Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.FC(F)(F)S(O[C@H:12]1[CH2:19][C@@:18]2([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C:20](=[O:21])[C@H:14]([C:15](=[O:29])[CH:16]=[C:17]2[O:27][CH3:28])[C@:13]1([CH3:36])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])(=O)=O.Cl[Si:40]([CH3:43])([CH3:42])[CH3:41].C([N-]C(C)C)(C)C.[Li+]>CCOC(C)=O.CCCCCC>[CH3:28][O:27][C:17]1[C:18]2([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C:20](=[O:21])[C:14]3([C:15](=[O:29])[C:16]=1[Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:12]([C:13]3([CH3:36])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[CH2:19]2
Reactant: COC1=CC(=O)[C@H]2C(=O)[C@]1(CC=C(C)C)C[C@H](OS(=O)(=O)C(F)(F)F)[C@@]2(C)CCC=C(C)C
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC1=C([Si](C)(C)C)C(=O)C23C(=O)C1(CC=C(C)C)CC2C3(C)CCC=C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A THF (6 mL) solution of 21 (148 mg, 0.300 mmol, 1 equiv.) and chlorotrimethylsilane (1.9 mL, 15 mmol, 50 equiv.) was cooled to −78° C. in a 25-mL recovery flask, and a freshly prepared THF solution of lithium diisopropylamide (0.50 M, 3.0 mL, 1.5 mmol, 5 equiv.) was added slowly. The resulting yellow-orange solution was stirred at −78° C. for 30 min and subsequently quenched at −78° C. with saturated aqueous NaHCO3. After warming to room temperature, the mixture was extracted thrice with EtOAc. The organic extracts were combined, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give an orange oil. Flash column chromatography (100 mL SiO2, 95:5 hexane:EtOAc) afforded 69.7 mg (0.168 mmol, 56% yield) of 22 as a faint yellow oil. TLC Rf 0.52 (8:2 hexane:EtOAc). 1H NMR (600 MHz; C6D6): δ 5.41 (t, J=7.4 Hz, 1H), 5.28 (t, J=7.1 Hz, 1H), 3.22 (s, 3H), 2.59 (dd, J=15.1, 6.4 Hz, 1H), 2.53-2.49 (m, 1H), 2.48 (dd, J=15.1, 8.4 Hz, 1H), 2.18 (m, 1H), 1.86 (ddd, J=13.5, 11.2, 5.2 Hz, 1H), 1.79 (ddd, J=13.5, 11.2, 5.4 Hz, 1H), 1.74 (dd, J=14.0, 5.4 Hz, 1H), 1.68-1.66 (m, 1H), 1.66 (s, 3H), 1.65 (s, 3H), 1.61 (s, 3H), 1.54 (s, 3H), 1.07 (s, 3H), 0.98 (dd, J=7.9, 5.4 Hz, 1H), 0.35 (s, 9H). 13C NMR (126 MHz; C6D6): δ 200.2, 194.7, 184.3, 134.4, 131.56, 131.55, 124.6, 119.5, 74.1, 61.8, 56.8, 48.0, 38.7, 37.7, 27.7, 26.21, 26.10, 25.8, 17.92, 17.77, 16.3, 0.7. FTIR (thin film) νmax: 2968, 2918, 2860, 1762, 1664, 1523, 1451, 1438, 1386, 1233, 1201, 1157, 1042, 962, 845, 761, 691 cm−1. HRMS-ESI (m/z): [M+H]+ calculated for C25H38O3Si, 415.2663. found, 415.2650.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)[CH2:3][C:4]([O-])=[O:5].[BH4-].[Na+].C(OCC)(=O)C.CCCCCC.O>CO>[NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)[CH2:3][CH2:4][OH:5]
Reactant: COc1ccc(C(N)CC(=O)[O-])cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: COc1ccc(C(N)CCO)cc1OC
Reaction time: 1 h
Yield: 90.8 %

