Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[CH:25][NH:26]3)[CH2:15][CH:16]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.00 g, 4.63 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.90 g, 4.8 mmol). The resulting free base was isolated as a white foam. Yield 1.04 g (55%). mp 95-100° C. FDMS m/e=405 (M+ of free base). α[D]589=5.91 (c=1.01, dimethylsulfoxide).
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].[F:14][C:15]([F:31])([F:30])[C:16]1[CH:17]=[C:18]([C:26](=O)[CH2:27]Br)[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1>>[F:14][C:15]([F:30])([F:31])[C:16]1[CH:17]=[C:18]([C:26]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:27]=2)[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: O=C(CBr)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COC(=S)c1cc(-c2nc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cs2)c(C)s1
Yield: 5 %

Procedure:
A solution of 75 mg (0.3 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was reacted with 101 mg (0.3 mmol) of 1-[3,5-bis(trifluoromethyl)phenyl]-2-bromoethane-1-one in a manner similar Example 8, step (a) to give methyl 4-{4-[3,5-bis(trifluoromethyl)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate (7 mg, 5%) as a solid. 1H-NMR (DMSO-d6; 300 MHz) δ8.75 (s, 1H), 8.73 (m, 2H), 8.29 (s, 1H), 8.13 (m, 1H), 3.87 (s, 3H), 2.79 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C18H11NO2S3F6, 484.0 (M+H), found 484.0.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([NH2:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@H:10]([NH:19][CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CN(Cc2ccccc2)CC1c1ccccc1
Reactant: O=C([O-])[O-]
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
To a solution of rac-(3S,4R)-1-benzyl-4-phenyl-pyrrolidin-3-ylamine (0.25 g, 1.0 mmol) in THF (5 ml) was added a solution of K2CO3 (0.25 g, 1.8 mmol) in H2O (2 ml). After 10 minutes, ethyl chloroformate (0.119 g, 1.1 mmol) was added and stirring was continued at RT for an additional 4 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (5 ml) and a solution of borane in THF (1M) was added (3.5 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (0.5 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (20 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 0.21 g (82%) of rac-((3S,4R)-1-benzyl-4-phenyl-pyrrolidin-3-yl)-methyl-amine as a colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:6]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[O:9][C:5]=2[CH:4]=1.[CH2:16](I)[CH3:17]>>[CH3:13][O:12][C:10]([C:8]1([CH2:16][CH3:17])[CH2:7][C:6]2[CH:14]=[CH:15][C:3]([OH:2])=[CH:4][C:5]=2[O:9]1)=[O:11]
Reactant: CCI
Reactant: COC(=O)c1cc2ccc(OC)cc2o1
Product: CCC1(C(=O)OC)Cc2ccc(O)cc2O1

Procedure:
The title compound was prepared following the procedure described in Example 1, Step 1 employing methyl 6-methoxy-benzofuran-2-carboxylate instead of methyl 5-methoxy-benzofuran-2-carboxylate and ethyl iodide instead of methyl iodide.
