Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:57])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47]([OH:54])([CH2:50][CH2:51][CH:52]=[CH2:53])[CH:46]([O:55][CH3:56])[CH2:45]2)[CH:7]([CH3:58])[CH:6]([O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[CH2:5][C:4]1=[O:67])[CH3:2].N1C(C)=CC=CC=1C.[CH2:76]([Si:78](OS(C(F)(F)F)(=O)=O)([CH2:81][CH3:82])[CH2:79][CH3:80])[CH3:77].CC(C)=[O:93]>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:57])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47]([O:54][Si:78]([CH2:81][CH3:82])([CH2:79][CH3:80])[CH2:76][CH3:77])([CH2:50][CH2:51][CH:52]=[CH2:53])[CH:46]([O:55][CH3:56])[CH2:45]2)[CH:7]([CH3:58])[C:6]([OH:93])([O:59][Si:60]([C:63]([CH3:64])([CH3:65])[CH3:66])([CH3:61])[CH3:62])[CH2:5][C:4]1=[O:67])[CH3:2]
Reactant: C=CCCC1(O)CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CC1OC
Reactant: CC(C)=O
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CO
Product: C=CCCC1(O[Si](CC)(CC)CC)CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CC1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-4"-[but-3-en-1-yl]-3"-methoxycyclohexyl)-1'-methylvinyl]-14-t-butyl-dimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (0.9 gm, 0.94 mmol) in CH2Cl2 (25 ml) at room temperature was added 2,6-lutidine (0.33 mL) followed by triethylsilyltriflate (0.52 mL, 2.3 mmole) and the reaction mixture was stirred at room temperature. The reaction progress was monitored by TLC (silica, 20% acetone:hexanes). After 1 hr, the reaction was diluted with CH3OH and partitioned between diethyl ether and H2O. The organic layer was washed successively with 1N H2SO4, H2O, NaHSO3 and brine solutions. The organic fraction was then dried over MgSO4, filtered and concentrated in vacuo to give the title compound (1.47 gm). MASS: (FAB) 1080 (M+ + Li).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[C:4]([F:15])[CH:3]=1.[H][H]>[Pt].C(O)C.O1CCCC1>[NH2:12][C:11]1[C:2]([Cl:1])=[CH:3][C:4]([F:15])=[C:5]([CH:10]=1)[NH:6][C:7](=[O:9])[CH3:8]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: [H][H]
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)Nc1cc(N)c(Cl)cc1F

Procedure:
A mixture of 4'-chloro-2'-fluoro-5'-nitroacetanilide (35.2 g, 151 mmol), and 5% platinum on carbon (7.0 g, 20 wt/wt %) in an ethanol/tetrahydrofuran (2:1) solution is hydrogenated until 28 psi of hydrogen is taken up. The reaction mixture is then filtered, and concentrated in vacuo to give the title product as a tan solid which is identified by 1H NMR spectral analysis.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17]CC)=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:23][CH:22]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(Cl)cc1
Yield: 42.9 %

Procedure:
The product is prepared according to the procedure described in Example 9, using 250 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 and 1.193 g of 4-chloroaniline in place of the 2-fluoroaniline. 140 mg of N-(4-chlorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [OH-:1].[Na+].Cl[CH:4]([C:10]1[C:15]([F:16])=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:11]=1[F:20])C(OCC)=O.[OH:21]O.S([O-])([O-])=O.[Na+].[Na+].Cl>C(O)C>[F:20][C:11]1[CH:12]=[C:13]([N+:17]([O-:19])=[O:18])[CH:14]=[C:15]([F:16])[C:10]=1[C:4]([OH:21])=[O:1]
Reactant: OO
Reactant: [OH-]
Reactant: CCOC(=O)C(Cl)c1c(F)cc([N+](=O)[O-])cc1F
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1c(F)cc([N+](=O)[O-])cc1F
Temperature: 18 °C
Reaction time: 2.5 h
Yield: 19 %