Procedure:
A solution of 3-amino-3-(3',4'-dimethoxyphenyl)-propionate (4.12 grams, 17.2 mmol) in methanol (50 milliliters) was slowly added to stirred sodium borohydride (6.51 grams, 17.2 mmol). After the initial effervescence had ceased the mixture was refluxed for 1 hour. Reaction progress was monitored by TLC (20% ethyl acetate/hexane, uv) and was complete after 1 hour. The reaction mixture was allowed to cool and then 20 milliliters of water was added. The methanol was removed in vacuo resulting in the formation of a gum which was extracted into methylene chloride (3×20 milliliters). The combined extracts were dried over magnesium sulfate and concentrated to afford an oil which was refrigerated. A waxy solid formed which was dried in vacuo (60° C.,<1 mm) to afford 3.30 g (86%) of the product as a white solid. 1H NMR (CDCl13)δ6.91-6.78(m, 3H), 4.15-4.04(m, 1H), 3.89(s, 3H), 3.88(s, 3H), 3.84-3.71(s, 2H), 3.91-2.45(broad m, 1H), 1.95-1.78(m, 2H).
Reaction SMILES: [N+:1]([N:4]=[C:5]1[NH:9][CH2:8][CH2:7][S:6]1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][N:18]=1>C(#N)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:9]2[CH2:8][CH2:7][S:6][C:5]2=[N:4][N+:1]([O-:3])=[O:2])=[CH:19][N:18]=1
Reactant: O=[N+]([O-])N=C1NCCS1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])N=C1SCCN1Cc1ccc(Cl)nc1

Procedure:
A mixture of 2.9 g of 2-nitroiminothiazolidine, 2.9 g of anhydrous potassium carbonate, 3.2 g of 2-chloro-5-pyridylmethylchloride and 50 ml of acetonitrile was refluxed for 5 hours with vigorously stirring. After the reaction, most of the acetonitrile was removed by distillation and water was added to the residue. As the solid product was separated, it was collected by filtration. The crude material was recrystallized from ethanol to give desired 3-(2-chloro-5-pyridylmethyl)-2-(nitroimino)thiazolidine.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26](I)=[CH:27][C:21]=4[S:20](=[O:30])(=[O:29])[N:19]=3)=[C:14]([OH:31])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:32][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:40]1[S:41](=[O:46])(=[O:45])[CH2:42][CH2:43][CH:44]=1)CCC>CN(C)C=O.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>[O:45]=[S:41]1(=[O:46])[CH2:42][CH2:43][CH:44]=[C:40]1[C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:18]([C:15]3[C:16](=[O:17])[N:7]([CH2:6][C:5]4[CH:33]=[CH:34][C:2]([F:1])=[CH:3][CH:4]=4)[C@@H:8]4[C@H:13]([C:14]=3[OH:31])[C@@H:12]3[CH2:32][C@H:9]4[CH2:10][CH2:11]3)=[N:19][S:20](=[O:30])(=[O:29])[C:21]=2[CH:27]=1
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCS1(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C1C(C2=NS(=O)(=O)c3cc(C4=CCCS4(=O)=O)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 22 h
Yield: 19.1 %

Procedure:
To a solution of (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 19, 200 mg, 0.34 mmol) and tributyl-(1,1-dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-stannane (prepared as described in US patent application US 2008/0031852, 180 mg, 0.44 mmol) in anhydrous N,N-dimethylformamide (7 mL) under a nitrogen atmosphere, Pd(PPh3)4 (20 mg, 0.017 mmol) was added. The resulting mixture was stirred at 90° C. for 22 h, and then allowed to cool to 25° C. The reaction mixture was concentrated in vacuo and the residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30%-95% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, (1R,2S,7R,8S)-5-[7-(1,1-dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (38 mg, 0.065 mmol, 20%), as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.19 (2H, m), 1.42-1.61 (4H, m), 2.50 (1H, m), 2.65 (1H, m), 2.97 (2H, m), 3.05 (1H, m), 3.53 (3H, m), 4.43 (1H, d, J=14.4 Hz), 4.96 (1H, d, J=15.6 Hz), 7.15 (2H, m), 7.33 (2H, m), 7.41 (1H, t, J=3.6 Hz), 7.66 (1H, d, J=9.2 Hz), 7.96 (1H, dd, J=8.8, 2.4 Hz), 8.10 (1H, d, J=2.4 Hz). LC-MS (ESI) calcd for C28H26FN3O6S2 583.12, found 584.2 [M+H+].
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH3:8][NH:9][C:10]1[S:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][CH:11]=1>ClCCCl.CN(C1C=CN=CC=1)C>[CH3:8][N:9]([C:10]1[S:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][CH:11]=1)[C:5](=[O:6])[CH2:4][CH2:3][S:2][CH3:1]
Reactant: CSCCC(=O)Cl
Reactant: CNc1cnc(-c2cccnc2)s1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CSCCC(=O)N(C)c1cnc(-c2cccnc2)s1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 74.4 %

