Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=2)=[CH:5][CH:4]=1>CCOC(C)=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[O:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Oc2c(-c3ccc(OC)cc3)sc3ccccc23)cc1
Solvent: CCOC(C)=O
Product: Oc1ccc(Oc2c(-c3ccc(O)cc3)sc3ccccc23)cc1
Yield: 87 %

Procedure:
By essentially following the procedure detailed in Example 5, Part B, the title compound was prepared from 2-(4-methoxyphenyl)-3-(4-methoxyphenoxy)benzo[b]thiophene (Part D) in 87% yield following radial chromatography (SiO2; 25% EtOAc in hexanes).
Reaction SMILES: [CH2:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][CH:9]([OH:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1)[CH3:2].[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>N1C=CC=CC=1>[C:15]([O:12][CH:9]([CH2:10][CH3:11])[CH2:8][O:7][C:6]1[CH:13]=[CH:14][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C(=O)Cl
Reactant: CCc1ccc(OCC(O)CC)cc1
Solvent: c1ccncc1
Product: CCc1ccc(OCC(CC)OC(=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
Cooling in an ice bath 0.93 g (5 mmol) of 1-(p-ethylphenoxy)-butan- 2-ol was dissolved in 10 ml of pyridine, and to this solution was added dropwise 0.53 g (5 mmol) of isobutyryl chloride. The mixture was stirred at room temperature for 3 hours after the addition was completed. The reaction mixture was treated in the same manner as in Example 7, and purified by column chromatography using silica gel to afford 1.3 g of 1 -(p-ethylphenoxy)-butan-2-ol isobutyrate (compound No. 15) in a yield of 83% as a colorless oily substance. The refractive index of the product was nD32 = 1.4799.
Reaction SMILES: [Al].[Li].[CH2:3]([O:13][C:14]1[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=1)/[CH:4]=[C:5](/[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])\[CH3:6]>O>[CH2:3]([O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][OH:19])=[CH:22][CH:23]=1)/[CH:4]=[C:5](/[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])\[CH3:6]
Reactant: COC(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)cc1
Agent: [Al]
Agent: [Li]
Solvent: O
Product: CC(C)=CCC/C(C)=C/COc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a suspension of lithium aluminum hydridete (7.59 g) in trahydrofuran (200 ml) was added a solution of the raw product of methyl 4-geranyloxybenzoate in tetrahydrofuran anhydride (100 ml) dropwise while being cooled with ice. After being stirred for 1 hour at room temperature, the reaction solution, with water (200 ml) added thereto, was extracted with ethyl acetate (400 ml). The extract was dried over sodium sulfite anhydride and then the solvent was evaporated under a vacuum. The residue was recrystallized from an n-hexane/ethyl acetate mixed solution, thereby yielding 34.4 g (66%) of the aimed compound.
Reaction SMILES: C(N(CC)C1C=C2C([C@H](N(C3C=CC(N(CC)CC)=CC=3)C(=O)C)C[C@H](C)N2C(=O)C2C=CC(N(C)C)=CC=2)=CC=1)C.[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([N:50]([C@H:54]2[C:63]3[C:58](=[CH:59][C:60]([N:64]4[CH2:69][CH2:68]O[CH2:66][CH2:65]4)=[CH:61][CH:62]=3)[N:57]([C:70](=[O:80])[C:71]3[CH:76]=[CH:75][C:74]([N:77]([CH3:79])[CH3:78])=[CH:73][CH:72]=3)[C@@H:56]([CH3:81])[CH2:55]2)[C:51](=[O:53])[CH3:52])=[CH:46][CH:45]=1.C(NCC)C.N1CCOCC1>>[Cl:43][C:44]1[CH:45]=[CH:46][C:47]([N:50]([C@H:54]2[C:63]3[C:58](=[CH:59][C:60]([N:64]([CH2:65][CH3:66])[CH2:69][CH3:68])=[CH:61][CH:62]=3)[N:57]([C:70](=[O:80])[C:71]3[CH:72]=[CH:73][C:74]([N:77]([CH3:78])[CH3:79])=[CH:75][CH:76]=3)[C@@H:56]([CH3:81])[CH2:55]2)[C:51](=[O:53])[CH3:52])=[CH:48][CH:49]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N(C)C)cc2)c2cc(N3CCOCC3)ccc21
Agent: CCN(CC)c1ccc(N(C(C)=O)[C@@H]2C[C@H](C)N(C(=O)c3ccc(N(C)C)cc3)c3cc(N(CC)CC)ccc32)cc1
Solvent: C1COCCN1
Solvent: CCNCC
Product: CCN(CC)c1ccc2c(c1)N(C(=O)c1ccc(N(C)C)cc1)[C@@H](C)C[C@H]2N(C(C)=O)c1ccc(Cl)cc1

