Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:23])[C:5]([N+:20]([O-:22])=[O:21])=[C:6]([C:8]([C:18]#[N:19])([CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:9]([OH:11])=[O:10])[N:7]=1.C.N[C:26]1NC(=O)C([N+]([O-])=O)=C(Cl)N=1.Cl>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[NH:3][C:4](=[O:23])[C:5]([N+:20]([O-:22])=[O:21])=[C:6]([C:8]([C:18]#[N:19])([CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:9]([O:11][CH3:26])=[O:10])[N:7]=1
Reactant: Nc1nc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Reactant: N#CC(Cc1cccs1)(C(=O)O)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Agent: C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C#N)(Cc1cccs1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
2-Amino-α-cyano-1,6-dihydro-5-nitro-6-oxo-α-(2-thienylmethyl)-4-pyrimidineacetic acid, methyl hydride (4.5 g, 60% suspension in oil washed with hexane) is suspended in dry DMF (50 mL) under an atmosphere of dry N2 and a solution of methyl 2-cyano- 3-(2-thienyl) propionate (U.S. Pat. No. 4,279,903) (22.0 g) in dry DMF (50 mL) is added dropwise when a dark blue solution is formed. A solution of freshly recrystallized 2-amino-6-chloro-5-nitro-4(3H)-pyrimidinone (8.57 g) in DMF (75 mL) is added in one portion. The reaction mixture is heated at 60° C. overnight and cooled and then is acidified to pH 5 with 1N HCl. It is poured into 1000 mL ethyl acetate and is extracted with water (4×300 mL). The organic layer is evaporated to near dryness and the residue is suspended in ether and collected by filtration. The crude product is washed with hexane until the washings are no longer green. The solid is dried under vacuum to give 2-Amino-α-cyano-1, 6-dihydro-5-nitro-6-oxo-α-(2-thienylmethyl)-4-pyrimidine-acetic acid, methyl ester. ##STR14##
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][C@@H:51]1[CH2:56][NH:55][CH2:54][C@H:53]([CH3:57])[NH:52]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:55]6[CH2:54][C@H:53]([CH3:57])[NH:52][C@H:51]([CH3:50])[CH2:56]6)[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(C=O)c3)c2)c1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(CN4C[C@@H](C)N[C@@H](C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (0.033 g, 0.05 mmol), (2R,6S)-2,6-dimethylpiperazine (0.00685 g, 0.06 mmol), and acetic acid (0.0036 g, 0.06 mmol) were combined in CH2Cl2 (2 mL). Sodium triacetoxyborohydride (0.0148 g, 0.07 mmol) was added and the mixture stirred overnight at room temperature. Solvents were concentrated, and the residue taken up in EtOAc, washed with 1N NaOH, brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The product was purified using a Gilson HPLC with a TFA system. The purified compound was taken up in EtOAc, washed 3× with 2.5 N NaOH, 1× with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound as a white solid. LC-MS m/z 757.2 (M+H)+, 1.37 min (ret time); mp 109-112° C. Analytical HPLC shows 99.8% purity, (ret time 10.205 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:6]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: CN1CCC(c2cn(S(=O)(=O)c3ccc(F)cc3)c3ccc(F)cc23)CC1

Procedure:
(22.6 mg, 58%) from 5-fluoro-3-(1-methyl-4-piperidinyl)-1H-indole (Example 5c, 25 mg, 0.1 mmol) and 4-fluorophenylsulfonyl chloride (29.2 mg, 0.15 mmol), HRMS- FAB+ for C20H20N2O2SF2, calculated MH+ : 391.12918; found: 391.12926.
