Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[C:8]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.O>C(Cl)Cl>[C:1]1(=[C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(=C2CCCCCC2)c2ccc(C#N)cc2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To a cold (5° C.) solution of 4-{cycloheptylidene[4-(methyloxy)phenyl]methyl}benzonitrile (207) (0.300 g, 0.94 mmol) in CH2Cl2 (20 mL) was added BBr3 (0.358 mL, 3.79 mL). The resultant reaction mixture was stirred between 5° C. and 20° C. for 3 h. Reaction mixture was poured into water (125 mL) and then extracted with CH2Cl2 (3×50 mL). The combined organic layer was dried and concentrated under reduced pressure to afford the crude product. The product was purified by flash column chromatography to give 0.245 g (86%) of compound 208 as a white solid. mp 110-111° C. IR (film): 3391, 2921, 2852, 2229, 1609, 1509, 1213, 829, 731 cm−1. 1H NMR (300 MHz, CDCl3): δ 7.57 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 6.79 (d, J=8.4 Hz, 2H), 4.97 (br s, 1H), 2.35 (br s, 2H), 2.29 (br s, 2H), 1.60 (br s, 8H). LCMS (ESI): m/z 302 (M−H)−. Anal. Calcd for C21H21NO, C, 83.13; H, 6.98; N, 4.62; Found: C, 83.13; H, 6.96; N, 4.62.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[N:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])[C:12]([O:21][CH3:22])=[CH:11][CH:10]=1)=[O:8]>CO.O1CCCC1.[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[N:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:12]([O:21][CH3:22])=[CH:11][CH:10]=1)[OH:8]
Reactant: COC(=O)/C=C/c1nc(C(=O)CCCC(=O)OC)ccc1OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCCC(O)c1ccc(OC)c(CCC(=O)OC)n1
Yield: 99.3 %

Procedure:
Under the conditions of example 1 C, a solution of 1.89 g of 5-[3-methoxy-2-(2-methoxycarbonyl-(1E)-1-ethenyl)-6-pyridyl]-5-oxopentanoic acid methyl ester in 75 ml of methanol and 15 ml of tetrahydrofuran is hydrogenated in the presence 400 mg of 10% palladium catalyst and worked up. 1.9 g of 5-[3-methoxy-2-(2-methoxycarbonylethyl)-6-pyridyl]-(5RS)-5-hydroxypentanoic acid methyl ester is obtained as oil.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[O:20][C:19]=2[CH3:31])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[O:20][C:19]=2[CH3:31])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:33]([CH3:32])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1oc(-c2ccc(F)cc2F)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Product: Cc1oc(-c2ccc(F)cc2F)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 94.7 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-{cyclohexyl[5-(2,4-difluorophenyl)-2-methyl-3-furyl]methoxy}benzoic acid (235 mg) as well as ethyl 3-(methylamino)propanoate (86 mg) to give the title compound (267 mg, 95%) as an amorphous compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:27](O)[CH2:28][OH:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:10]3[N:19]=[C:18]([NH:20][C:21]4[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=4)[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=3)[O:29][CH2:28][CH2:27][O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(Nc2nc(C3(c4ccc(F)cc4)OCCO3)nc3ccccc23)n[nH]1
Yield: 1 %

Procedure:
To (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 3 (0.20 g, 0.58 mmol) in toluene (20 mL) were added ethylene glycol (0.2 mL) and p-toluenesulfonic acid monohydrate (catalytic quantity). The mixture was heated under reflux overnight while collecting water in a Dean-Stark trap. Additional ethylene glycol (1.5 mL) and p-toluenesulfonic acid monohydrate (50 mg) were added and mixture was heated at reflux overnight with collection of water. After cooling, the mixture was evaporated to dryness, and then dissolved in DMSO (8 mL). A 5 mL aliquot of this solution was purified by preparative reverse-phase HPLC (Varian diphenyl reverse phase column eluting with gradient of solvent B=0.05% HOAC/ACN and solvent A=0.05% HOAc/H2O) followed by additional purification by preparative reverse-phase HPLC (Phenomenex C-18 reverse phase column, eluted with gradient of solvent B=0.05% HOAC/ACN and solvent A=0.05% HOAc/H2O) to afford 2-(2-(4-fluorophenyl)-1,3-dioxolan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (2 mg, 1%). 1H NMR (300 MHz, DMSO-d6) δ 2.20 (s, 3H) 4.05-4.22 (m, 4H) 6.2 (s, 1H) 7.19 (t, 2H) 7.5-7.65 (m, 3H) 7.81 (m, 2H) 8.59 (d, 1H) 10.38 (s, 1H) 12.08 (s, 1H); LC-MS (ESI) m/z 392 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]2[N:7]([CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:6]=[CH:5][C:4]=2[CH2:3]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=13)[N:7]([CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:6]=[CH:5]2
Reactant: CC(=O)NCCn1ccc2c1-c1ccccc1C(C)C2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CC(=O)NCCn1ccc2cc(C)c3ccccc3c21
Temperature: 80 °C
Reaction time: 4 h
Yield: 6 %

