Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:14][C@@H:13]2[C@@H:9]([N:10]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][N:33]6[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=56)[CH:27]=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH2:39])[CH2:11][CH2:12]2)[CH2:8]1>C1COCC1.C(Cl)Cl>[CH3:6][N:7]1[CH2:14][C@@H:13]2[C@@H:9]([N:10]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][N:33]6[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=56)[CH:27]=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH:39][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11][CH2:12]2)[CH2:8]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1N1CC[C@@H]2CN(C)C[C@@H]21
Temperature: -15 °C
Reaction time: 1 h

Procedure:
A solution of acryloyl chloride (13 mg, 0.14 mmol) in THF (1 mL) was added dropwise to a stirred solution of 4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-6-methoxy-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 160, 100 mg, 0.13 mmol) in THF (3 mL), which was cooled in an ice/CH3OH bath to approximately −15° C. The mixture was stirred for 1 h and allowed to warm to −0° C. The mixture was then diluted with CH2Cl2 (50 mL) and the resulting solution was washed with sat. NaHCO3 (50 mL). The aqueous solution was further extracted with CH2Cl2 (2×25 mL) and the combined organic solutions were dried (MgSO4) and concentrated in vacuo onto silica. Patrial purification by FCC, eluting with 0-3.5% 7N methanolic ammonia in CH2Cl2 provided some of the title compound. Further purification by FCC, eluting with 0-1.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (33 mg, 49%) as a yellow solid; 1H NMR: 1.77 (1H, s), 1.94-2.15 (1H, m), 2.10 (3H, s), 2.29 (1H, d), 2.39-2.48 (1H, m), 2.87 (1H, s), 3.11-3.20 (1H, m), 3.33-3.42 (2H, m), 3.81 (3H, s), 4.26-4.34 (1H, m), 5.68 (1H, dd), 6.18 (1H, dd), 6.53 (1H, dd), 6.67 (1H, s), 7.04 (1H, td), 7.21 (1H, d), 7.36-7.43 (1H, m), 8.03 (1H, s), 8.08 (1H, s), 8.30 (1H, d), 8.42 (1H, d), 8.73-8.79 (2H, m), 9.41 (1H, s); m/z: ES+ MH+ 511.16.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[Cl:14][CH2:15][CH2:16][N:17]([CH2:25][CH2:26]Cl)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Br-].C([P+](CC)(CC)CC)CCCCCCCCCCCCCCC.Cl>CO.O>[ClH:14].[CH2:18]([N:17]1[CH2:25][CH2:26][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([C:9]#[N:10])[CH2:15][CH2:16]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: N#CCc1ccc(F)cc1
Agent: CCCCCCCCCCCCCCCC[P+](CC)(CC)CC
Agent: Cl
Agent: [Br-]
Solvent: CO
Solvent: O
Product: N#CC1(c2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
4-Fluorophenyl-acetonitrile (5.89 g, 40 mmol), and aqueous sodium hydroxide solution (60 mL, 50% by weight) are combined and then N,N-Bis(2-chloroethyl)-N-benzylamine hydrochloride (11.28 g, 42 mmol) and hexadecyltriethyl phosphonium bromide (1.02 g, 2 mmol) were added. The reaction mixture was heated to 100° C. and stirred vigorously for 1 hour. The reaction mixture is cooled to ambient temperature and water was added. The diluted reaction mixture was acidified with 6M hydrochloric acid solution and extracted with diethyl ether. The aqueous layer is then made basic with solid potassium hydroxide and extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, filtered, and evaporated in vacuo to give a residue. The residue was added to a solution of hydrochloric acid in methanol and the solution was evaporated in vacuo to give a solid. The solid was recrystallized from methanol/ethyl acetate to the title compound: mp=263-264.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])=[N:3][CH:4]=1
Reactant: Nc1ccc(F)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(F)cn2)cc1
Temperature: 80 °C

