Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[C:3]([C:5]1[C:6]([CH3:32])=[C:7]([C:17]([N:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[O:18])[N:8]2[C:13]=1[CH:12]=[C:11]([CH:14]([CH3:16])[CH3:15])[CH:10]=[CH:9]2)=[O:4].[OH-].[Na+].CC(O)=O>O1CCOCC1.O>[CH3:34][C:2]([CH3:1])([CH3:33])[C:3]([C:5]1[C:6]([CH3:32])=[C:7]([C:17]([N:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:18])[N:8]2[C:13]=1[CH:12]=[C:11]([CH:14]([CH3:16])[CH3:15])[CH:10]=[CH:9]2)=[O:4]
Reactant: COC(=O)CCN(C(=O)c1c(C)c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn12)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)N(CCC(=O)O)c1ccccc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a stirred solution of methyl N-{[1-(2,2-dimethylpropanoyl)-2-methyl-7-(propan-2-yl)indolizin-3-yl]carbonyl}-N-phenyl-beta-alaninate (60 mg, 0.13 mmol) in 1,4-dioxane (5 mL) and water (1 mL) is added 10M aqueous NaOH (50 μL). The mixture is stirred at 23° C. for 2 h then acidified with HOAc, diluted water (5 mL), extracted with CH2Cl2, dried with MgSO4, filtered, and concentrated in vacuo to afford the title compound (42 mg, 72%).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:16][CH2:17][CH2:18][NH:19][S:20]([C:23]3[CH:27]=[CH:26][N:25]([CH3:28])[CH:24]=3)(=[O:22])=[O:21])=[CH:11][CH:12]=2)[CH:7]1[CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].O>O1CCCC1.C(OCC)(=O)C>[F:37][C:32]1[CH:31]=[C:30]([CH:35]=[C:34]([F:36])[CH:33]=1)[CH2:29][CH:7]1[C:8]2[CH:9]=[C:10]([O:16][CH2:17][CH2:18][NH:19][S:20]([C:23]3[CH:27]=[CH:26][N:25]([CH3:28])[CH:24]=3)(=[O:22])=[O:21])[CH:11]=[CH:12][C:13]=2[CH2:14][CH2:15][CH:6]1[NH:5][CH:4]=[O:3]
Reactant: CCOC(=O)NC1CCc2ccc(OCCNS(=O)(=O)c3ccn(C)c3)cc2C1Cc1cc(F)cc(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1ccc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2cc(F)cc(F)c2)C(NC=O)CC3)c1
Temperature: 50 °C

Procedure:
Ethyl[1-(3,5-difluorobenzyl)-7-(2-{[(1-methyl-1H-pyrrol-3-yl)sulfonyl]amino}ethoxy)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (200 mg, 0.365 mmol) was dissolved in tetrahydrofuran (16 mL). A 1 M solution of lithium aluminium hydride in tetrahydrofuran (0.73 mL, 0.73 mmol) was added dropwise at room temperature. The reaction mixture was heated to 50° C. for 2 h. Under cooling 2N sodium hydroxide solution (3 mL) was added dropwise. Water (30 mL) and ethyl acetate (30 mL) were added. The aqueous phase was extracted twice with ethyl acetate. The combined extracts were dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, dichloromethane, methanol). Yield: 61 mg (0.116 mmol, 32%).
Reaction SMILES: [OH-].[K+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]2=[O:9])=[CH:14][CH:13]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CCCCN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(CN2CCCCC2=O)cc1
Yield: 52.1 %

Procedure:
A suspension of potassium hydroxide (85%, 18.6 g) and tetrabutylammonium bromide (4.88 g) in toluene (250 ml) was refluxed overnight under nitrogen atmosphere using Deenschtark device. The mixture was cooled to 80° C., to which a solution of 2-piperidone (25.0 g) and 4-methoxybenzylchloride (51.3 g) in toluene (50 ml) were added dropwise. After refluxing for 8 hours, the reaction mixture was returned to room temperature and washed with water and saturated brine. The resultant was dried with magnesium sulfate, after which the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 1-(4-methoxybenzyl)piperidin-2-one (28.8 g) as a colorless oily material.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:11]([SH:15])[CH2:12][CH2:13][SH:14].B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:1]1[S:15][CH2:11][CH2:12][CH2:13][S:14]1
Reactant: SCCCS
Reactant: COc1ccccc1C=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccccc1C1SCCCS1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.3 %

