Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].C(O)[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28].C(C(CCCC)C([O-])=O)C.C(C(CCCC)C([O-])=O)C.C(C(CCCC)C([O-])=O)C.C([Sn+3])CCC>>[C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)CCCCCO
Agent: CCCCC(CC)C(=O)[O-]
Agent: CCCC[Sn+3]
Product: CC(C)CCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
In a three-necked, round-bottomed flask fitted with a stirrer, thermometer, reflux condenser with a trap to collect distilled off methanol and later isooctanol and a vacuum connection are added 200 g (0.684 mole) of methyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate, 178 g (1.37 moles, 100% excess) of isooctanol (Exxal®-8, Exxon) and 0.05 g (0.0000826 mole; 50 ppm of tin in final product) of butyltin tris-(2-ethylhexanoate) (Fascat® 9102, Elf-Atochem). The reaction mixture is subjected to a reduced pressure of 400 mm Hg and the flask is heated to 140°-150° C. Methanol begins to be evolved and is collected in the trap receiver. When the reaction mixture reaches 160° C., reflux of isooctanol is observed and becomes vigorous at 170°-180° C. while the evolution of methanol subsides. At this point, the excess isooctanol is then stripped into the trap receiver and the pressure in the system is ultimately reduced to 5 mm Hg. When all the excess isooctanol is removed, the residue in the flask is cooled under nitrogen and is the desired title compound in essentially quantitative yield (over 99% by weight).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:23].[Cl:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[CH:30]=1>>[ClH:24].[CH3:36][O:35][C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([O:37][CH3:38])[CH:32]=1)[O:28][CH2:27][CH2:26][CH2:25][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:23]
Reactant: COc1cc2c(cc1OC)C(=O)N(CCC1CCCCN1)CC2
Reactant: COc1cc(OC)cc(OCCCCl)c1
Product: COc1cc(OC)cc(OCCCN2CCCCC2CCN2CCc3cc(OC)c(OC)cc3C2=O)c1
Product: Cl

Procedure:
Prepared from 2-[2-(piperid-2-yl)-ethyl]-6,7-dimethoxy-1-oxo- 1,2,3,4-tetrahydro-isoquinoline and 1-chloro-3-(3,5-dimethoxy-phenoxy)-propane analogously to Example 1.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][NH:24][CH3:25])[CH2:18][CH2:17]2)=[CH:14][CH:13]=[CH:12][N:11]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:9][C:10]1[C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:25])[S:33]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[CH2:18][CH2:17]2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNCCN1CCN(c2cccnc2Cl)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCN1CCN(c2cccnc2Cl)CC1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
Add triethylamine (0.850 mL, 6.103 mmol) to a stirring solution of {2-[4-(2-chloro-pyridin-3-yl)-piperazin-1-yl]-ethyl}-methyl-amine hydrochloride salt (2.000 g, 6.103 mmol) in dichloromethane (10 mL). Stir at room temperature for 5 min. Add 4-fluoro-benzenesulfonyl chloride (0.356 g, 1.831 mmol) at room temperature. Stir at room temperature for 18 hr. Dilute with dichloromethane and saturated aqueous sodium bicarbonate. Separate the phases and extract the aqueous phase with dichloromethane. Combine the organic phases, dry over sodium sulfate, filter, and concentrate. Purify the resulting material by silica gel chromatography eluting with hexanes:acetone 1:1 to afford the title preparation (0.525 g, 83% yield). MS ES: m/z=413 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:19])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29]([NH:31][C@H:32]([C:41](O)=[O:42])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:41](=[O:42])[C@H:32]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)[NH:31][C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)OC(C)(C)C)CCN1C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 59.5 %

Procedure:
In 15 ml of dichloromethane were dissolved 1.65 g of (S)-3-methoxycarbonylmethyl-2-oxopiperazine-1-acetic acid tert-butyl ester and 1.9 g of N-benzyloxycarbonyl-L-tyrosine. To the solution was added, while stirring for one hour, 1.44 g of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, and the mixture was stirred for one hour. The reaction mixture was concentrated under reduced pressure to leave an oily substance, which was dissolved in ethyl acetate. The organic layer was washed with a 5% aqueous solution of potassium hydrogen carbonate and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was subjected to a silica gel column chromatography (eluent: ethyl acetate: hexane=7:3) to afford 2.0 g of (S)-4-(N-benzyloxycarbonyl-L-tyrosyl)-3-methoxycarbonylmethyl-2-oxopiperazine-1-acetic acid tert-butyl ester as a colorless oily product. IR γmax cm-1 : 3332, 2952, 1740, 1646, 1613, 1514, 1444, 1367, 1227, 1153. NMR(CDCl3) δ: 1.46(9H,s), 2.30-2.53(1H,m), 2.72-3.13(5H,m), 3.50-3.72(2H,m), 3.63(3H,s), 3.85(1H,d,J=12 Hz), 4.07(1H,d,J=12 Hz), 4.70-4.90(1H,m), 4.90-5.05(1H,m), 5.11(2H,s), 5.50-5.67(2H,m), 6.76(2H,d,J=8.2 Hz), 7.03(2H,d,J=8.2 Hz), 7.36(5H,s).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([CH3:12])[C:9]=1[C:10]#N)(=O)[CH3:2].[C:18](OCC)(=[O:20])[CH3:19].BrCC(OCC)=[O:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:16]([O:15][C:13]([C:7]1[S:6][C:5]2[NH:4][C:1]([C:2]([O:20][CH2:18][CH3:19])=[O:27])=[CH:10][C:9]=2[C:8]=1[CH3:12])=[O:14])[CH3:17]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1sc(NC(C)=O)c(C#N)c1C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2c(C)c(C(=O)OCC)sc2[nH]1

Procedure:
1 mole of 2-acetamido-3-cyano-5-ethoxycarbonyl-4-methylthiophene (prepared according to the method described by Gewald K. et al., Chem. Ber. (1966), 99, p. 94 and 2712, from ethyl acetate) is brought to reflux for 24 hours in 1.6 l of acetone with 187 g of ethyl bromoacetate and 250 g of potassium carbonate. Subsequently, the mixture is precipitated in 6 liters of an ice-water mixture (1:1). The whole is vigorously stirred, the resulting precipitate is filtered, dried with air, washed with 500 ml of an iced mixture of water and ethanol (60:40), dried again, and finally washed with 700 ml of a mixture of cyclohexane and benzene (6:1). The resulting product (320 g-0.95 mole) is then stirred in 1.2 liters of H2SO4 at 30% maintained at a temperature of less than 10° C., in a current of nitrogen. 85 g of potassium nitrite in 180 ml of water are progressively added whilst maintaining the temperature. When the addition is complete, stirring is continued for a few minutes, then 7.2 liters of an ice-water mixture are added. The whole is stirred vigorously. The yellow precipitate obtained is briefly suction-filtered and rinsed with water until almost neutral. It is then brought to reflux in 3 liters of ethanol until the evolution of nitrogen is complete. Subsequently, the reaction mixture is concentrated to 1 liter by distillation, 300 ml of water are added and the whole is stirred vigorously. Once crystallisation is complete, the precipitate is filtered and dried. In this manner 205 g (0.73 mole) of 2,5-diethoxycarbonyl 3-methyl-thieno[2,3-b]pyrrole are obtained, m.p.: 139° C. The following was prepared in the same manner:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11](O)=[O:12])=[C:9]([CH3:14])[N:8]([C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:6]=2[N:7]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:52][CH2:53][C:54]1[C:55]([OH:62])=[N:56][C:57]([CH3:61])=[CH:58][C:59]=1[CH3:60]>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([NH:52][CH2:53][C:54]3[C:55]([OH:62])=[N:56][C:57]([CH3:61])=[CH:58][C:59]=3[CH3:60])=[O:12])=[C:9]([CH3:14])[N:8]([C@@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[C:6]=2[N:7]=1
Reactant: Cc1c(C(=O)O)c2cnc(Cl)nc2n1[C@H](C)c1ccccc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(Cl)ncc23)c(O)n1
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To a solution of (R)-2-chloro-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (100 mg 0.32 mmol) in dichloromethane (10 mL) was added with 1-hydroxybenzotriazole (65 mg, 0.48 mmol), (3-dimethylaminopropyl)ethyl-carbodiimid hydrochloride (92 mg, 0.48 mmol) and triethylamine (97 mg, 0.96 mmol). After stirred for 30 minutes, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (49 mg, 0.32 mmol) was added and the reaction mixture was stirred at room temperature for 12 hours. The solution was concentrated, diluted with water (20 mL), extracted with ethyl acetate (20 mL). The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to afford (R)-2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (100 mg, 70%). LRMS (M+H+) m/z: calcd 449.16; found 449.