Procedure:
2.5M Aqueous sodium hydroxide solution (300 ml) was added over 5 minutes to a solution of ethyl 2-chloro-2-(2,6-difluoro-4-nitrophenyl)ethanoate (34.86 g 125 mmol) in ethanol (300 ml) at 5° C. such that the reaction temperature was kept below 25° C. The mixture was cooled to 18° C. and 30% hydrogen peroxide (40 ml) was added. The mixture was stirred at 20° C. for 2.5 hours. Sodium sulphite was added until the peroxide test was negative, the mixture was acidified to pH1 with 6M hydrochloric acid and extracted with ethyl acetate. The organic extracts were back extracted with saturated aqueous sodium hydrogen carbonate solution, the aqueous extracts were acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The extracts were dried (MgSO4) and the solvent removed by evaporation to give 2,6-difluoro-4-nitrobenzoic acid (4.89 g, 19%).
Reaction SMILES: [OH2:1].[OH-:2].[K+].[Cl-].[Li+].Cl[C:7](Cl)(Cl)[CH:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[OH:9]>O1CCOCC1.C(OCC)C>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[CH:8]([OH:9])[C:7]([OH:2])=[O:1]
Reactant: OC(c1cccs1)C(Cl)(Cl)Cl
Reactant: O
Reactant: [OH-]
Agent: [Cl-]
Agent: [K+]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(O)C(O)c1cccs1
Reaction time: 12 h

Procedure:
Into 2.4 ml of water, potassium hydroxide (0.67 g, 12 mmol) and lithium chloride (0.254 g, 6 mmol) were dissolved. Then, into the solution above, α-trichloromethyl-2-thiophenemethanol (0.693 g, 3 mmol) solution in dioxane (2.4 ml) was added and agitation was conducted for 12 hr. at room temperature and for 3 hr. at 80° C. Thereafter, water (20 ml) was added thereto and diethylether was further added into the reaction mixture. The ether soluble part was separated. The water layer was acidified with hydrochloric acid and then, extracted with diethylether. The organic layer was dried with anhydrous magnesium sulfate and was treated with activated carbon and filtered. Thereafter, the filtrate was concentrated and gave 0.246 g of 2-thiopheneglycolic acid as crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH3:9].C([N-]C(C)C)(C)C.[Li+].[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[C:29]([CH3:35])[CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:1][O:2][C:3](=[O:10])[CH:4]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:31]([C:30]1[CH:33]=[CH:34][C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:28][C:29]=1[CH3:35])[OH:32]
Reactant: Cc1cc(OCc2ccccc2)ccc1C=O
Reactant: CCCCOCC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCOC(C(=O)OC)C(O)c1ccc(OCc2ccccc2)cc1C

Procedure:
In analogy to the procedure described in example 125 a], butoxy-acetic acid methyl ester (V. Franzen, L. Fikentscher, Ann. 1958, 617, 1-10) was deprotonated with lithium diisopropylamide and treated with 4-benzyloxy-2-methyl-benzaldehyde in tetrahydrofuran at −78° C. for 3 h to obtain 3-(4-benzyloxy-2-methyl-phenyl)-2-butoxy-3-hydroxy-propionic acid methyl ester as a mixture of two diastereomeric racemates as yellow liquid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]1[O:26][CH:19]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[OH:26][CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:18][NH:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])[CH:11]=1
Reactant: NCCc1ccn(S(=O)(=O)c2ccccc2)c1
Reactant: c1ccc(C2CO2)cc1
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)n1ccc(CCNCC(O)c2ccccc2)c1

Procedure:
A mixture of 2-(1-phenylsulphonyl-3-pyrrolyl)ethylamine (1.8 g), styrene oxide (0.51 g) and acetonitrile (20 ml) were refluxed for three days. The solution was evaporated and the brown oil was purified by chromatography on silica, eluting with dichloromethane, chloroform then with increasing amounts of methanol (1→10%) in chloroform, to give the title product as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1.[CH3:31][N:32]1[CH:36]=[C:35]([S:37](Cl)(=[O:39])=[O:38])[N:34]=[CH:33]1>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)[S:37]([C:35]2[N:34]=[CH:33][N:32]([CH3:31])[CH:36]=2)(=[O:39])=[O:38])=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CCCCCNc1nc(N)nc(C)c1CCCNCc1cccc(CC(=O)OC)c1
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1CCCN(Cc1cccc(CC(=O)OC)c1)S(=O)(=O)c1cn(C)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To a stirred solution of the product from Example 1 (80 mg) dissolved in DCM (5 mL) was added 1-methylimidazole-4-sulfonyl chloride (38.4 mg) and TEA (0.032 mL) under nitrogen. The resulting solution was stirred at rt for 16 h, the solvents were evaporated and the residue redissolved in MeOH and the crude product purified by RPHPLC to afford the title compound 69 mg.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35].[H-].[Na+].O>CN(C)C=O>[F:28][C:3]1[CH:4]=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)CCCCBr
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCCCNc1c(F)cc(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 71.2 %

