Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[F:69][C:70]1([F:121])[C:82]2[CH:81]=[C:80]([C:83]3[CH:84]=[CH:85][C:86]4[N:90]=[C:89]([C@@H:91]5[C@H:96]6[CH2:97][C@@H:93]([CH2:94][CH2:95]6)[N:92]5[C:98](=[O:109])[C@@H:99]([NH:104][C:105](=[O:108])[O:106][CH3:107])[C@H:100]([O:102][CH3:103])[CH3:101])[NH:88][C:87]=4[CH:110]=3)[CH:79]=[CH:78][C:77]=2[C:76]2[C:71]1=[CH:72][C:73]([C:111]1[NH:115][C:114]([C@@H:116]3[CH2:120][CH2:119][CH2:118][NH:117]3)=[N:113][CH:112]=1)=[CH:74][CH:75]=2>>[CH3:107][O:106][C:105](=[O:108])[NH:104][C@@H:99]([C@H:100]([O:102][CH3:103])[CH3:101])[C:98]([N:92]1[C@H:91]([C:89]2[NH:88][C:87]3[CH:110]=[C:83]([C:80]4[CH:79]=[CH:78][C:77]5[C:76]6[C:71](=[CH:72][C:73]([C:111]7[NH:115][C:114]([C@@H:116]8[CH2:120][CH2:119][CH2:118][N:117]8[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]8[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=8)=[N:113][CH:112]=7)=[CH:74][CH:75]=6)[C:70]([F:69])([F:121])[C:82]=5[CH:81]=4)[CH:84]=[CH:85][C:86]=3[N:90]=2)[C@H:96]2[CH2:97][C@H:93]1[CH2:94][CH2:95]2)=[O:109]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@H](C2)[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6)[nH]5)ccc3-4)cc2[nH]1)[C@@H](C)OC
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@H](C2)[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]5)ccc3-4)cc2[nH]1)[C@@H](C)OC

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (2S,3R)-1-((1R,3S,4R)-3-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methoxy-1-oxobutan-2-ylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 913.74 [M+H]+. (91.4 mg, 56%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:16])[NH:12][CH2:13][CH2:14][OH:15])[N:10]=2)[CH2:3]1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].N1C=CN=C1.CO>CN(C)C=O>[Si:17]([O:15][CH2:14][CH2:13][NH:12][C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:5][CH:2]([OH:1])[CH2:3]2)[S:7][CH:8]=1)=[O:16])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(NCCO)c1csc(N2CC(O)C2)n1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCNC(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of 3-hydroxy-1-(4-hydroxyethylcarbamoyl-1,3-thiazol-2-yl)azetidine (481.2 mg, 1.98 mmol) (obtained as described in Reference Example 33(3)) in dimethylformamide (24.0 ml) were added t-butyldimethylsilyl chloride (352 mg, 2.3 mmol) and imidazole (116.3 mg, 2.4 mmol) in an ice bath, and the mixture was stirred in the ice bath for 4 hours. After checking the completion of the reaction, methanol was added thereto and the reaction mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (2:3) as the eluant to afford 1-{4-[2-(t-butyldimethylsilyloxy)-ethylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (531.1 mg, yield 75%) as a colorless and transparent syrup.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([CH3:28])([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[N:11]1[CH2:16][CH2:15][C:14]2[NH:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)C.C(O)C.[OH-].[Na+]>O>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:10]([N:11]1[CH2:16][CH2:15][C:14]2[NH:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:28])([CH3:27])[C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCCC(c1ccccc1Cl)N1CCc2[nH]ccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCCC(c1ccccc1Cl)N1CCc2[nH]ccc2C1)C(=O)O
Temperature: 96.5 °C
Reaction time: 26 h
Yield: 55.5 %

