Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:44])C=1.[OH-:47].[Na+]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([S:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:44])=[O:47])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [OH-]
Reactant: Cc1cccc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)sc2-c2ccnc(Sc3ccccc3)c2)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)sc2-c2ccnc(S(=O)(=O)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-5-(2-phenylthio-4-pyridyl)-1,3-thiazole (0.48 g, 0.93 mmol) in N,N-dimethylformamide (10 mL) was added m-chloroperbenzoic acid (0.51 g, 2.4 mmol) and the mixture was stirred at room temperature for 1 hour. An 8N aqueous solution of sodium hydroxide was added to the reaction mixture and the resulting solid was collected by filtration. The solid was recrystallized from ethanol to obtain 0.42 g (yield 82%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:7]2[CH:31]=[C:30]([OH:32])[C:10]3[C:11]4[CH2:29][CH2:28][S:27][C:12]=4[C:13]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[O:14][C:9]=3[CH:8]=2)[CH3:6])[CH2:3][CH2:2]1.[O:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40](O)=[O:41])[CH2:35][CH2:34]1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH:1]1([CH2:4][CH:5]([C:7]2[CH:31]=[C:30]([O:32][C:40](=[O:41])[CH2:39][N:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)[C:10]3[C:11]4[CH2:29][CH2:28][S:27][C:12]=4[C:13]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[O:14][C:9]=3[CH:8]=2)[CH3:6])[CH2:3][CH2:2]1
Reactant: O=C(O)CN1CCOCC1
Reactant: CCCCCCC1(CCCCCC)Oc2cc(C(C)CC3CC3)cc(O)c2C2=C1SCC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCCC1(CCCCCC)Oc2cc(C(C)CC3CC3)cc(OC(=O)CN3CCOCC3)c2C2=C1SCC2

Procedure:
By reacting 7-(3-cyclopropyl-2-propyl)-1,2-dihydro9-hydroxy-4-oxo-4H-thieno[2,3-c][1]benzopyran with n-hexyl magnesium bromide, using the procedure described above in Example 8, there is obtained 7-(3-cyclopropyl-2-propyl)-4,4-di(1-hexyl)-1,2-dihydro-9-hydroxy-4H-thieno[2,3-c][1]benzopyran. The benzopyran is then reacted with morpholinoacetic acid and dicyclohexylcarbodiimide according to the method of Example 9 to yield the desired ester.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[S:10]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14](=[O:15])N1)(=[O:12])=[O:11].N.S(=O)(=O)(O)O>O.C(#N)C>[CH3:1][Si:2]([N:3]1[C:14](=[O:15])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10]1(=[O:12])=[O:11])([CH3:9])[CH3:8]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: C[Si](C)(C)N1C(=O)c2ccccc2S1(=O)=O
Yield: 102 %

Procedure:
2 ml (9.6 mmoles) of hexamethyldisilazane were added to a refluxing mixture of 1.83 mg (10 mmoles) of saccharin, 10 mg (0.02 mmole) of di-4-nitrophenyl N-(4-toluenesulfonyl)-phosphoramidate and 20 ml of acetonitrile under dry nitrogen and the ammonia evolved was led into water by the nitrogen stream and was titrated with 1 N sulfuric acid. The calculated amount of ammonia was evolved within 0.5 hour and the solvent and other volatile materials were removed by evaporation in a rotating film evaporator. Then, the residue was dried under vacuum to obtain 2.50 g (98%) of trimethylsilylsaccharin melting at 90°-92° C.
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:6]=1)([CH3:4])[CH3:3].[CH2:16]([Mg]Br)[CH3:17].Cl>O1CCOCC1.O1CCCC1.[Cu]I>[OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]([CH:11]([C:12]#[N:13])[C:14]#[N:15])[CH2:16][CH3:17])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC[Mg]Br
Reactant: CC(C)(O)c1cc(C=C(C#N)C#N)no1
Agent: [Cu]I
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCC(c1cc(C(C)(C)O)on1)C(C#N)C#N
Reaction time: 1 h

