Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([NH2:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH3:11].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:11][C:10]([NH:19][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12]
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)c1ccccc1)c1ccccc1
Yield: 97.6 %

Procedure:
In a similar manner to Step 1 of Example 16, benzoyl chloride (10.0 g, 71.1 mmol) was dissolved in dichloromethane (200 mL), and the solution was treated with cumylamine (11.3 mL, 78.3 mmol), triethylamine (14.9 mL, 107 mmol) and DMAP (870 mg, 7.11 mmol), followed by purification by slurry using diisopropylether to obtain N-(1-methyl-1-phenylethyl)benzamide (16.6 g, yield 98%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][C:16](=[O:21])[CH:15]=[CH:14]2>>[O:17]1[C:18]2[C:13](=[CH:12][C:11]([NH:10][C:2]3[N:7]=[C:6]([NH:10][C:11]4[CH:12]=[C:13]5[C:18](=[CH:19][CH:20]=4)[O:17][C:16](=[O:21])[CH:15]=[CH:14]5)[C:5]([F:9])=[CH:4][N:3]=3)=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:16]1=[O:21]
Reactant: Nc1ccc2oc(=O)ccc2c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: O=c1ccc2cc(Nc3ncc(F)c(Nc4ccc5oc(=O)ccc5c4)n3)ccc2o1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 6-aminocoumarin were reacted to yield N2,N4-bis(coumarin-6-yl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.17 (d, 2H, J=3.6 Hz), 7.97-7.74 (m, 5H), 7.40 (1H, d, J=8.7 Hz), 7.30 (d, 1H, J=9 Hz), 6.50 (d, 1H, J=10.2 Hz), 6.40 (d, 1H, J=9.3 Hz); LCMS: ret. time: 19.05 min.; purity: 94%; MS (m/e): 417 (MH+).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][C:13]1[C:18]([NH2:19])=[C:17]([CH3:20])[CH:16]=[C:15]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:14]=1.C(N(CC)C(C)C)(C)C>ClCCCl>[CH2:5]([O:4][C:2](=[O:3])[NH:19][C:18]1[C:13]([CH3:12])=[N:14][C:15]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:16][C:17]=1[CH3:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cc(N2CCOCC2)nc(C)c1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCOCC2)nc(C)c1NC(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 31 %

Procedure:
Benzyl chloroformate (18 mg) was added to a solution of 0.085 M 2,4-dimethyl-6-morpholin-4-yl-pyridin-3-ylamine and 0.17 M N,N-diisopropyl-ethylamine in 1,2-dichloroethane (1 mL). The vial was shaken for 16 hours under argon and concentrated in vacuo. Aqueous sodium hydroxide (1 M, 1 mL) was added and the crude mixture was extracted with isopropyl acetate/tetrahydrofuran (4:1, 2×1 mL). The organic phase was washed with brine (1 mL), concentrated in vacuo and redissolved in 1-propanol/dimethyl sulfoxide (1:1, 0.4 mL) of which 0.2 mL was subjected to preparative LC-MS purification to furnish 4.5 mg (31% yield) of the title compound as an oil. LC-MS (m/z) 342 (MH+); tR=1.58, (UV, ELSD) 99%, 99%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:15]#[N:16])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)C(C#N)Cc1ccc(F)cc1
Product: CCOC(=O)CC(C#N)(Cc1ccc(F)cc1)C(=O)OCC

Procedure:
In the same manner as Example 1-(b), 100 g of ethyl 3-(4-fluorophenyl)-2-cyanopropionate was reacted with ethyl bromoacetate to obtain ethyl 4-(4-fluorophenyl)-3-cyano-3-ethoxycarbonylbutyrate.
Reaction SMILES: CO[N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[O:7][CH2:6][CH2:5]1>N.CO.[Ni]>[CH3:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[O:7][CH2:6][CH2:5][CH:4]2[NH2:3]
Reactant: CON=C1CCOc2ccc(C)cc21
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1ccc2c(c1)C(N)CCO2