Procedure:
7-(2-Chlorophenyl)-2,2 dimethyl-7-(1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-yl)-heptanoic acid ethyl ester (0.21 g, 0.51 mmol) was added to a mixture of ethanol (10 mL), water (2.70 mL), and sodium hydroxide (0.14 g, 3.54 mmol). The mixture was heated to reflux (95-98° C. oil bath) for 16 hours. After 26 hours, the flask was cooled to room temperature and the solvent was evaporated under reduced pressure. Water (15 mL) was added to the residue and the product was extracted with diethyl ether (15 mL). The extract was discarded and the aqueous portion was adjusted pH=6 with 10 N hydrochloric acid. The product was extracted with dichloromethane (3×15 mL) and the combined dichloromethane layers were washed with water (20 mL) and brine (20 mL). The dichloromethane solution was dried over sodium sulfate, filtered, and concentrated in under reduced pressure. The crude product was purified by column chromatography (silica gel, MeOH/CH2Cl2=1/9) to afford 7-(2-chlorophenyl)-2,2 dimethyl-7-(1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-yl)-heptanoic acid (Compound Ik, 0.11 g, 57.9% yield) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: DMSO/TMS) δ (ppm): 12.10 (br, 1H), 10.30 (br, 1H), 7.53 (m, 1H), 7.43 (d, 1H, J=7.2 Hz), 7.36-7.25 (m, 2H), 6.50 (s, 1H), 5.71 (s, 1H), 4.10 (m, 1H), 3.39 (m, 2.75 (m, 1H), 1.14 (m, 2H), 1.34 (m, 2H), 1.23-1.07 (m, 4H), 1.03 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: DMSO/TMS) δ (ppm) 178.45, 178.97, 133.83, 129.07, 128.23, 126.93, 123.97, 115.83, 113.99, 104.19, 63.11, 48.27, 47.60, 41.19, 40.06, 31.59, 25.84, 25.03, 24.96, 24.55, 23.34.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:9][CH:10]([CH3:14])[C:11](O)=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:8][C:11](=[O:12])[CH:10]([SH:9])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CC(S)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(S)C(=O)OCc1ccccc1

Procedure:
Into a 100 ml reaction flask equipped with thermometer, reflux condenser, hot plate (equipped with magnetic stirring apparatus) and spin bar are placed 21.6 grams benzyl alcohol; 29.6 grams of 2-mercaptopropionic acid; and 0.5 grams of para-toluene sulphonic acid.
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:26])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3F)noc2C)nc1
Product: Cc1onc(-c2ccc(F)cc2F)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 92 %

Procedure:
As described for example 263f, 6-[3-(2,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (219 mg, 92%) which was obtained as a white solid. MS: m/e=428.1 [M−H]−.
Reaction SMILES: CN(CCO)C.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[C:16]([Cl:23])=[N:17][C:18]([Cl:22])=[CH:19][C:20]=1[Cl:21].C([Li])CCC.[Br:29]C(F)(F)C(F)(F)Br.Cl>O1CCCC1>[Br:29][C:19]1[C:20]([Cl:21])=[C:15]([C:9]2[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=2[Cl:7])[C:16]([Cl:23])=[N:17][C:18]=1[Cl:22]
Reactant: Fc1cccc(Cl)c1-c1c(Cl)cc(Cl)nc1Cl
Reactant: FC(F)(Br)C(F)(F)Br
Agent: CN(C)CCO
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1cccc(Cl)c1-c1c(Cl)nc(Cl)c(Br)c1Cl
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
At room temperature, 2.0 g (22.4 mmol) of N,N-dimethylaminoethanol were added to 2.0 g (6.4 mmol) of 3-(2-chloro-6-fluorophenyl)-2,4,6-trichloropyridine (see Example Ab) dissolved in 25 ml of tetrahydrofuran, and the mixture was cooled to −78° C. 26 ml (41.9 mmol) of n-butyllithium (1.6 M in hexane) were then added dropwise, and the mixture was stirred at −75° C. to −50° C. for 1.5 h. 4.0 g (15.4 mmol) of 1,2-dibromotetra-fluoroethane were then added dropwise, and the mixture was stirred at −50° C. to −70° C. for 1 h, thawed to room temperature, added to 70 ml of 10% strength hydrochloric acid, extracted three times with in each case 80 ml of methyl tert-butyl ether, dried over sodium sulfate, concentrated under reduced pressure and triturated with hexane. Yield 1.6 g. 1H-NMR (CDCl3) δ=7.15 (m); 7.40 (m).
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21]C(OC(C)(C)C)=O)[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.C(OC([NH:37][C:38]1[S:42][C:41]([C:43]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([O:50][CH3:51])[C:44]=2[F:52])=[N:40][C:39]=1[C:53](O)=[O:54])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[NH2:37][C:38]1[S:42][C:41]([C:43]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([O:50][CH3:51])[C:44]=2[F:52])=[N:40][C:39]=1[C:53]([NH:29][C:12]1[C:13]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH2:21])[CH2:15]2)=[C:8]2[CH2:7][CH2:6][CH:5]([OH:4])[C:9]2=[N:10][CH:11]=1)=[O:54]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Reactant: COc1ccc(F)c(-c2nc(C(=O)O)c(NC(=O)OC(C)(C)C)s2)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)C[C@H](N)C3)CCC4O)c(N)s2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.5 %