Procedure:
A solution of 20.4 g (150 mmol) of o-anisaldehyde and 24 mL (239 mmol) of propane-1,3-dithiol in 300 mL of methylene chloride was cooled to 0° C. Boron trifluoride etherate (4.0 mL, 33 mmol) was added dropwise to the cooled solution and the reaction mixture was stirred at 0° C. for 0.5 h, then at ambient temperature for 18 h. The methylene chloride solution was washed with 2×100 mL of 10% aqueous sodium hydroxide solution, 100 mL of water and 100 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 35.4 g (95% yield) of 2-(2'-methoxyphenyl)-1,3-dithiane, m.p. 127°-128° C.; 1H NMR (CDCl3) δ 1.8-2.0 (m, 1H), 2.1-2.25 (m, 1H), 2.87 (t, 1H), 2.92 (t, 1H), 3.05-3.2 (m, 2H), 3.85 (s, 3H), 5.69 (s, 1H), 6.87 (d, 1H), 6.97 (t, 1H), 7.25 (dt, 1 H), 7.59 (dd, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]2.[H-].[Na+].[CH3:24]I.[BrH:26]>CN(C)C=O.CC(C)=O>[BrH:26].[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:24])[C:16](=[O:21])[CH2:15][CH2:14]2
Reactant: CI
Reactant: Cc1c(-c2ccc3c(c2)CCC(=O)N3)nc2ccccn12
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc3c(c2)CCC(=O)N3C)nc2ccccn12

