Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C@@H:14]([NH:24][C:25](=[O:31])OC(C)(C)C)CC2C=C(F)C=C(F)C=2)=[N:4]C(N2CC(O)(C)C2)=CC=1.Cl[C:33]1[N:38]=[C:37]([C@@H:39]([NH:49][C:50](=[O:67])[CH2:51][N:52]2[C:56]3[C:57]([F:62])([F:61])[C@@H:58]4[CH2:60][C@@H:59]4[C:55]=3[C:54]([C:63]([F:66])([F:65])[F:64])=[N:53]2)[CH2:40][C:41]2[CH:46]=[C:45]([F:47])[CH:44]=[C:43]([F:48])[CH:42]=2)[C:36]([C:68]2[CH:69]=[CH:70][CH:71]=[C:72]3[C:76]=2[N:75]([CH3:77])[N:74]=[C:73]3[NH:78][S:79]([CH3:82])(=[O:81])=[O:80])=[CH:35][CH:34]=1.BrC1C([C@@H](NC(=O)OC(C)(C)C)CC2C=C(F)C=C(F)C=2)=NC(Br)=CC=1>>[NH2:4][CH:3]1[CH2:14][N:24]([C:33]2[N:38]=[C:37]([C@@H:39]([NH:49][C:50](=[O:67])[CH2:51][N:52]3[C:56]4[C:57]([F:62])([F:61])[C@@H:58]5[CH2:60][C@@H:59]5[C:55]=4[C:54]([C:63]([F:66])([F:65])[F:64])=[N:53]3)[CH2:40][C:41]3[CH:46]=[C:45]([F:47])[CH:44]=[C:43]([F:48])[CH:42]=3)[C:36]([C:68]3[CH:69]=[CH:70][CH:71]=[C:72]4[C:76]=3[N:75]([CH3:77])[N:74]=[C:73]4[NH:78][S:79]([CH3:82])(=[O:81])=[O:80])=[CH:35][CH:34]=2)[C:25](=[O:31])[CH2:2]1
Reactant: CC1(O)CN(c2ccc(Br)c([C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)n2)C1
Reactant: Cn1nc(NS(C)(=O)=O)c2cccc(-c3ccc(Cl)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(Br)ccc1Br
Product: Cn1nc(NS(C)(=O)=O)c2cccc(-c3ccc(N4CC(N)CC4=O)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21

Procedure:
Compound 43B was prepared according to the method presented in the synthesis of compound 42G of Example 42 substituting N—((S)-1-(6-chloro-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (43A) for (S)-Atert-butyl (1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (42F). 1H NMR (400 MHz, methanol-d4) δ 8.69-8.34 (m, 2H), 7.91-7.67 (m, 2H), 7.38-6.89 (m, 1H), 6.93-6.52 (m, 1H), 6.48-6.14 (m, 2H), 5.39-4.92 (m, 1H), 4.84-4.70 (m, 2H), 4.69-4.33 (m, 2H), 4.27 (m, 1H), 3.48-2.72 (m, 10H), 2.62-2.28 (m, 2H), 1.61-1.27 (m, 1H), 1.08 (m, 1H). MS (m/z) 820.00[M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:34]=[C:35]([NH:39][C:40](=[O:42])[CH3:41])[CH:36]=[CH:37][CH:38]=2)[CH2:29][CH2:28]1>>[C:40]([NH:39][C:35]1[CH:34]=[C:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][CH2:24][NH:23][C:8](=[O:9])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:28][CH2:29]2)[CH:38]=[CH:37][CH:36]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 105 was prepared from triphenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.34–7.22 (m, 19H), 6.91 (d, 1H, J=7.6 Hz), 6.30 (t, 1H, J=5.6 Hz), 3.43 (dd, 2H, J=6.4, 12.0 Hz), 2.87 (d, 2H, J=12.0 Hz), 2.42 (m, 1H), 2.30 (t, 2H, J=6.8 Hz), 2.17 (s, 3H), 1.93 (t, 2H, J=11.6 Hz), 1.74–1.66(m, 4H), 1.60–1.50 (m, 2H); ESMS m/e: 546.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)=[C:7]2[N:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:4]=1.[NH4+].[OH-].Cl.O.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C1COCC1>[F:32][C:2]([F:1])([F:31])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:37](=[O:39])[CH3:38])=[N:18][CH:19]=3)=[C:7]2[N:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=2)[CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A mixture of 5-[7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-ylethynyl]-pyridin-2-ylamine (example 55) (2.00 g, 4.47 mmol) in acetic anhydride (15 mL) was stirred at 120° C. for 1 h. Cooled to 60° C., concentrated in vacuum to dryness (water bath temperature 60° C.) and dried in HV to give an orange solid (2.465 g, 113%, mixture of mono- and diacetylated compound). Suspended in THF (30 mL) at 23° C., added NH4OH (25%, 13.3M, 1.0 mL, 13.4 mmol) and stirred at 23° C. for 1.5 h resulting in a clear red solution, adjusted pH with 1N HCl until pH 1, added H2O (total volume 200 mL), filtered the precipitate off, washed with H2O and dried in HV, followed by trituration with ether and drying in HV to give the title compound as an orange solid (2.130 g, 97%). MS [ISN] 488.1 [(M−H)−]; mp 266° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:12][CH3:13])=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:15].[K+].[OH-:20].[Na+]>>[C:1]([C:5]1[C:6]([O:12][CH3:13])=[C:7]([CH:8]=[CH:9][CH:10]=1)[C:11]([OH:15])=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: [OH-]
Reactant: COc1c(C)cccc1C(C)(C)C
Agent: [K+]
Agent: [Na+]
Product: COc1c(C(=O)O)cccc1C(C)(C)C