Reaction SMILES: CO[C:3]1[C:4](=[O:10])[C:5](=[O:9])[C:6]=1[O:7][CH3:8].C[Si](C)(C)[Sn:13]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17]>C1COCC1.[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:8][O:7][C:6]1[C:5](=[O:9])[C:4](=[O:10])[C:3]=1[Sn:13]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCC[Sn](CCCC)(CCCC)[Si](C)(C)C
Reactant: COc1c(OC)c(=O)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(OC)c(=O)c1=O
Temperature: 25 °C

Procedure:
To a solution of 3,4-dimethoxy-cyclobut-3-ene-1,2-dione (1.5 g, 10.6 mmol) and trimethyl(tributylstannyl)silane (3.7 mL, 10.6 mmol) in anhydrous THF (75 mL) at −30° C. was added drop-wise a solution of tetrabutylammonium cyanide (57 mg, 0.2 mmol) in THF (3 mL). The clear solution quickly turned yellow and was left to warm to rt overnight. The reaction was concentrated in vacuo revealing a black oil which was dissolved in ether and filtered through a plug of silica (100% ether). The crude material was further purified by silica gel chromatography (100% hexanes to 3% Et2O in hexanes) to yield 3-methoxy-4-tributylstannanylcyclobut-3-ene-1,2-dione as a light yellow oil. 1H NMR (DMSO-d6, 400 MHz): δ0.90 (t, J=7.2 Hz, 9H), 1.09-1.23 (m, 6H), 1.23-1.38 (m, 6H), 1.43-1.63 (m, 6H), 4.38 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(O)=O.C([NH2:16])=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:16])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NC=O
Reactant: CC(=O)c1cccc(Cl)c1
Solvent: O=CO
Solvent: O
Product: CC(N)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
1-(3-Chlorophenyl)ethanone (11.9 g, 77.5 mmol) and formic acid (3.72 g, 77.5 mmol) were heated in formamide (10 mL) at 170-180° C. for 20 h. The mixture was cooled to room temperature, diluted with water and extracted with benzene. After removal of benzene by rotary evaporation the crude mixture was heated under reflux conditions in 3M HCl for 30 h. After cooling, the reaction was added to ether and extracted. The aqueous layer was basified with NaOH to pH 9 and extracted with dichloromethane. The dichloromethane was evaporated to collect the title compound (3.93 g, 33%). 1H NMR (400 MHz, CDCl3): δ 7.34 (s, 1H), 7.21 (m, 3H), 4.07 (m, 1H), 1.35 (d, 3H); MS (ESI) m/z: Calculated for C8H11ClN: 156.06; Observed: 156.0 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C1(=O)O[CH2:15][CH2:14][O:13]1.N1C=CN=C1.C(=O)=O>C(OCC)C>[OH:13][CH2:14][CH2:15][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10]
Reactant: NS(=O)(=O)c1ccccc1O
Reactant: O=C1OCCO1
Agent: O=C=O
Agent: c1c[nH]cn1
Solvent: CCOCC
Product: NS(=O)(=O)c1ccccc1OCCO
Reaction time: 18 h

Procedure:
A mixture of 74.6 g of (0.43 mol) of 2-hydroxybenzenesulfonamide, 45.3 g (0.51 mol) of ethylene carbonate and 0.9 g of imidazole was heated to 160° with vigorous stirring. After about four hours the carbon dioxide solution had subsided and no unreacted 2-hydroxybenzenesulfonamide was present in the reaction mixture. The mixture was allowed to cool and about 400 ml of diethyl ether was added to the thick oil. The two-phase mixture was stirred vigorously and was heated to reflux for about one hour. The diethyl ether was decanted off and a fresh portion of diethyl ether was added. The mixture was again stirred and heated to reflux. After the diethyl ether was decanted off a fresh portion of diethyl ether was added and the mixture was allowed to stand at ambient temperature for about 18 hours. The resulting light brown solid was isolated by filtration and was recrystallized from nitromethane to afford 49 g (53%) of trum exhibited a broad peak at approximately 3400 cm-1 consistent with the primary alcohol of the product and peaks at 3370 cm-1 and 3270 cm-1 consistent with the NH2 of a primary sulfonamide.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Li+].C[Si]([N-:17][Si](C)(C)C)(C)C.[OH-].[Na+].CO>C1(C)C=CC=CC=1>[F:1][CH:2]([F:11])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:17]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(c1ccccc1)C(F)F
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: NC(c1ccccc1)C(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