Procedure:
2-Amino-5-fluoropyridine (4.0 g, 0.036 mol) was dissolved in pyridine (40 mL) and p-toluenesulfonyl chloride (7.5 g, 0.039 mol) was added. The reaction was heated at 80° C. for 24 hours then cooled and the pyridine was removed under vacuum. The residue was partioned between water (100 mL) and ethyl acetate (100 mL). The layers were separated and the organic layer was washed (3×100 mL) with water then dried and solvent stripped to give clean N-(5-fluoropyridin-2-yl)-4-methylbenzenesulfonamide 1 Rf 0.42, 50% E/H; MS m/z 267 (M+H).
Reaction SMILES: N[C@H](C(O)=O)CCCNC(=N)N.[NH2:13][C@H:14]([C:23]([OH:25])=[O:24])[CH2:15][C:16]1[CH:21]=CC(O)=C[CH:17]=1>>[NH2:13][C@H:14]([C:23]([OH:25])=[O:24])[CH2:15][CH:16]([CH3:21])[CH3:17]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
1.1/1/; His: 0.95/1/; Arg: 1.0/1/; Tyr: 0.7/1/.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[N:10][OH:11])[CH2:4][C:3]1([CH3:13])[CH3:12].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH:14]=[N+:10]([CH:5]2[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([CH3:1])[C:3]([CH3:13])([CH3:12])[CH2:4]2)[O-:11])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN1C(C)(C)CC(=NO)CC1(C)C
Reactant: O=Cc1ccccc1
Product: CN1C(C)(C)CC([N+]([O-])=Cc2ccccc2)CC1(C)C

Procedure:
Following the general procedure of Example 1, the title compound is prepared from 5.0 g (29.4 mmol) of 1,2,2,6,6-pentamethylpiperidin-4-one oxime and 3.1 g [29 mmol) of benzaldehyde in a yield of 2.3 g (30%) of a white solid which after recrystallization from heptane melts at 104°-105° C. 1HMR (200 MHz, CDCl3)δ 8.26 (m, 2H's); 7.45 (s, 1H); 7.40 (m, 3H's); 4.18 (tt, IH); 2.28 (s, 3H's); 2.13 (t, 2H's); 1.93 (dd, 2H's); 1.23 (s, 6H's); 1.10 (s, 6H's). IR (CDCl3) 3020, 2950, 1570, 1550,
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B(F)(F)F.CCOCC.[N+](=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N-].C([O-])(O)=O.[Na+]>CCOCC>[CH2:30]([O:29][C:27]([CH:26]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]1=[O:14])=[O:28])[CH3:31]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)CC1=O
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a 0° C. solution of 3-oxo-piperidine-1-carboxylic acid tert-butyl ester (11.3 g, 56.7 mmol) in Et2O (170 mL) was added BF3.Et2O (7.2 mL, 56.7 mmol) and ethyl diazoacetate (7.2 mL, 68.0 mmol) dropwise over 30 min. After an additional 1 h, satd. aq. NaHCO3 was added and the solution was stirred for 1 h, then was extracted with Et2O (2×). The combined organic layers were washed with brine, dried and concentrated. The resulting residue was purified via SiO2 chromatography (10-30% EtOAc/hexanes) to give 5.48 g (34%) of 3-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester. In addition, 5.25 g (32%) of the more polar 4-oxo-azepane-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester was isolated.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[C:16]([C:17]4[C:22]([C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][C:14](B(O)O)=[C:13]1[C:8]=3[CH:9]=[CH:10][CH:11]=[CH:12]1.[Br:26][C:27]1[CH:28]=[C:29](I)[CH:30]=[CH:31][CH:32]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CO.O.C(COC)OC>[Br:26][C:27]1[CH:28]=[C:29]([C:14]2[CH:15]=[C:16]3[C:7](=[C:8]4[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]4)[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:22]2[C:17]3=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Brc1cccc(I)c1
Reactant: OB(O)c1cc2c3ccccc3c3ccccc3c2c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: Brc1cccc(-c2cc3c4ccccc4c4ccccc4c3c3ccccc23)c1
Reaction time: 8 h
Yield: 34.2 %

Procedure:
In argon atmosphere, a mixture of 5.00 g (15.52 mmol) of 10-benzo[g]chryseneboronic acid, 4.39 g (15.52 mmol) of 3-bromoiodobenzene, 0.90 g (0.78 mmol) of tetrakis(triphenylphosphine)palladium (0), 30 ml of toluene, 30 ml of dimethoxyethane, and 23.28 g of a 2 M sodium carbonate aqueous solution was refluxed for 8 h under stirring and left standing overnight. The reaction mixture was added with water and stirred at room temperature for one hour. After adding methanol, the solid matter was collected by filtration and purified by silica gel chromatography to obtain 2.30 g (yield: 34.2%) of 10-(3-bromophenyl)benzo[g]chrysene.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH2:23]([O:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][C:31]1[CH:32]=[C:33]([NH:34][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])[CH:35]=[CH:36][CH:37]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: Nc1cccc(OCc2ccccc2)c1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4cccc(OCc5ccccc5)c4)cc3)c2)o1

