Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][N:32]=1)[C:27](O)=[O:28]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:27]([C:26]3[CH:30]=[CH:31][N:32]=[C:24]([CH3:23])[CH:25]=3)=[O:28])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: Cc1cc(C(=O)O)ccn1
Agent: Cl
Product: Cc1cc(C(=O)N2CCCC[C@@H]2COc2cccc3c2C(N)=NS(=O)(=O)N3)ccn1

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-methylisonicotinic acid. 1H NMR (400 MHz, CD3OD) δ 1.51-2.00 (m, 6H), 2.57 (s, 3H), 3.27 (m, 1H), 3.45 (m, 1H), 4.28 (m, 1H), 4.73 (t, 1H, J=10.5 Hz), 5.42 (m, 1H), 6.66 (d, 1H, J=8.1 Hz), 6.87 (d, 1H, J=8.1 Hz,), 7.22 (m, 1H), 7.26 (s, 1H), 7.48 (t, 1H, J=8.6 Hz), 8.50 (d, 1H, J=4.8 Hz). MS 430 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:3]=12.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[CH3:8][C:6]1[N:5]=[C:4]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:3]2=[C:2]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:7]=1
Reactant: C1CCNCC1
Reactant: Cc1cc(Cl)c2oc(-c3ccccc3)cc2n1
Solvent: CN(C)C=O
Product: Cc1cc(N2CCCCC2)c2oc(-c3ccccc3)cc2n1
Temperature: 120 °C
Reaction time: 26 h
Yield: 68.4 %

Procedure:
To a mixture of 7-chloro-5-methyl-2-phenylfurano[3,2-b]pyridine (Example 228 (c)) (365 mg, 1.50 mmol) and piperidine (5 mL, 50.5 mmol) was added DMF (2 mL). Mixture stirred at 120° C. under N2 for 26 h. After cooling, the reaction mixture was concentrated. The residue was diluted with H2O (70 mL) and Et2O (50 mL). The mixture was transferred to a separatory funnel and the organic solution was collected. The aqueous solution was washed with Et2O (2×40 mL). The organic solutions were combined, washed with H2O (50 mL), saturated NaCl (70 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with 50:50 EtOAc:hexanes as elutant to give 300 mg (68%) of 5-methyl-2-phenyl-7-piperidylfurano[3,2-b]pyridine as a cream colored solid. This material (298 mg, 1.02 mmol) was dissolved in EtOAc (20 mL) and heated to boiling. To the hot solution was added 1M etheral HCl (1.00 mL, 1.00 mmol). The solution was left to cool to 25° C. The resulting solid was collected by filtration, washed with EtOAc (2×5 mL), Et2O (3×5 mL) and dried under vacuum at 25° C. to give 290 mg (59%) of the title compound as a white colored powder. Mp: >280° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.67 (br s, 6), 2.49 (s, 3), 3.94 (br s, 4), 6.93 (s, 1), 7.46-7.54 (m, 4), 7.98 (dd, 2, J=1.5, 7.6), 14.14 (s, 1). MS m/z: 293 (M+1 for free base). Anal. Calcd for C19H20N2O.HCl.0.25H2O: C, 68.46; H, 6.50; N, 8.41; Cl, 10.64. Found C, 68.60; H, 6.44; N, 8.43; Cl, 10.56.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][O:29][CH2:30][CH2:31][C:32](O)=[O:33]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH2:30][O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: COCCC(=O)O
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (78 mg, 62%), MS (ISP) m/z=417.5 [(M+H)+], mp 180° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (132 mg, 0.3 mmol) and 3-methoxypropionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][CH:4]=1.[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH:11]=[CH2:12]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:12]=[CH:11]/[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COc1ccc(I)cc1
Product: COc1ccc(/C=C/C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
Following the general procedure using 4-methoxyiodobenzene (117 mg, 0.50 mmol) and tert-butyl acrylate (145 μL, 1.00 mmol), the reaction was stirred for 4 h at rt. Column chromatography on silica gel (eluting with 3% EtOAc/hexanes) afforded the product as a colorless oil (113 mg, 97%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26]>O1CCOCC1.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: C1COCCO1
Solvent: O
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 37 g (0.1 mol) of p-nitrophenyl ester of benzyloxycarbonylproline in 360 ml of dioxane there is added a solution of 16 g (0.09 mol) of arginine in 160 ml of water under vigorous stirring. Two hours thereafter the solvent is evaporated and the precipitate is dissolved in 100 ml of dimethylformamide. The solution is stirred at room temperature for 72 hours and poured into 1 liter of ethylacetate. The resulting residue is filtered-off, washed on the filter with ethylacetate and reprecipitated from a mixture ethanol-ethylacetate. The yield of product (I) is 35 g (96%); the product has the following properties: M.p. 190° C., [α]D20 -46.6°; (c 1.0; H2O); Rf =0.53 (A, "Silufol") 0.66 (B, "Eastman"); EHis =0.56 (pH=2.4).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[CH3:11][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#CCc1ccc(Br)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C#N)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.6 %