Procedure:
(±)-Cis-N-[7-diethylamino-1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-(4-diethylamino-phenyl)-acetamide was made in the same way as (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-dimethylamino-benzoyl)-2-methyl-7-morpholin-4-yl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide except diethylamine was substituted for morpholine. The reaction was non-selective and yielded (±)-cis-N-(4-chloro-phenyl)-N-[7-diethylamino-1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide in addition to the titled compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[O:6][CH:7]=1.[F:15][C:16]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21]([F:26])[C:17]=1[C:18]([NH2:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:15][C:16]1[C:24]([O:25][CH2:2][C:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)[O:6][CH:7]=2)=[CH:23][CH:22]=[C:21]([F:26])[C:17]=1[C:18]([NH2:20])=[O:19]
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: Cc1ccc(-c2nc(CCl)co2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)co2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.4 %

Procedure:
To a solution of 4-Chloromethyl-2-p-tolyl-oxazole (0.10 g, 0.50 mmol) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.08 g, 0.50 mmol) and potassium carbonate (0.233 g, 1.50 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.03 g, 18%). 1H NMR (DMSO-d6, 400 MHz): δ 2.37 (s, 3H), 5.13 (s, 2H), 7.11 (m, 1H), 7.36 (d, J=8.0 Hz, 2H), 7.41 (m, 1H), 7.88 (m, 3H), 8.12 (br s, 1H) and 8.29 (s, 1H). MS ES+(345.24), HPLC (method I) Rt=16.07 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[CH:28]1([CH:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37][CH2:36][NH:35]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([C:14]([N:35]2[CH2:36][CH2:37][C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:34]2[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:16])([OH:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1(O)CCN(Cc2ccccc2)CC1
Reactant: c1ccc2c(c1)CCNC2C1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N1CCc2ccccc2C1C1CCCCC1)C1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 6.6 %

Procedure:
1-benzyl-4-hydroxypiperidine-4-carboxylic acid (951 mg) was dissolved in DMF (25 mL), and N,N′-carbonyldiimidazole (720 mg) was added thereto, followed by stirring at room temperature for 18 hours. Thereafter, N,N-diisopropylethylamine (784 mg) and 1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.22 g) were added to the reaction liquid, followed by stirring at 60° C. for 18 hours. The solvent was evaporated, and water and EtOAc were added to the reaction liquid. The resulting insoluble materials were separated through celite, extracted with EtOAc and dried over magnesium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform-MeOH) and dissolved in 1,4-dioxane (12 mL), and di-tert-butyl dicarbonate (1.3 g) was added thereto, followed by stirring at room temperature for 1 hour. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc and then chloroform-MeOH) to obtain 1-benzyl-4-[(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperidin-4-ol (115 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.N1C(C)=CC=CC=1C.Cl[Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>ClCCl>[O:1]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: OCCc1ccncc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCc1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
Commercially available 4-(2-hydroxyethyl)pyridine (10.0 g, 81.2 mmol) was dissolved in dichloromethane (400 mL), then 2,6-lutidine (26.1 g, 244 mmol) and chloro-tert-butyldimethylsilane (32.0 g, 121 mmol) were added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction was confirmed by thin-layer chromatography, water was added to the reaction mixture, and the resulting mixture was separated into organic layer and aqueous layer. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated under reduced pressure to give 4-[2-(tert-butyldimethylsiloxy)ethyl]pyridine (19.2 g, quantitative yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[N:14]=[C:13]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=2)=[CH:8][CH:7]=1.[CH:36]1([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:1][O:2][C:3](=[O:35])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[N:14]=[C:13]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:39]3[CH:38]=[CH:37][C:36]([CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:41][CH:40]=3)=[CH:30][CH:29]=2)=[CH:8][CH:7]=1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(S(C)(=O)=O)cc3)nc2Cc2ccc(Br)cc2)cc1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(S(C)(=O)=O)cc3)nc2Cc2ccc(-c3ccc(C4CCCCC4)cc3)cc2)cc1

