Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f52) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[N:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][C:7]=1[CH3:15].[CH3:20][C:21]([S@:24]([NH2:26])=[O:25])([CH3:23])[CH3:22]>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH:26][S@@:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25])[CH3:13])=[CH:8][C:7]=1[CH3:15]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(Oc2ccc(F)c(F)c2)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1Oc1ccc(F)c(F)c1
Yield: 73 %

Procedure:
The title compound is prepared in 73% yield (2.03 g, white solid) from 1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethanone (2.00 g, 7.60 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.38 g, 11.4 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=S)[CH:16]([CH3:18])[CH3:17].[C:20]([NH:28][NH2:29])(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)CCC>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[N:14]1[C:15]([CH:16]([CH3:18])[CH3:17])=[N:29][N:28]=[C:20]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)C(=S)Nc1ccc2c(c1)Cc1ccccc1-2
Reactant: NNC(=O)c1ccccc1
Solvent: CCCCO
Product: CC(C)c1nnc(-c2ccccc2)n1-c1ccc2c(c1)Cc1ccccc1-2
Temperature: 130 °C
Yield: 7.4 %

Procedure:
In a 200 mL three-neck flask were put 13 g (50 mmol) of N-(9H-fluoren-2-yl)isobutyrthioamide, 8.2 g (60 mmol) of benzoylhydrazine, and 70 mL of 1-butanol, and the mixture was heated and refluxed at 130° C. for 10 hours. After that, the solid in the reaction mixture was removed by suction filtration. The resulting filtrate was concentrated to precipitate a solid. After that, 1-buthanol was distilled off to precipitate a solid. The precipitated solid was removed by suction filtration, and the filtrate was purified by silica gel column chromatography. A mixed solvent of ethyl acetate and toluene (ethyl acetate: toluene=1:1) was used as a developing solvent. The resulting fraction was concentrated to give a solid. The obtained solid was recrystallized from ethyl acetate to give 1.3 g of a white solid of 4-(9H-fluoren-2-yl)-5-isopropyl-3-phenyl-4H-1,2,4-triazole in a yield of 7%. The synthesis scheme of Step 3 is shown in (c-3) below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[CH:12](O)=O.C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:12]=[N:8][CH2:7][CH2:6]2
Reactant: COc1cccc(CCN)c1
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)CCN=C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In tetrahydrofuran (100 ml), 3-methoxyphenethylamine (75.0 g) was dissolved. To the resulting solution, formic acid (60 ml) and acetic anhydride (108 ml) were added under ice cooling, followed by stirring overnight at room temperature. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture to separate the organic layer. The organic layer was washed with saturated aqueous NaCl solution and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in benzene (200 ml), followed by the dropwise addition of phosphorus oxychloride (140 ml) under ice cooling. After stirring at 70° C. for 15 minutes, the reaction mixture was successively added with ice and 2N hydrochloric acid. The resulting mixture was stirred for 1 hour under ice cooling. The water layer was separated from the reaction mixture, neutralized with potassium carbonate and then extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane˜dichloromethane:methanol=100:1), whereby the title compound (13.5 g, 17%) was obtained.
Reaction SMILES: [C:1]([N:4]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[O:21][N:20]=[C:19]([O:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH:18]=2)=[O:16])[C@@H:7]([CH3:29])[CH2:6]1)(=[O:3])[CH3:2].O.[OH-].[Li+]>CO>[C:1]([N:4]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[O:21][N:20]=[C:19]([O:22][CH2:23][C:24]([OH:26])=[O:25])[CH:18]=2)=[O:16])[C@@H:7]([CH3:29])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)COc1cc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)on1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2cc(OCC(=O)O)no2)c2ccccc21
Yield: 60 %

