Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][S:3]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH:12]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:13]2=[O:16])=[CH:9][CH:8]=1)(=[O:5])=[O:4].C(=O)(O)[O-].[Na+].S(O[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[CH:37][CH:36]=1)(=O)(=O)C.[I-].[K+]>C(OCC)(=O)C.C(#N)C>[ClH:1].[CH3:2][S:3]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH:12]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:33][CH2:34][C:35]4[CH:36]=[CH:37][C:38]([NH:41][S:42]([CH3:45])(=[O:43])=[O:44])=[CH:39][CH:40]=4)[CH2:19][CH2:18]3)[C:13]2=[O:16])=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)C(C1CCNCC1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CS(=O)(=O)Nc1ccc(CCN2CCC(C3Cc4ccc(NS(C)(=O)=O)cc4C3=O)CC2)cc1
Yield: 79.5 %

Procedure:
A mixture of 0.100 g (0.00029 mol) of 6-methanesulfonamido-2-(4-piperidyl)indan-1-one hydrochloride, 0.073 g (0.00087 mol) of sodium bicarbonate, 0.128 g (0.00044 mol) of 4-methanesulfonamidophenethyl alcohol mesylate, 15 mg of potassium iodide, and 10 mL of acetonitrile was stirred and refluxed for 32 hours. The cooled solution, transferred to a separatory funnel using 25 mL of ethyl acetate, was washed with water and then with brine. The organic phase was extracted with three 4 mL portions of 1N HCl. The combined acid extracts were made basic by addition of solid sodium bicarbonate, and the basic phase was extracted with three 30 mL portions of ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure to afford 0.125 g (86%) of product. A hydrochloride salt was prepared in methanol; mp 130°-135° (foams).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][N:3]=1.C[O-].[Na+].[CH:19]([C:21]([CH3:23])=[O:22])=[CH2:20]>C1C=CC=CC=1.CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:9]([CH2:20][CH2:19][C:21](=[O:22])[CH3:23])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:15])=[CH:4][N:3]=1
Reactant: CCOC(=O)CC(=O)c1ccc(C)nc1
Reactant: C=CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CCOC(=O)C(CCC(C)=O)C(=O)c1ccc(C)nc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a stirred solution containing 48 g. of ethyl 3-(2-methyl-5-pyridinyl)-3-oxopropanoate in a mixture of 300 ml. of dry benzene and 100 ml. of dry methanol, said solution kept under nitrogen, was added 0.1 g. of sodium methoxide followed by the dropwise addition over a period of about one hour of the solution containing 16 g. of freshly distilled methyl vinyl ketone in a mixture of 60 ml. of benzene and 10 ml. of methanol. After the reaction had proceeded slowly at room temperature overnight, an additional 0.1 g. of sodium methoxide plus 4 ml. of additional methyl vinyl ketone were added and the reaction mixture was heated with stirring at 40° C. for eight hours. The solvent was distilled-off in vacuo; 300 ml. of benzene was added; the benzene solution was washed once with brine, dried over anhydrous sodium sulfate and heated in vacuo to remove the benzene thereby yielding a quantative yield (63.5 g.) of ethyl 2-(2-methyl-5-pyridinylcarbonyl)-5-oxohexanoate which was added to a mixture containing 95 ml. of concentrated sulfuric acid and 185 ml. of water. The acidic reaction mixture was slowly heated. After about thirty minutes, the temperature reached 55° C. and the evolution of carbon dioxide became noticeable. The temperature of the reaction mixture was maintained at 65° C. for about one hour and then heated to 80° C. and held there for several minutes. By this time the evolution of carbon dioxide appeared to be over. The reaction mixture was cooled and poured into a solution of 305 g. of potassium carbonate in 1 liter of ice water. Chloroform was added; the mixture was shaken well and filtered to remove the precipitated potassium sulfate; and, the layers were separated. The aqueous layer was extracted further with chloroform; the combined chloroform extracts were dried over anhydrous sodium sulfate and filtered; the dried filtrate was heated in vacuo to remove the chloroform to yield, after air-drying, 27.4 g. (80%) of 1-(2-methyl-5-pyridinyl)hexan-1,5-dione, a tan solid melting at 85°-87° C.
Reaction SMILES: C([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20](=[O:23])[NH:21][CH3:22])[CH:12]=1)=[O:10])C1C=CC=CC=1>CO.C(Cl)Cl.[Pd]>[CH3:22][NH:21][C:20]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:9]([OH:10])=[O:8])=[CH:12]1)=[O:23]
Reactant: CNC(=O)n1cc(C(=O)OCc2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)n1cc(C(=O)O)c2ccccc21
Reaction time: 1 h

