Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([NH:29]S(C(C)(C)C)=O)([C:12]1[S:13][C:14]2[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:18]=[CH:17][C:15]=2[N:16]=1)[CH3:11])(C(C)(C)C)(C)C.Cl>CO>[NH2:29][C:10]([C:12]1[S:13][C:14]2[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:18]=[CH:17][C:15]=2[N:16]=1)([CH3:11])[CH2:9][OH:8]
Reactant: CCCCCCCCc1ccc2nc(C(C)(CO[Si](C)(C)C(C)(C)C)NS(=O)C(C)(C)C)sc2c1
Agent: Cl
Solvent: CO
Product: CCCCCCCCc1ccc2nc(C(C)(N)CO)sc2c1
Yield: 20.6 %

Procedure:
A methanol (5 mL) solution of N-(1-(tert-butyldimethylsilyloxy)-2-(6-octylbenzo[d]thiazol-2-yl)propan-2-yl)-2-methylpropane-2-sulfinamide (90 mg) and 4N HCl (0.325 mL, 1.3 mmol) was stirred at r.t. for 24 h. Then the mixture was extracted with EtOAc and purified by silica gel chromatography using PE/EA (1/2) to give product the title compound (11 mg, 26%). EDI-MS (M+1): 321. 1H NMR (300 MHz, CDCl3) δ 7.840 (d, 1H), 7.699 (s, 1H), 7.276 (d, 1H), 4.031 (d, 1H), 3.722 (d, 1H), 2.730 (t, 2H), 2.632 (b, 3H), 1.666 (t, 2H), 1.564 (s, 3H), 1.330-1.283 (m, 10H), 0.866 (t, 3H). HPLC: 96.9% (214 nm); 98.0% (254 nm).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:4][CH2:3]1.[CH:28]1[CH:33]=[C:32]([OH:34])[CH:31]=[C:30]([CH:35]([OH:38])[CH2:36][NH2:37])[CH:29]=1>>[OH:38][CH:35]([C:30]1[CH:29]=[CH:28][CH:33]=[C:32]([OH:34])[CH:31]=1)[CH2:36][NH:37][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:4][CH2:3]1
Reactant: NCC(O)c1cccc(O)c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2N2CCC(=O)CC2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2N2CCC(NCC(O)c3cccc(O)c3)CC2)cc1

Procedure:
The title compound was prepared from N-{4-[2-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 222) and DL-norphenylephrine according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.70–1.90 (m, 2 H), 1.90–2.10 (m, 2 H), 2.06 (s, 3 H), 2.50–3.20 (m, 7 H), 4.75–4.95 (m, 1 H), 6.10 (brs, 1 H), 6.50–7.40 (m, 8 H), 7.65–7.80 (m, 4 H), 9.48 (s, 1 H), 10.42 (s, 1 H); MS (ES) m/z: 525.6 (MH+); HRMS Calcd. for C27H33N4O5S (MH+): 525.2172. Found: 525.2164.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26](O)=[O:27])=[CH:9]2.[CH2:29]([S:36][C:37]1([CH2:43][NH2:44])[CH2:42][CH2:41][S:40][CH2:39][CH2:38]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:29]([S:36][C:37]1([CH2:43][NH:44][C:26]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=3[N:15]([CH3:25])[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)(=[O:17])=[O:18])=[O:27])[CH2:42][CH2:41][S:40][CH2:39][CH2:38]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Reactant: NCC1(SCc2ccccc2)CCSCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC3(SCc4ccccc4)CCSCC3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.9 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (1.60 g), 1-[4-(benzylthio)tetrahydro-2H-thiopyran-4-yl]methanamine (1.00 g), 1H-1,2,3-benzotriazol-1-ol (0.90 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.12 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hr. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:1, volume ratio) to give the title compound (1.92 g, yield 77%) as a colorless amorphous solid.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=O.[Cl-].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][PH3+]>>[F:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:1][C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][CH:4]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Fc1cccc(C[PH3+])c1
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [Cl-]
Product: Fc1cccc(C=Cc2c[nH]c3ccccc23)c1
Yield: 36.6 %

Procedure:
3-Formylindole (1.0 g) and 3-fluorobenzylphosphonium chloride (2.8 g) were treated as in the above Production Example 41-1 to give the title compound (0.598 g) as colorless crystals (yield: 73.1%).
Reaction SMILES: [CH3:1][N-:2][CH3:3].[C:4]1([S:10][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](O)=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O=P(Cl)(Cl)Cl.N>C1(C)C=CC=CC=1.O>[CH3:1][N:2]([CH3:3])[C:12]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:10][C:11]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[N-]C
Reactant: O=C(O)C(Sc1ccccc1)c1ccccc1
Agent: N
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1c(-c2ccccc2)sc2ccccc12