Procedure:
1.02 g of {[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]methylidene}malononitrile was dissolved in 50 ml of 1,4-dioxane. Thereto, 0.05 g of copper(I) iodide was added and ml of a 3 M solution of ethylmagnesium bromide in tetrahydrofuran was then added under ice-cooling. The mixture was stirred for 1 hour under ice-cooling. The reaction mixture was added to 0.1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.40 g of {1-[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]propyl}malononitrile.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:16]([CH:20]=2)[C:17]([NH2:19])=[O:18])=[N:4][CH:3]=1.[F:27][C:28]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:29]=1[C:30]([NH2:32])=[O:31]>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>[NH3:4].[C:17]([C:16]1[CH:20]=[C:12]([NH:11][C:5]2[C:6]3[N:7]([CH:8]=[CH:9][N:10]=3)[C:2]([C:35]3[CH:34]=[C:33]([F:46])[C:29]([C:30]([NH2:32])=[O:31])=[C:28]([F:27])[CH:36]=3)=[CH:3][N:4]=2)[CH:13]=[CH:14][C:15]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)(=[O:18])[NH2:19]
Reactant: NC(=O)c1cc(Nc2ncc(Br)n3ccnc23)ccc1N1CCOCC1
Reactant: CC1(C)OB(c2cc(F)c(C(N)=O)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N
Product: NC(=O)c1cc(Nc2ncc(-c3cc(F)c(C(N)=O)c(F)c3)n3ccnc23)ccc1N1CCOCC1
Yield: 41.9 %

Procedure:
In the same way as described for Compound 178, step 4, using 5-(5-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-2-morpholin-4-yl-benzamide (120 mg, 0.29 mmol), 2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (163 mg, 0.58 mmol) 1.5M K2CO3 (1.7 mL, 2.55 mmol), and Pd(PPh3)4 (84 mg, 0.073 mmol) in dioxane (3 mL). Purification by silica gel column chromatography eluting with 98:8 DCM:NH3 (7M in MeOH) affords the title compound as a pale yellow solid (30 mg, 21%). Following the usual procedure, using methanesulfonic acid (0.593 mL), the free base (29.3 mg, 0.060 mmol) is converted into the mesylate salt (27 mg, 99%). LCMS: Rt 2.47 min (98%), m/z (ES+) 494 (M+H)+, 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.35 (3H, s, MsOH), 2.97-3.05 (4H, m), 3.74-3.83 (4H, t), 7.35 (1H, d), 7.60-7.65 (4H, m), 7.80 (1H, s), 7.98 (1H, br s), 8.05-8.08 (1H, m), 8.13 (1H, s), 8.26 (1H, br s), 8.50 (1H, d), 8.68 (1H, br s), 10.00 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:16])[C:9]1[CH:14]=[CH:13][C:12](N)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:22]([O:21][C:17](=[O:20])[CH:18]=[CH:19][C:12]1[CH:11]=[N:10][C:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:16])=[CH:14][CH:13]=1)[CH3:23]
Reactant: C=CC(=O)OCC
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(N)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(N(C)C(=O)OC(C)(C)C)nc1
Temperature: 110 °C

Procedure:
A mixture of 12-3 (6.0 g, 20.9 mmol), ethyl acrylate (6.3 mL, 62.7 mmol), triethylamine (17 mL, 125.5 mmol), tri-o-tolylphosphine (1.3 g, 6.2 mmol) and Pd(OAc)2 (0.5 g, 2.1 mmol) in 50 mL CH3CN was purged with argon for 5 min and subsequently refluxed at 110° C. for 20 hr. The mixture was cooled and concentrated. The residue was purified using silica gel flash chromatography (EtOAc/hexanes 1:3) to afford the desired product 12-4 as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[NH:16][CH:10]([CH2:11][O:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32](C3CC(=O)N(O)C3=O)=[O:33])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32]([N:16]3[CH:14]4[CH2:15][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]3[CH2:11][O:12][CH2:13]4)=[O:33])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)C1CC(=O)N(O)C1=O
Reactant: CC(C)(C)OC(=O)N1CC2COCC(C1)N2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2COCC(C1)N2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester (716 mg, 3.14 mmol, WuXy AppTech) and 9-fluorenylmethoxycarbonyl-N-hydroxysuccinimide (1058 mg, 3.14 mmol) was prepared in anhydrous THF (11 mL) and stirred at RT for 2.5 hours. The reaction mixture was concentrated under vacuum to give a yellow oil. After purification by flash chromatography (silica, heptane/EtOAc), the title compound was obtained as a white foam (1.36 g, 93%). 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J=7.5 Hz, 2H), 7.55 (d, J=7.3 Hz, 2H), 7.45-7.37 (m, 2H), 7.36-7.28 (m, 2H), 4.65-4.57 (m, 2H), 4.35-3.49 (m, 9H), 3.17-2.78 (m, 2H), 1.46 (s, 9H). HPLC (max plot) 96.5%; Rt 5.07 min. UPLC/MS: (MS+) 451.4 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:18]=[C:17]([F:28])[CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:36][C:37]([Cl:42])([Cl:41])[C:38](Cl)=[O:39]>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:23][CH2:24][N:25]([C:38](=[O:39])[C:37]([Cl:42])([Cl:41])[Cl:36])[CH2:26][CH2:27]3)[CH:18]=[C:17]([F:28])[CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cc(F)cc(OC2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cc(F)cc(OC2CCN(C(=O)C(Cl)(Cl)Cl)CC2)c1
Temperature: 22 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To an ice-water cooled solution of 1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-(piperidin-4-yloxy)-phenyl}-urea (390.6 mg, 1.0 mmol) and triethylamine (280 μL, mmol) in dichloromethane (5 mL) is added trichloroacetyl chloride (115 μL, 1.0 mmol). The reaction mixture is allowed to warm up to 22° C. and stirred for 1 hour. After removal of solvent, the residue is purified on a silica gel chromatography with hexanes and ethyl acetate to provide a white solid (520.0 mg, 97% yield, ES+(m/z) 535.9 [M+H]).
Reaction SMILES: [N+]([O-])([O-])=O.[Co+2:5].[N+]([O-])([O-])=O.[C:10]([OH:21])(=[O:20])[C:11]1[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([OH:16])=[O:15])[CH:12]=1>O>[C:10]([O-:21])(=[O:20])[C:11]1[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([O-:16])=[O:15])[CH:12]=1.[Co+2:5]
Reactant: O=C(O)c1cccc(C(=O)O)c1
Agent: [Co+2]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: O=C([O-])c1cccc(C(=O)[O-])c1
Temperature: 75 °C
Yield: 89.7 %

