Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]([OH:12])=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].CO.[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([O:12][C:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][NH:9][C:10]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: Oc1c(-c2ccccc2)n[nH]c1-c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: c1ccc(COc2c(-c3ccccc3)n[nH]c2-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 3,5-diphenyl-4-pyrazolol (10 g, 0.042 mole), sodium methoxide (2.27 g, 0.042 mole) and methanol (60 ml) is heated at 60° C for 2 hours. Then benzyl chloride is added slowly at 60° C. A white solid forms. Heating is continued overnight at 60° C. The reaction mixture is examined by glc and the reaction is found to be complete. The mixture is poured into water and the solid isolated by filtration. The solid is washed well with water, dried and recrystallized from acetonitrile to give pale yellow crystals, melting point 152°-152.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[N:28][NH:27][C:26]2=[O:30])=[CH:21][CH:20]=1)([CH3:17])[CH3:16]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:27]1[C:26](=[O:30])[N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH:15]([CH3:17])[CH3:16])=[CH:24][CH:23]=2)[CH:29]=[N:28]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: CC(C)Oc1ccc(-n2cn[nH]c2=O)cc1
Product: CC(C)Oc1ccc(-n2cnn([C@H](C)[C@@]3(c4ccc(F)cc4F)CO3)c2=O)cc1
Yield: 48.8 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.43 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.94 g of 4-(4-isopropoxyphenyl)-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(4-isopropoxyphenyl)-3(2H,4H)-1,2,4-triazolone (0.84 g) was obtained as a colorless oil.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(C)(C)C.[NH2:12][CH2:13]CCO.C=O.P(=O)(O)(O)O>C(O)C.O>[OH:11][C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][C:9]=1[CH2:13][NH2:12]
Reactant: NCCCO
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: C=O
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCO
Product: NCc1ccccc1O

Procedure:
An o-hydroxybenzylamine compound of the present invention composition is prepared according to the procedure of Example 1, except that 50 g of 4-t-butylphenol is employed in place of the Bisphenol-A, 25 g of 3-aminopropanol is employed in place of the 2-(methylamino)ethanol and that heating of the reactants was only begun after the formaldehyde addition was completed. A 0.5 g sample of the product is dissolved in 500 ml of ethanol/water (1:4 by volume) and the pH of the solution is adjusted to 3.0 with phosphoric acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[C:15]3[C:10](=[CH:11][C:12]4[CH2:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:13]=4[CH:14]=3)[CH:9]=[N:8]2)=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:32](=O)[CH3:33]>C1COCC1>[CH:32](=[C:20]1[C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][C:13]=2[CH2:16][CH2:17][CH2:18][C:19]1=[O:21])[N:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[N:8]=[CH:9]3)[CH3:33]
Reactant: O=C1CCCc2cc3c(cnn3-c3ccncc3)cc2C1
Reactant: CC=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC=C1C(=O)CCCc2cc3c(cnn3-c3ccncc3)cc21
Temperature: -77 °C
Reaction time: 0.08 h

Procedure:
A round bottom flask was charged with 1-(pyridin-4-yl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (14.419 g, 52.0 mmol) and THF (200 mL). The solution was cooled to about −77° C. and then 1 M LiHMDS solution (54.6 mL, 54.6 mmol) was added over about 30 min, keeping the internal temp below about −75° C. After complete addition of the LiHMDS the mixture was stirred for about 5 min, the cold bath was removed and the mixture was allowed to warm to about 0° C. (over about 1 h). The mixture was re-cooled to about −65° C. then acetaldehyde (14.6 mL, 260 mmol) was added. The cold bath was removed and the mixture was allowed to warm to about 0° C. brine (50 mL) and water (50 mL) were added to the mixture, then collected the organic layer. Extracted the aqueous layer with EtOAc (2×50 mL). Combined organics and dried over MgSO4 and concentrated in vacuo. Purified by 120 g silica column, eluting with 20-100% EtOAc/DCM to provide 5-ethylidene-1-(pyridin-4-yl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (83, R1=4-Pyridyl, R2′=Methyl) (12.3 g, 78%); LC/MS, method 3, Rt=2.17 min MS m/z 304 (M+H)+, 1H NMR (400 MHz, DMSO) δ 8.75-8.72 (m, 2H), 8.50-8.49 (m, 1H), 8.13 (s, 1H), 7.98-7.95 (m, 2H), 7.75 (s, 1H), 7.18-7.11 (q, J=7.3 Hz, 1H) 2.93-2.85 (m, 2H), 2.35-2.22 (m, 2H), 2.04-1.95 (m, 2H), 1.90-1.85 (d, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[CH3:14][O:15][C:16]([CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22])=[O:17]>>[CH3:1][N:2]([C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:16]([O:15][CH3:14])=[O:17])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1
Reactant: COC(=O)CCCC(=O)Cl
Reactant: CNCCc1c[nH]c2ccccc12
Product: COC(=O)CCCC(=O)N(C)CCc1c[nH]c2ccccc12
Yield: 92.9 %

