Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.C(=O)=O.CC(C)=O.[F:17][C:18]([F:37])([S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)O>ClCCl>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([CH:19]([F:7])[C:18]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])([F:37])[F:17])=[CH:22][CH:23]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1ccc(C(O)C(F)(F)S(=O)(=O)c2ccccc2)cc1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1ccc(C(F)C(F)(F)S(=O)(=O)c2ccccc2)cc1
Yield: 71.6 %

Procedure:
A solution of 0.24 mL (1.8 mmol) of diethylaminosulfur trifluoride in 5 mL of dichloromethane was cooled to -78° C. (dry ice-acetone bath) and treated dropwise with a solution of 0.50 g (1.6 mmol) of 2,2-difluoro-1-(4-methylphenyl)-2-phenylsulfonylethanol in 2 mL of dichloromethane. The cooling bath was removed, and 30 minutes later 2 mL of saturated NaHCO3 was added with vigorous stirring. The organic layer was removed, washed with one 2 mL portion of water, dried (MgSO4), and concentrated in vacuo to give a residue which was crystallized from toluene-hexane, affording 0.36 g (71% yield) of 2-(4-methylphenyl)-1-phenylsulfonyl-1,1,2-trifluoroethane; mp 80°-82° C.; IR (KBr) 2924, 1447, 1352, 1185, 1163, 1117, 1054, 1013, 787, 757, 720, 686, 603, 567, 533, cm--1 ; lHNMR (CDCl3) δ2.36 (s, 3H), 6.10 (ddd, lH, JHF = 44, 18, 5 Hz), 7.16-8.07 (m, 9H); 19F NMR (CDCl3, relative to CFCl3)-44.0 ppm (dt, IF J=44, 16 Hz)-109.3 ppm (dd, lF, J=247, 15 Hz),-118.8 ppm (dt, IF, J=248, 17 Hz); mass spectrum (70 eV) m/e (relative intensity) 314 (11, M+), 172 (41), 123 (100), 77 (31). Anal. Calcd. for C15H13F3O2S: C, 57.32; H, 4.17. Found: C, 56.90; H, 4.47.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CO>[N:12]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: C1COCCN1
Solvent: CO
Product: COC(=O)c1ccc(N2CCOCC2)nc1
Reaction time: 14 h
Yield: 79 %

Procedure:
There was dissolved, in methanol (50 mL), methyl 6-chloro-nicotinate (4.00 g, 23.3 mM), then morpholine (6.10 mL, 69.9 mM) was added to the solution and the solution was stirred for 14 hours while refluxing the same with heating. The solvent was distilled off from this reaction liquid, the resulting residue was diluted with water and then extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off to thus obtain methyl 6-(morpholin-4-yl)-nicotinate (4.07 g, yield: 79%). Subsequently, acetonitrile (1.61 mL, 30.6 mM) was added to a solution of 18-crown-6 (476 mg, 1.80 mM) and potassium tert-butoxide (1M THF solution, 27.0 mL, 27.0 mM) in THF (10 mL) at 60° C. and then the mixture was stirred for 5 minutes. To this solution, there was added the methyl 6-(morpholin-4-yl)-nicotinate (4.00 g, 18.0 mM) prepared above and the mixture was stirred for 30 minutes. This suspension was filtered and the resulting solid was washed with diethyl ether.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][N:24]([C:27]2[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23](=[O:36])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][N:24]([C:27]2[S:28][C:29]([C:33]([NH:10][CH2:9][C:6]3[CH:7]=[N:8][C:3]([C:2]([F:11])([F:1])[F:12])=[CH:4][CH:5]=3)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23](=[O:36])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccc(C(F)(F)F)nc1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ccc(C(F)(F)F)nc1
Yield: 38 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (6-(trifluoromethyl)pyridin-3-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 38% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.89 (t, J=5.6 Hz, 1H), 8.69 (br s, 1H), 8.61 (d, J=8.1 Hz 1H), 7.98-7.96 (m, 1H), 7.87-7.84 (m, 1H), 7.45-7.33 (m, 5H), 6.39 (dd, J=8.1, 2.6 Hz, 1H), 6.23 (d, J=2.6 Hz, 1H), 5.16 (s, 2H), 4.50 (d, J=5.6 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 501.1 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([NH2:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=O)C.C(O)(=O)C.[CH:30](N)=[NH:31]>C(OCCO)C>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[N:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[N:7]=[C:6]3[C:4]([OH:3])=[N:31][CH:30]=[N:11][C:10]=23)=[CH:17][CH:16]=1
Reactant: N=CN
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1N
Solvent: CCOCCO
Solvent: CC(=O)O
Product: Oc1ncnc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester I-2A-1a (19.27 g, 51.2 mmol) and formamidine acetate (15.99g, 153.6 mmol) in 2-ethoxyethanol (100 ml) was refluxed for 3.5 h under nitrogen. The reaction mixture was then cooled to room temperature and poured into ice-cold water. The yellow precipitate that formed was collected by filtration and washed with water. The solid was stirred in 45 ml methyl tert-butyl ether for 30 minutes. Cyclohexane (90 ml) was added, and the stirring was continued for another 45 minutes. The pale yellow solid was collected by filtration and dried to give 3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ol 1-2A-1 b (17.55 g, 87%): MS: 357.1 (M+1)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][N:19]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:20]3=[O:23])=[CH:16][C:15]=2[Cl:30])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:31]1([CH:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:38][CH2:39]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:30][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][C:14]=1[N:11]1[CH2:10][CH2:9][N:8]([CH2:39][CH2:38][CH:37]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:13][CH2:12]1)[C:20](=[O:23])[N:19]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:18]2
Reactant: BrCCC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2Cl)CN(C2CCCCC2)C3=O)CC1
Product: O=C1c2cc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)c(Cl)cc2CN1C1CCCCC1