Procedure:
A solution of 14.4 g (53 mmole) of the dimethylamide of α-phenylthio-phenylacetic acid, 24.5 milliliters (160 mmole) of POCl3 in 250 milliliters of absolute toluene is refluxed for 6 hours. After mixing with water, it is neutralised with ammonia and the organic phase is dried over a mixture of K2CO3 and activated charcoal and evaporated: 3-dimethylamino-2-phenyl-benzo(b)thiophene in the form of a crude oily produce which, triturated with methanol, yields 11.1 g (83% of theory) of colourless rods, mp 84°-85° (methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21](SC)[N:20]=4)=[CH:17][C:11]=3[N:10]=2)=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28].O[O:32][S:33]([O-:35])=O.[K+].[CH3:37]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([S:33]([CH3:37])(=[O:35])=[O:32])[N:20]=4)=[CH:17][C:11]=3[N:10]=2)=[CH:4][C:3]=1[C:27]([F:30])([F:28])[F:29]
Reactant: CSc1nccc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(C(F)(F)F)c4)nc3c2)n1
Reactant: CO
Reactant: O=S([O-])OO
Agent: [K+]
Product: CS(=O)(=O)c1nccc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(C(F)(F)F)c4)nc3c2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (4-chloro-3-trifluoromethyl-phenyl)-[5-(2-methylsulfanyl-pyrimidin-4-yloxy)-1H-benzimidazol-2-yl]-amine (Step A, 280 mg, 0.6 mmol, 1.0 eq.) in MeOH (10 mL) was added dropwise an aqueous solution (10 mL) of Oxone® (1.14 g, 1.8 mmol, 3.0 eq.), and a white solid formed. The reaction was stirred for 4 h at RT. The MeOH was removed under reduced pressure, the residue was diluted with 10% aq. NaHCO3 and extracted with CH2Cl2. The organic layer was washed with 10% aq. NaHCO3 and the organic layers were extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude was further purified by column chromatography (0-100% EtOAc/hexanes) to yield (4-chloro-3-trifluoromethyl-phenyl)-[5-(2-methylsulfonylpyrimidin-4-yloxy)-1H-benzimidazol-2-yl]-amine. MS m/z=484.0 (M+H)+; MW Calc'd for C19H13ClF3N5O3S: 483.86.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]2[CH:20]=CC=C[CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[CH4:21]>CO.[Pd]>[CH3:21][C:15]([CH3:16])([CH3:20])[CH:14]=[N:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: c1ccc(CNC2CCN(Cc3ccccc3)C2)cc1
Reactant: C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C=NC1CCNC1
Yield: 58 %

