Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH:8][CH:9]([CH3:13])[CH2:10][CH:11]=[CH2:12])[CH:3]=[CH:4][C:5](=[O:7])[CH3:6]>[Ru].CO>[CH3:1][CH:2]([CH2:8][CH:9]([CH3:13])[CH2:10][CH2:11][CH3:12])[CH2:3][CH2:4][CH:5]([OH:7])[CH3:6]
Reactant: C=CCC(C)C=C(C)C=CC(C)=O
Agent: [Ru]
Solvent: CO
Product: CCCC(C)CC(C)CCC(C)O
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 86.8 %

Procedure:
To a glass autoclave liner is added 249 g of 5,7-dimethyl-3,5,9-decatrien-2-one, 2.2 g or 5% ruthenium on carbon and 200 ml of methanol. The glass liner is sealed inside a 3 L, stainless steel, rocking autoclave and the autoclave purged once with 250 psig N2, once with 250 psig H2 and then charged with 500 psig H2. With mixing, the reaction mixture is heated. At about 75° C., the reaction initiates and begins consuming H2 and exotherms to 170° C. In 10 minutes, the temperature has dropped to 115-120° C. and the pressure dropped to 270 psig. The autoclave is boosted to 1000 psig with H2, mixed at 110-115° C. for an additional 7 hours and 15 minutes then cooled to 30° C. The reaction mixture is removed from autoclave, filtered to remove catalyst and concentrated by evaporation of methanol under vacuum to yield 225.8 g of 5,7-dimethyl-2-decanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[N:4]([C:14](=[O:16])[CH3:15])[CH2:3]1>CO>[C:14]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=2)[C:2]([CH3:17])([CH3:1])[CH2:3]1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Solvent: CO
Product: CC(=O)N1CC(C)(C)c2ccc(N)cc21
Reaction time: 8 h

Procedure:
1-(3,3-Dimethyl-6-nitro-2,3-dihydro-indol-1-yl)ethanone (250 mg) was dissolved in MeOH (20 mL), the mixture was bubbled with H2 for 10 min. 10% Pd/C (50 mg) was added and the mixture was stirred under H2 overnight. The mixture was filtered through Celite® and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 1:1 EtOAc:CH2Cl2 to afford the title compound as a white crystalline material. MS: 205 (M+1). Calc'd. for C12H16N2O—204.27.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH:6]([CH2:11][N:12]1[CH2:17][CH2:16][O:15][C@H:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:13]1)[C:7]([F:10])([F:9])[F:8])C.[OH-].[Na+]>C(O)C>[F:10][C:7]([F:8])([F:9])[CH:6]([CH2:11][N:12]1[CH2:17][CH2:16][O:15][C@H:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=2)[CH2:13]1)[CH2:5][C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)CC(CN1CCO[C@H](c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC(CN1CCO[C@H](c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Reaction time: 0.42 h
Yield: 100.7 %

Procedure:
A mixture of 0.589 g (1.4 mmol) of 4,4,4-trifluoro-3-[(R)-2-(3-trifluoromethyl-phenyl)-morpholin-4-ylmethyl]-butyric acid ethyl ester, ca. 1.07 mL of 2 M sodium hydroxide solution and 14 mL of ethanol was heated at reflux and stirred under an atmosphere of argon. After 25 min, volatiles were removed under reduced pressure. The mixture was treated with 40 mL of saturated sodium dihydrogen phosphate solution, and extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.543 g (99%) of 4,4,4-trifluoro-3-[(R)-2-(3-trifluoromethylphenyl)-morpholin-4-ylmethyl]-butyric acid as a glass. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.10-2.21 (m, 1H) 2.31-2.66 (m, 3H overlapping DMSO) 2.79 (dd, J=16.81, 11.54 Hz, 1H) 2.95-3.21 (m, 2H) 3.34 (s, 2H) 3.65 (dtd, J=18.23, 11.34, 11.34, 2.26 Hz, 1H) 3.91-4.02 (m, 1H) 4.45-4.64 (m, 1H) 7.53-7.75 (m, 4H) 12.49 (br. s., 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:18]2=[CH:19][CH:20]=[N:21][CH:22]=[C:17]2[C:5]2[C:6]([OH:16])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH3:15])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:24].[N:25]1([CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:24].[CH3:23][C:2]1([CH3:1])[C:18]2=[CH:19][CH:20]=[N:21][CH:22]=[C:17]2[C:5]2[C:6]([O:16][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH3:15])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCCCC1
Reactant: CCCCC(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCC(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(2-hexyl)-10-[4-(piperidino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(2-hexyl)-5H-[1]benzopyrano[3,4-d]pyridine and γ-piperidinobutyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[C:20]([CH3:25])=[N:21][NH:22][C:23]=2[CH3:24])=[CH:8][CH:7]=1.[H-].[K+].Br[CH2:30][CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>O1CCCC1.CS(C)=O>[CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[C:20]([CH3:25])=[N:21][N:22]([CH2:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:23]=2[CH3:24])=[CH:10][CH:11]=1
Reactant: COC(=O)/C=C/c1ccc([C@@H]2CCCN2CCc2c(C)n[nH]c2C)cc1
Reactant: BrCC1CCOCC1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COC(=O)/C=C/c1ccc([C@@H]2CCCN2CCc2c(C)nn(CC3CCOCC3)c2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.6 %

