Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]([CH3:36])[CH:28]=3)[CH:24]=[CH:23][N:22]=2)=[C:13]([O:37][CH3:38])[CH:12]=1.[CH3:39][N:40]1[CH2:44][C@@H:43]2[NH:45][CH2:46][CH2:47][C@@H:42]2[CH2:41]1>FC(F)(F)CO>[CH3:39][N:40]1[CH2:41][C@@H:42]2[C@@H:43]([N:45]([C:11]3[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]4[N:26]=[C:25]([C:27]5[C:35]6[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=6)[N:29]([CH3:36])[CH:28]=5)[CH:24]=[CH:23][N:22]=4)=[C:13]([O:37][CH3:38])[CH:12]=3)[CH2:46][CH2:47]2)[CH2:44]1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: CN1C[C@H]2CCN[C@H]2C1
Solvent: OCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 84.3 %

Procedure:
DIPEA (0.411 mL, 2.36 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129, 425 mg, 0.94 mmol) and (3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-b]pyrrole (Intermediate 37, 250 mg, 1.98 mmol) in 2,2,2-trifluoroethanol (4 mL). The mixture was heated in a microwave at 140° C. for 1 h. The cooled mixture was then purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and concentrated in vacuo. Further purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave impure title compound (396 mg, 84%) as an orange/red solid. This solid was dissolved in the minimum amount of CH2Cl2 and the resulting solution was triturated with methanol. The resulting solid was collected by filtration to give the title compound (272 mg, 58%) as a red solid which was used without further purification; 1H NMR: 1.86 (1H, dd), 1.94-2.06 (1H, m), 2.12 (3H, s), 2.23 (1H, dd), 2.36-2.45 (2H, m), 2.52-2.58 (1H, m) partially obscured by DMSO peak, 2.91-3.04 (1H, m), 3.18 (1H, t), 3.49 (1H, td), 3.87 (3H, s), 3.95 (3H, s), 4.40 (1H, t), 6.61 (1H, s), 7.11 (1H, t), 7.18 (1H, d), 7.24 (1H, t), 7.51 (1H, d), 8.02 (1H, s), 8.27-8.31 (2H, m), 8.34 (1H, d), 8.51 (1H, s); m/z: ES+ MH+ 500.17.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][C:12]#[CH:13].C1(NC2CCCCC2)CCCCC1>C(#N)C>[N:4]1[CH:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:14])[CH:7]=[N:6][CH:5]=1
Reactant: C#CCCCCO
Reactant: Brc1cncnc1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC#N
Product: OCCCCC#Cc1cncnc1
Yield: 86.5 %

Procedure:
A mixture of 5-bromopyrimidine (3.96 g), 5-hexynol (2.44 g), dicyclohexylamine (4 g) and acetonitrile (50 ml) was de-oxygenated by bubbling nitrogen through the solution for 10 min. BTPC (150 mg) and copper (I) iodide (25 mg) were added and the mixture was heated to 60°-70° under nitrogen for 1 h, cooled and evaporated in vacuo. Ether (175 ml) was added, the mixture filtered and evaporated in vacuo and the residue purified by FCC. Elution with ether followed by System C (19:1-92:8) gave the title compound as a pale yellow oil (3.79 g), t.l.c. (System C (17:3) Rf 0.55.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](O)=[O:24].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:23]([C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)=[O:24])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: O=C(O)c1cccs1
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ncnc2c1cnn2-c1cccc(NC(=O)c2cccs2)c1
Reaction time: 0.17 h
Yield: 12.5 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (39 mg, 1.1 eq, 0.17 mmol) was added to a solution 2-thiophenecarboxylic acid (20 mg, 1.0 eq, 0.16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27 mg, 1.1 eq, 0.17 mmol), 1-hydroxybenzotriazole (21 mg, 1.0 eq, 0.16 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 17 hours, after which methanol (1 ml) was added, and the solvents were removed in vacuo. The residue was then triturated with methanol and the resultant solid was isolated by filtration to yield the title compound as a pale yellow solid (6 mg, 0.02 mmol, 11%). LCMS: [M+H]+=337, Rt=1.60 min, 100% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]1(C)[O:18]C(=O)[CH2:16][C:15](=O)[O:14]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=[O:11])[CH2:12][C:13]([O:14][CH2:15][CH3:16])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)Cc1cccc(Cl)c1
Product: CCOC(=O)CC(=O)Cc1cccc(Cl)c1
Yield: 43 %