Procedure:
36.8 g (0.138 mol) of 1-benzyl-3-benzylaminopyrrolidine are hydrogenated in 160 ml of methanol over 5 g of 5% strength palladium on active charcoal at 130° C. under a hydrogen pressure of 100 bar for 10 hours. The catalyst is filtered off and 16.6 g (0.138 mol) of 71% strength pivalaldehyde are added to the filtrate, while stirring, after which the temperature rises from 20° C. to 28° C. The mixture is subsequently stirred for 30 minutes, the methanol is removed on a rotary evaporator and the residue is distilled. 12.7 g of 3-(2,2-dimethyl-propylidene-amino)-pyrrolidine of boiling point: 61° C./10 mbar are obtained with a purity, determined by gas chromatography, of 97%, corresponding to a yield of 58% of theory.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[N:4]=1.Cl.[NH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[OH:19][NH:18][C:11](=[NH:12])[CH2:10][CH2:9][CH2:8][N:7]1[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[N:4]=[C:3]1[CH2:2][OH:1]
Reactant: N#CCCCn1c(CO)nc2ccccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N=C(CCCn1c(CO)nc2ccccc21)NO
Temperature: 80 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture containing 4-(2-hydroxymethyl-benzoimidazol-1-yl)-butyronitrile, 25a, (40.0 g, 186 mmol), hydroxylamine hydrochloride (46.5 g, 0.689 mole) and potassium carbonate (51.4 g, 0.372 mole) in ethanol (400 mL) and water (200 mL) was heated at 80° C. and stirred overnight. The solvents were removed in vacuo and water was added. The white precipitate was collected by filtration, washed with water and dried in vacuo to afford N-hydroxy-4-(2-hydroxymethyl-benzoimidazol-1-yl)-butyramidine (35.8 g, 78%) as a white solid:
Reaction SMILES: [CH2:1]([C@@:4]1([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:5]1[OH:27])[CH:2]=C.I([O-])(=O)(=O)=[O:37].[Na+].C(O)(C)(C)C>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH2:29]([O:28][C@:4]1([CH2:1][CH2:2][OH:37])[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:5]1[OH:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn([C@@H]2O[C@H](COCc3ccccc3)[C@@](CCO)(OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of nucleoside 2 (1.00 g, 2.09 mmol) in THF (5.4 cm3) and water (5.4 cm3) was added sodium periodate (1.34 g, 6.27 mmol) and a 2.5% solution of osmium tetraoxide in tert-butanol (w/w, 0.265 cm3, 19 μmol). The solution was stirred at room temperature for 45 min. Water (25 cm3) was added and the solution was extracted with dichloromethane (2×50 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×30 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was redissolved in THF (5.4 cm3) and water (5.4 cm3). The mixture was stirred at room temperature and sodium boronhydride (79 mg, 2.08 mmol) was added. After stirring for 1.5 h, water (25 cm3) was added and the solution was extracted with dichloro-methane (2×50 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×30 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (98:2, v/v) as eluent to give nucleoside 9 as a white solid material (488 mg, 48%). δH (CDCl3) 9.14 (1 H, br s, NH), 7.60 (1 H, d, J 1.1, 6-H), 7.40-7.22 (10 H, m, Bn), 6.25 (1 H, d, J 7.7, 1′-H), 4.59 (1 H, d, J 7.1 Bn), 4.49 (1 H, d, J 7.1 Bn), 4.39-3.30 (m, 8H, 4′-H, 2′-H, Bn, 5′-Ha, 5′-Hb, 2″-Ha, 2″-Hb), 2.23-2.00 (2 H, m, 1″-Ha, 1″-Hb), 1.49 (3 H, d, J 0.7, CH3). δC (CDCl3) 163.5 (C-4), 151.2 (C-2), 137.1, 136.5 (Bn), 135.7 (C-6), 128.7, 128.5, 128.2, 127.8, 127.6, 127.2 (Bn), 111.3 (C-5), 87.0, 82.7, 81.1, 78.3 (C-1′, C-2′, C-3′, C-4′), 73.7, 69.6 (Bn), 64.4 (C-5′), 57.0 (C-2″), 32.4 (C-1″), 11.8 (CH3) (Found: C, 63.9; H, 6.3; N, 5.4. C26H30N2O7,0.25H2O requires C, 64.1; H, 6.3; N, 5.75%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13](Cl)=[N:12][CH:11]=[N:10][C:9]=3[S:15][C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([NH2:32])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1.Cl>O1CCOCC1.CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13]([NH:32][C:19]4[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=5)=[C:17]([Cl:16])[CH:18]=4)=[N:12][CH:11]=[N:10][C:9]=3[S:15][C:4]=2[CH:3]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: Clc1ncnc2sc3cc(Br)ccc3c12
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Fc1cccc(COc2ccc(Nc3ncnc4sc5cc(Br)ccc5c34)cc2Cl)c1
Yield: 85.8 %

Procedure:
7-Bromo-4-chloro[1]benzothieno[2,3-d]pyrimidine (7.00 g, 23.4 mmol), 3-chloro-4-(3-fluoro-benzyloxy)-phenylamine (5.88 g, 23.4 mmol), and HCl in dioxane (1 mL, 4.0 M) were heated to reflux in IPA (140 mL) for 3 days. The suspension was filtered to collect a light tan solid. The solid was re-suspended in EtOAc (350 mL) and treated with satd NaHCO3 (350 mL) to generate two clear phases. The organic phase was washed with water (350 mL), collected, dried with sodium sulfate, filtered, concentrated on a rotavap, and finally placed under high vacuum to yield an off-white solid (10.34 g, 86%). 1H NMR (DMSO-d6) δ 9.06 (s, 1H), 8.53 (s, 1H), 8.49 (d, 1H), 8.43 (s, 1H), 7.74 (d, 1H), 7.71 (s, 1H), 7.50 (d, 1H), 7.47-7.42 (m, 1H), 7.32-7.16 (m, 4H), 5.26 (s, 2H), LCMS RT=4.42 min, [M+H]+=514.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5]2.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCn1ccc2cc(Br)ccc21
Reactant: COc1ccc(B(O)O)cc1
Product: CCCCn1ccc2cc(-c3ccc(OC)cc3)ccc21

