Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19](O)=[O:20])=[CH:11][N:10]=1.[O:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[C:12]([C:19]([NH:29][CH2:28][CH:25]2[CH2:26][CH2:27][O:22][CH2:23][CH2:24]2)=[O:20])=[CH:11][N:10]=1
Reactant: NCC1CCOCC1
Reactant: O=C(O)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC1CCOCC1)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.2 %

Procedure:
To a mixture of rac-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (150 mg) and N,N-dimethyl formamide (3.0 mL) were added 1-(tetrahydro-2H-pyran-4-yl)methylamine (69 mg), 1-hydroxybenzotriazole (81 mg), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg) in this order at room temperature, and then the mixture was stirred at room temperature for 5 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine in this order, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate). The obtained colorless oily substance was solidified using ethanol-water to obtain rac-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-N-(tetrahydro-2H-pyran-4-ylmethyl)-4-(trifluoromethyl)pyrimidine-5-carboxamide (173 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]C)=[O:8])[N:4]([CH3:11])[N:3]=1.O.[Li+].[OH-]>O1CCOCC1>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([CH3:11])[N:3]=1
Reactant: COC(=O)c1cc(Cl)nn1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(Cl)cc1C(=O)O
Reaction time: 16 h
Yield: 90.5 %

Procedure:
To a solution of methyl 3-chloro-1-methyl-1H-pyrazole-5-carboxylate (6.0 g, 34.4 mmol) in dioxane (10 ml) was added H2O (10 ml) and LiOH (1.65 g, 68.7 mmol). After stirring for 16 h, the reaction mixture was washed with CH2Cl2 and then the aqueous phase acidified by drop wise addition of conc. HCl. The resulting residue was filtered off, washed with water and dried to yield the title compound (5.0 g, 91%). [1H-NMR (DMSO-d6, 360 MHz) δ 13.77 (br. s, 1H), 6.88 (d, 1H), 4.05 (s, 3H); HPLC-MS RtJ=0.47 min; [M+H]+=160.9, 163.0]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[C@@H:22]([O:24][CH3:25])[CH3:23])[C:11](=[O:28])[C@:10]([CH2:30][C:31]([O:33]C)=[O:32])([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[C@@H:22]([O:24][CH3:25])[CH3:23])[C:11](=[O:28])[C@:10]([CH2:30][C:31]([OH:33])=[O:32])([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H]([C@H](C)OC)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC[C@@H]([C@H](C)OC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-methoxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (34 mg, 0.067 mmol; Example 153, Step B) in THF/MeOH/H2O (1/1/1, 0.48 mL) was added 2 M lithium hydroxide (67 uL, 0.134 mmol) at rt. After being stirred at rt for 4 h, the reaction was quenched saturated aqueous NH4Cl and extracted (2×DCM) and the combined organic layers were washed (1×sat. aq. NaCl solution) and concentrated under the reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 70 to 100% EtOAc/hexanes) provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][N:3]=1.[CH:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([CH3:17])[CH3:16]>>[ClH:1].[F:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:21]3[CH2:22][CH2:23][N:18]([CH:15]([CH3:17])[CH3:16])[CH2:19][CH2:20]3)=[N:3][CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Fc1cccc(-c2ccc(Cl)nc2)c1
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(c2ccc(-c3cccc(F)c3)cn2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 2-chloro-5-(3-fluorophenyl)pyridine and 1-isopropylpiperazine.
Reaction SMILES: C([Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])(C)C)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CO>[Si:33]([O:32][CH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:14]([S:15]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)(=[O:16])=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])([C:46]([CH3:49])([CH3:47])[CH3:48])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCC(c1ccccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)S(=O)(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](OCc1ccccc1C(CCCCCO)S(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
In methanol (30 ml) was dissolved t-butyl [[6-[2-[(t-butyldiphenylsilyloxy)methyl]phenyl]-6-[(4-chlorophenyl)sulfonyl]hexyl]oxy]dimethylsilane (830 mg, 1.13 mmol), followed by the addition of p-toluenesulfonic acid monohydrate (25 mg, 0.13 mmol). The resulting mixture was stirred at room temperature for 2 hours. Triethylamine (0.080 ml, 0.57 mmol) was added and then, the residue obtained by concentrating the resulting mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the dichloromethane:methanol=100:1 eluate was concentrated under reduced pressure, whereby the title compound (580 mg, 0.934 mmol, 83%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.[CH2:33]([SH:36])[CH:34]=[CH2:35]>>[CH2:33]([S:36][CH2:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([O:23][CH3:22])[CH:29]=3)[CH:8]=2)[NH:3][C:2]([CH3:1])([CH3:21])[CH:11]=1)[CH:34]=[CH2:35]
Reactant: C=CCS
Reactant: COc1cccc(B(O)O)c1
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: C=CCSCC1=CC(C)(C)Nc2ccc(-c3cccc(OC)c3)cc21

