Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=1[F:40])[C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22]C)=[O:21])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Li+]>C1COCC1.O>[CH2:1]([N:5]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:32][C:31]=1[F:40])[C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([OH:22])=[O:21])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(C(F)(F)F)cc1F)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(Cc1ccc(C(F)(F)F)cc1F)C(=O)COc1ccc(CCOc2ccccc2C(=O)O)cc1
Yield: 94.4 %

Procedure:
Methyl 2-{2-[4-(2-{butyl[2-fluoro-4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]ethoxy}benzoate (0.230 g, 0.410 mmol) was dissolved in a mixture of THF/water (1/1, 4 ml). Lithium hydroxide (0.015 g, 0.617 mmol) was added. The reaction was performed in an single node microwave oven (14 min, 150 deg). Work-up by removing the solvent by evaporation and addition of HCl (2 ml, 1 M). The water-phase was extracted with two portions of EtOAc (20 ml). The organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 0.212 g of 2-{2-[4-(2-{butyl[2-fluoro-4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]ethoxy}benzoic acid (yield 94.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][C:16]1([CH3:30])[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][C:19](=[O:28])[CH2:18][C:17]1=[O:29].C(N(CC)CC)C.CC(C)(O)C#N>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([CH:18]1[C:17](=[O:29])[C:16]([CH3:30])([CH3:15])[CH:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:20][C:19]1=[O:28])=[O:5]
Reactant: CC1(C)C(=O)CC(=O)CC1c1ccccc1
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c(Cl)c1
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)C(=O)C(C(=O)c2ccc(S(C)(=O)=O)cc2Cl)C(=O)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
2-Chloro-4-(methylsulfonyl)benzoyl chloride (2.3 g, 9 mmol) and 4,4-dimethyl-5-phenyl-1,3-cyclohexanedione (2.0 g, 9 mmol) were dissolved in 50 ml of acetonitrile. Triethylamine (1.8 g, 18 mmol) was added dropwise and the resulting solution was stirred at room temperature for 1 hour. Acetone cyanohydrin (0.17 g, 2 mmol) and triethylamine (1.8 g, 18 mmol) were added and the reaction mixture was stirred at room temperature for 1.5 hour. The reaction mixture was concentrated under vacuum and the residue dissolved in 100 ml of methylene chloride. The methylene chloride solution was washed with 2N hydrochloric acid, 10% cupric acetate, wter, 5% potassium carbonate, 2N hydrochloric acid, and water. The methylene chloride solution was dried over anhydrous magnesium sulate and concentrated under vacuum, yielding 1.2 g of the desired product as a viscous oil. It was identified as such by nuclear magnetic resonance spectroscopy, infrared spectroscopy and mass spectroscopy.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:30])=O>ClCCl>[CH2:1]([O:8][C:9](=[O:10])[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([Cl:30])=[O:17])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CN(CCCCC(=O)O)C(=O)OCc2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CN(CCCCC(=O)Cl)C(=O)OCc2ccccc2)cc1

Procedure:
5.6 g (15 mmol) of the 5-{[(benzyloxy)carbonyl](4-methoxybenzyl)amino}valeric acid obtained in this way are dissolved in 60 ml of dichloromethane, and 2.2 ml of thionyl chloride are added. The mixture is heated under reflux for 30 min. It is then concentrated in vacuo, and the residue is again mixed with dichloromethane and concentrated once again. A viscous oil remains and is dried under high vacuum. 5.7 g (98% of theory) of the target compound are obtained and are reacted further without further purification and characterization.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([NH:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[OH:23])=[O:15])=[CH:4][C:5]([Br:13])=[C:6]2[C:11]=1[N:10]([CH3:12])[CH2:9][CH2:8][CH2:7]2.[C:24]1(C)C=CC=CC=1>CN(C(OC)OC)C>[Br:13][C:5]1[CH:4]=[C:3]2[C:2](=[C:11]3[N:10]([CH3:12])[CH2:9][CH2:8][CH2:7][C:6]=13)[N:1]=[CH:24][N:16]([C@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]1[OH:23])[C:14]2=[O:15]
Reactant: CN1CCCc2c(Br)cc(C(=O)N[C@H]3CCCC[C@@H]3O)c(N)c21
Reactant: Cc1ccccc1
Agent: COC(OC)N(C)C
Product: CN1CCCc2c(Br)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21

