Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][C:7]1[N:12]=[C:11](Cl)[C:10]([F:14])=[C:9]([Cl:15])[N:8]=1.[Cl-].[Na+]>O>[CH3:6][C:7]1[N:12]=[C:11]([OH:2])[C:10]([F:14])=[C:9]([Cl:15])[N:8]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(O)c(F)c(Cl)n1
Reaction time: 3 h
Yield: 86 %

Procedure:
To a mixture of water (3 mL) and concentrated sulfuric acid (7 mL) was added 1.81 g (10 mmol) of 2-methyl-4,6-dichloro-5-fluoropyrimidine. The reaction mixture was stirred for 3 hours and then poured onto ice. The mixture was saturated with sodium chloride and extracted with ethyl acetate. The organic extracts were combined, dried (MgSO4), filtered, and concentrated in vacuo to give crude product (1.4 g, 86%), m.p. 214°-216° C. This product was used in subsequent reactions without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[C:45]([F:47])[CH:46]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:20][C:19]=1[NH:31][CH2:32][CH:33]1[CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]1)=[O:17].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:35]1[CH2:34][CH:33]([CH2:32][NH:31][C:19]2[CH:20]=[C:21]([N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)[CH:22]=[CH:23][C:18]=2[C:16]([NH:15][C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([CH2:5][C:4]4[CH:3]=[C:2]([F:1])[CH:46]=[C:45]([F:47])[CH:44]=4)[CH:7]=3)[NH:11][N:10]=2)=[O:17])[CH2:36]1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NCC3CN(C(=O)OC(C)(C)C)C3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NCC3CNC3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
tert-butyl 3-({[2-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-5-(4-methylpiperazin-1-yl)phenyl]amino}methyl)azetidine-1-carboxylate (289 mg, 0.45 mmol) was dissolved in DCM (3 mL) and TFA (0.7 mL) was added. The resulting reaction solution was stirred overnight at room temperature. The mixture was diluted with DCM and extracted with 10% acqueous NH3. Organic phase was evaporated. Reverse phase column chromatography purification afforded 104 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([O:15][CH3:16])=[C:7](C)[C:4]=1[CH:5]=O.[C:18](O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1>N1C=CC=CC=1>[CH3:16][O:15][C:8]1([CH:7]=[C:4]([CH3:5])[C:3]([O:2][CH3:1])=[C:10]([O:11][CH3:12])[CH:9]1[O:13][CH3:14])[CH:18]=[CH:19][C:20]([OH:22])=[O:21]
Reactant: O=C(O)CC(=O)O
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COC1=C(OC)C(OC)C(C=CC(=O)O)(OC)C=C1C
Reaction time: 5 h
Yield: 69.8 %

Procedure:
2,3,4,5-Tetramethoxy-6-methylbenzaldehyde (17.3 g, 72.1 mmol), malonic acid (22.5 g, 216 mmol) and piperidine (1.7 ml) were dissolved in pyridine (50 ml). The reaction was conducted for 5 hours, while the temperature was gradually raised from 50° C. to 100° C. The solvent was removed under reduced pressure. The residue was acidfified with 2 N hydrochloric acid, extracted and concentrated. Recrystallization of the product from ethyl acetate-isopropyl ether gave 1,2,3,4-tetramethoxy-5-methylcinnamic acid (Compound 20, 14.3 g, 70%). m.p. 117°-118° C. δ 2.31 (3H), 3.78 (3H), 3.83 (3H), 3.90 (3H), 3.96 (3H), 6.59 (1H), 7.94 (1H), 11.2 (1H).
Reaction SMILES: CO[CH:3](OC)[CH:4]([CH3:13])[CH2:5][Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8].COC(OC)C(=C)C.CO[SiH](OC)OC.[CH2:31]([SH:34])[CH2:32][SH:33]>[Cl-].[Zn+2].[Cl-]>[CH3:13][CH:4]([CH:3]1[S:34][CH2:31][CH2:32][S:33]1)[CH2:5][Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8]
Reactant: COC(OC)C(C)C[Si](OC)(OC)OC
Reactant: SCCS
Agent: C=C(C)C(OC)OC
Agent: CO[SiH](OC)OC
Agent: [Cl-]
Product: CO[Si](CC(C)C1SCCS1)(OC)OC

