Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([C:27]([N:30]5[C@H:35]([CH3:36])[CH2:34][CH2:33][CH2:32][C@@H:31]5[CH3:37])=[N:28][N:29]=4)[CH:26]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:38]2[CH:39]=[N:40][N:41]([CH2:43][CH2:44][OH:45])[CH:42]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:46][S:47](Cl)(=[O:49])=[O:48].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([C:27]([N:30]5[C@H:31]([CH3:37])[CH2:32][CH2:33][CH2:34][C@@H:35]5[CH3:36])=[N:28][N:29]=4)[CH:26]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:38]2[CH:39]=[N:40][N:41]([CH2:43][CH2:44][O:45][S:47]([CH3:46])(=[O:49])=[O:48])[CH:42]=2)[N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(OC3CCC(NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCO)c4)CC3)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(OC3CCC(NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCOS(C)(=O)=O)c4)CC3)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A mixture of Intermediate 17b (0.75 g, 1.21 mmol), methanesulfonyl chloride (140 μL, 1.81 mmol) and DIPEA (0.63 mL, 3.62 mmol) in DCM (15 mL) was stirred at RT for 1 h. The reaction mixture was partitioned between DCM and water. The organic layer was washed with brine, separated through a phase separating cartridge and concentrated in vacuo to afford the title compound (0.82 g, 97%). LCMS (Method 3): Rt 3.59 min, m/z 697 [MH+].
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([S:13]([NH:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[NH2:19])(=[O:15])=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([S:13]([NH:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[NH:19][C:34]([NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[Br:26])=[O:35])(=[O:14])=[O:15])[CH:4]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:8]=1
Reactant: O=C=Nc1ccccc1Br
Reactant: Nc1ccccc1NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1ccccc1Br)Nc1ccccc1NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from [2-(3,5-bistrifluoromethylphenyl) sulfonylaminoaniline (591 mg, 1.5 mmol) and 2-bromophenylisocyanate (305 mg, 1.5 mmol) according to General Method B. The product was purified by flash chromatography on silica gel (ethyl acetate:hexane 30/70) (10 mg, 1%).EI-MS m/z 580 (M-H)-
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:3]1.C([O:16][C:17](=O)[CH2:18][C:19]([C:21]([F:24])([F:23])[F:22])=[O:20])C>C(O)(=O)C>[OH:20][C:19]1([C:21]([F:24])([F:23])[F:22])[CH2:18][C:17](=[O:16])[NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:5]1=2
Reactant: Cn1nc(-c2ccccc2)cc1N
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CC(=O)O
Product: Cn1nc(-c2ccccc2)c2c1NC(=O)CC2(O)C(F)(F)F
Reaction time: 2.5 h
Yield: 15.5 %

Procedure:
2-Methyl-5-phenyl-2H-pyrazol-3-ylamine (vii) (100 mg, 0.58 mmol) was dissolved in glacial acetic acid (1 mL), ethyl-4,4,4-trifluoracetoacetate (0.13 mL, 0.85 mmol) was added at RT and stirring was continued for 2.5 h at 120° C. The mixture was evaporated to dryness and the isomeric mixture was directly purified by preparative HPLC (Agilent 1100 Series, Chromolith prep RP-18e, 100-25). A colorless solid (29 mg, 0.09 mmol, 16%) was obtained, characterized as compound (viii).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([F:4])[CH3:3]>C1COCC1.CO.[Pt](=O)=O>[F:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(F)(F)c1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
Platinum(IV) oxide (45 mg) was added to a mixture of 9-(4-(1,1-difluoroethyl)phenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (207 mg) in THF (dry) (120 mL) and MeOH (120 mL). The mixture was stirred at room temperature under hydrogen overnight. Activated carbon powder was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (80.4 mg) as colorless crystals.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32][CH:33]([N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH3:34])=[CH:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[Br:41]C(F)(F)C(F)(F)Br>O1CCCC1>[Br:41][C:24]1[N:23]([C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:22])[C:31]2[C:26]([C:25]=1[CH2:32][CH:33]([N:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[CH3:34])=[CH:27][CH:28]=[CH:29][CH:30]=2