Procedure:
A solution of 3-methylsulfanyl-propionyl chloride (120 mg, 0.9 mmol) in DCE (1 mL) was pipetted at a dropwise rate into an ice-cold suspension of methyl-(2-pyridin-3-yl-thiazol-5-yl)-amine (114 mg, 0.6 mmol) in DCE (5 mL), and the mixture was stirred for 5 min before adding a solution of DMAP (80 mg, 0.6 mmol) in DCE (1 mL). The ice bath was removed after 30 min, and the mixture was stirred at reflux under nitrogen for 15 min. The reaction mixture was cooled, diluted with DCE (70 mL), washed with saturated aqueous NaHCO3 (50 mL), dried over MgSO4 and purified by silica gel chromatography (3:1 ethyl acetate/hexanes) to afford a fine yellow powder (131 mg, 75%): mp 116-118° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J=2.0 Hz, 1H), 8.61 (dd, J=4.8, 1.4 Hz, 1H), 8.24 (dt, J=9.8, 1.8 Hz, 1H), 7.81 (s, 1H), 7.51 (dd, J=7.7, 4.7 Hz, 1H), 3.56 (s, 3H), 3.02 (t, J=7.0 Hz, 2H), 2.76 (t, J=7.2 Hz, 2H), 2.12 (s, 3H); ESIMS m/z 294 (M+1).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[CH3:23].O>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH3:23])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
1-Acetyl-4-hydroxypiperidine (9.2 g) was dissolved in dimethylformamide (20 ml) and to the solution was added sodium hydride (oily, 60%, 2.6 g). The mixture was stirred at room temperature for 30 minutes, followed by adding dropwise 2-fluoro-5-nitrotoluene (10 g). The mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added water (50 ml) which was extracted with methylene chloride (50 ml×3). The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel chromatography (developing solvent: methylene chloride/methanol=20/1 (v/v)) to obtain 1-acetyl-4-(4-nitro-2-methylphenyloxy)piperidine (12.6 g) as yellow crystals, m.p. 139°-141° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]2[O:7][C:8]3[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=3[CH2:10][N:11]([C:12]([NH:14][NH2:15])=[O:13])[C:5]=2[CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:30](Cl)(=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[C:30]([NH:15][NH:14][C:12]([N:11]1[CH2:10][C:9]2[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=2[O:7][C:6]2[CH:20]=[CH:21][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:4][C:5]1=2)=[O:13])(=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(C(F)(F)F)cc21
Reactant: CCCCCCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCCCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(C(F)(F)F)cc21

Procedure:
By substituting equivalent quantities of 8-trifluoromethyl-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acid hydrazide, sodium carbonate and octanoyl chloride in the procedure of Example 1, there is obtained 1-octanoyl-2-(8-trifluoromethyl-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine, which melts at about 97°-100° and is represented by the following structural formula ##SPC4##
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[OH:22][N:23]=[C:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.FC(F)(F)C([O-])=O.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:27]2[CH2:28][CH2:29][C:24](=[N:23][OH:22])[CH2:25][CH2:26]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: ON=C1CCNCC1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: O=C([O-])C(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1c(F)c(N2CCC(=NO)CC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 38.2 %

