Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH:21]([NH:23][CH2:24][CH2:25][CH3:26])[CH3:22]>>[C:5]([NH:3][C:2](=[S:1])[N:23]([CH:21]([C:20]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[Cl:14])[CH3:22])[CH2:24][CH2:25][CH3:26])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#C[S-]
Reactant: CCCNC(C)c1ccncc1Cl
Reactant: O=C(Cl)c1ccccc1
Agent: [NH4+]
Product: CCCN(C(=S)NC(=O)c1ccccc1)C(C)c1ccncc1Cl

Procedure:
Prepare this compound according to the process described in Step A of Preparation XV, from 1.14 g of ammonium thiocyanate, 1.74 ml of benzoyl chloride and 2.7 g of N-[1-(3-chloro-4-pyridyl)ethyl]propylamine (Compound 22).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].O=[C:10]([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl[Sn](Cl)(Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.CO.C(Cl)Cl>[NH2:8][C:7]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH3:17])[N:1]=[C:2]2[S:3][CH:4]=[CH:5][C:6]=12
Reactant: N#Cc1ccsc1N
Reactant: CCOC(=O)CC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1c(C)nc2sccc2c1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Alternatively, a mixture of 2-amino-3-thiophenecarbonitrile (2.5 g, 20.13 mmol), ethyl 3-oxobutanoate (2.80 mL, 22.15 mmol) and SnCl4 (4.73 mL, 40.3 mmol) in toluene (135 mL) was stirred at RT for 30 min, and then refluxed for 2 h. The mixture was then basified with 6M NaOH (ca. 25 mL), diluted with 10% MeOH in DCM (40 mL), and the mixture filtered through celite. The organic layer of the filtrate was then separated and the aqueous layer re-extracted with 10% MeOH in DCM (50 mL×3). The combined organic layers were dried and concentrated. The residue was then purified by chromatography on silica, eluting with a gradient of 0-10% ethyl acetate in DCM, to give the title compound. Another batch of 2-amino-3-thiophenecarbonitrile (2.5 g, 20.13 mmol) was subjected to the same procedure and the products from each reaction were combined to give the title compound (2.36 g).
Reaction SMILES: [K+].[N:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.CN(C=O)C.Cl[CH2:27][N:28]([CH3:39])[S:29]([C:32]1[CH:37]=[CH:36][C:35](C)=[CH:34][CH:33]=1)(=[O:31])=[O:30].O>C1COCC1>[C:32]1([S:29]([N:28]([CH2:39][O:19][C:18]([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:20])[CH3:27])(=[O:31])=[O:30])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)CCl)cc1
Reactant: O=C([O-])c1[nH]c2ccccc2c1Nc1ccncc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CN(COC(=O)c1[nH]c2ccccc2c1Nc1ccncc1)S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 24.3 %

Procedure:
Under N2 at 60° C. dissolve 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid potassium salt (2.2 g, 7.55 mmol) in a mixture of anhydrous THF and DMF (150:40 mL). Cool to 0° C. and add N-chloromethyl-N-methyl-4-methylbenzenesulfonamide (2.0 g, 9.10 mmol) in anhydrous THF (10 mL) dropwise. After 20 min., add water (100 mL) and then extract with dichloromethane (3×100 mL). Combine the organic layers wash with NaHCO3 (sat), water, brine, dry with Na2SO4 and then concentrate. Purify the residue on an ISCO RediSep 35-gram silicagel cartridge, eluting with 50% heptane/ethyl acetate, ethyl acetate and then 10% methanol/ethyl acetate. Combine product containing fractions and concentrate to an oil. Dissolve the oil in methanol and add ether to obtain the title compound as a white solid (800 mg): MS: 437(M+H), 1H NMR (DMSO-d6) δ 11.52 (1H, s), 8.29 (1H, s), 8.04 (2H, d, J=5.5 Hz), 7.76 (2H, d, J=7.2 Hz), 7.43 (6H, m), 7.03 (1H, m), 6.46 (2H, d, J=6.0 Hz), 5.60 (2H, s), 2.79 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[CH2:31]([CH2:33][NH2:34])[OH:32].O.CN1[C:41](=[O:42])CCC1>CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12]([NH:34][CH2:33][CH2:31][OH:32])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12]([NH:34][CH:33]([CH2:41][OH:42])[CH2:31][OH:32])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Reactant: NCCO
Reactant: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(F)ccc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2-c1ccccc1C
Product: Cc1cc(F)ccc1-c1nc(NCCO)nc2c1ccc(=O)n2-c1ccccc1C
Yield: 88 %