Procedure:
To an ice cold mixture of (E)-3-(4-{(S)-1-[2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethyl]-pyrrolidin-2-yl}-phenyl)-acrylic acid methyl ester (0.85 g, 2.4 mmol) and potassium hydride (115 mg, 2.88 mmol) in 4.0 mL tetrahydrofuran:dimethyl sulfoxide (9:1 v/v) was added 4-bromomethyltetrahydropyran (945 mg, 5.28 mmol). The mixture was slowly warmed to room temperature and stirred under nitrogen for 16 h. It was then quenched with aqueous ammonium chloride and added with ethyl acetate. The layers were separated and the organic layer was washed with more aqueous ammonium chloride. The aqueous layers were then washed with more ethyl acetate and the combined organic extracts were dried over magnesium sulfate and concentrated to a yellow oil. The oil was then purified via silica gel column chromatography (100:0 to 0:100 heptane:ethyl acetate) to give (E)-3-[4-((S)-1-{2-[3,5-dimethyl-1-(tetrahydropyran-4-ylmethyl)-1H-pyrazol-4-yl]-ethyl}-pyrrolidin-2-yl)-phenyl]-acrylic acid methyl ester (160 mg, 0.35 mmol, 14% yield) as a yellow oil. LC/MS (m/z): 452.5 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][C:7]1[N:8]([C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:31])[NH2:30])=[CH:25][C:24]=2[CH3:32])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][NH:21][N:22]=3)=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)C.[OH-].[Li+]>CO.C1COCC1>[N:22]1[NH:21][N:20]=[N:19][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]([C:23]3[CH:28]=[CH:27][C:26]([C:29](=[O:31])[NH2:30])=[CH:25][C:24]=3[CH3:32])[C:7]([CH2:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:11][CH:10]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(-c3nn[nH]n3)cc2)n1-c1ccc(C(N)=O)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(N)=O)ccc1-n1c(CCC(=O)O)ccc1-c1ccc(-c2nn[nH]n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.9 %

Procedure:
To 3-{1-(4-carbamoyl-2-methyl-phenyl)-5-[4-(2H-tetrazol-5-yl)-phenyl]-1H-pyrrol-2-yl}-propionic acid ethyl ester (26B) (16 mg, 0.035 mmol.) in 1:1 MeOH/THF (1.0 mL) was added aq. 1.0 N lithium hydroxide (2 eq). The reaction mixture was allowed to stir at rt for 16 h. The reaction mixture was poured into 10 mL ice-water solution which was extracted with diethyl ether. The aqueous layer was acidified with aq HCl (2 N) to pH=2, and then was extracted with diethyl ether. The combined organic layers were dried over Na2SO4. The solvent was removed under vacuum to yield the desired target 3-(5-(4-(2H-tetrazol-5-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid (26C) (15 mg, 95%).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:15]I.O>CN(C)C=O>[CH3:15][N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=2)[CH:10]=[CH:11]1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2ccc([N+](=O)[O-])cc21
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a slurry of 0.33 g (8.3 mmol) of NaH (60% dispersion in oil) in 30 ml of dried dimethylformamide ("DMF"), was added 0.973 g (6.00 mmol) of commercially available (Lancaster, Windham, N.H.) 6-nitro-IH-indole (1) at 0-5° C. over a period of 10 minutes. After 1 hour stirring at the same temperature, 0.75 ml (12.1 mmol) of methyl iodide was added and the mixture was stirred at the same temperature for 30 minutes, then at room temperature for 1 hour, poured into ice and water and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, and concentrated to yield 0.814 g (77.5%) of 1-methyl-6-nitro-1H-indole (2) as a yellow solid. This material was used without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCOCC2)c2ccc(O)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(C(=C2CCOCC2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.7 %