Procedure:
A solution of 8-amino-5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxamide (758 mg, 1.98 mmol) in toluene (6 mL) and DMF-DMA (5.3 mL) was heated in a sealed tube at 135° C. for 3 h. The resulting mixture was concentrated and purified by silica gel chromatography (0-4% MeOH/CH2Cl2) to afford 6-bromo-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-7,8,9,10-tetrahydropyrido[3,2-h]quinazolin-4(3H)-one in pure form.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH2:25].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH2:10]([O:26][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH2:25]
Reactant: C=CCC=CCC=CCCCCCCCCO
Reactant: O=C(O)c1ccc(Br)o1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: C=CCC=CCC=CCCCCCCCCOc1ccc(C(=O)O)o1
Temperature: 110 °C

Procedure:
A mixture of 57.0 g (0.300 mole) of 5-bromo-2-furoic acid, 119.0 (0.450 mole) of 9,12,15-hexadecatrienol, and 84 g (0.750 mole) of potassium tert-butoxide in dry toluene is stirred with heating. The tert-butanol formed in the reaction is allowed to distill off, and the mixture is refluxed at 110° C. with stirring from 48 hours. The mixture is allowed to cool, then is acidified with acetic acid and diluted with ice water. The toluene organic layer is separated, washed with water, then extracted three times with 5% sodium bicarbonate solution. The combined aqueous extracts are cooled and acidified with 10% HCl solution to give 5-(9,12,15-hexadecatrienyloxy)-2-furoic acid.
Reaction SMILES: C(OC(N1C[C@@H](P(C2C=C(C)C(OC)=C(C)C=2)C2C=C(C)C(OC)=C(C)C=2)C[C@H]1CP(C1C=C(C)C(OC)=C(C)C=1)C1C=C(C)C(OC)=C(C)C=1)=O)(C)(C)C.C(N(CC)CC)C.[C:63]([NH:66][C:67](=[CH:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:68]([OH:70])=[O:69])(=[O:65])[CH3:64]>C(O)C>[C:63]([NH:66][C@@H:67]([C:68]([OH:70])=[O:69])[CH2:71][C:72]1[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=1)(=[O:65])[CH3:64]
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Agent: COc1c(C)cc(P(C[C@@H]2C[C@H](P(c3cc(C)c(OC)c(C)c3)c3cc(C)c(OC)c(C)c3)CN2C(=O)OC(C)(C)C)c2cc(C)c(OC)c(C)c2)cc1C
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: 50 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
0.005 m-mole of rhodium-dinorbornadieneperchlorate, 0.0065 m-mole of (2S,4S)-N-tert.-butoxycarbonyl-2-bis(3,5-dimethyl-4-methoxyphenyl)phosphinomethyl-4-bis(3,5-dimethyl-4-methoxyphenyl)phosphinopyrrolidine (Ii) and 0.25 m-mole of triethylamine were dissolved in 20 ml of ethanol and 5 m-mol of α-acetamidocinnamic acid was added to the solution. The mixture was stirred for 20 hours at 50° C. and under a hydrogen pressure of 20 atm. The reaction mixture was concentrated under reduced pressure and then dissolved in 0.5N aqueous solution of caustic soda. Insolubles were filtered off and the filtrate was made acid with diluted hydrochloric acid and extracted with ether. The organic layer was washed with water and dried. The solvent was distilled off to obtain optically active (R)-N-acetylphenylalanine. Conversion 100%; optical yield 98%.
Reaction SMILES: [CH2:1]([CH:7]1[CH2:11][CH:10]=[CH:9][O:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19].[S:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>>[Cl-:12].[CH2:1]([CH:7]1[CH2:11][CH2:10][CH:9]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:21]2[S:20][CH:24]=[CH:23][NH+:22]=2)[O:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OCCCCCCCl
Reactant: CCCCCCC1CC=CO1
Reactant: c1cscn1
Product: CCCCCCC1CCC(OCCCCCCc2[nH+]ccs2)O1
Product: [Cl-]