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (10.0 mg, 0.025 mmol), 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazole-4-carboxylic acid (9.6 mg, 0.025 mmol), HATU (23.5 mg, 0.062 mmol) in DMF (0.06 mL) and DIPEA (0.013 mL, 0.074 mmol) was stirred at room temperature for 3 h. The mixture was diluted with MeOH and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a white powder (5.5 mg, 29%). LCMS calc. for C37H47F2N6O8S (M+H)+: m/z=773.3. Found: 773.3.
Reaction SMILES: CN(C)C=O.[C:6]([NH:10][C:11]1[C:16]([F:17])=[C:15]([F:18])[N:14]=[C:13]([NH:19][CH:20]=[C:21]([C:27](=[O:38])[C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([Cl:36])[C:29]=2F)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12]=1[F:39])([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:6]([NH:10][C:11]1[C:16]([F:17])=[C:15]([F:18])[N:14]=[C:13]([N:19]2[C:29]3[C:28](=[CH:33][C:32]([F:34])=[C:31]([F:35])[C:30]=3[Cl:36])[C:27](=[O:38])[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20]2)[C:12]=1[F:39])([CH3:9])([CH3:7])[CH3:8]
Reactant: CCOC(=O)C(=CNc1nc(F)c(F)c(NC(C)(C)C)c1F)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(-c2nc(F)c(F)c(NC(C)(C)C)c2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 114.1 %

Procedure:
To 6 ml of N,N-dimethyl-formamide solution of 1.14 g of ethyl 3-[(4-t-butylamino-3,5,6-trifluoropyridin-2-yl)amino]-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate was added 700 mg of potassium carbonate, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was poured into ice water, and ethyl acetate was added for extraction. The organic layer was separated and dried over magnesium sulfate, and solvent was distilled off. The solid content was collected by filtration to obtain 1.25 g of the title compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C1C=CC(C[C:32]([NH:34]CN[C@H](C(O)=O)CC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1.CN>CS(C)=O.C(N(C(C)C)CC)(C)C.[Cl-].[Na+].O>[NH2:1][C:2]1[N:23]=[C:22]([NH:34][CH3:32])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Agent: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CNc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Temperature: 135 °C
Yield: 73 %