Procedure:
tert-Butyl (2E)-3-{4-[(4-hydroxyphenyl)(tetrahydro-4H-pyran-4-ylidene)methyl]phenyl}prop-2-enoate (47) (0.071 g, 0.182 mmol) was dissolved in CH2Cl2 (1 mL) and TFA (1 mL). The solution was stirred at RT for 4 h, then was concentrated. The residue was recrystallized from EtOAc to provide 0.020 g (33%) of compound 48 as a tan solid. 1H NMR (DMSO-d6): δ 12.34 (s, 1H), 9.37 (s, 1H), 7.58 (d, J=8.2 Hz, 2H), 7.53 (d, J=16.0 Hz, 1H), 7.07 (d, J=8.2 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 6.67 (d, J=8.4 Hz, 2H), 6.45 (d, J=16.0 Hz, 1H), 3.59 (m, 4H), 2.25 (m, 4H). LRMS (ESI): m/z 335 (M−H)−.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]([NH2:14])[CH3:13])=[CH:9][CH:10]=2)[CH:5]=[N:4]1.[F:15][C:16]([F:34])([F:33])[C:17]([C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][C@@H:25]([C:30](O)=[O:31])[CH2:24][CH2:23][C:22]=2[N:21]=1)([CH3:19])[CH3:18].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>CN1C(=O)CCC1>[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]([NH:14][C:30]([CH:25]3[CH2:24][CH2:23][C:22]4[N:21]=[C:20]([C:17]([CH3:19])([CH3:18])[C:16]([F:34])([F:33])[F:15])[CH:29]=[CH:28][C:27]=4[CH2:26]3)=[O:31])[CH3:13])=[CH:9][CH:10]=2)[CH:5]=[N:4]1
Reactant: CC(C)(c1ccc2c(n1)CC[C@H](C(=O)O)C2)C(F)(F)F
Reactant: C[C@@H](N)c1ccc2[nH]ncc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)C1CCc2nc(C(C)(C)C(F)(F)F)ccc2C1)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A 2 mL vial was charged sequentially with a solution of (R)-1-(1H-indazol-5-yl)ethanamine dihydrochloride (34 mg, 0.15 mmol) in NMP (0.2 mL), a solution of (S)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (38 mg, 0.13 mmol) and N,N-diisopropylethylamine (93 μL, 0.53 mmol) in NMP (0.1 mL). A solution of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (61 mg, 0.16 mmol) in NMP (0.3 mL) was added to the resulting mixture and the solution stirred at room temperature. After 30 min the mixture was filtered and purified by reverse-phase HPLC (20-75% MeCN in 10 mM Et2NH/H2O) to afford the amide as a solid (41 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 12.99 (br s, 1H), 8.42 (d, J=8.0 Hz, 1H), 8.04 (s, 1H), 7.66 (s, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.38-7.32 (m, 2H), 5.05 (app pentet, J=7.0 Hz, 1H), 2.96-2.78 (m, 4H), 2.68-2.60 (m, 1H), 2.05-1.97 (m, 1H), 1.82-1.69 (m, 1H), 1.53 (s, 6H), 1.42 (d, J=7.0 Hz, 3H); m/z=431.2 (M+1)+.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](Cc2ccccc2)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 3.90 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 64-2 (16.8 mmol, crude form) as starting material, respectively 1.91 g (Isomer A, colorless powder) and 2.99 g (Isomer B, colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:30])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C@H:13]1[CH2:18][CH2:19][CH:20]([OH:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1.Cl>C1COCC1>[Cl:28][C:24]1[CH:23]=[C:22]([CH2:21][CH:20]([OH:29])[CH2:19][CH2:18][C@@H:13]2[CH2:14][CH2:15][C:16](=[O:17])[N:12]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][C:5]([OH:30])=[O:4])[CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)COCCCCN1C(=O)CC[C@H]1CCC(O)Cc1cccc(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COCCCCN1C(=O)CC[C@H]1CCC(O)Cc1cccc(Cl)c1
Reaction time: 1 h
Yield: 44 %