Procedure:
In the same manner as in Example 47, the title compound was prepared from 6-[4-(t-butoxycarbonyl)piperazin-1-yl]-5-chloro-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one obtained in Example 45 and 3,3-diphenylpropyl bromide.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[O:20][C:21]([F:24])([F:23])[F:22])C>CCOCC>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][CH2:10][OH:9])=[C:14]([O:20][C:21]([F:22])([F:23])[F:24])[CH:15]=1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1OC(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCCc1ccc(Br)cc1OC(F)(F)F
Temperature: 4 °C
Reaction time: 1.5 h
Yield: 43.4 %

Procedure:
A suspension of lithium aluminum hydride (834 mg, 22.0 mmol) in Et2O (20 mL) was cooled at 4° C. A solution of (E)-3-(4-bromo-2-trifluoromethoxy-phenyl)-acrylic acid ethyl ester (2.98 g, 8.79 mmol) in Et2O (9 mL) was added dropwise, and the mixture was stirred at ambient temperature for 90 min. The reaction was quenched with EtOAc (6 mL) and saturated aqueous NH4Cl was added dropwise. The aqueous layer was extracted with EtOAc (three times). The combined organic layer was washed with 1 M aqueous HCl, dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel, 25% EtOAc in hexane) to give 3-(4-bromo-2-trifluoromethoxy-phenyl)-propan-1-ol (1.14 g, 43%) as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH:15]1[CH2:20][O:19][C:17](=[O:18])[CH2:16]1.N1C=CC=CC=1>C(OCC)(=O)C.O>[Cl:1][CH2:2][C:3]([N:14]([CH:15]1[CH2:20][O:19][C:17](=[O:18])[CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH3:6])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: COc1ccccc1NC1COC(=O)C1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1N(C(=O)CCl)C1COC(=O)C1
Temperature: 46 °C
Reaction time: 0.25 h

Procedure:
A 5.4 g (0.044 mol) sample of chloroacetyl chloride was added dropwise to a solution of 9 g (0.044 mol) 3-(N-2-methoxyphenylamino)-gamma-butyrolactone and 3.8 g (0.048mol) pyridine in 150 ml ethyl acetate at 37°-46° C. After stirring at 46° C for 15 minutes, the reaction mixture was cooled and diluted with water. The organic layer was separated, washed with 10% aqueous sodium bicarbonate, washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give the product, as a colorless solid. The melting point and elemental analysis for the product is tabulated in Table I, as compound No. 3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.Cl[CH2:18][CH2:19][C:20]1[C:25](=[O:26])[N:24]2[CH:27]=[CH:28][CH:29]=[C:30]([CH3:31])[C:23]2=[N:22][C:21]=1[CH3:32].C(NC(C)C)(C)C.[I-].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:18][CH2:19][C:20]2[C:25](=[O:26])[N:24]3[CH:27]=[CH:28][CH:29]=[C:30]([CH3:31])[C:23]3=[N:22][C:21]=2[CH3:32])[CH2:15][CH:16]=1
Reactant: Cc1nc2c(C)cccn2c(=O)c1CCCl
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: Cc1nc2c(C)cccn2c(=O)c1CCN1CC=C(c2c[nH]c3ccc(F)cc23)CC1