Procedure:
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (200 mg, 0.56 mmol) was dissolved in a mixture solution of dimethylsulfoxide (1 mL) and diisopropylethylamine (0.5 mL), methylamine (2M tetrahydrofuran solution) (2 mL, 4 mmol) was added thereto, followed by heating in a sealed tube for 14 hours (oil bath temperature: 135° C.). The reaction mixture was allowed to room temperature, poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then concentrated, the obtained residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=2:1), and the title compound (144 mg, 0.41 mmol, 73%) was obtained.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]=O.[C:18]([CH:21]1[CH2:25][CH2:24][O:23][C:22]1=[O:26])(=[O:20])[CH3:19]>O>[C:18]([C:21]1([CH2:16][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:25][CH2:24][O:23][C:22]1=[O:26])(=[O:20])[CH3:19]
Reactant: C=O
Reactant: CC(=O)C1CCOC1=O
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: O
Product: CC(=O)C1(CN(Cc2ccccc2)Cc2ccccc2)CCOC1=O
Temperature: 90 °C

Procedure:
To a mixture of 10.2 g of dibenzylamine and 29.7 g of water, 8.9 g of 37% by weight formaldehyde aqueous solution was added dropwise at room temperature, followed by dropwise addition of 12.8 g of 3-acetyltetrahydrofuran-2-one at room temperature. After the completion of addition, the mixture was heated to 90° C. and thereby yielded a solution. The solution was cooled to room temperature, was filtrated, the resulting solid matter was heated with diethyl ether and thereby yielded a solution. The solution was gradually cooled to 0° C., the resulting crystal was filtrated and thereby yielded 19.2 g of 3-acetyl-N,N-dibenzyl-3-aminomethyltetrahydrofuran-2-one as a white crystal.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][O:14][CH:15]([C:17]3[CH:18]=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:20]=[C:21]4[C:25]=3[NH:24][N:23]=[C:22]4[C:26]#[N:27])[CH3:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:34]([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[CH3:34][N:10]1[CH2:11][CH2:12][C:7]([CH2:13][O:14][CH:15]([C:17]2[CH:18]=[C:19]([C:28]([F:29])([F:30])[F:31])[CH:20]=[C:21]3[C:25]=2[NH:24][N:23]=[C:22]3[C:26]#[N:27])[CH3:16])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: CC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc2c(C#N)n[nH]c12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(OCC1(c2ccccc2)CCN(C)CC1)c1cc(C(F)(F)F)cc2c(C#N)n[nH]c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-7-(1-((4-Phenylpiperidin-4-yl)methoxy)ethyl)-5-(trifluoromethyl)-1H-indazole-3-carbonitrile (24 mg, 0.06 mmol) and formaldehyde (37 wt. % solution in water, 77 μL) were combined in acetonitrile (2 mL) and cooled to 0° C. The reaction was treated with sodium cyanoborohydride (18 g, 0.28 mmol) and a few drops of acetic acid. The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were evaporated and the compound purified by flash chromatography on silica gel (1% aq. methanolic ammonia/8% methanol/methylene chloride) to afford 15 mg (59%). 1H-NMR (CDCl3, 500 MHz) δ 8.05 (s, 1H), 7.37-7.40 (m, 2H), 7.31-7.34 (m, 2H), 7.22-7.23 (m, 2H), 4.66 (q, J=6.7 Hz, 1H), 3.36-3.43 (m, 2H), 3.34 (q, J=9.2 Hz, 1H), 3.17 (d, J=9.2 Hz, 1H), 2.73-2.84 (m, 2H), 2.59 (s, 3H), 2.53-2.58 (m, 2H), 2.13-2.29 (m, 2H), 1.59 (m, 3H). Mass spec.: 442.48 (MH)+.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[OH:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.[C:15]1(=O)[CH2:18][CH2:17][CH2:16]1.ClCCl>CC(C)=O>[OH:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][C:15]2([C:5]#[N:6])[CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1
Reactant: Nc1ccc(O)cc1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCC1
Solvent: ClCCl
Solvent: CC(C)=O
Product: N#CC1(Nc2ccc(O)cc2)CCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
Trimethylsilyl cyanide (0.93 ml, 7 mmol) was added dropwise to a mixture of 4-hydroxyaniline (0.545 g, 5 mmol) and cyclobutanone (0.42 g, 6 mmol). The reaction mixture was stirred at room temperature for 6 h and then concentrated under vacuum to obtain a brown liquid which was subjected to chromatography (dichloromethane:acetone, 98:2) to yield 11a (0.903 g, 4.8 mmol, 96%) as a yellowish solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9]O)[CH:3]=1.[BrH:11].[C:12]1([PH+:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[Br-:11].[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:3]=1)[CH2:9][P+:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: OCc1cc(F)ccc1O
Reactant: Br
Solvent: CC#N
Product: Oc1ccc(F)cc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
18.6 g (130.87 mmol) of 4-fluoro-2-(hydroxymethyl)phenol and 42.67 g (124.32 mmol) of triphenylphosphonium hydrobromide in 186 ml of acetonitrile are stirred under reflux for 3 h. After cooling, the precipitate formed is filtered off and dried. This gives 58 g (124 mmol, 100% of theory) of the title compound.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[C:21]([OH:28])=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[C:23]([C:22]1[C:21]([OH:28])=[C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:27]=[CH:26][CH:25]=1)#[N:24]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: N#Cc1cccc(N)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#Cc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1O
Yield: 18.9 %

