Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[NH:12][C:11](=[O:14])[CH:10]=[CH:9][C:8]=2[CH:7]=[CH:6][C:5]1=[O:15])[CH:2]=[CH2:3].[CH3:16]C(C)([O-])C.[K+].C1COCC1.CI>CN(C=O)C>[CH3:16][O:14][C:11]1[N:12]=[C:13]2[C:8]([CH:7]=[CH:6][C:5](=[O:15])[N:4]2[CH2:1][CH:2]=[CH2:3])=[CH:9][CH:10]=1
Reactant: C=CCn1c(=O)ccc2ccc(=O)[nH]c21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCn1c(=O)ccc2ccc(OC)nc21

Procedure:
A solution of 1-(2-propen-1-yl)-1,8-naphthyridine-2,7(1H,8H)-dione (123 mg, 0.61 mmol) in DMF (2 ml) was treated under argon with a solution of potassium t-butoxide in THF (1M; 0.7 ml, 0.7 mmol) then methyl iodide (0.06 ml, 142 mg, 1 mmol) was added. After 30 minutes the mixture was evaporated and the residue chromatographed eluting with 0-100% ethyl acetate in hexane affording an oil (120 mg, 92%).
Reaction SMILES: S(O)(=O)(C1C=CC([NH2:9])=CC=1)=O.C(=O)([O-])[O-].[Na+].[Na+].N([O-])=O.[Na+].Cl.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:9][C:30]1[CH:29]=[CH:28][C:27]([OH:31])=[CH:26][C:25]=1[O:24][CH3:23]
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: COc1cc(O)ccc1N
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
Sulphanilic acid (43.3 g) and anhydrous sodium carbonate (13.25 g) were dissolved in water (250 ml) and cooled to 15 C. Sodium nitrite (18.5 g) in water (100 ml) was added and the mixture was immediately poured onto a mixture of ice (300 ml) and hydrochloric acid (54 ml), and stirred at 0° for 20 minutes. The suspension was then added to a cooled solution of 3-methoxyphenol (31 g) and sodium hydroxide (55 g) in water (300 ml). The resulting deep red solution was stirred for 1 hour then heated to 70°. Sodium dithionite was added portionwise until the colour discharged on cooling, crystals of 4-amino-3-methoxyphenol (23 g, 66%) formed which were filtered, washed with water and dried, m.p. 168°-170°.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].CC(C)=O.C(=O)=O.[H-].[Na+].[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[CH2:22]Cl)([O-:18])=[O:17]>C1COCC1.C(O)(=O)C>[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[CH2:22][O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cc(CCl)cc([N+](=O)[O-])c1
Reactant: COC(=O)CO
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COC(=O)COCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
To a solution of methyl glycolate (10 mL, 130 mmol) in THF (50 mL) at -70° C. (acetone-dry ice) was added in small portions, with stirring 60% NaH in oil (1.6 g, 111 mmol). To the resulting white suspension was added a solution of 3,5-dinitrobenzylchloride (5.0 g, 23 mmol). The reaction was allowed to warm to room temperature and acetic acid (2 mL) was added to quench excess NaH. The reaction mixture was concentrated and the residual tan oil was partitioned between water and CH2Cl2. The organic phase was washed with water and dried over Na2SO4. The crude product obtained after concentration was chromatographed on a silica gel column (4×25 cm) eluting with 33% ethyl acetate in hexane. Concentration of appropriate fractions followed by drying in vacuo gave 5.1 g (93%) of the desired product 2.1 as a pale yellow crystalline solid: 1H NMR (CDCl3) δ 8.98 (s, 1H, C4 --H), 8.59 (s, 2H, C2 --H), 4.85 (s, 2H, CH2), 4.29 (s, 2H, CH2), 3.81 (s, 3H, CH3); 13C NMR (CDCl3) δ 170.16, 148.58, 142.33, 127.30, 118.15, 71.10, 68.07, 52.18.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([NH:12][C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[C:21]([O:23]CC)=O)=[O:14])=[CH:4][CH:3]=1.Cl>C(O)C>[Cl:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([N:12]2[C:21](=[O:23])[CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][N:15]3[C:13]2=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCCCN1C(=O)Nc1ccc(Cl)c2c1CC(C)O2
Agent: Cl
Solvent: CCO
Product: CC1Cc2c(N3C(=O)C4CCCCN4C3=O)ccc(Cl)c2O1