Reaction SMILES: Cl.[CH2:2]([S:4][C:5]1[N:6]=[CH:7][C:8]2[CH2:14][CH2:13][NH:12][CH2:11][C:9]=2[N:10]=1)[CH3:3].[CH3:15][C:16]([CH3:36])([O:18][C:19]([NH:21][C@H:22]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[F:35])[CH2:23][C:24](O)=[O:25])=[O:20])[CH3:17].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:17][C:16]([CH3:36])([O:18][C:19]([NH:21][C@H:22]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[F:35])[CH2:23][C:24]([N:12]1[CH2:13][CH2:14][C:8]2[CH:7]=[N:6][C:5]([S:4][CH2:2][CH3:3])=[N:10][C:9]=2[CH2:11]1)=[O:25])=[O:20])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Reactant: CCSc1ncc2c(n1)CNCC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCSc1ncc2c(n1)CN(C(=O)C[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
A mixture of 47 mg (0.19 mmol) of 2-(ethylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride, 59 mg (0.19 mmol) of (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid, 37 mg (0.19 mmol) of EDC, 26 mg (0.19 mmol) of HOBt, and 0.15 mL (0.57 mmol) of diisopropylethylamine in 1.5 mL of dichloromethane was stirred at ambient temperature overnight. The mixture was subjected directly to purification by flash chromatography (5 g silica gel cartridge, 20-to-50% ethyl acetate/hexane step gradient) to give 85 mg (91%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:33]=[CH:32][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH:60]2[CH2:62][O:61]2)=[CH:54][CH:53]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH3:31][O:30][C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:15]([N:12]2[CH2:13][CH2:14][CH:9]([NH:8][C:7]3[CH:32]=[CH:33][C:4]([CH2:3][CH2:2][NH:1][CH2:62][CH:60]([OH:61])[CH2:59][O:58][C:55]4[CH:56]=[CH:57][C:52]([OH:51])=[CH:53][CH:54]=4)=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)=[O:16])[CH:27]=[CH:26][C:25]=1[O:28][CH3:29]
Reactant: COc1ccc(CCCCNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1OC
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCCCNC(=O)N2CCC(Nc3ccc(CCNCC(O)COc4ccc(O)cc4)cc3)CC2)cc1OC
Yield: 52.8 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-[4-(3,4-dimethoxyphenyl)butyl]-1-piperidinecarboxamide (0.79 g, 1.42 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.36 g, 0.89 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.40 g, 0.47 mmol).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[N:5][N:6]=1.[CH:20]([NH2:23])([CH3:22])[CH3:21]>C(O)(C)C>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:19])[CH2:18][NH:23][CH:20]([CH3:22])[CH3:21])=[N:5][N:6]=1
Reactant: CC(C)N
Reactant: Cc1nnc(C=Cc2ccccc2OCC2CO2)s1
Solvent: CC(C)O
Product: Cc1nnc(C=Cc2ccccc2OCC(O)CNC(C)C)s1

Procedure:
7 g (0.025 mole) of 2-methyl-5-[2-(2,3-epoxy-propoxy)-styryl]-1,3,4-thiadiazole and 2.9 g (0.05 mole) of isopropylamine are brought together in 100 ml of isopropanol and the mixture is refluxed for 7 hours. After cooling, the solvent is distilled off and the residue obtained is recrystallized from toluene.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[CH2:6][O:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[C:38](Cl)(=[O:42])[CH:39]([CH3:41])[CH3:40]>ClCCl.O>[CH3:16][O:15][C:14]1[C:13]([O:17][CH3:18])=[CH:12][CH:11]=[C:10]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:9]=1[O:8][CH2:7][C:3]1([CH2:2][NH:1][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH2:4][O:5][CH2:6]1
Reactant: CC(C)C(=O)Cl
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)COC2)c1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(=O)C(C)C)COC2)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 4-[2-(3-Aminomethyl-oxetan-3-ylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 191) (150 mg, 0.3916 mmol) in dichloromethane (15 mL), were added diisopropylethylamine (50 mg, 0.390 mmol) and isobutyryl chloride (41 mg, 0.391 mmol) and the resultant reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined dichloromethane layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-2% methanol in dichloromethane) afforded the title compound as a solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]([F:45])([F:44])[C:9]1[C:10]([C:35]#[C:36][Si](CC)(CC)CC)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[N:13][CH:14]=1>CO.O>[C:35]([C:10]1[C:9]([C:8]([F:44])([F:7])[F:45])=[CH:14][N:13]=[C:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)[N:11]=1)#[CH:36]