Procedure:
To a solution of 6-(3-methylimidazo[1,2-a]-pyridine-2-yl)-3,4-dihydrocarbostyril (3 g) in dimethylformamide (50 ml) was added 50% oily sodium hydride (590 mg) and the mixture was reacted for 2 hours at room temperature. Then, after adding methyl iodide (1.85 g), the mixture was further reacted for 3 hours at room temperature. After completion of reaction, dimethylformamide was evaporated. Chloroform and 0.5 N sodium hydroxide were added to the residue for extraction. The chloroform layer was washed with water thoroughly and dried followed by evaporation of chloroform. The residue was purified using silica gel column chromatography and the oily product thus obtained was dissolved in acetone. The solution was adjusted to pH of about 1 by the addition of 48% hydrobromic acid and crystals which formed were collected by filtration. The crude crystals thus obtained were recrystallized from water to give 2.9 g of 6-(3-methylimidazo[1,2-a]pyridine-2-yl)-1-methyl-3,4-dihydrocarbostyril monohydrobromide.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:19])[CH3:18])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[Br:26]Br.C([O-])(O)=O.[Na+]>C(OCC)C.[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:19])[CH2:18][Br:26])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: CC(=O)c1cccc(NC(=O)OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(C(=O)CBr)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
3-acetylphenyl carbamic acid benzyl ester (3.50 g, 13.0 mmol) was dissolved in diethyl ether (70 mL) and THF (20 mL) and brought to 0° C. A catalytic amount of aluminum (III) chloride (0.010 g) was added followed by the drop-wise addition of bromine (0.731 mL, 14.3 mmol) in diethyl ether (10 mL). The reaction was kept at 0° C. for 30 mins before being allowed to warm to room temperature on its own accord. Sat. NaHCO3 (30 mL) was added to quench the reaction and the solution was poured into ethyl acetate (30 mL). The combined organics were washed with sat. NaHCO3 (3×30 mL) and brine (1×30 mL) before being dried (Na2SO4), filtered, and evaporated to dryness. Trituration of the resulting crude product with a 2:1 mixture of dichloromethane/diethyl ether (6 mL) followed by filtration afforded 2.57 g (57%) of 3-(2-bromoacetyl)phenyl carbamic acid benzyl ester as a light pink solid: 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.11 (s, 1H), 7.69 (m, 2H), 7.43 (m, 6H), 5.18 (s, 2H), 4.88 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 201.5, 163.4, 149.8, 146.5, 144.6, 139.4, 138.5, 138.2, 133.3, 131.9, 127.6, 126.7, 76.0, 44.1; HRMS (ESI) calcd for C16H14BrNO3 (M+) 347.0157. found 347.0151.
Reaction SMILES: [O:1]([CH2:8][CH:9]([OH:12])[CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:14]([CH3:31])[CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>CO>[O:1]([CH2:8][CH:9]([OH:12])[CH2:10][NH:11][CH:14]([CH3:31])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: NCC(O)COc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)COc1ccccc1
Yield: 76.1 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 0.98 g of 3-phenoxy-2-hydroxypropylamine (prepared as described in Preparation 15), 3.39 g of 5-[4-(2-oxopropoxy)benzyl]thiazolidine-2,4-dione, 1.11 g of sodium cyanoborohydride and 60 ml of anhydrous methanol were used. The resulting crude product was purified by silica gel column chromatography (using a 10:1 by volume mixture of ethyl acetate and ethanol as the eluent) to give 1.92 g of the title compound, melting at 64° C. to 68° C.
Reaction SMILES: [C:1]([C:3](=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([O:6][CH2:7][CH2:8][OH:9])=[O:5])#[N:2].[CH2:23]([O:27][CH2:28][CH:29]=[CH2:30])[CH:24]1[O:26][CH2:25]1.C>[Cl-].C[N+](C)(C)C.C(Cl)Cl>[CH2:28]([O:27][CH2:23][CH:24]([OH:26])[CH2:25][O:9][CH2:8][CH2:7][O:6][C:4](=[O:5])[C:3]([C:1]#[N:2])=[C:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH:29]=[CH2:30]
Reactant: N#CC(C(=O)OCCO)=C(c1ccccc1)c1ccccc1
Reactant: C=CCOCC1CO1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: ClCCl
Product: C=CCOCC(O)COCCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
Into a round bottom flask was charged 29 g. (0.1 moles) of 2-hydroxyethyl 2-cyano-3,3-diphenylacrylate, 12.4 g. (0.11 moles) of allyl glycidyl ether and 250 mg. of tetramethylammonium chloride. The flask was stoppered and the mixture was heated at 50° C. for 16 hours. Then cooled mixture was diluted with 50 ml. methylene dichloride, treated with decolonizing charcoal and filtered. The filtrate was evaporated, leaving a pale yellow oil characterized as the product.
Reaction SMILES: F[C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4](F)[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[F:19][CH:20]([F:30])C1C=CC=CC=1B(O)O>>[F:19][CH:20]([F:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: OB(O)c1ccccc1C(F)F
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: O=C(O)c1csc(-c2ccccc2C(F)F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (2-(difluoromethyl)phenyl)boronic acid gave the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[CH2:3][O:4][C:5]([N:7]1[CH2:27][C@H:26]([OH:28])[CH2:25][C@H:8]1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:49][O:50][CH:51]=[CH:52][C:53]1[CH:58]=[CH:57][C:56](O)=[CH:55][CH:54]=1>C1C=CC=CC=1>[CH3:1][CH:2]([CH3:29])[CH2:3][O:4][C:5]([N:7]1[CH2:27][C@@H:26]([O:28][C:56]2[CH:57]=[CH:58][C:53]([CH:52]=[CH:51][O:50][CH3:49])=[CH:54][CH:55]=2)[CH2:25][C@H:8]1[C:9]([O:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:10])=[O:6]
Reactant: CC(C)COC(=O)N1C[C@H](O)C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: COC=Cc1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COC=Cc1ccc(O[C@H]2C[C@@H](C(=O)OC(c3ccccc3)c3ccccc3)N(C(=O)OCC(C)C)C2)cc1