Procedure:
Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester was coupled with 3-methoxyphenylboronic acid. Bromination and coupling reaction with allyl mercaptan gave 20 mg of the title compound.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([Sn](CCCC)(CCCC)CCCC)[N:32]=1>CN(C=O)C.C(Cl)Cl.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>[Cl:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:15][C:14]([NH:16][CH:17]([CH3:18])[CH3:19])=[N:13][N:12]=4)[CH:9]=3)[N:4]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:3]=2)[N:32]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(Cl)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 100 °C
Yield: 56.5 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (1.00 g, 1.914 mmol) and 4-chloro-2-(tributylstannyl)pyrimidine (0.966 g, 2.393 mmol) in DMF (5 mL) followed by Pd(PPh3)4 (0.111 g, 0.096 mmol, Strem) and Cut (0.072 g, 0.383 mmol, Aldrich). The reaction was stirred and heated in a Initiator microwave reactor at 100° C. for 1 h. The mixture was then diluted with DCM and washed with H2O, brine. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified with flash chromatography (eluent: 25%-60% EtOAc in Hexanes) to give 5-(3-(4-chloropyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (550 mg, 1.081 mmol, 56.4%) as a green solid. MS (ESI, pos. ion) m/z: 508.9 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24]>C(O)CO.O>[CH3:20][O:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[N:24]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: COc1ccccc1N
Reactant: O=C1N=c2c(OC(F)(F)F)cccc2=C2OCCC12
Solvent: O
Solvent: OCCO
Product: COc1ccccc1N1CCc2c1c1cccc(OC(F)(F)F)c1[nH]c2=O
Temperature: 210 °C
Yield: 76 %

Procedure:
4-Oxo-6-trifluormethoxy-2,3-dihydrofuro[3,2-c] quinoline (272 mg, 1.0 mmol) was dissolved in 10 ml of ethylene glycol in a pressure tube and 2-methoxyaniline (282 μl, 1.0 mmol) was added under nitrogen. The reaction mixture was heated at 210° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 286 mg of desired compound as solid in 76% of yield.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5](Cl)=[N:6][CH:7]=[CH:8][CH:9]=1.[CH2:11]([OH:14])[CH2:12][OH:13]>>[Br:3][C:4]1[C:5]([O:13][CH2:12][CH2:11][OH:14])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: Clc1ncccc1Br
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Product: OCCOc1ncccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.6 g, 42 mmol) was added to cooled (ice-water bath) ethane-1,2-diol (5 mL) and the resulting mixture stirred at rt for 30 min before adding 3-bromo-2-chloropyridine (2.0 g, 100 mmol). The mixture was then heated at 130° Celsius under a N2 atmosphere overnight before cooling to rt and subjecting the reaction mixture to FCC purification to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 8.05 (dd, J=4.9, 1.7, 1H), 7.82 (dd, J=7.6, 1.7, 1H), 6.80 (dd, J=7.6, 4.9, 1H), 4.54-4.50 (m, 2H), 3.97 (dd, J=8.8, 5.5, 2H), 3.18 (t, J=5.8, 1H).
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH2:4][CH:5]=[CH2:6])#N.[H-].C([Al+]CC(C)C)C(C)C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:29]>C1(C)C=CC=CC=1>[Cl:14][C:9]1[CH:8]=[C:7]([CH:3]([CH:1]=[O:29])[CH2:4][CH:5]=[CH2:6])[CH:12]=[CH:11][C:10]=1[Cl:13]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: C=CCC(C#N)c1ccc(Cl)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCC(C=O)c1ccc(Cl)c(Cl)c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
4-Cyano-4-(3,4-dichlorophenyl)but-1-ene (13 g) (see Preparation 20) was dissolved in anhydrous toluene (100 ml) and cooled to −70° C. under a nitrogen atmosphere. Diisobutylaluminium hydride (50 ml of a 1.5M solution in toluene) was added to the solution over 30 minutes, the mixture stirred at −70° C. for a further 30 minutes and then allowed to warm slowly to −10° C. Water (6 ml) was carefully added (exothermic reaction) before pouring the mixture into a 15% (by weight) aqueous solution of citric acid (500 ml), followed by further addition of toluene (300 ml) and vigorous stirring of the mixture for 30 minutes. The two phases were separated, the organic phase washed with brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give 4-(3,4-dichlorophenyl)-4-formylbut-1-ene as an oil (14 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[CH:3]=1.[Br:11]Br>CC(O)=O>[Br:11][C:9]1[C:2]([F:1])=[CH:3][C:4]([OH:10])=[C:5]([CH:8]=1)[CH:6]=[O:7]
Reactant: BrBr
Reactant: O=Cc1ccc(F)cc1O
Solvent: CC(=O)O
Product: O=Cc1cc(Br)c(F)cc1O
Temperature: 2.5 °C
Yield: 17 %