Procedure:
A solution of Example 7A (4.24 g) in 20% ammonia in methanol (50 mL) was treated with Raney Nickel, 40 g, under hydrogen (60 psi) for 4 hours at ambient temperature. The mixture was filtered, and the solvent was evaporated under reduced pressure. The residue dissolved in diethyl ether which was washed sequentially with water and saturated aqueous sodium bicarbonate, dried with magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound. H NMR (300 MHz, CDCl3) δ ppm 1.78-1.88 (m, 1H), 2.10-2.21 (m, 1H), 2.27 (s, 3H), 4.01 (m, 1H), 4.22 (m, 2H), 6.71 (d, J=8.5 Hz, 1H), 6.95 (d, J=8.5 Hz, 1H), 7.11 (s, 1H). MS (DCI) m/z 164 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([Cl:35])[CH:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([Cl:35])[CH:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: N[C@@H](Cc1ccc(Oc2ccnc(Cl)c2)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccnc(Cl)c2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(2-chloro-pyridin-4-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [S:1](Cl)(Cl)(=[O:3])=[O:2].[NH2:6][C:7]1[CH:8]=[C:9]([CH:35]=[CH:36][CH:37]=1)[O:10][CH2:11][C@@H:12]([O:31][C:32](=[O:34])[CH3:33])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH2:15]1>C(Cl)Cl.N1C=CC=CC=1>[C:32]([O:31][C@@H:12]([CH2:13][N:14]1[CH2:15][CH2:16][N:17]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH2:18][CH2:19]1)[CH2:11][O:10][C:9]1[CH:35]=[CH:36][CH:37]=[C:7]([N:6]=[S:1](=[O:3])=[O:2])[CH:8]=1)(=[O:34])[CH3:33]
Reactant: COc1ccc(S(=O)(=O)N2CCN(C[C@@H](COc3cccc(N)c3)OC(C)=O)CC2)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCN(C[C@@H](COc3cccc(N=S(=O)=O)c3)OC(C)=O)CC2)cc1
Temperature: 25 °C

Procedure:
A suitable sulfonyl chloride is added (1.2 mM) to a solution of (S)-1-(3-aminophenoxy)-2-acetoxy-3-[4-(4-methoxyphenylsulfonyl)piperazin-1-yl)propane (1 mM) in CH2Cl2 (1.2 ml) and pyridine (0.5 ml). The mixture is shaken at room temperature up to the completion of the reaction. It is then diluted with CH2Cl2, and washed with saturated aqueous solution of Na2CO3 and then with water. The organic phase is dried with anhydrous Na2SO4, filtered and the solvent is distilled under vacuum. (S)-2-acetoxy-3-[4-(4-methoxyphenylsulfonyl)piperazin-1-yl]-1-(3-sulfonylaminophenoxy)propane is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])(=[O:11])=[O:12])[CH2:7][N:6]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.2 %

Procedure:
To a solution of (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (see example xx) (1.03 g, 1.0 eq) in dry dichloromethane (25 mL) were added freshly powdered molecular sieves (2.88 g). Phenyl boronic acid (0.74 g, 2.0 eq) was added, followed by triethylamine (0.62 g, 2.0 eq) and copper(II)acetate (0.61 g, 1.1 eq). Oxygen gas was bubbled through the reaction mixture for 5 min. The flask was sealed with a rubber septum and left under an atmosphere of oxygen by means of a balloon. After stirring at room temperature for 24 h, the mixture was filtered and the filtrate was treated with water and filtered again. The phases were separated and the organic phase dried over sodium sulfate, filtered and evaporated. Purification by flash chromatography on silica gel with an heptane/ethyl acetate gradient yielded the title compound as a light yellow solid (0.23 g, 18%). MS (ESI): m/z=414.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:24]12([CH2:34][NH2:35])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>CN(C)C=O>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:35][CH2:34][C:24]12[CH2:33][CH:28]3[CH2:27][CH:26]([CH2:32][CH:30]([CH2:29]3)[CH2:31]1)[CH2:25]2)=[O:6]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cccc(F)c1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc(F)c1Cl
Reaction time: 8 h