Procedure:
A mixture of 2.0 g of 34B, 25 mL of ethanol and 25 mL of 2N hydrochloric acid was stirred and refluxed for 2 hours. Then the solvent was evaporated, the residue was mixed with 50 mL of water, and the resulting mixture was extracted with methylene chloride The extract was dried (MgSO4) and the solvent was evaporated. The residue was purified by filtration through a short pad of silica gel, with a 1:1 v:v mixture ethyl acetate and hexane as eluent, to give the title compound, as a solid, m.p.: 145°-148° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([CH2:16][C:17](OC(C)(C)C)=O)=[CH:11][CH:10]=2.[C:24]1([C:30]2[N:35]=[N:34][C:33]([NH:36][NH2:37])=[CH:32][CH:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.[OH-].[Na+]>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([CH2:16][C:17]1[N:34]3[N:35]=[C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:31]=[CH:32][C:33]3=[N:36][N:37]=1)=[CH:11][CH:10]=2
Reactant: COCCOc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Reactant: NNc1ccc(-c2ccccc2)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCOc1cnc2ccc(Cc3nnc4ccc(-c5ccccc5)nn34)cc2c1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To a 5 ml CEM microwave tube was added tert-butyl 2-(3-(2-methoxyethoxy)quinolin-6-yl)acetate (0.080 g, 0.25 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.094 g, 0.50 mmol), HYDROCHLORIC ACID (0.063 ml, 0.76 mmol), and water (0.2 mL) as solvent. The vial was scaled and first heated at 90° C. for 30 min then placed into CEM microwave for 15 min. at 140° C., with 100 Watts of power via Powermax. The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH and the precipitate was collected via filtration. The brown ppt. was dissolved in DCM. The organic was washed with water, dried over MgSO4, and removed solvent in vacuo. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-026, 12 g SiO2, DCM:EtOAc:MeOH=60%:37%:3%, Flow=30 mL/min) to afford the desired product as light yellowish solid. MS m/z: 412.3 (M+H). Calc'd. for C24H21N5O2—411.45.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C@H:12]([CH2:15][CH3:16])[CH2:13][OH:14].C(O[CH:20](O)[C:21]([F:24])([F:23])[F:22])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C@H:12]([CH2:15][CH3:16])[CH2:13][O:14][CH:20]1[C:21]([F:24])([F:23])[F:22]
Reactant: CCOC(O)C(F)(F)F
Reactant: CC[C@H](CO)Nc1ccc([N+](=O)[O-])cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC[C@@H]1COC(C(F)(F)F)N1c1ccc([N+](=O)[O-])cc1F
Yield: 17.2 %

Procedure:
This compound was prepared according to General Method 19 (EXAMPLE 45) from (2R)-2-(2-fluoro-4-nitrophenyl)amino-1-butanol (1.6 g, 70 mmol), trifluoroacetaldehyde ethyl hemiacetal (4.9 g, 34 mmol) and p-toluenesulfonic acid (0.13 g, 0.68 mmol) in 70 mL anhydrous benzene to afford 1.8 g (85%) of (4R)-3-(2-fluoro-4-nitrophenyl)-4-ethyl-2-trifluoromethyloxazolidine, after flash chromatography (gradient elution, hexanes:ethyl acetate 90:10 to 50:50). Data for (4R)-3-(2-fluoro-4-nitrophenyl)-4-ethyl-2-trifluoromethyloxazolidine: 1H NMR (500 MHz, CDCl3) δ 8.01 (m, 1H), 7.98 (m, 1H), 6.95 (dd, J=8.8, 8.8, 1H), 5.68 (m, 1H), 4.30 (m, 1H), 4.08 (m, 1H), 3.92 (m, 1H), 2.00 (m, 1H), 1.67 (m, 1H), 0.97 (t, J=7.8, 3H).
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]1[CH:7]=[C:8]([CH:12]2[C:16]([OH:17])=[C:15]([C:18]([CH3:20])=[O:19])[CH2:14][S:13]2)[CH:9]=[CH:10][CH:11]=1.S(Cl)(Cl)(=O)=O>O>[F:5][C:6]1[CH:7]=[C:8]([C:12]2[S:13][CH:14]=[C:15]([C:18]([CH3:20])=[O:19])[C:16]=2[OH:17])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)C1=C(O)C(c2cccc(F)c2)SC1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: CC(=O)c1csc(-c2cccc(F)c2)c1O
Temperature: 0 °C
Yield: 44.3 %