Procedure:
The product is prepared according to the procedure described in example 5, using 1 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 513 mg of 3-amino-2-hydroxybenzonitrile and 734 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 5 ml of pyridine and 5 ml of N,N-dimethylformamide. 257 mg of N-(3-cyano-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14]C(C)([O-])C.[K+].CI>CN(C=O)C>[CH3:14][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]=[CH:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: C(=Nc1ncc[nH]1)c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccnc1N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
N-(2-imidazolyl)benzylideneamine (0.2 g) was dissolved in DMF (4 ml), and potassium t-butoxide (0.15 g) and methyl iodide (0.18 g) were added. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated, and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform). The resulting crude crystals were recrystallized from diethyl ether--hexane to give the title compound (0.1 g, 49.9%) as pale yellow needles.
Reaction SMILES: N1C=CC=CC=1.[F:7]N1N=C(F)C=C(F)N1.[NH2:16][C:17]1([C:22]2[N:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])[CH2:21][CH2:20][CH2:19][CH2:18]1>ClCCl>[NH2:16][C:17]1([C:22]2[N:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=2[C:24]([F:7])=[O:25])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1(c2nc(Cl)ccc2C(=O)O)CCCC1
Reactant: FC1=CC(F)=NN(F)N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: NC1(c2nc(Cl)ccc2C(=O)F)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
0.34 ml (4.15 mmol) of pyridine and 0.53 ml (6.23 mmol) of 2,4,6-trifluorotriazine are added to a suspension of 1.0 g (4.15 mmol) of 2-(aminocyclopentyl)-6-chloronicotinic acid in 12 ml of dichloromethane. The mixture is stirred for 2 hours at ambient temperature and then diluted with dichloromethane. The organic phase is washed twice with an ice-cold solution of NaHCO3aq and then dried over Na2SO4, filtered, and concentrated under reduced pressure. 1 g of product is obtained in the form of a brown oil, which is used immediately in the next step. Quantitative crude yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:24]([O-])=O.C(N(CC)C(C)C)(C)C.[C:36](Cl)(=[O:40])[CH:37]([CH3:39])[CH3:38]>ClCCl>[CH3:23][O:22][C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:24][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:4]=1)[C:17]([CH3:19])([CH3:18])[CH2:16]2)=[O:21]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c([N+](=O)[O-])c1)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)C(C)C)c1)N2
Yield: 99.8 %

Procedure:
To a solution of methyl 2-(4-fluoro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (150 mg, 0.46 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.91 mmol) in dichloromethane (10 mL) was added isobutyryl chloride (0.053 mL, 0.50 mmol) via syringe with ice cooling. The resultant mixture was stirred for an additional 20 h. The solvent was removed in vacuo and the residue was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to afford 183 mg of methyl-2-(4-fluoro-3-isobutyramidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate. Yield: 97%.