Procedure:
A solution of 2-chloro-3-fluorobenzoic acid (0.098 g) and carbonyldiimidazole (0.091 g), in N,N-dimethylformamide (3.0 ml) was stirred for 2.5 hours at room temperature. 1-Adamantanemethylamine (0.1 ml) was then added and stirring continued overnight. The reaction mixture was partitioned between ethyl acetate and 2N hydrochloric acid and the organic layer was separated, washed with 10% aqueous sodium hydroxide, water and brine and then dried over sodium sulphate (Na2SO4). The organic layer was subsequently concentrated under reduced pressure to yield the title compound as a white solid (0.138 g).
Reaction SMILES: C(O)C.[NH2:4][OH:5].[CH3:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:33])[N:22]([CH:24]([C:29]([NH:31][CH3:32])=[O:30])[C:25](OC)=[O:26])[CH3:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>O1CCCC1>[OH:5][NH:4][C:25](=[O:26])[CH:24]([N:22]([C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][O:7][CH3:6])=[CH:14][CH:13]=2)=[CH:16][CH:17]=1)=[O:33])[CH3:23])[C:29]([NH:31][CH3:32])=[O:30]
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(-c2ccc(COC)cc2)cc1
Reactant: NO
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)C(C(=O)NO)N(C)C(=O)c1ccc(-c2ccc(COC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
Ethanol (5.0 mL) and a 50% aqueous solution (5.0 mL) of hydroxylamine were added to a tetrahydrofuran (5.0 mL) solution of 4-(methoxymethyl)-4′-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (0.40 g) as obtained in Example 3-(4), and the mixture was stirred for 2 hours at room temperature. Then, the reaction mixture was concentrated under reduced pressure, and purified by preparative silica gel thin-layer chromatography (chloroform/methanol=85/15). IPE was added, and the precipitated solid was filtered off and dried to obtain N-hydroxy-2-[{[4′-(methoxymethyl)biphenyl-4-yl]carbonyl}(methyl)amino]-N′-methylpropanediamide (Compound 4, pink solid) (0.18 g, 46%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].Cl.Cl.Cl.[C:8]([C:12]1[CH:13]=[C:14]([NH2:28])[C:15]([NH2:27])=[C:16]([O:18][CH2:19][CH:20]([OH:26])[CH2:21][NH:22][CH:23]([CH3:25])[CH3:24])[CH:17]=1)([CH3:11])([CH3:10])[CH3:9]>>[C:8]([C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]([OH:26])[CH2:21][NH:22][CH:23]([CH3:24])[CH3:25])[C:15]2[NH:27][C:1](=[O:2])[NH:28][C:14]=2[CH:13]=1)([CH3:10])([CH3:9])[CH3:11]
Reactant: CC(C)NCC(O)COc1cc(C(C)(C)C)cc(N)c1N
Reactant: O=C(Cl)Cl
Agent: Cl
Product: CC(C)NCC(O)COc1cc(C(C)(C)C)cc2[nH]c(=O)[nH]c12

Procedure:
Excess phosgene is passed at 20° to 25° C. into a solution of 5.5 g 5-tert.-butyl-2,3-diamino-1-[2-hydroxy-3-(2-propylamino)-propoxy]-benzene trihydrochloride in 50 ml. water, then thoroughly flushed with nitrogen, evaporated and the residue taken up in isopropanol. After a short time 2.3 g. (43% of theory) crystalline 6-tert.-butyl-4-[2-hydroxy-3-(2-propylamino)-propoxy]-2-benzimidazolinone hydrochloride precipitates out; decomposition point above 280° C.
Reaction SMILES: [C:1]1(=[O:18])[N:5]([CH2:6][CH2:7][CH2:8][C:9]([CH2:11][F:12])=[O:10])[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.[BH4-].[Na+].Cl>O1CCCC1.CO>[F:12][CH2:11][CH:9]([OH:10])[CH2:8][CH2:7][CH2:6][N:5]1[C:1](=[O:18])[C:2]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:3]2[C:4]1=[O:13]
Reactant: O=C(CF)CCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCC(O)CF
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To a solution of 550 mg (2.2 mmole) of fluoromethyl 3-phthalimidopropyl ketone in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol cooled to -20° C is added a solution of 0.8 mmole of sodium borohydride in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol precooled to -20° C. The reaction mixture is stirred for 15 minutes at -20° C and then neutralized with 2 M HCl to a pH of 1. The solvents are evaporated under reduced pressure and the residue is partitioned between water and chloroform. The organic phase is washed with brine, dried over magnesium sulfate and concentrated to give a residue which is recrystallized from tetrahydrofuran-diethylether to afford 1-fluoro-5-phthalimido-2-pentanol, m.p. 85° C. A mixture of 264 mg (1.05 mmole) of 1-fluoro-5-phthalimido-2-pentanol, 170 mg (1.05 mmole) of the phthalimide, 302 mg (1.05 mmole) of triphenylphosphine and 201 mg (1.15 mmole) of diethylazodicarboxylate in 8 ml of tetrahydrofuran is stirred under nitrogen for 2 hours at 25° C. The solvent is evaporated under reduced pressure and the residue taken up in benzene. The insoluble material is discarded and the residue obtained after concentration of the filtrate is recrystallized from tetrahydrofuran-diethylether to give 1-fluoromethyl-1,4-butanediyl-bis-phthalimide, m.p. 112° C. A suspension of 3.1 g of 1-fluoromethyl-1,4-butanediyl-bis-phthalimide in 140 ml of concentrated HCl is heated at reflux temperature for 3 days. The phthalic acid which precipitates on cooling to 4° C is filtered off. The filtrate is concentrated to about 20 ml and cooled to 4° C. The remaining phthalic acid which separates is filtered off and the filtrate is concentrated under reduced pressure. The residue is treated with 40 ml of boiling isopropyl alcohol 3 times and then recrystallized from absolute ethanol to give 1-fluoromethyl-1,4-butanediamine dihydrochloride, m.p. 154° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][OH:12].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccccc1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccccc1CCO
Temperature: 0 °C
Yield: 23 %

