Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14](=[O:22])[NH:15][CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[C:23]([OH:29])=[O:24].[CH3:19][C:18]([CH3:21])([CH3:20])[CH2:17][CH2:16][NH:15][C:14]([C@@H:13]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[NH:8]1)=[O:22]
Reactant: CC(C)(C)CCNC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CCNC(=O)[C@@H]1C[C@H]2C[C@H]2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1R,3S,5R)-3-(3,3-dimethyl-butylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane 2-carboxylic acid tert-butyl ester (310 mg, 1 mmol) in CH2Cl2 (8 mL) was added TFA (0.769 mL, 10 mmol) and the solution was stirred at RT for 2 h. The crude reaction mixture was concentrated under vacuum and was used without further purification in the next step. UPLC/MS: 211.3 [M+H]+; tR (HPLC conditions b): 1.07 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[CH2:10]([NH2:13])[CH:11]=[CH2:12]>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[NH:13][CH2:10][CH:11]=[CH2:12]
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: C=CCN
Solvent: CCO
Product: C=CCNc1cc(Cl)nnc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 91.7 g of 3,4,6-trichloropyridazine in 1000 ml of ethanol is added slowly with cooling 85.9 g of allylamine. After stirring 2 hours at room temperature, the mixture is cooled and the resultant precipitate 3,6-dichloro-4-allylamino pyridazine is collected by filtration. Concentration of the filtrate to 200 ml gives a second crop and concentration to 100 ml gives a third crop; m.p. 95° to 98°C.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]([C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:17]=[N:18][C:19]([N+:22]([O-])=O)=[CH:20][CH:21]=3)[CH:12]=[CH:11][N:10]=2)=[CH:7][N:8]=1)([CH3:3])[CH3:2]>CO.[Pd]>[CH:1]([C:4]1[NH:5][C:6]([C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[N:18][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[CH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ncc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ncc(-c2cc(Oc3ccc(N)nc3)ccn2)[nH]1
Yield: 95.2 %

Procedure:
A mixture of 2-(2-isopropyl-1H-imidazol-5-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (612 mg, 1.881 mmol) and 10% Pd/C (50% wet, 200 mg, 0.188 mmol) in MeOH (10 mL) was hydrogenated (1 atm) for 24 h. The solids were removed via filtration through diatomaceous earth, washed with MeOH and the filtrate concentrated to dryness to afford 5-((2-(2-isopropyl-1H-imidazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (529 mg, 95%). 1H NMR (400 MHz, DMSO-d6): δ 11.96 (s, 1H), 8.30 (d, J=5.6 Hz, 1H), 7.81 (d, J=2.9 Hz, 1H), 7.51 (s, 1H), 7.29 (dd, J=8.9, 3.0 Hz, 1H), 7.20 (d, J=2.5 Hz, 1H), 6.67 (dd, J=5.7, 2.5 Hz, 1H), 6.52 (d, J=8.9 Hz, 1H), 6.03 (s, 2H), 2.97 (m, 1H), 1.21 (d, J=7.0 Hz, 6H); MS (ESI) m/z: 296.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH:20]1[OH:29]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([C:19]2([NH2:18])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21][CH:20]2[OH:29])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1c2ccccc2CCC1O
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)c2ccccc2CCC1O

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 1-amino-1,2,3,4-tetrahydro-2-naphthol, the title compound was prepared.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=[O:32])C(=O)OC1C=CC=CC=1.[OH-].[Na+]>CCO.O>[CH3:1][NH:2][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=[O:32]
Reactant: CN(CCN1C(=O)CCc2cc(NC(=N)c3cccs3)ccc21)C(=O)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNCCN1C(=O)CCc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C