Procedure:
To 1-Methylcarbamoyl-1H-indole-3-carboxylic acid benzyl ester (115 mg, 0.373 mmol) dissolved in a mixture of MeOH/CH2Cl2 1-1 (4 mL), Pd/C 10% (20 mg) was added and the solution was degassed 3 times replacing air by nitrogen and finally nitrogen by hydrogen. The reaction mixture was further stirred under hydrogen atmosphere for 1 h. The mixture was placed under a nitrogen atmosphere and the catalyst was removed through a pad of Celite and washed with MeOH. Solvents were concentrated under vacuum to give the desired compound. MS (LC/MS): 219.1 [M+H]+; tR (HPLC conditions a): 2.54 min.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6](Cl)=[O:7])[C:2]#[CH:3].[CH3:9][NH:10][CH3:11]>O1CCCC1>[CH3:9][N:10]([CH3:11])[C:6](=[O:7])[CH2:5][O:4][CH2:1][C:2]#[CH:3]
Reactant: CNC
Reactant: C#CCOCC(=O)Cl
Solvent: C1CCOC1
Product: C#CCOCC(=O)N(C)C

Procedure:
Prop-2-ynyloxyacetyl chloride (1.74 g) in tetrahydrofuran (20 ml) was added dropwise over 5 min. to a stirred solution of dimethylamine (12 ml of 33% solution in ethanol) in tetrahydrofuran (15 ml) at ambient temperature. After 30 minutes the solvent was evaporated and the residue was partitioned between saturated aqueous sodium bicarbonate (20 ml) and ethyl acetate (30 ml). The aqueous layer was separated and then re-extracted with ethyl acetate (20 ml). The combined ethyl acetate extracts were washed with brine (20 ml), dried over sodium sulphate and then evaporated. There was thus obtained the title compound as a liquid (1.15 g). NMR Spectrum: (CDCl3) 2.47 (t, 1H), 2.96 (s, 3H), 3.02 (s, 3H), 4.27 (s, 2H), 4.33 (d, 2M); Mass Spectrum: M+H+ 142.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][C:16]2[CH:17]=[C:12]([Cl:11])[N:13]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[N:15]=2)=[C:4]([F:10])[CH:3]=1
Reactant: Nc1cc(F)c(O)cc1F
Reactant: CC(=O)Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(Cl)cc(Oc2cc(F)c(N)cc2F)n1
Temperature: 25 °C
Yield: 43.7 %

Procedure:
A solution of 4-amino-2,5-difluoro-phenol (3.5 g, 24 mmol), N-(4,6-dichloro-pyrimidin-2-yl)-acetamide (5.30 g, 24 mmol) and potassium carbonate (3.4 g, 24 mmol) in DMF (100 mL) was stirred at 50° C. under nitrogen overnight. After cooling to room temperature the reaction mixture was suspended in water (300 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (15%-20% ethyl acetate in petroleum ether) to give N-[4-(4-amino-2,5-difluoro-phenoxy)-6-chloro-pyrimidin-2-yl]-acetamide (3.3 g, 44% yield) as a white solid. 1HNMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 7.20-7.24 (dd, J=11.2 Hz, J=7.6 Hz, 1H), 7.00 (s, 1H), 6.64 (dd, J=12.0 Hz, J=8.4 Hz, 1H), 5.48 (s, 2H), 2.03 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]2[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH:9]12)C1C=CC=CC=1.C=O>CCO.CC#N.[OH-].[OH-].[Pd+2]>[C:20]([O:19][C:17]([N:15]1[CH2:16][CH:9]2[CH:10]([O:11][CH2:12][CH2:13][N:8]2[CH3:1])[CH2:14]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC2OCCN(Cc3ccccc3)C2C1
Agent: [Pd+2]
Agent: C=O
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Product: CN1CCOC2CN(C(=O)OC(C)(C)C)CC21
Temperature: 25 °C
Reaction time: 6 h
Yield: 43.4 %