Reactant: CC[Si](C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F)(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of K2CO3 (1.72 g, 12.4 mmol) and tert-butyl 4-(4-((5-(trifluoromethyl)-4-((triethylsilyl)ethynyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate A50 (4.64 g, 8.28 mmol) in MeOH (250 mL) was stirred for 15 minutes at room temperature. The mixture was diluted with water (250 mL) and extracted with DCM (3×250 mL). The organics were combined and adsorbed onto silica gel. Purification by silica gel column chromatography (Biotage Isolera, 0-100% EtOAc in petroleum benzine 40-60° C.) gave the title compound A51 as a yellow solid (2.196 g, 59%). LCMS-A: rt 6.615 min; m/z 445 [M−H]−.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[NH:15][C:16]([C:18]2[N:19]=[C:20]([C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])[S:21][C:22]=2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:17])[CH2:4][CH2:3]1.I[CH2:40][C:41]1([CH3:45])[CH2:44][O:43][CH2:42]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C1COCC1>[F:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=1[C:20]1[S:21][C:22]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:18]([C:16](=[O:17])[NH:15][C:10]2[CH:11]=[N:12][N:13]([CH3:14])[C:9]=2[N:5]2[CH2:6][CH2:7][CH2:8][C@@H:2]([NH:1][CH2:40][C:41]3([CH3:45])[CH2:44][O:43][CH2:42]3)[CH2:3][CH2:4]2)[N:19]=1
Reactant: CC1(CI)COC1
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@H](N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NCC2(C)COC2)CC1
Temperature: 65 °C
Yield: 108.3 %

Procedure:
To a solution of (S)-tert-butyl (4-((5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-2-(2,6-difluorophenyl)thiazol-5-yl)carbamate (103 mg, 0.19 mmol) in acetonitrile (2 mL) and THF (2 mL) was added 3-(iodomethyl)-3-methyl-oxetane (78 mg, 0.38 mmol) and potassium carbonate (130 mg, 0.94 mmol). The mixture was heated at 65° C. for 3 days. After cooling to room temperature, water (20 mL) was added and the mixture extracted with DCM (50 mL×3). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0 to 15% methanol/DCM) gave tert-butyl N-[2-(2,6-difluorophenyl)-4-[[1-methyl-5-[(4R)-4-[(3-methyloxetan-3-yl)methylamino]azepan-1-yl]pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (130 mg, quantitative). This solid (130 mg, 0.21 mmol) was stirred with TFA (3 mL) and DCM (3 mL) at room temperature for 1 h. The solvent was removed under reduced pressure, basified with saturated NaHCO3, and extracted with ethyl acetate (3×). The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure and the residue purified by preparative HPLC to afford 334 (55.7 mg, 51%). 1H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 8.18 (s, 1H), 7.56 (s, 1H), 7.55-7.41 (m, 3H), 7.26 (t, J=8.7 Hz, 2H), 4.28 (d, J=5.6 Hz, 2H), 4.12 (d, J=5.5 Hz, 2H), 3.65 (s, 3H), 3.23-3.00 (m, 4H), 2.83-2.70 (m, 1H), 2.70-2.58 (m, 2H), 1.99-1.77 (m, 3H), 1.68-1.51 (m, 3H), 1.17 (s, 3H). LCMS (ES+) m/z 532 (M+1)
Reaction SMILES: [OH-:1].[Na+].[OH2:3].Cl[CH:5](Cl)[C:6]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH3:15])=[CH:10][C:9]=1[CH3:16])=[O:7]>CC(OC)(C)C>[CH3:16][C:9]1[CH:10]=[C:11]([CH3:15])[C:12]([CH3:14])=[CH:13][C:8]=1[CH:6]([OH:7])[C:5]([OH:3])=[O:1]
Reactant: Cc1cc(C)c(C(=O)C(Cl)Cl)cc1C
Reactant: O
Reactant: [OH-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: Cc1cc(C)c(C(O)C(=O)O)cc1C
Reaction time: 1.5 h

Procedure:
222 g of 45% sodium hydroxide solution and 400 ml of water are initially charged and heated to reflux. Within approx. 90 minutes, 115.6 g of 2,2-dichloro-1-(2,4,5-trimethylphenyl)ethanone are added dropwise. Subsequently, the reaction mixture is boiled for a further hour, then admixed at 45° C. with 400 ml of water and at room temperature with 400 ml of MTBE, the phases are separated, the aqueous phase is extracted once again with 300 ml of MTBE, and is then acidified with sulfuric acid and the precipitated solid is filtered off with suction. The solid is then washed three times with 50 ml each time of water and then dried. 102.4 g of white solid are obtained which, by GC, contains 91.9% of target product=94.1 g=96.9% of theory.
