Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[S:10])[CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[NH:6]1)[CH2:2][CH2:3][CH3:4].[C:15](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH2:1]([N:5]1[C:9]([S:10][CH3:15])=[CH:8][C:7]([C:11]([F:13])([F:12])[F:14])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCn1[nH]c(C(F)(F)F)cc1=S
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCCCn1nc(C(F)(F)F)cc1SC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 123.6 %

Procedure:
3.35 g of compound (8-6) and 4.07 g of potassium carbonate were suspended in 100 ml of acetonitrile. The suspension was stirred at room temperature for 15 minutes. A solution of 3.35 g of methyl iodide in 10 ml of acetonitrile was added dropwise. The mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. After water was added to the residue, the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce 4.40 g of 1-butyl-5-methylthio-3-(trifluoromethyl)pyrazole (15).
Reaction SMILES: [C:1]([Si:5]([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[O:6][CH2:7][CH:8]([CH3:41])[O:9][C:10]1[CH:11]=[C:12]([O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25](OCC)=[O:26])[CH2:22][N:23]=1)=[CH:15]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].Cl.C(OCC)(=O)C>O1CCCC1.CCCCCC>[C:48]([Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[O:6][CH2:7][CH:8]([CH3:41])[O:9][C:10]1[CH:11]=[C:12]([O:30][C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:38])=[O:39])=[CH:35][CH:36]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][CH2:25][OH:26])[CH2:22][N:23]=1)=[CH:15]2)([CH3:51])([CH3:49])[CH3:50]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC(C)CO[Si](c4ccccc4)(C(C)(C)C)C(C)(C)C)c3[nH]2)S1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(CO[Si](c1ccccc1)(C(C)(C)C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CCO)S3)[nH]c12
Reaction time: 1 h
Yield: 26.1 %

Procedure:
Ethyl (2-{7-(2-{[di-tert-butyl(phenyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (500 mg) was dissolved in tetrahydrofuran (20 mL), lithium borohydride (21 mg) was added under ice-cooling, and the mixture was stirred for 1 hr. Lithium borohydride (28 mg) was added again to the reaction solution, and the mixture was further stirred at room temperature for 1 hr, and then at 50° C. for 7 hr. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=20:80 to 70:30, volume ratio) to give the title compound (123 mg, yield 55%) as a yellow oil. MS 729 (MH+).
Reaction SMILES: C([N:3](CC)CC)C.[CH:8]1([O:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2/[CH:22]=[CH:23]/[C:24]2[N:28]([C:29]3[N:34]=[N:33][C:32]([C:35](O)=[O:36])=[CH:31][CH:30]=3)[C:27]3[CH:38]=[CH:39][CH:40]=[CH:41][C:26]=3[N:25]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1.ClC(OCC)=O.N>C1COCC1>[CH:8]1([O:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2/[CH:22]=[CH:23]/[C:24]2[N:28]([C:29]3[N:34]=[N:33][C:32]([C:35]([NH2:3])=[O:36])=[CH:31][CH:30]=3)[C:27]3[CH:38]=[CH:39][CH:40]=[CH:41][C:26]=3[N:25]=2)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCN(CC)CC
Reactant: COc1cccc(/C=C/c2nc3ccccc3n2-c2ccc(C(=O)O)nn2)c1OC1CCCC1
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: COc1cccc(/C=C/c2nc3ccccc3n2-c2ccc(C(N)=O)nn2)c1OC1CCCC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
This compound was prepared by adding triethylamine (66.44 mg, 0.657 mmol) to the stirred solution of Step 1 product (200 mg, 0.43 mmol) in dry THF (5 ml) under nitrogen atmosphere. Ethyl chloroformate (71.40 mg, 0.657 mmol) was added to the reaction mixture which was cooled to −10° C., after a time interval of 30 minutes aqueous ammonia (2 ml, 25%) was added and the reaction mixture was stirred for 30 minutes. Reaction mixture was quenched with water to get off-white solid which was filtered, washed with diethylether and dried under vaccum to get 131 mg of yellow solid.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C@H:16]1[NH:38][CH2:37][C:20]2=[C:21]3[C:25](=[CH:26][CH:27]=[C:19]2[O:18][CH2:17]1)[N:24]([S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:23]=[CH:22]3.C=O>C1COCC1>[CH3:1][N:38]1[CH2:37][C:20]2=[C:21]3[C:25](=[CH:26][CH:27]=[C:19]2[O:18][CH2:17][C@H:16]1[CH3:15])[N:24]([S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:29])=[O:30])[CH:23]=[CH:22]3
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[C@@H]1COc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2CN1
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1COc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2CN1C
Reaction time: 0.33 h
Yield: 38.7 %

