Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Cl.[CH:3]1([C:6](=[NH:8])[NH2:7])[CH2:5][CH2:4]1.C([O:11][C:12](=O)[CH:13]([F:19])[C:14](OCC)=[O:15])C.Cl>CO.O>[CH:3]1([C:6]2[N:7]=[C:14]([OH:15])[C:13]([F:19])=[C:12]([OH:11])[N:8]=2)[CH2:5][CH2:4]1
Reactant: CCOC(=O)C(F)C(=O)OCC
Reactant: N=C(N)C1CC1
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: Oc1nc(C2CC2)nc(O)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.6 %

Procedure:
Sodium (646 mg, 28 mmol) is dissolved in methanol (50 ml) under a nitrogen atmosphere. Cyclopropanecarboximidamide hydrochloride (3.40 g, 28 mmol) is added in one portion. The mixture is stirred at room temperature for 0.25 h, then filtered upon hyflocel. The filtrate is concentrated in vacuo. This free base is added to a solution of sodium (1.29 g, 56 mmol) in methanol (50 ml) under a nitrogen atmosphere, at room temperature. Diethylfluoromalonate (5 g, 28 mmol) is added and the mixture is stirred at 60° C. for 5 h. The solvent is evaporated and the yellowish solid obtained is dissolved in 60 ml of water. The pH is adjusted at 6 with a 5 N HCl solution and the white precipitate formed is filtered and dried. 2-cyclopropyl-5-fluoro-4,6-pyrimidinediol 3 (3.6 g, 76%) is obtained as a white powder and used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[CH:14]=[CH:13][C:12]([OH:18])=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3]([OH:19])[CH:2]=1.[CH:20]1[C:25]([C:26]2[C:35](=[O:36])[C:34]3[C:33]([OH:37])=[CH:32][C:31]([OH:38])=[CH:30][C:29]=3[O:28][CH:27]=2)=[CH:24][CH:23]=[C:22]([OH:39])[CH:21]=1>[Pd]>[CH2:8]1[O:9][C:10]2[CH:11]=[C:12]([OH:18])[CH:13]=[CH:14][C:15]=2[C:16](=[O:17])[CH:7]1[C:6]1[CH:1]=[CH:2][C:3]([OH:19])=[CH:4][CH:5]=1.[CH2:27]1[O:28][C:29]2[C:34](=[C:33]([OH:37])[CH:32]=[C:31]([OH:38])[CH:30]=2)[C:35](=[O:36])[CH:26]1[C:25]1[CH:20]=[CH:21][C:22]([OH:39])=[CH:23][CH:24]=1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)cc(O)c12
Agent: [Pd]
Product: O=C1c2c(O)cc(O)cc2OCC1c1ccc(O)cc1
Product: O=C1c2ccc(O)cc2OCC1c1ccc(O)cc1

Procedure:
Hydrogenation of daidzein and genistein using palladium on calcium carbonate as a catalyst gives dihydrodaidzein and dihydrogenistein in good yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@@H:12]1[CH2:16][C@@H:15]([C:17](O)=[O:18])[C@H:14]([C:20]([N:22]2[CH2:26][CH2:25][C:24]([F:28])([F:27])[CH2:23]2)=[O:21])[CH2:13]1)(=[O:11])=[O:10].[CH2:29]1[C:31]([NH2:34])([C:32]#[N:33])[CH2:30]1.Cl>>[C:32]([C:31]1([NH:34][C:17]([C@@H:15]2[CH2:16][C@@H:12]([S:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[CH2:13][C@H:14]2[C:20]([N:22]2[CH2:26][CH2:25][C:24]([F:28])([F:27])[CH2:23]2)=[O:21])=[O:18])[CH2:29][CH2:30]1)#[N:33]
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)C[C@H]1C(=O)N1CCC(F)(F)C1
Reactant: N#CC1(N)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to example 117 step 7 using (1R,2R,4S)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (example 186 step 6) and 1-amino-cyclopropyl cyanic hydrochloride. Yellow foam (85%). MS (EI): 504.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([OH:11])=O)[CH:3]=1.[NH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1>>[NH:14]1[C:13]([NH:12][C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([CH3:8])[N:5]=2)=[O:11])=[N:17][N:16]=[N:15]1
Reactant: Nc1nnn[nH]1
Reactant: Cc1cc(Cl)cc(C(=O)O)n1
Product: Cc1cc(Cl)cc(C(=O)Nc2nnn[nH]2)n1
Yield: 68.7 %