Reaction SMILES: [CH2:1]([Si:4]([CH2:30][CH:31]=[CH2:32])([CH2:27][CH:28]=[CH2:29])[CH2:5][CH2:6][CH2:7][Si:8]([CH2:14][CH2:15][CH2:16][Si:17]([CH2:24][CH:25]=[CH2:26])([CH2:21][CH:22]=[CH2:23])[CH2:18][CH:19]=[CH2:20])([C:10]([CH3:13])([CH3:12])[CH3:11])[OH:9])[CH:2]=[CH2:3].[CH2:33](N(CC)CC)C.C(OCC)C.Cl>C1COCC1>[CH2:21]([Si:17]([CH2:18][CH:19]=[CH2:20])([CH2:24][CH:25]=[CH2:26])[CH2:16][CH2:15][CH2:14][Si:8]([CH2:7][CH2:6][CH2:5][Si:4]([CH2:1][CH:2]=[CH2:3])([CH2:30][CH:31]=[CH2:32])[CH2:27][CH:28]=[CH2:29])([C:10]([CH3:11])([CH3:12])[CH3:13])[O:9][CH3:33])[CH:22]=[CH2:23]
Reactant: C=CC[Si](CC=C)(CC=C)CCC[Si](O)(CCC[Si](CC=C)(CC=C)CC=C)C(C)(C)C
Reactant: CCN(CC)CC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC[Si](CC=C)(CC=C)CCC[Si](CCC[Si](CC=C)(CC=C)CC=C)(OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 37 h
Yield: 33 %

Procedure:
Bis{3-(triallylsilyl)propyl}tert-butyl silanol (29) (10.3 mg, 0.02 mmol) was dissolved in distilled THF, two equivalents of Meerwein Reagent (Me3OBF4) and two equivalents of triethylamine were added dropwise and stirred at room temperature for 37 hours. To the reacted mixture, diethyl ether was added then 1N hydrochloric acid was added then the obtained water layer was extracted with diethyl ether. The collected organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, then filtered and concentrated under reduced pressure, obtaining bis{3-(triallylsilyl)propyl}(tert-butyl)methoxysilane (30) represented by the following chemical reaction equation (yield: 3.5 mg, yield (%): 33%).
Reaction SMILES: [O:1]([CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:18]>C(O)C>[O:1]([CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][CH2:10][NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: ClCCC(Oc1ccccc1)c1ccccc1
Solvent: CCO
Product: NCCC(Oc1ccccc1)c1ccccc1

Procedure:
Eight grams of 3-phenoxy-3-phenylpropylchloride were heated with 150 ml. of liquid ammonia in a high pressure reactor at 100° C. for 20 hours. The volatile constituents of the reaction mixture were evaporated, and the residue, comprising 3-phenoxy-3-phenylpropylamine formed in the above reaction, was dissolved in ethanol and the volatile constituents again removed by evaporation. The resulting residue was dissolved in a mixture of ether and 5 N aqueous sodium hydroxide. The ether layer was separated, and the alkaline aqueous layer extracted three more times with ether. The ether extracts were combined, and the combined extracts washed with water. The combined ether extracts were in turn extracted twice with 2 N aqueous hydrochloric acid, the primary amine passing into the acidic layer. The acidic extracts were combined and made basic by the addition of an excess of 5 N aqueous sodium hydroxide. The primary amine, being insoluble in the basic layer, separated and was extracted into ether. The ether extract was separated, and the basic solution extracted twice more with ether. The ether extracts were combined, the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the ether in vacuo yielded 3-phenoxy-3-phenylpropylamine as an oil. The oxalate salt of the primary amine was prepared and melted at 170°-173° C.