Procedure:
Phenyl methyl(2-(2-oxo-6-(thiophene-2-carboximidamido)-3,4-dihydroquinolin-1(2H)-yl)ethyl)carbamate (700 mg, 1.56 mmol) was stirred in EtOH (20 mL). To this suspension was added solid NaOH (624 mg, 15.6 mmol), followed by water (10 mL). The flask was then fitted with a condenser and was heated to reflux for 2 h. When TLC analysis showed that the reaction was complete, the mixture was cooled to room temperature and diluted with water. The product was extracted with dichloromethane (3×) and the combined organics were dried, filtered and concentrated, then chromatographed in EtOAc, followed by 10% 2M NH3/MeOH in dichloromethane. The isolated spot was then triturated with methanol and ether. Yield (223 mg, 43%). 1H NMR (DMSO-d6) δ 7.73 (d, 1H, J=3.6 Hz), 7.59 (d, 1H, J=5.4 Hz), 7.10 (m, 2H), 6.73 (m, 2H), 6.45 (brs, 2H), 3.91 (t, 1H, J=7.2 Hz), 2.81 (t, 1H, J=7.2 Hz), 2.65 (t, 1H, J=7.2 Hz), 2.50 (t, 1H, J=7.2 Hz); ESI-MS (m/z, %): 329 (MH+, 70), 149 (100), 141 (80), 127 (96).
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:20][C:19]([CH3:22])([CH3:21])[O:18][C:6]2([CH2:11][CH2:10][N:9](C(=O)C(F)(F)F)[CH2:8][CH2:7]2)[CH2:5]1)[CH3:3].[OH-].[Li+].O>C1COCC1>[CH2:2]([N:4]1[CH2:5][C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[O:18][C:19]([CH3:21])([CH3:22])[CH2:20]1)[CH3:3]
Reactant: CCN1CC(C)(C)OC2(CCN(C(=O)C(F)(F)F)CC2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCN1CC(C)(C)OC2(CCNCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To 1-(8-ethyl-10,10-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-2,2,2-trifluoro-ethanone hydrochloride salt (47 mg, 0.14 mmol) and lithium hydroxide (10 mg, 0.42 mmol) was added water (0.15 mL) and THF (0.6 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, partitioned between DCM (10 mL)/1:1 brine:NH4OH (2 mL), extracted with DCM (5×10 mL), dried over MgSO4 and concentrated in vacuo to give 4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecane (24 mg, 81%). ESI-MS m/z calc. 212.2. found 213.5 (M+1)+; Retention time: 0.19 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH2:7][C:6](Br)([CH2:17][CH2:18][CH3:19])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22].[Br-].[Li+].O>CN(C)C=O>[CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH2:7][C:6](=[CH:17][CH2:18][CH3:19])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22]
Reactant: CCCC1(Br)Cc2c3c(c(C)c(C)c2C1=O)OC(C(=O)O)C3
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC=C1Cc2c3c(c(C)c(C)c2C1=O)OC(C(=O)O)C3

Procedure:
A stirred solution of 4,5-dimethyl-6-oxo-7-bromo-7-propyl-1,2,7,8-tetrahydro-6H-indeno[5,4-b]furan-2-carboxylic acid (0.7 g., 0.0019 mole) and lithium bromide (0.5 g., 0.0057 mole) in dimethylformamide (10 ml.) is heated at 95°C. for one hour in an inert atmosphere then poured into water (50 ml.) affording 4,5-dimethyl-6-oxo-7-propylidene-1,2,7,8-tetrahydro-6H-indeno[5,4-b]-furan-2-carboxylic acid as a cream colored solid which melts at 229°C. after recrystallization from ethanol.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:33]=[CH:32][C:25]([O:26][CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:9]([C:10]([N:29]2[CH2:30][CH2:31][CH:27]([O:26][C:25]3[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:35])[F:34])=[CH:33][CH:32]=3)[CH2:28]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1ccc(OC2CCNC2)cc1
Reactant: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)N2CCC(Oc3ccc(C(F)(F)F)cc3)C2)c1
Yield: 20 %

Procedure:
Prepared in analogy to Example 1 from 5-methanesulfonyl-2-morpholin-4-yl-benzoic acid (Example A4) and 3-(4-trifluoromethyl-phenoxy)-pyrrolidine. The crude material was purified by chromatography (methanol/dichloromethane) to yield the title compound as a white solid (yield 20%). MS (m/e): 499.4 (M+H+, 100%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13])=[O:3].[C:14]([OH:18])([CH3:17])([CH3:16])[CH3:15].N1C2C(=CC=CC=2)C=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13])[O:18][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)Oc1cc(Cl)c(Cl)cc1Cl
Solvent: c1ccc2ncccc2c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Oc1cc(Cl)c(Cl)cc1Cl

