Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.CC1(C)C(C)(C)OB([C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=1
Reactant: FC(F)(F)c1ccc(Br)c(I)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2Br)CC1

Procedure:
A solution of 1-bromo-2-iodo-4-(trifluoromethyl)benzene (1.598 ml, 9.70 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (3.00 g, 9.70 mmol), Pd(dppf)-CH2Cl2 adduct (0.396 g, 0.485 mmol), and potassium carbonate (2.329 g, 38.8 mmol) in 1,4-dioxane (36.4 ml) and water (12.13 ml) was stirred at 70° C. for 18 hours. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (Redi-Sep Gold 80 g silica gel column (Teledyne Isco, Lincoln, Nebr.), gradient elution 0 to 100% Et2O:Heptane) to afford tert-butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate as a light yellow oil. m/z (ESI) 428.1 (M+Na)+.
Reaction SMILES: [CH3:1][CH:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12]O.Br>ClCCl>[CH3:1][CH:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:12][CH2:11][NH:9]1
Reactant: CC(N)c1ccccc1
Reactant: OCCBr
Agent: Br
Solvent: ClCCl
Product: CC1NCCc2ccccc21
Temperature: 51 °C
Reaction time: 50 h
Yield: 139 %

Procedure:
76.61 g(630 mmole) of α-methylbenzylamine was dissolved in 77 ml of dichloromethane and 94.8 g(760 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 286.4 ml(2500 mmole) of 48% aqueous hydrobromic acid solution was added thereto and allowed to react at 126° C. for 30 minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 250 ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 350 ml of isopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10° C. and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 50 ml of ethyl acetate and then dried to obtain 128.9 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH3:12])=[N:8][CH:9]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH3:12])=[N:8][CH:9]=1
Reactant: CCCc1ccc([N+](=O)[O-])cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccc(N)cn1

Procedure:
A suspension of 5-nitro-2-n-propylpyridine (8.31 g, 50 mmol) and 400 mg 5% palladium on charcoal in 200 ml of ethanol was stirred in a hydrogen atmosphere until no more hydrogen was absorbed. The reaction mixture was filtered twice and the solvent was evaporated. The resulting oil was purified by kugelrohr destillation at 150° C. and high vacuum pressure. This gave 6.72 g (98%) of 5-amino-2-n-propylpyridine as a colourless oil. MS(GC): m/z 136 (M+). 1H-NMR (CDCl3, 200 MHz) δ: 0.83 (t, 3H); 1.60 (sext, 2H); 2.54 (t, 2H); 3.67 (br s, 2H); 6.81 (d, 2H); 7.91 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+:14]>C(O)C.O>[CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O-:7])=[O:6])[CH3:2].[Na+:14]
Reactant: CCOC(=O)C(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(OCC)C(=O)[O-]
Yield: 96.1 %