Procedure:
Sodium triacetoxyborohydride (7.5 mg, 0.040 mmol) was added to a solution of (3R)-3-methyl-8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole (Example 73, 0.010 g, 0.029 mmol) and formaldehyde (37 wt. % in H2O, 0.020 mL, 0.25 mmol) in THF (1 mL). The mixture was stirred for 20 minutes, evaporated and the crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a white solid (4 mg) in the form of the trifluoroacetate salt. MS m/z 357 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([CH:10]([OH:13])[CH2:11][CH3:12])[C:7]([C:14]([F:17])([F:16])[F:15])=[CH:6][C:5]=1[NH:18]C(=O)C.O.[C:24]1(C)[CH:29]=CC(S(O)(=O)=O)=C[CH:25]=1>C(O)CC.O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([CH:10]([O:13][CH2:25][CH2:24][CH3:29])[CH2:11][CH3:12])[C:7]([C:14]([F:15])([F:16])[F:17])=[CH:6][C:5]=1[NH2:18]
Reactant: CCC(O)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCCOC(CC)c1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 240 h
Yield: 139.2 %

Procedure:
A solution of 2-acetylamino-5-(1-hydroxy-propyl)-4-trifluoromethyl-benzoic acid methyl ester (200 mg, 0.626 mmol) in 1-propanol (2 mL) at r.t. was treated with p-toluenesulfonic acid monohydrate (38 mg, 0.198 mmol) and the reaction was stirred for 10 d at r.t. The reaction mixture was diluted with water and EtOAc and basified to pH 8 with sat. aq KHCO3. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (20 g silica gel, EtOAc/hexanes (0:1→3:7)) to give the title product (88 mg, 44% yield) as light yellow oil. ESI-MS: m/z 320 [M+H]+, m/z 318 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([O:9][CH2:10][CH3:11])[C:7]=1[I:8]>ClCCl.O=[Mn]=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([O:9][CH2:10][CH3:11])[C:7]=1[I:8])[CH:12]=[O:13]
Reactant: CCOc1cc(CO)cc(N)c1I
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C=O)cc(N)c1I
Yield: 64.5 %