Procedure:
T-Butyl 2,4,5-trichlorophenyl carbonate is a known compound and one method for its preparation is described in an article by W. Broadbent, J. S. Morley and B. E. Stone in the Journal of the Chemical Society (C), 1967 pages 2632-2637. Briefly, in this method a solution of phosgene in toluene is treated with 2,4,5-trichlorophenol at -10° C, followed by addition of dimethylaniline at such a rate that the reaction temperature is maintained at 5°-10° C. The mixture is heated to 20°-24° C and maintained at this temperature for 12 hours. The mixture is cooled by addition of ice and the suspension filtered. From the organic layer in the filtrate, 2,4,5-trichlorophenyl chloroformate is isolated. A solution of the crude 2,4,5-trichlorophenyl chloroformate in methylene chloride is reacted with a solution of t-butanol and quinoline in methylene chloride. The reaction mixture is maintained at 20°-24° C for 12 hours. The mixture is cooled by addition of ice and the suspension is filtered. From the organic layer in the filtrate t-butyl 2,4,5-trichlorophenyl carbonate is isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[C:10]([O:12][CH3:13])[CH:11]=1)[C:7]([OH:9])=[O:8].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.O>O1CCCC1>[CH3:13][O:12][C:10]1[C:6]2[C:7](=[O:9])[O:8][C:16](=[O:18])[NH:14][C:5]=2[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=1
Reactant: COc1cc(N)c(C(=O)O)c(OC)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)c2c(=O)oc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 262.9 %

Procedure:
To a cooled (0° C.) brown solution of 4,6-dimethoxy anthranilic acid (76.0 g, 0.385 mol), prepared as in Example 2, in tetrahydrofuran (1.3 L) was added triphosgene (40.0 g, 0.135 mol) in portions over a 20 min period. After 30 min, the reaction was warmed to room temperature and stirred for an additional 1.5 h. The reaction mixture was poured into an Erlenmeyer flask containing water and cooled to 0° C. with an ice bath. Additional water was added to facilitate the stirring of the thick solid formed. After stirring for 30 min, the reaction mixture was filtered to give a beige solid. The solid was washed with water, air-dried, and then dried under high vacuum to give 79.2 g (92%) of the isatoic anhydride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([N:16]([CH2:28][CH3:29])[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]([CH3:27])[NH:24][CH2:23][CH2:22]2)[CH3:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:24]3[CH2:23][CH2:22][C:21]4[C:26](=[C:17]([N:16]([CH2:28][CH3:29])[CH2:14][CH3:15])[CH:18]=[CH:19][CH:20]=4)[CH:25]3[CH3:27])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CCN(CC)c1cccc2c1C(C)NCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CCN(CC)c1cccc2c1C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with Diethyl-(1-methyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-amine to provide the title compound in moderate yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:12])[CH2:9][C:10]#[CH:11]>C(N(CC)CC)C.[Cu+2].[I-].[I-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][OH:12]
Reactant: C#CCCO
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu+2]
Agent: [I-]
Solvent: CCN(CC)CC
Product: OCCC#Cc1ccccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.7 %

Procedure:
In a dry reaction tube containing in suspension iodide copper (38 mg, 0.2 mmol) and triethylamine (11 mL, 80 mmol), were added 2-bromopyridine (632 mg, 4 mmol) and Pd(PPh3)2Cl2 (140 mg, 0.2 mmol). A yellow suspension is obtained and after a few minutes of stirring at room temperature, was added a solution of but-3-yn-1-ol (280 mg, 4 mmol) in triethylamine (2.2 mL). Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and then at 80° C. for 20 h. Triethylamine was concentrated under reduced pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NH4Cl, water and brine, dried (MgSO4) and concentrated. The product was purified by flash chromatography (prepacked 15 g silicagel column, from DCM 100% to DCM/MeOH: 98/2 as eluent) to afford 440 mg of 4-(pyridin-2-yl)but-3-yn-1-ol (Yield: 74%) as brown oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[Mg].II.[N:16]1([CH:21]([CH3:26])[C:22]([O:24]C)=O)[CH:20]=[CH:19][CH:18]=[N:17]1.Cl>O1CCCC1.O>[F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:22]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:11])[F:12])=[CH:9][CH:8]=2)([OH:24])[CH:21]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[CH3:26])=[CH:6][CH:5]=1
Reactant: COC(=O)C(C)n1cccn1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CC(n1cccn1)C(O)(c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.6 %