Procedure:
Ethyl [(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}isoxazol-3-yl)oxy]acetate was prepared following the procedure for N-(4-chlorophenyl)-N-{(2S,4R)-1-[(1-isopropyl-1H-pyrazol-4-yl)carbonyl]-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl}acetamide substituting ethyl {[5-(chlorocarbonyl)isoxazol-3-yl]oxy}acetate for 1-isopropyl-1H-pyrazole-4-carbonyl chloride. (Ethyl {[15-chlorocarbonyl)isoxazol-3-yl]oxy}acetate was prepared in 4 steps from methyl 3-hydroxy 5-isoxazole carboxylate. Methyl 3-hydroxy 5-isoxazole carboxylate (1.00 g, 6.95 mmol) was alkylated using ethyl bromoacetate (0.850 mL, 7.64 mmol) in presence of potassium carbonate (1.05 g, 7.64 mmol) and catalytic potassium iodide in DMF (3.00 mL) at room temperature overnight. Water was added to the reaction mixture and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired methyl 3-(2-ethoxy-2-oxoethoxy)isoxazole-5-carboxylate (60%). (Ref: WO 03/063800 PCT/US03/03224). Methyl 3-(2-ethoxy-2-oxoethoxy)isoxazole-5-carboxylate was further treated with aqueous 5% sodium hydroxide in methanol to yield 3-(carboxymethoxy)isoxazole-5-carboxylic acid (86%). This diacid (0.700 g, 3.76 mmol) was selectively esterified in the presence of catalytic p-toluenesulfonic acid monohydrate (100 mg) in ethanol at room temperature. Water was added to the reaction and the mixture was extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired 3-(2-ethoxy-2-oxoethoxy)isoxazole-5-carboxylic acid (90%). 3-(2-Ethoxy-2-oxoethoxy)isoxazole-5-carboxylic acid was treated with oxalyl chloride and catalytic DMF in dichloromethane to yield the desired ethyl {[5-(chlorocarbonyl)isoxazol-3-yl]oxy}acetate). Ethyl [(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}isoxazol-3-yl)oxy]acetate was treated with a solution of lithium hydroxide monohydrate (aq) in methanol at room temperature overnight to afford [(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}isoxazol-3-yl)oxy]acetic acid in 60% yield.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][CH2:11][CH:12]([OH:14])[CH3:13].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>N1C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][CH2:11][CH:12]([O:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH3:13]
Reactant: CC(O)CNc1c(Cl)cccc1Cl
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(CNc1c(Cl)cccc1Cl)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
5.0 g (19.5 mmoles) of 1-(2,6-dichlorophenyl-amino)-2-propanol hydrochloride are added in small portions to 50 ml of dry pyridine, and then 3.1 ml (4.6 g, 40 mmoles) of methanesulfonyl chloride are added dropwise, within 0.5 hours, to the mixture at 15° C. The mixture is stirred at room temperature for one hour, then further 0.8 ml (1.2 g, 10 mmoles) of methanesulfonyl chloride are added, and stirring is continued for one hour. The mixture is poured then onto 100 ml of ice water, and the aqueous mixture is extracted thrice with 70 ml of 1,2-dichloroethane, each. The dichloroethane solutions are combined, washed thrice with 50 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. 5.52 g (79.5%) of 1-(2,6-dichlorophenyl-amino)-2-methanesulfonyloxy-propane are obtained as a dark yellow oil; this substance can be utilized in the subsequent reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[CH3:15][O-:16].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:11]([O:16][CH3:15])=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[C:7]([CH3:13])[CH:8]=2)[N:3]=1
Reactant: Cc1cc2nc(N)c(Cl)nc2cc1C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc2cc(C)c(C)cc2nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To 2-amino-3-chloro-6,7-dimethyl quinoxaline (2.59 g, 12.5 mmol) dissolved in tetrahydrofuran (40 ml), 25 wt % sodium methoxide (4.05 g, 18.7 mmol) in methanol was added at room temperature and stirred further at room temperature for 1 hour. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with ethyl acetate and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 2.38 g of the titled compound (yield, 94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Cl:13])=[CH:6][C:5]=1[NH2:14].[Br:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24](Cl)=[O:25])[CH:20]=[CH:21][CH:22]=1>ClC(Cl)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Cl:13])=[CH:6][C:5]=1[NH:14][C:24](=[O:25])[CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([Br:16])[CH:18]=1
Reactant: O=C(Cl)Cc1cccc(Br)c1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1N
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1NC(=O)Cc1cccc(Br)c1
Reaction time: 18 h