Procedure:
298 mg (1 mmol) of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was dissolved in 5 ml of dimethyl sulfoxide, and 570 mg (2.5 mmol) of 4-hydroxyiminopiperidine-trifluoroacetate and 404 mg (4 mmol) of triethylamine were added thereto. The mixture was stirred at 80° C. for 6 hours. After cooling, the precipitate thereby formed was collected by filtration and washed with water, isopropanol and diethyl ether to give 150 mg of the desired product as yellow powder.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][NH:23][CH3:24].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:23]([CH3:24])[CH3:22])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CNC
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)C(=O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A suspension of 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol), dimethylamine (0.031 g, 0.69 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (EDCI) (0.16 g, 0.83 mmol) and 1-hydroxybenzotriazole hydrate (HOBt) (0.11 g, 0.83 mmol) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (DIPEA) (0.106 mL, 1.74 mmol) and stirred at room temperature under nitrogen overnight. Reaction mixture was diluted with ethyl acetate and subsequentially washed with aqueous sodium hydroxide and brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give 2-(4-(adamantan-1-yl)phenoxy)-N,N-dimethylacetamide as a white solid (0.198 g, 90.3% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[CH2:4][CH3:5])[CH3:2].[NH3:17]>C(O)C.[Ni]>[CH2:1]([N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:17])=[CH:11][CH:10]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CCOc1ccc(C=O)cc1
Reactant: N
Agent: [Ni]
Solvent: CCO
Product: CCN(CC)CCOc1ccc(CN)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
To the solution of 4-diethylaminoethoxybenzaldehyde X in 180 ml 10% solution of ammonia in anhydrous ethanol, 4.5 g RaNi was added and the mixture was heated to 80° C. at the pressure 68 atm in the autoclave under hydrogen input to the reaction mixture under stirring for 12 hours. The mixture was cooled, the catalyst was filtered off, washed with ethanol. The solvent was distilled off from the solution and the distillation residue was purified by distillation under the reduced pressure. Afforded 13 g (65%) of 4-diethylaminoethoxybenzylamine XI. Colourless fluid 138-140° C./0.5 torr, n20D=1.520. Lit. [6.7] reports 130° C./0.3 torr, n20D=1.5220.
Reaction SMILES: [CH:1]([C:4]1[C:9]2[C:10](=[O:32])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([O:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]CC2C=CC=CC=2)=[O:38])[CH:5]=1)([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH:1]([C:4]1[C:9]2[C:10](=[O:32])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[C:19]([C:28]([F:31])([F:29])[F:30])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([O:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)c1cc(OCCCC(=O)OCc2ccccc2)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)S2(=O)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)c1cc(OCCCC(=O)O)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)S2(=O)=O
Yield: 90.4 %

Procedure:
A mixture of 4-isopropyl-6-[3-(phenylmethyloxycarbonyl)propoxy]-2-(1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (820 mg) and 200 mg of 10% Pd/C in 40 ml of ethyl acetate was hydrogenated (hydrogen balloon). The catalyst was removed on a pad of CELIITEO and the filtrate was concentrated in vacuo to afford 640 mg (90%) of 4-isopropyl-6-[3-(carboxy)propoxy]-2-(1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =CH3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-O(CH2)3CO2 as a foam.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:3]=1.[OH:26][CH2:27][C:28]1[S:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[OH:26][CH2:27][C:28]1[S:32][C:31]([C:2]2[C:11]3[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=3[CH:5]=[C:4]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:3]=2)=[CH:30][CH:29]=1
Reactant: Cn1cnc2cc(-c3ccc(N4CCOCC4)cc3)nc(Cl)c2c1=O
Reactant: OCc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cnc2cc(-c3ccc(N4CCOCC4)cc3)nc(-c3ccc(CO)s3)c2c1=O
Temperature: 140 °C