Procedure:
853 mg (2.19mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-1-benzopyran-4-one obtained in Example 66 was dissolved in 20 mL of dimethylformamide under argon atmosphere, 788 mg (4.38 mmol) of 1-bromo-5-methylhexane and 266 mg (6.65mmol) of sodium hydride (60% oil dispersion) were added under ice-cooling and the mixture was stirred at room temperature for 5.5 hours. The reaction solution was cooled on ice, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform: n-hexane=3:1) to give 762 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(5-methylhexylamino)-4H-1-benzopyran-4-one (yield: 71%).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][CH:13]=[CH:14][N:15]=2)[N:10]=[C:9]1[CH:19](Br)[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C>[N:24]([CH:19]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17](=[O:18])[C:16]2[C:11](=[N:12][CH:13]=[CH:14][N:15]=2)[N:10]=1)[CH:20]([CH3:22])[CH3:21])=[N+:25]=[N-:26]
Reactant: CC(C)C(Br)c1nc2nccnc2c(=O)n1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(N=[N+]=[N-])c1nc2nccnc2c(=O)n1Cc1ccccc1

Procedure:
Formula 106 where R2 and R3 are H; R5 is Benzyl: R6 is Isopropyl; R6′ is H; X and Y are —C═; and W and Z are —N═: A DMF (50 mL) solution of 3-benzyl-2-(1-bromo-2-methyl-propyl)-3H-pteridin-4-one (1.4 g, 3.75 mmol) and sodium azide (0.488 g, 7.50 mmol) was stirred at 60° C. for two hours and concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give desired azido product of Formula 106, 2-(1-azido-2-methyl-propyl)-3-benzyl-3H-pteridin-4-one, which was taken on without further purification. MS (Cl) M/E: 336.1.
Reaction SMILES: [C:1]([O-])(=O)CC.[CH2:6]([NH+:13]1[CH2:18][CH2:17][C:16]([C:30]2[NH:34][N:33]=[N:32][N:31]=2)([N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:23])[CH2:21][CH3:22])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].IC>CN(C=O)C>[CH2:6]([N:13]1[CH2:18][CH2:17][C:16]([C:30]2[N:34]([CH3:1])[N:33]=[N:32][N:31]=2)([N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:23])[CH2:21][CH3:22])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCC(=O)N(c1ccccc1)C1(c2nnn[nH]2)CC[NH+](Cc2ccccc2)CC1
Reactant: CCC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCC(=O)N(c1ccccc1)C1(c2nnnn2C)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
To a stirring mixture of 1-benzyl-4-(1H-tetrazol-5-yl)-4-(N-phenylpropionamido)piperidinium propionate (18.9 g, 40.7 mmol) and DMF (120 ml), NaH (2.4 g, 100 mmol) was added. The mixture was stirred at room temperature for 30 minutes. To the resulting brown solution, iodomethane (15 g, 106 mmol) was added slowly. It was stirred for 30 minutes and poured onto H2O (400 ml). The mixture was extracted with CH2Cl2 (2×250 ml). The CH2Cl2 solution was washed with H2O (4×400 ml), dried over Na2SO4 and concentrated in vacuo. The resulting residue was chromatographed (SiO2, 1% MeOH/CH2Cl2) to give 1-benzyl-4-(1-methyl-1H-tetrazol-5-yl)-4-(N-phenylpropionamido)piperidine (4.58 g, 11.3 mmol) as a colorless viscous oil: IR (neat) 1660 cm-1 ; NMR (270 MHZ, CDCl3) δ0.834, (t, 3H, CH3CH2CO), 1.789 (q, 2H, CH3CH2), 3.334 (s, 2H, phCH2), 4.435 (s, 3H, tetrazolyl CH3), 7.15 to 7.47 (m's, 10H, phenyl H's), and 1-benzyl-4-(2-methyl-2H-tetrazol-5-yl)-4-(N-phenylpropionamido)piperidine (2.75 g, 6.8 mmol) as a viscous oil: IR (neat) 1660 cm-1 ; NMR (270 MHz, CDCl3) δ0.830 (t, 3H, CH3CH2CO), 1.810 (q, 2H, CH3CH2), 3.402 (s, 2H, phCH2), 4.369 (s, 3H, tetrazolyl CH3), 7.20 to 7.54 (3m's, 10H, phenyl H's). ##STR29##
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1C(=CC=CC=1)S.[C:11]([NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17](SC1C=CC(Cl)=CC=1)[C:18]([CH3:28])(CC(O)=O)[NH:19]2)(=[O:13])[CH3:12].F[C:38](F)(F)[C:39](O)=O>>[C:11]([NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[C:18]([CH3:28])[N:19]2[CH2:2][C:1]([O:10][CH2:38][CH3:39])=[O:9])(=[O:13])[CH3:12]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)c1ccccc1S
Reactant: CC(=O)Nc1cccc2c1C(Sc1ccc(Cl)cc1)C(C)(CC(=O)O)N2
Product: CCOC(=O)Cn1c(C)cc2c(NC(C)=O)cccc21
Temperature: 60 °C