Procedure:
N-[2-(4,5-Dihydro-5-methyl-1H-benzo[g]indol-1-yl)ethyl]acetamide (5.0 g) was suspended in 80 ml of toluene under argon, treated with 4.7 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and stirred at 80° C. for 4 hours. A further 1.0 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was added and the mixture was stirred at 80° C. for a further 1 hour. The solution was cooled and filtered over 60 g of aluminium oxide (neutral, III) with ethyl acetate as the eluent. The filtrate was concentrated and yielded 0.3 g (6%) of N-[2-(5-methyl-1H-benzo[g]indol-1-yl)ethyl]acetamide as an amorphous, yellow solid which was processed without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)([CH3:3])[CH3:2].Cl.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:29])[CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:29])[CH2:22][N:23]2[CH2:24][CH2:25][N:26]([C:9]([C:7]3[NH:6][N:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:8]=3)=[O:11])[CH2:27][CH2:28]2)=[CH:17][CH:16]=1
Reactant: CC(C)c1cc(C(=O)O)[nH]n1
Reactant: O=C(CN1CCNCC1)c1ccc(F)cc1
Agent: Cl
Product: CC(C)c1cc(C(=O)N2CCN(CC(=O)c3ccc(F)cc3)CC2)[nH]n1
Yield: 75.7 %

Procedure:
The title compound was prepared in a similar manner as described in Example 1.2, using 3-isopropyl-1H-pyrazole-5-carboxylic acid (23.1 mg), and 1-(4-fluorophenyl)-2-(piperazin-1-yl)ethanone dihydrochloride (29.5 mg) as starting materials, to afford the title compound (27.1 mg) as a white solid. Exact mass calculated for C19H23FN4O2: 358.2. Found: LCMS m/z=359.3 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][N:16]=[N+:17]=[N-:18])[CH:9]=[C:8]([C:19](OCC)=[O:20])[N:7]=1)=O)C.[BH4-].[Na+].[Cl-].[Cl-].[Ca+2].[H][H]>ClCCl.C(O)C.O>[N:16]([CH2:15][CH2:14][CH2:13][O:12][C:10]1[CH:11]=[C:6]([CH2:4][OH:3])[N:7]=[C:8]([CH2:19][OH:20])[CH:9]=1)=[N+:17]=[N-:18]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(OCCCN=[N+]=[N-])cc(C(=O)OCC)n1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: [N-]=[N+]=NCCCOc1cc(CO)nc(CO)c1
Reaction time: 2 h

Procedure:
To a stirred solution of diethyl-4-(3-azidopropoxy)-2,6-pyridinedicarboxylate (4.2 mmol) in dichloromethane (10 mL) and absolute ethanol (15 mL), was added in portions, NaBH4 (4.2 mmol) at 25° C. Powdered CaCl2 (4.2 mmol) was added cautiously in small portions and the evolution of hydrogen was allowed to cease before each further addition. The reaction mixture was stirred for 2 hours. Water (100 mL) was added and the reaction mixture was extracted several times with ethyl acetate. The ethyl acetate layers were combined, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by silica gel flash column chromatography to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([P:17]([C:31]2[CH:36]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:34]([O:41][CH3:42])=[C:33]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:32]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[P:24](OCC)OCC)[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C[Si](Cl)(C)C>>[C:13]([C:9]1[CH:8]=[C:7]([P:17]([C:31]2[CH:36]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:34]([O:41][CH3:42])=[C:33]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:32]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[PH2:24])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[O:11][CH3:12])([CH3:14])([CH3:15])[CH3:16]
Reactant: CCOP(OCC)c1ccccc1P(c1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1)c1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1
Agent: C[Si](C)(C)Cl
Agent: [Al+3]
Agent: [H-]
Product: COc1c(C(C)(C)C)cc(P(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccccc2P)cc1C(C)(C)C