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: CC(Cc1cn(C(=O)OC(C)(C)C)c2ccccc12)N1CCCCC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(Cc1c(Br)n(C(=O)OC(C)(C)C)c2ccccc12)N1CCCCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 34 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (5.3 ml, 31.6 mmol) in anhydrous tetrahydrofuran (50 ml) cooled to −78° C. under an atmosphere of nitrogen was added in a dropwise manner n-butyllithium (12.6 ml of a 2.5M solution in hexanes, 31.6mmol). On complete addition the reaction mixture was allowed to warm to 0° C. and stirred at this temperature for 5 minutes. Re-cooled to −78° C. and a solution of the 1-tert-butoxycarbonyl-3-[2-(piperidin-1-yl)prop-1-yl]-1H-indole in anhydrous tetrahydrofuran (50 ml) added via a cannula at such a rate that the temperature did not rise above −50° C. On complete addition the reaction mixture was stirred at −78° C. for 4 hours then 1,2-dibromotetrafluoroethane (3.78 ml, 31.6 mmol) added; the reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was removed in vacuo and the residue purified by column chromatography on silica eluting with 2% CH3OH in CH2Cl2+0.5% 0.88 ammonia to give the title compound (1.5 g, 34%); δH (360 MHz; CDCl3) 1.32 (3H, d, J 6.7 Hz, CH3), 1.71 (9H, s, O2C(CH3)3), 2.99-3.05 (1H, m, indole CHAHB), 3.55-3.67 (1H, m, indole CHAHBCH), 3.74 (1H, d, J 13.2 Hz, indole CHAHB), 7.26-7.33 (2H, m, indole H5+H6), 7.92 (1H, dd, J 6.6 and 3.7 Hz, indole H4), 8.05 (1H, d, J 5.8 and 2.2 Hz, indole H7), piperidine protons very broad and merged into baseline; m/z (ES+) 421/423 (M++H, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][CH2:18][C:13]3(OCC[O:14]3)[CH2:12][CH2:11]2)[CH:5]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.CC(C)=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][CH2:18][C:13](=[O:14])[CH2:12][CH2:11]2)[CH:5]=1
Reactant: COC(=O)c1cccc(N2CCC3(CC2)OCCO3)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cccc(N2CCC(=O)CC2)c1
Yield: 79.3 %

Procedure:
A mixture of methyl-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-benzoate (1.80 g, 6.49 mmol) and p-toluenesulfonic acid monohydrate (123 mg, 0.649 mmol) in water (30 mL) and acetone (15 mL) was heated at reflux for 17 hours. The organic solvent was removed in vacuo and the aqueous mixture was extracted with dichloromethane. The organic extract was washed with saturated NaHCO3(aq.), dried (MgSO4), filtered and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 3:2 hexanes:EtOAc) followed by concentration gave the title compound as a yellow oil (1.20 g, 79%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:36][C:37]1[N:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[NH2:28][CH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:40]3[CH:41]=[N:42][C:37]([CH3:36])=[CH:38][CH:39]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:12][CH:11]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@H](CN)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (R)-tert-butyl ((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate (Stage 105.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition 6) tR=0.81 min, m/z=472.0 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[CH:10]3[CH2:19][CH2:18][CH2:17][CH:11]3[C:12](=O)[NH:13][C:14]=2[CH:15]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[CH:10]3[CH2:19][CH2:18][CH2:17][CH:11]3[C:12](=[S:29])[NH:13][C:14]=2[CH:15]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2cc(-c3ccco3)ccc2C2CCCC12
Product: S=C1Nc2cc(-c3ccco3)ccc2C2CCCC12
Yield: 98 %

Procedure:
Analogously to Example 4, 7-(2-furanyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (100 mg, 0.39 mmol) is reacted with Lawesson's reagent (404 mg, 1.0 mmol) to form 103 mg (98%) of product.