Procedure:
Analogous to example 9 but starting from 2-hexyl-2,3-dihydrofuran and 6-chlorohexanol. Substitution of the chloro atom was performed with thiazole instead of pyridine in the same conditions but on a mixture of cis+trans isomers leading to the title compound as an highly hygroscopic compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21](N)=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([I:26])=[N:9]2)=[CH:5][CH:4]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]2([C:42](F)=[O:43])[CH2:41][CH2:40]2)=[O:38])=[CH:32][CH:31]=1.C(#[N:47])C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:36]([C:33]5[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=5)[C:37]([C:39]5([C:42]([NH2:47])=[O:43])[CH2:41][CH2:40]5)=[O:38])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([I:26])=[N:9]2)=[CH:27][CH:28]=1
Reactant: O=C(F)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: CC#N
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Product: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
4-(1-(4-Methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.490 g, 1.0 mmol, prepared according to Example 7, Step B) and acetonitrile (5 mL) were heated with 1-((4-fluorophenyl)carbamoyl)-cyclopropanecarbonyl fluoride (0.450 g, 2.00 mmol, prepared according to Example 6, Step A) at 100° C. in a sealed vessel for 4 hours. The suspension was allowed to cool to ambient temperature, and then in an ice bath for 15 minutes. The solid was filtered to provide pure desired product (0.52 g, 75%) by LRMS (APCI−): 100% purity, 220 nm, m/z 694 (M−1) detected.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:19][CH:20]=2)=[C:8]([CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])[C:7]=1[OH:32])(=[O:5])[CH3:4].[CH3:33]I.Cl>CN(C)C=O>[C:3]([C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:19][CH:20]=2)=[C:8]([CH2:26][CH2:27][C:28]([F:29])([F:31])[F:30])[C:7]=1[O:32][CH3:33])(=[O:5])[CH3:4]
Reactant: CC(=O)c1ccc(OCCCOc2cccc([N+](=O)[O-])c2)c(CCC(F)(F)F)c1O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C(C)=O)ccc(OCCCOc2cccc([N+](=O)[O-])c2)c1CCC(F)(F)F

Procedure:
5,530 mg of sodium hydride are added to a solution of 7.46 g of 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-nitrobenzene in 75 ml of dimethylformamide and the reaction mixture is warmed to 40°. 5.7 g of methyl iodide are added dropwise in the course of 15 minutes. Thereafter, the reaction mixture is kept at 40° C. for a further hour. After cooling, it is poured onto dilute hydrochloric acid and extracted with methylene chloride and the extract is evaporated. Recrystallisation from ether/hexane gives 3-{3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-nitrobenzene.
Reaction SMILES: CN(C)CCCN=C=NCC.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)[CH2:14][CH2:13]1.[NH:24]1[CH2:34][CH2:33][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25]1.C(N(CC)CC)C>ClCCl.O.OC1C2N=NNC=2C=CC=1>[N:15]1([CH2:18][CH2:19][CH2:20][C:21]([N:24]2[CH2:34][CH2:33][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25]2)=[O:23])[CH2:14][CH2:13][O:12][CH2:17][CH2:16]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(O)CCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=O)CCCN2CCOCC2)CC1
Temperature: 20 °C
Reaction time: 20 h
Yield: 83.9 %

Procedure:
0.95 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide in solution in 20 cm3 of dichloromethane is added, at 20° C., to 1.0 g of 4-morpholinobutyric acid, 0.78 g of ethyl isonipecotate, 2.1 cm3 of triethylamine and 20 mg of hydroxybenzotriazole hydrate, in solution in 80 cm3 of dichloromethane. After stirring for 20 hours at 20° C., the reaction mixture is washed with 20 cm3 of water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a pale yellow oil which is purified by chromatography on a CBT1 alumina column [eluent: dichloromethane/methanol (97/3 by volume)]. 1.30 g of ethyl 1-(4-morpholin-4-ylbutyryl)-4-piperidinecarboxylate are thus obtained in the form of a pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](OC)[CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.[C:22]([O-])([O-])=O.[Na+].[Na+].O>C(OCC)(=O)C>[CH3:22][C:4]1[CH:3]=[C:2]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: OB(O)c1cccnc1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(-c2cccnc2)ccc1[N+](=O)[O-]
Temperature: 82 °C
Yield: 85 %