Procedure:
The procedure and apparatus of Example 1 were used with 25.0 g (0.102 m) of (3,3-dimethoxy-2-methylpropyl)trimethoxysilane (boiling point, 125°/25 mm, prepared by the hydrosilation of methacrolein dimethyl acetal with trimethoxysilane, as characterized by GC/MS and NMR), 9.6 g (0.102 m) of ethane-1,2-dithiol, and 0.07 g of anhydrous zinc chloride catalyst. The crude product, after distillation to a pot temperature of 195°, was 27.1 g, containing 64.3% of the title product as determined by GC/MS.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]#[N:7].[N+:19]([O-])([OH:21])=[O:20].[K]>C(O)(=O)C>[N+:19]([C:8]1[CH:9]=[C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:6]#[N:7])([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C#N)ccc1OCc1ccccc1
Agent: [K]
Solvent: CC(=O)O
Product: COc1cc(C#N)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
3-methoxy-4-benzyloxybenzonitrile (4.78 g, 20 mmol) in acetic acid (10 ml) was slowly added to nitric acid (d=1.42, 25 ml) at 20-30° with cooling in an ice bath. The mixture was then stirred at room temperature for 6 hours. The reaction mixture was treated with potassium hydroxyde (10N) at 0° C. The basic mixture (pH 10) was extracted with CH2Cl2, the organic phase was dried over MgSO4, concentrated to give title compound (3.62 g, 64%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]([CH3:14])=[CH:12][CH2:11][CH2:10][CH:9]1[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O.CCOC(C)=O>C(Cl)Cl>[C:6]([N:8]1[C@@H:9]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:11][CH2:12][C@@H:13]1[CH3:14])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC1=CCCC(C2CCCC2)N1C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CCC[C@H](C2CCCC2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.2 %

Procedure:
To a stirred solution 1-(tert-Butoxycarbonyl)-6-methyl-2-cyclopentyl-1,2,3,4-tetrahydropyridine (1.14 g, 4.29 mmol) in 290 mL of CH2Cl2 was added sodium cyanoborohydride (1.62 g, 25.8 mmol). After being stirred 15 minutes at room temperature, the heterogeneous solution was cooled to −42° C. and TFA (4.9 mL, 42.95 mmol) was added slowly dropwise. After being stirred for 4 h at −42° C., the cold bath was removed, and the reaction mixture was immediately quenched with 200 mL of a saturated aqueous NaHCO3/THF mixture (50:50). The aqueous phase was extracted with CH2Cl2 (2×70 mL) and the combined organic extracts were washed with water and brine. The organic phase was dried with K2CO3, filtered through Celite, and evaporated to give crude product. Column chromatography using 5% EtOAc in hexanes gave 1.15 g (73%) of the product which was homogeneous by TLC analysis. 1H NMR (300 MHz) δ 4.12-3.91 (m, 1H), 3.79-3.74 (m, 1H), 2.21 (m, 1H), 2.19-1.15 (m, 26H).
Reaction SMILES: [Mg].[CH2:2](I)[CH3:3].[CH3:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[N:9]2[CH:18]=[N:19][C:20]([CH:21]=[O:22])=[C:8]2[CH2:7]1>C(I)C.C(OCC)C.O1CCCC1>[OH:22][CH:21]([C:20]1[N:19]=[CH:18][N:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12](=[O:13])[N:6]([CH3:5])[CH2:7][C:8]=12)[CH2:2][CH3:3]
Reactant: CN1Cc2c(C=O)ncn2-c2ccccc2C1=O
Reactant: CCI
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Temperature: 25 °C

Procedure:
1.22 g (50.2 mmol) of magnesium shavings are covered with 60 ml of absolute diethyl ether under an argon atmosphere and treated with 2-3 drops of ethyl iodide. When the Grignard reaction starts, a solution of 4.3 ml (51 mmol) of ethyl iodide in 10 ml of absolute diethyl ether is added dropwise at the boiling point. After the magnesium has dissolved completely, the mixture is treated dropwise with a solution, warmed to 30° C., of 0.65 g (40 mmol) of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehye in 200 ml of absolute tetrahydrofuran. The yellow coloured suspension is heated to boiling under reflux for ca 5.5 hours, cooled to room temperature and poured into 600 ml of ice/water. The mixture is filtered over Dicalit while rinsing with tetrahydrofuran. After concentration of the filtrate in vacuo, the residue is taken up in 250 ml of chloroform. The chloroform phase is washed twice with 60 ml of water each time, dried over magnesium sulphate and concentrated. The crude product is chromatographed on silica gel using chloroform/methanol (19:1, vol/vol) for the elution. After recrystallisation from ca 40 ml of ethyl acetate, there is obtained 4,5-dihydro-3-(1-hydroxypropyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 145°-147° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][CH2:16][CH:17]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:28][CH2:29][N:30]([CH2:17][CH2:16][CH2:15][C:9]2[CH:10]=[C:11]([CH2:12][CH2:13][CH3:14])[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:31][CH2:32]1
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: CCCc1cc(CCC=O)nn1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3cccc(C)c3C)CC2)nn1-c1ccccc1