Procedure:
The title compound was prepared from 5-bromo-1-butyl-1H-indole (Step 1 of Example 29) and 4-methoxyphenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 280. 1HNMR (400 MHz, DMSO-d6): δ 7.72 (s, 1H), 7.58 (dd, 2H, J=8.86 and 1.99 Hz), 7.54-7.49 (m, 2H), 7.37-7.35 (m, 2H), 6.98 (dd, 1H, J=7.33 and 7.34 Hz), 6.44 (d, 1H, J=3.05 Hz), 4.17 (t, 2H, J=7.01 Hz), 3.78 (s, 3H), 1.73 (p, 2H, J=7.16 Hz), 1.25 (h, 2H, J=7.46 Hz), and 0.88 ppm (t, 3H, J=7.3, 1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:21][N:20]=[CH:19][N:18]=3)(=[O:15])=[O:14])=[CH:9][C:8]=2[C:22]#[N:23])=[C:4](I)[CH:3]=1.CC1(C)C(C)(C)OB([N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)O1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:21][N:20]=[CH:19][N:18]=3)(=[O:15])=[O:14])=[CH:9][C:8]=2[C:22]#[N:23])=[C:4]([C:38]2[CH:39]=[N:35][NH:36][CH:37]=2)[CH:3]=1
Reactant: CC1(C)OB(n2cccn2)OC1(C)C
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(Cl)cc1I
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(Cl)cc1-c1cn[nH]c1

Procedure:
The title compound was prepared from 4-(4-chloro-2-iodophenoxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 355) and (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole using Method E above with microwave irradiation for 1 hour at 85° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1.O.C(=O)([O-])[O-:23].[K+].[K+].[CH2:28](Cl)[C:29]1[CH:37]=[CH:36][C:35]2[O:34][CH2:33][O:32][C:31]=2[CH:30]=1>C(Cl)(Cl)Cl>[C:28]([NH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:14])[CH2:6][CH2:5]1)(=[O:23])[C:29]1[CH:37]=[CH:36][C:35]2[O:34][CH2:33][O:32][C:31]=2[CH:30]=1
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Reactant: O=C([O-])[O-]
Reactant: ClCc1ccc2c(c1)OCO2
Agent: Cl
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(CCCN1CCC(NC(=O)c2ccc3c(c2)OCO3)CC1)c1ccccc1
Reaction time: 18 h