Procedure:
29.1 Grams (0.1 mole) of cobalt nitrate. 6H2O in 200 ml of water were added to 200 ml. of 1 N sodium hydroxide to precipitate cobalt (II) hydroxide. The precipitate was filtered and washed. 16.6 Grams (0.1 mole) of isophthalic acid and 300 ml of water were added to the precipitate. The mixture was stirred and heated at 75° C. for 11/2 hours until all solids dissolved. The solution was evaporated to yield 20.0 grams of cobalt (II) isophthalate which analyzed: C, 39.7%; H, 3.0%; Co, 15.0%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH3:14])[C:8](C)=[CH:9][CH:10]=[CH:11][CH:12]=1.C([O:17][CH2:18]C)C.CCCCCC.C1(C)C=CC=CC=1.C[CH2:34][O:35]CC>O1CCCC1>[C:7]1([CH:14]([CH2:18][OH:17])[CH2:34][OH:35])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccccc1C
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: OCC(CO)c1ccccc1
Temperature: 0 °C
Yield: 72 %

Procedure:
The reaction is carried out in a nitrogen atmosphere in a predried 250 ml RB flask with a side arm and a distillation apparatus leading to a nitrogen outlet. 180 mmoles of lithium aluminum hydride is added to the flask in sufficient tetrahydrofuran to dissolve the lithium aluminum hydride. The solution is cooled with rapid stirring to about 0° C. and 30 mmoles of diethyl phenylmalonic acid ester is slowly added followed by four ml of dry xylene which functions as a heat transfer material and prevents the contents of the flask from "bumping". The solution is heated to about 135° C. and maintained at such temperature for approximately two hours. The reaction mixture is cooled to about 0° C. and an extract solvent composed of equal parts tetrahydrofuran and ethyl ether is added and residual hydride is quenched with water. 90 ml of 2N hydrochloric acid is added to complete hydrolysis. The solution is then extracted twice with ether, the aqueous phase is made alkaline (pH 9-10) with a saturated potassium carbonate solution and extracted with ether. The organic phases are combined, washed with saturated potassium carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield crude 2-phenyl-1,3-propanediol. Purified 2-phenyl-1,3-propanediol (mp 51°-53° C.) was obtained by recrystallization from a mixture of hexane/toluene/ether (10:5:1) in a yield of 72%.
Reaction SMILES: [N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6](Cl)=[O:7])=[N+:2]=[N-:3].[NH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Cl>ClCCCl>[N:11]1([C:6](=[O:7])[CH2:5][C:4]([N:1]=[N+:2]=[N-:3])([CH3:10])[CH3:9])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Reactant: C1CCCNCC1
Agent: Cl
Solvent: ClCCCl
Product: CC(C)(CC(=O)N1CCCCCC1)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred ice cold solution of 3-azido-3-methylbutanoyl chloride (8.00 g, 49.5 mmol) in anhydrous DCE (160 mL) was added azepane (12.6 mL, 3 equiv, 0.11 mol) in one portion. The reaction was stirred and left at 0° C. for 15 min and room temperature for 45 min. Aqueous 1 M HCl (100 mL) was added to the reaction mixture and the contents poured into a separatory funnel. The organic layer was separated and washed with 1 M HCl (100 mL) and saturated NaHCO3 (150 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (8.24 g, quant). This material was used without further purification. LRMS (ESI+) for C11H20N4O (224.1); Found: 225 (MH+).