Procedure:
The product of Example 121 (400 mg, 0.95 mmol) and ethanolamine (0.29 mL, 4.73 mmol) in NMP (2 mL) was stirred at 23° for 1 h. The mixture was diluted with EtOAc, washed with H2O, the organic phase was separated, EtOAc was removed in vacuo and the residue was purified by Flash chromatography on silica gel, eluting with EtOAc/hexane/triethylamine (50/50/2, v/v/v), followed by evaporation of solvent to afford a gummy residue. Trituration with H2O, gave the title compound compound 4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-ortho-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one as a white solid (340 mg, 88%). LC-MS: 405.4 (MH+, m/z), Rt=1.85 min
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.N1C=CC=CC=1[CH:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[CH2:23][CH2:24][C:25]#[CH:26]>C(N(CC)CC)C.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:26]#[C:25][CH2:24][CH2:23][N:18]2[CH2:17][CH2:22][N:21]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:20][CH2:19]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: C#CCCN1CCNCC1c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(C#CCCN2CCN(c3ccccn3)CC2)nc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2-bromo-5-nitropyridine (3.11 g, 0.015 mol) and the alkyne prepared in Step (a) (3.0 g, 0.014 mol) in 5.8 mL of triethylamine and 60 mL of acetonitrile is degassed by bubbling in dry nitrogen for 15 minutes, and 0.2 g (0.0003 mol) of bis(triphenylphosphine)palladium chloride and 0.05 g (0.0003 mol) of cuprous iodide are added. The flask is flushed with nitrogen and the mixture is stirred at room temperature for 5 hours. The solvent is removed under reduced pressure, and the residue is partitioned between 50 mL of dichloromethane and 50 mL of saturated aqueous sodium bicarbonate. The aqueous layer is extracted with 30 mL of dichloromethane and the combined organic layers are washed with water and dried (sodium sulfate), and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 1% methanol/ 99% dichloromethane) to give the title compound as a brown solid; mp 126°-126.5° C.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH:16]=[CH:17][C:18]3[CH:23]=[C:22]([Si](C)(C)C)[C:21]([O:28][CH2:29][CH3:30])=[C:20]([F:31])[C:19]=3[C:32]([F:35])([F:34])[F:33])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].O>C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[CH2:1]([CH:4]1[CH2:5][CH2:6][CH:7]([CH:10]2[CH2:11][CH2:12][CH:13]([CH:16]=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([O:28][CH2:29][CH3:30])=[C:20]([F:31])[C:19]=3[C:32]([F:35])([F:33])[F:34])[CH2:14][CH2:15]2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(C2CCC(C=Cc3cc([Si](C)(C)C)c(OCC)c(F)c3C(F)(F)F)CC2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(C=Cc3ccc(OCC)c(F)c3C(F)(F)F)CC2)CC1
Reaction time: 2 h

Procedure:
16.03 g of crude of β-(4-(4-propylcyclohexyl)cyclohexyl)-2-trifluoromethyl-3-fluoro-4-ethoxy-5-trimethylsilyl styrene was dissolved in 35 mL of THF, to which 23.4 mL of tetrabutyl ammonium fluoride/THF solution (1 mol/L) was dropped and stirred for 2 hours. The reaction solution was poured into 100 ml of water and extracted with 200 ml of toluene. The organic layer was washed with 100 ml of an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (eluent: heptane/toluene=8/2) and further recrystallized twice from a heptane/ethanol mixed solvent to obtain 7.89 g of β-(4-(4-propylcyclohexyl)cyclohexyl)-2-trifluoromethyl-3-fluoro-4-ethoxy styrene. The compound showed a liquid crystal phase and the transition points were as shown below.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=1)[CH2:11][NH:12][C:13]([C:15]1[CH:16]=[N:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:19][CH:20]=1)=[O:14])(=[O:7])=[O:6].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:38]1[C:43]([C:44](O)=[O:45])=[CH:42][C:41]2[C:47]([O:49][C:50]3([C:60]4[CH:61]=[CH:62][C:63]([OH:65])=[CH:64][C:59]=4[O:58][C:52]4[CH:53]=[C:54]([OH:57])[CH:55]=[CH:56][C:51]3=4)[C:40]=2[CH:39]=1)=[O:48]>CN(C)C=O>[OH:57][C:54]1[CH:53]=[C:52]2[C:51](=[CH:56][CH:55]=1)[C:50]([C:40]1[CH:39]=[CH:38][C:43]([C:44](=[O:45])[NH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]3[CH:29]=[CH:28][CH:27]=[C:10]([CH2:11][NH:12][C:13]([C:15]4[CH:20]=[N:19][C:18]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)=[N:17][CH:16]=4)=[O:14])[CH:9]=3)(=[O:6])=[O:7])=[CH:42][C:41]=1[C:47]([OH:49])=[O:48])=[C:60]1[C:59](=[CH:64][C:63](=[O:65])[CH:62]=[CH:61]1)[O:58]2
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC21c2ccc(O)cc2Oc2cc(O)ccc21
Reactant: NCCNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3ccccc3)nc2)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCCNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3ccccc3)nc2)c1)c1ccc(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c(C(=O)O)c1