Procedure:
A mixture of 0.01 mole of 3-t-butyl-2-methoxytoluene, 0.01 mole of potassium permanganate, and 100 ml. of 1 N sodium hydroxide solution is heated to reflux and another 0.01 mole of potassium permanganate is added each hour until a total of 0.05 mole has been added (4 hours). After another 2 hours of reflux the unreacted starting material is steam distilled. Ethanol is added to the residue to decompose excess permanganate and mixture is filtered hot. Acidification with sulfuric acid of the filtrate causes precipitation of the product which is collected, washed with water and dried to give 3-t-butyl-2-methoxybenzoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40]>>[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[S:39]([N:19]1[CH2:18][CH:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:16])[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:20]1=[O:28])(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cccc(Cl)c4Cl)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 2,3-dichlorobenzenesulfonyl chloride to give the title compound as a colorless solid. MS: 588.7 ([M+H]+)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1ccccc1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), phenylboronic acid (65 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-phenyl-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10].[NH2:15][C:16]1[S:20][N:19]=[C:18]([CH3:21])[N:17]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([OH:33])[CH:31]=2)[N:26]=[CH:25][N:24]=1>>[Cl:8][C:7]1[C:2]([O:33][C:30]2[CH:31]=[C:32]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][N:24]=[C:23]3[NH:15][C:16]2[S:20][N:19]=[C:18]([CH3:21])[N:17]=2)=[C:3]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1nsc(N)n1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: CN(C)S(=O)(=O)c1cccc(Cl)c1Cl
Product: Cc1nsc(Nc2ncnc3ccc(Oc4c(Cl)cccc4S(=O)(=O)N(C)C)cc23)n1