Reaction SMILES: N1N[N:3]=[N:4][C:5]=1[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][CH:7]=1.[C:18](Cl)(=[O:28])[C:19]1[CH:27]=[CH:26][CH:25]=[C:21]([C:22](Cl)=[O:23])[CH:20]=1.O>N1C=CC=CC=1>[N:11]1[C:6]([C:5]2[O:28][C:18]([C:19]3[CH:27]=[CH:26][CH:25]=[C:21]([C:22]4[O:23][C:5]([C:6]5[N:11]=[C:10]([C:12]6[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=6)[CH:9]=[CH:8][CH:7]=5)=[N:4][N:3]=4)[CH:20]=3)=[N:3][N:4]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: c1ccc(-c2cccc(-c3nn[nH]n3)n2)nc1
Solvent: O
Solvent: c1ccncc1
Product: c1ccc(-c2cccc(-c3nnc(-c4cccc(-c5nnc(-c6cccc(-c7ccccn7)n6)o5)c4)o3)n2)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
0.63 g of 6-(2H-tetrazol-5-yl)-2,2′-bipyridine was dissolved in 10 ml of dehydrated pyridine, and 0.29 g of isophthaloyl dichloride was gradually added. Temperature was elevated to 115° C., and stirring was conducted for 6 hours under reflux. After cooling to room temperature, the reaction solution was poured into water, and a precipitated white solid was taken out by suction filtration, and washed with water. The solid obtained was vacuum dried at 80° C. for 20 hours, and purified with column chromatography (carrier: silica gel, eluting solution: chloroform/methanol=20/1) to obtain 0.62 g (yield 81%) of BpyOXDm. The product was identified with NMR analysis. The result of NMR analysis (CDCl3) was as follows. 9.071 ppm (1H), 8.639-8.714 ppm (6H), 8.325-8.477 ppm (4H), 8.037 ppm (2H), 7.756-7.854 ppm (3H), 7.330 ppm (2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[OH:10][C:8]([C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)c1cccc(O)c1
Reaction time: 2 h

Procedure:
3′-Hydroxyacetophenone (500 mg) was dissolved in tetrahydrofuran (10 ml), and the solution was slowly added dropwise with a 3 M solution of methylmagnesium bromide in diethyl ether (3.7 ml) under ice cooling. The mixture was stirred at the same temperature for 2 hours, and then added with saturated aqueous ammonium chloride, the mixture was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1 to 1:1) to obtain the title compound (224.3 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([F:28])([F:27])([F:26])([F:25])[F:24])[CH:18]=2)=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[N+:29]([O-])([OH:31])=[O:30]>>[CH3:1][S:2]([C:5]1[C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:29]([O-:31])=[O:30])=[C:19]([S:23]([F:27])([F:26])([F:28])([F:24])[F:25])[CH:18]=2)=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Oc2cccc(S(F)(F)(F)(F)F)c2)cc1C
Product: COC(=O)c1cc(S(C)(=O)=O)c(Oc2ccc([N+](=O)[O-])c(S(F)(F)(F)(F)F)c2)cc1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3.50 g of methyl 5-methanesulfonyl-2-methyl-4-(3-pentafluorosulfanylphenoxy)-benzoate were dissolved in 100 ml of 90% HNO3 at −40° C. The reaction mixture was stirred at this temperature for 10 minutes and then poured into 800 g of ice. This mixture was stirred for 10 minutes and then the product was filtered off with suction. 3.89 g of a pale yellow solid were obtained, mp 145-148° C. (with decomposition). Rf (DIP)=0.09
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37]1([N:47]=[C:48]=[S:49])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>CN(C)C=O>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:22]2[CH:31]=[CH:32][C:19]([O:18][CH2:17][C:15]3[N:14]([CH3:33])[C:13]4[CH:34]=[C:9]([O:8][C:7]5[CH:35]=[CH:36][C:4]([NH:3][C:48]([NH:47][C:37]6[C:46]7[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=7)[CH:40]=[CH:39][CH:38]=6)=[S:49])=[CH:5][CH:6]=5)[CH:10]=[CH:11][C:12]=4[N:16]=3)=[CH:20][CH:21]=2)[S:28]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: S=C=Nc1cccc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=S)Nc4cccc5ccccc45)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A mixture of 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), 1-naphthyl isothiocyanate (148 mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (8 ml) was stirred at room temperature for 1 hour and then allowed to stand overnight. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3:2→2:1→4:1→1:0 as the eluant to afford the title compound (301 mg, mp 185.8-188.1° C.).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:5])C.O.[Li].CO.Cl>O>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH:7]2[CH2:8][CH:6]2[C:4]([OH:5])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1CC1c1ccc(F)cc1
Agent: Cl
Agent: [Li]
Solvent: CO
Solvent: O
Product: O=C(O)C1CC1c1ccc(F)cc1
Temperature: 80 °C
Yield: 109.5 %

Procedure:
In a round flask was charged with 2-(4-fluoro-phenyl)-cyclopropanecarboxylic acid ethyl ester (1700 mg, 8.16 mmol), lithium monohydrate (1370 mg, 32.7 mmol), methanol (25 mL) and water (10 mL). The mixture was heated at 80° C. for 2 hours. The reaction mixture was rotavaped. The residue was neutralized with 4N hydrochloric acid and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over sodium sulfate and evaporated to give 1.61 grams of white solid as desired product. LC-MS m/e 179 (MH−).