Procedure:
Thiosalicylic acid was added to a solution of the product from Example 1 part (iv) (474 mg) in trifluoroacetic acid (10 ml) was added thiosalicylic acid (351 mg) and the resulting suspension was heated to 60° C. for 4 hours. The mixture was concentrated in vacuo and the residue dissolved in EtOAc and washed with NaHCO3 (aq), brine, dried (MgSO4) and evaporated to give crude material. Purification by column chromatography (50% EtOAc/hexane as eluent) gave the sub-title compound (0.13 g).
Reaction SMILES: [C:1]([C:3](=[C:6]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)SC)[C:4]#[N:5])#[N:2].O.[NH2:20][NH2:21]>CO>[NH2:2][C:1]1[NH:21][N:20]=[C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(CNC(SC)=C(C#N)C#N)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: COc1ccc(CNc2n[nH]c(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 15 g (57.8 mmol) of 2-cyano-3-(4-methoxy-benzylamino)-3-methylmercapto-acrylonitrile, 3.03 ml (61.1 mmol) of hydrazine hydrate and 40 ml of methanol is stirred for 1 hour at RT, heated under reflux for 2 hours and then concentrated by evaporation in vacuo. Recystallization of the residue from ethanol/hexane yields the title compound; m.p. 148-149° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16])[C:5]([OH:7])=O)[CH3:2].[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>>[C:18]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[F:16])=[CH:21][CH:20]=1)#[N:17]
Reactant: CCOC(C(=O)O)c1ccc(OC)cc1F
Reactant: N#Cc1ccc(CN)cc1
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OC)cc1F

Procedure:
(RS)-Ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide. Yellow oil. MS 343.2 ([M+H]+)
Reaction SMILES: O.OO.N[C:5]([NH2:7])=[O:6].[OH-].[Na+].[C:10]([O:14][C:15]([N:17]1[CH2:42][CH2:41][C:20]2([CH2:23][N:22]([C@H:24]3[C:32]4[C:27](=[CH:28][C:29]([C:33]5[CH:34]=[N:35][C:36](C#N)=[CH:37][CH:38]=5)=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[CH2:21]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CCO>[C:10]([O:14][C:15]([N:17]1[CH2:42][CH2:41][C:20]2([CH2:23][N:22]([C@H:24]3[C:32]4[C:27](=[CH:28][C:29]([C:33]5[CH:34]=[N:35][C:36]([C:5](=[O:6])[NH2:7])=[CH:37][CH:38]=5)=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[CH2:21]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4ccc(C#N)nc4)ccc31)C2
Reactant: NC(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4ccc(C(N)=O)nc4)ccc31)C2
Temperature: 25 °C
Yield: 60.2 %