Procedure:
10.3 g of N-methyl-tryptamine (i.e., 3-(2-methylaminoethyl)-indole) and 11.7 g of 4-methoxycarbonylbutyryl chloride were treated in the same manner as described in Example 1. 16.6 g of N-methyl-N-(4-methoxycarbonylbutyryl)-tryptamine (i.e., 3-[2-(N-methyl-4-methoxycarbonylbutanamido)ethyl]indole) were therby obtained. Yield: 92.8%
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].Cl.[NH2:26][CH2:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([OH:32])=[O:31]>C[O-].[Na+].CO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:26][CH2:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([OH:32])=[O:31])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(CN)CC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)CC(=O)O
Yield: 7.7 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (70 mg, 0.22 mmol) and 4-amino-3,3-dimethyl-butyric acid HCl salt (110 mg, 0.66 mmol) (Oakwood Products) in 0.5 M NaOMe/MeOH (2.62 mL, 1.3 μmol) was microwaved at 120° C. for 1 h. Reaction mixture was concentrated and residue was dissolved in water (50 mL), It was acidified by 1 N HCl to pH=3-4 and extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude product was purified by chromatography, eluting with 50-100% EtOAc/hexanes to provide the title compound 7.2 mg (0.017 mmol) in 7.8% yield. LC-MS ESI−: 417.95 (M-1)−.
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14]C1C=C(C(=O)C)C=CC=1>CCOC(C)=O>[CH3:14][C:5]1[CH:6]=[C:1]([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH3:10])[CH:2]=[CH:3][CH:4]=1
Reactant: CCC(=O)CC(=O)c1ccccc1
Reactant: CC(=O)c1cccc(C)c1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)c1cccc(C)c1

Procedure:
The title compound was prepared (as described above for Intermediate 16) from 2.72 mL of 3′-methylacetophenone and 3.95 mL of EtOAc to yield 2.94 grams of Intermediate 21 as an oil: 1H NMR (400 MHz, CDCl3enol form) δ7.70 (m, 2H), 7.34 (m, 2H), 6.17 (s, 1H), 2.41 (s, 3H), 2.20 (s, 3H); low resolution MS (ES)m/e 177.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[S:28][C:21]=12.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[O:17][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[S:28][C:21]=12)=[O:18]
Reactant: COC(=O)c1cc2nccc(Cl)c2s1
Reactant: Cc1ccc(F)c(NC(=O)c2cccc(O)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)c1cc2nccc(Oc3cccc(C(=O)Nc4cc(C)ccc4F)c3)c2s1
Temperature: 68 °C

Procedure:
A mixture of N-(2-fluoro-5-methylphenyl)-3-hydroxybenzamide (270 mg, 1.1 mmol), methyl 7-chlorothieno[3,2-b]pyridine-2-carboxylate (300 mg, 1.3 mmol) and cesium carbonate (1.0 g, 3.07 mmol) in 10 ml of anhydrous DMSO was heated at 68° C. for 16 hours, cooled to room temperature and partitioned between water (100 ml) and EtOAc (100 ml). The aqueous layer was extracted with more EtOAc (2×50 ml). All the organic layers were combined, washed with brine (50 ml), dried over Na2SO4, and evaporated to dryness to give the crude, which was purified by silica gel chromatography eluted with 1˜2% of MeOH in CHCl3 to give methyl 7-(3-((2-fluoro-5-methylphenyl)carbamoyl)phenoxy)thieno[3,2-b]pyridine-2-carboxylate as light brown oil. Yield: 170 mg, 37%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A cooled (0° C.) solution of 4-bromobenzoyl chloride (250 mg; 1.14 mmol) in THF (5 ml) was treated with a 2 M solution of morpholine in THF (219 μl; 2.51 mmol). The reaction mixture was allowed to warm to RT and stirred for 2 days, diluted with EtOAc and washed with a saturated NH4Cl solution in water. The organic phase was dried over MgSO4, filtered and concentrated to dryness affording the title compound as a pink solid (307 mg, quantitative yield).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[NH:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)=[O:11]
Reactant: Clc1nc2ccccc2o1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CNc2nc3ccccc3o2)c(-c2ccc(F)cc2)s1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 2-chlorobenzoxazole, and DIPEA in CH2Cl2 was stirred at 60° C. overnight. The reaction mixture was concentrated in vacuo to leave a near colorless solid. This solid was triturated with Et2O/hex to leave the title compound as a colorless solid homogeneous by HPLC analysis. MS (ESI) 465.03 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][C:10]([OH:12])=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][C:31]([C:35]([F:38])([F:37])[F:36])([OH:34])[CH2:30][CH2:29]2)=[C:22]([Cl:39])[CH:21]=1>>[Cl:39][C:22]1[CH:21]=[C:20]([NH:19][C:10](=[O:12])[C:9]#[C:8][C:7]2[CH:6]=[CH:5][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:3][C:2]=2[Br:1])[CH:25]=[CH:24][C:23]=1[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][C:31]([OH:34])([C:35]([F:37])([F:38])[F:36])[CH2:30][CH2:29]1
Reactant: O=C(O)C#Cc1ccc(-c2ccccc2)cc1Br
Reactant: Nc1ccc(CCN2CCC(O)(C(F)(F)F)CC2)c(Cl)c1
Product: O=C(C#Cc1ccc(-c2ccccc2)cc1Br)Nc1ccc(CCN2CCC(O)(C(F)(F)F)CC2)c(Cl)c1