Procedure:
Aqueous lithium hydroxide (1.0 N, 0.04 mL) was added to a solution of (4-{(R)-2-[4-(3-chlorophenyl)-3-hydroxy-butyl]-5-oxo-pyrrolidin-1-yl}-butoxy)-acetic acid methyl ester (15 mg, 0.036 mmol) in THF (0.5 mL) at rt. After 1 h, aqueous HCl (1.0 N, 3 mL) was added and the mixture was extracted with CH2Cl2 (3×5 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (0%→3% MeOH/CH2Cl2) to afford 6.3 mg (43%) of (4-{(R)-2-[4-(3-chlorophenyl)-3-hydroxy-butyl]-5-oxo-pyrrolidin-1-yl}-butoxy)-acetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[F:24][C:25]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:3]=1
Reactant: COc1cccc(B(O)O)c1F
Reactant: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2ccccc21
Product: COc1cccc(-c2cccc(C3(c4ccncc4)N=C(N)c4ccccc43)c2)c1F
Yield: 50 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-pyridin-4-yl-1H-isoindol-3-amine (Scheme #9, C) as described in Example 67 Scheme #10, D in 50% yield using 2-fluoro-3-methoxyphenyl boronic acid. 1H NMR (DMSO-d6) δ 8.42-8.32 (m, 2 H), 7.78-7.67 (m, 2 H), 7.44-7.34 (m, 3 H), 7.34-7.20 (m, 5 H), 7.15-7.02 (m, 2 H), 6.92-6.74 (m, 3 H), 3.78 (s, 3 H); MS (ESI) m/z 410 [M+1]+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)C.CC[O-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>O>[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
12 ml of diethyl malonate were introduced into 120 ml of ethanol and then 5.5 grams of sodium ethylate at 98% were added over 10 minutes at 0° to +5° C. The mixture was stirred for 15 minutes at 0°+5° C. and then 8.8 ml of ethyl bromoacetate were added over 30 minutes. The mixture was stirred for 48 hours at ambient temperature and then the mixture was poured into 600 ml of water and extracted 3 times with 300 ml of methylene chloride. The organic phase was washed twice with 300 ml of water, then evaporated to dryness. The oil obtained was distilled under reduced pressure to obtain 12.4 grams of the expected product with a boiling point of 110° to 120° C. at 1.0 mm of Hg.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>>[CH3:1][O:2][C:3]([C:5]1([C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ncnc3cc(OC)c(OC)cc23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.04 h

Procedure:
To a mixture of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (17.1 g, 70.5 mmol), as prepared in the previous step, and 4-chloro-6,7-dimethoxyquinazoline (15.0 g, 67.0 mmol) (Oakwood Products, Inc.) immersed in a −78° C. bath was added 1.08 M LiHMDS/THF (71 mL, 77 mmol) in ˜20 mL portions under argon via syringe along the sides of the flask (to allow cooling of the hindered base before reaction with the ester). Following completion of LiHMDS/THF addition, the reaction was allowed to sit in the −78° C. bath for 2-3 min before removing the cold bath and allowing the mixture to stir with gradual warming to rt. After 18 h stirring at rt, and an additional 2 d sitting at rt, the mixture was quenched with 0.5 M NaH2PO4 (150 mL) and extracted with DCM (1×150 mL and 1×100 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure to provide the crude title compound as a translucent yellow oil that was used in the next step without further purification (33g). A small sample was purified by flash chromatography (1:1 hex/EtOAc) for characterization. 1H-NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.34 (s, 1H), 7.29 (s, 1H), 4.05 (s, 3H), 3.96 (s, 3H), 3.76-3.67 (m, 2H), 3.62-3.49 (m, 2H), 3.61 (s, 3H), 2.50-2.36 (br s, 4H), 1.46 (s, 9H). LC/MS (ESI): calcd mass 431.2, found 432.2 (MH)+.
Reaction SMILES: [Cl:1][C:2]1([C:22]([O:24]CC)=[O:23])[CH:7]=[CH:6][C:5]([N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:9](=[O:11])[NH2:10])=[CH:4][CH2:3]1.[OH-].[K+]>CO>[Cl:1][C:2]1([C:22]([OH:24])=[O:23])[CH:3]=[CH:4][C:5]([N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])[C:9](=[O:11])[NH2:10])=[CH:6][CH2:7]1
Reactant: CCOC(=O)C1(Cl)C=CC(N(C(N)=O)c2ccccc2C(F)(F)F)=CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)N(C1=CCC(Cl)(C(=O)O)C=C1)c1ccccc1C(F)(F)F
Reaction time: 12 h
Yield: 91.5 %