Procedure:
Nitrogen was bubbled through dioxane for 15 minutes (100 mL) prior to the addition of 4-chloro-2-(methyloxy)-1-nitrobenzene (5.0 g, 29.1 mmol, Aldrich). To the solution were added 3-pyridinylboronic acid (4.3 g, 34.9 mmol, Frontier Science), dichloro(triphenylphosphine)palladium (1.0 g, 1.46 mmol, Aldrich) and degassed aqueous Na2CO3 (30 mL, 3 N, 87.3 mmol). The reaction mixture was heated at 82° C. for 4 h. Additional water (100 mL) was added to the reaction when it was cooled down to rt, and ethyl acetate was used to extract the crude product. The combined organic phases were dried (Na2CO3), concentrated, and purified by silica column chromatography (10-60% Ethyl acetate/hexane) to afford 3-(3-methyl-4-nitrophenyl)pyridine (5.3 g, 85% yield.) 1H NMR (400 MHz, DMSO-d6) δ ppm 2.58 (s, 3 H), 7.52 (ddd, J=8.0, 4.8, 0.9 Hz, 1 H), 7.80 (dd, J=8.5, 2.1 Hz, 1 H), 7.90 (d, J=1.1 Hz, 1 H), 8.08 (d, J=8.4 Hz, 1 H), 8.16 (ddd, J=8.0, 2.5, 1.6 Hz, 1 H), 8.62 (dd, J=4.8, 1.5 Hz, 1 H), 8.95-8.97 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([CH:11]=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[O-:13]Cl=O.[Na+]>O.CS(C)=O>[Cl:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1csc2c(Cl)ncnc12
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1csc2c(Cl)ncnc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
NaH2PO4.2H2O (170 mg, 1.07 mmol) was dissolved in water (0.6 mL) and 4-chlorothieno[3,2-d]pyrimidine-7-carbaldehyde (100 mg, 0.47 mmol) dissolved in DMSO (4.8 mL) was added thereto at 10° C. The reaction mixture was cooled to 0° C. and NaClO2 (170 mg, 1.88 mmol) dissolved in water (0.6 mL) was added thereto at 0° C. The reaction mixture was heated to room temperature, stirred for 2 hours, and water (10 mL) was added thereto. The reaction mixture was stirred for 2 hours and then filtered. The filtrate was concentrated to obtain the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][S:10](=[O:14])(=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH2:26][N:27]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:28][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:33]([N:27]1[CH2:28][CH:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:11][S:10](=[O:14])(=[O:13])[CH:9]2[CH2:26]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=S1(=O)C=CC(c2ccccc2)(c2ccccc2)CC1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S1(=O)CCC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC21
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
2 drops of trifluoroacetic acid are added to a solution of 1.3 g of 3,4-dihydro-4,4-diphenyl-2H-thiapyran 1,1-dioxide and 1.75 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine in 12 cm3 of anhydrous dichloromethane, and the mixture is stirred for 30 minutes at 30° C. 1.75 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine and 2 drops of trifluoroacetic acid are again added and the mixture is stirred for 2 hours at 35° C. This last procedure is once again repeated and after stirring for 1 hour, 1 g of potassium carbonate is added. The suspension is filtered and the filtrate concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.2 cm, height 35 cm), eluting under a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (80/20 by volume) and collecting fractions of 30 cm3. Fractions 20 to 28 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 0.7 g of (4aRS,7aRS)-6-benzyl4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide is obtained in the form of white crystals; melting point 186° l C.
Reaction SMILES: CI.[Cl:3][C:4]1[N:9]=[C:8]([NH:10][C:11]2[C:12]3[CH:13]=[N:14][N:15]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[C:16]=3[CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:6][N:5]=1.[C:29](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:3][C:4]1[N:9]=[C:8]([N:10]([CH3:29])[C:11]2[C:12]3[CH:13]=[N:14][N:15]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[C:16]=3[CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:6][N:5]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(Cn2ncc3c(Nc4ccnc(Cl)n4)cccc32)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(Cn2ncc3c(N(C)c4ccnc(Cl)n4)cccc32)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
Methyl iodide (1.021 mL, 16.40 mmol) was added dropwise to a stirred suspension of N-(2-chloropyrimidin-4-yl)-1-(4-methoxybenzyl)-1H-indazol-4-amine (4 g, 10.93 mmol, Example 3 starting material) and potassium carbonate (2.267 g, 16.40 mmol) in DMF (40 mL) at 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 15 minutes and was allowed to warm to room temperature. The reaction mixture was stirred at room temperature overnight, filtered off and washed with ethyl acetate. The filtrate was concentrated to dryness, diluted with dichloromethane (40 ml), washed with water (40 ml), brine (40 ml), dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0 to 45% ethyl acetate in petroleum ether to afford N-(2-chloropyrimidin-4-yl)-1-(4-methoxybenzyl)-N-methyl-1H-indazol-4-amine (3.4 g, 82%) as a pale orange solid. NMR Spectrum: (DMSOd6) 3.50 (s, 3H), 3.71 (s, 3H), 5.63 (s, 2H), 6.19 (d, 1H), 6.89 (d, 2H), 7.16 (d, 1H), 7.29 (d, 2H), 7.49 (dd, 1H), 7.81 (d, 1H), 7.96 (d, 1H), 8.00 (s, 1H); Mass spectrum: MH+ 380.
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.C([N:17]([CH:20]([CH3:22])C)[CH2:18][CH3:19])(C)C.[CH2:23](O)[CH3:24]>>[CH2:10]([O:9][C:7](=[O:8])[C:6]1[CH:12]=[CH:13][C:3]([CH2:2][N:17]2[CH2:18][CH2:19][C:23]3([C:24]4[C:5](=[CH:4][CH:3]=[CH:13][CH:12]=4)[CH:6]=[CH:7]3)[CH2:22][CH2:20]2)=[CH:4][CH:5]=1)[CH3:11]
Reactant: CCO
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(CN2CCC3(C=Cc4ccccc43)CC2)cc1
Temperature: 85 °C
Yield: 60 %