Procedure:
0.68 g of 4-chloro-6-methyl-2-pyridinecarboxylic acid, 0.67 g of N,N'-carbonyldiimidazole and 0.37 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 0.65 g of N-(5-tetrazolyl)-4-chloro-6-methyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH2:11][CH2:12][OH:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][C:5]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=1[CH3:3]
Reactant: BrCCCCCCBr
Reactant: Cc1cccc(C)c1CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C)c1CCOCCCCCCBr
Yield: 52.7 %

Procedure:
NaH (46% dispersion in oil; 4.2 g) was added portionwise to a solution of 2,6-dimethylbenzeneethanol (6.0 g) and 1,6-dibromohexane (19.52 g) in THP (50 ml) under nitrogen. The mixture was refluxed for 18 h and treated cautiously with H2O (20 ml). The resulting emulsion was extracted with ER (3×100 ml) and the dried extract was evaporated to leave a yellow oil. Excess 1,6-dibromohexane was removed under reduced pressure and the residue was purified on a column of silica (300 ml) [B] to give the title compound as a colorless oil (6.6 g) b.p. 110°-115°/0.4 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>N1C=CC=CC=1>[CH2:16]([O:15][C:13]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)=[O:14])[CH3:17]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc2c(c1)CCC2=O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc2c(c1)CCC2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Aminoindan-1-one was dissolved in the minimum of hot pyridine and the solution was cooled to 0° C. Ethyl chloroformate (1.2 mole equivalents) was added dropwise to the cold stirred solution which was then stirred for one hour at room temperature. Evaporation under reduced pressure and trituration of the residue with water afforded 5-ethoxycarbonylaminoindan-1-one, m.p. 181°-2° C. (from ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15].C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:14]([C:3]1[CH:4]=[CH:5][C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])=[CH:7][C:2]=1[NH:1][C:24](=[O:26])[CH3:25])(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1ccc(S(F)(F)(F)(F)F)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cc(S(F)(F)(F)(F)F)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-[2-Amino-4-(pentafluorosulfanyl)phenyl]ethanone (150 mg, example 19d) was dissolved in methylene chloride (5 ml). After adding triethylamine (95 μl) and acetyl chloride (51 μl), the mixture was stirred at RT for 4 h. Then methylene chloride, water and saturated sodium hydrogencarbonate solution were added. The organic phase was removed, washed three times with water, dried over magnesium sulfate, filtered and concentrated. 165 mg of the desired product were obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13](=[O:16])[CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:17].[Na+]>>[OH2:16].[NH2:14][C:15]1[C:11]([CH2:12][C:13]([OH:16])=[O:17])=[CH:10][CH:9]=[CH:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Cc2cccc(-c3ccccc3)c2N1
Reactant: [OH-]
Agent: [Na+]
Product: Nc1c(CC(=O)O)cccc1-c1ccccc1
Product: O