Procedure:
The title compound was prepared in 43% yield from 2-(3-chlorophenyl)acetic acid and 2,2-dimethyl-1,3-dioxane-4,6-dione according to the procedure for the preparation of Example 162, part A.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][CH2:18][S:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])[CH3:24]
Reactant: O=C(O)c1cccc(S)c1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCSc1cccc(C(=O)O)c1
Reaction time: 0.08 h

Procedure:
A solution of 3-mercaptobenzoic acid (3.4 g) in DMF (50 mL) was treated with potassium carbonate (3.18 g) and stirred for 5 minutes. A solution of ethyl 3-bromopropionate (2.8 mL) in DMF (10 mL) was added dropwise over 30 minutes and the resulting mixture was stirred for a further 30 minutes. The mixture was partitioned between ethyl acetate and water, and the phases separated. The aqueous phase was acidified with aqueous HCl and extracted further with ethyl acetate. The organic phases were washed with water, dried, filtered and concentrated under reduced pressure to afford the subtitled compound. Yield 5.3 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][O:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([S:24][CH3:25])[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][O:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([S:24]([CH3:25])=[O:39])[N:8]=1
Reactant: COc1ccc(COc2nc(SC)ncc2C(=O)NCc2ccc(F)cc2)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(COc2nc(S(C)=O)ncc2C(=O)NCc2ccc(F)cc2)cc1Cl

Procedure:
4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)-N-(4-fluorobenzyl)pyrimidine-5-carboxamide (206 mg, 0.46 mmol) was dissolved in 20 mL dichloromethane, m-CPBA (80 mg, 0.46 mmol) was added and reacted at room temperature for 12 h, the reaction solution was washed with water after the reaction is complete, extracted with dichloromethane, the organic layer was dried, dried by rotation to obtain yellow solid, the product was directly used in the next reaction without purification.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[C:3](=[O:37])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH2:30][C:31]([OH:33])=[O:32])[CH3:29])=[O:27])=[CH:22][C:20]=3[CH:21]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH:34]([CH3:36])[CH3:35].[BH4-].[Na+]>C1COCC1>[CH2:13]([C:12]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH2:30][C:31]([OH:33])=[O:32])[CH3:29])=[O:27])=[CH:22][C:20]=2[CH:21]=1)([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH:3]([OH:37])[C:2]([CH3:39])([CH3:1])[CH3:38])=[C:7]([CH:34]([CH3:35])[CH3:36])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(CCC(=O)C(C)(C)C)c(C(C)C)c1)c1cc2cc(C(=O)N(C)CC(=O)O)ccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C(C)C)c1)c1cc2cc(C(=O)N(C)CC(=O)O)ccc2o1
Reaction time: 2 h

Procedure:
A solution of [(2-{1-[4-(4,4-Dimethyl-3-oxo-pentyl)-3-isopropyl-phenyl]-1-ethyl-propyl}-benzofuran-5-carbonyl)-methyl-amino]-acetic acid (27 mg, 0.05 mmol) (Example 55) in THF (2 mL) is treated with NaBH4 (4 mg, 0.1 mmol) at room temp. The resulting mixture is stirred for 2 hours. The mixture is concentrated and neutralized to pH 3 and extracted with EtOAc (3×5 mL). The organic layer is dried over sodium sulfate, concentrated to afford the desired compound. (17 mg, 63%) MS (ES) m/e: 536.3 (M−1)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:10]1[CH2:15][CH2:14][O:13][CH:12]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:11]1)(=O)[CH3:8].O>O1CCCC1>[CH2:7]([N:10]1[CH2:15][CH2:14][O:13][CH:12]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:11]1)[CH3:8]
Reactant: CC(=O)N1CCOC(CN2c3ccccc3CCc3ccccc32)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1CCOC(CN2c3ccccc3CCc3ccccc32)C1