Procedure:
The compound of Example 136 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2,3-dichloro-N,N-dimethyl-benzenesulfonamide, 5-amino-3-methyl-[1,2,4]thiadiazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([N:11]([CH:13]([CH3:15])[CH3:14])C)[CH2:8][CH2:7][C@@H:6]1[N:16]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=O)OCC2C=CC=CC=2)[C:17]1=[O:32])(=[O:3])[CH3:2].ClC1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([C:44]([F:47])([F:46])[F:45])[CH:42]=2)[N:37]=[CH:36][N:35]=1.C(N(C(C)C)CC)(C)C.[CH3:57][OH:58]>[Pd]>[CH:13]([NH:11][C@H:9]1[CH2:10][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C@@H:6]([N:16]2[CH2:20][CH2:19][C@H:18]([NH:21][C:22]3[C:39]4[C:38](=[CH:43][CH:42]=[C:41]([C:44]([F:45])([F:46])[F:47])[CH:40]=4)[N:37]=[CH:36][N:35]=3)[C:17]2=[O:32])[CH2:7][CH2:8]1)([CH3:14])[CH3:15].[C:57]([OH:3])([C:44]([F:47])([F:46])[F:45])=[O:58]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: CO
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H]1C[C@H](NC(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
To a solution of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (30 mg, 0.07 mmol; see Example 1, Step 8) in methanol (3 mL) was added 10% Pd/C (30 mg of 50% wet catalyst). The flask was evacuated and back-filled with hydrogen from a hydrogen balloon. The mixture was stirred at room temperature for 1.5 h under 1 atm hydrogen and then the catalyst was removed by filtration. The filtrate was concentrated in vacuo. The residue was dissolved in isopropanol (3 mL) and charged sequentially with 4-chloro-6-(trifluoromethyl)quinazoline (19.4 mg, 1.2 eq) and diisopropylethylamine (18 mg, 2 eq). The mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The residue was purified by preparative reverse-phase HPLC to provide the title compound as its TFA salt (47 mg, 93%). LC/MS found [M+H]+=493. 1H-NMR (400 MHz, CD3OD), δ ppm: 8.90 (1H, s), 8.81 (1H, s), 8.25-8.29 (1H, m), 7.96 (1H, d, J=8.65 Hz), 5.44 (1H, t, J=9.92 Hz), 4.42 (1H, d, J=2.54 Hz), 4.15-4.24 (1H, m), 3.90 (1H, t, J=8.65 Hz), 3.70-3.79 (1H, m), 3.46-3.62 (2H, m), 2.56-2.67 (1H, m), 2.33-2.47 (1H, m), 1.70-2.23 (9H, m), 1.35 (6H, d, J=6.10 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(N(CC)CC)C.[C:20](Cl)(Cl)=[S:21].[NH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][C:30]([N:39]([CH3:41])[CH3:40])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>C(Cl)(Cl)Cl>[CH3:41][N:39]([CH3:40])[C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:31][CH2:32][CH:27]([CH2:26][CH2:25][NH:24][C:20]([NH:1][CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[S:21])[CH2:28][CH2:29]1
Reactant: S=C(Cl)Cl
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(CCN)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)C1(c2ccccc2)CCC(CCNC(=S)NCCc2c[nH]c3ccccc23)CC1
Reaction time: 16 h

Procedure:
Tryptamine (320 mg, 2 mmole) was dissolved in dry chloroform (10 ml) and combined with triethylamine (555 μl, 4 mmole). Thiophosgene (153 μl, 2 mmole) was added to this mixture. After a reaction time of 16 h, [4-(2-aminoethyl)-1-phenylcyclohexyl]dimethylamine (491 mg, 2 mmole) was added and stirring continued for a further 16 h at RT. Working up was performed by extracting the batch with saturated NaHCO3 solution (3×20 ml). The organic phase was dried with Na2SO4 and evaporated. The product was a mixture of the expected diastereoisomers and could be purified by column chromatography [silica gel 60 (100 g); MeOH (1000 ml)]. The more polar diastereoisomer of 1-[2-(4-dimethylamino-4-phenylcyclohexyl)ethyl]-3-[2-(1H-indol-3-yl)ethyl]thiourea was obtained as a colorless oil in a yield of 330 mg (36%). The more nonpolar diastereoisomer of 1-[2-(4-dimethylamino-4-phenylcyclohexyl)ethyl]-3-[2-(1H-indol-3-yl)ethyl]thiourea was obtained as a colorless oil in a yield of 230 mg (25%).
Reaction SMILES: Cl.CS[C:4]1[N:9]=[C:8]([O:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:5]=1.O[O:30][S:31]([O-:33])=O.[K+].[C:35]([O-])([O-])=O.[Na+].[Na+]>CCOCC.CCOC(C)=O>[CH3:35][S:31]([C:4]1[N:9]=[C:8]([O:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH:7]=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=2)[N:5]=1)(=[O:33])=[O:30]
Reactant: CSc1nc(OCCN2CCCCC2)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: O=S([O-])OO
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1nc(OCCN2CCCCC2)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 90 %