Procedure:
A mixture of 4.5 g. (0.0215 mole) of 7-phenylindolin-2-one and 60 ml. of 3N sodium hydroxide was heated at reflux under nitrogen for 17 hrs. The reaction mixture was cooled, filtered, and the filtrate was diluted with 60 ml. of water. The solution was cooled, made acidic with glacial acetic acid and the resulting tan solid was immediately collected by filtration, washed with cold water and dried under vacuum to yield 4.6 g. (98%) of product as a tan solid, m.p. 98°-100° C. (dec.).
Reaction SMILES: [C:1]([C:3]1[S:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[C:23](=[O:35])[N:24]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[N:25]=[CH:26][CH:27]=3)=[O:21])=[CH:15][C:14]=2[F:36])[CH:4]=1)#[N:2].[OH:37]S(O)(=O)=O>>[F:36][C:14]1[CH:15]=[C:16]([NH:19][C:20]([C:22]2[C:23](=[O:35])[N:24]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[N:25]=[CH:26][CH:27]=2)=[O:21])[CH:17]=[CH:18][C:13]=1[O:12][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:4]=[C:3]([C:1]([NH2:2])=[O:37])[S:11][C:10]=12
Reactant: N#Cc1cc2nccc(Oc3ccc(NC(=O)c4ccnn(-c5ccc(F)cc5)c4=O)cc3F)c2s1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cc2nccc(Oc3ccc(NC(=O)c4ccnn(-c5ccc(F)cc5)c4=O)cc3F)c2s1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of N-(4-(2-cyanothieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 173, Step B, 10 mg, 0.02 mmol) and H2SO4 (0.53 mL, 9.97 mmol) was stirred at room temperature for 17 hours. The reaction mixture was quenched with ice. The mixture was treated with 2N NaOH, extracted with CH2Cl2 (500 mL) and DMF (40 mL), dried over MgSO4, and concentrated to afford the desired product which was rinsed with Et2O. LRMS (APCI pos) m/e 520.3 (M+1). 1H-NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.59 (d, 1H), 8.38 (d, 1H), 8.27 (m, 2H), 8.06 (d, 1H), 7.69 (m, 2H), 7.57 (m, 2H), 7.42 (t, 2H), 6.79 (d, 1H); 19F NMR (376 MHz, CDCl3/CD3OD) δ −112.9, −128.3.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(C(C)C)C(C)C)C.[F:32][C:33]1[CH:34]=[C:35]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH:36]=[CH:37][C:38]=1[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][C@@H:42]([CH3:46])[CH2:41]1>CN(C)C1C=CN=CC=1.O.ClCCl>[F:32][C:33]1[CH:34]=[C:35]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH:36]=[CH:37][C:38]=1[CH2:39][N:40]1[CH2:45][CH2:44][N:43]([C:2]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:4])[C@@H:42]([CH3:46])[CH2:41]1
Reactant: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2F)CCN1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2F)CCN1C(=O)OC(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 131.2 %

Procedure:
A 100 mL round-bottom flask was charged with triphosgene (142 mg, 0.480 mmol, 0.70 equiv), dichloromethane (15 mL). 1,1,1,3,3,3-hexafluoropropan-2-ol (229 mg, 1.36 mmol, 2.00 equiv) and N-ethyl-N-isopropylpropan-2-amine (352 mg, 2.72 mmol, 4.00 equiv) were added at 0° C. The mixture was stirred for 2 h at room temperature. 4-(3-Fluoro-4-[[(3S)-3-methylpiperazin-1-yl]methyl]phenyl)morpholine (200 mg, 0.68 mmol, 1.00 equiv) and 4-dimethylaminopyridine (83.0 mg, 0.680 mmol, 1.00 equiv) were added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (500 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 307 mg (92% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl(2S)-4-[[2-fluoro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate as orange oil. 1H NMR 300 MHz (CDCl3) δ 7.19-7.27 (m, 1H), 6.64-6.67 (m, 1H), 6.53-6.58 (m, 1H), 5.72-5.84 (m, 1H), 4.26 (br, 1H), 3.84 (t, J=4.8 Hz, 5H), 3.50 (s, 2H), 3.21-3.29 (m, 1H), 3.15 (t, J=4.8 Hz, 4H), 2.82 (d, J=10.5 Hz, 1H), 2.65 (d, J=11.4 Hz, 1H), 2.22-2.27 (m, 1H), 2.05-2.13 (m, 1H), 1.30 (d, J=6.6 Hz, 3H). LCMS (ESI, m/z): 488 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:12].C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=CN2)C1C=CC=CC=1)C>>[CH2:11]([O:13][C:14](=[O:23])[CH:15]=[C:16]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:12]
Reactant: CCOC(=O)C=Cc1ccccn1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1ccc2cc[nH]c2c1)c1ccccn1