Procedure:
To a solution of tert-butyl 4-benzylhexahydropyrrolo[3,4-b][1,4]oxazine-6(2H)-carboxylate (1.00 g) in EtOH (20 mL) was added 20% Pd(OH)2/C (0.30 g). The reaction mixture was heated to reflux for 8 h and filtered. The filtrate was evaporated in vacuo. To a solution of the residue in CH3CN (30 mL) was added formaldehyde aqueous solution (15 eq) and NaB(OCOCH3)3H (2.5 eq). The mixture was stirred at room temperature for 6 h under N2. The solvent of the mixture was removed under reduce vacuum pressure, and the residue was chromatographed with a silica gel column to give the title compound (0.33 g, 43.42%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 243.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:34]=[CH:33][C:21]([O:22][CH2:23][CH2:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH3:26])=[CH:20][CH:19]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][N:25]([CH3:26])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:33][CH:34]=2)[N:5]=1)[CH3:2]
Reactant: CN(CCOc1ccc(CCl)cc1)c1ccccn1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCCN(C)c3ccccn3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl]propionate (415 mg), 2-[N-[2-(4-chloromethylphenoxy) ethyl]-N-methylamino]pyridine (554 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 80.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-1H-pyrazol-4-yl]propionate (771 mg, yield: 85%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:31][CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[CH2:25]2)[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].CCN(C(C)C)C(C)C.[Cl:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1[S:49](Cl)(=[O:51])=[O:50]>C(Cl)Cl>[Cl:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1[S:49]([N:28]1[CH2:29][CH:30]2[CH2:31][N:24]([CH2:23][CH2:22][CH2:21][N:9]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=3)[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]3)=[O:11])[CH2:25][CH:26]2[CH2:27]1)(=[O:51])=[O:50]
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CC3CNCC3C2)c2ccc(C)c(Cl)c2)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)N(CCCN2CC3CN(S(=O)(=O)c4ccc(F)cc4Cl)CC3C2)c2ccc(C)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 42b (0.016 g, 0.035 mmol) and DIPEA (0.02 mL, 0.105 mmol) in DCM (1 mL) at RT was added 2-chloro-4-fluorobenzenesulfonyl chloride (104, 0.016 g, 0.07 mmol) and the mixture shaken overnight at rt. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC to afford II-296: ms (ES+) m/z 639 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].S(Cl)(Cl)=O.O[C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26](=[O:30])[O:27]2)=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][C:20]2[CH:21]=[CH:22][C:23]3[CH:24]=[CH:25][C:26](=[O:30])[O:27][C:28]=3[CH:29]=2)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCOc1ccc(C(=O)O)cc1
Reactant: O=c1ccc2ccc(O)cc2o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCCOc1ccc(C(=O)Oc2ccc3ccc(=O)oc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
4.85 g (0.025 mol of 4-(but-3-enyloxy)-benzoic acid were treated with 9 ml of thionyl chloride and 2 drops of DMF and boiled under reflux for 2 hours. The excess thionyl chloride was removed completely, firstly in a water-jet vacuum and subsequently in a high vacuum. The acid chloride remaining was taken up in 10 ml of dichloromethane and slowly added dropwise at 0° C. to a suspension of 3.9 g (0.024 mol) of 7-hydroxy-coumarin and 3.9 ml of triethylamine in 5 ml of dichloromethane. The batch was stirred at room temperature overnight, filtered and the filtrate was evaporated. For purification, the residue was chromatographed on silica gel wiith dichloromethane and subsequently recrystallized from ethanol. There were isolated 5.2 g of 2-oxo-2H-1-benzopyran-7-yl 4-(but-3-enyloxy)-benzoate in the form of fine white needles; m.p. 108-109° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21].[NH4+].[Cl-]>C1COCC1>[Si:1]([O:8][CH2:9]/[C:10](=[N:25]/[S@@:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)c1cccc(F)c1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)/N=C(/CO[Si](C)(C)C(C)(C)C)c1cccc(F)c1
Yield: 48.6 %