Procedure:
For example, referring to the reaction sequence shown below, 2-bromophenol (4) is reacted with trifluoromethanesulfonic anhydride to form 2-(trifluoromethanesulfonyl)oxy-bromobenzene (5), which is then reacted with bis(3,5-di-t-butyl-4-methoxyphenyl)phosphine oxide in the presence of a palladium complex catalyst to obtain bis(3,5-di-t-butyl-4-methoxyphenyl)(2-bromophenyl)phosphine oxide (6). Next, the compound (6) is reduced with trichlorosilane in the presence of N,N′-dimethylaniline to obtain bis(3,5-di-t-butyl-4-methoxyphenyl)(2-bromophenyl)phosphine (7). The compound (7) is reacted with diethyl chlorophosphonite in the presence of n-butyllithium to obtain diethyl 2-[bis(3,5-di-t-butyl-4-methoxyphenyl)phosphino]phenylphosphonite (8). Then, the compound (8) is reduced with lithium aluminum hydride in the presence of trimethylsilyl chloride to form 2-[bis(3,5-di-t-butyl-4-methoxyphenyl)phosphino]phenylphosphine (9). Thereafter, in the presence of n-butyllithium, the compound (9) is reacted with dimesylate of (2R,5R)-2,5-hexanediol, which is producible, for example, according to the method described in the literature (Tetrahedron: Asymmetry, 1991, 2, 569), whereby the aimed (S,S)-Me-UCAP-DTBM (3) can be produced in a high efficiency.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([O:6][C:7]1[CH:17]=[CH:16][C:10]2[C:11](=[O:15])[CH:12]=[CH:13][O:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1CCCC1>CO>[F:19][C:2]([F:1])([F:18])[S:3]([O:6][C:7]1[CH:17]=[CH:16][C:10]2[C:11](=[O:15])[C:12]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][O:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4]
Reactant: O=Cc1ccccc1
Reactant: O=c1ccoc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Solvent: CO
Solvent: C1CCNC1
Product: O=c1c(Cc2ccccc2)coc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a stirred solution of the product of Step C (27 g, 91.2 mmole) in 183 mL of methanol was added benzaldehyde (11.1 mL, 109 mmole) followed by pyrrolidine (9.1 mL, 109 mmole). The mixture was stirred at room temperature overnight, cooled to 0° C. and filtered. The solid was washed once with 50 mL of ice-cold methanol and then dried in vacuo; 35.2 g, (75% yield) of the title product was recovered. M.P. 133°-135° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[F:14][C:15]([F:26])([F:25])[O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br>>[F:14][C:15]([F:25])([F:26])[O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: FC(F)(F)Oc1ccccc1CBr
Product: N#Cc1ccnc(-c2cn(Cc3ccccc3OC(F)(F)F)cn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 4) and 2-(trifluoromethoxy)benzyl bromide according to the procedure for the preparation of Example 43, part A using room temp. [M+H] Calc'd for C17H11F3N4O, 345. Found, 345.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]=[CH:14][C:15]2[CH:28]=[CH:27][C:18]3[N:19]([CH2:25][CH3:26])[C:20](=[O:24])[N:21]([CH2:22][CH3:23])[C:17]=3[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[CH3:33][N:34]([CH3:37])C=O>>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[C:14]([C:15]3[CH:28]=[CH:27][C:18]4[N:19]([CH2:25][CH3:26])[C:20](=[O:24])[N:21]([CH2:22][CH3:23])[C:17]=4[CH:16]=3)=[C:37]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=3)[N:34]=[CH:33]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CCn1c(=O)n(CC)c2cc(C=N[C@@H]3CCN(Cc4ccccc4)C3)ccc21
Agent: O=C([O-])[O-]
Product: CCn1c(=O)n(CC)c2cc(-c3c(-c4cccc(C)c4)ncn3[C@@H]3CCN(Cc4ccccc4)C3)ccc21
Reaction time: 40 h