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]2[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C[OH:40].O>O1CCOCC1>[OH:1][C:2]1[CH:38]=[CH:37][C:5]2[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26]([CH2:27][CH2:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:32])([F:33])[F:34])=[O:40])[C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CO
Reactant: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCSCCCC(F)(F)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[8-(4,4,5,5,5-pentafluoropentylthio)octyl]-2,3-dihydro-4H-benzopyran (53 mg, 0.095 mmol) was dissolved in 1,4-dioxane (1.2 ml), methanol (1.2 ml) and water (0.3 ml). NaIO4 (24 mg, 0.11 mmol) was added dropwise thereto, and the reaction mixture was stirred for 8 hours at room temperature and then filtered. The filtrate was concentrated and the residue was subjected to column chromatography (n-hexane:ethyl acetate=2:1) to obtain 38 mg (yield: 70%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Br[CH2:13][C:14]#[N:15]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:13][C:14]#[N:15])[CH2:8][CH2:7]1
Reactant: N#CCBr
Reactant: COCCCC1CCNCC1
Product: COCCCC1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of 4-(3-Methoxy-propyl)-piperidine (commercially available from ChemBridge Corporation) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=197.2; 1HNMR(DMSO-d6) 3.65 (s, 2H), 3.30 (t, 2H), 3.00 (s, 3H), 2.75-2.70 (m, 2H), 2.10-2.00 (m, 2H), 1.65-1.40 (m, 4H), 1.20-1.00 (m, 5H).
Reaction SMILES: C(S([C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=2)[CH:14]=[C:13]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][N:32]=3)[CH2:27][C@H:26]2[CH3:38])[N:12]=1)(=O)=O)C1C=CC=CC=1.[CH3:39][CH:40]1[CH2:44][CH2:43][CH2:42][NH:41]1>O1CCOCC1>[Cl:24][C:19]1[CH:18]=[C:17]([C:15]2[CH:14]=[C:13]([N:25]3[CH2:30][CH2:29][N:28]([C:31]4[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][N:32]=4)[CH2:27][C@H:26]3[CH3:38])[N:12]=[C:11]([N:41]3[CH2:42][CH2:43][CH2:44][CH:40]3[CH3:39])[N:16]=2)[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: CC1CCCN1
Reactant: C[C@@H]1CN(c2ncccc2Cl)CCN1c1cc(-c2ccc(F)c(Cl)c2)nc(S(=O)(=O)Cc2ccccc2)n1
Solvent: C1COCCO1
Product: CC1CCCN1c1nc(-c2ccc(F)c(Cl)c2)cc(N2CCN(c3ncccc3Cl)C[C@H]2C)n1
Reaction time: 72 h

Procedure:
Dissolve 2-(benzylsulfonyl)-4-(3-chloro-4-fluorophenyl)-6-((R)-4-(3-chloropyridin-2-yl)-2-methylpiperazin-1-yl)pyrimidine (57 mg, 0.1 mmol) and 2-methylpyrrolidine (0.5 mmol) in dioxane (1.0 mL) under nitrogen atmosphere and beat at 110° C. for 72 hours. Concentrate under vacuum to afford crude product and purify by flash column chromatography using 5% EtOAc/hexane to afford the title product as white amorphous solid. NMR (CDCl3) δ 1.31 (3H, d, J=1.5), 1.41 (3H, dd), 1.69 (1H, m), 1.9 (1H, m), 2.0 (2H, m), 2.98 (2H, m), 3.39 (1H, m), 3.65 (2H, m), 3.82 (2H, m), 4.35 (2H, m), 4.68 (1H, m), 6.22 (1H, s), 6.86 (1H, m), 7.16 (1H, t), 7.61 (1H, d, J=1.6), 7.88 (1H, m), 8.07 (1H, m), 8.20 (1H, m). Mass spec m/z=501.13.