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccc(F)cc1)C1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4-fluorobenzoyl)piperidine hydrochloride (53.30 g, 0.219 mol) and benzenesulfonyl chloride (44 g, 0.25 mol) in 500 mL of pyridine was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and dilute NaOH. The CH2Cl2 solution was extracted with dilute H2SO4 and then dried (MgSO4). The volume was reduced to 400 mL, hexane was added, and 39.20 g (50.6%) of the title compound was collected as a white crystalline solid, mp 156.5°-158° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([C:9]([C:11]2[CH:16]=[C:15]([I:17])[C:14]([OH:18])=[C:13]([I:19])[CH:12]=2)=[O:10])=[CH:4][C:3]=1[I:20].Br[CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CC(N(C)C)=O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:1][C:2]1[C:3]([I:20])=[CH:4][C:5]([C:9](=[O:10])[C:11]2[CH:12]=[C:13]([I:19])[C:14]([OH:18])=[C:15]([I:17])[CH:16]=2)=[CH:6][C:7]=1[I:8])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C(c1cc(I)c(O)c(I)c1)c1cc(I)c(O)c(I)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: O=C(COc1c(I)cc(C(=O)c2cc(I)c(O)c(I)c2)cc1I)OCc1ccccc1
Yield: 2.3 %

Procedure:
A solution of bis-(4-hydroxy-3,5-diiodophenyl)-methanone (prepared according to Example 9, 3.59 g, 5.0 mmol) and benzyl 2-bromoacetate (1.15 g, 5.0 mmol) in 20 mL DMAc was stirred with cesium carbonate (3.3 g, 10 mmol) for 14 hours. Next was added 1 M HCl, and a yellow oil formed along with a hazy white precipitate. The precipitate was isolated by filtration and was recrystallized from hot isopropanol/chloroform, yielding the title compound as colorless crystals (98 mg, 2.2%). No attempt was made to isolate more product from the oil. 1H NMR (400 MHz, CDCl3): δ 8.11 (s, 2H), 8.10 (s, 2H), 7.45-7.35 (m, 5H), 6.22 (s, 1H), 5.33 (s, 2H), 4.72 (s, 2H). HPLC (40-90), 19.17 min. (EI−) calc'd for [C22H14I4O5—H] 864.7, found 864.6.
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[N:21]=[N:22][NH:23][CH:24]=3)=[C:9]([OH:25])[C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28].C1(N2C=CC(CCCC3N=NNC=3)=C(O)C2=S)C=CC=CC=1>>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[N:21]=[N:22][NH:23][CH:24]=3)=[C:9]([OH:25])[C:8]2=[S:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1c(O)c(CCCCCCCc2c[nH]nn2)ccn1-c1ccccc1
Agent: Oc1c(CCCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Product: Oc1c(CCCCCCCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Yield: 86.2 %

Procedure:
Reaction of 159f (0.12 g, 0.532 mmol) and P4S10 (0.076 g, 0.17 mmol) under neat conditions as described for synthesis of 162b gave compound 162f (0.054 g, 43%) as a olive green semi-solid. 1H NMR (400 MHz, DMSO) δ 8.55 (m, 1H), 7.81 (d, J=8.2 Hz, 2H), 7.65 (d, J=6.2 Hz, 1H), 7.42 (m, 2H), 7.30 (m, 1H), 7.02 (m, 1H), 6.85 (m, 1H), 4.50 (m, 2H), 4.36 (t, J=7.1 Hz, 2H), 1.85 (d, J=7.0 Hz, 4H), 1.33 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 147.76, 130.66, 128.76, 130.39, 128.98, 128.80, 128.06, 125.97, 125.67, 119.46, 60.10, 50.25, 30.11, 29.67, 28.33, 26.13, 26.10. HRMS (FAB) calcd for C20H25N4OS [M+H]+ 369.174. found 369.1762.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[N+:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([O-:28])=[O:27]>O1CCCC1>[N+:26]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:2][CH:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:34])=[CH:36][CH:37]=1)([O-:28])=[O:27]
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CC(NC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(OC)c(OC)c1
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