Procedure:
To a stirred solution of 2-(4-bromo phenyl) acetonitrile (20 g, 102.04 mmol) in dry tetrahydrofuran (200 mL) was added sodium bis(trimethylsilyl)amide (18.71 g, 102.04 mmol) at 0° C. under a nitrogen atmosphere. After stirring for 20 minutes at room temperature, methyl iodide (14.48 g, 102 mmol) was added and then stirred for 1 h at room temperature. The reaction mixture was quenched with an aqueous ammonium chloride solution and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water (2×100 mL), a saturated aqueous sodium chloride solution (2×25 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (3-4% ethyl acetate/hexanes) afforded 2-(4-bromo-phenyl)-propionitrile as a light yellow liquid (11.5 g, 53.6%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][N:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH3:12]>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][N:7]=[N:8]2)=[C:4]([NH2:12])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]nnc2n1
Reactant: N
Product: Nc1nc(N)c2[nH]nnc2n1

Procedure:
A solution of 428 mg. of the 2-amino-6-chloro-8-azapurine of Example 8 in 25 ml. of liquid ammonia was heated for 18 hours at 60° C. in a stainless steel bomb containing a glass liner. The bomb was chilled and opened, and ammonia was evaporated with a current of nitrogen. The residual solid was triturated with water (12 ml.), collected by filtration, washed with cold water, and dried in vacuo at 56° C.: yield, 359 mg. (90%); m.p. 245°-247° C. dec. (inserted at 200° C., 3° C./min.). A second crop of the carbocyclic analog of 2,6-diamino-8-azapurine 2'-deoxyribofuranoside was isolated in the same way from the concentrated filtrate: weight 31 mg. (total yield, 98%); m.p. 244°-246° C. dec. (inserted at 200° C., 3° C./min.). A solution of the two portions in boiling water (35 ml.) was treated with a small amount of activated charcoal, concentrated to about one-half of the original volume, and refrigerated. The white crystalline compound (Formula VII, X=NH2) was separated by filtration, washed with cold water, and dried in vacuo at 56° C.: weight, 350 mg. (92% recovery); m.p. 246°-248° C. dec. (inserted at 200° C., 3° C./min.); TLC, 1 spot (40 mcg., 2:1 chloroform-methanol as developing solvent); UV max 285 nm (ε7700), 255 (ε9800), 214 (ε26,000) at pH 1; 287 (ε10,600), 258 (ε5800), 223 (ε25,800) at pH 7; 287 (ε10,700), 258 (ε5800), 223 (ε26,000) at pH 13; MS (direct-probe temperature, 220° C.), m/e 265 (M), 248 (M-OH), 235, 234 (M-CH2OH), 218 (M-OH-CH2OH+H), 206 (M-CH2OH-N2), 190 (M-75), 178 (P+C2H4), 152 (P+2H), 151 (P+H); IR (strong bands; 1800-600 cm-1 region) 1670, 1630, 1600, 1585 vs, 1480 vs, 1420, 1020, 785, 670.
Reaction SMILES: [I-].Cl[C:3]1[CH:8]=CC=C[N+:4]=1C.C(N(CC)CC)C.C(N)C.[C:20]([NH:23][CH2:24][CH2:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[CH:28]=[C:27]1[C:37]([OH:39])=O)(=[O:22])[CH3:21]>ClCCl>[C:20]([NH:23][CH2:24][CH2:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[CH:28]=[C:27]1[C:37]([NH:4][CH2:3][CH3:8])=[O:39])(=[O:22])[CH3:21]
Reactant: COc1ccc2cc(C(=O)O)n(CCNC(C)=O)c2c1
Reactant: C[n+]1ccccc1Cl
Agent: CCN
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)c1cc2ccc(OC)cc2n1CCNC(C)=O