Procedure:
To a suspension of 2-amino-4-chloro-5-nitrobenzoic acid methyl ester (Example 9, 780 mg in 10 mL dichloroethane) was added a solution of (3-bromophenyl)acetyl chloride (prepared essentially as described in Example 9, 866 mg in 5 mL dichloroethane) and the mixture heated to reflux on an oil bath. After 18 hours, the reaction mixture was concentrated in vacuo and the title compound obtained by crystallization from methanol (1.18 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[N:22]=[C:21]([N:23]5[C:28](=[O:29])[CH2:27][CH2:26][C@H:25]([NH:30]C(=O)OC(C)(C)C)[CH2:24]5)[CH:20]=[CH:19][CH:18]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.O1CCOCC1>Cl.O>[NH2:30][C@@H:25]1[CH2:24][N:23]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([N:16]3[C:10]4[CH:9]=[C:8]([C:6]5[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=5)[N:13]=[CH:12][C:11]=4[CH:14]=[N:15]3)[N:22]=2)[C:28](=[O:29])[CH2:27][CH2:26]1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3C[C@@H](NC(=O)OC(C)(C)C)CCC3=O)n2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3C[C@@H](N)CCC3=O)n2)n1
Yield: 18.3 %

Procedure:
A solution of tert-butyl N-[(3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-6-oxo-3-piperidyl]carbamate (45 mg, 0.15 mmol) in hydrogen chloride (4 mol/l) in 1,4-dioxane (2.0 ml, 8.0 mmol) and 1,4-dioxane 2.0 mL was stirred at RT 18 h. The reaction was diluted with water then wash with EtOAc. The aqueous layer was basified with 1M NaOH to pH 10 and extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was submitted for reverse phase HPLC to give 202 (11 mg) in 18% yield. MS (ESI) m/z: 401.1. 1H NMR (400 MHz, DMSO) δ 9.61 (s, 1H), 9.47 (s, 1H), 9.35 (s, 1H), 8.73 (s, 1H), 8.63 (s, 1H), 8.04 (t, J=8.1 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 4.24 (dd, J=12.2, 3.8 Hz, 1H), 3.94 (dd, J=12.3, 6.3 Hz, 1H), 3.49 (s, 1H), 2.75 (dd, J=12.2, 5.3 Hz, 1H), 2.69 (s, 3H), 2.63-2.55 (m, 1H), 2.10 (dd, J=13.0, 4.3 Hz, 1H), 1.85-1.72 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][N:4]=1.[N+:13]([CH:15](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:16])#[C-:14].C([O-])([O-])=O.[K+].[K+]>CO>[CH3:16][C:15]1[N:13]=[CH:14][O:8][C:7]=1[C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:1])([F:11])[F:12])=[N:4][CH:5]=1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ncoc1-c1ccc(C(F)(F)F)nc1
Yield: 88.3 %

Procedure:
6-(trifluoromethyl)nicotinaldehyde (7 g, 40 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (8.41 g, 40.0 mmol) and K2CO3 (6.63 g, 48.0 mmol) were heated to reflux in methanol (200 mL) overnight. The solution was cooled and the solvents removed in vacuo. The orange semi-solid was partitioned between water and ethyl acetate. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and the solvents removed in vacuo. The crude product was purified by column chromatography with 10% to 45% ethyl acetate/hexanes as eluent to afford 8.06 g (88% yield) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 9.01 (d, J=2.03 Hz, 1H), 8.08 (dd, J=7.97, 1.86 Hz, 1H), 7.93 (s, 1H), 7.77 (d, J=8.48 Hz, 1H), 2.51 (s, 3H,). MS (ESI+) m/z 229 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[C:12]2[C:7]([C:8](=[O:19])[C:9]([C:14]([O:16]CC)=[O:15])=[CH:10][NH:11]2)=[CH:6][CH:5]=1)[CH3:2].Br[CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]1[N:13]=[C:12]2[C:7]([C:8](=[O:19])[C:9]([C:14]([OH:16])=[O:15])=[CH:10][N:11]2[CH2:21][CH2:22][OH:23])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2nc(OCC)ccc2c1=O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc2c(=O)c(C(=O)O)cn(CCO)c2n1