Procedure:
124 mg (66%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (100 mg, 0.413 mmol), 1-(2,3-dimethylphenyl)piperazine (79 mg, 0.413 mmol), DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)3 (263 mg, 1.239 mmol).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]([CH3:23])=[C:10]2[CH2:24][C:25]([NH2:27])=[O:26])C.[OH-].[Na+].Cl>CCO.C1COCC1>[NH2:27][C:25](=[O:26])[CH2:24][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([O:6][CH2:5][C:4]([OH:28])=[O:3])[CH:8]=2)[N:12]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]=1[CH3:23]
Reactant: CCOC(=O)COc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(CC(N)=O)c2cc(OCC(=O)O)ccc2n1Cc1ccccc1
Yield: 88 %

Procedure:
A solution of 190 mg (0.5 mmol) of 2-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]acetic acid ethyl ester and 2 mL of 5N NaOH in 30 mL of EtOH and 10 mL of THF was stirred for approximately 15 hours, the mixture made acidic with 5N HCl and extracted with EtOAc. The EtOAc solution was washed with saturated NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was washed with ether to give 155 mg (90% yield) of 2-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]acetic acid, mp, 196°-198° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][C:6]([CH2:8][C:9]([O:11]C)=[O:10])=[CH:5][CH:4]=[C:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].Cl>C(O)C.O>[CH3:1][C:2]1([CH3:19])[CH2:7][C:6]([CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)CC1=CC=C(c2ccccc2)C(C)(C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(CC(=O)O)=CC=C1c1ccccc1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
A mixture of 2,2-dimethyl-(4-biphenyl)acetic acid, methyl ester (4.18 g, 16.5 mmol) and sodium hydroxide (3.29 g) in ethanol (57 mL) and water (25 mL) was heated under reflux for 18 hours. The mixture was cooled to rt and acidified to pH 2 with 6N HCl. The precipitate was collected by filtration, and recrystallized from ether to give 2,2-dimethyl-(4-biphenyl)acetic acid (1.37 g, 5.7 mmol, 35%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:4][C:3]=1[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(O)ccc1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
A 12 L flask was charged with 4-bromo-3-methyl phenol (428 g, 2.29 mol), CH2Cl2 (7.5 L), triethylamine (480 mL, 3.45 mol), and tert-butyldimethylsilyl chloride (324 g, 2.15 mol). To the solution was added 4-dimethylaminopyridine (15.0 g, 0.123 mol). The reaction mixture was stirred at ambient temperature overnight. The reaction was washed with saturated ammonium chloride (2.2 L) and then DI water (0.9 L). The organic layer was dried (Na2SO4), filtered, and concentrated to crude product (699 g). This material was purified by silica gel chromatography (heptane) to give the title compound (637 g, 98.5%).
Reaction SMILES: N[N:2]1[C:6]([CH3:7])=[N:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]1=[O:14].N([O-])=O.[Na+].[OH-].[Na+]>O.Cl.S(=O)(O)[O-].[Na+]>[CH3:7][C:6]1[NH:2][C:3](=[O:14])[N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=1
Reactant: Cc1nn(-c2cccnc2)c(=O)n1N
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])O
Solvent: O
Product: Cc1nn(-c2cccnc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
750 mg (3.923 mmol) of 4-amino-5-methyl-2-(pyridin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one were dissolved in a mixture of 9 ml of water and 3 ml of concentrated hydrochloric acid. At 5° C., a solution of 314 mg (4.55 mmol) of sodium nitrite in 1 ml of water was then added dropwise. The reaction mixture was then allowed to warm to room temperature and stirred for another 1 hour. The reaction mixture was neutralized using 30% strength aqueous sodium hydroxide solution and a few drops of an aqueous sodium bisulfite solution were added such that the test with potassium iodide/starch paper is negative. The mixture was extracted repeatedly with ethyl acetate, and the combined organic phases were dried with sodium sulfate and concentrated. This gave 253 mg of 5-methyl-2-(pyridin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one in the form of a white solid (content LC-MS: 100%) which was used for the next reaction.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:33])[CH2:31][CH3:32]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:30](=[O:33])[CH2:31][CH3:32])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCCC(Nc3ccccc3)C2)cc1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N(c1ccccc1)C1CCCN(Cc2ccccc2)C1
Reaction time: 2 h