Procedure:
To a solution of (3-amino-5-ethoxy-4-iodo-phenyl)-methanol (4.9 g, 16.72 mmol, 1.0 equiv) in dichloromethane (100 mL) was added activated MnO2 (7.27 g, 83.59 mmol, 5.0 equiv) and the reaction mixture heated to reflux for 3 h. Filtration through Hyflo Super Cel, concentration by evaporation under reduced pressure and purification with column chromatography on silica eluting with hexane/ethyl acetate (3:1) yielded 3.14 g (60%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.37 (t, J=7.0 Hz, 3H), 4.15 (q, J=7.0 Hz, 2H), 4.49 (d, J=5.6 Hz, 2H), 5.21 (t, J=5.6 Hz, 1H), 6.82 (s, 1H), 6.85 (s, 1H), 11.64 (br s, 1H). 13C NMR (75 MHz, DMSO): δ 14.61, 62.89, 64.26, 100.74, 106.46, 117.80, 137.50, 142.74, 144.05, 154.54. MS (ISP): 291.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>C(Cl)Cl>[CH2:19]([S:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)(=[O:23])=[O:22])[CH3:20]
Reactant: CCS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a solution of 16.5 g (0.1 mol) of ethyl 4-aminobenzoate and 16 g (0.2 mol) of pyridine in 200 mL of methylene chloride cooled to 0° C. add dropwise 13 g (0.1 mol) of ethanesulfonyl chloride. After the addition is complete stir the mixture at 20° C. for 4 hr. After this time extract the mixture with three 100 mL portions of 1N sodium hydroxide. Heat the basic extracts at reflux for 2 hr, cool to 0°-10° C. and carefully add 60 mL of concentrated hydrochloric acid. Collect the resulting precipitate to obtain the title compound.
Reaction SMILES: CC([PH+](C(C)(C)C)CCCS([O-])(=O)=O)(C)C.[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[N:22][CH:23]=1.Br[C:28]1[CH:29]=[CH:30][C:31]2[O:42][C:41]3([CH2:47][CH2:46][CH:45]([O:48][CH3:49])[CH2:44][CH2:43]3)[C:34]3([N:38]=[C:37]([NH2:39])[C:36]([CH3:40])=[N:35]3)[C:32]=2[CH:33]=1.CC1CCCO1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl.CCOC(C)=O.O>[Cl:17][C:18]1[CH:19]=[C:20]([C:28]2[CH:29]=[CH:30][C:31]3[O:42][C:41]4([CH2:43][CH2:44][CH:45]([O:48][CH3:49])[CH2:46][CH2:47]4)[C:34]4([N:38]=[C:37]([NH2:39])[C:36]([CH3:40])=[N:35]4)[C:32]=3[CH:33]=2)[CH:21]=[N:22][CH:23]=1
Reactant: COC1CCC2(CC1)Oc1ccc(Br)cc1C21N=C(C)C(N)=N1
Reactant: OB(O)c1cncc(Cl)c1
Agent: Cl[Pd]Cl
Agent: CC(C)(C)[PH+](CCCS(=O)(=O)[O-])C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CC1CCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC1CCC2(CC1)Oc1ccc(-c3cncc(Cl)c3)cc1C21N=C(C)C(N)=N1
Temperature: 90 °C
Yield: 54.8 %

Procedure:
Sodium tetrachloropalladate (II) (2.294 mg, 7.80 μmol), 3-(di-tert-butylphosphonium)propane sulfonate (4.19 mg, 0.02 mmol), 5-chloropyridin-3-ylboronic acid (25.8 mg, 0.16 mmol) and 5′-bromo-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine (Example 29, 59 mg, 0.16 mmol), was added to a vial. 2-Methyl-tetrahydrofuran (1 mL) and 2 M aq. K2CO3 (0.234 mL, 0.47 mmol) was added and the mixture was degassed by bubbling nitrogen gas through the solution. The vial was sealed and heated in a microwave reactor at 90° C. for 30 min and the crude mixture was combined with a second reaction from 20 mg (0.05 mmol) of 5′-bromo-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine. Water (5 mL) and EtOAc (5 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (5 mL) and the combined organic layers were dried over MgSO4, filtered and evaporated. Purification by flash chromatography using a 0-10% gradient of MeOH, containing 1.2% 7M NH3 in MeOH, in DCM afforded 36 mg of the title compound (56% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.22 (m, 1 H), 1.46 (m, 3 H), 1.81 (m, 2 H), 1.97 (m, 2 H), 2.21 (s, 3 H), 3.10 (m, 1 H), 3.22 (s, 3 H), 6.71 (br. s., 2 H), 7.01 (m, 2 H), 7.61 (dd, 1 H), 8.08 (t, 1 H), 8.51 (d, 1 H), 8.72 (d, 1 H); MS (APCI+) m/z 411 [M+H]+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Product: CCS(=O)(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, off-white solid (18 mg, 27%), MS (ISP) m/z=423.3 [(M+H)+], mp 190° C., was prepared in accordance with the general method of example 26 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) and ethanesulfonyl chloride.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)=O)=[CH:6][CH:5]=1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[OH:31]/[N:30]=[C:12](/[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1)\[CH2:11][C@H:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:2][CH3:1])=[O:28])=[CH:5][CH:6]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]
Reactant: CNC(=O)c1ccc([C@@H](CC(=O)c2ccnc(C)c2)c2ccccc2C)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CNC(=O)c1ccc([C@@H](C/C(=N\O)c2ccnc(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 132, step 6, from N-methyl-4-[(R)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-benzamide and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a colourless oil, MS (ESI+): m/z=388.2 ([M+H]+).
Reaction SMILES: [C:1](=[O:38])([O:8][CH:9]1[CH2:13][CH:12]([OH:14])[C@H:11]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH3:25])=[O:22])[C@H:10]1/[CH:26]=[CH:27]/[C@@H:28]([OH:37])[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:2][CH2:3][CH2:4][CH2:5][CH2:6]Cl.[I-:39].[Na+]>CC(C)=O>[C:1](=[O:38])([O:2][CH2:3][CH2:4][CH2:5][CH2:6][I:39])[O:8][CH:9]1[CH2:13][CH:12]([OH:14])[C@H:11]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH3:25])=[O:22])[C@H:10]1/[CH:26]=[CH:27]/[C@@H:28]([OH:37])[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCNC(=O)CCC/C=C\C[C@H]1C(O)CC(OC(=O)OCCCCCl)[C@@H]1/C=C/[C@@H](O)CCc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCNC(=O)CCC/C=C\C[C@H]1C(O)CC(OC(=O)OCCCCI)[C@@H]1/C=C/[C@@H](O)CCc1ccccc1
Yield: 79.7 %