Reaction SMILES: O=[C:2]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:3][NH:4][C:5](=O)[CH2:6][C@H:7]1[N:14]([S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)(=[O:17])=[O:16])[CH2:13][C:12]2[CH:28]=[CH:29][CH:30]=[CH:31][C:11]=2[CH2:10][O:9][CH2:8]1.C([O-])(C)=O.[NH4+].C[N:45](C=O)C>O>[C:33]1([C:2]2[N:45]=[C:5]([CH2:6][C@H:7]3[N:14]([S:15]([C:18]4[CH:19]=[CH:20][CH:21]=[C:22]5[C:27]=4[N:26]=[CH:25][CH:24]=[CH:23]5)(=[O:16])=[O:17])[CH2:13][C:12]4[CH:28]=[CH:29][CH:30]=[CH:31][C:11]=4[CH2:10][O:9][CH2:8]3)[NH:4][CH:3]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(C[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12)NCC(=O)c1ccccc1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: O=S(=O)(c1cccc2cccnc12)N1Cc2ccccc2COC[C@H]1Cc1nc(-c2ccccc2)c[nH]1
Temperature: 150 °C
Yield: 30 %

Procedure:
A microwave tube was charged with compound 28a (100 mg, 0.19 mmol), AcONH4 (44 mg, 0.57 mmol) and DMF (3 mL), and then was sealed and heated to 150° C. for 1 h under microwave irradiation. The mixture was taken up in H2O (10 mL) and extracted with DCM (30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by Prep-TLC to give compound 28 (30 mg, 30% yield). LCMS (m/z): 511.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1ccccc1
Product: CN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccccc4)cc23)CC1
Yield: 28.8 %

Procedure:
Beginning with 1.13 gm (5.0 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 0.58 mL (5.0 mMol) benzoyl chloride, 0.477 gm (28.9%) of the title compound were recovered as a light green solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][C:11]([NH:13][C:14](=[NH:17])[NH:15][CH3:16])=[O:12].[CH3:18]N(C=O)C.CC(N(C)C)=O>C(#N)C>[CH3:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH3:2])[C:4]=1[N:10]1[CH:16]=[N:15][C:14]([NH:17][CH3:18])=[N:13][C:11]1=[O:12]
Reactant: CN(C)C=O
Reactant: CNC(=N)NC(=O)Nc1c(C)cccc1C
Agent: Cl
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: CNc1ncn(-c2c(C)cccc2C)c(=O)n1
Temperature: 105 °C

Procedure:
About 200 mg of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride was introduced in a gas chromatograph hypo vial and dissolved in 1 ml of acetonitrile. To the solution was added 0.2 ml of DMF DMA reagent. The vial was sealed with crimper and heated at 105° C. for 15 minutes in an oven. Seven vials were made. The contents of the vials were then put into a long-neck round bottom flask and evaporated to dryness by a flask evaporator. The solid mass was dissolved in a mixture of 30 ml of CHCl3 and 20 ml of water and shaken vigorously in a 60 ml separatory funnel. The aqueous layer was discarded and 20 ml of water was added and shaken. The CHCl3 layer was then taken and about 10 g of anhydrous Na2SO4 was added, the CHCl3 solution was decanted into a flask and evaporated to dryness. The solid material was dissolved in 2-pentanone (about 80 ml) at 70° C. The solution was concentrated and crystallized upon cooling. The crystals were collected and dried in a desiccator with P2O5 with vacuum for one hour.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13](Cl)[C:12]3[C@@H:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[O:23][C:24]4([CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:40]([B-](F)(F)F)([CH3:42])=[CH2:41].[K+].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.O>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([C:40]([CH3:42])=[CH2:41])[C:12]3[C@@H:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[O:23][C:24]4([CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)Cc2nc(Cl)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)O[C@@H]3c1ccc(C(F)(F)F)cc1
Reactant: C=C(C)[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)cc1)OC31CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: 100 °C
Reaction time: 72 h