Procedure:
A solution of HCl (720 μl, 2N in Et2O, 1.43 mmol) was added to a solution of 2-methylthio-4-(2-piperidin-1-yl-ethoxy)-6-(3-trifluoromethyl-phenyl)-pyrimidine (190 mg, 0.48 mmol) in Et2O (1 ml). The solvent was evaporated and the precipitate was dissolved in a mixture of water (1 ml) and acetonitrile (6 ml). Oxone (586 mg, 0.96 mmol) was added and the reaction mixture was stirred at room temperature for 60 h. An aqueous Na2CO3 saturated solution (6 ml) was added (pH=9) followed by AcOEt. The organic layer was washed with Na2SO3, with brine, dried over MgSO4 and concentrated under reduced pressure to give the above titled compound: 184 mg (yield: 90%) which was used in the next step without any further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32].Br[CH2:40][CH:41]([CH3:43])[CH3:42].C(N(C(C)C)CC)(C)C.[I-].[Na+]>C(#N)C>[CH2:40]([N:36]1[CH2:35][CH2:34][N:33]([C:31]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][C:7]([O:11][C:12]2[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=4)=[CH:14][CH:13]=2)=[CH:8][CH:9]=3)=[O:32])[CH2:38][CH2:37]1)[CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)CBr
Reactant: Cn1c(C(=O)N2CCNCC2)cc2cc(Oc3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cn3)ccc21
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)CN1CCN(C(=O)c2cc3cc(Oc4ccc(NC(=O)c5ccc(C(F)(F)F)cc5)cn4)ccc3n2C)CC1
Yield: 36.1 %

Procedure:
To a solution of N-{6-[1-methyl-2-(piperazine-1-carbonyl)-1H-indol-5-yloxy]pyridin-3-yl}-4-trifluoromethyl-benzamide (250 mg, 0.478 mmol) in acetonitrile (2 mL) were added 1-bromo-2-methylpropane (0.123 mL, 1.13 mmol), diisopropylethylamine (0.25 mL, 1.44 mmol) and sodium iodide (180 mg, 1.2 mmol). The reaction mixture was stirred under reflux for 14 hours. The solvent was removed under reduced pressure. Water was added to the residue and extracted with AcOEt. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=40:1) and solidified with EtOH (2 mL). The precipitate was collected by filtration and dried to give 100 mg of the title compound as a white powder.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH3:4])[C@:16]1([CH2:17][OH:18])[C@H:11]([CH2:12][C:13](=[O:23])[CH2:14][C@@H:15]1[CH3:22])[CH2:10][CH2:9]3.[CH3:24][Si:25]([CH3:28])([CH3:27])Cl.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:22][C@@H:15]1[C@@:16]2([CH2:17][O:18][Si:25]([CH3:28])([CH3:27])[CH3:24])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:19]2[CH2:20][CH2:21][C@@:3]2([CH3:4])[C@H:5]3[CH2:6][CH2:7][C@@H:2]2[O:1][Si:25]([CH3:28])([CH3:27])[CH3:24])[CH2:12][C:13](=[O:23])[CH2:14]1
Reactant: C[C@H]1CC(=O)C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Reactant: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C[C@H]1CC(=O)C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](O[Si](C)(C)C)[C@@]4(C)CC[C@@H]3[C@]21CO[Si](C)(C)C

Procedure:
A mixture of 17β,19-dihydroxy-1α-methyl-5α-androstan-3-one, trimethylchlorosilane and pyridine in benzene is heated to its reflux temperature for a period of about 14 hours. The reaction mixture is vacuum filtered, the organic layer is washed with water, dried over magnesium sulfate and concentrated in vacuum. Crystallization of the residue from hexane yields 1α-methyl-17β,19-di(trimethylsiloxy)-5α-androstan-3-one.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[OH:23][C@@H:24]([CH2:28][NH2:29])[C:25]([OH:27])=[O:26].CO>C[O-].[Na+]>[OH:23][C@@H:24]([CH2:28][NH:29][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:9]=2)=[O:4])[C:25]([OH:27])=[O:26]
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: NC[C@H](O)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NC[C@H](O)C(=O)O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Yield: 93.5 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (90 mg, 0.31 mmol) and 2-(S)-hydroxy-3-amino-propionic acid (Sigma-Aldrich) (96 mg, 0.92 mmol) in 0.5 N NaOMe in MeOH solution (1.22 mL, 0.61 mmol) was microwaved at 120° C. for 1 h and concentrated. Residue was dissolved in water (70 mL) and acidified by 1 N HCl solution to pH=3-4. It was extracted with EtOAc, Organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give the title compound (105 mg, 0.29 mmol) in 92% yield. LC-MS ESI−: 366.99 (M−1)−.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]([CH3:33])[C:18]2[N:23]=[C:22]([N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[N:26]=[CH:25]3)[CH:21]=[CH:20][N:19]=2)[CH2:12]1)=O)C1C=CC=CC=1>C1COCC1.[Pd]>[NH3:11].[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]([CH3:33])[C:18]2[N:23]=[C:22]([N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[N:26]=[CH:25]3)[CH:21]=[CH:20][N:19]=2)[CH2:12]1
Reactant: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Product: N
Reaction time: 1 h
Yield: 152.7 %