Procedure:
4-Chlorobutyl (2R,3R)-3-[(2Z)-7-(ethylamino)-7-oxohept-2-en-1-yl]-4-hydroxy-2-[(1E,3S)-3-hydroxy-5-phenylpent-1-en-1-yl]cyclopentyl carbonate (g-1; 25 mg, 0.045 mmol) was dissolved in acetone (0.9 mL). Sodium iodide (68 mg, 0.45 mmol) was added to the solution. The mix was microwaved at 135° C. for 35 mins and then concentrated under reduced pressure. The residue was dissolved in EA+water. EA phase was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated to give 23 mg (80%) crude iodide g-2, which was used immediately without further purification.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38]S(CC1C=CC=CC=1)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:49][C:50]([F:67])([F:66])[C:51]1[CH:52]=[C:53]([CH:59]=[C:60]([C:62]([F:65])([F:64])[F:63])[CH:61]=1)[CH2:54][S:55](Cl)(=[O:57])=[O:56]>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:55]([CH2:54][C:53]1[CH:52]=[C:51]([C:50]([F:67])([F:66])[F:49])[CH:61]=[C:60]([C:62]([F:65])([F:64])[F:63])[CH:59]=1)(=[O:57])=[O:56])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 79 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added 3,5-bis(trifluoromethyl)benzylsulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 79% yield.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[Cl:32][C:33]1[CH:34]=[C:35]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([Cl:32])[CH:34]=3)(=[O:41])=[O:40])=[O:24])=[CH:16][CH:15]=2)[N:3]=1
Reactant: NS(=O)(=O)c1cccc(Cl)c1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3cccc(Cl)c3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 3-chlorobenzenesulfonamide: 1H-NMR (CDCl3) δ 7.91-7.90 (1H, m), 7.83-7.79 (1H, m), 7.53-7.20 (11H, m), 6.32 (1H, br.s), 3.47-3.40 (2H, m), 2.81 (2H, t, J=6.6 Hz), 2.30 (3H, s), 2.22 (3H, s).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:37][C:38]1[CH:43]=[C:42](B(O)O)[CH:41]=[CH:40][N:39]=1>>[Cl:37][C:38]1[CH:43]=[C:42]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:27][CH2:28]2)=[O:22])[CH:41]=[CH:40][N:39]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(C(=O)N5CCCCC5)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(C(=O)N4CCCCC4)CC2)n3-c2ccnc(Cl)c2)CC1
Yield: 62 %