To an ice bath cooled stirred suspension of methyl 3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride(1.38 grams, 5.00 mmol) and triethylamine (1.5 milliliters, 10.8 mmol) in 25 milliliters of tetrahydrofuran was added 4-nitrobenzoyl chloride (0.928 grams, 5.00 mmol) in a single portion. After 15 minutes, the cooling bath was removed and the reaction mixture stirred for 45 minutes. The reaction mixture was then diluted with 50 milliliters of water. The reaction slurry was filtered and the solid washed with water, air-dried, and then dried in vacuo (60 C., <1 mm) to afford 1.86 grams (94%) of the product as a yellow powder: 1H NMR (CDCl3 /TMS, 250 MHz) δ 8.27 (d, J=8.8 Hz, 2 H), 7.98 (d, J=8.8 Hz, 2 H), 7.77 (d, J=8.1 Hz, 1 H, NH), 6.95-6.75 (m, 3 H, Ar), 5.55 (m, 1 H, CH), 3.86 & 3.85 (2 s, 6 H, 2 OCH3), 3.68 (s, 3 H, CO2 CH3), 3.00 (m, 2 H, CH2); 13C NMR (CDCl3 /TMS) δ 172.2, 164.4, 149.6, 1491, 148.7, 139.7, 132.6, 128.2, 123.8, 118.1, 111.2, 109.9, 55.9, 55.8, 52.0, 50.0, 39.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42](Cl)=[O:43]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:42]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=3)=[O:43])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)C(=O)c3ccccn3)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, picolinoyl chloride hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[C:24]([N:14]1[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:16][CH2:15]1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(CCNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
0.5 g of 4-(2-tert-butoxycarbonylaminoethyl)-piperidine and 0.61 ml of triethylamine are dissolved in 5 ml of dichloromethane and, at 0° C., 0.22 ml of acetyl chloride is added. The reaction mixture is stirred at room temperature for 7 hours and then washed with water. The organic phase is concentrated by evaporation and purified by FC (10 g of silica gel, ethyl acetate/methanol=9:1). The title compound is obtained: Rf (ethyl acetate/methanol=9:1)=0.39.
Reaction SMILES: I[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].Cl[C:9]1[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[N:10]=1>C1(C)C=CC=CC=1.CN(C)C(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:11]1[CH:12]=[C:13]([CH3:15])[N:14]=[C:9]([CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])[N:10]=1
Reactant: COC(=O)CCI
Reactant: Cc1cc(C)nc(Cl)n1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: COC(=O)CCc1nc(C)cc(C)n1
Temperature: 110 °C
Yield: 9.1 %

Procedure:
A suspension of Zn—Cu couple (3.45 g) in toluene/N,N-dimethylacetamide (14:1, 30 mL) was degassed by bubbling N2 through the suspension for 15 min. Then methyl 3-iodopropanoate (1.96 g, 9.14 mmol) was added to the suspension, and the resulting mixture was heated at 110° C. for 6 h. The reaction mixture was allowed to cool to 70° C., and 2-chloro-4,6-dimethylpyrimidine (961 mg, 6.77 mmol) and tetrakis(triphenylphosphine) palladium (235 mg, 0.203 mmol) were added. The reaction mixture was maintained at 70° C. for 22 h. Upon cooling to r.t., the mixture was filtered, and the filter cake was rinsed with ether (10 mL×3). The filtrate was extracted with 1 M hydrochloric acid (75 mL×2). The acidic extracts were basified with the addition of sodium bicarbonate, and the resulting solution was extracted with ether (75 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and the solution was concentrated to give a residue, which was purified by prep-TLC to afford methyl 3-(4,6-dimethylpyrimidin-2-yl)propanoate as a pale-yellow solid (120 mg). MS (ESI): m/z 195 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.[CH2:12]1[O:16][C@@H:15]2[C@H:17]([OH:20])[CH2:18][O:19][C@@H:14]2[C@@H:13]1O>C(Cl)Cl>[N+:1]([O-:4])([O:3][C@@H:13]1[CH2:12][O:16][C@@H:15]2[C@H:17]([OH:20])[CH2:18][O:19][C@H:14]12)=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Temperature: 0 °C