Procedure:
Prepared analogously to Example 2.3.f. from (3-bromobiphenyl-4-yl)propynoic acid and 1-[2-(4-amino-2-chlorophenyl)ethyl]4-trifluoromethylpiperidin-4-ol. Yield: 36 mg (10.5% of theory); C29H25BrClF3N2O2 (M=605.87); calc.: molecular ion peak (M+H)+: 605/07/09; found: molecular ion peak (M+H)+: 605/07/09.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:7][CH2:8][Cl:9])[CH2:5][CH3:6])[CH3:3].[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1.[OH-].[Na+]>O.C(O)C>[ClH:9].[CH2:5]([N:4]([CH2:7][CH2:8][O:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:14]2[CH:23]=[CH:24][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:21][CH:20]=1)[CH2:2][CH3:3])[CH3:6]
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCN(CC)CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 82.6 %

Procedure:
A solution of 13.2 g (0.075 mol) of 2-(N,N-diethylamino)-1-chloroethane hydrochloride in 30 ml of water is run over the course of 30 minutes into a solution, kept at about 60° C., of 15 g (0.068 mol) of p-(p-chlorophenoxy)-phenol and 6.3 g (0.157 mol) of sodium hydroxide pellets in 20 ml of water and 20 ml of ethanol. The mixture is heated to the reflux temperature for 1 hour and the ethanol is evaporated under reduced pressure. The aqueous phase is extracted with diethyl ether and the organic phase obtained is washed with water until neutral, dried over dry sodium sulphate and evaporated to dryness under reduced pressure. The oily residue is treated in a solution of hydrogen chloride in diethyl ether, to give 20 g of a white powder. Recrystallisation from ethyl acetate gives 18 g of CRL 40 330
Reaction SMILES: C(#N)C.[CH:4]([C:7]([CH:9]([CH3:11])[CH3:10])=[O:8])([CH3:6])[CH3:5].[I-].[Na+].Cl[Si:15]([CH3:18])([CH3:17])[CH3:16]>C(N(CC)CC)C>[CH3:5][C:4](=[C:7]([O:8][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]([CH3:11])[CH3:10])[CH3:6]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)C(=O)C(C)C
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)=C(O[Si](C)(C)C)C(C)C
Yield: 96.6 %