Procedure:
2-[2-(2-Hydroxy-ethyl)-phenyl]-ethanol (6.77 g/40 mmol) was dissolved in methylene chloride (100 mL) and cooled to 0° C. Triethylamine (11.0 mL/80 mmol) and methanesulfonyl chloride (5.25 mL/65 mmol) were added sequentially via addition funnel (dropwise). After an hour the reaction was poured into a separatory funnel and sequentially washed with 1 N hydrochloric acid (100 mL), water (100 mL) and saturated aqueous sodium bicarbonate (100 mL). The resulting organic solution was dried over magnesium sulfate, filtered and concentrated. Column chromatography on silica gel (eluting with 0→10% methanol/methylene chloride afforded methanesulfonic acid 2-[2-(2-hydroxy-ethyl)-phenyl]-ethyl ester (2.25 g/23%). 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 4H), 4.42 (t, J=7.1 Hz, 2H), 3.88 (m, 2H), 3.15 (t, J=7.1 Hz, 2H), 2.93 (t, J=7.1 Hz, 2H), 2.85 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.C(C1C=CC(OC2N=CC(N[C:32]([C@H:34]([NH:37][C:38](=O)[O:39]C(C)(C)C)[CH2:35]C)=[O:33])=CC=2)=CC=1C(C)C)#N.Cl>ClCCl>[CH3:35][C@H:34]1[NH:37][C:38](=[O:39])[N:13]([C:12]2[CH:14]=[CH:15][C:9]([O:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:10][CH:11]=2)[C:32]1=[O:33]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C#N)c(C(C)C)c2)nc1
Reactant: Cc1cccc(Oc2ccc(N)cc2)c1
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cc2)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To 4-[(3-methylphenyl)oxy]aniline (90 mg, 0.45 mmol) in dichloromethane (1 mL) was added with shaking at 35° C. an aliquot of approximately ⅓ of solution 1 slowly via syringe (over ca. 1 min). After 30 min, HCl (ca. 0.8 mL) was added and the heterogeneous mixture was heated at 100° C. for 2 hours with shaking, allowing the dichloromethane to distill off through a glass capillary. After cooling to room temperature the aqueous HCl was pipetted off and the residue dried under vacuum. The residue was purified by silica gel chromatography (Biotage instrument, 10 g column) eluting with 0-100% EtOAc/cHex to give after drying the title compound as a solid (30 mg).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[CH:21](Cl)Cl)=[N:9]2)=[CH:4][CH:3]=1.[OH2:25]>CN(C)C=O.[N+]([O-])([O-])=O.[Ag+]>[Cl:20][C:18]1[CH:19]=[C:14]2[C:15]([CH:21]([OH:25])[N:12]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[N:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[C:13]2=[O:24])=[CH:16][CH:17]=1
Reactant: O
Reactant: O=C(Nc1ccc2ccc(Cl)nc2n1)c1cc(Cl)ccc1C(Cl)Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CN(C)C=O
Product: O=C1c2cc(Cl)ccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 110 °C

Procedure:
A solution of silver nitrate (12.1 g.) in water (50 cc.) is added to a solution of 7-chloro-2-(5-chloro-2-dichloromethyl-benzoylamino)-1,8-naphthyridine (9.5 g.) in dimethylformamide (300 cc.) heated to a temperature of about 110° C. The reaction mixture is further heated to a temperature of about 110° C for 20 minutes and the suspension obtained is filtered hot. The filtrate obtained is poured into water (500 cc.) and the product which precipitates is filtered off. Recrystallisation from dimethylformamide gives 6-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (5 g.) melting at 306° C.
Reaction SMILES: [CH3:1][S:2](Cl)=[O:3].[CH2:5]([OH:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1>C(OCC)C>[CH3:1][S:2]([O:15][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:3]
Reactant: CS(=O)Cl
Reactant: CCCCCCCCCCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCCCCOS(C)=O
Temperature: 50 °C