Procedure:
N-(3-Benzyloxyphenyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 3-benzyloxyaniline using method I. LCMS; retention time 3.79 min, MH+ 476.
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[CH2:3][C:4](=[O:6])[CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:18][C:16]([F:17])([F:19])[C:13]1[CH:14]=[CH:15][C:10]([S:9][CH2:8][CH2:7][CH:2]=[CH:3][C:4](=[O:6])[CH3:5])=[CH:11][CH:12]=1
Reactant: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=CCCSc1ccc(C(F)(F)F)cc1

Procedure:
0.3 Gram of 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-hexanone was dissolved in 30 ml of toluene, and 0.004 g of p-toluenesulfonic acid was added thereto. The resulting mixture was refluxed for 30 minutes with stirring, allowed to cool and then treated in the same manner as in Production example 34. Thus, 6-(4-trifluoromethylphenylthio)-3-hexen-2-one was obtained (purity: 98.5%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C1C[O:12][CH2:11]C1>>[N:7]1[C:11](=[O:12])[N:8]=[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=12
Reactant: Nc1ccccc1N
Reactant: C1CCOC1
Product: O=C1N=c2ccccc2=N1
Reaction time: 16 h

Procedure:
A solution of phenylene diamine 6.48 g in dry THF (150 ml) was cooled to 5° C. A suspension of 1,1-carbonyldiimidazole (10.7 g) in THF (100 ml) was added to this solution over 15 minutes keeping the temperature below 10° C. The mixture was stirred for 16 hours and the resultant solid was collected and dried to give the title compound (4.5 g); NMR: 6.9 (s, 4H), 10.5 (s, 2H); MS (ESP−): 135 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[C:17](N(OC)C)=[O:18])[CH:5]=[CH:6][CH:7]=1.[CH3:23][Mg]Br.CCOCC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[C:17](=[O:18])[CH3:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1cc2ccccc2n1-c1cccc(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cc2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a mixture of 1-(3-fluorophenyl)-N-methoxy-N-methyl-1H-indole-2-carboxamide (0.52 g, 1.7 mmol) in tetrahydrofuran (10 mL) was added 3.0 M methylmagnesium bromide in ether (4.6 mL, 0.014 mol). The reaction was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated to give crude product (0.4 g, 91%). The crude product was used directly in next step. LCMS calculated for C16H13FNO(M+H)+: m/z=254.1. Found: 254.1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[CH2:8](O)[CH2:9][OH:10]>>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH:6]1[O:10][CH2:9][CH2:8][O:7]1
Reactant: OCCO
Reactant: O=Cc1ccco1
Product: C1COC(C2OCCO2)C1

Procedure:
Note: 2-(2-oxolanyl)-dioxolane was prepared in similar manner by reacting 2-furaldehyde and ethylene glycol and then hydrogenating the reaction product. The product characterization was confirmed by I. R., 1 H nmr and 13 C nmr.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[NH:8][N:7]=1.[C:14]([S:17][CH2:18][CH2:19][C:20](Cl)=[O:21])(=[O:16])[CH3:15]>C([O-])([O-])=O.[Na+].[Na+]>[C:14]([S:17][CH2:18][CH2:19][C:20]([N:8]1[CH:9]([C:11]([OH:13])=[O:12])[CH2:10][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:7]1)=[O:21])(=[O:16])[CH3:15]
Reactant: CC(=O)SCCC(=O)Cl
Reactant: O=C(O)C1CC(c2cccs2)=NN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)SCCC(=O)N1N=C(c2cccs2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(±)-4,5-Dihydro-3-(2-thienyl)-1H-pyrazole-5-carboxylic acid is dissolved in aqueous Na2CO3 (1.38 g) at pH 8.6. The temperature is lowered to 5° C. and 3-(acetylthio)propionyl chloride (4.15 g) and a 25% solution of Na2CO3 are added simultaneously maintaining the pH at 8-9. The final pH is 8.9 and the reaction is stirred for 2 hours at room temperature. It is then extracted with ethyl acetate and the ethyl acetate is discarded. The aqueous layer is made strongly acid with 20% HCl and the gummy precipitate is extracted with ethyl acetate. The ethyl acetate is dried over MgSO4 and removed to yield a viscous residue (7.2 g) which is triturated with ether to yield 5.1 g of material, melting point 127°-130° C., dec. After recrystallization from CH3CN (very soluble) the melting point is constant at 134°-136° C., dec.
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([I:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.F[C:13]1C(F)=CC=CC=1N.FC1C=CC(C)=CC=1N>>[I:11][C:8]1[S:9][C:10]2[CH:2]=[CH:3][C:4]([CH3:13])=[CH:5][C:6]=2[N:7]=1
Reactant: Fc1cccc2nc(I)sc12
Reactant: Nc1cccc(F)c1F
Agent: Cc1ccc(F)c(N)c1
Product: Cc1ccc2sc(I)nc2c1