Procedure:
A mixture of 1-[(2,2-dimethylethoxy)carbonyl]-(trans)-4-hydroxy-L-proline, diphenylmethyl ester, triphenylphosphine, and 4-(2-methoxyethenyl)phenol is taken up in benzene and evaporated to dryness. The residue is dissolved in dry tetrahydrofuran, cooled to -10° under argon, and treated with diethylazodicarboxylate. The reaction mixture is worked up according to the procedure of Example 1(b) to yield 1-[(2,2-dimethylethoxy)carbonyl]-(cis)-4-[4-(2-methoxyethenyl)phenoxy]-L-proline, diphenylmethyl ester.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:33])=[C:4]([F:32])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][OH:31].[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>N1C=CC=CC=1>[F:1][C:2]1[C:3]([CH3:33])=[C:4]([F:32])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][O:31][S:35]([CH3:34])(=[O:37])=[O:36]
Reactant: Cc1c(F)c(NCCCO)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1c(F)c(NCCCOS(C)(=O)=O)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Reaction time: 1 h
Yield: 99.7 %

Procedure:
3.96 g (8.57 mmol) of the above 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-hydroxypropylamino)-7-methyl-4H-1-benzopyran-4-one was dissolved in 100 mL of pyridine under ice-cooling, 1.3 mL (17 mmol) of methanesulfonyl chloride was added and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction solution and the precipitated crystals were collected by filtration to give 4.62 g of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-7-methyl-4H-1-benzopyran-4-one (yield: 100%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]3([CH2:15][CH2:16][CH2:17][CH:18]=2)[O:14][CH2:13][CH2:12][O:11]3)O1.Br[C:21]1[CH:26]=[C:25]([Cl:27])[N:24]=[N:23][C:22]=1[NH2:28].C(=O)([O-])[O-].[Cs+].[Cs+].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.O>[Cl:27][C:25]1[N:24]=[N:23][C:22]([NH2:28])=[C:21]([C:9]2[C:10]3([CH2:15][CH2:16][CH2:17][CH:18]=2)[O:11][CH2:12][CH2:13][O:14]3)[CH:26]=1
Reactant: Nc1nnc(Cl)cc1Br
Reactant: CC1(C)OB(C2=CCCCC23OCCO3)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nnc(Cl)cc1C1=CCCCC12OCCO2
Yield: 42.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 39a by using the 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaspiro[4.5]dec-6-ene (0.64 g, 2.40 mmol) prepared in Example 82a, 4-bromo-6-chloropyridazin-3-amine (0.50 g, 2.40 mmol), tetrakis(triphenylphosphine)palladium (0) (0.14 g, 0.12 mmol), cesium carbonate (1.72 g, 5.29 mmol), dioxane (8.0 mL) and water (4.0 mL), to yield the title compound (275.7 mg, 43%) as a colorless oil.
Reaction SMILES: [N:1]1([CH:5]2[CH:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]3[CH:12]=[C:11]([CH2:22][NH2:23])[CH:10]=[CH:9][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]1[CH:29]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[N:27]=[CH:26]1>CN(C1C=CN=CC=1)C.ClCCl>[N:1]1([CH:5]2[CH:14]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:13]3[CH:12]=[C:11]([CH2:22][NH:23][S:30]([C:28]4[N:27]=[CH:26][N:25]([CH3:24])[CH:29]=4)(=[O:32])=[O:31])[CH:10]=[CH:9][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccc2c(c1)C(Cc1ccccc1)C(N1CCC1)CC2
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)NCc2ccc3c(c2)C(Cc2ccccc2)C(N2CCC2)CC3)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(7-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)methanamine (250 mg, 0.816 mmol) and N,N-dimethyl-4-aminopyridine (199 mg, 1.632 mmol) were dissolved in dichloromethane (18 mL). 1-Methyl-1H-imidazole-4-sulfonyl chloride (147 mg, 0.816 mmol) dissolved in dichloromethane (2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with dichloromethane (20 mL) and washed successively with saturated ammonium chloride (3×15 mL) and water (2×10 mL). The organic phase was dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, dichloromethane, methanol). Yield: 64 mg (0.142 mmol, 17%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1>>[N:1]1([CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:7][CH2:4][CH2:3][CH2:2][NH2:1])=[CH:9][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(O)cc1
Product: NCCCOc1ccc(CN2CCCCC2)cc1

Procedure:
Starting materials:piperidine and 4-hydroxybenzaldehyde
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:32][CH2:31][CH2:30][O:29][CH3:28])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Product: COCCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1
Yield: 50.5 %