Procedure:
A chloroform (6.2 mL) solution of 2-(3-fluorophenyl)-3-hydroxy-4-methylcarbonyl-2,5-dihydrothiophene (0.61 g, 2.58 mmol, purity: 78%) was cooled to −40° C., and to this solution, a chloroform (1.2 mL) solution of sulfuryl chloride (0.21 mL, 1.0 equivalent amount) was dropwise added over a period of 3 minutes. The temperature of the solution was raised to 0° C., and water (1.2 mL) was dropwise added over a period of 1 minute, followed by liquid separation. The obtained chloroform solution was sequentially washed with water, a saturated salt solution, a saturated sodium hydrogencarbonate aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to obtain a crude product. The obtained crude product was isolated and purified by column chromatography (eluent: hexane/ethyl acetate=5/1 (v/v)) to give the desired product as a green solid (0.27 g, yield: 44%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O.[Br-].[Br-].C([N+]1C=CC(C2C=C[N+](CCCCCCC)=CC=2)=CC=1)CCCCCC>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[Br:1])[CH:6]=[O:7]
Reactant: O=Cc1ccc(Br)c([N+](=O)[O-])c1
Agent: CCCCCCC[n+]1ccc(-c2cc[n+](CCCCCCC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: Nc1cc(C=O)ccc1Br
Temperature: 5 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
(Reference: Park, K. K.; Oh, C. H.; Joung, W. K. Tetrahedron Lett. 1993, 34, 7445-7446) The product from Example 60A (992 mg, 4.31 mmol) in CH2Cl2 at 23° C. (6 mL) was treated with water (1.5 mL) and N,N′-diheptyl-4,4′-bipyridinium dibromide (43 mg, 10 mg/mmol of substrate). The biphasic mixture was cooled to 5° C. and treated with a solution of sodium dithionite (3.00 g, 17.2 mmol) and K2CO3 (2.68 g, 19.4 mmol) in water (3.5 mL). The cooling bath was removed and the biphasic mixture stirred vigorously at 23° C. for 4 hours. The mixture was partitioned between additonal CH2Cl2 (15 mL) and water (10 mL) and the aqueous layer was extracted with CH2Cl2 (10 mL). The combined organic portions were washed with brine (10 mL) and dried (Na2SO4). Ethyl acetate (5 mL) was added along with silica gel (5 g) and the suspension was filtered through a small pad of Celite, rinsing with 10% ethyl acetate/CH2Cl2 (15 mL). The filtrate was concentrated to provide the title compound (716 mg, 3.58 mmol, 82%) as an off-yellow powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]2)=[N:23][CH:24]=1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[C:2]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]2)=[N:23][CH:24]=1
Reactant: CC(C)C(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(N)cn2)C1
Product: CC(C)C(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 90.6 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)-2-methylpropan-1-one (500 mg, 1.85 mmol) was reacted with (R)-tert-butyl (1-(5-aminopyridin-2-yl)piperidin-3-yl)carbamate (815 mg, 2.78 mmol) to afford the desired product (880 mg, 88%) as a red solid: ESI MS m/z 525 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:11]2([CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:10][CH:9]1[NH:16][C:17]([O:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=1)=[O:18].F[C:32]1[CH:37]=[CH:36][C:35]([Br:38])=[CH:34][N:33]=1>ClCCl.CO>[Br:38][C:35]1[CH:36]=[CH:37][C:32]([N:13]2[CH2:14][CH2:15][C:11]3([CH2:10][CH:9]([NH:16][C:17]([O:19][CH2:20][C:21]4[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=4)=[O:18])[CH2:8]3)[CH2:12]2)=[N:33][CH:34]=1
Reactant: CCOC(=O)c1cc(COC(=O)NC2CC3(CCNC3)C2)on1
Reactant: Fc1ccc(Br)cn1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(COC(=O)NC2CC3(CCN(c4ccc(Br)cn4)C3)C2)on1
Yield: 137.7 %