Procedure:
To a suspension of lithium aluminium hydride (0.08 g) in tetrahydrofuran was added a solution of 5-(4-acetyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine (0.34 g) in tetrahydrofuran under ice-cooling, and the resulting mixture was stirred under reflux for 1 hour. the reaction mixture was cooled, admixed with water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-(4-ethyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oily substance. M.P. 210°-211° C (oxalate).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=1)(=[O:15])=[O:14].NC1C=C(C=CC=1O)[C:31]([OH:33])=[O:32]>>[CH2:22]([C:19]1[CH:18]=[CH:17][C:16]([S:13]([NH:12][CH2:11][CH2:10][C:2]2[O:1][C:5]3[CH:6]=[CH:7][C:8]([C:31]([OH:33])=[O:32])=[CH:9][C:4]=3[N:3]=2)(=[O:14])=[O:15])=[CH:21][CH:20]=1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCc1ccc(S(=O)(=O)NCCc2nc3ccccc3o2)cc1
Reactant: Nc1cc(C(=O)O)ccc1O
Product: CCCCCc1ccc(S(=O)(=O)NCCc2nc3cc(C(=O)O)ccc3o2)cc1

Procedure:
The title compound of Step 1 was prepared following the procedure described above for the preparation of the product of Step 3 of Example 1, substituting 3-amino-4-hydroxybenzoic acid in place of o-aminophenol. MS m/e 417; HPLC retention time 3.50 min.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=1)(=O)=O.[C-:18]#[N:19].[K+]>C(O)C.O>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:18]#[N:19])=[CH:8][C:9]=1[C:14]([F:17])([F:16])[F:15]
Reactant: CS(=O)(=O)OCc1ccc(Br)c(C(F)(F)F)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-3-(trifluoromethyl)benzyl methanesulfonate 46-4 (1.295 g, 3.75 mmol) in ethanol (10 mL) was added a solution of potassium cyanide (364 mg, 5.6 mmol) in water (2 mL). The mixture was refluxed for 2 hours. After the mixture was cooled down to the room temperature, all the solvents were evaporated and the residue was redissolved in dichloromethane (50 mL), washed with water and brine, dried over Na2SO4, and concentrated to dryness to give 2-(4-bromo-3-(trifluoromethyl)phenyl)acetonitrile 46-5 as dark brown oil, which was used for next step directly. MS m/z 264.1 (M+1)
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][C:9]2[NH:10][CH2:11][CH2:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](Cl)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([N:13]1[CH2:12][CH2:11][N:10]=[C:9]1[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:22])[CH3:21]
Reactant: c1ccc(C(CC2=NCCN2)c2ccccc2)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)N1CCN=C1CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5.0 g of 2-(2,2-diphenyl ethyl)-2-imidazoline and 50 ml of pyridine, 1.1 g of acetyl chloride was dropwise added and the solution stirred at room temperature for about 2 hours. After the reaction, pyridine was removed by distillation. To the resulting residue there was added 100 ml of benzene and the same amount of water, and the solution was well shaken. The benzene layer was separated, washed with water and dried with sodium sulfate. After removing benzene from the solution, the resulting residue was recrystallized from ether to give 1-acetyl-2-(2,2-diphenyl ethyl)-2-imidazoline having a melting point of 104°-106° C.
Reaction SMILES: C[N:2]([CH3:14])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1)=O.N[C:16]1[C:20]([C:21]#[N:22])=C[NH:18][N:17]=1>C(O)(=O)C>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:18]3[N:17]=[CH:16][C:20]([C:21]#[N:22])=[C:14]3[N:2]=[CH:3][CH:4]=2)=[N:8][CH:9]=1
Reactant: Cc1ccc(C(=O)C=CN(C)C)nc1
Reactant: N#Cc1c[nH]nc1N
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccnc3c(C#N)cnn23)nc1