Procedure:
A solution of 5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)indole (5.5 g, 0.025 mol), 3-(2-chloroethyl)-2,9-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (7.2 g, 0.030 mol), diisopropylamine (5 ml) and potassium iodide (1 g) in acetonitrile (100 ml) was heated under reflux for 24 h. After cooling the precipitate was collected and washed with acetonitrile (20 ml), isopropyl alcohol (3×20 ml) and petroleum ether (25 ml) respectively. Yield 7.13 g (67%) of a pale yellow solid. M.p.: 229-230° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8]C(C2ON=C(C(C)(C)C)C=2)=O)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>COCCOC.O>[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1cc(C(=O)Nc2nc(Br)ccc2[N+](=O)[O-])on1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: Nc1nc(-c2ccccc2C(F)(F)F)ccc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
A solution of 3-tert-butyl-isoxazole-5-carboxylic acid (6-bromo-3-nitro-pyridin-2-yl)-amide (139 mg, 0.377 mmol, prepared as described in the previous step) in DME (15 mL) and water (5 mL) was treated with 2-trifluoromethylphenylboronic acid (85.8 mg, 0.452 mmol) and cesium carbonate (245 mg, 0.753 mmol). The resulting mixture was de-gassed via sonication, placed under Ar, treated with PdCl2(dppf).DCM (15.4 mg, 0.019 mmol), and heated to 80° C. for 18 h. The cooled mixture was diluted with water (50 mL) and extracted twice with EtOAc (50 mL, 25 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 50 SPE column (Isco system: Flow rate=15 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 10 min, then 1:99 to 3:17 v/v over 40 min) to yield 6-(2-trifluoromethyl-phenyl)-3-nitro-pyridin-2-ylamine as a yellow solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C12H8F3N3O2: 284.1 (M+H); Measured: 284.0.
Reaction SMILES: CN1C2C(C(F)(F)F)=CC(NC3C=NC=CC=3)=CC=2C2CNCCC12.[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][C:32]([NH:38]C3C=NC=CC=3C(F)(F)F)=[CH:33][C:34]=2[C:36]#[N:37])[C@@H:29]2[CH2:49][NH:50][CH2:51][CH2:52][C@H:28]12.Br[C:54]1[C:55]([O:61][CH3:62])=[N:56][CH:57]=[C:58]([CH3:60])[CH:59]=1.CC([O-])(C)C.[Na+]>>[CH3:62][O:61][C:55]1[C:54]([NH:38][C:32]2[CH:31]=[C:30]3[C:35](=[C:34]([C:36]#[N:37])[CH:33]=2)[N:27]([CH3:26])[C@H:28]2[CH2:52][CH2:51][NH:50][CH2:49][C@@H:29]32)=[CH:59][C:58]([CH3:60])=[CH:57][N:56]=1
Reactant: COc1ncc(C)cc1Br
Reactant: CN1c2c(C#N)cc(Nc3cnccc3C(F)(F)F)cc2[C@@H]2CNCC[C@@H]21
Agent: CC(C)(C)[O-]
Agent: CN1c2c(cc(Nc3cccnc3)cc2C(F)(F)F)C2CNCCC21
Agent: [Na+]
Product: COc1ncc(C)cc1Nc1cc(C#N)c2c(c1)[C@@H]1CNCC[C@@H]1N2C