Procedure:
Acetonitrile (300 mL) was mixed with 20.3 g of diisopropyl ketone, 32 g of sodium iodide, and 21.6 g of triethylamine, to which was gradually added 23.1 g of chlorotrimethylsilane. The mixed solution was reacted at 50° C. for 4 hours and then allowed to stand for cooling. The reaction mixture was poured into ice and extracted with hexane. An organic phase was rinsed with a sodium hydrogencarbonate solution, dried, and then concentrated. The resultant was purified by distillation in vacuo to obtain 32 g of 2,4-dimethyl-3-trimethylsilyloxy-2-pentene (silylenol ether of diisopropyl ketone). The resulting silylenol ether (15 g) and 8.8 g of tetramethylene sulfoxide were dissolved in 150 mL of chloroform under a nitrogen gas stream. The solution was cooled to −30° C. or lower, and 17.7 g of trifluoroacetic anhydride was added dropwise thereto over 30 minutes. The mixture was reacted at room temperature for 1 hour, and a solution of potassium nonafluorobutanesulfonate in acetonitrile/water was added to the reaction mixture. The mixture was extracted with chloroform, and an organic phase was subjected to alkali rinsing with a 5% by weight tetramethylammonium hydroxide aqueous solution, followed by rinsing with distilled water until aqueous phases had become neutral. An organic phase was concentrated, and diisopropyl ether was added to the resulting crude product to deposit a powder. The powder was collected by filtration to obtain 17 g of Compound (I-1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:4]([C:5](O)=O)[C:3]=1[C:12](O)=O.[ClH:15].[CH2:16]([O:18][C:19]([C:21]1([NH2:32])CC2C(=CC=C(F)C=2F)C1)=[O:20])[CH3:17]>>[ClH:15].[CH2:16]([O:18][C:19]([C:21]1([NH2:32])[CH2:5][C:4]2[C:3](=[C:2]([F:1])[CH:10]=[CH:9][C:8]=2[F:11])[CH2:12]1)=[O:20])[CH3:17]
Reactant: O=C(O)c1c(F)ccc(F)c1C(=O)O
Reactant: CCOC(=O)C1(N)Cc2ccc(F)c(F)c2C1
Agent: Cl
Product: CCOC(=O)C1(N)Cc2c(F)ccc(F)c2C1

Procedure:
2-Amino-4,7-difluoro-indan-2-carboxylic acid ethyl ester HCl salt was prepared from 3,6-difluoro-phthalic acid as indicated by the scheme above regarding A7-D7 utilizing the same procedures as for the synthesis of 2-amino-4,5-difluoro-indan-2-carboxylic acid ethyl ester HCl salt.
Reaction SMILES: [CH:1]1([NH:5][C:6](=[O:30])[NH:7][C:8]2[CH:28]=[CH:27][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[O:13])=[CH:10][C:9]=2[F:29])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([NH:5][C:6]([NH:7][C:8]2[CH:28]=[CH:27][C:11]([C:12]([N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)=[O:13])=[CH:10][C:9]=2[F:29])=[O:30])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NC(=O)NC3CCC3)c(F)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(C(=O)N2CCNCC2)cc1F)NC1CCC1
Yield: 7.5 %

Procedure:
tert-Butyl 4-(4-(3-cyclobutylureido)-3-fluorobenzoyl)piperazine-1-carboxylate (2.8 g, 66.67 mmol), trifluoracetic acid and dichloromethane were stirred for 20 hours then concentrated under reduced pressure. The residue was taken up in dichloromethane/methanol, loaded on to a strong cation exchange column and washed with dichloromethane/methanol. Elution of the column with 2M ammonia in methanol gave the title compound (1.6 g). MS (ESI) m/z: 321.4 [M+H]+
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[CH3:5][CH:6]([CH2:8][CH2:9][CH2:10][CH:11]([CH2:13][CH:14]=[O:15])[CH3:12])[CH3:7]>CN(C)C=O>[CH3:12][C:11]([CH:10]=[CH:9][CH2:8][CH:6]([CH3:5])[CH2:7][CH2:9][CH2:8][CH:6]([CH3:7])[CH3:5])=[CH:13][C:14]([O:1][CH2:2][CH3:3])=[O:15]
Reactant: CC(C)CCCC(C)CC=O
Reactant: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(C)C=CCC(C)CCCC(C)C
Reaction time: 8 h

Procedure:
Sodium ethoxide (9 g. sodium in 600 ml. of ethanol) is added slowly to a mixture of 42 g. of dihydrocitronellal and 75 g. of diethyl 3-ethoxycarbonyl-2-methylprop-2-enyl phosphonate (about 49% trans) in one liter of dimethylformamide, under nitrogen and at 0°, with stirring. The mixture is allowed to stand overnight at about 5° and the reaction worked up by extraction with ether, washing with water and brine and filtering through Florisil to yield ethyl 3,7,11-trimethyldodeca-2,4-dienoate as a cis/trans mixture, mostly trans,trans.
Reaction SMILES: [NH2:1][C@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH2:27][C:28]([C:31](O)=[O:32])=[N:29][N:30]=2)[CH:21]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@H:2]([NH:1][C:31]([C:28]3[CH:27]=[C:26]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)[NH:30][N:29]=3)=[O:32])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1c(-c2ccn(C[C@@H](C)N)n2)ccc(C#N)c1Cl
Reactant: O=C(O)C1=NN=C(c2cccnc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccn(C[C@@H](C)NC(=O)c3cc(-c4cccnc4)[nH]n3)n2)ccc(C#N)c1Cl
Yield: 43.9 %