Procedure:
A miture of 0.01 mole of 3-dimethylamino-1-(5-methyl-2-pyridyl)-2-propen-1-one and 0.01 mole of 3-aminopyrazole-4-carbonitrile in glacial acetic acid is refluxed for 8 hours and worked up as for Example 53 to give the product of the example.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]3([CH3:18])[CH3:17])=[C:8]([C:19]([NH2:21])=[O:20])[CH:7]=[N:6][N:5]2[CH:22]=1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:13][C:12]3([CH3:18])[CH3:17])=[C:8]([C:19]([NH2:21])=[O:20])[CH:7]=[N:6][N:5]2[CH:22]=1
Reactant: CC1(C)CNCCC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(S(C)(=O)=O)CCC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a cloudy solution of (+/−)-6-bromo-4-(3,3-dimethylpiperidin-4-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide from Step 3 of Example 1 (300 mg, 0.625 mmol) and DIPEA (0.436 mL, 2.499 mmol) in dichloromethane (10 mL) at 0° C. was added methanesulfonyl chloride (0.058 mL, 0.750 mmol) and the resulting mixture was stirred at rt for 3 h. Reaction was diluted with dichloromethane (150 mL), washed with water and brine, dried over MgSO4, filtered and concentrated to afford the title compound as a tan solid (94% yield). HPLC (condition B): retention time=3.11 min. LCMS (condition H): m/z 444, 446 +ve.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][S:12][CH3:13])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[CH3:29])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)C2C3C(=C(CS(C)=[O:49])C=CC=3)NC=2)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][S:12]([CH3:13])=[O:49])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[CH3:29])[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1
Reactant: CSCc1cc(F)cc2c(C(c3ccc(F)cc3)c3ccc(F)cc3C)c[nH]c12
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Product: Cc1cc(F)ccc1C(c1ccc(F)cc1)c1c[nH]c2c(CS(C)=O)cc(F)cc12

Procedure:
The title compound was prepared starting from 75 mg (0.18 mmol) of the compound from Example 292 in analogy to the synthesis of the compound from Example 296. 75 mg (96% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)=[CH:6][CH:5]=1.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)=[O:20].N1C=CC=CC=1.Cl>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:16][C:2]([F:1])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[CH:13][N:12]([C:25]3[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=3)[C:19]([O:18][CH3:17])=[O:20])[N:11]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)Oc1ccc(-c2cc[nH]n2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-n2ccc(-c3ccc(OC(F)(F)F)cc3)n2)c1
Temperature: 60 °C

Procedure:
A solution of 3-(4-trifluoromethoxy-phenyl)-1H-pyrazole (250 mg), 3-methoxycarbonylphenylboronic acid (540 mg) and pyridine (0.18 mL) in dimethylformamide (5 mL) is treated with copper (II) acetate (214 mg) and powdered activated 4 Å molecular sieves (0.5 g). The resulting mixture is heated to 60° C. for 16 h and cooled. The reaction mixture is poured into 1M aq. HCl (300 mL), and the resulting mixture is filtered through a glass microfiber filter pad. The pad is washed with ethyl acetate, and the filtrate is evaporated to afford the product, methyl 3-[3-(4-trifluoromethoxy-phenyl)-pyrazol-1-yl]-benzoate, as a solid (204 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br.C([O-])([O-])=O.[Na+].[Na+]>>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3)CC2)cc1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3cccc(F)c3)CC2)cc1
Yield: 94.4 %

Procedure:
The title compound (D28) (62 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (R)-methyl 4-(1-(piperidine-2-carboxamido)cyclopropyl)benzoate (D13) (50 mg, 0.16 mmol) and 3-fluoro benzyl bromide (0.03 ml, 0.25 mmol). (Na2CO3: 2.5 eq; reaction time: 6 hrs; 60° C.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:12])[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[OH:9].Br[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][CH2:14][O:9][C:8]2[C:7]([O:10][CH3:11])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=2[O:2][CH3:1])=[CH:18][CH:19]=1
Reactant: Fc1ccc(CCCBr)cc1
Reactant: COc1cc(C)cc(OC)c1O
Product: COc1cc(C)cc(OC)c1OCCCc1ccc(F)cc1
Yield: 90.6 %