To a solution of 2,2-difluoro-1-phenylethanone (1 g, 6.4 mmol) in toluene (32 mL) at room temperature was added LiHMDS (1M in THF) (7.05 mL, 7.05 mmol). The reaction mixture was stirred for 30 min, followed by addition of BH3-DMS (1.216 mL, 12.81 mmol). The reaction mixture was stirred for 1 h. After cooling at 0° C., aqueous 2 N NaOH solution was carefully added over 5 min (Caution! gas evolution). The reaction was stirred for 1 h. The layer was separated and washed with water and brine. After dried over sodium sulfate, HCl in MeOH (7.17 mL, 8.97 mmol) was added to form a white precipitate. The precipitate was filtered off, washed with ether, and dried in vacuo yielding 2,2-difluoro-1-phenylethanamine (21%). 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (s, 5H), 6.52-6.07 (m, 1H), 4.78-4.69 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([S:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH:24]O>C(O)(=O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([S:17]([C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[O:24])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(Sc1ccc2c(-c3ccc(Cl)cc3)noc2c1)C(=O)O
Reactant: OO
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C(=O)O)S(=O)c1ccc2c(-c3ccc(Cl)cc3)noc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
5.56 g (16.0 mmol) of 2-[[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]thio]-2-methylpropionic acid and 6 ml of 30% H2O2 were combined in 200 ml glacial acetic acid. The mixture was stirred at room temperature and monitored by TLC for the disappearance of starting material and the appearance of product. After about four hours the reaction was stopped by diluting with excess 3N HCl. The resulting precipitate was filtered and washed several times with cold toluene to yield white crystals, 3.38 g (58%) of 2-[[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]sulfinyl]-2-methylpropionic acid, m.p. 184°-185° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:16][CH:17]([CH3:22])[CH2:18][C:19](Cl)=[O:20]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:19](=[O:20])[CH2:18][CH:17]([CH3:22])[CH3:16])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: CC(C)CC(=O)Cl
Product: CC(C)CC(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using 3-methyl-butyryl chloride (67 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-3-methyl butanamide (0.042 g).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([CH3:20])([CH3:19])[C:17]#N)=[CH:14][CH:13]=1.[OH2:23].Cl>CCCCCC.C(OCC)C>[Cl:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([CH3:20])([CH3:19])[CH:17]=[O:23])=[CH:14][CH:13]=1
Reactant: CC(C)(C#N)c1ccc(Cl)cc1
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Diisobutylaluminum hydride (0.236 mol, 236 mL of a 1M solution in hexane) is added over 90 minutes to a solution of p-chloro-α-methylhydratroponitrile (32.6 g, 0.181 mol) in diethyl ether under nitrogen at 0° C. After the addition is complete, water and 6N hydrochloric acid are added to the reaction mixture while maintaining the temperature below 30° C. The resultant aqueous solution is stirred overnight at room temperature and extracted with diethyl ether The organic extracts are combined, washed sequentially with 2N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as an oil (31.1 g, 94% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[NH2:20][CH2:21][CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([NH:20][CH2:21][CH2:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[O:19])[CH:16]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCCc1ccc(C(=O)O)cc1
Product: CCc1cc(-c2cncc(C(=O)NCCc3ccc(C(=O)O)cc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 4-(2-amino-ethyl)-benzoic acid to afford the title compound. MS: m/e=406 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[C:3]=1[N+:16]([O-])=O>[Pd].CCO.C1COCC1>[NH2:16][C:3]1[C:4](=[O:15])[N:5]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccn(Cc2ccccc2)c(=O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccn(Cc2ccccc2)c(=O)c1N
Reaction time: 1 h
Yield: 93.1 %

Procedure:
A solution of 4-amino-1-benzyl-3-nitro-1H-pyridin-2-one (1.10 g, 4.49 mmol) in 1:3 EtOH/THF (20 mL) was hydrogenated over 10% Pd/C (0.48 g, 0.45 mmol) at room temperature. After 1 h, the catalyst was removed by filtration, rinsing with MeOH. The filtrate was concentrated to provide 3,4-diamino-1-benzyl-1H-pyridin-2-one (0.90 g, 93% yield). 1H-NMR (DMSO): δ 7.32 (m, 2H), 7.23 (m, 3H), 6.98 (d, 1H, J=7.6 Hz), 5.80 (d, 1H, J=7.2 Hz), 5.22 (m, 2H), 5.0 (s, 2H), 4.11 (m, 2H). MS: calculated for C12H13N3O+H 216.1; found: 216.1.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([CH3:15])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[NH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>>[CH2:16]([N:11]1[C:12]2[C:7](=[C:6]([OH:30])[C:5]([C:3]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])=[N:14][C:13]=2[CH3:15])[CH:8]=[C:9]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:10]1=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1nc(C)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: Cc1nc(C(=O)NCCC(=O)O)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 26.2 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-8-methyl-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.075 mmol), β-alanine (668 mg, 7.5 mmol) and NaOMe solution (11 mL, 5.6 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in water washed several times with ether. The aqueous layer was acidified to pH 2 with 4 M HCl, and the resulting precipitate was collected by filtration and dried to give 9 mg of the title compound. MS: (+) m/z 458.36 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11][O:12][Si](C(C)(C)C)(C)C)[N:5]=1)(=[O:3])[CH3:2].Cl>CO>[C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11][OH:12])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C)n(CCO[Si](C)(C)C(C)(C)C)n1
Agent: Cl
Solvent: CO
Product: CC(=O)c1cc(C)n(CCO)n1
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
3-Acetyl-1-(2-t-butyldimethylsilyloxyethyl)-5-methylpyrazole (1.6 g, 5.7 mM) in methanol (50 ml) was treated with 2M hydrochloric acid (10 ml). After stirring for 0.5 h the mixture was evaporated to remove methanol and the residual oil extracted repeatedly with dichloromethane and ethyl acetate to give the title compound as a colouless oil (0.633 g, 66%); δH (CDCl3) 2.30 (3H, s), 2.48 (3H, s), 3.98-4.09 (2H, m), 4.12-4.21 (2H, m), and 6.49 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[N:44]1([CH2:50][CH:51]([N:55]2[CH:59]=[C:58]([C:60]3[C:61]4[CH:68]=[CH:67][N:66](COCC[Si](C)(C)C)[C:62]=4[N:63]=[CH:64][N:65]=3)[CH:57]=[N:56]2)[CH2:52][C:53]#[N:54])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:8]([N:47]2[CH2:46][CH2:45][N:44]([CH2:50][CH:51]([N:55]3[CH:59]=[C:58]([C:60]4[C:61]5[CH:68]=[CH:67][NH:66][C:62]=5[N:63]=[CH:64][N:65]=4)[CH:57]=[N:56]3)[CH2:52][C:53]#[N:54])[CH2:49][CH2:48]2)=[O:10])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Reactant: O=C(O)c1ncc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CCC(CN1CCN(C(=O)c2ncc(Cl)cc2F)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 0.25 h

Procedure:
To a solution of 5-chloro-3-fluoropyridine-2-carboxylic acid (23.5 mg, 0.134 mmol, prepared as described in Eur. J. Org. Chem. (24), 4174-4180; 2002) and triethylamine (86.2 uL, 0.618 mmol) in THF (1.1 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (47.0 mg, 0.124 mol). After stirring for 15 minutes, 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (61 mg, 0.10 mmol; from Example 12, Step 2) was added. The reaction was stirred for two hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed successively with water, 0.1 N NaOH and brine, dried over sodium sulfate and concentrated. The residue was stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, and stirred in methanol (1 mL) containing ethylenediamine (0.2 mL) for 1 hour. Preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH, was used to purify the product (29 mg, 57%). 1H NMR (300 MHz, d6-dmso): δ □12.10 (br s, 1H), 8.81 (s, 1H), 8.61 (s, 1H), 8.55 (dd, 1H), 8.37 (s, 1H), 8.24 (dd, 1H), 7.60 (d, 1H), 6.97 (d, 1H), 4.98 (tt, 1H), 3.65-3.56 (m, 2H), 3.26-3.12 (m, 4H), 2.92-2.77 (m, 2H), 2.64-2.25 (m, 4H); LCMS (M+H)+: 494.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([OH:21])[C:18]([Br:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)[CH3:2].[CH3:24]I.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([O:21][CH3:24])[C:18]([Br:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:9]=1)[CH3:2]