Procedure:
To a flask charged with 5-[((3R)-1-Benzyl-pyrrolidin-3-ylimino)-methyl]-1,3-diethyl-1,3-dihydro-benzoimidazol-2-one was added a stir bar and 4-methylphenyl-toylsulfonomethylisocyanide (326 mg, 1.15 mmoles) (Joseph Sisko, Mark Mellinger, Peter W. Sheldrake, and Neil H. Baine, Organic Synthesis, Vol. 77, 198–205 (1999); Joseph Sisko, Mark Mellinger, Peter W. Sheldrake, and Neil H. Baine, Tetrahedron Letters, Vol. 37, No. 45, 8113–8116, (1996); U.S. Pat. No. 5,756,499; prepared in an analogous manner starting with 3-methylbenzylaldehyde). N,N-dimethylformamide (2 mL, 0.58 M) was added and within 5 minutes a light yellow solution was obtained. To this stirred solution was added MP-carbonate (498 mg, 1.37 mmoles) (Argonaut Tech); the flask was sealed with a plastic cap and the mixture was stirred for 40 hours. The mixture was filtered into a separatory funnel with ethyl acetate. The ethyl acetate layer was extracted with 3 N HCl (3 times). The aqueous extracts were made basic to approximately pH 9.5 with solid potassium carbonate. The basic mixture was extracted with ethyl acetate (3 times). These ethyl acetate extracts were washed with water (2 times), dried with sodium sulfate, filtered and the filtrate was concentrated to give a yellow oil. This oil was purified by flash chromatography (95:5 ethyl acetate/methyl alcohol) to give 240 mg of the named compound as a light yellow foam/gum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([N:17]2[CH:21]=[C:20]([C:22](O)=[O:23])[C:19]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:18]2)([CH2:14][C:15]#[N:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:33][N:34](C(C)C)C(C)C.CN.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[C:15]([CH2:14][C:11]1([N:17]2[CH:21]=[C:20]([C:22](=[O:23])[NH:34][CH3:33])[C:19]([NH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:18]2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]1)#[N:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(=O)O)c(Nc3ccccc3)n2)CC1
Agent: CN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CNC(=O)c1cn(C2(CC#N)CCN(C(=O)OC(C)(C)C)CC2)nc1Nc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 1-[1-(tert-butoxycarbonyl)-4-(cyanomethyl)piperidin-4-yl]-3-(phenylamino)-1H-pyrazole-4-carboxylic acid (25 mg, 0.059 mmol) in DCM (0.6 mL) was added DIPEA (0.030 mL, 0.18 mmol), methylamine (0.040 mL, 0.082 mmol, 2.0 M in THF), HOBT (13 mg, 0.082 mmol), and EDC (16 mg, 0.082 mmol). The resulting mixture was maintained at ambient temperature for 18 hours, then purified directly by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14]>>[C:16]1([C:13](=[O:15])[CH:14]=[CH:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)c1ccccc1
Product: O=C(C=Cc1ccc(C(F)(F)F)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-trifluoromethylbenzaldehyde and acetophenone, 1-phenyl-3-[4-(trifluoromethyl)phenyl]prop-2-en-1-one was obtained as yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:33]([C:30]4[CH:29]=[CH:28][C:27]([C:24]5[CH:25]=[CH:26][C:21]([S:18]([CH3:17])(=[O:20])=[O:19])=[CH:22][CH:23]=5)=[CH:32][CH:31]=4)=[O:34])=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: CS(=O)(=O)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(S(C)(=O)=O)cc4)cc3)cn12

Procedure:
Conducting the operations similar to those of Example 1 using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4′-(methylsulfonyl)[1,1′-biphenyl]-4-carboxylic acid, the title compound was obtained as white solid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C:8]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:13])[N:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([S:21][CH3:22])=[N:9]1.CI.O>O1CCCC1>[CH3:7][C:8]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:13])[N:11]([N:14]([CH3:1])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([S:21][CH3:22])=[N:9]1
Reactant: CC(C)(C)[O-]
Reactant: CSC1=NC(C)(c2ccccc2)C(=O)N1Nc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CSC1=NC(C)(c2ccccc2)C(=O)N1N(C)c1ccccc1
Temperature: 0 °C
Yield: 70.1 %