Procedure:
To a slurry of N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-ethoxycarbonylphenyl)urea (Method C1e; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added an aqueous KOH solution (2.5 N, 10 mL, 23 mmol). The resulting mixture was heated at the reflux temp. for 12 h, cooled to room temp., and concentrated under reduced pressure. The residue was diluted with water (50 mL), then treated with a 1 N HCl solution to adjust the pH to 2 to 3. The resulting solids were collected and dried under reduced pressure to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-carboxyphenyl)urea as a white solid (5.05 g, 92%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[N:39]1([CH2:45][CH2:46][CH2:47][NH2:48])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.NN>CCO.O>[NH2:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:48][CH2:47][CH2:46][CH2:45][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:34])[C:15]1=[O:38]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Reactant: NCCCN1CCOCC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCn1c(=O)c(C(=O)NCCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.252 g, 0.49 mmol) in EtOH (15 mL) under nitrogen was treated with 3-(4-morpholinyl)-1-propanamine (0.357 mL, 2.44 mmol) for 15 min. (150° C. in a microwave vessel. The reaction was transferred to a test tube, diluted with EtOH (30 mL), and treated with hydrazine (0.4 mL, 13 mmol)@50° C. overnight. After the reaction was cooled to ambient temperature the resulting suspension was diluted with water (120 mL) and refrigerated overnight. The resulting suspension was filtered, washed with 2:1 water:EtOH and thoroughly dried under high vacuum to provide the title compound as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.68-1.76 (m, 2 H), 2.31-2.38 (m, 7 H), 2.78 (t, J=6.81 Hz, 2 H), 3.35-3.46 (m, 3 H), 3.55-3.62 (m, 5 H), 4.16 (s, 2 H), 4.22 (t, J=6.81 Hz, 2 H), 7.10-7.17 (m, 2 H), 7.38 (ddd, J=9.02, 5.79, 3.02 Hz, 2 H), 8.15 (s, 1 H), 8.50 (d, J=1.26 Hz, 1 H), 10.41 (d, J=3.93 Hz, 1 H); ES+ MS: 484 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH2:6])=[S:5].[CH2:14](N)[CH:15]=[CH2:16]>>[CH2:16]([NH:6][C:4](=[S:5])[CH:3]([N:2]([CH3:13])[CH3:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH:15]=[CH2:14]
Reactant: C=CCN
Reactant: CN(C)C(C(N)=S)c1ccccn1
Product: C=CCNC(=S)C(c1ccccn1)N(C)C

Procedure:
2-Dimethylamino-2-(2-pyridyl)thioacetamide is reacted with allylamine by the procedure of Example 7 to give N-allyl-2-dimethylamino-2-(2-pyridyl)thioacetamide.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24]3[N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:27]=[CH:26][CH:25]=3)=[N:16]2)=[C:11]([F:35])[CH:10]=1)C1C=CC=CC=1.C1COCC1>[Pd].CO>[F:35][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[N:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24]2[N:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:27]=[CH:26][CH:25]=2)=[N:16]1
Reactant: COc1cn(-c2ccc(OCc3ccccc3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cn(-c2ccc(O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
A mixture of 1-[4-(benzyloxy)-2-fluorophenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (5.53 g, 11.8 mmol), 10% Pd—C (50% wet, 3.0 g), THF (150 mL), and MeOH (150 mL) was hydrogenated for 1.5 h at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from MeOH/H2O to give the title compound (4.07 g, 91% yield) as a pale yellow solid: mp 223-224° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 3.75 (3H, s), 6.60 (1H, ddd, J=1.1, 2.6, 8.7 Hz), 6.73 (1H, dd, J=2.6, 12.8 Hz), 6.90-6.96 (2H, m), 7.28-7.44 (5H, m), 7.78 (1H, d, J=1.9 Hz), 8.39 (1H, d, J=1.9 Hz), 10.44 (1H, brs). LC-MS (ESI) m/z 379 [M+H]+. Anal. Calcd for C20H15FN4O3.0.5H2O: C, 62.01; H, 4.16; N, 14.46. Found: C, 62.18; H, 4.16; N, 14.49.