Procedure:
Under nitrogen, add 0.18 g of 2-chloro-1-methylpyridinium iodide, 0.25 ml of triethylamine and 0.04 ml of ethylamine in dichloromethane to a solution of 0.20 g of the compound obtained in Step C of Example 1 in 20 ml of dichloromethane and then heat at reflux for 14 hours. Dilute the reaction mixture with dichloromethane and wash with saturated aqueous sodium chloride solution. Extract and dry the organic phase over sodium sulfate and then filter and evaporate. Purify the compound by column chromatography on silica gel using as eluant a 19/1 dichloromethane/ethanol mixture. After triturating in diisopropyl ether, the title compound is obtained in the form of a white solid.
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)CCCC1.[C:28]([CH:32]1[CH2:37][CH2:36][CH:35]([NH:38][CH:39]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29].C(OC(=O)CSC1SC(N)=NC=1)C>>[C:28]([C@H:32]1[CH2:37][CH2:36][C@H:35]([N:38]([CH:39]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)[CH2:34][CH2:33]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)C1CCC(NC2CCCCCC2)CC1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(C)(C)[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via (4-tert-butyl-cyclohexyl)-cycloheptyl-amine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester to give the title compound.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](Cl)[C:4]=1[C:19]([O:21][CH3:22])=[O:20].[CH2:24]([N:26](CC)[CH2:27]C)C.CNC.Cl>CN(C=O)C>[F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([N:26]([CH3:27])[CH3:24])[C:4]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1Cl
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1N(C)C
Yield: 64.5 %

Procedure:
A solution of 3.46 g (0.010 mol) of the compound produced in Example 103, 0.97 g (0.010 mol) of triethylamine and 2.00 g (0.012 mol) of a 26% W/V solution of aqueous dimethylamine in 50 ml of DMF was stirred at room temperature for 18 hours. The reaction mixture was poured into 3.7% HCl and extracted with diethyl ether. The ether phase was washed with H2O, and dried (MgSO4). The dry ether phase was con-centrated in vacuo to 2.6 g of a yellow solid. This crude product was purified using the HPLC in 5% ethyl acetate/cyclohexane, affording 2.39 g (67%) of a yellow solid; mp 80°-81° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16]Br)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH2:23]>CO.C(N(CC)CC)C>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][NH:23][CH2:22][C:21]([O:20][CH3:19])=[O:24])([O:5][CH2:6][CH3:7])=[O:8])[CH3:2]
Reactant: CCOP(=O)(Cc1ccccc1CBr)OCC
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOP(=O)(Cc1ccccc1CNCC(=O)OC)OCC

Procedure:
A solution of the diethyl[[2(bromomethyl)phenyl]methyl]phosphonate (Example A) (0.9 g, 2.8 mmol) in methanol (25 ml) and triethylamine (5 ml) is treated with glycine methyl ester hydrochloride (0.71 g, 5.6 mmol) and heated at reflux in an oil bath for 19 hours. The solvent is removed in vacuo and the residue dissolved in water and extracted with chloroform. The chloroform layer is dried over magnesium sulfate, filtered, and evaporated. The oily residue is purified via silica gel chromatography (2-4% methanol in chloroform as eluant).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17](N)=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].C([OH:28])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:28])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCO
Reactant: C=C(C)COc1ccc(Cl)cc1CN(CC)c1ccc(C(N)=O)nn1
Product: C=C(C)COc1ccc(Cl)cc1CN(CC)c1ccc(C(=O)O)nn1