Procedure:
4-Amino-1-(4-phenyl-4-oxobutyl)piperidine dihydrochloride (3.19 g.) was stirred in chloroform (50 ml.). Water (20 ml.) containing potassium carbonate (8.28 g.) was added followed by dropwise addition of piperonyl chloride (1.84 g.) in chloroform (10 ml.). The mixture was stirred for 18 hr. Some of the title compound separated as the free base and was filtered off. The two-phase filtrate was separated and the remainder of the title compound (base) obtained. The combined bases were dissolved in ethanol/HCl and ether added until crystallisation occurred. Filtration afforded the title compound as the hydrochloride, three-quarter hydrate, colorless prisms (3.876 g.) m.p. 235.7°.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8]1[N:13]=[C:12]([NH2:14])[C:11]([NH2:15])=[C:10]([NH2:16])[N:9]=1.O.O.[Cl-:19].[Ba+2].[Cl-].C1(C)C=CC=CC=1>O>[ClH:19].[ClH:19].[NH2:16][C:10]1[C:11]([NH2:15])=[C:12]([NH2:14])[N:13]=[C:8]([S:7][CH3:6])[N:9]=1
Reactant: [Cl-]
Agent: CSc1nc(N)c(N)c(N)n1
Agent: O=S(=O)(O)O
Agent: [Ba+2]
Solvent: O
Solvent: Cc1ccccc1
Product: Cl
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a suspension of a 2-methylmercapto-4,5,6-triamino-pyrimidine sulfate (44.3 mmole), which may be prepared and characterised for instance as disclosed by Taylor et al. in J. Am. Chem. Soc. (1952) 74:1644-1647, in water (135 ml) at 80° C. was added dropwise a solution of barium chloride dihydrate (39.8 mmole) in water (25 ml). The suspension was stirred for 30 minutes at 80° C. The reaction mixture was cooled down and barium sulfate was filtered off over Celite. The filtrate was evaporated in vacuo and co-evaporated with toluene yielding the title compound as a yellow powder (10.2 g, 94% yield).
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[N:13][N:14]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=2[CH:6]=1.[H-].[Na+].[CH3:30]I>CN(C)C=O.C(OCC)(=O)C.O>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[C:10](=[O:11])[N:9]([CH3:30])[C:8]2[CH:12]=[N:13][N:14]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:20])[CH3:21])[C:7]=2[CH:6]=1
Reactant: CI
Reactant: C[Si](C)(C)CCOCn1ncc2[nH]c(=O)c(Oc3ccc(F)cc3F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2c1cnn2COCC[Si](C)(C)C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 6-(2,4-difluorophenoxy)-1-(2-trimethylsilanyl-ethoxymethyl)-1,4-dihydro-pyrazolo[4,3-b]pyridin-5-one (98 mg, 0.249 mmol) in dimethylformamide (1 mL) was added sodium hydride (60% dispersion in oil, Aldrich) (15 mg, 1.5 eq) and the resulting mixture was stirred at for 30 minutes, after which methyl iodide (25 μL, 1.5 eq) was added and the mixture was stirred additional 1 hour with warming from 0° C. to room temperature. The reaction mixture was diluted with ethyl acetate (35 mL) and water (25 mL). The organic layer was separated, washed with water (2×25 mL) and brine (1×25 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound as a tan powder (118 mg, (M+H)+=408).
Reaction SMILES: CON(C)[C:4]([C:6]12[CH2:13][CH2:12][C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.CCOC(C)=O>C1COCC1>[C:14]1([C:9]23[CH2:12][CH2:13][C:6]([CH:4]=[O:5])([CH2:11][CH2:10]2)[CH2:7][CH2:8]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CON(C)C(=O)C12CCC(c3ccccc3)(CC1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=CC12CCC(c3ccccc3)(CC1)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice water cooled solution of N-methoxy-N-methyl-1-phenylbicyclo[2.2.2]octane-4-carboxamide (Intermediate 5; 8.49 g, 31.05 mmol) in anhydrous THF (100 mL) under nitrogen was added lithium aluminium hydride (1M solution in THF, 62 mL) dropwise and the reaction mixture was allowed to stir at 0° C. for 1 hr. Water (25 mL) was added cautiously followed by EtOAc (˜100 mL) and the mixture was filtered through a pad of celite washing with EtOAc (50 mL). The filtrate was washed with brine (150 mL), the organic phase separated, dried (MgSO4) and concentrated to leave the title compound as a colourless oil which formed a solid on standing (6.92 g, 32.28 mmol, 100%); 1H NMR (CDCl3) δ 1.72-1.83 (6H, m), 1.87-1.94 (6H, m), 7.17-7.22 (1H, m), 7.31-7.33 (4H, m), 9.53 (1H, s); GC-MS EI m/e M+ 214.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1.[C:17]1([O:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33]Br)=[C:26]([CH2:35][CH2:36][CH3:37])[CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>>[CH2:35]([C:26]1[CH:25]=[C:24]([O:23][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH2:31][CH2:32][CH2:33][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1)[CH2:36][CH3:37]
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCBr
Reactant: CCOC(=O)C1CCc2ccc(O)cc2O1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc2c(c1)OC(C(=O)OCC)CC2
Temperature: 70 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
To a 50 ml round-bottom flask were added ethyl 7-hydroxychromane-2-carboxylate (100 mg, 0.45 mmol), 4-(3-bromopropoxy)-3-propylphenyl phenyl ether (U.S. Pat. No. 6,008,237) (188 mg, 0.54 mmol), cesium carbonate (176 mg, 0.54 mmol), and DMF 3 ml. The resulting suspension was stirred at 70° C. for 5 hr. The solvent was removed under reduced pressure. The residue was diluted with AcOEt and water. The organic layer was separated. The aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel. Eluting with 10% AcOEt/hexanes gave the title compound as a pale yellow oil 167 mg (76%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:19]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:20]=1[C:21]#[N:22].O>CS(C)=O>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:19]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:20]=2[C:21]#[N:22])=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccc(C(=O)c2ccccc2)cc1
Temperature: 60 °C
Yield: 94.1 %

Procedure:
To a solution of 11.4 g (0.0575 moles) of 4-hydroxybenzophenone dissolved in 150 ml of DMSO was added 2.3 g (0.0575 moles) of NaOH. The mixture was heated to 60° C. and 10.0 g (0.0548 moles) of 2-chloro-5-nitrobenzonitrile was added and the mixture heated at 75° C. for 3 hrs. The reaction mixture was cooled and poured into a solution of 100 ml of 2 N aqueous NaOH and 700 ml of water. The product was collected by filtration, washed well with water and dried to obtain 17.75 g of product (89.6% yield). Recrystallization from a mixture of ethanol and dimethylformamide and a second recrystallization from chloroform afforded purified 2-(4-benzoylphenoxy)-5-nitrobenzonitrile, mp 179.5°-180.5° C.