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloroquinol-2-one (150 mg, 0.4 mmol), sodium hydride (15 mg, 0.6 mmol), N-phenyl(trifluoromethylsulfon)imide (208 mg, 0.56 mmol), and 2-methoxyethylamine (362 μL, 4.0 mmol) are treated according to method E yielding 85 mg of 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-7-chloro-2-(2-methoxyethylamino)quinoline. 74 mg thereof are treated with TFA-CH2Cl2 1:1 (0.6 mL) for 1 h and concentrated. The residue is converted into the title product with 4-fluorophenyl isocyanate (30 μL) and triethylamine (230 μL).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:11]=[C:5]2[NH:4][C:3]1=[O:29].Br[CH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]([CH2:31][C:32]2[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=2)[C:35]([O:37][CH3:38])=[O:36])[C:3]1=[O:29]
Reactant: Cn1c(=O)[nH]c2nn(Cc3cccc4ccccc34)c(-c3ccncc3)c2c1=O
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(=O)n(C)c(=O)c3c(-c4ccncc4)n(Cc4cccc5ccccc45)nc32)c1

Procedure:
This compound was synthesized by the reaction of 5-methyl-2-(1-naphthylmethyl)-3-pyridin-4-yl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and methyl 3-(bromomethyl)benzoate using potassium carbonate as a base in DMF at 80° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[Br:17]N1C(=O)CCC1=O.[OH-].[Na+]>C1COCC1>[Br:17][C:12]1[CH:13]=[N:14][N:15]([CH3:16])[C:11]=1[C:3]1[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[S:6][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1cc(C(=O)O)sc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 27.9 %

Procedure:
To a solution of methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (300 mg, 1.169 mmol)[prepared according to the procedure of Example 193] in THF (10 ml) was added N-bromosuccinimide (212 mg, 1.19 mmol). The mixture was sealed and heated at 70° C. After 2 h, a solution of 6N NaOH (2.0 ml, 6.0 M, 11.84 mmol) was added in one portion. The resulting mixture stirred for an additional 2 h and was partitioned between DCM-H2O. The pH of the aqueous phase was adjusted to ˜3 and extracted several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated affording the title compound as a colorless oil (105 mg, 28%): LC-MS (ES) m/z=322 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[N+:21]([O-])=O>[Pd].C(O)C>[NH2:21][C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Reaction time: 2 h

Procedure:
A suspension of N-(4-methyl-3-nitro-phenyl)-3-trifluoromethyl-benzamide (9.91 g, 30.6 mmol) and 10% palladium on charcoal (990 mg) in ethanol (180 ml) is hydrogenated at atmospheric pressure and room temperature. After 2 h the reaction is complete, the catalyst is removed by filtration through Celite, and the filtrate is evaporated to dryness. Recrystallization of the crude product from ethyl acetate/hexanes followed by vacuum drying at 45° C. overnight affords the title compound as fluffy light grey needles: HPLC: tR=5.38 min (purity: >99%, gradient A), ESI-MS: 295.3 [MH]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[C:14]2[N:15]([N:19]=[C:20]([NH2:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:11])([F:12])[F:10])=[CH:5][C:4]=1[C:13]1[C:14]2[N:15]([N:19]=[C:20]([NH:22][C:26]([CH:23]3[CH2:25][CH2:24]3)=[O:27])[N:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(N)nc12
Reactant: O=C(Cl)C1CC1
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(NC(=O)C3CC3)nc12

Procedure:
Cyclopropanecarboxylic acid [8-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl]-amide was prepared from 8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl-amine (0.07 g, 0.2 mmol) and cyclopropanecarbonyl chloride (0.021 mL, 0.23 mmol) in a manner analogous to Example 240b. Product was isolated as a foam (0.063 g, 70%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.61 (d, J=6.7 Hz, 1H), 7.76-7.66 (m, 2H), 7.60-7.50 (m, 1H), 7.51-7.45 (m, 1H), 7.13-7.06 (m, 1H), 3.86 (s, 3H), 1.56 (m, 1H), 1.19-1.14 (m, 2H), 1.01-0.95 (m, 2H), MS=377 (MH)+.