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([O:25][CH2:26][C:27]([NH2:29])=[O:28])=[CH:14][CH:13]=2)(C)(C)C.Cl>C(OCC)(=O)C>[NH2:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([O:25][CH2:26][C:27]([NH2:29])=[O:28])=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(OCC(N)=O)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(OCC(N)=O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To a solution of tert-butyl[6-(2-amino-2-oxoethoxy)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.38 g, 0.8 mmol) in ethyl acetate (5 mL) was added a solution of 4N hydrogen chloride in ethyl acetate (5 mL) and the obtained solution was stirred at room temperature for 2 h. The reaction, mixture was concentrated under reduced pressure, and the residue was suspended in 1N aqueous sodium hydroxide solution. The suspension was stirred at room temperature for 10 min, and the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitated crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-[[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]oxy]acetamide (0.19 g, 63.3%) as crystals.
Reaction SMILES: Cl[N:2]1[CH2:7][N:6]([NH:8][CH2:9][C:10]([CH3:28])([CH3:27])[CH2:11][C:12]2[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([OH:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=2)[CH2:5][N:4]([NH:29][CH2:30][C:31]([CH3:49])([CH3:48])[CH2:32][C:33]2[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([OH:43])=[C:35]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH:34]=2)[CH2:3]1.[CH2:50]([SH:62])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61].CC(C)=O.[OH-].[Na+]>O>[CH2:50]([S:62][N:2]1[CH2:7][N:6]([NH:8][CH2:9][C:10]([CH3:28])([CH3:27])[CH2:11][C:12]2[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([OH:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=2)[CH2:5][N:4]([NH:29][CH2:30][C:31]([CH3:49])([CH3:48])[CH2:32][C:33]2[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([OH:43])=[C:35]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH:34]=2)[CH2:3]1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]
Reactant: CC(C)(CNN1CN(Cl)CN(NCC(C)(C)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCCCCCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCSN1CN(NCC(C)(C)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CN(NCC(C)(C)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1
Reaction time: 5 h

Procedure:
10.0 g (0.014 mol) of 1-chloro-3,5-di-[3-(3,5-di-tert.butyl-4-hydroxyphenyl)-2,2-dimethylpropylamino]-s-triazine (the product of Example 64) and 2.91 g (0.044 mol) of dodecylmercaptan are initially introduced into 50 ml of acetone and 0.58 g (0.0144 mol) of sodium hydroxide, dissolved in 1 ml of water, is added at room temperature. The mixture is then heated to the point of reflux and is stirred at this temperature for 5 hours. It is then cooled, insoluble matter is filtered off and the filtrate is concentrated completely. The residue is purified through a silica gel column using toluene:methanol (98:2) as the migrating agent. The 1-dodecylmercapto-3,5-di-[3-(3,5-di-tert.butyl-4-hydroxyphenyl)-2,2-dimethylpropylamino]-s-triazine obtained in this way is produced as a yellowish resin. (Stabiliser No. 68).
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(OCC)(=O)C>[CH3:1][O:2][N:3]1[CH2:8][CH2:7][CH:6]([O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:5][CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: CON1CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CON1CCC(OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 126.3 %

Procedure:
21 g 1-Methoxy-piperidin-4-ol (from Step 1) and 19.4 g triethylamine were dissolved in 200 ml ethyl acetate, and cooled to 0° C. 15.0 g Methanesulfonyl chloride was added slowly. The resulting white suspension was stirred at 0° C. for 1 hour, then at room temperature for an additional 1 hour. Then the mixture was filtered and the solvent evaporated, yielding 34.6 g of methanesulfonic acid 1-methoxy-piperidin-4-yl ester. This material was used for the next step without further purification.