Procedure:
500 mg (3R,9S)-9-(tert-butyldimethylsilyloxy)-4-chloro-7,7-dimethyl-3-(4-(trifluoromethyl)phenyl)-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran] and 254 mg potassium isopropenyltrifluoroborate are dissolved in 3 ml tetrahydrofurane, 0.5 ml toluene and 3 ml of a 2 M solution of caesium carbonate in water. The mixture is purged for 15 minutes with argon. Then 42 mg 1,1′-bis-(diphenylphosphino)-ferrocene-dichloro-palladium-(II) complex with dichloromethane are added and the mixture is stirred for 72 hours at 100° C. The mixture is partitioned between water and dichloromethane. The aqueous phase is twice extracted with dichloromethane. The combined organic phases are dried with sodium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 90:10).
Reaction SMILES: [N:1]([CH:4]1[CH2:22][CH2:21][C:7]2[C:8]3[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=3[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]=2[CH2:5]1)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[NH2:1][CH:4]1[CH2:22][CH2:21][C:7]2[C:8]3[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=3[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]=2[CH2:5]1
Reactant: [N-]=[N+]=NC1CCC2=C(C1)c1ccccc1Oc1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NC1CCC2=C(C1)c1ccccc1Oc1ccccc12
Yield: 85 %

Procedure:
3.7 g of 2-azido-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine are added to a suspension of 3 g of lithiumaluminiumhydride in 100 ml of dry ether. The mixture is refluxed for one hour. After the mixture has been cooled down, 12 ml of water are added carefully after which the mixture is stirred for some time. The suspension is filtered and after that the filtrate is dried and evaporated to dryness. The residue is converted with maleic acid into the maleate. Melting point of the maleate: 198°-202°C. Yield 85%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[S:29]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1oncc1C(=O)Nc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: Cc1oncc1C(=S)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
A solution of 24 grams of 5-methyl-4-(4-trifluoromethyl-phenyl)aminocarbonylisoxazole and 39 grams of Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] in 400 ml of toluene was refluxed for three hours. Upon cooling of mixture to room temperature, all the solid was filtered off and the filtrate was concentrated. The resulting crude product from the filtrate was then purified on a silica gel column with 3% methanol in dichloromethane to yield 16.5 grams of 5-methyl-4-(4-trifluoromethylphenyl)aminothiocarbonylisoxazole.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=3)[C:10]([C:20]([CH:22]3[C:24]([CH3:26])([CH3:25])[C:23]3([CH3:28])[CH3:27])=[O:21])=[CH:9]2)[CH2:3][CH2:2]1.C(N1C=CN=C1)([N:31]1C=CN=C1)=O.[NH4+].[OH-]>CCOC(C)=O.C1COCC1>[O:1]1[CH2:2][CH2:3][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH2:31])=[O:18])=[CH:14][CH:15]=3)[C:10]([C:20]([CH:22]3[C:23]([CH3:27])([CH3:28])[C:24]3([CH3:25])[CH3:26])=[O:21])=[CH:9]2)[CH2:5][CH2:6]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(=O)O)cc23)C1(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(N)=O)cc23)C1(C)C
Yield: 20 %

Procedure:
A mixture 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxylic acid (0.10 g, 0.26 mmol, the minor product of Example 114B), 1,1′-carbonyldimidazole (55 mg, 0.34 mmol) and concentrated aqueous NH4OH (2 mL) in 5 mL of EtOAc and 3 mL of THF was processed as described in Example 93 to provide the title compound (20 mg, 0.052 mmol, 20% yield). 1H NMR (CDCl3, 300 MHz) δ ppm 1.32 (s, 6H), 1.36 (s, 6H), 1.39-1.58 (m, 4H), 1.92 (s, 1H), 2.08-2.23 (m, 1H), 3.34 (dt, J=11.4, 2.5 Hz, 2H), 3.94-4.04 (m, 2H), 4.08 (d, J=7.1 Hz, 2H), 7.41 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.98 (dd, J=8.5, 1.4 Hz, 1H), 8.84 (d, J=1.0 Hz, 1H); MS (DCI/NH3) m/z 383 (M+H)+; Anal. Calculated for C23H30N2O3.0.4H2O: C, 70.89; H, 7.97; N, 7.19. Found: C, 70.77; H, 7.91; N, 7.32.