Procedure:
To a mixture of 58a (11.3 g, 42.1 mmol) and (R)-2-methylpropane-2-sulfinamide (6.60 g, 54.7 mmol) in THF (200 mL) at RT was added Ti(Oi-Pr)4 (29.9 g, 105 mmol). The reaction mixture was heated to reflux under N2 overnight. The mixture was cooled then treated with saturated NH4Cl (5.0 mL), and the insoluble material was filtered. The filtrate was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc gradient (60:1 to 20:1) to afford 7.6 g (49%) of (R,E)-N-(2-(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (58b) as yellow oil. LCMS (ESI) m/z: 372.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=4)[CH2:23][CH:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1>CO.CCOCC.Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:39]=[CH:38][CH:37]=[C:22]([CH2:23][CH:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]5)[CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Fc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5cccc(CC6CCNCC6)c5)cc34)cn2)c1
Yield: 97.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(3-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzyl)piperidine-1-carboxylate (50 mg, 0.088 mmol) was deprotected in methanol/ether HCl (5/1 ml). This afforded 40 mg (90.9% yield) of the titled compound. 1H NMR (DMSO-d6, 300 MHz): δ 11.9 (s, 1H), 8.75-8.65 (bs, 1H), 8.53-8.52 (d, 1H), 8.42-8.38 (m, 2H), 7.98 (s, 1H), 7.78-7.77 (d, 2H), 7.62-7.57 (m, 2H), 7.43-7.35 (m, 2H), 7.19-7.05 (m, 4H), 5.40 (s, 2H), 3.23-3.18 (d, 2H), 2.80-2.54 (m, 5H), 2.25-2.15 (bs, 1H), 1.76-1.71 (d, 2H), 1.45-1.30 (m, 2H). MS: m/z=466.2 (M+1), HPLC: 97.04% in method A.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[F:11][C:12]1[CH:13]=[C:14]([CH:18]2[S:32][C:25]3([CH2:30][CH2:29][N:28](C)[CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]2=3)[CH:15]=[CH:16][CH:17]=1>ClCCl>[F:11][C:12]1[CH:13]=[C:14]([CH:18]2[S:32][C:25]3([CH2:26][CH2:27][N:28]([C:2]([O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:3])[CH2:29][CH2:30]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]2=3)[CH:15]=[CH:16][CH:17]=1
Reactant: CN1CCC2(CC1)SC(c1cccc(F)c1)c1ccccc12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC2(CC1)SC(c1cccc(F)c1)c1ccccc12
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To 5.0 g of phenyl chloroformate in 80 ml of dichloromethane is added 7.89 g of the free base, 3-(3-fluorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine] of Example 55, in 10 ml of dichloromethane over 20 minutes. The reaction mixture is stirred at room temperature for 21 hours, then diluted with 200 ml of dichloromethane. The resultant mixture is washed with two 175 ml portions of 10% aqueous sodium hydroxide solution, two 150 ml portions of water and one 70 ml portion of saturated aqueous sodium chloride solution, and dried over magnesium sulfate to give an oil. The oil is chromatographed on silica gel with dichloromethane to give an oil, which crystallizes to yield 3-(3-fluorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine], m.p. 134°-142° C. A portion is recrystallized twice from toluene:hexane, m.p. 144°-146° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[C:12](Cl)(Cl)=[O:13].C1(C)C=CC=CC=1.Cl>O1CCOCC1>[OH:1][C:2]1[CH:10]=[C:6]2[C:7]([O:9][C:12](=[O:13])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(O)cc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(O)cc2c(=O)o1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of 5-hydroxyanthranilic acid (46.0 g, 300 mmol) in p-dioxane was added 1.93 M phosgene in toluene (186 mL, 360 mmol) and the resulting mixture stirred for 30 min. The mixture was heated at 65° C. for 4 h. After cooling, 1 N aqueous hydrochloric acid (150 mL) was added and the mixture stirred vigorously. The resulting precipitate was filtered and vacuum dried at 70° C./0.1 mm for 14 h to give 40.7 g (76%) of the title compound as a gray solid.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][C:4]([NH:7][CH2:8][CH:9]([OH:28])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[C:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)([CH3:6])[CH3:5]>C(O)C>[CH3:6][C:4]([NH:7][CH2:8][CH:9]([OH:28])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[C:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]([NH2:25])=[O:1])=[CH:22][CH:21]=1)([CH3:3])[CH3:5]
Reactant: [OH-]
Reactant: CC(C)(C)NCC(O)COc1ccccc1C#Cc1ccc(C#N)cc1
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)NCC(O)COc1ccccc1C#Cc1ccc(C(N)=O)cc1
Yield: 71.8 %