Procedure:
{-4-[2-(4-Bromo-benzyl)-4-(4-methanesulfonyl-phenyl)-imidazol-1-yl]-phenyl-amino}-acetic acid methyl ester (1.4 g, 2.5 mmol) was coupled with 4-cyclohexyl-phenyl boronic acid (615 mg, 3.0 mmol) according to general procedure G to give {4-[2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(4-methanesulfonyl-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: [H-].[Na+].[CH:3]([Si:6]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[O:7][CH:8]1CN[C:11](=O)[NH:10][CH2:9]1)([CH3:5])[CH3:4].CI.[CH3:23][N:24]([CH:26]=[O:27])[CH3:25]>>[CH3:23][N:24]1[CH2:25][CH:8]([O:7][Si:6]([CH:15]([CH3:17])[CH3:16])([CH:3]([CH3:5])[CH3:4])[CH:18]([CH3:19])[CH3:20])[CH2:9][N:10]([CH3:11])[C:26]1=[O:27]
Reactant: CC(C)[Si](OC1CNC(=O)NC1)(C(C)C)C(C)C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CC(C)[Si](OC1CN(C)C(=O)N(C)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (141 mmol) was added portionwise to a solution of 5-triisopropylsilanyloxy-tetrahydro-pyrimidin-2-one (Step P9) (28.2 mmol) in DMF (200 mL) at 0° C. After 15 min, the reaction was warmed to rt. After 2 h, the mixture was cooled to 0° C., treated with methyl iodide (197 mmol) and then allowed to warm to rt overnight. The reaction mixture was quenched by addition of water and extracted with toluene. The aqueous layer was washed with EtOAc. The combined organic layers were washed with a saturated aqueous NaHCO3 solution, dried (Na2SO4), filtered, and concentrated. The residue was used without further purification. ESI-MS: tR=1.33 min, [M+H]+ 301.3 (LC-MS 1).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.[S:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.C([O-])(=O)C.[K+]>CN(C)C(=O)C>[S:19]1[C:23]([C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:22][N:21]=[CH:20]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Reactant: c1cscn1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cncs3)ncnc21
Temperature: 200 °C
Yield: 63.8 %

Procedure:
4-Chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (3.00 g, 0.0106 mol), and 1,3-thiazole (7.50 mL, 0.106 mol) were dissolved in N,N-dimethylacetamide (40.0 mL). The solution was distributed in equal portions into four 20 mL microwavable vessels. Into each reaction vessel was then added potassium acetate (0.777 g, 7.93 mmol) followed by tetrakis(triphenyl-phosphine)palladium(0) (0.60 g, 2.1 mmol). Each reaction vessel was heated at 200° C. in the microwave reactor for 30 minutes. The reactions were combined and most of the solvent was removed in vacuo. The residue was diluted with DCM, filtered and concentrated. Purification by flash column chromatography (ethyl acetate/hexanes) afforded the desired product (2.25 g, 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=1.C([CH:19]([C:23]([OH:25])=[O:24])C(O)=O)(C)(C)C>>[C:9]([O:25][C:23](=[O:24])[CH2:19][C:10](=[O:12])[C:9]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=1)([CH3:14])[CH3:13])([CH3:13])([CH3:10])[CH3:7]
Reactant: CC(C)(C)C(C(=O)O)C(=O)O
Reactant: COc1cccc(C(C)(C)C(=O)O)n1
Product: COc1cccc(C(C)(C)C(=O)CC(=O)OC(C)(C)C)n1

Procedure:
The title compound was synthesized from 2-(6-methoxy-pyridin-2-yl)-2-methyl-propionic acid and mono-tert-butyl malonic acid according to the method used for the synthesis of Compound PR4. The resultant was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:18])[CH:15]([NH2:17])[CH3:16])[N:10]=[CH:9]1)([CH3:7])[CH3:6].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:18])[CH:15]([NH:17][C:29](=[O:30])[CH2:28][C:23]2[CH:22]=[C:21]([F:20])[CH:26]=[C:25]([F:27])[CH:24]=2)[CH3:16])[N:10]=[CH:9]1)([CH3:7])[CH3:6]
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: COC(=O)CC(C)(C)n1cnc(NC(=O)C(C)N)c1
Product: COC(=O)CC(C)(C)n1cnc(NC(=O)C(C)NC(=O)Cc2cc(F)cc(F)c2)c1