Procedure:
3-(1H-Indol-6-yl)-3-pyridin-2-yl-acrylic acid ethyl ester CLVII was prepared from 6-bromo-1H-indole and 3-pyridin-2-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[CH2:29](Br)[CH:30]([CH3:32])[CH3:31]>>[CH2:29]([N:25]1[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]2[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=2)[CH2:27][CH2:26]1)[CH:30]([CH3:32])[CH3:31]
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: CC(C)CBr
Product: Cc1nc(OCC(=O)N(C)C2CCN(CC(C)C)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and isobutyl bromide in the sane manner as in Example 32.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](O)=[O:32].CCN=C=NCCCN(C)C>>[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:32]
Reactant: O=C(O)c1cccs1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)c4cccs4)c3)c2c1
Yield: 27.6 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 2-thiophenecarboxylic acid (0.92 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 56 mg (26% yield) of the title compound. 1H NMR (DMSOd6) δ 13.2 (br s, 1H), 10.4 (s, 1H), 8.6 (s, 1H), 8.4 (br s, 1H), 8.1 (br s, 1H), 8.0 (d, 1H), 7.94-7.86 (m, 2H), 7.8 (d, 1H), 7.6 (d, 1H), 7.5 (t, 1H), 7.3 (br s, 1H), 7.2 (t, 1H); ES-MS (m/z) 363 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:15]1([CH2:20][C:21](O)=[O:22])[CH:19]=[CH:18][N:17]=[CH:16]1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[N:15]1([CH2:20][C:21]([NH:1][C:2]2[C:3]([NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:22])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: Nc1cccnc1Nc1ccccc1
Reactant: O=C(O)Cn1ccnc1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cn1ccnc1)Nc1cccnc1Nc1ccccc1
Yield: 25.3 %

Procedure:
To a mixture of 3-amino-2-anilinopyridine (0.5 g), 2-(imidazol-1-yl)acetic acid (0.38 g) and pyridine (0.24 ml) in chloroform (5 ml) was dropwise added phosphorus oxychloride (0.28 ml) and the mixture was refluxed for 1.5 hours. After being cooled, the reaction mixture was decanted and the residue was poured into saturated aqueous sodium bicarbonate. The mixture was extracted three times with ethyl acetate. The combined extract was dried over magnesiumsulfate and the solvent was evaporated under reduced pressure. The resultant residue was triturated in ethyl acetate (10 ml) to give 2-(imidazol-1-yl)-N-(2-anilinopyridin 3-yl)acetamide (200 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[CH:13]([OH:18])[C:14]([O:16]C)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:19][CH:20]1[CH2:21][CH2:22]1)[CH:13]([OH:18])[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)[C@H](CC1CC1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H](CC1CC1)C(O)C(=O)O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of the methyl ester of Step 2 (400 mg; 1.3 mmol) in THF (8 mL) and water (6.63 mL) was added LiOH (1 N; 1.37 mL). The reaction mixture was stirred for 30 minutes and then acidified with 1.0 N HCl to pH=3˜4. The mixture was extracted with EtOAc (20 mL, twice). The combined organic layer was washed with water, brine, and then concentrated in vacuo to afford the title compound (370 mg). (M+1) 294.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30][CH:29]=3)[CH:19]=[CH:20][C:21]=2[O:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[CH:8]=[CH:9][C:10]=1N1CCCC1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CS(C)=O.C(C1C=C(C2C=C(C3C=CC(C(OCC)=O)=CC=3)C=CC=2OCCCC=O)C=CC=1[N:59]1[CH2:63][CH2:62][CH2:61][CH2:60]1)(C)(C)C>C(N(CC)CC)C>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:21]([O:22][CH2:23][CH2:24][CH2:25][CH:26]=[O:27])([N:59]3[CH2:63][CH2:62][CH2:61][CH2:60]3)[CH2:20][CH:19]=[C:18]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:33]=3)[CH:17]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCO)c(-c3ccc(N4CCCC4)c(C(C)(C)C)c3)c2)cc1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCC=O)c(-c3ccc(N4CCCC4)c(C(C)(C)C)c3)c2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(C2=CCC(OCCCC=O)(N3CCCC3)C(c3cccc(C(C)(C)C)c3)=C2)cc1
Yield: 78 %