Procedure:
To a solution of water (150 mL) and urea hydrogen peroxide (916 mg, 9.45 mmol) was added sodium hydroxide (220 mg, 5.51 mmol) and the reaction was stirred at room temperature. Once a clear solution was obtained, the reaction was placed in an ice bath and fitted with an addition funnel. A solution of 2-[(R)-5-(6-cyano-pyridin-3-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (4-1c, 700 mg, 1.58 mmol) in 50 mL EtOH was added dropwise via the funnel over 30 minutes. The reaction was warmed to room temperature and was stirred overnight. The reaction mixture (a white suspension) was filtered and the solids were washed with 50 mL water and air-dried to give 440 mg (60%) of the title compound as an off-white powder. MS (ES+) 463.1 (M+H)+. 1H NMR (DMSO-d6) δ 1.39 (s, 9H), 1.54-1.62 (m, 4H), 1.81-1.91 (m, 1H), 2.06 (dd, 1H), 2.76-2.87 (m, 1H), 2.94-3.02 (m, 3H), 3.10 (d, 2H), 3.24 (br s, 4H), 3.86 (dd, 1H), 7.40 (d, 1H), 7.55 (d, 1H), 7.62-7.68 (m, 2H), 8.09 (d, 1H), 8.12 (br s, 1H), 8.22 (dd, 1H), 8.89 (d, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:12])[C:7]=1[NH:8][CH:9]([CH3:11])[CH3:10].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl>C1(C)C(C)=CC=CC=1>[Cl:12][C:6]1[C:7]([NH:8][CH:9]([CH3:11])[CH3:10])=[C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:3]=[N:4][CH:5]=1
Reactant: C1CNCCN1
Reactant: CC(C)Nc1c(Cl)cncc1Cl
Agent: Cl
Solvent: Cc1ccccc1C
Product: CC(C)Nc1c(Cl)cncc1N1CCNCC1

Procedure:
A mixture of 3,5-dichloro-4-(1-methylethyl)aminopyridine (PREPARATION 41, 1.77 g) and piperazine (2.96 g) in xylene (18 ml) is refluxed for 40 hr. The mixture is cooled and then treated with concentrated hydrochloric acid (8 ml). After further cooling, a precipitate forms and the organic liquid is separated. The aqueous phase is diluted with an excess of a solution of aqueous sodium hydroxide (10%) and then is extracted with chloroform (3×). The combined organic extracts are washed with water, then saline, dried over sodium sulfate, and concentrated to an oil. The crude product is flash chromatographed on silica gel eluting with methanol. The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 1.20, 3.04, 3.18, 4.46, 4.73 and 8.50δ; CMR (CDCl3) 24.0, 44.3, 45.9, 50.2, 118.2, 135.8, 148.3 and 155.4 δ.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:10]1([N:13]2[C:21]3[C:16](=[CH:17][C:18]([CH2:22][NH:23][S:24]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[CH:19][CH:20]=3)[CH:15]=[N:14]2)[CH2:12][CH2:11]1>>[CH:10]1([N:13]2[C:21]3[C:16](=[CH:17][C:18]([CH2:22][N:23]([C:3]4[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=4)[S:24]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[CH:19][CH:20]=3)[CH:15]=[N:14]2)[CH2:12][CH2:11]1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3C3CC3)c2)cc1
Reactant: Fc1ncc(Cl)cc1Cl
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3C3CC3)c2)c2ncc(Cl)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and methyl 4-(N-((1-cyclopropyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-5 of Example 28).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: Nc1ccc(Cl)cn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Cl)cn2)cc1Cl
Temperature: 0 °C
Yield: 40.9 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it was completely dissolved and became light purple in color. The reaction mixture was then treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 92, 200 mg, 0.61 mmol) and stirred at 0° C. for 20 min and then warmed to 25° C. where it was stirred for 30 min. After such time, the reaction mixture was treated with 2-amino-5-chloropyridine (117 mg, 0.91 mmol) and pyridine (0.088 mL, 1.09 mmol), and the reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (10 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80/20 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-chloro-pyridin-2-yl)-propionamide (110 mg, 41%) as a yellow foam: EI-HRMS m/e calcd for C20H22Cl2N2O3S (M+) 440.0728, found 440.0728.