Procedure:
Ethyl diethoxyacetate (Ex. Fluka) (25 g) was added to sodium hydroxide (5.68 g) in ethanol (60 ml) and water (30 ml). After heating under reflux for 5 hours the solvents were removed at reduced pressure and the residue dried in vacuo to give sodium diethoxyacetate (23.2 g). The salt was then converted to diethoxyacetyl chloride and reacted with benzylamine to give N-benzyl diethoxyacetamide which was cyclised with conc. sulphuric acid according to Fukumi and Hideshi, Heterocycles, 9, 1197 (1978) to give 3-hydroxyisoquinoline.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][N:11]=[C:10]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:9]=1)(C)(C)C.C(C1NC=CN=1)(C1[NH:26]C=CN=1)=O.N>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:14][C:13]1[C:8]([CH2:7][C:6]([NH2:26])=[O:5])=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[N:11][CH:12]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Cc1cnc(N2CCN(C)CC2)cc1CC(=O)OC(C)(C)C
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(N2CCN(C)CC2)cc1CC(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[5-Methyl-2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-acetic acid tert-butyl ester (320 mg, 1.05 mmol) is dissolved in a mixture of TFA and CH2Cl2 (10 ml/10 ml) and stirred at RT. After 1 h at RT, TLC analysis indicated complete conversion of starting material. The solvent is removed by rotary evaporation, and replaced by dry DMF (1.5 ml). Under an atmosphere of argon, carbonyl diimidazole (187 mg, 1.16 mmol) is added. After 30 minutes at RT, TLC analysis indicated complete conversion of the carboxylic acid. An aqueous solution of ammonia (25%, 16 ml) is added at RT. After 15 minutes at RT, solvents are removed under high vacuum. The residue is dissolved in CH2Cl2/MeOH (9:1) and purified by FCC (CH2Cl2/MeOH, slow gradient from 95:5 to 40:60) to yield the title compound. 1H NMR (d6-DMSO, 400 MHz): δ 2.07 (s, 3H), 2.38 (s, 3H), 2.64 (s, broad, 4H), 3.34 (s, 2H), 3.46 (s, broad, 4H), 6.72 (s, 1H), 6.95 (s, broad, 1H), 7.44 (s, broad, 1H), 7.87 (s, 1H). ES+−MS: 249.3 [M+H]+, ES−−MS: 247.3 [M−H]−.
Reaction SMILES: BrBr.[C:3]([NH:11][C:12]1[CH:17]=[C:16]([CH2:18][C:19]([C:21]2[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=2)=O)[CH:15]=[CH:14][N:13]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:29][C:30]([NH2:32])=[S:31].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(O)(=O)C>[NH2:32][C:30]1[S:31][C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:17]=2)=[C:19]([C:21]2[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=2)[N:29]=1
Reactant: NC(N)=S
Reactant: Cc1cc(C)cc(C(=O)Cc2ccnc(NC(=O)c3ccccc3)c2)c1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2nc(N)sc2-c2ccnc(NC(=O)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
Bromine (1.0 mL, 19 mmol) was added to a solution of 2-(2-benzoylamino-4-pyridyl)-1-(3,5-dimethylphenyl)ethanone (6.4 g, 19 mmol) in acetic acid (80 mL) at 0° C. and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was dissolved in acetonitrile (100 mL), to the solution were added thiourea (1.5 g, 19 mmol) and triethylamine (2.8 mL, 20 mmol) and the mixture was stirred at 80° C. for 3 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate (200 mL) was added and the resulting solid was collected by filtration and washed with water. The resulting crude crystals were collected by filtration and washed with water. The crude crystals were recrystallized from ethanol to obtain 5.0 g (13 mmol, yield 68%) of the title compound.
Reaction SMILES: [CH:1]1([C:7]2[N:12]([OH:13])[C:11](=[O:14])[CH:10]=[C:9]([CH3:15])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]1([C:22](Cl)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:22]([O:13][N:12]1[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:8][C:9]([CH3:15])=[CH:10][C:11]1=[O:14])(=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(C2CCCCC2)n(O)c(=O)c1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C2CCCCC2)n(OC(=O)c2ccccc2)c(=O)c1
Temperature: 7 °C
Reaction time: 1.5 h