Reaction time: 3 h
Yield: 41.3 %

Procedure:
To a solution of fuming nitric acid (0.92 mL, 22.2 mmol) in CH2Cl2 (44 mL) and acetic anhydride (2.10 mL, 22.2 mmol) cooled to −20° C., 1,4:3,6-dianhydro-D-mannitol (2.50 g, 17.1 mmol) was added as solid. After the reaction mixture was stirred at 0° C. for 3 hours, it was slowly poured into ice/NaHCO3. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography (Biotage SP1, column SNAP 100, EtOAc/n-hexane from 30 to 100%), affording the title product as a white solid (1.35 g, yield 41%). 1H-NMR (300 MHz, CDCl3); δ 5.39 (1H, q), 4.89 (1H, t), 4.49 (1H, t), 4.35-4.27 (1H, m), 4.10-4.04 (2H, m), 3.58 (2H, t), 2.40 (1H, d).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[C-:22]=[N:21][N:20]=[N:19]1.[Na+]>CN(C)C=O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:19]2[N:20]=[N:21][CH:22]=[N:18]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [c-]1nnn[nH]1
Reactant: CS(=O)(=O)OC1CCN(Cc2ccccc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CN2CCC(n3ncnn3)C2)cc1
Temperature: 87.5 °C
Yield: 19.2 %

Procedure:
A suspension of N-benzyl-3-[(methylsulphonyl)oxy]pyrrolidine (2.2 g, 9.37 mmol) and sodium 1,2,3,4-tetrazolide (1.8 g, 19.6 mmol) in 50 ml of dimethylformamide was heated at 85-90° C. overnight. The reaction mixture was worked up the same as described in Example U. The crude product was purified over silica gel using hexane, ether and ethyl acetate as eluant to afford in order of elution 0.413 g of N-benzyl-3-(1,2,3,4-tetrazol-2-yl) pyrrolidine as an oil. 1H NMR (CDCl3) δ: 8.51 (s, 1H), 7.37-7.17 (m, 5H), 5.51-5.35 (m, 1H), 3.8-3.65 (q, 2H), 3.3-2.4 (m, 6H); and.26 g of N-benzyl-3-(1,2,3,4-tetrazol-1-yl)pyrrolidine as an oil. 1H NMR (CDCl3) 6 : 8.88 (s, 1H), 7.4-7.2 (m, 5H), 5.35-5.2 (m, 1H), 3.83-3.6 (q, 2 H), 3.2-2.3 (m, 5H), 2.15-2.00 (m, 1H).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[C:14]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(C(=O)c2ccccc2)c2ccccc21
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
14.7 g (0.10 mole) of isatin (dissolved in 100 ml of N,N-dimethylformamide) are added to 2.6 g (0.11 mole) of sodium hydride in 100 ml of N,N-dimethylformamide, while stirring. After the mixture has been stirred for one hour at room temperature, 14.1 g (0.10 mole) of benzoyl chloride are added dropwise at 0° C. Stirring is then continued for 10 minutes at 0° C. and the mixture is poured onto ice. The precipitate which separates out is filtered off under suction and dried to give 20 g (80%) of N-benzoylisatin as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(O)(O)(=O)=O.[CH3:33][O:34][C:35](=[NH:37])[NH2:36].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:37][C:35]([O:34][CH3:33])=[N:36][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:24]([F:26])([F:27])[F:25])[O:13][N:12]=2)=[CH:15][C:16]=1[CH3:23]
Reactant: COC(=N)N
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC#N
Product: COC(N)=NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C

Procedure:
To a solution of 1.00 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methylbenzoyl-chloride synthesized in Process 4 of Synthetic Example 1 in 20 mL of acetonitrile, 0.85 g of O-methylisourea sulfate and 1.26 g of potassium carbonate were added and the resultant mixture was stirred at room temperature for 1.5 hours. After the completion of the reaction, the insoluble substance was filtered off and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (1:1) to obtain 0.40 g of the objective substance as a yellow resin-state substance.