Procedure:
Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 4-fluoro-2-hydroxybenzaldehyde (545 g, 3.89 mol, 1.00 equiv) in AcOH (5 L), followed by the addition of Br2 (623 g, 3.90 mol, 1.00 equiv) dropwise with stirring at 0-5° C. The resulting solution was stirred overnight at room temperature, quenched by the addition of 3 L of saturated aqueous Na2SO3 and diluted with 6 L of ice/water. The solids were collected by filtration, washed with 2×1.5 L of water and dried to afford 145 g (crude) of 5-bromo-4-fluoro-2-hydroxybenzaldehyde as a yellow solid.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:30]#[N:31])[CH2:10][C@H:11]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:33].[K+].[K+].OO>CS(C)=O.O>[CH2:1]([NH:8][CH:9]([C:30](=[O:33])[NH2:31])[CH2:10][C@H:11]1[N:15]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](CC(C#N)NCc2ccccc2)N1C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](CC(NCc2ccccc2)C(N)=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2.6 g of di-tert-butyl (2S,5S)-5-(2-benzylamino-2-cyanoethyl)pyrrolidine-1,2-dicarboxylate were dissolved in 6.5 ml of dimethyl sulfoxide. 373 mg of finely ground potassium carbonate and 1.08 ml of a 30% strength hydrogen peroxide solution were added thereto. The mixture was stirred at room temperature for 14 h and was then heated at 35° C. for 30 min. The solution was diluted with 60 ml of water and extracted 3 times with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 120 ml of a saturated sodium chloride solution and dried with sodium sulfate. The solvents were removed in vacuo, and the residue was chromatographed on silica gel.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH:9](OCC)[O:10]CC)=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[CH:4][N:3]=1>C1COCC1.Cl>[Cl:1][C:2]1[C:7]([CH2:8][CH:9]=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[CH:4][N:3]=1
Reactant: CCOC(Cc1c(Cl)ncnc1-c1ccccc1)OCC
Agent: Cl
Solvent: C1CCOC1
Product: O=CCc1c(Cl)ncnc1-c1ccccc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a stirred solution of 4-chloro-5-(2,2-diethoxyethyl)-6-phenylpyrimidine (800 mg) in dry THF (10 mL), concentrated HCl (2.0 mL) was added. The reaction mixture was stirred at 45° C. for 1 hour and solvents were removed under reduced pressure. The resulting oil was diluted with dichloromethane (50 mL), washed with 10% NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography using MeOH\CHCl3 (0.1:9.9) as eluent to afford 2-(4-chloro-6-phenylpyrimidin-5-yl)acetaldehyde (450 mg) as white solid. 1H NMR (DMSO-d6): δ 4.04 (s, 2H), 7.42-7.53 (m, 5H), 9.02 (s, 1H), 9.72 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:24]=[CH:23][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[CH3:22])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH:51]2[CH2:53][O:52]2)=[CH:45][CH:44]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:52][C@H:51]([CH2:50][O:49][C:46]1[CH:47]=[CH:48][C:43]([OH:42])=[CH:44][CH:45]=1)[CH2:53][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[CH3:22])=[O:16])[CH2:13][CH2:14]2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccsc1C(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Product: Cc1ccsc1C(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 21.9 %

Procedure:
{4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}(3-methyl-2-thienyl)methanone (0.174, 0.507 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.206 g, 0.51 mmol) according to Procedure G to give the title compound (0.083 g, 0.111 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]([N:8]([O:20][CH2:21][CH2:22][CH3:23])[C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13]CC)=O)=[O:7])[CH3:2].C(ON(C(=O)CC(OCC)=O)C1N=CC=CC=1C(OCC)=O)C1C=CC=CC=1>>[OH:13][C:11]1[C:10]2[C:9](=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]([O:20][CH2:21][CH2:22][CH3:23])[C:6](=[O:7])[C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:24]
Reactant: CCCON(C(=O)CC(=O)OCC)c1ccccc1C(=O)OCC
Agent: CCOC(=O)CC(=O)N(OCc1ccccc1)c1ncccc1C(=O)OCC
Product: CCCOn1c(=O)c(C(=O)OCC)c(O)c2ccccc21

