)propionic acid. Similar results were achieved via hydrogenation of the corresponding cyclohexylamine salt form. To access (S)-3-tert-butylsulfonyl-2-(1-naphthylmethyl)propionic acid in >99% e.e. required additional processing, with concomitant loss of yield, by crystallisation of diastereomeric salts formed with (R)-1-phenylethylamine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:24]1([N:21]2[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:14][CH:9]3[CH2:10][O:11][CH2:12][CH2:13][NH:8]3)=[O:17])[CH2:19][CH2:20]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCOCC1COC(=O)N1CCN(c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCC1COCCN1)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
3-(4-Phenyl-piperazine-1-carbonyloxymethyl)-morpholine-4-carboxylic acid tert-butyl ester (3.31 g, 8.16 mmol) was stirred in DCM (30 mL) at 0° C. TFA (6 mL) dissolved in DCM (24 mL) was added dropwise. The reaction mixture was stirred overnight at room temperature. The solvents were removed in vacuo and the residue was partitioned between DCM (30 mL) and aq NaHCO3 (5 g in 30 mL). The aqueous layer was extracted with DCM (3×30 mL), dried (MgSO4) and the solvents were removed in vacuo to give morpholin-3-ylmethyl 4-phenylpiperazine-1-carboxylate (2.55 g, quant.) as a white solid.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][N:14]=[C:13]([O:16][CH2:17][CH:18]3[O:20][CH2:19]3)[C:12]=2[CH:21]=1.O>C(#N)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][N:14]=[C:13]([O:16][CH2:17][CH:18]([OH:20])[CH2:19][OH:2])[C:12]=2[CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc2onc(OCC3CO3)c2c1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: OCC(O)COc1noc2ccc(Cl)cc12
Yield: 74.2 %

Procedure:
256 ml of a 10% w/v aqueous solution of potassium carbonate were added to a suspension of 21.0 g (92.7 mmoles) of 5-chloro-3-(2,3-epoxypropoxy)-1,2-benzisoxazole (prepared according to the method described in Japanese Patent Provisional Publication No. Sho. 52-31070) in 100 ml of acetonitrile, and the mixture was then heated under reflux for 3 hours. At the end of this time, the reaction mixture was cooled by allowing it to stand, and then 500 ml of water were added. The reaction mixture was then extracted with 1 liter of ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was removed by distillation to give a solid residue. This was then recrystallized from a mixture of ethyl acetate and diethyl ether, to give 16.7 g (yield 74.2%) of the title compound as a colorless amorphous powder, melting at 61°-62° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][N:18]2N)=[CH:14][CH:13]=1>N1C=CC=CC=1>[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][N:18]2[C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:14][CH:13]=1
Reactant: NN1CCc2ccc(Cl)cc21
Reactant: Clc1ncnc2[nH]ccc12
Solvent: c1ccncc1
Product: Clc1ccc2c(c1)N(c1ncnc3[nH]ccc13)CC2
Temperature: 85 °C
Yield: 6.3 %

Procedure:
To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (10.0 g, 0.065 mol) in dry pyridine (90 ml) was added 6chloro2,3dihydroindol-1-yl amine (14.8 g, 0.078 mol), and the mixture was heated in an 85° C. oil bath for 2 days. The reaction was cooled to ambient temperature and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (375 g, 40 mm mesh) using 5% MeOH/CH2Cl2 to afford the title compound as a pink-orange solid (1.1 g, 4.3%): HRMS: Calculated 271.0750, Found 271.0729; anal. RP18-HPLC RT: 4.88 minutes.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O>[O:22]=[C:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:9][CH:10]=1)[C:3]([OH:23])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCCCc2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCCCCc2cccnc2)cc1

Procedure:
A mixture of alpha-oxo-4-[4-(3-pyridinyl)butoxy]benzeneacetic acid methyl ester (4:1) molar hydrate (1.1 g) in hot methanol (10 mL) was treated with 1N sodium hydroxide (5 mL) and diluted with water. The organic solvent was removed under vacuum and the residue in water was washed with diethyl ether. The aqueous layer was concentrated to about 25 mL and chilled in ice. Cold 2N hydrochloric acid (2.5 mL) was added dropwise and the product was allowed to crystallize and was filtered and air dried. Recrystallization from acetone provided 0.64 g of alpha-oxo-4-[4-(3-pyridinyl)butoxy]benzeneacetic acid as a colorless solid, mp 163°-165° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]1([CH2:54][NH2:55])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:55][CH2:54][CH:47]4[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NCC1CCCCCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCC2CCCCCC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with N-cycloheptylmethyl-amine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C44H58Cl2N5O3 [(M+H)+] 774.391 1, observed 774.3909.
Reaction SMILES: [OH-].[NH4+:2].[CH2:3]([O:5][C:6](=[O:40])[CH2:7][CH2:8][C:9]1[N:10]([C:30]2[CH:35]=[CH:34][C:33]([C:36](=[O:38])[NH2:37])=[CH:32][C:31]=2[CH3:39])[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23]C3C=CC=CC=3)=O)=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH3:4].CS(C)=O>O>[CH2:3]([O:5][C:6](=[O:40])[CH2:7][CH2:8][C:9]1[N:10]([C:30]2[CH:35]=[CH:34][C:33]([C:36](=[O:38])[NH2:37])=[CH:32][C:31]=2[CH3:39])[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH2:2])=[O:23])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH3:4]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1-c1ccc(C(N)=O)cc1C
Reactant: [NH4+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CCc1ccc(-c2ccc(NC(N)=O)cc2)n1-c1ccc(C(N)=O)cc1C
Temperature: 85 °C
Yield: 35 %