Procedure:
To 6-cyclohexyl-1-hydroxy-4-methylpyridin-2(1H)-one (0.5 g) in CH2Cl2 (20 mL) were added DMAP (0.44 g) and PhCOCl (0.5 mL) at 7° C. After the mixture was stirred at 7° C. for 90 min, solvent was partially removed in vacuum. Water (20 mL) and ethyl acetate (20 mL) were added. The organic layer was collected and concentrated. The desired compound was recrystallized from ethyl acetate and petroleum ether to yield compound 338 (0.22 g).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:35])([F:34])[C:5]1[CH:6]=[C:7]([C@H:15]([O:17][C@@H:18]2[C@@H:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=3)[C@H:22]([CH:32]=[O:33])[CH2:21][CH2:20][O:19]2)[CH3:16])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1>CO>[F:35][C:4]([F:3])([F:34])[C:5]1[CH:6]=[C:7]([C@H:15]([O:17][C@@H:18]2[C@@H:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=3)[C@H:22]([CH2:32][OH:33])[CH2:21][CH2:20][O:19]2)[CH3:16])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: C[C@@H](O[C@H]1OCC[C@@H](C=O)[C@@H]1c1ccc(F)c(F)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](O[C@H]1OCC[C@@H](CO)[C@@H]1c1ccc(F)c(F)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
Sodium borohydride (24 mg, 0.63 mmol) was added to solution of 2-[1-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3,4-difluorophenyl)-tetrahydropyran-4-carbaldehyde (see Example 2 in WO 02/16344; 107 mg, 0.23 mmol) in methanol (3 ml). The mixture was stirred for 30 minutes then quenched with saturated aqueous NaHCO3 and extracted into ethyl acetate. The combined organic extracts were dried and concentrated to give the title compound (104 mg).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:22]([OH:45])[CH2:23][NH:24][C:25]([CH3:44])([CH3:43])[CH2:26][CH2:27][N:28]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[C:31]([CH2:40][CH3:41])([CH2:38][CH3:39])[O:30][C:29]2=[O:42])[C:12]2[O:17][C:16]([CH3:19])([CH3:18])[C:15](=[O:20])[NH:14][C:13]=2[CH:21]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:40]([C:31]1([CH2:38][CH3:39])[O:30][C:29](=[O:42])[N:28]([CH2:27][CH2:26][C:25]([NH:24][CH2:23][CH:22]([OH:45])[C:11]2[C:12]3[O:17][C:16]([CH3:18])([CH3:19])[C:15](=[O:20])[NH:14][C:13]=3[CH:21]=[C:9]([OH:8])[CH:10]=2)([CH3:43])[CH3:44])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]1=2)[CH3:41]
Reactant: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OC(C)(C)C(=O)N3)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(O)cc3c2OC(C)(C)C(=O)N3)c2ccccc21

Procedure:
130 mg (0.21 mmol) 1-{3-[2-(6-benzyloxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4,4-diethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one are dissolved in 5 mL methanol and hydrogenated in the presence of palladium on charcoal (10%) at ambient temperature. The catalyst is suction filtered, the filtrate is evaporated down and the residue is purified by chromatography (Reverse phase; acetonitrile/water gradient). White solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][CH:10]([CH3:20])[C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1CCCCC1.O>C1C=CC=CC=1>[C:2]1([CH:1]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11](=[O:19])[CH:10]([CH3:20])[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Cc1ccccc1
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CC(C)C(=O)C(=Cc1ccccc1)c1ccccc1

Procedure:
A solution of benzaldehyde (6.5g, 0.0617 mole), 3-methyl-1-phenyl-2-butanone (10 g, 0.0617 mole) and piperidine (0.2 g) in benzene (50 ml) was heated to reflux for 20 hours. Water formed during the reaction was removed (azeotrope) by the use of a Dean-Stark trap. The reaction was concentrated to an oil, and the product was purified by silica gel chromatography.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14]2)=[CH:9][CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)O1>C(COC)OC.C([O-])([O-])=O.[Na+].[Na+]>[OH:37][C:34]1[CH:35]=[CH:36][C:31]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14]3)=[CH:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc2ccc(-c3ccc(O)cc3)cc2c1
Temperature: 70 °C
Yield: 101.8 %

Procedure:
A solution of methyl 7-{[(trifluoromethyl)sulfonyl]oxy}-2-naphthalenecarboxylate (100 mg, 0.3 mmol), tetrakistriphenylphosphine palladium (14 mg, 0.012 mmol) and 4-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl-)phenol (79 mg, 0.36 mmol) in a mixture of dimethoxyethane (1.6 mL) and 2 M aqueous Na2CO3 (1.3 mL) was heated in a 70° C. oil bath for one hour. The solution was partitioned between ethyl acetate and water. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The crude material was purified by chromatography on silica gel, (hexane to 3:7 ethyl acetate:hexanes) to provide the title compound (0.085 g, 95.5% as 0.20 ethyl acetate). 1H NMR (DMSO-d6): 9.64 (s, 1H), 8.65 (s, 1H), 8.31 (s, 1H), 8.03-7.99 (m, 2H), 7.93-7.90 (m, 2H), 7.66 (d, J=9 Hz, 2H), 6.88 (d, J=9 Hz, 2H), 3.90 (s, 3H).
Reaction SMILES: Cl.C([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[C:14]([Cl:18])[N:15]=[C:16]([Cl:17])[C:11]=2[CH2:10]1)C1C=CC=CC=1.C(N(CC)CC)C.Cl[C:29]([O:31][CH:32]([Cl:34])[CH3:33])=[O:30].O>ClCCCl>[Cl:18][C:14]1[N:15]=[C:16]([Cl:17])[C:11]2[CH2:10][N:9]([C:29]([O:31][CH:32]([Cl:34])[CH3:33])=[O:30])[CH2:20][CH2:19][C:12]=2[N:13]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: Clc1nc(Cl)c2c(n1)CCN(Cc1ccccc1)C2
Agent: Cl
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(Cl)OC(=O)N1CCc2nc(Cl)nc(Cl)c2C1