Procedure:
7-Ethoxy-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester (3.6 g), 2-bromoethanol and potassium carbonate (7.5 g) in dimethylformamide (50 ml) (4.95 ml) were stirred and heated on a steam bath for 16 hours. The solid was filtered off and the filtrate evaporated. The residue was crystallized from dimethylformamide. This ester (2.0 g) and aqueous sodium hydroxide (40 ml, 2N) were heated on a steam bath for 3 hours, cooled and acidified to pH 2 with aqueous hydrochloric acid. The solid was collected and crystallized from ethanol, m.p. 219.5°-220° (24%).
Reaction SMILES: FC1C(CSC)=C2C(C=CN2)=CC=1.[F:14][C:15]([F:25])([F:24])C1C=CC(C=O)=CC=1.Cl[C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:44]2[C:52]3[C:47](=[C:48]([CH2:54][S:55][CH3:56])[C:49]([F:53])=[CH:50][CH:51]=3)[NH:46][CH:45]=2)[CH:34]2[C:39](=[O:40])[O:38][C:37]([CH3:42])([CH3:41])[O:36][C:35]2=[O:43])=[CH:29][CH:28]=1>>[CH3:41][C:37]1([CH3:42])[O:38][C:39](=[O:40])[CH:34]([CH:33]([C:44]2[C:52]3[C:47](=[C:48]([CH2:54][S:55][CH3:56])[C:49]([F:53])=[CH:50][CH:51]=3)[NH:46][CH:45]=2)[C:30]2[CH:31]=[CH:32][C:27]([C:15]([F:25])([F:24])[F:14])=[CH:28][CH:29]=2)[C:35](=[O:43])[O:36]1
Reactant: CSCc1c(F)ccc2c(C(c3ccc(Cl)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CSCc1c(F)ccc2cc[nH]c12
Product: CSCc1c(F)ccc2c(C(c3ccc(C(F)(F)F)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12

Procedure:
The title compound is prepared starting from 2.00 g (10.24 mmol) of the compound from Example 9A and 1.78 g (10.24 mmol) of 4-(trifluoromethyl)benzaldehyde in analogy to the synthesis of the compound from Example 21A. 3.83 g (75% of theory) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:14]=1[C:15](OC)=[O:16]>Cl.CO>[Cl:23][C:21]1[CH:20]=[CH:19][C:14]2[C:15](=[O:16])[NH:1][C:2]3[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=3[NH:12][C:13]=2[CH:22]=1
Reactant: COC(=O)c1ccc(Nc2cc(Cl)ccc2C(=O)OC)c(N)c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Temperature: 25 °C
Yield: 87.7 %