Reactant: CI
Reactant: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(OC)c(Br)cc1F

Procedure:
using 2-ethoxy-1-(4-bromo-2-fluoro-5-hydroxyphenyl)-4-trifluoromethyl-6(1H)-pyrimidinone and methyl iodide with sodium hydride in dimethylformamide there is obtained 2-ethoxy-1-(4-bromo-2-fluoro-5-methoxyphenyl)-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 126°-128° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([CH3:48])([CH3:47])[CH2:10][NH:11][C:12](=[O:46])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:25]=[C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([CH2:38][Cl:39])=[CH2:37])=[CH:30][CH:29]=3)[N:23]=[C:22]([O:40][CH2:41][C:42]([F:45])([F:44])[F:43])[N:21]=2)=[CH:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]([CH3:48])([CH3:47])[CH2:10][NH:11][C:12](=[O:46])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:25]=[C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([CH2:38][Cl:39])=[CH2:37])=[CH:30][CH:29]=3)[N:23]=[C:22]([O:40][CH2:41][C:42]([F:45])([F:44])[F:43])[N:21]=2)=[CH:15][CH:14]=1
Reactant: C=C(CCl)COc1ccc(CNc2nc(Nc3ccc(C(=O)NCC(C)(C)CNC(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(CCl)COc1ccc(CNc2nc(Nc3ccc(C(=O)NCC(C)(C)CN)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
To a solution of tert-butyl(3-(4-((4-((4-((2-(chloromethyl)allyl)oxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)-2,2-dimethylpropyl)carbamate (1 g) in DCM (10 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 3 hours. All the solvents were removed under vacuum. The residue was diluted with EtOAc (200 mL), washed with 10% of NaHCO3 (50 mL), brine (50 mL), dried over MgSO4 and concentrated to give N-(3-amino-2,2-dimethylpropyl)-4-(4-(4-(2-(chloromethyl)allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamide (0.8 g).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([OH:11])[C:3]=1[C:4]#[N:5].[CH3:12][O-:13].[Na+]>CO>[OH:11][C:6]1[C:3]([C:4]#[N:5])=[C:2]([O:13][CH3:12])[N:9]=[C:8]([CH3:10])[CH:7]=1
Reactant: Cc1cc(O)c(C#N)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C)cc(O)c1C#N
Temperature: 60 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
A mixture of 2-chloro-4-hydroxy-6-methylnicotinonitrile (2.0 g, 11.9 mmol), sodium methanolate (3.2 g, 59.5 mmol) in methanol (20 mL) was stirred at 60° C. overnight under N2. The mixture was quenched with HCl (1M) to pH=2. It was partitioned between water (500 mL) and ethyl acetate (500 mL), the organic layer was dried and concentrated to afford 4-hydroxy-2-methoxy-6-methylnicotinonitrile (2.0 g brown solid, 100% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[C:4]([F:11])[C:3]=1[I:12].[Cl:13]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[N:7][OH:8])[Cl:13])=[C:4]([F:11])[C:3]=1[I:12]
Reactant: ON=Cc1ccc(Cl)c(I)c1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccc(Cl)c(I)c1F
Temperature: 55 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-chloro-2-fluoro-3-iodobenzaldehyde oxime (0.860 g, 2.87 mmol) in DMF (5 mL) at RT was added N-chlorosuccinimide (140 mg). The mixture was heated at 55° C. for 5 min. The mixture was allowed to cool below 50° C. and additional N-chlorosuccinimide (282 mg) was added, and heating continued at 55° C. for 20 min. The resulting reaction mixture was allowed to cool to RT and treated with water (20 mL), and extracted with ethyl acetate (3×30 mL). The combined ethyl acetate layers were washed with brine, dried over magnesium sulfate and concentrated to afford 4-chloro-2-fluoro-3-iodobenzoyl chloride oxime as a light yellow amorphous solid. MS (ESI, pos.ion) m/z: 335 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[ClH:10].C([OH:13])C>>[ClH:10].[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[OH:13])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: CCO
Agent: Cl
Product: N=C(O)c1ccc(F)cc1

Procedure:
In anhydrous ethanol, compound [I'], commercially available 4-fluorobenzonitrile is reacted with gaseous hydrogen chloride to yield compound [J'], 4-fluorobenzimidate hydrogen chloride. Compound [J'] is reacted with gaseous ammonia to yield compound [K'], 4-fluorobenzamidine hydrogen chloride.