Procedure:
6-Benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride (35.0 g, 0.106 mol) prepared according to Process Step 2 was dissolved in 1,2-dichloroethane (850 mL), and the solution was mixed with triethylamine (14.9 mL, 0.107 mol) and 1-chloroethyl chloroformate (34.1 mL, 0.316 mol), followed by stirring under reflux for five hours. After checking the completion of the reaction by thin layer chromatography, the reaction mixture was cooled and was mixed with water, followed by separation. The organic layer was washed with brine, was dried over anhydrous magnesium sulfate and was concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) and thereby yielded a 2,4-dichloro-6-(1-chloroethoxycarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine fraction. After distilling off the solvent, the residue was dissolved in methanol (850 mL), followed by stirring under reflux for one hour. After checking the completion of the reaction by thin layer chromatography, the reaction mixture was concentrated and thereby yielded 2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride (23.5 g, in a total yield from 6-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride of 95%).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[C:8]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])[C:7]([CH3:24])=[C:6]([Cl:25])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+].O1CCCC1>CO.C(#N)C>[NH2:32][CH:1]([C:4]1[C:9]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[C:8]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])[C:7]([CH3:24])=[C:6]([Cl:25])[CH:5]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c(C)c(N2CCCC2=O)c1-c1cc(F)cc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: Cc1c(Cl)cc(C(C)N)c(-c2cc(F)cc(F)c2)c1N1CCCC1=O
Temperature: 25 °C

Procedure:
A mixture of 1-(6-acetyl-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-yl)pyrrolidin-2-one (0.015 g, 0.041 mmol), ammonium acetate (0.032 g, 0.41 mmol), 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.10 mL, 0.10 mmol) in methanol (0.1 mL) and acetonitrile (0.1 mL) was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C19H17ClF2NO (M−NH2)+: m/z=348.1. found: 348.0.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[NH:63]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:64][C:65](O)=[O:66].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(Cl)(Cl)Cl.CO>[NH:63]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:64][C:65]([NH:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=1)(=[O:11])=[O:12])=[O:66]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
At 0° C. the solution of 930 mg (1.01 mmol) of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12) in 15 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which the pre-cold solution of 200 mg (1.14 mmol) of Boc-Gly-OH, 150 mg (1.11 mmol) of 1-hydroxybenzotriazole and 235 mg (1.14 mmol) of dicyclohexylcarbodiimide in 40 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 12 h and TLC (chloroform/methanol, 10:1) indicated complete disappearance of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12). The resulted precipitates of N,N-dicyclohexylurea were filtrated and the filtrate was diluted with 100 ml of ethyl acetate. The solution obtained was washed successively with saturated NaCO3 in water (50 ml×3), saturated NaCl in water (50 ml×3) and KHSO4 in water (5%, 50 ml×3). The separated ethyl acetate layer was dried with anhydrous MgSO4, and then evaporated. The residue was purified on sinica gel chromatography (CHCl3/CH3OH, 30/1) to provide 770 mg (73%) of the title compound as a glassy mass. Mp 82–84° C., FAB-MS (m/e) 1038.6[M+H]+, 1061.7[M+Na]+.
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5]([OH:21])=[C:6](C(OCC)=O)[C:7](=[O:15])[NH:8]2)[CH3:2]>O.O1CCOCC1.Cl>[CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5]([OH:21])=[CH:6][C:7](=[O:15])[NH:8]2)[CH3:2]
Reactant: CCOC(=O)c1c(O)c2c(CC)nc(CC)cc2[nH]c1=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc2[nH]c(=O)cc(O)c2c(CC)n1
Yield: 55.9 %