Procedure:
To a solution of 5-chloro-3-methyl-7-(4-morpholinophenyl)pyrido[4,3-d]pyrimidin-4(3H)-one (6.0 mg, 0.017 mmol) in 1,4-dioxane (0.5 mL) were added crude 5-(hydroxymethyl)thiophen-2-ylboronic acid from Step A, 2M aqueous Na2CO3 solution (0.1 mL, 0.2 mmol), and a catalytic amount of Pd(PPh3)4. The reaction mixture was purged with N2 and heated at 140° C. by a microwave reactor for 15 minutes. The mixture was then cooled, quenched with H2O, extracted with EtOAc, and purified by preparatory LC/MS to provide the title compound; ESI-MS m/z 435.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([OH:14])=[CH:4][CH:3]=1.F[C:16]1[CH:21]=[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])[C:19]([F:35])=[CH:18][C:17]=1[N+:36]([O-:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:35][C:19]1[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:21][C:16]([O:14][C:5]2[C:6]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:17]([N+:36]([O-:38])=[O:37])[CH:18]=1
Reactant: COC(=O)COc1nc(Cl)ccc1O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1nc(Cl)ccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a mixture of 6-chloro-3-hydroxy-2-(methoxycarbonyl)methoxypyridine, 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and N,N-dimethylformamide is added potassium carbonate, and the mixture is stirred for 2 hours at 70° C. The reaction solution is cooled to room temperature, then, poured into ice water, and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-6-chloro-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19]CC2C=CC=CC=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]>C(OCC)(=O)C.[Pd]>[CH3:8][O:7][C:5](=[O:6])[CH:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=1)[C:3]([O:2][CH3:1])=[O:27]
Reactant: COC(=O)C(Cc1ccc(OCCOCc2ccccc2)cc1)C(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(OCCO)cc1)C(=O)OC

Procedure:
A solution of 2-[4-(2-benzyloxy-ethoxy)-benzyl]-malonic acid dimethyl ester (64.0 g, 172 mmol) in ethyl acetate (700 mL) was hydrogenated at 3 atm. in the presence of 10% palladium on charcoal (3.0 g). The solution was filtered, and the filtrate evaporated under vacuo to give 2-[4-(2-hydroxy-ethoxy)-benzyl]-malonic acid dimethyl ester. 1H NMR (300 MHz, CDCl3): δ2.06 (bs, 1H), 3.18 (d, 2H), 3.63 (t, 1H), 3.70 (s, 6H), 3.94 (t, 2H), 4.05 (t, 3H), 6.83 (d, 2H), 7.12 (d, 2H).
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][NH:7][CH2:8][C@@H:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21](Br)[CH:22]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[Br:16][C:17]1[CH:22]=[C:21]([N:7]2[CH2:6][C@@H:5]3[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C@@H:4]3[CH2:8]2)[CH:20]=[N:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Reactant: Brc1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(Br)c3)C[C@@H]2C1
Temperature: 80 °C
Yield: 66.7 %

Procedure:
The product from Example 1C (1.01 g, 4.76 mmol) and 3,5-dibromopyridine (1.22 g, 5.15 mmol) were dissolved in toluene (20 mL). Pd2(dba)3 (86.8 mg, 0.095 mmol), BINAP (175.0 mg, 0.28 mmol) and sodium tert-butoxide (665.4 mg, 1.460 mmol) were added to the reaction mixture. The reaction was heated to 80° C. for 22 h, then allowed to cool to ambient temperature, diluted with water (100 mL) and extracted with CH2Cl2 (3×100 mL). The organic extracts were combined and washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (EtOAc, Rr=0.33) to afford the title compound as a white solid (1.17 g, 67%). MS (DCI/NH3) m/z 370 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:26])[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=3)[S:8][C:7]=2[CH:35]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:26])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[CH:16][CH:17]=3)=[C:9]([C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[S:8][C:7]=2[CH:35]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC3CCN(C)CC3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: CN1CCC(Oc2ccc(C(=O)c3c(-c4ccc(O)cc4)sc4cc(O)ccc34)cc2)CC1
Yield: 63.9 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-[1-methylpiperidin-4-oxy]benzoyl)benzo[b]thiophene (749 mg, 1.54 mmol) was dissolved in 30 mL of methylene chloride. This solution was stirred and ethane thiol (7.68 mmol) and aluminum chloride (1.23 g, 9.22 mmol) were added. The reaction mixture was stirred vigorously for 30 minutes and then quenched with brine and saturated sodium bicarbonate. Any resulting residue was dissolved by the addition of methanol and ethyl acetate. The pH was adjusted to make it slightly basic and the mixture was diluted with 150 mL of ethyl acetate. After separation of the aqueous layer, the organic layer was washed with 75 mL of aqeous potassium sodium tartrate. The organic layer was dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by rotary chromatography (4 mm. Plate, eluting solvent 4:1 ethyl acetate:methanol) to give 452 mg (64%) of the title compound as a yellow solid. MS(FD) 459(M+). IR (CHCl3) ν max 3221, 2960, 1598, 1467, 1241, 1166.