Procedure:
The title compound was prepared by following the general method for (5-methyl-6-trifluoromethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-8-yl)-pyridin-3-yl-amine (Method B) as a tan solid (57 mg, 39%) from (4aS,9bR)-8-amino-6-cyano-3,4,4a,9b-tetrahydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylic acid tert-butyl ester (Example 162, 150 mg, 0.46 mmol), 3-bromo-2-methoxy-5-methylpyridine (84 mg, 0.42 mmol) and NaOt-Bu (66 mg, 0.69 mmol): mp 76–80° C.; 1H NMR (300 MHz, CDCl3) δ 7.38 (m, 1H), 7.07 (d, J=2.2 Hz, 1H), 7.00 (d, J=1.8 Hz, 1H), 6.91 (d, J=1.8 Hz, 1H), 5.79 (br s, 1H), 3.99 (s, 3H), 3.63–3.51 (m, 1H), 3.23–3.00 (m, 4H), 2.98–2.79 (m, 2H), 2.73–2.26 (m, 2H), 2.18 (s, 3H), 1.99–1.81 (m, 2H); ESI MS m/z 350 [C20H23N5O+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][CH:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>C(#N)CC.O>[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([N:43]2[CH2:48][CH2:47][N:46]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][S:15][CH2:16][CH:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:45][CH2:44]2)=[CH:41][CH:42]=1
Reactant: O=C1Nc2cc(CO)cnc2N2CCSCC12
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc2N2CCSCC12
Temperature: 90 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (Compound 86C; 100 mg, 0.36 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 1-(4-chlorophenyl)piperazine hydrochloride (104.9 mg, 0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and diluted with water (3 mL) and filtered. The solids were collected and refluxed in ethanol (5 mL) for 1 h. The suspension was cooled back to room temperature and filtered. The solids were collected to afford the title compound (86.1 mg, 56%) as a white solid. 1H NMR (DMSO-d6) δ: 10.66 (s, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.16-7.26 (m, 2H), 7.00 (d, J=2.0 Hz, 1H), 6.86-6.96 (m, 2H), 4.88 (dt, J=13.6, 2.7 Hz, 1H), 4.26 (dd, J=10.7, 2.9 Hz, 1H), 3.34-3.42 (m, 2H), 3.07-3.16 (m, 4H), 3.02 (td, J=12.8, 2.3 Hz, 1H), 2.65-2.83 (m, 3H), 2.43-2.48 (m, 5H). [M+H] calc'd for C21H24ClN5OS, 430. found, 430.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[F:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20](Cl)=[O:21]>ClCCl>[F:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:21]
Reactant: Oc1ccccc1
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Oc1ccccc1)c1cc(F)c(F)cc1F
Reaction time: 2 h