Procedure:
The process is performed according to the procedure described in Example 2 (step 2.6.). Starting with 0.43 g (1.03 mmol) of ethyl 5-(6-azaspiro[3.4]oct-2-ylcarbamoyloxymethyl)isoxazole-3-carboxylate trifluoroacetate (isomer 5′), obtained in step 12.5., and 0.45 g (2.60 mmol) of 2-fluoro-5-bromopyridine, and after chromatography on silica gel, eluting with a 97/3 mixture of dichloromethane and methanol, 0.68 g of pure product is obtained in the form of an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH3:16])=[C:6]2[C:17]([O:19][C:20](=O)[C:5]=12)=[O:18])[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][CH:24]=1.O>C(O)(=O)C>[CH2:15]([O:14][C:7]1[C:6]2[C:17](=[O:18])[N:22]([C:23]3[CH:24]=[CH:25][C:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][CH:28]=3)[C:20](=[O:19])[C:5]=2[C:4]([O:3][CH2:1][CH3:2])=[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12)[CH3:16]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCOc1c2c(c(OCC)c3ccccc13)C(=O)OC2=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
1,4-Diethoxy-2,3-naphthalenedicarboxylic anhydride (23.3 g, 81.5 mmol) and ethyl (4-aminophenyl)acetate (14.8 g, 82 mmol) were refluxed under nitrogen in acetic acid (160 ml) overnight. The mixture was cooled to room temperature and poured into water (1 L). The white solid was filtered, washed with water and dissolved in dichloromethane (800 ml). The solution was washed with water, brine and dried (MgSO4) and the solvent evaporated under vacuum to give ethyl [4-(4,9-diethoxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate as an off-white solid (33 g, 96%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([CH2:26][C:27]([OH:29])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].O[N:37]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([CH2:26][C:27]([NH2:37])=[O:29])=[CH:15][CH:14]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: On1nnc2ccccc21
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CC(=O)O)ccc2c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CC(N)=O)ccc2c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 80.9 %

Procedure:
A mixture of (3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yl)acetic acid (0.15 g, 0.32 mmol), 1-hydroxybenzotriazole ammonium salt (0.074 g, 0.48 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.093 g, 0.48 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 17 h. The reaction mixture was poured into 0.1N aqueous citric acid solution (50 mL) and extracted with ethyl acetate (25 mL×2). The organic layers were combined, washed with 0.1N aqueous citric acid solution (50 mL), saturated aqueous sodium hydrogencarbonate (50 mL), and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give tert-butyl[6-(2-amino-2-oxoethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.12 g, 81%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([NH2:6])=[O:5].[C:12](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O.C(OCC)(=O)C.C(OCC)C>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1c(O)cccc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1cccc(O)c1C(N)=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 69.6 %

Procedure:
To a solution of 2,6-dihydroxybenzamide (2 g, 12.66 mmol) in dimethylformamide (100 mL) were added cesium carbonate (3.922 g, 12.03 mmol) and methyl iodide (756 μL, 12.03 mmol). The reaction mixture was stirred at room temperature for 36 h and was taken in 200 mL of ethyl acetate and diethyl ether (1:1 ratio). It was washed with water, brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 25% ethyl acetate in hexanes yielded 2-hydroxy-6-methoxy-benzamide (1.4 g, 66%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([C:26]2[CH:27]=[C:28]3[C:32](=[C:33]([CH3:35])[CH:34]=2)[NH:31][C:30](=[O:36])[CH2:29]3)=[O:25])[CH:19]=1.CCN(C(C)C)C(C)C.C(#N)C.O>CN(C=O)C>[CH3:35][C:33]1[CH:34]=[C:26]([C:24]([C:20]2[N:21]=[CH:22][N:23]=[C:18]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH:19]=2)=[O:25])[CH:27]=[C:28]2[C:32]=1[NH:31][C:30](=[O:36])[CH2:29]2
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2c1NC(=O)C2
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2c1NC(=O)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
91 mg (0.42 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 120 mg (0.42 mmol) 5-(6-chloro-pyrimidine-4-carbonyl)-7-methyl-1,3-dihydro-indol-2-one and 0.080 mL (0.46 mmol) DIPEA were combined in 2 mL DMF and shaken overnight at RT. Then the reaction mixture was in taken up acetonitrile/water and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[CH3:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([CH3:46])=[C:24]([NH:23][C:8]([C:7]5[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=5)=[O:10])[CH:25]=4)=[CH:33][N:32]3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: CCn1nc(C)cc1C(=O)O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CCn1nc(C)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1C
Yield: 53.8 %