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]>CN(C=O)C.CC(OC)(C)C>[Si:47]([O:46][CH2:45][CH2:44][N:11]1[CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:33][CH2:34][CH2:35][CH3:36])[N:9]=[C:10]1[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CCCCN(CCCC)C(=O)c1cn(CCO[Si](C)(C)C(C)(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
To a stirred solution of 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (190 mg, 0.40 mmol) in dry DMF (5 mL) was added K2CO3 (160 mg, 1.16 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (92 mg, 0.38 mmol) at 0° C. The mixture was allowed to warm to room temperature and heated at 50° C. for 24 h. The reaction mixture was cooled to 0° C., diluted with MTBE and quenched with water. The organic layer was separated and the aqueous layer was extracted with MTBE (3×). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to provide crude product. The crude material was purified by flash chromatography (gradient 10 to 30% ethylacetate/hexane) to provide the title compound (144 mg, 54%). 1H NMR (CD3OD) 8.66 (d, J=1.6 Hz, 1H), 8.30 (dd, J=8.0, 2.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.65 (s, 1H), 7.38-7.29 (m, 5H), 5.20 (s, 2H), 3.99 (s, 3H), 3.83-3.82 (m, 2H), 3.77 (t, J=5.0 Hz, 2H), 3.70 (t, J=5.0 Hz, 2H), 3.49 (br s, 2H), 1.70-1.55 (m, 4H), 1.45-1.26 (m, 4H), 1.05-0.85 (m, 6H), 0.83 (s, 9H), 0.03 (s, 6H); MS(ESI+) m/z 650.2 (M+H)+.
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[CH:12]([CH:15]([CH3:17])[CH3:16])[NH:11][S:10]2(=[O:19])=[O:18])C=CC=CC=1.S(Cl)([Cl:23])(=O)=O>C(Cl)Cl>[Cl:23][CH2:8][N:9]1[C:13](=[O:14])[CH:12]([CH:15]([CH3:17])[CH3:16])[NH:11][S:10]1(=[O:19])=[O:18]
Reactant: CC(C)C1NS(=O)(=O)N(CSc2ccccc2)C1=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)C1NS(=O)(=O)N(CCl)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94 %

Procedure:
To a solution of 2-phenylthiomethyl-4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (3.8 g) in 60 ml of methylene chloride was added sulfuryl chloride (1.52 ml) and the mixture was stirred for 2.5 hours at room temperature. The mixture was concentrated in vacuo, the residue triturated in hexane (200 ml) for 2 hours, and the resulting solid filtered and dried to afford 2.7 g (94%) of 2-chloromethyl-4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula II: R1 =H; R2 =isopropyl; R3 =H; X'=Cl) as a solid, m.p. 71°-72° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([OH:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][C:38]1[C:43]([F:44])=[CH:42][CH:41]=[CH:40][N:39]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([O:22][CH2:37][C:38]3[C:43]([F:44])=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(O)cc(C)cc12)NC(=O)OC(C)(C)C
Reactant: Fc1cccnc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3ncccc3F)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
A solution of 49 mg (0.12 mmol) of rac-[1-{[7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carbonyl)amino]}-1-methylbutyl)carbamic acid tert-butyl ester (Example 141A) in 2.1 ml of DMF was admixed with 78 mg (0.24 mmol) of caesium carbonate and 69 mg (0.360 mmol) of 2-bromomethyl-3-fluoropyridine (Example 143A). The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated off under reduced pressure and the residue was partitioned between dichloromethane and water. The organic phase was removed and concentrated under reduced pressure. The residue was purified by preparative HPLC chromatography (Method 21), which gave 21 mg (33% yield, 96% pure) of the target compound.