Procedure:
To a mixture consisting of N-(3-(N-(2-aminoethyl)sulfamoyl)benzyl)-2-phenylpyrimidine-5-carboxamide (Compound 19, 8.7 mg) in N,N-dimethylformamide (1 mL) was added 250 mM potassium phosphate buffer, pH 8 (2 mL) and 5-carboxyfluorescein, succinimidyl ester (5-FAM, SE; Biotium Catalog No. 90029; 10 mg). The mixture was stirred in the dark until the reaction was complete. The crude product was purified by preparative thin-layer chromatography (75:15:2 chloroform-methanol-water) to afford the title compound (approximately 4 mg); MS (ESI−) m/z 768 (M−1).
Reaction SMILES: Cl[S:2]([C:5]1[N:9]=[CH:8][N:7]([C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[N:6]=1)(=[O:4])=[O:3].Cl.[CH:16]12[NH:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH2:18][CH2:17]2.C(N(CC)CC)C>C(OCC)(=O)C>[CH:20]12[N:23]([S:2]([C:5]3[N:9]=[CH:8][N:7]([C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[N:6]=3)(=[O:4])=[O:3])[CH:16]([CH2:22][CH2:21]1)[CH2:17][CH2:18][CH2:19]2
Reactant: C1CC2CCC(C1)N2
Reactant: CN(C)C(=O)n1cnc(S(=O)(=O)Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)C(=O)n1cnc(S(=O)(=O)N2C3CCCC2CC3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
A mixture of 3-chlorosulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 54-a) (470 mg), 8-azabicyclo[3.2.1]octane hydrochloride (350 mg), triethylamine (0.7 ml), and ethyl acetate (10 ml) was stirred overnight at room temperature. The reaction solution was washed with water, followed by saturated aqueous sodium chloride solution, and concentrated. The residue was subjected to a silica-gel column chromatography with 50 to 100% ethyl acetate/hexane to yield the title compound (150 mg).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[CH:13]=[CH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9][C:8]=2[CH:18]=1)#N.[OH2:19]>CCOCC>[CH:6]1[C:7]2[CH:13]=[CH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9][C:8]=2[CH:18]=[C:4]([CH:2]=[O:19])[CH:5]=1
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1C=C2
Reactant: O
Agent: Cl
Solvent: CCOCC
Product: O=Cc1ccc2c(c1)Sc1ccccc1C=C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Saturate a suspension of anhydrous stannous chloride (378 mg; 2 mmole) in 7.5 ml dry ether with hydrogen chloride at a temperature of 0°-5° C., and add 235 mg (1 mmole) of 3-cyano-dibenzo[b,f]thiepin. Stir for one hour at 0° C. and allow to warm to room temperature (25° C.). Continue stirring at room temperature for approximately 48 hours. Add 5 ml of water and 1 ml 2N hydrochloric acid, and extract with a mixture of 5 ml ether and 5 ml ethyl acetate. When the hydrolysis of the chloro stannate is complete, evidenced by the disappearance of solids from the solution, separate the organic layer containing the product, wash with water/sodium chloride solution, and after drying, evaporate the solution to produce a dark oil which solidifies when triturated with hexane. The title product is obtained when the above solid material is crystallized from acetonitrile, m.p. 114.5°-115.5° C.
Reaction SMILES: [S:1]1[C:5]([C:6]2[S:10][C:9]([N:11]([CH3:22])[CH:12]3[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][C:14]([CH3:21])([CH3:20])[CH2:13]3)=[N:8][N:7]=2)=[CH:4][C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]1=2.[Cl:27]N1C(=O)CCC1=O>ClCCCl.CC(O)=O.C(=O)(O)[O-].[Na+]>[Cl:27][C:4]1[C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=2[S:1][C:5]=1[C:6]1[S:10][C:9]([N:11]([CH3:22])[CH:12]2[CH2:17][C:16]([CH3:18])([CH3:19])[NH:15][C:14]([CH3:20])([CH3:21])[CH2:13]2)=[N:8][N:7]=1
Reactant: CN(c1nnc(-c2cc3ccccc3s2)s1)C1CC(C)(C)NC(C)(C)C1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(c1nnc(-c2sc3ccccc3c2Cl)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 90 °C
Yield: 44.5 %