Procedure:
A mixture of 6-[N-(5-Chloro-2-(2-methylprop-2-en-1-yloxy)benzyl)-N-ethylamino]-pyridazine-3-carboxamide (example 18) (10.5 g, 29.3 mol) and caustic liquor, 40% w/v (10 ml, 100 mmol) in ethanol (150 ml) was stirred at reflux for 16 hours. The solvent was evaporated at reduced pressure and the residue partitioned between 2N hydrochloric acid (70 ml) and dichloromethane (200 ml). The organic layer was dried over anhydrous magnesium sulphate, filtered and evaporated to give a brown gum (10.0 g), which was redissolved in ether (200 ml) and allowed to crystallise slowly over 12 hours to give the title compound as a pale yellow solid (4.6 g, 45%) m.p. 130-131° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH2:9][CH3:10])[CH:3]=1.C([Li])CCC.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].O>C(OCC)C>[CH2:9]([C:4]1[CH:3]=[C:2]([Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[C:6]([CH3:8])[N:5]=1)[CH3:10]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCc1cc(Br)cc(C)n1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)nc(CC)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of 19.4 g of 4-bromo-2-ethyl-6-methylpyridine from (a) above in 275 ml of diethyl ether chilled to -70° C. under argon was added dropwise over 1/2 hour 38.8 ml of n-butyllithium while maintaining the reaction temperature below -65° C. Stirring was continued at -70° C. for 1 hour and then 22 ml (26.4 g) of tributyltin chloride in 25 ml of diethyl ether were added over 20 minutes. The mixture was allowed to warm to 20° C. and 200 ml of water was added. The ether layer was separated, dried over magnesium sulfate and concentrated in vacuo (90° C.; 50 mm). Hexane was added and the mixture was filtered and the filtrate was concentrated in vacuo (15 mm) to give the title product as a yellow liquid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[N:10]=[CH:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7]1)=[S:5])[CH3:2].[C:15]1(C)C=CC(S(OC)(=O)=O)=CC=1>CO>[CH3:15][S:5][C:4]([N:6]1[N:10]=[CH:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7]1)=[N:3][CH2:1][CH3:2]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CCNC(=S)N1CC2(C=N1)CCCC2
Solvent: CO
Product: CCN=C(SC)N1CC2(C=N1)CCCC2
Yield: 31.9 %

Procedure:
To a solution of 1.0 g (4.7 mmol) 2,3-diazaspiro[4.4]non-3-ene-2-carbothioic acid ethylamide in 10 mL methanol was added 1.1 g (5.7 mmol) methyl p-toluenesulfonate. The mixture was refluxed for 48 hrs and concentrated under reduced pressure. The residue was triturated with 30 mL diethyl ether and all volatiles were removed from the isolated oily product under reduced pressure. The residual oil was taken up in 40 mL dichloromethane and extracted 3 times with a saturated aqueous NaHCO3 solution. The organic layer was dried over MgSO4, filtered and evaporated to dryness under reduced pressure to afford 0.33 g (1.5 mmol, 31%) of N-ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboximidothioic acid methyl ester as a light-brown oil. 1H NMR identical to spectrum obtained from material prepared by using iodomethane as methylating agent (vide supra).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11]/[C:12](=[CH:17]\[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)/[C:13](OC)=[O:14]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:11]/[C:12](=[CH:17]\[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)/[CH2:13][OH:14]
Reactant: COC(=O)/C(C)=C/c1ccc2ccccc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C/C(=C\c1ccc2ccccc2c1)CO
Temperature: -78 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A solution of diisobutylaluminum hydride in toluene (1.5M, 26 ml) was added dropwise to a solution of methyl (E)-2-methyl-3-(2-naphthyl)acrylate (3.52 g) in CH2Cl2 (100 ml) at −78° C. and the mixture was stirred at −78° C. for 1 hour. The mixture was washed with 1N HCl and brine, dried and concentrated. The residue was crystallized from CH2Cl2-hexane to give the titled compound (2.89 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[C:5]#[N:6].[NH2:14][OH:15]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])/[C:5](=[N:14]/[OH:15])/[NH2:6]
Reactant: CC(C)Oc1ccc(C#N)cc1Br
Reactant: NO
Solvent: CCO
Product: CC(C)Oc1ccc(/C(N)=N/O)cc1Br
Temperature: 65 °C
Yield: 98.2 %