Procedure:
3-[4-(2-Amino-propionylamino)-imidazol-1-yl]-3-methyl-butyric acid methyl ester was coupled with (3,5-Difluoro-phenyl)-acetic acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 19.6, 28.1, 28.2, 3.0, 46.9, 49.1, 51.9, 56.4, 102.5, 102.8, 103.0, 105.1, 112.3, 112.5, 112.6, 131.0, 137.9, 138.7, 164.3, 169.1, 170.0; MS 423.2 m/z (M+1).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[C:3](N)[CH:2]=1.N([O-])=O.[Na+].[BrH:19]>O.[Cu](Br)Br>[Br:19][C:3]1[CH:2]=[CH:1][C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=1
Reactant: Br
Reactant: Nc1ccc2c(c1)oc1ccccc12
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1ccc2c(c1)oc1ccccc12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Combine N-dibenzofuran-3-ylamine (2.0 g, 10.8 mmol), water (20 ml), and conc. hydrobromic acid (6 ml). Cool to 0° C. Add a solution of sodium nitrite (0.7 g, 10.8 mmol) in water (16 ml). After 15 minutes add the mixture above to a mixture of copper bromide (1.7 g, 12.3 mmol) in water (9.2 ml) and hydrobromic acid (4 ml). Warm to ambient temperature. After 18 hours, add water and extract with dichloromethane. Combine the organic layers and wash sequentially with distilled water and brine and then dry (Na2SO4), filter, and concentrate to give a residue. Chromatograph the residue eluting with 8:2 hexane:EtOAc to give the title compound.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.Br[CH2:30][C:31]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[CH3:39])=O>>[CH3:39][C:38]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[C:31]1[N:26]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:27][CH:30]=1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: Cc1ccncc1C(=O)CBr
Agent: Cl
Product: Cc1ccncc1-c1csc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
100 mg (0.224 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 67 mg (0.269 mmol) of 2-bromo-1-(4-methylpyridin-3-yl)ethanone hydrochloride were reacted according to the General Method 3. Yield: 13 mg (12% of theory).
Reaction SMILES: C[O-].[Na+].C(OP([CH2:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[C:22]3[S:26][C:25]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[N:24][C:23]=3[CH:33]=2)=[CH:15][N:14]=1)(OCC)=O)C.[CH:40](=O)[CH3:41]>C1COCC1.CCOC(C)=O>[CH2:31]([NH:30][C:28]([NH:27][C:25]1[S:26][C:22]2[C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[CH:20][C:19]([C:16]3[CH:15]=[N:14][C:13](/[CH:12]=[CH:40]/[CH3:41])=[N:18][CH:17]=3)=[CH:33][C:23]=2[N:24]=1)=[O:29])[CH3:32]
Reactant: CC=O
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(CP(=O)(OCC)OCC)nc3)cc(-c3ccccn3)c2s1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C/C=C/c1ncc(-c2cc(-c3ccccn3)c3sc(NC(=O)NCC)nc3c2)cn1
Reaction time: 1.5 h

Procedure:
Sodium methoxide (0.5 M MeOH solution; 0.9 mL, 0.43 mmol) was added drop-wise to a suspension of iv (104 mg, 0.198 mmol) in THF (10 mL). Acetaldehyde (40 μL, 0.69 mmol) was introduced and the mixture stirred for 90 min. The reaction was diluted with EtOAc (60 mL), washed with sat. NaHCO3(aq) (60 mL). The organic fraction was dried (MgSO4), concentrated in vacuo, and purified over silica (gradient elution: 0-10%, DCM-MeOH) affording v (79 mg, 96%). MS: 417.1 [M+H]+.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:6]([C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)([CH3:9])([CH3:8])[CH3:7].S(=O)(=O)(O)O>C(O)(=O)C>[C:1]([OH:5])(=[O:4])[CH3:2].[C:6]([C:10]1[CH:11]=[C:12]([CH3:17])[C:13]([CH:2]([OH:3])[C:1]([OH:5])=[O:4])=[C:14]([CH3:16])[CH:15]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: Cc1cc(C)cc(C(C)(C)C)c1
Reactant: O=CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc(C(C)(C)C)cc(C)c1C(O)C(=O)O
Temperature: 35 °C
Reaction time: 9 h