Procedure:
In a manner similar to that of Example 30a, by reacting 900 mg of ethyl 3″-tert-butyl-4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate obtained in Example 18e with 0.3 mL of oxalyl chloride, 0.54 mL of DMSO and 0.25 mL of triethylamine, 700 mg of ethyl 3″-tert-butyl-4′-(4-oxobutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=78%) in the form of a yellow oil.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6](=O)[C:7]([F:10])([F:9])[F:8])=[O:4].[CH3:14][C:15](C)=[CH:16]C(Cl)=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:14][C:15]1[CH:16]=[C:6]([C:7]([F:10])([F:9])[F:8])[O:5][C:3](=[O:4])[CH:2]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)=CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)oc(=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trifluoroacetic anhydride (10.63 g, 50.61 mmol) and 3,3-dimethylacryloyl chloride (5.0 g, 42 mmol) in chloroform (85 mL) at 0° C. was added triethylamine (12.91 mL, 92.60 mmol). The resulting reaction mixture was stirred at same temperature for 1 h, then allowed to warm to room temperature overnight. The reaction solution was washed with water (2×), saturated sodium bicarbonate, water, and brine, and then dried over Na2SO4, filtered and concentrated. The crude residue was used in next step.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[C:4]([F:11])[CH:3]=1.[CH2:12](B([O-])OC(C(C)(C)C)C)[CH:13]=[CH2:14].[F-].[Cs+]>O1CCCC1.C(OCC)C.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>[CH2:14]([C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[C:4]([F:11])[CH:3]=1)[CH:13]=[CH2:12]
Reactant: C=CCB([O-])OC(C)C(C)(C)C
Reactant: COc1cc(Br)cc(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCc1cc(F)c(F)c(OC)c1

Procedure:
3.06 g of 1-bromo-3,4-difluoro-5-methoxybenzene (D2), 4.54 ml of pinacolyl allylboronate, 3.04 g of tetrakis(triphenylphosphine)palladium(0) and 7.62 g of caesium fluoride are suspended in 115 ml of tetrahydrofuran under an argon atmosphere. The reaction mixture is subsequently heated under reflux for 48 h. For work-up, the mixture is diluted with 400 ml of diethyl ether and extracted with 100 ml of water and 100 ml of saturated NaCl solution. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness in vacuo. The residue is purified by flash column chromatography on silica gel (solvent: cyclohexane), giving 1.59 g of the title compound as a colourless oil; MS: 184.0 (M+); TLC: Rf=0.69 (cyclohexane/ethyl acetate 8:1 parts by volume).
Reaction SMILES: [C:1]1([C:7]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)(O)[O-].[Na+].O>C(Cl)Cl>[C:1]1([C:7]2([CH:12]=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1(c2ccccc2)CCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=CC1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of (1-Phenyl-cyclopentyl)-methanol (1.0 g, 5.7 mmol) in DCM (20 mL) was added Dess-Martin Periodine (6.8 mmol, 1.2 eq) and sodium bicarbonate (6.8 mmol, 1.2 eq) at 0° C. The reaction mixture stirred at this temperature for 2 h and allowed to warm up slowly to room temperature. After completion of the reaction, the mixture was poured into water (50 mL) and extracted with DCM (50 mL). The organic mixture was then dried over sodium sulfate and concentrated under reduced pressure to give 1-Phenyl-cyclopentanecarbaldehyde (812 mg) which was immediately used to synthesize title compound (14 mg) from Intermediate B (20 mg, 0.025 mmol) following general procedures D and B. LC-MS (m/z): 923.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][C:6]2([CH2:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:20]=[CH:21]/[C:22](O)=[O:23])[CH:15]=3)[O:10]2)[CH2:5]1)(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:39][O:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1>C(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][C:6]2([CH2:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:20]=[CH:21]/[C:22]([NH:39][O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)=[O:23])[CH:15]=3)[O:10]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)N1CCCC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(±)-(E)-3-[1′-Acetyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid (crude compound from STEP B, 590 mg) was dissolved in DCM (30 ml) and TEA (0.498 ml, 3.59 mmol). EDC (513 mg, 2.68 mmol) and HOBt (362 mg, 2.68 mmol) were added and the mixture was stirred for 10 min at RT. NH2OTHP (251 mg, 2.15 mmol) was added and the solution was stirred overnight at RT and was then partitioned between 5% NaHCO3 and DCM. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The crude mixture was purified by column chromatography (eluent: DCM/MeOH 99:1 to 97:3) to give (±)-(E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide that was dissolved in DCM and treated with 4 M HCl in dioxane for 3 h. The precipitate was collected by filtration and washed with DCM to give (±)-(E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide as pale yellow powder (404 mg).