Procedure:
3-bromo-4-isopropoxybenzonitrile (0.68 g, 2.83 mmol) and hydroxylamine (0.208 ml, 3.12 mmol) were combined in EtOH (20 ml). The reaction mixture was heated at 65° C. for 16 hr. The reaction mixture was concentrated to afford (Z)-3-bromo-N′-hydroxy-4-isopropoxybenzimidamide (0.76 g, 2.78 mmol, 98% yield) as pale yellow solid. LC/MS (Table 1, Method a) Rt=2.89 min.; MS m/z: 275.00 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:46])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][CH2:38][C:39]([OH:41])=[O:40])=[O:36])=[CH:33][C:32]=2[O:44][CH3:45])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:80][O:81][CH2:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH2:88][CH2:89]O>O1CCCC1>[CH3:80][O:81][CH2:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH2:88][CH2:89][O:40][C:39]([CH2:38][O:37][C:35](=[O:36])[C:34]1[CH:42]=[CH:43][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:46])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:44][CH3:45])[CH:33]=1)=[O:41]
Reactant: COc1cc(C(=O)OCC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: COCCOCCOCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCCOCCOC(=O)COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(OC)c1
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
In a 20 mL round-bottomed flask, 2-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)acetic acid (Example 69, 150 mg, 222 μmol), HATU (84.6 mg, 222 μmol) and Hunig's base (86.2 mg, 117 μL, 667 μmol) were combined with dry tetrahydrofuran (1 mL) to give a light brown suspension at room temperature. It was stirred for 30 min and the solution became clear. Triethylene glycol monomethyl ether (76.9 mg, 73.4 μL, 445 μmol) was added drop wise to the mixture. After stirring at room temperature overnight, the reaction mixture was concentrated. The residue was reconstituted with ethyl acetate. It was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was absorbed on small amount of silica gel and loaded on a 24 g pre-packed silica gel column. Eluting the column with ethyl acetate gave 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxycarbonylmethyl ester as an off-white solid (65 mg, 35% yield). LCMS (ES+) m/z calcd. for C40H46Cl2F2N3O9 [(M+H)+]: 820. found: 820.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.[CH3:16][C@@H:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:25](=[O:26])[NH:24][C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:16])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CO
Reactant: C[C@@H](N=C=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1noc(-c2ccc(Br)cc2)c1COC(=O)N[C@H](C)c1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol (0.120 g, 0.45 mmol) and (R)-(+)-α-methylbenzyl isocyanate (0.17 mL, 1.2 mmol) were combined in toluene and stirred overnight at 90° C. The mixture was diluted with CH2Cl2 and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10]1.C(N(CC)CC)C.[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:25][C:26]([CH3:31])([CH3:30])[C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10]1)=[O:28]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1C1Cc2ccccc2N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C1Cc2ccccc2N1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a solution of 5.00 g 2-(2-amino-5-chlorophenyl)-2,3-dihydro-1H-indole in 70 ml CH2Cl2 at 10° C. were added 3.14 ml triethylamine and then dropwise 2.52 ml trimethylacetylchloride. The resulting solution was stirred for one hour at 10° C. and then quenched with water. The organic phase was separated, washed with 7.5% NaHCO3 and saturated NaCl, dried (MgSO4), and concentrated to yield 5.67 g solid. Recrystallization from cyclohexane yielded 3.09 g solid, m.p. 195°-198° C.