Procedure:
A solution of phenol (13.3 g, 141 mmol) in dry dichloromethane (370 mL) was cooled in ice bath and treated with N,N-diisopropylethylamine (34 mL, 193 mmol) followed by dropwise addition of 2,4,5-trifluorobenzoyl chloride (25 g, 129 mmol) over a period of 15 minutes. The ice bath was removed, stirring was continued for two hours at room temperature and the solution was then transferred to a separatory funnel and the organic layer was washed successively with hydrochloric acid solution (2N, 150 mL), saturated aqueous sodium bicarbonate solution (150 mL), and brine (150 mL), dried over anhydrous sodium sulfate, filtered, evaporated and the resulting solid product was purified on silica in portions by eluting successively with hexane, and then 0-5% ether in hexane in a gradient fashion to yield phenyl 2,4,5-trifluorobenzoate as white solid.
Reaction SMILES: C([O:3][C:4](=[O:32])/[C:5](/[O:29][CH2:30][CH3:31])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:28])C.[OH-].[Na+]>>[CH2:30]([O:29]/[C:5](=[CH:6]\[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:28])/[C:4]([OH:32])=[O:3])[CH3:31]
Reactant: CCOC(=O)/C(=C/c1ccc(OCc2nc(-c3ccccc3F)oc2C)cc1C)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO/C(=C\c1ccc(OCc2nc(-c3ccccc3F)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1a f], (Z)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-acrylic acid ethyl ester was treated with NaOH to obtain (Z)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-acrylic acid as colorless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].[NH:23]1[C:31]2[C:26](=CC=C[CH:30]=2)[C:25]2(COC3C=C4C(=[CH:42][C:32]2=3)CCO4)C1=O.Br.BrCC1C=CC=CN=1.BrCC1CCCCO1>>[N:23]1[CH:42]=[CH:32][CH:25]=[CH:26][C:31]=1[CH2:30][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Br
Agent: BrCC1CCCCO1
Agent: BrCc1ccccn1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (80%) as a colorless solid: mp 208-209° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ8.58 (d, J=4.8 Hz, 1H), 7.65 (ddd, J=7.7, 7.7, 1.7 Hz, 1H), 7.28-7.15 (m, 4H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.31 (s, 1H), 5.21 (d, J=16.0 Hz, 1H), 4.97 (d, J=16.0 Hz, 1H), 4.96 (d, J=8.7 Hz, 1H), 4.68 (d, J=8.7 Hz, 1H), 4.22-4.17 (m, 2H), 4.15-4.10 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.6, 155.6, 155.3, 149.6, 144.6, 142.2, 138.3, 137.1, 132.2, 128.9, 123.8, 123.5, 122.8, 121.6, 121.1, 111.8, 109.6, 99.4, 80.2, 64.5, 63.9, 58.2, 46.1; MS (ES+) m/z 387.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:39])[CH2:18][C@H:19]([NH:31]C(=O)OC(C)(C)C)[CH2:20][C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=4)[CH2:12]3)[N:8]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:7]=2[CH:45]=1>C(Cl)Cl>[NH2:31][C@H:19]([CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[CH2:18][C:17]([N:13]1[CH2:14][CH2:15][CH2:16][CH:11]([C:9]2[N:8]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:7]3[CH:45]=[C:3]([CH2:2][OH:1])[CH:4]=[CH:5][C:6]=3[N:10]=2)[CH2:12]1)=[O:39]
Reactant: COCCCn1c(C2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccc(CO)cc21
Solvent: ClCCl
Product: COCCCn1c(C2CCCN(C(=O)C[C@H](N)Cc3ccc4ccccc4c3)C2)nc2ccc(CO)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
tert-Butyl (2R)-4-(3-(6-(hydrox ymethyl)-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (45A) (0.20 mmol, 120 mg) in DCM (10 mL) was added TEA (2 mL). The reaction solution was stirred at rt for 1 hr and then concentrated in vacuo. The residue was purified by preparative LC/MS (5-45% CH3CN in H2O) to afford (3R)-3-amino-1-(3-(6-(hydroxymethyl)-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-(naphthalen-2-yl)butan-1-one (113) (0.016 mmol, 8 mg, two-step yield: 13.3%). ESI-MS: m/z 515.5 (M+H)+. 1H NMR (400 MHz, MeOD) δ ppm 1.56-1.70 (m, 1H) 1.77-2.09 (m, 2H) 1.85-1.86 (m, 3H) 2.12-2.34 (m, 3H) 2.63-3.02 (m, 4H) 3.03-3.11 (m, 2H) 3.13 (d, J=7.26 Hz, 2H) 3.15-3.27 (m, 3H) 3.29 (s, 1H) 3.36-3.51 (m, 3H) 3.67-4.29 (m, 4H) 4.50-4.72 (m, 1H) 7.39-7.44 (m, 2H) 7.49 (ddd, J=9.32, 6.06, 2.81Hz, 3H) 7.56 (d, 0.7=8.65 Hz, 1H) 7.69-7.74 (m, 1H) 7.79-7.94 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[C:9]([S:17][CH3:18])=[C:8]2[CH2:19][C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1.[OH:25]OS([O-])=O.[K+].[OH2:31]>C(O)C.[Cl-].[Na+].O.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[C:9]([S:17]([CH3:18])(=[O:25])=[O:31])=[C:8]2[CH2:19][C:20]([OH:22])=[O:21])=[CH:23][CH:24]=1
Reactant: CSc1c(CC(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12
Reactant: O=S([O-])OO
Reactant: O
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CS(=O)(=O)c1c(CC(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12
Reaction time: 6 h

Procedure:
To 200 mg of 1-(p-chlorobenzyl)-5-fluoro -3-methylthioindole-2-acetic acid from Example 4 in a mixture of 3 mL water and 3 mL ethanol was added 1.6 g of oxone. After stirring for 6 h the reaction mixture was diluted with brine and ether. The ether layer was washed with 1 N HCl, and brine and dried over MgSO4. Filtration and concentration gave the title compound, mp 202°-202.5°.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[C:9]1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:21][CH:20]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:29]([O:28][C:26](=[O:27])[NH:25][C:22]1[CH:21]=[CH:20][C:19]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)=[CH:24][CH:23]=1)([CH3:31])[CH3:30]
Reactant: COc1ccc2cc(-c3ccc(NC(=O)OC(C)C)cc3)n(C(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2cc(-c3ccc(NC(=O)OC(C)C)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
A mixture of 2-(4-Isopropoxycarbonylamino-phenyl)-6-methoxy-indole-1-carboxylic acid tert-butyl ester (17.4 g, 41 mmol), CH2Cl2 (50 mL), and TFA (50 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated, diluted in CH2Cl2, and washed with sat. aq. NaHCO3. The organic layer was dried, concentrated, and triturated with ether to provide [4-(6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (11.4 g, 86%) as a grayish solid.