Procedure:
Into a 50 ml three-necked flask equipped with a magnetic stirrer, thermometer, nitrogen purge and dropping funnel is added 9.9 gms (0.10 moles) of methanesulfinyl chloride. The methane sulfinyl chloride is cooled to -10°C and 17.4 gms (0.11 moles) of decanol is added dropwise while maintaining the temperature of -5° to -10°C. When the addition of the decanol is complete, the reaction mass is warmed to 50°C under 20 mm of vacuum. The resulting product is then cooled and dissolved in 100 ml of diethyl ether admixed with 2 gms. of pyridine. The reaction mass is then extracted with two 10 ml portions of water. A drop of pyridine is added to the ether layer in order to remove additional chloride. In the event that no precipitation occurs the ether layer is then extracted with two 10 ml portions of 3% aqueous hydrochloric acid. The ether layer is then dried over anhydrous sodium sulfate and is then evaporated by means of rotary evaporation yielding an oil which is then subjected to a distillation operation. The resulting product is distilled at 98°C at 0.50-0.65 mm Hg pressure. (Yield 16 gms). GLC, mass spectral and infrared analysis yield the information that the structure of this material is as follows: ##EQU13##
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:33])=[CH:4][C:5]([F:32])=[C:6]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([N:18]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH3:19])[CH:12]=3)[CH:7]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1[N:42]=[C:43]=[O:44]>O1CCOCC1>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:18]([CH3:19])[C:13]2[N:14]=[CH:15][CH:16]3[CH:11]([CH:12]=2)[N:10]([CH2:29][CH3:30])[C:9](=[O:31])[C:8]([C:6]2[C:5]([F:32])=[CH:4][C:3]([F:33])=[C:2]([NH:1][C:43]([NH:42][C:36]4[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=4[F:34])=[O:44])[CH:7]=2)=[CH:17]3)=[CH:22][CH:23]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Reactant: O=C=Nc1cc(F)ccc1F
Solvent: C1COCCO1
Product: CCN1C(=O)C(c2cc(NC(=O)Nc3cc(F)ccc3F)c(F)cc2F)=CC2C=NC(N(C)Cc3ccc(OC)cc3)=CC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
A solution of Example A7 (0.12 g, 0.266 mmol) in dioxane (5 mL) was treated with 2,5-difluorophenyl isocyanate (0.034 mL, 0.293 mmol) and stirred at RT overnight. The resulting solid was collected via filtration and dried to yield 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(2,5-difluorophenyl)urea (129 mg, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H), 9.10 (s, 1H), 8.52 (s, 1H), 8.16 (t, 1H), 8.01-7.98 (m, 1H), 7.86 (s, 1H), 7.38 (t, 1H), 7.31-7.27 (m, 1H), 7.18 (d, 2H), 6.87 (d, 2H), 6.82-6.80 (m, 1H), 6.32 (s, 1H), 4.85 (s, 2H), 4.19 (q, 2H), 3.70 (s, 3H), 3.13 (s, 3H), 1.13 (t, 3H); MS (ESI) m/z: 606.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=1)=[CH:5]2.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6]([C:12]1[CH:13]=[C:14]([Cl:19])[CH:15]=[C:16]([Cl:18])[CH:17]=1)=[C:5]2[N+:20]([O-:22])=[O:21]
Reactant: Clc1cc(Cl)cc(-c2cc3cc(Cl)cc(Cl)c3[nH]2)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(-c2cc(Cl)cc(Cl)c2)[nH]c2c(Cl)cc(Cl)cc12
Temperature: 90 °C
Yield: 42 %

Procedure:
A mixture of 5, 7-dichloro-2-(3,5-dichlorophenyl)indole (1.25 g, 3.8 mmole) in acetic acid is treated dropwise with 3 mL of concentrated HNO3 at 90° C., maintained at 90° C. for 1 hour, cooled and filtered. The filtercake is air-dried and recrystallized from methanol/water to afford the title product as a yellow solid, 0.60 g, (42% yield), mp 272°-273° C., identified by IR, 1HNMR and elemental analyses.