Procedure:
Under a nitrogen atmosphere, ammonium hydroxide (2 mL) was slowly added to 3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-phenoxycarbonylaminophenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (13B) (66 mg, 0.13 mmol). Dimethylsulfoxide (1 mL) was slowly added. The reaction was then heated to 85° C. for 24 hrs. After cooling, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by preparative TLC plate (1500 microns, 10% IPA/CH2Cl2). The desired band (rf=0.2) was isolated and dried under high vacuum to yield 3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-ureidophenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (13C) (20 mg, 35%, light yellow powder).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[N:5]([S:7]([NH2:10])(=[O:9])=[O:8])[CH3:6].C[O-].[Na+]>CO>[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][CH:4]1[N:5]([CH3:6])[S:7](=[O:9])(=[O:8])[NH:10][C:3]1=[O:2]
Reactant: COC(=O)C(CCC(C)C)N(C)S(N)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCC1C(=O)NS(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 100.8 %

Procedure:
A solution of N-(aminosulfonyl)-2-(3-methylbutyl)sarcosine methyl ester (12.25 g, 48.17 mmol) in methanol (150 ml) was added to a solution of sodium methoxide (Na=2.4 g) in 150 ml of ice-cold methanol. The resulting reaction mixture was stirred at room temperature under nitrogen for 18.5 hours, and then the mixture was treated with 25 g of ion-exchange resin (BIO RAD® 50W x 8; 200-400 mesh) for 40 minutes and filtered. The filtrate was concentrated in vacuo to afford 10.7 g (99.8%) of 4- (3-methylbutyl)-5-methyl--1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IV: R1 =(CH2)2CH(CH3)2 ; R2 =H; R3 =CH3) as a solid, m.p. 212°-214° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.Cl.Cl.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=4)[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: ClCc1cn2cc(Br)ccc2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: OCCO
Product: Clc1ccc(N2CCN(Cc3cn4cc(Br)ccc4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 6-bromo-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 15, Step 1; 0.3042 g), 1-(4-chlorophenyl)piperazine dihydrochloride (Aldrich; 0.3708 g), triethylamine (Aldrich; 0.55 mL), and ethylene glycol (5.6 mL) is stirred for 1 h at 80° C. After cooling, the mixture is partitioned between water and dichloromethane. The combined organic layers are washed with brine, dried with MgSO4, and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (4/96) to give, after crystallization from ethyl acetate/methanol/dichlormetane, 0.1756 g of the title compound; mp 154-155° C.; MS m/z 404, 406, 408; IR (mineral oil) 1495, 1500, 1224, 823, 812 cm-1 ; 1H NMR (CDCl3) δ2.72, 3.19, 3.76, 6.83, 7.20, 7.22, 7.47, 7.52, 8.24.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH2:20])[N:14]=2)[C:9](F)=[N:10][CH:11]=1)=[CH2:5])C.[C:21]1([S:27]([C:30]2[CH:31]=[C:32]([NH2:36])[CH:33]=[N:34][CH:35]=2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.CCOC(C)=O>[NH2:20][C:15]1[N:16]=[C:17]([CH3:19])[N:18]=[C:13]([C:8]2[CH:7]=[C:6]([C:4](=[O:3])[CH3:5])[CH:11]=[N:10][C:9]=2[NH:36][C:32]2[CH:33]=[N:34][CH:35]=[C:30]([S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[CH:31]=2)[N:14]=1
Reactant: Nc1cncc(S(=O)(=O)c2ccccc2)c1
Reactant: C=C(OCC)c1cnc(F)c(-c2nc(C)nc(N)n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1cnc(Nc2cncc(S(=O)(=O)c3ccccc3)c2)c(-c2nc(C)nc(N)n2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
4-(5-(1-Ethoxyvinyl)-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (255 mg, 0.925 mmol) and 5-(phenylsulfonyl)pyridin-3-amine (260 mg, 1.110 mmol) were dissolved in THF (9.2 mL) and the resulting mixture was cooled to 0° C. and NaHMDS in THF (1.0 M, Aldrich; 2775 μL, 2.77 mmol) was added. The reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was then diluted with 100 mL of EtOAc, added to a separatory funnel, and partitioned with ammonium chloride (saturated, aqueous). The organic layer was separated, washed 2 times with 50 mL of ammonium chloride (saturated, aqueous), dried over sodium sulfate, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 3% (2 M ammonia in MeOH)/DCM) gave the title compound (44% yield) as a yellow amorphous solid. m/z (ESI, +ve ion) 462.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]([NH:19][C:20]([C:22]3[N:23]=[C:24]([C:35]([O:37]CC)=[O:36])[N:25]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=3)=[O:21])[CH3:18])[N:12]=2)[CH:5]=[C:6]([F:10])[C:7]=1[C:8]#[N:9].[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]([NH:19][C:20]([C:22]3[N:23]=[C:24]([C:35]([OH:37])=[O:36])[N:25]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])[CH:26]=3)=[O:21])[CH3:18])[N:12]=2)[CH:5]=[C:6]([F:10])[C:7]=1[C:8]#[N:9]
Reactant: CCOC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1COCC[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(COCC[Si](C)(C)C)c(C(=O)O)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(d) starting from (S)-ethyl 4-((1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)carbamoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (5.22 mmol, 3 g) and sodium hydroxide (7.83 mmol, 313 mg). Yield 1.49 g. LC-MS: [M+1]=547.28.