Procedure:
A mixture of 5-(benzo[b]thiophen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (37 mg, 0.096 mmol) and N-chlorosuccinimide (15.34 mg, 0.115 mmol) in DCE:AcOH (1:1) (1 mL) was heated at 90° C. for six hours. The reaction was cooled to RT, diluted with saturated sodium bicarbonate, extracted with ethyl acetate (3×), and DCM (2×). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to a crystalline yellow solid. Purification by flash column chromatography (4 g silica gel, 1-17% 3.5 N ammonia in MeOH gradient in DCM over 30 column volumes) provided 5-(3-chlorobenzo[b]thiophen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine as a yellow solid (18 mg). LC/MS Rt=0.58 min. MS=420.9 (M−1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.84-7.99 (m, 2H), 7.47-7.60 (m, 2H), 4.53 (m, 1H), 3.14 (s, 3H), 1.83 (d, J=9.6 Hz, 2H), 1.55-1.68 (m, 2H), 1.38 (s, 6H), 1.26 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[C:3]([OH:9])([C:2]([F:10])([F:11])[F:1])[CH:12]=[CH2:13])[CH3:8]
Reactant: C=C[Mg]Br
Reactant: CCOC(=O)C(=O)C(F)(F)F
Solvent: C1CCOC1
Product: C=CC(O)(C(=O)OCC)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of ethyl 3,3,3-trifluoropyruvate (14.2 g) in THF (200 mL) at −78° C. was added vinyl magnesium bromide (84 mL of 1 M in THF) dropwise via addition funnel. The resulting mixture was then warmed to ambient temperature over 2 h. The reaction was quenched by pouring the mixture over ice. To the resulting mixture was then added 2 N HCl, the mixture was extracted with EtOAc, and dried over Na2SO4. After concentration, the resulting crude material was filtered through a plug of silica gel and rinsed with 50% Et2O/hexanes. The resulting mixture was concentrated to yield the title compound as a golden oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:31])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:30])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25](OC)=[CH:24][CH:23]=2)[CH2:14][CH2:13]1.[F:32][C:33]([F:43])([F:42])C1C=CC(CCl)=CC=1.COC1C=CC(CCl)=CC=1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:31])[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([OH:30])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:33]([F:43])([F:42])[F:32])=[CH:26][CH:27]=2)[CH2:16][CH2:17]1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Reactant: COc1ccc(CCC(O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)cc1
Agent: COc1ccc(CCl)cc1
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)CCc2ccc(C(F)(F)F)cc2)CC1

Procedure:
Compound 21 was prepared in a manner similar to that of compound 16 substituting 4-trifluoromethylbenzyl chloride for 4-methoxybenzyl chloride. (M+1)=464.2
Reaction SMILES: [CH3:1][C@@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12][OH:13]>ClCCl>[OH:13][CH2:12][CH2:11][NH:9][C@H:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: OCCBr
Solvent: ClCCl
Product: C[C@@H](NCCO)c1ccccc1
Temperature: 51 °C
Reaction time: 50 h
Yield: 76003 %

Procedure:
51.45 g (0.43 mmole) of (R)-(+)-α-methylbenzylamine was dissolved in 52 ml of dichloromethane and 63.78 g (0.51 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and the residue was subjected to fractional distillation to obtain 54 g of the title compound having pale yellow color.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([C:9]([OH:11])=O)[CH:5]=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:9]([C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=4[CH3:8])=[O:11])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: CCn1ncc(C(=O)O)c1C
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)c1C
Temperature: 79 °C
Reaction time: 3 h
Yield: 59.2 %

Procedure:
A dry flask was charged with 1-Ethyl-5-methyl-1H-pyrazole-4-carboxylic acid (0.159 g, 1.03 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (10 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 1-Ethyl-5-methyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.236 g, 0.61 mmol, 59%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:35]1([CH2:41][CH2:42][S:43][CH:44]([C:48](O)=[O:49])[C:45](O)=[O:46])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[OH:49][C:48]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([CH3:19])[C:11]=2[OH:18])[O:17][C:45](=[O:46])[C:44]=1[S:43][CH2:42][CH2:41][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C)c1O
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(OCc2ccccc2)ccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)c1O