Procedure:
A mixture of 89 g of 50% aqueous glyoxylic acid solution [0.6 mol], 400 ml of glacial acetic acid and 81.1 g [0.5 mol] of 1-tert-butyl-3,5-dimethylbenzene is initially charged. Starting at room temperature, 85.8 g of 96% strength sulfuric acid [0.84 mol] are added dropwise over a period of 15 minutes, during which time the temperature of the reaction mixture increases to about 35° C. The mixture is heated to 60° C. and stirred at this temperature for 9 hours. The cooled reaction mixture is then stirred into 750 ml of ice-water. The mixture is extracted three times with in each case 150 ml of methylene chloride, the combined organic phases are washed with 100 ml of saturated aqueous NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. This gives 136.7 g of a yellowish thick oil, which, according to GC/MS(sil.), has the following composition:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Li]CCCC.CCCCCC.[BH4-].[Na+].[Cl-].[NH4+].[CH3:27][OH:28]>C1(C)C=CC=CC=1.CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([CH2:27][OH:28])=[N:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(I)nc1
Reactant: CO
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: OCc1ccc(C(F)(F)F)cn1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To the solution of 2-iodo-5-(trifluoromethyl)pyridine (CAS number 100366-75-4; 10 g, 69.4 mmol) in toluene (250 ml) at −78° C. was added n-BuLi in hexane (2.5 M, 15.0 mL, 37.5 mmol). The reaction was stirred at −78° C. for 15 minutes. To this was then added drop wise DMF (3.5 ml) and then stirred at −78° C. for 1 hour. Sodium borohydride (2.74 g, 72.0 mmol) and methanol (50 ml) were added and the resulting reaction mixture was stirred for 30 minutes and then allowed to warm to room temperature. The reaction was cooled to −10° C. and to this was then added a saturated solution of ammonium chloride. The organics were extracted with ethyl acetate (2×200 ml) and the combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[CH2:15][C:16]([C:18]1[N:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:21]=[C:20]([C:31]#[N:32])[CH:19]=1)=[O:17].S(O)(O)(=O)=[O:34].C(OCC)(=O)C>O>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[CH2:15][C:16]([C:18]1[N:22]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:21]=[C:20]([C:31]([NH2:32])=[O:34])[CH:19]=1)=[O:17]
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(-n2nc(C#N)cc2C(=O)Cc2ccc(-n3ccccc3=O)cc2F)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-n2nc(C(N)=O)cc2C(=O)Cc2ccc(-n3ccccc3=O)cc2F)cc1
Reaction time: 2 h
Yield: 41 %

Procedure:
Part I. To 5-{[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)-phenyl]acetyl}-1-(4-methoxyphenyl)-1H-pyrazole-3-carbonitrile (75 mg, 0.175 mmol) was added concentrated aqueous dihydrogen sulfate (4.5 mL). After 2 h, the reaction was poured into ethyl acetate (50 mL) and water (50 mL), and the layers were separated. The organic layer was washed with saturated aqueous sodium chloride (50 mL), dried over sodium sulfate, and concentrated to dryness. The resulting residue was purified by radial chromatography (2% methyl alcohol in dichloromethane) to afford 5-{[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]acetyl}-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxamide (32 mg, 41%) as a white solid upon lyophilization from 10% acetonitrile in water. LC/MS (ESI+): 448.2 (M+H)+. 1H NMR (CD3OD) δ 7.70 (s, 1H), 7.60 (m, 2H), 7.43 (t, 1H), 7.16-7.32 (m, 4H), 6.97 (d, 2H), 6.60 (d, 1H), 6.45 (t, 1H), 4.40 (s, 2H), 3.83 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][CH:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][CH:19]([NH:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CC(N=C=O)c1ccccc1
Product: CC(NC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1)c1ccccc1
Yield: 97.3 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 12.51 mg (0.0852 mMol) α-methylbenzyl isocyanate, 24.0 mg (97%) of the title compound were recovered.