Procedure:
The title compound was prepared following the route for 7-fluoro-2-iodo-1,3-benzothiazole from 2,3-difluoroaniline, starting from 2-fluoro-5-methylaniline and conducting the first step at 180° C. for 48 h in a sealed tube.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24]C)[CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=3)[CH:15]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2cc(C3(O)CCN(Cc4ccccc4)CC3)ccc2c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Oc1ccc2cc(C3=CCN(Cc4ccccc4)CC3)ccc2c1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
A solution of 1.0 gm (2.9 mMol) 1-benzyl-4-hydroxy-4-(6-methoxynaphth-2-yl)piperidine and 0.65 mL (5.8 mMol) 48% hydrobromic acid in 10 mL acetic acid was heated at reflux for 18 hours. The reaction mixture was cooled to room temperature, neutralized with 5N sodium hydroxide, and extracted well with ethyl acetate. The organic extracts were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The residual solid was suspended in a mixture of ethyl acetate and hexane and the suspension sonicated. The suspension was then filtered to provide 0.57 gm (63%) of the desired compound as a grey solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([CH3:21])[C:11]([CH2:13][NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])(=[O:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH:26]=O>[OH-].[Na+].CO>[Cl:22][C:23]1[CH:24]=[C:25](/[CH:26]=[CH:2]/[C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]([CH3:21])[C:11]([CH2:13][NH:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])=[O:12])=[O:3])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)c1ccccc1N(C)C(=O)CNC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C(=O)CNC(=O)C(C)(C)C)c1ccccc1C(=O)/C=C/c1ccc(Cl)c(Cl)c1
Yield: 27.9 %

Procedure:
5 drops of 3M sodium hydroxide solution were added to a mixture of 160 mg (0.52 mmol) of N-[[N-(2-acetylphenyl)-N-methylcarbamoyl]methyl]pivalamide and 100 mg (0.57 mmol) of 3,4-dichlorobenzaldehyde in 3 ml of methanol. After 1 hr at room temperature the solvent was removed by evaporation and the residue chromatographed on silica gel using ethyl acetate/petrol (55:45) for the elution. There was obtained 65 mg of (E)-N-[[N-[2-[3-(3,4-dichlorophenyl)acryloyl]phenyl]-N-methylcarbamoyl]methyl]pivalamide as a yellow gum. MS: m/e 463 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].C(N(CC)CC)C.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[C:15]([Si:19]([CH3:21])([CH3:20])[O:4][CH2:3][C:2]([CH3:7])([CH3:1])[CH2:5][OH:6])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(CO)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CO)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a solution of 2,2-dimethyl-propane-1,3-diol (5.0 g, 48 mmol) in DCM (20 mL) was added triethylamine (14.6 g, 144.3 mmol) and tert-butyl-chloro-dimethyl-silane (7.2 g, 48.1 mmol). The solution was stirred overnight at room temperature. The reaction mixture was then washed with water (×3) and concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound (6.1 g, 58%): 1H NMR (CDCl3, 400 MHz) delta 0.04 (s, 6H), 0.86 (s, 6H), 0.87 (s, 9H), 2.94 (s, 1H), 3.43 (s, 4H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[Cl:13][C:14]1[C:19]2[NH:20][CH:21]=[N:22][C:18]=2[CH:17]=[C:16]([Cl:23])[N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(N(C)C)=O>[Cl:13][C:14]1[C:19]2[N:20]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=3)[CH:21]=[N:22][C:18]=2[CH:17]=[C:16]([Cl:23])[N:15]=1
Reactant: Clc1cc2nc[nH]c2c(Cl)n1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1ccc(Cn2cnc3cc(Cl)nc(Cl)c32)cc1
Reaction time: 2 h