Procedure:
A solution of 4-trifluoromethoxybromobenzene (6.3 g.) in dry tetrahydrofuran (40 cm3) was added dropwise to a stirred mixture of magnesium turnings (0.62 g.), dry tetrahydrofuran (10 cm3) and a crystal of iodine under a nitrogen atmosphere. The reaction commenced after about 3 cm3 of the solution had been added and the mixture was warmed gently for a few minutes. When the addition was complete the mixture was stirred for 2 hours after which a solution of methyl 2-(1H-pyrazol-1-yl)propionate (2.0 g) in dry tetrahydrofuran (5.0 cm3) was added dropwise and the mixture then stirred for a further 2 hours at the ambient temperature. Finally the mixture was warmed to 40° C. to complete the reaction. The mixture was poured into water, acidified with dilute hydrochloric acid and extracted with two portions of diethyl ether 2×50 cm3. The extracts were combined, washed with water (3×50 cm3), dried over anhydrous magnesium sulphate and concentrated by removal of the solvent by evaporation under reduced pressure. The residual oil was subjected to purification by repeated chromatographic separation on a silica gel column eluted with a mixture of petroleum ether (boiling range 60°-80° C., 4 parts by volume) and ethyl acetate (1 part by volume) to yield 1,1-bis(4-trifluoromethoxyphenyl)-2-(1H-pyrazol-1-yl) propanol (500 mg.) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:24])[CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[NH:16]C(=O)OC(C)(C)C)=[CH:6][CH:5]=[CH:4][N:3]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:16][C:15]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH2:9][CH:8]([C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[OH:24]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1CC(O)c1cccnc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccncc1CC(O)c1cccnc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-[2-(2-fluoropyridin-3-yl)-2-hydroxyethyl]pyridin-4-ylcarbamate (2.00 g, 6.00 mmol, Intermediate D-3) was dissolved in methylene chloride (40 mL) and trifluoroacetic acid (40 mL). The solution was stirred at room temperature for one hour. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with NaHCO3/water. The aqueous layer was then saturated with solid NaCl, and extracted with ethyl acetate repeatedly (8 times). The combined extracts were dried over MgSO4, filtered, and concentrated to provide an oil which slowly solidified. The desired product was isolated as an off-white solid and was used directly in the next step without further purification. 1H NMR (DMSO-d6) δ 8.10 (d, 1H), 8.01 (m, 1H), 7.90 (d, 1H), 7.77 (s, 1H), 7.34 (m, 1H), 7.18 (m, 1H), 6.59 (m, 2H), 5.80 (bs, 1H), 5.00 (m, 1H), 2.83 (m, 2H). LC/MS: 234 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20]C)[CH:16]=2)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C(O)(=O)C>O>[CH2:1]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2cc(CNCc3ccccc3)ccc2c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc2cc(CNCc3ccccc3)ccc2c1
Yield: 61.4 %