Procedure:
The title compound was synthesized in analogy to example 5, after stirring for 3.5 days at 35° C., from {4-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carbonyl]-piperazin-1-yl}-piperidin-1-yl-methanone (example 14) and 2-chloropyridine-4-boronic acid to afford the desired product as a light-brown foam (62%). MS (ISP): 606.1 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:20]1[N:24]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:23]=[N:22][N:21]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][C:10]=1[CH2:9][C@@H:8]([NH2:7])[C:20]1[N:24]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:23]=[N:22][N:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)c1nnnn1CCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](Cc1ccc2ccccc2c1)c1nnnn1CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
((1R )-2-(2-Naphthyl)-1-(1-phenethyl-1H-tetrazol-5-yl)ethyl)carbamic acid tert-butylester (0.30 g; 0.68 mmol) was dissolved in methylene chloride (20 ml) and trifluoroacetic acid (2 ml) was added. The mixture was stirred for 3 h at RT. The solvent was removed in vacuo and the residue was dissolved in methylene chloride (50 ml) and washed with sodium hydrogencarbonate (10%; 30 ml). The organic phase was dried (Magnesium sulfate) and the solvent removed in vacuo. The residue was chromatographed on silica (2.5×15 cm) using ethyl acetate as eluent to afford 170 mg of (1R)-2-(2-naphthyl)-1-(1-phenethyl-1H-tetrazol-5-yl)ethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH3:22])[N:7]([C@@H:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH3:13])[C:8]2=[O:11])=[CH:4][CH:3]=1.Cl[C:24]1[C:29]([F:30])=[CH:28][N:27]=[CH:26][N:25]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].Cl>O1CCCC1.O.COC(C)(C)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:24]3[C:29]([F:30])=[CH:28][N:27]=[CH:26][N:25]=3)([CH3:22])[N:7]([C@@H:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH3:13])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: Fc1cncnc1Cl
Reactant: COc1ccc([C@@H](C)N2C(=O)c3cc(Br)ccc3C2C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: COc1ccc([C@@H](C)N2C(=O)c3cc(Br)ccc3C2(C)c2ncncc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
Dissolve 6-bromo-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-isoindolin-1-one (2.814 mmol, 1.014 g) in tetrahydrofuran (28 mL). Add 4-chloro-5-fluoro-pyrimidine (5.628 mmol, 518 μL) and cool to 0° C. Add potassium hexamethyldisilazide (4.502 mmol, 9 mL, 0.5 M in toluene) over 7 minutes and stir for 1 hour, then warm to ambient temperature and stir for 90 minutes. Pour into methyl-tert-butyl ether and aqueous 1 M HCl, add water and separate the layers. Wash with aqueous 1 N HCl, filter, wash with saturated aqueous sodium chloride, dry over magnesium sulfate, filter through a 2 cm pad of silica gel, and evaporate under reduced pressure to provide an oil. Purify on silica gel with 20-40% ethyl acetate/hexane to give the title compound as a foam (547 mg, 43%). ES/MS m/z: 456 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=3)[C:9]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:32][C:33]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36].C(=O)(O)[O-].[Na+]>ClCCl>[F:32][C:33]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:34]=1[C:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=3)[C:9]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:8]2)=[CH:23][CH:24]=1)=[O:36]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2cc(F)ccc12
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc(F)cc3F)cc2)c2cc(F)ccc12
Yield: 45.6 %

Procedure:
The crude ethyl 2-[1-(4-aminobenzyl)-6-fluoro-1H-indazol-3-yl]acetate (about 1.0 mmol) obtained in the last step and triethylamine (0.5 mL) were dissolved in dichloromethane (15 mL), and in an ice bath dichloromethane solution (10 mL) of 2,4-difluorobenzoyl chloride (177 mg, 1.0 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was reacted at room temperature for 16 hours. An aqueous solution of sodium bicarbonate was added to quench, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduce pressure, chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a white solid 213 mg, at a total yield over two steps of reactions of 45.6%.