Procedure:
The title compound was prepared by Method A using 4'-benzyloxy-2'-hydroxy-3'-methylacetophenone (1.29 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (2.11 g, 12.6 mmol), chlorotrimethylsilane (1.60 mL, 12.6 mmol), THF (127 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 147-148° C.; 1H NMR (400 MHz, DMSO-d6) δ2.14 (s, 3 H), 2.77 (t, 2 H), 2.98 (t, 2 H), 5.17 (s, 2 H), 5.29 (s, 1 H), 6.79 (d, 1 H), 7.30 (m, 13H), 9.36 (s, 1 H), 11.85 (bs, 1 H).
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH:18]2[CH:4]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[O:11][C:12]3[CH:13]=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=32)[CH2:3]1>C(#N)C>[CH3:1][N:2]1[CH2:19][C@@H:18]2[C:17]3[CH:16]=[C:15]([Cl:20])[CH:14]=[CH:13][C:12]=3[O:11][C:10]3[C:5]([C@H:4]2[CH2:3]1)=[CH:6][CH:7]=[CH:8][CH:9]=3.[ClH:20]
Reactant: CN1CC2c3ccccc3Oc3ccc(Cl)cc3C2C1
Solvent: CC#N
Product: CN1C[C@@H]2c3ccccc3Oc3ccc(Cl)cc3[C@H]2C1
Product: Cl
Temperature: 25 °C

Procedure:
To 105 mg of Asenapine hydrochloride dihydrate was added 2.0 ml acetonitrile and the obtained suspension was stirred for one week at room temperature, then filtered and the solid product dried in air at room temperature. The obtained sample was characterized by powder X-ray diffraction and a PXRD pattern as depicted in FIG. 3 with the most important peaks as listed in Table 4 was obtained. The H-NMR spectrum confirmed the presence of protonated Asenapine.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:16])([F:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C=O)C>[F:15][C:8]([F:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:7][N:19]=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(OCC(F)(F)c1ccccn1)C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC(F)(F)c1ccccn1
Temperature: 60 °C

Procedure:
To a stirred solution of 5.5 g of 2,2-difluoro-2-(2-pyridyl)ethyl trifluoromethanesulfonate 6-4 in 70 mL of DMF was added 6.74 g (104 mmol) of sodium azide under Ar. The mixture was heated to 60° C. overnight. A second batch was run in the same manner, and after cooling to rt, both reactions were poured into 600 mL of water, and extracted with 3×500 mL of ether. The combined extracts were washed with brine, dried over Na2SO4 and concentrated at reduced pressure to give an oil that was purified by SiO2 (10×6 cm) using hexane 1:3 EtOAc-hexane and 1:1 EtOAc-hexane. The product-containing fractions were concentrated at reduced pressure to give 6-5 as a yellow oil: 1H NMR (CDCl3) δ 4.05 (t, 2H), 7.4-7.45 (m, 1H), 7.73 (d, 1H), 7.83-7.89 (m, 1H), 8.67 (d, 1H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([N:39]1[CH2:42][CH:41]([OH:43])[CH2:40]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].O[C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1>C1COCC1>[C:35]([O:34][C:32]([N:39]1[CH2:42][CH:41]([O:43][C:45]2[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=2)[CH2:40]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Oc1cccnc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Oc2cccnc2)C1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
To 315 mg (1.2 mmol) of PPh3 in 5 mL of dry THF at −20° C. was added 189 μL (1.2 mmol) of DEAD dropwise. The solution was allowed to stir 10 min. at −20° C. After 10 min, a solution containing 173 mg (1 mmol) of N-Boc-3-hydroxyazetidine and 2 mL of dry THF was added dropwise. The solution was again allowed to stir 10 min at −20° C. After 10 min, to the solution was added 95 mg (1 mmol) of 3-hydroxypyridine at once. The solution was then slowly heated to 70° C. and allowed to stir at 70° C. overnight. Next day, solvent was removed under reduced pressure. The crude product was purified by flash chromatography (2:1, Hexane:Ethyl Acetate) to obtain 160 mg (64% yield) of a yellow oil: 1H NMR (300 MHz, CD3OD) δ8.27 (1H, d, J=4.8 Hz), 8.18 (1H, d, J=2.7 Hz), 7.23 (1H, m), 7.05 (1H, m), 4.92 (1H, m), 4.34-4.00 (2H, AB, J=6.6, 9.7 Hz), 1.45 (9H, s).