Procedure:
The title compound was prepared from (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.3 g, 1.092 mmol), 5-pyridin-3-yl-4H-pyrazole-3-carboxylic acid (0.227 g, 1.201 mmol), DIPEA (0.285 ml, 1.638 mmol), HOBt (0.221 g, 1.638 mmol) and EDCI (0.314 g, 1.638 mmol) using the method of Example 34(d) affording 0.214 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.15-1.21 (m, 3H), 2.54 (s, 3H), 4.28-4.41 (m, 2H), 4.45-4.54 (m, 2H), 6.61 (d, 1H), 7.22 (d, 1H), 7.45-7.52 (m, 1H), 7.62-7.70 (m, 1H), 7.76-1.86 (m, 2H), 8.09-8.18 (m, 1H), 8.25-8.47 (m, 1H), 8.53-8.57 (m, 1H), 8.99 (d, 1H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:13]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C:17](=[O:19])[CH2:16][C:15](=[O:20])[CH2:14]1)([O:10][CH2:11][CH3:12])=[O:9].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>O1CCCC1>[CH:26]1([C:29]([O:20][C:15]2[CH2:14][C:13]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C:17](=[O:19])[CH:16]=2)=[O:30])[CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)C1(C(=O)OCC)CC(=O)CC(=O)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)OCC)CC(=O)C=C(OC(=O)C2CC2)C1
Reaction time: 1 h

Procedure:
0.94 g (9.4 mmol) of triethylamine was added to a solution of 2.4 g (9.4 mmol) of 5,5-biscarbethoxy-cyclohexane-1,3-dione in 25 ml of anhydrous tetrahydrofuran. A solution of 0.98 g (9.4 mmol) of cyclopropanecarboxylic chloride in 5 ml of tetrahydrofuran was added dropwise to this mixture at 0° to 10° C. After the mixture had been stirred at 0° to 10° C. for about 1 hour, no more starting material could be detected by thin-layer chromatography. Subsequently, the solvent was removed and the residue was taken up in ethyl acetate. The organic phase was washed twice with 1% strength acetic acid and twice with water, dried and evaporated down. The tube [sic] product was purified chromatographically (developer: cyclohexane/ethyl acetate 8:2). Yield: 1.2 g.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([I:13])=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN(C)C=O>[Cl:3][C:4]1[C:5]([I:13])=[C:6]2[CH:12]=[CH:11][N:10]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:7]2=[N:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1cnc2[nH]ccc2c1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(I)c(Cl)cnc32)cc1
Reaction time: 0.5 h

Procedure:
To an ambient suspension of sodium hydride (0.560 g, 23.34 mmol) in N,N-dimethylformamide (40 mL) was added a solution of 5-chloro-4-iodo-1H-pyrrolo[2,3-b]pyridine (5.0 g, 17.95 mmol) (Example 1E) in N,N-dimethylformamide (10 mL) slowly. The reaction was stirred for 0.5 hours, and a solution of para-toluenesulfonyl chloride (3.59 g, 18.85 mmol) in N,N-dimethylformamide (8 mL) was added. The reaction was stirred for 1 hour and was then quenched by pipetting the reaction portionwise into water (50 mL) with vigorous stirring. The solid was filtered and air-dried to give the title compound as a solid. MS ESI(+) m/z 433 [M+H]+.
Reaction SMILES: C(N)C1C=CC=CC=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.[O:18]=[C:19]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:22][CH2:21][N:20]1[C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][N:40]=1)[C:34](OC)=[O:35]>>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:34](=[O:35])[C:33]2[CH:38]=[CH:39][N:40]=[C:31]([N:20]3[CH2:21][CH2:22][N:23]([CH2:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:19]3=[O:18])[CH:32]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccncc3)C2=O)c1
Reactant: NCc1ccc(F)cc1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccc(F)cc1)c1ccnc(N2CCN(Cc3ccncc3)C2=O)c1
Yield: 48 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with 4-fluorobenzylamine to react with methyl 2-(2-oxo-3-(pyridin-4-ylmethyl)imidazolidin-1-yl)isonicotinate, N-(4-fluorobenzyl)-2-(2-oxo-3-(pyridin-4-ylmethyl)imidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 48% yield: mp 161-163° C.; 1H NMR (300 MHz, CDCl3) δ 8.67-8.50 (m, 3H), 8.37 (d, J=5.1 Hz, 1H), 7.49-7.20 (m, 5H), 7.02-6.96 (m, 2H), 6.84 (br s, 1H), 4.57 (d, J=5.7 Hz, 2H), 4.45 (s, 2H), 4.09 (t, J=8.1 Hz, 2H), 3.42 (t, J=8.1 Hz, 2H); MS (ES+) m/z 405.8 (M+1).