Procedure:
1-(Bromomethyl)-4-(trifluoromethyl)benzene (6.36 g, 26.6 mmol) was added to a stirred solution of 4,6-dichloro-3H-imidazo[4,5-c]pyridine (5.0 g, 26.6 mmol) and cesium carbonate (10.40 g, 31.9 mmol) in DMA (30.0 ml) at room temperature and was stirred for 2 h. Water was added, and the solids were filtered and dried overnight. Crude 1H NMR showed ˜4:1 ratio of undesired 4,6-dichloro-1-(4-(trifluoromethyl)benzyl)-1H-imidazo[4,5-c]pyridine:desired 4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine. The crude residue was purified by silica gel chromatography (EtOAc/DCM, 0% to 20%) to afford the desired 4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine (fraction 1) and the undesired 4,6-dichloro-1-(4-(trifluoromethyl)benzyl)-1H-imidazo[4,5-c]pyridine (fraction 2). 4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine: MS ESI calc'd for C14H8Cl2F3N3 [M+H]+ 346. found 346.
Reaction SMILES: C(N(CC)CC)C.O[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].[C:16](#[N:20])[CH2:17][C:18]#[N:19]>CO>[NH2:20][C:16]1[O:15][C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[C:17]=1[C:18]#[N:19]
Reactant: N#CCC#N
Reactant: O=C1CCCCC1O
Solvent: CCN(CC)CC
Solvent: CO
Product: N#Cc1c(N)oc2c1CCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
2.1 4.8 ml of triethylamine are added dropwise to a solution of 11.0 g of 2-hydroxycyclohexanone and 9.6 g of malononitrile in 25 ml of methanol, and the mixture is stirred at room temperature for a further 4 hours. The crystals which deposit are separated off and washed with methanol, giving 12.8 g of 2-amino-4,5,6,7-tetrahydrobenzofuran-3-carbonitrile (“BA”), m.p. 179°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:8]23[CH2:13][C@H:12]2[CH2:11][O:10][C:9]3=[O:14])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Li+].C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.CCCCCCC>[F:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH2:9][OH:14])[CH2:13][C@H:12]2[CH2:11][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC[C@@H]2C[C@]12c1cccc(F)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: OC[C@@H]1C[C@@]1(CO)c1cccc(F)c1
Temperature: -7.5 °C
Reaction time: 15 h

Procedure:
(1S,5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexan-2-one (4, 10.08 g, 0.052 mol, 1.0 equiv.) was dissolved in 2-methyl-THF (75.60 mL) under nitrogen. The solution was cooled to −5 to −10° C., and 2.0 M Lithium tetrahydroborate in THF (39.34 mL, 0.079 mol, 1.5 equiv.) was added to the reaction mixture while maintaining the internal temperature below 0° C. The reaction was stirred at 20-25° C. for 14-16 hours and monitored by HPLC and TLC (EtOAc/Heptane=1/1). Once the reaction was completed, the reaction mixture was cooled to 0-5° C. and reverse quenched into a pre-cooled (0-5° C.) 20% aqueous citric acid solution (50.40 mL, 1.67 equiv.) at such a rate as to maintain the internal temperature below 5° C. Once the quench was complete, the reaction mixture was warmed to 20-25° C. and stirred for at least 20 min. The aqueous layer was back extracted once with 2-methyl-THF (50.40 mL). The organic layers were combined and washed once with saturated aqueous sodium bicarbonate solution (20.16 mL) and once with 20% aqueous NaCl (20.16 mL). The solvent was removed under reduced pressure then azeotroped with 2-methyl-THF until KF is less than 1500 ppm to afford the title compound, ((1S,2R)-1-(3-fluorophenyl)cyclopropane-1,2-diyl)dimethanol; 5 (10.29 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10](=[NH:14])OCC)[CH2:9][CH2:8]2)[CH:6]=1.N[C:16]1[C:21]([NH2:22])=[CH:20][N:19]=[C:18]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)[N:17]=1>C(O)(=O)C>[F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]3[NH:14][C:20]4[C:21]([N:22]=3)=[CH:16][N:17]=[C:18]([N:23]3[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:30])[CH2:24]3)[N:19]=4)[CH2:8][CH2:9]2)[CH:6]=1
Reactant: CCOC(=N)C1(n2cc(F)cn2)CC1
Reactant: Nc1cnc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Solvent: CC(=O)O
Product: O=C([C@@H]1CCCN(c2ncc3nc(C4(n5cc(F)cn5)CC4)[nH]c3n2)C1)N1CCCC1

Procedure:
Ethyl 1-(4-fluoro-1H-pyrazol-1-yl)cyclopropanecarbimidate (148 mg, 0.75 mmol) and acetic acid (0.8 mL) were added to the filtrate containing (R)-(1-(4,5-diaminopyrimidin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone, prepared in the previous step. The reaction mixture was heated at reflux for 16 h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 0-4% methanol in ethyl acetate) to afford the title compound. MS (ES+APCI) (M+H) 425.2; LCMS retention time: 3.545 min (Method V1).