Procedure:
Compound B (1 g) was dissolved in a mixture of water (1 ml), 1,4-dioxan (2 ml) and concentrated hydrochloric acid (1 ml) and the mixture was heated at reflux for 3 hours. The reaction mixture was then cooled and the suspended solid was collected by filtration. The solid was washed with ethanol and ether and dried under vacuum to give 5,7-diethyl-4-hydroxy-1,6-naphthyridin-2(1H)-one (C) (0.42 g), m.p. 322°-325° C.; NMR (d6 -DMSO): 1.3(dt, 6H), 2.99(q, 2H), 3.47(q, 2H), 6.0(s, 1H), 7.28(s, 1H), 12.3(s, 1H); mass spectrum (CI, ammonia): 219 (M+H)+ ; microanalysis, found: C, 55.7; H, 5.9; N, 10.5%; C12H14N2O2.HCl.0.25H2O requires: C, 55.6; H, 5.6; N, 10.8%.
Reaction SMILES: [CH3:1][C:2]1[C:9]2[C:8]([CH3:10])=[CH:7][S:6][C:5]=2[S:4][C:3]=1[CH:11]=O.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[CH3:1][C:2]1[C:9]2[C:8]([CH3:10])=[CH:7][S:6][C:5]=2[S:4][C:3]=1[CH2:11][N:27]1[CH2:28][CH2:29][CH:24]([C:20]2[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=2)[CH2:25][CH2:26]1
Reactant: Cc1csc2sc(C=O)c(C)c12
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: Cc1csc2sc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(C)c12

Procedure:
Prepared by Procedure F and Scheme R using 3,4-dimethylthieno[2,3-b)thiophene-2-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 427.1 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:42])[C:14]=1[NH:15][C:16]1[C:25]2[C:20](=[C:21]([O:28][CH2:29][C@H:30]3[C@H:37]4[C@H:33]([O:34]C(C)(C)[O:36]4)[C:32](=[O:40])[O:31]3)[C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[O:19][C:18](=[O:41])[CH:17]=1.O>C1COCC1>[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:42])[C:14]=1[NH:15][C:16]1[C:25]2[C:20](=[C:21]([O:28][CH2:29][C@H:30]3[C@H:37]([OH:36])[C@H:33]([OH:34])[C:32](=[O:40])[O:31]3)[C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[O:19][C:18](=[O:41])[CH:17]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OC[C@@H]1OC(=O)[C@H]2OC(C)(C)O[C@@H]12
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OC[C@@H]1OC(=O)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Trifluoroacetic acid (0.1 mL) was added to a mixture of 4-(3,5-dichloropyridin-4-ylamino)-8-(((3aS,4S,6aS)-2,2-dimethyl-6-oxotetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-7-methoxy-2H-chromen-2-one (60 mg, 0.12 mmol, Example 50), water (0.1 mL), and THF (3 mL). The mixture was stirred at rt for 2 d. Then, more trifluoroacetic acid (3 mL) was added over time until the reaction was complete by LCMS. The mixture was concentrated to give 4-(3,5-dichloropyridin-4-ylamino)-8-(((2S,3R,4S)-3,4-dihydroxy-5-oxotetrahydrofuran-2-yl)methoxy)-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.81 (s, 2H), 7.97 (d, 1H), 7.21 (d, 1H), 5.74 (s, 1H), 4.63 (s, 1H), 4.61 (d, 1H), 4.49 (m, 1H), 4.42 (d, 1H), 4.23 (d, 1H), 3.91 (s, 3H); MS (ESI): 482.8.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[S:23][CH:24]=3)[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:29]=[CH:30][C:25]([C:22]2[S:23][CH:24]=[C:20]([CH2:19][CH2:18][O:17][C:14]3[CH:15]=[C:16]4[C:11]([CH:10]=[CH:9][N:8]4[CH2:7][C:6]([OH:35])=[O:5])=[CH:12][CH:13]=3)[N:21]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(OCCc3csc(-c4ccc(C(F)(F)F)cc4)n3)cc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ccc(OCCc3csc(-c4ccc(C(F)(F)F)cc4)n3)cc21

Procedure:
In analogy to the procedure described in example 2 c], (6-{2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester was treated with LiOH to obtain (6-{2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-indol-1-yl)-acetic acid as brown solid.