Procedure:
In the same manner as in Example 18-4 and using 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (572 mg, 3.71 mmol), tetrahydrofuran (10 mL), oxalyl chloride (536 μL, 6.17 mmol), N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.619 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (153 mg, 54%) was obtained as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](O)=[O:26]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)=[O:26])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ccccn1
Product: C[C@]1(c2cc(NC(=O)c3ccccn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=365.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][NH:16][CH2:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC(CC)CBr
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)CNCC(c1ccccc1F)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57 %

Procedure:
To 4-[2-Amino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (207) (0.18 g, 0.56 mmol) in DMF (3 mL) was added 1-bromo-2-ethyl-butane (0.083 mL, 0.59 mmol) and potassium carbonate (0.093 g, 0.68 mmol). The reaction was allowed to stir at room temperature for 18 h. The reaction mixture was then diluted with EtOAc (30 mL) and H2O (30 mL). The organic phase was dried with sodium sulfate and concentrated to dryness. The crude material was purified by chromatography (silica gel 60 mesh, eluting with 3% (2M NH3 in MeOH) in MeCl2) yielding 0.13 g (59%) pure product.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C:5]2[CH:7]=[C:8]3[O:12][C:11]([CH3:14])([CH3:13])[O:10][C:9]3=[CH:15][C:4]=2[O:3]1.C([Li])CCC.CN([CH:25]=[O:26])C.O>C1COCC1.C1(C)C=CC=CC=1.CC(O)=O>[CH:25]([C:15]1[C:4]2[O:3][C:2]([CH3:16])([CH3:1])[O:6][C:5]=2[CH:7]=[C:8]2[O:12][C:11]([CH3:14])([CH3:13])[O:10][C:9]=12)=[O:26]
Reactant: CC1(C)Oc2cc3c(cc2O1)OC(C)(C)O3
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)Oc2cc3c(c(C=O)c2O1)OC(C)(C)O3
Temperature: 25 °C

Procedure:
2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']bis(1,3)dioxole (20.0 g, 90 mmol (Example 5)) was dissolved in THF (300 mL) and cooled to -20° C. n-Butyl lithium (38.0 mL), 2.5M in toluene, 100 mmol) was added and the temperature was allowed to rise to 0° C. The mixture was recooled to -20° C. and DMF (6.9 mL, 90.0 mmol) was added. The reaction mixture was stirred over night while allowing the temperature to increase to room temperature. Water (200 mL) and AcOH (5 mL) was added. The color changed from light yellow to strong orange. The mixture was extracted with diethyl ether (3×300 mL) and the combined organic phase was washed with water (2×100 mL), dried (Na2SO4) and evaporated. The product was trituated twice with petroleum ether and dried, yielding the pure title compound; 16.3 g (72%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][C:14]1([CH3:27])[C:23]2[C:18](=[CH:19][C:20]([NH2:25])=[C:21]([NH2:24])[CH:22]=2)[NH:17][C:16](=[O:26])[CH2:15]1>>[CH3:13][C:14]1([CH3:27])[C:23]2[CH:22]=[C:21]3[NH:24][C:6]([C:5]4[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=4[O:11][CH3:12])=[N:25][C:20]3=[CH:19][C:18]=2[NH:17][C:16](=[O:26])[CH2:15]1
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Product: COc1cc(Cl)ccc1-c1nc2cc3c(cc2[nH]1)C(C)(C)CC(=O)N3
Yield: 58 %

Procedure:
In a manner analogous to that described in Example 2, from 4-chloro-2-methoxybenzoyl chloride and 4,4-dimethyl-6,7-diamino-1,2,3,4-tetrahydroquinolin-2one (see Example 13 a)), after column chromatography, there was obtained a yield of 58% of theory of the title compound; m.p. 300 -303° C.