Procedure:
0.4 g (3.5 mmol) of potassium tert-butoxide is added to a solution of 4-methyl-1-phenylamino-2-methylthio-4-phenyl-2-imidazolin-5-one (Compound 9) (1 g, 3.2 mmol) in anhydrous tetrahydrofuran (30 ml), cooled beforehand to 0° C. The mixture is left to react for 0.5 hour at 0° C. 0.5 g (3.5 mmol) of methyl iodide is then added and then the mixture is left to react for 0.5 hour at room temperature. The reaction mixture is poured into 100 ml of water and the product is extracted with 100 ml of diethyl ether. The ethereal solution is dried over magnesium sulfate and then concentrated. The product crystallizes when triturated in 10 ml of diisopropyl ether. It is filtered and then dried under vacuum. 0.73 g (yield: 70%) of Compound 22 is thus obtained in the form of a pale-yellow powder melting at 124° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][CH:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[CH3:26])[C:13]21[C:34]1[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=1)[NH:28][C:27]2=[O:36].[CH3:37][N:38]([CH3:42])[C:39](Cl)=[O:40].C(N(CC)CC)C>>[Cl:35][C:31]1[CH:30]=[C:29]2[NH:28][C:27](=[O:36])[C:13]3([CH:12]([C:6]4[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:1][C:39]([N:38]([CH3:42])[CH3:37])=[O:40])[CH2:17][C:16](=[O:18])[NH:15][CH:14]3[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[CH3:26])[C:34]2=[CH:33][CH:32]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCN)C12C(=O)Nc1cc(Cl)ccc12
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCNC(=O)N(C)C)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
At room temperature, a mixture of racemic (2′S,3S,4′R)-4′-[2-(2-amino-ethoxy)5-chloro-phenyl]-6-chloro-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.076 mmol), dimethylcarbamoyl chloride (41 mg, 0.379 mmol) and triethylamine (38 mg, 0.379 mmol) was stirred 0.5 h. Then the mixture was filtered, concentrated and the residue was purified by Prep-HPLC to give the title compound as a white solid (10 mg).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][C:16]([C:23]#[C:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)([OH:27])[CH3:26])=[CH:17][CH:18]=2)[C:13]=1[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][C:16]([C:23]#[C:24][C:25]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)([OH:27])[CH3:26])=[CH:17][CH:18]=2)[C:13]=1[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccc(C#CC(C)(O)c3ccc(F)cc3)cc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2ccc(C#CC(C)(O)c3ccc(F)cc3)cc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (2S)-ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-(4-fluorophenyl)-3-hydroxybut-1-ynyl)-3-methylnaphthalen-2-yl)acetate (22 mg, 0.045 mmol) in 2:2:1 THF/MeOH/H2O (1 mL total) was added a NaOH solution (4 M, 0.2 mL). The reaction mixture was stirred at 60° C. for 2 h. The mixture was partially concentrated and diluted with MeCN and H2O and purified by reverse phase HPLC (MeCN/H2O) to give the titled compound. 1H-NMR: 400 MHz, (CD3OD) δ: 7.75 (d, J=8 Hz, 1H), 7.67 (m, 4H), 7.56 (m, 2H), 7.43 (m, 1H), 7.35 (s, 1H), 7.31 (d, J=8 Hz, 1H), 7.05 (m, 2H), 5.12 (s, 1H), 2.62 (s, 3H), 1.74 (s, 1H), 0.96 (s, 9H). LCMS-ESI+ (m/z): [M-OH]+ calcd for C33H29ClFO3: 527.2. Found: 527.2.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)=[C:14]([O:28][CH3:29])[CH:13]=3)[C:5]2=[N:6][CH:7]=1.Cl.[C:31]([C:33]1([CH3:39])[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]1)#[CH:32].N1CCCCC1>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:29][O:28][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:32]3[N:35]4[CH2:34][C:33]([CH3:39])([CH2:38][CH2:37][CH2:36]4)[CH:31]=3)[CH:3]=[C:4]2[N:10]=[CH:9]1
Reactant: C#CC1(C)CCCNC1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)cnc43)cc2OC)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(Cn3cnc4cc(C5=CC6(C)CCCN5C6)cnc43)cc2OC)cn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a stirred suspension of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine (Step 3, Example 19, 0.20 g, 0.40 mmol) in tetrahydrofuran (3.0 mL) was added 3-ethynyl-3-methylpiperidine hydrochloride (0.13 g, 1.00 mmol), bis(triphenylphosphine)palladium(II) chloride (0.055 g, 0.078 mmol), copper(I) iodide (0.030 g, 0.16 mmol), and piperidine (0.17 g, 2.00 mmol). The mixture was heated to 60° C. in a microwave reactor. After 30 min, the mixture was allowed to cool to room temperature and was filtered through Celite. The filtrate was concentrated, and the residue was purified by Prep-HPLC to afford 0.020 g (10%) of the product as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.77 (d, J=2.0 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 8.01 (s, 1H), 7.68 (dd, J=8.0, 2.0 Hz, 1H), 6.94-6.76 (m, 4H), 6.02 (s, 1H), 5.40 (s, 2H), 5.04 (s, 2H), 3.95 (s, 3H), 3.82 (s, 3H), 3.22 (d, J=8.5 Hz, 1H), 2.94-2.86 (m, 2H), 2.80 (d, J=9.5 Hz, 1H), 1.91-1.85 (m, 1H), 1.60-1.46 (m, 3H), 1.16 (s, 3H) ppm; (M+1)=498.