Procedure:
A solution of 11.5 ml (31.5 mmoles) of 3N NaOH solution was added to a solution of 5.8 g (15.3 m moles) of 4-[2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]phenylethynyl]benzonitrile, the product of Example 14 in 50 ml of 95% ethanol. The mixture was heated under reflux for 30 min. The solution of 25 ml of 95% ethanol and 5.0 ml of 3N aqueous NaOH was added. The mixture was heated under reflux for 15 min. The solution was cooled and the solid collected by filtration. The solid was recrystallized from 95% ethanol to give 4.38 g of 4-[[2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]phenyl]ethynyl]benzamide, mp 199°-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:26][C:27]([F:37])([F:36])[C:28]([NH:30][CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)=[O:29].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:33]1[CH2:34][CH2:35][CH:31]([NH:30][C:28](=[O:29])[C:27]([F:37])([F:36])[F:26])[CH2:32]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(NC1CCNC1)C(F)(F)F
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCC(NC(=O)C(F)(F)F)C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 3-(2,2,2-trifluoroacetylamino)pyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.34 minutes; C23H20Cl2F3N5O3 (542.34); mass spectrum: (M−H)−=541/543/545 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N:15]([O-])=O.[Na+]>O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[N:15][NH:9][C:5]2=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)nc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Clc1ccc2[nH]nnc2n1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
6-Chloropyridine-2,3-diamine (Example 23, Step 1) (226 mg, 1.57 mmol) was taken up in warm water (6.3 ml). Sulfuric acid (0.26 ml, 4.72 mmol) was added, and the solution was cooled to −15° C. In a separate flask, sodium nitrite (119 mg, 1.73 mmol) was dissolved in 2 mL cold water. The sodium nitrite solution was added dropwise to the reaction mixture over 15 minutes. The mixture was allowed to stir at −15° C. for 1 hour, then filtered, and the yellow-brown precipitate was collected. The solid was recrystallized from water to yield the title compound as a yellow-brown solid. The filtrate from the separation was neutralized with aqueous sodium bicarbonate and extracted 3× with ethyl acetate. All organic fractions were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an additional portion of the title compound as a yellow-brown solid.
Reaction SMILES: [Br:1]Br.[C:3]1([C:9]2[CH:13]=[C:12]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C>[C:3]1([C:9]2[C:13]([Br:1])=[C:12]([S:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:11][N:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(Sc2cc(-c3ccccc3)n[nH]2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: Brc1c(-c2ccccc2)n[nH]c1Sc1ccccc1
Reaction time: 12 h
Yield: 96.7 %

Procedure:
At 25° C, 8 parts of bromine is slowly added, with stirring, to a solution of 12.6 parts of 3-phenyl-5-phenylthiopyrazole in 150 parts of glacial acetic acid. After 12 hours, the solution is concentrated in vacuo and the residue treated with about 50 parts of water. There is obtained 16 parts (96.7% of theory) of 3-phenyl-4-bromo-5-phenylthiopyrazole; m.p.: 121° to 122° C (recrystallized from cyclohexane).
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][C:8](=O)[CH2:7][C:6]1([CH3:15])[CH3:14])[CH2:2][CH3:3].C([O-])(=O)C.[NH4+].[BH3-]C#[N:23].[Na+]>>[NH2:23][CH:8]1[CH2:9][C:10]([CH3:12])([CH3:11])[N:5]([O:4][CH2:1][CH2:2][CH3:3])[C:6]([CH3:15])([CH3:14])[CH2:7]1
Reactant: [BH3-]C#N
Reactant: CCCON1C(C)(C)CC(=O)CC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Product: CCCON1C(C)(C)CC(N)CC1(C)C
Yield: 61.2 %

Procedure:
4-Amino-N-propoxy-2,2,6,6-tetramethylpiperidine (1.6 g, 62%) is prepared from N-propoxy-4-oxo-2,2,6,6-tetramethylpiperidine (12.2 mmol, 2.60 g) by the same method as described above, with the exception of the addition of ammonium acetate (122 mmol, 9.40 g), 6 g molecular sieves (10−10 m) and 95% NaBH3CN (12.2 mmol, 0.8 g). 1H-NMR (CDCl3); δ=3.61 (t, J=6.6 Hz, 2H, CH2—O), 2.99 (m, 1H, NH2—CH), 1.58 (d, J=11.4 Hz, 2H, NH2), 1.46 (m, 2H, CH2—CH3), 1.20 (m, 4H), 1.16 (s, 6H, CH3), 1.13 (s, 6H, CH3), 0.93 (t, J=7.4 Hz, 3H, CH2—CH3); 13C-NMR (CDCl3): δ=78.3, 59.8, 49.9, 41.4, 33.2, 21.9, 20.9, 10.9.