Procedure:
To a solution of 2-[(1-benzyloxycarbonyl-piperidin-3-yl)-methylamino]-4-[benzimidazol-1-yl]pyrimidine (100 mg, 0.226 mmol, 1 eq) in THF (5 mL) ws added 10% Pd on carbon (24 mg). The flask was purged with hydrogen and the mixture was stirred under a balloon of hydrogen. After 1 h, no reaction was observed by thin layer chromatography analysis. Added 12 mg of Pd(OH)2 and let stir overnight under hydrogen. Still very little reaction by thin layer chromatography analysis. Filtered off catalyst and washed with THF and MeOH. Concentrated under reduced pressure. Dissolved the residue in MeOH (5 mL) and added Pd(OH)2 (24 mg). Purged flask with H2 and stirred under a balloon of H2 for several hours. Purged the vessel with nitrogen and filtered off and washed the catalyst with methanol. Concentrated the mixture under reduced pressure and purified by silica gel chromatography (eluted with 3.5% MeOH/CH2Cl2 then 7% (2N NH3 in MeOH)/CH2Cl2) to give 53.2 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 1.2-1.3 (1H, m), 1.4-1.5 (1H, m), 1.55-1.95 (3H, m), 2.61 (1H, dd, J=10 Hz, J=11.5 Hz), 2.62 (1H, dd, J=2.5 Hz, J=12 Hz), 3.03 (1H, d, J=12 Hz), 3.19 (1H, d, J=11.5 Hz), 3.4-3.45(2H, m), 5.5 (1H br s), 6.8 (1H, d, 5.5 Hz), 7.40-7.45 (2H, m), 7.87 (1H, d, J=8.5 Hz), 8.20 (1H br d), 8.39 (1H, br s), 8.64 (1H, s). Mass spectrum (ESI) 309.1 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][N:12]=2)[CH:4]=1)[CH3:2].[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([NH:24][C:17]([C:15]1[CH:14]=[CH:13][N:12]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:16]=1)=[O:19])[CH2:21][CH2:22][CH3:23]
Reactant: CCc1cc(-c2cc(C(=O)O)ccn2)c(C)[nH]c1=O
Reactant: CCCCN
Product: CCCCNC(=O)c1ccnc(-c2cc(CC)c(=O)[nH]c2C)c1

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-4-carboxylic acid and n-butyl amine to afford the title compound. MS: m/e=314 (M+H).
Reaction SMILES: Cl[Si:2]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4].[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH:21]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([CH2:35][OH:36])=[CH:32][CH:33]=4)[N:28]([CH3:37])[CH:27]=3)[C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:15]=2[O:14][CH2:13]1.N1C=CN=C1>CN(C)C=O>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH:21]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([CH2:35][O:36][Si:2]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4])=[CH:32][CH:33]=4)[N:28]([CH3:37])[CH:27]=3)[C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(CO)ccc12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc12
Yield: 80.9 %

Procedure:
Chlorotriisopropylsilane (0.19 ml, 0.88 mmol) was added to a solution of methyl 2-(1,3-benzodioxol-5-yl)-2-[6-(hydroxymethyl)-1-methyl-1H-3-indolyl]acetate (from step (d), 260 mg, 0.74 mmol) and imidazole (100 mg, 1.47 mmol) in anhydrous dimethylformamide (3 ml). After 3 hours the mixture was partitioned between diethyl ether and water, the organic layer was separated and washed with water. The organic layer was dried (magnesium sulphate), and the solvent removed in vacuo. The residue was flash chromatographed (using 50% dichloromethane, 50% hexane as eluent) to give the subtitle compound (305 mg) as an oil.