Procedure:
3,5-Dimethoxy-4-hydroxy-toluene (1.0 g, 5.95 mmol) and 1-(3-bromopropyl)-4-fluorobenzene (1.5 g, 6.15 mmol) were reacted as described under General Procedure A and the crude product was purified by flash chromatography (silica-gel, hexane/Et2O 19:1) to afford the title compound (1.64 g, 91%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 7.31-7.19 (m, 6H), 4.06 (t, J=6.4 Hz, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 2.81 (t, J=7.7 Hz, 2H), 2.46 (s, 3H), 2.10-2.05 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:38]([O:42][C:43]([NH:45][NH2:46])=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([C:13]([NH:46][NH:45][C:43]([O:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:44])=[O:15])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1nc2ccccc2cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1nc2ccccc2cc1C(=O)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
To a stirred suspension of 2-methoxyquinoline-3-carboxylic acid (0.92 g, 4.55 eq) in DCM (45 mL) under N2, HOBT (6.83 mmol, 1.5 eq), EDC.HCl (6.83 mmol, 1.5 eq) triethylamine (5.0 mmol, 1.1 eq) and tert-butylhydrazine carboxylate (5.00 mmol, 1.1 eq) were added. The mixture was stirred at room temperature for 3 h, diluted with DCM and washed with sat. aq. NaHCO3 and sat. aq. NaCl. The organic phase was dried (Na2SO4), concentrated under reduced pressure and the product was purified by flash chromatography (SiO2, Petroleum ether/EtOAc 9:1 to 0:100) affording 1.23 g of product as a white solid (85% yield). MS (ES) C16H19N3O4 requires: 317.34, found: 318.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24]Cl.C(N(CC)CC)C>C1COCC1>[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24][O:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: CCCCOC(=O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: COCCOCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOC(=O)C12CC3CC(CC(OCOCCOC)(C3)C1)C2
Yield: 94.1 %

Procedure:
A mixture of 200 mmol of n-butyl 3-hydroxy-1-adamantanecarboxylate, 220 mmol of 2-methoxyethoxymethyl chloride, 220 mmol of triethylamine and 200 ml of THF was refluxed for 3 hours. The reaction mixture was concentrated and subjected to column chromatography on a silica gel to give n-butyl 3-(2-methoxyethoxymethoxy)-1-adamantanecarboxylate (yield: 94.1%) at a conversion rate from n-butyl 3-hydroxy-1-adamantanecarboxylate of 99%.
Reaction SMILES: [CH2:1]1[CH2:30][O:29][C:20]2([O:25][CH2:26][CH2:27][O:28][C:3]2([CH:4]=[CH:5][C@@H:6]2[C@@H:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:9][CH2:8][CH2:7]2)[O:2]1)[CH2:21][CH2:22][CH2:23][CH3:24].[N+](=[CH2:33])=[N-]>>[CH3:33][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[C@@H:6]([CH:5]=[CH:4][C:3]23[O:28][CH2:27][CH2:26][O:25][C:20]2([O:29][CH2:30][CH2:1][O:2]3)[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:7][CH2:8][CH2:9]1
Reactant: CCCCC12OCCOC1(C=C[C@H]1CCC[C@@H]1CCCCCCC(=O)O)OCCO2
Reactant: C=[N+]=[N-]
Product: CCCCC12OCCOC1(C=C[C@H]1CCC[C@@H]1CCCCCCC(=O)OC)OCCO2

Procedure:
Into 0.2 g of 9,9;15,15-bis-(ethylenedioxy)-13-prostenoic acid, ethereal diazomethane solution is dropped until a pale yellow color just remains. The organic solution is washed several times with aqueous sodium acetate solution. The organic phase is dried over MgSO4 and the solvent distilled. As the residue, 9,9;15,15-bis-(ethylenedioxy)-13-prostenoic acid methyl ester is obtained.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[F:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11]>C(O)(=O)C>[F:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH:11][C:5](=[O:7])[CH3:6]
Reactant: Nc1ccccc1F
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccccc1F
Temperature: 0 °C

Procedure:
25 ml of acetic anhydride was added to a mixture of 11.1 g of 2-fluoroaniline and 25 ml of glacial acetic acid. The mixture was heated at reflux for 5 minutes, then diluted with ice water. The resulting mixture was filtered, and the solid was dried to give N-(2-fluorophenyl)acetamide (3A), as a white solid, m.p.: 76°-77° C.
Reaction SMILES: [CH3:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[N:6]=[CH:7][N:8](C(=O)C)[CH:9]=1>Cl>[CH3:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[N:6]=[CH:7][NH:8][CH:9]=1
Reactant: CC(=O)n1cnc(Cc2cccc(C)c2C)c1
Agent: Cl
Product: Cc1cccc(Cc2c[nH]cn2)c1C
Reaction time: 4 h

Procedure:
A mixture of 7.6 g of 4-(2',3'-dimethylbenzyl)-N-acetylimidazole and 30 ml of 6 N hydrochloric acid is refluxed with stirring for 4 hours. The mixture is distilled to a smaller volume and 50 ml of water are added. The pH is adjusted with sodium hydroxide to 8-9. The mixture is then cooled and filtered and the filter cake is washed with water and dried. The product melts at 110°-115° C.