Procedure:
To the crude (1-benzyl-piperidin-3-yl)-phenyl-amine (164) (1.11 g) in CH2Cl2 (5 ml) at 0° C. was added i-Pr2NEt (1.45 ml) and propionyl chloride (0.54 ml). The mixture was stirred for 2 hr. The mixture was diluted with CH2Cl2 (20 ml), washed with sat. NaHCO3 (2×10 ml), brine (10 ml) and water (10 ml) and dried with Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (0.5% to 2% MeOH in CH2Cl2) to give 165 as a colorless oil. LRMS (calculated for C21H26N2O) 322, found 322; IR (film) 3059, 2937, 2863, 2797, 1657, 1594, 1499, 1390, 1264, 1101, 1074, 739, 703 cm−1.
Reaction SMILES: I[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].N[C@H]1CCCC[C@H]1O>C(O)(C)C>[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:2]2[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N[C@H]1CCCC[C@H]1O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC(c2ccc(N)cc2)C1
Temperature: 150 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
A mixture of tert-butyl 3-iodoazetidine-1-carboxylate (1 g, 3.53 mmol), 4-aminophenylboronic acid (630 mg, 4.59 mmol), NiI2 (66 mg, 0.212 mmol), NaHMDS (1.94 g, 10.6 mmol), (1R,2S)-2-aminocyclohexanol (24 mg, 0.212 mmol) in isopropanol (8 mL) was stirred at 150° C. in microwave for 2 h. It was then evaporated and the residue was dissolved with water and ethyl acetate. The water phase was separated and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography to give 298a (360 mg, 40%). MS: [M+H]+ 249.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)=O.Cl.[O:17]([CH2:24][C:25](=[NH:27])[NH2:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:17]([CH2:24][C:25]1[NH:27][CH:2]=[C:3]([C:5]2[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=2)[N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Reactant: N=C(N)COc1ccccc1
Agent: Cl
Product: CCOC(=O)c1ccc(-c2c[nH]c(COc3ccccc3)n2)cc1

Procedure:
This compound is prepared according to a method analogous to that described in Example 1.3 using ethyl 4-(bromoacetyl)benzoate (2 g, 0.0074 mol) and 2-phenoxyethanimidamide hydrochloride (1.6 g, 0.0086 mol) as starting compounds. After treatment, a white-coloured powder is obtained.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([O:13]CC)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH3:3].[OH-].[Na+].O1CCCC1>CO>[CH2:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCO[C@H]1CC[C@H](C(=O)OCC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCO[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
cis/trans-Ethyl 4-(propyloxy)cyclohexanecarboxylate (D11) (39.1 g), 40% w/w sodium hydroxide solution (150 mL), tetrahydrofuran (200 mL) and methanol (150 mL) was stirred for approx. 72 hours. The solvent was partially removed then the resulting mixture was treated with ethyl acetate and water. The aqueous layer was separated, acidified with concentrated hydrochloric acid and extracted with diethyl ether. The ether layer was washed with brine, dried with anhydrous sodium sulphate and the solvent was removed to give the title compounds as oil (15.42 g).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[N:5][C:6]2[CH2:7][CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][C:11]=2[CH:12]=1.I([O-])(=O)(=O)=[O:23].[Na+]>C(Cl)(Cl)(Cl)Cl.CC#N.O.C(Cl)Cl.O.[Ru](Cl)(Cl)Cl>[O:23]=[C:10]1[N:9]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:8][CH2:7][C:6]2[N:5]=[CH:4][C:3]([C:2]([F:20])([F:1])[F:21])=[CH:12][C:11]1=2
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCc2ncc(C(F)(F)F)cc2C1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCc2ncc(C(F)(F)F)cc2C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a 250 mL round-bottom flask, was placed a solution of tert-butyl 3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (as prepared in the previous step, 3.84 g, 0.01 mol, 1.00 equiv) in CCl4/CH3CN=10/1 (66 mL), a solution of sodium periodate (8.135 g, 38.01 mmol, 3.00 equiv) in water (20 mL) and Ruthenium(III)Chloride Hydrate (0.992 g, 0.30 equiv). The resulting solution was stirred for 12 h at room temperature, and then the mixture was diluted with 50 mL of CH2Cl2. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by chromatography over a silica gel column with ethyl acetate/petroleum ether (1:50-1:10). The title compound was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.CN(C)C=O.[H-].[Na+].[CH2:18]([O:20][CH2:21][CH2:22]Cl)[CH3:19]>C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[N:6]([CH2:19][CH2:18][O:20][CH2:21][CH3:22])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CCOCCCl
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOCCn1c(Cl)nc2ccccc21
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Combine 2-chloro-1H-benzimidazole (21.1.4 g, 138.4 mmol) and dimethylformamide (200 mL). Add portionwise, sodium hydride (24.0 g, 60% in oil, 153.3 mmol). After 15 minutes, add 2-chloroethyl ethyl ether (21.9 g, 201,5 mmol). Heat to 60° C. After 18 hours, cool the reaction mixture and dilute with ethyl acetate. Extract with a saturated aqueous sodium bicarbonate solution, water, and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 10% ethyl acetate/hexane and then 30% ethyl acetate hexane to give the 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole: Rf=0.74 (silica gel, 7/3 ethyl acetate/hexane).
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:13][CH:12]=1>C1COCC1>[C:6]([O:5][C:3]([NH:1][N:2]=[C:17]([C:14]1[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=1)[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=C(O)CCCC(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN=C(CCCC(=O)O)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 98.7 %