Procedure:
To a solution of spiro-[indene-1,4-piperidine]trifluoroacetate (4 g, 14 mmol) in ethanol (25 mL) is added ethyl 4-(bromomethyl)-benzoate (2.9 g, 12.6 mmol), followed by diisopropylethylamine (9.6 mL, 56 mmol). The reaction mixture is refluxed at 85° C. for overnight. The ethanol is removed under reduced pressure and the residue is partitioned between EtOAc (150 mL) and water (50 mL). The organic layer is washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with hexane:ethyl acetate (8.0:2.0) to give the title compound as brown solid (2.8 g, 60%). 1H NMR (400 MHz) 7.94 (d, J=8 Hz, 2H), 7.51 (d, J=8 Hz, 2H), 7.43 (d, J=7.2 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.18 (m, J=7.2 Hz, 2H), 6.94 (d, J=5.6 Hz, 1H), 6.78 (d, J=5.6 Hz, 1H), 4.30 (q, J=7.2 Hz, 2H), 3.67 (s, 2H), 2.85 (d, J=11.6 Hz, 2H), 2.38 (t, J=11.6 Hz, 2H), 2.09 (t, J=10.4 Hz, 2H), 1.31 (t, J=7.2 Hz, 2H), 1.19 (d, J=12.8 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:6]([CH2:7][CH:2]([CH3:1])[C:3]([OH:5])=[O:4])=[O:8])=[CH:16][CH:15]=1
Reactant: CC1CC(=O)OC1=O
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(CC(=O)c1ccc(Cl)cc1)C(=O)O
Temperature: 65 °C

Procedure:
To a solution of 114 g. of methylsuccinic anhydride in 400 ml. of chlorobenzene is added carefully 270 g. of aluminum chloride. The mixture is heated to 65° C. for 11/2 hours, is cooled, quenched with ice and concentrated hydrochloric acid and extracted with benzene. The benzene layer is extracted with aqueous sodium bicarbonate. After adjusting the pH of the bicarbonate solution to 6.3, concentrated hydrochloric acid is added slowly over a period of several hours with stirring. At pH 5.7, 78 g. of white crystals are filtered off. Recrystallization of this material from ethanol-water affords 3-(p-chlorobenzoyl)-2-methylpropionic acid as white crystals. A mixture of 35.50 g. of the preceding compound, 85 ml. of hydrazine hydrate and 400 ml. of ethyl alcohol is allowed to stir at reflux for 18 hours. The reaction mixture is concentrated to about 75% of the original volume, cooled in an ice bath and filtered to yield 26.62 g. of 6-(p-chlorophenyl)-4,5-dihydro-4-methyl-3(2H)-pyridazinone as a yellow solid. An additional 4.7 g. of product is obtained from the filtrate above.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][S:21]([CH3:20])(=[O:23])=[O:22])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(F)cc1-c1ccc2cc(NS(C)(=O)=O)ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (150 mg, 0.595 mmol) in pyridine (5 mL) was added methanesulfonyl chloride (137 mg, 1.20 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. A small amount of water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic phase was pooled and concentrated. It was purified by prep-HPLC to give the desired product (80.5 mg, 41.0%). LCMS (ESI): RT (Min)=1.181, M+H+=330.9, method=A; 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 9.17 (s, 1H), 8.04 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.44 (s, 1H), 7.38-7.34 (m, 1H), 7.15 (d, J=9.2 Hz, 2H), 3.30 (s, 3H), 2.22 (s, 3H).