Procedure:
A solution of Example 1A (0.43 g, 1.28 mmol) in 37% HCl (20 mL) and methanol (50 mL) was heated to reflux for 20 hours, cooled to room temperature, and filtered. The filter cake was washed with 1:1H2O/methanol and dried in a vacuum oven at 65° C. to provide 0.34 g (87%) of the desired product. MS (DCI) m/e 303 (M+H)+, 320 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.50 (s, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.55-7.60 (m, 2H), 7.08 (d, J=2 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.96 (dd, J=8.5, 2 Hz, 1H), 3.80 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[NH2:17][CH2:18][C:19]1[C:20]([N:29]([CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:30][CH3:31])=[N:21][C:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=2[CH:28]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:17][CH2:18][C:19]1[C:20]([N:29]([CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:30][CH3:31])=[N:21][C:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=2[CH:28]=1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(CC1CCCC1)c1nc2c(cc1CN)CCCC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN(CC1CCCC1)c1nc2c(cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of 3,5-bis-trifluoromethyl benzaldehyde (0.185 g, 0.76 mmol) in MeOH (3 mL) was added (3-aminomethyl-5,6,7,8-tetrahydro-quinoline-2-yl)-cyclopentylmethyl-ethylamine (0.2 g, 0.69 mmol), followed by the addition of acetic acid (0.08 mL, 1.39 mmol). This reaction mixture was stirred at RT for 1 h, after which time sodium cyanoborohydride (0.172 g, 2.78 mmol) was added, and stirring was continued for another 8 h. The solvent was then evaporated under vacuum and water was added, followed by extraction of the product with ethyl acetate. The organic layer was washed with saturated sodium bisulfite solution, the organic layer was separated and dried over sodium sulfate, and the solvent was evaporated to give the {3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-5,6,7,8-tetrahydro-quinolin-2-yl}-cyclopentylmethyl-ethylamine (0.250 g, yield: 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:40])=[C:17]([CH3:39])[C:18]4[O:22][C:21]([CH3:24])([CH3:23])[CH:20]([O:25][CH2:26][C:27]5[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=5)[C:19]=4[C:37]=3[CH3:38])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C1COCC1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[C:16]([CH3:40])=[C:17]([CH3:39])[C:18]4[O:22][C:21]([CH3:24])([CH3:23])[CH:20]([O:25][CH2:26][C:27]5[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:35][CH:36]=5)[C:19]=4[C:37]=3[CH3:38])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(COC2c3c(C)c(N4CCN(c5ccc(OC)cc5)CC4)c(C)c(C)c3OC2(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(OCc3ccc(C(=O)O)cc3)C(C)(C)O4)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
To a solution of methyl 4-(((5-(4-[4-methoxyphenyl]piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl)oxy)methyl)benzoate (0.18 g, 0.33 mmol) obtained in Example 135 in methanol (1 mL)-THF (1 ml) was added 1N sodium hydroxide (0.5 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The residue was recrystallized from hexane-ethyl acetate to obtain 0.13 g (yield 75%) of the title compound. mp. 162–163° C.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].COC([O:11][CH2:12][C:13]1C=CC=C[C:14]=1Br)(C)C.[CH3:20][CH2:21][CH2:22][CH2:23]CC>>[CH3:5][C:4]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:2]2[C:3]=1[CH2:14][CH2:13][C:12]2=[O:11]
Reactant: [Li]CCCC
Reactant: CCCCCC
Reactant: COC(C)(C)OCc1ccccc1Br
Product: Cc1ccc(C)c2c1CCC2=O
Temperature: -70 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
30 ml of n-BuLi 2.5 M in hexane (75 mmoles) are added to 20 g of 2-methoxy-2-(o-bromobenzyloxy)propane (77.22 mmoles) obtained as in example 1.1, in a solution of 150 ml of hexane. At the end of the addition the mixture is left under stirring for 2 hours. The precipitation of the corresponding lithium salt takes place, as previously described in example 1. The hexane is decanted and the solid is again washed with hexane and then dissolved in 100 ml of THF. The mixture is cooled to −70° C. and 12.12 g (75.75 mmoles) of 4,7-dimethyl-1-indanone obtained as described above, dissolved in-a sufficient quantity of THF, are then added slowly. The temperature is left to rise to room temperature for a night, the reaction mass is poured into ice, acidified with 50 ml of aqueous HCl 1/1 and left under stirring for 2 hours. It is extracted with ethyl ether, the organic phase is washed until neutrality with a solution of sodium bicarbonate and water, and is anhydrified on sodium sulfate. After evaporation of the solvent the residue is purified by chromatography on a silica gel column, eluating with a mixture of hexane/ethyl acetate 9:1. After evaporation of the eluant, 10 g of the alcohol having formula (XIX) are obtained (scheme V; 53% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].C1(SC)C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[O:8])[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CSc1ccccc1
Product: O=Cc1cccc([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
3-nitrobenzoylchloride (5.0 g, 26.94 mmol) was added to a solution of thioanisole (3.16 ml, 26.94 mmol) and 1,2-dichlorethane (95 mL). The resulting reaction mixture was cooled to 0° C. (ice/H2O bath) and 0.5 equivalents of aluminum trichloride (1.8 g, 13.47 mmol) was added. The reaction was allowed to stir for 15 min at this temperature and the cold bath was removed followed by addition of the remaining equivalents of AlCl3 (2.51 g, 18.87). The reaction solution turned a dark greenish/yellow and was allowed to stir at room temp. for 18 h, after which time the reaction was quenched slowly with H2O (50 mL). The mixture was diluted with CH2Cl2 (50 mL) and washed with H2O (3×50 mL), and the combined organic phases were washed with satd NaHCO3 (50 mL), dried (MgSO4) and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (EtOAc/hexane, ¼) to afford 3.3 g (44%) of 4-(methylsulfanyl)phenyl](3-nitrophenyl)methanone as a solid. EI-LRMS m/z 274 (M+); TLC Rf 0.68 (EtOAc/Hex, ⅔). Step 2. Preparation of (3-aminophenyl)[4-(methylsulfanyl)phenyl]methanone