Procedure:
The title compound is prepared according to the procedure of Example 157C substituting the product of Example 172C for the product of Example 157B.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][C:13]1([CH3:28])[C:24]2[C:16](=[CH:17][C:18]3[CH2:19][C:20]([CH3:25])=[CH:21][C:22]=3[CH:23]=2)[C:15]([CH3:27])([CH3:26])[CH2:14]1.[Si:29]([CH3:33])([CH3:32])(Cl)[Cl:30]>CCOCC>[Cl:30][Si:29]([CH:21]1[C:20]([CH3:25])=[CH:19][C:18]2[CH:17]=[C:16]3[C:24]([C:13]([CH3:28])([CH3:12])[CH2:14][C:15]3([CH3:27])[CH3:26])=[CH:23][C:22]1=2)([CH3:33])[CH3:32]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=Cc2cc3c(cc2C1)C(C)(C)CC3(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=Cc2cc3c(cc2C1[Si](C)(C)Cl)C(C)(C)CC3(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A 2.5 M n-BuLi solution in hexane (3.8 mL, 9.50 mmol, n-BuLi:indacene=1:1) was added dropwise at 0° C. to a solution of 2.16 g of 1,1,3,3,6-pentamethyl-1,2,3,5-tetrahydro-s-indacene (9.54 mmol) in 40 mL of Et2O. At the end of the addition, the resulting light yellow solution was allowed to warm up to room temperature and stirred for 1 h with final formation of a white suspension. An aliquot of this suspension was quenched with CD3OD and dried: the related 1H NMR analysis in CDCl3 showed complete conversion of the starting indacene to the corresponding lithium salt. The latter was then cooled again to 0° C. and added to a solution of Me2SiCl2 (98%, 1.27 g, d=1.064, 9.64 mmol) in 10 mL of Et2O, previously cooled to 0° C. too. The reaction mixture was allowed to warm up to room temperature and stirred for 16 h with final formation of a white suspension. After 40 min stirring at r.t. the conversion was ca. 80% by 1H NMR analysis. The solvents were removed in vacuo and the residue extracted with 70 mL of toluene to remove the LiCl. The filtrate was brought to dryness in vacuo at 40° C. to give a thick yellow oil as product (3.03 g), which tended to crystallize by standing at room temperature. Isolated yield=97.9% (purity 97.9% wt. by 1 H NMR analysis). Starting indacene was still present in 2.1% wt.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C(Cl)Cl>[Si:27]([O:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=1[C:14]([F:15])([F:16])[F:17])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(CO)Cc1ccc(N)cc1C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)Cc1ccc(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.7 %

Procedure:
To a mixture of 3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropan-1-ol (300 mg, 1.213 mmol) in DCM (150 mL) was added imidazole (124 mg, 1.820 mmol) and TBSCl (219 mg, 1.456 mmol). Then the mixture was stirred at 25° C. for 5 h. The mixture was filtered and the filtrate was concentrated. The crude material was purified by preparative TLC (PE/EA=2:1, Rf=0.5) to yield a light yellow solid of 4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)aniline (350 mg, 0.930 mmol, 77.0% yield): 1H NMR (400 MHz, CD3Cl) δ: 7.14 (d, J=8.4 Hz, 1H), 6.86 (d, J=2.8 Hz, 1H), 6.70 (dd, J=2.8, 8.4 Hz, 1H), 3.20 (s, 2H), 2.62 (d, J=1.2 Hz, 2H), 0.87 (s, 9H), 0.73 (s, 6H), 0.00 (s, 6H); ES-LCMS m/z 362 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:27][CH2:26]1>>[CH2:31]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:26][CH2:27]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCN(Cc3ccccc3)CC2)cn1
Yield: 77 %

Procedure:
As described for example 34, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 4-amino-1-benzylpiperidine instead of 1-methylpiperidin-4-amine, to the title compound (120 mg, 77%) which was obtained as an off white foam. MS: m/e=483.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.[CH3:30][N:31]([CH3:38])[C:32](=[O:37])[CH2:33][CH2:34][NH:35][CH3:36]>ClCCl>[C:19]([C:7]1[C:5]2[N:6]=[C:2]([N:35]([CH3:36])[CH2:34][CH2:33][C:32]([N:31]([CH3:38])[CH3:30])=[O:37])[O:3][C:4]=2[C:10]([F:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[CH3:18])#[N:20]
Reactant: CNCCC(=O)N(C)C
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(N(C)CCC(=O)N(C)C)nc2c1C#N

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.20 g, 0.84 mmol) was dissolved in dichloromethane (10 ml), and diisopropylethylamine (0.16 ml, 0.94 mmol) and N,N-dimethyl-3-(methylamino)propionamide (I-149) (0.11 g, 0.84 mmol) were added. After heated under reflux for 3 hours, this was diluted with dichloromethane.