Procedure:
Step AAG (1): A mixture of tert-butyl hydrazinecarboxylate (1.45 g, 11.0 mmol) and 5-(4-fluorophenyl)-5-oxopentanoic acid (2.1 g, 10 mmol) in THF (20 mL) was stirred at 50° C. for 16 h. The reaction mixture was concentrated in vacuo to afford 5-(2-(tert-butoxycarbonyl)hydrazono)-5-(4-fluorophenyl)pentanoic acid (3.2 g, 9.87 mmol, 99% yield). LC-MS (M+H)+ 325.24. The crude product was used for subsequent chemistry without purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([N:14]2[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]2)=[N:4][C:3]=1[C:20]#[N:21].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)(C)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]([N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1)=[N:4][C:3]([C:20]#[N:21])=[C:2]2[N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNC1
Reactant: COc1ccc2c(-n3cnc(C)c3)nc(C#N)c(Cl)c2c1
Solvent: CC(C)O
Product: COc1ccc2c(-n3cnc(C)c3)nc(C#N)c(N3CCCC3)c2c1
Temperature: 160 °C

Procedure:
4-chloro-6-methoxy-1-(4-methyl-1H-imidazol-1-yl)isoquinoline-3-carbonitrile (0.010 g, 0.033 mmol) and pyrrolidine (0.048 g, 0.067 mmol) were combined in isopropanol (1 mL) in a sealed tube and heated at 160° C. in a microwave reactor for 1.5 h. Cooled to rt and partitioned between aqueous saturated NaHCO3 and EtOAc. The organic layer was washed with brine (1×), dried over Na2SO4 and concentrated. Purified by r.p. HPLC. The titled compound was obtained as a tan solid (free base, 0.0065 g, 58%). 1H NMR (500 MHz, CDCl3): δ 7.95 (d, J=9.0 Hz, 1H), 7.91 (s, 1H), 7.55 (d, J=2.7 Hz, 1H), 7.36 (dd, J=9.3, 2.7 Hz, 1H), 7.18(s, 1 H), 4.00 (s, 3H), 3.71-3.69 (m, 4H), 2.19-2.14 (m, 4H). HRMS 334.1666 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:11])[CH:7]=[C:8]([Br:10])[CH:9]=1)=[O:4].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]=[CH:18][C:17]2[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:22])[F:23])=[CH:21][CH:20]=2)[CH:7]=[C:8]([Br:10])[CH:9]=1)=[O:4]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cc(Br)cn1N
Product: COC(=O)c1cc(Br)cn1N=Cc1ccc(C(F)(F)F)cc1

Procedure:
Prepared according to the imine formation condition used in Example 18 step b) from 1-amino-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester and 4-trifluoromethylbenzaldehyde. 1H NMR (CDCl3, δ in ppm): 8.44 (s, 1H), 7.96 (d, 2H, J=7.8 Hz), 7.70 (d, 2H, J=7.8 Hz), 7.27 (d, 1H, J=1.8 Hz), 6.99 (d, 1H, J=1.6 Hz), 3.85 (s, 3H).