Procedure:
A mixture of benzyl-(6-methoxy-naphthalen-2-ylmethyl)-amine (1.3 g, 4.7 mmol), prepared in the previous step, 65 mL of 48% HBr and 50 mL of glacial acetic acid was refluxed under nitrogen for 19 h (overnight). The solvent was removed under reduced pressure to give a red solid. The solid was suspended in 250 mL of water and heated until most of the solid dissolved. The mixture was filtered, the filtrate made basic with sodium bicarbonate and extracted three times with ethyl acetate. The organic extracts were combined, dried (MgSO4) and the solvent removed under reduced pressure to give 6-(benzylamino-methyl)-naphthalen-2-ol (0.76 g, 62%) as a green solid, mp 120-122° C.
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2.N1CCCCC1>C(O)C>[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 69.8 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f (490 mg, 1.53 mmol), 5-fluoro-1,3-dihydro-indol-2-one (219 mg, 1.45 mmol) and piperidine (100 μL, 1.0 mmol) were dissolved in 5 mL of ethanol under stirring at room temperature. The reaction system was stirred at 80° C. in an oil bath in dark for 2 hours. The reaction was completed until TLC showed the disappearance of starting materials, and the oil bath was removed. The reaction mixture was naturally cooled down to room temperature to precipitate solids. The resulting solids were filtered to give the title compound (S,Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 5 (460 mg, 69.9%) as a yellow solid.
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].[Li+].CC([N-]C(C)C)C.Br[CH2:27][C:28]([CH3:30])=[CH2:29]>C1COCC1>[CH3:29][C:28](=[CH2:27])[CH2:30][C:5]1([C:3]([O:2][CH3:1])=[O:4])[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
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=C(C)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)CC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-Boc-piperidine-4-carboxylic acid methyl ester (2.00 g, 8.22 mmol) in THF (40 mL) was cooled to −78° C. Under nitrogen, a 2.0 M THF solution of LDA (6.17 mL, 12.3 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 30 minutes before a solution of 3-bromo-2-methylpropene (1.60 g, 11.9 mmol) in THF (2 mL) was added. After the reaction was stirred for 1 hour at this temperature, a sample was taken for LC-MS analysis and it showed that the reaction was completed. The reaction was quenched by adding saturated ammonium chloride solution (5 mL) and the mixture was allowed to warm up to room temperature. The mixture was then extracted with EtOAc (50 mL twice). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrates were concentrated and the crude product was purified by column chromatography eluting with 0-30% ethyl acetatehexane to give the title compound. LC-MS (IE, m/z): 242.21 [M−56+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[H-].[Na+].[C:28](Cl)(=[O:30])[CH3:29]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([C:28](=[O:30])[CH3:29])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(F)cc1Cl
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)n1c2c(c(=O)n(-c3cc(C(=O)OC(C)C)c(Cl)cc3F)c1=O)CCC2
Reaction time: 2 h

Procedure:
A solution of 3.6 g of isopropyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate in 50 ml of absolute dimethylformamide is stirred at room temperature for 2 hours with 0.43 g of a 55% sodium hydride dispersion. A solution of 0.93 g of acetyl chloride in 10 ml of absolute dimethylformamide is subsequently added dropwise during 10 minutes and the mixture is stirred for 2 hours. The reaction mixture is dissolved in 100 ml of ethyl acetate and the solution is washed thoroughly with water. The organic phase is dried over anhdrous sodium sulphate and evaporated to dryness. The residue is purified by chromatography on a silica gel column using methylene chloride/ethyl acetate (3:1) as the eluent. There is obtained isopropyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-acetyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.86 ppm (d, 1H), 7.37 ppm (d, 1H), 5.24 ppm (m, 1H), 3.13 ppm (m, 2H), 2.75 ppm (m, 2H), 2.68 ppm (s, 3H), 2.12 ppm (m, 2H), 1.36 ppm (d, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH3:2].C(O[CH2:23][N:24]([CH2:32][Si](C)(C)C)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)CCCC.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C@H:5]1[C@@H:6]([CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:32][N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23]1)=[O:16])[CH3:2]
Reactant: CCCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)C=CCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1CNC(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
To a solution of 2 g of 4-tert-butoxycarbonylamino-but-2-enoic acid ethyl ester (8.72 mmol) and 5.12 g N-[(pentyloxy)methyl]-N-[(trimethylsilyl)methyl]-benzene-methanamine (17.4 mmol) in ml dichloromethane was added 10 micro-1. trifluoroacetic acid. The reaction was monitored by TLC. The reaction was complete after 10 min. The mixture was diluted with dichloromethane, washed with sat. sodium bicarbonate solution and brine, dried over Mg sulfate, filtered and the filtrate evaporated. The residue was purified by filtration over a short silica column, using a 7/3 hexane/ethyl acetate mixture as eluent.