Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([S:17]([CH3:20])(=[O:19])=[O:18])[C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9].[OH-].[K+].CO.Cl>O1CCCC1>[CH3:16][O:15][C:13]([C:5]1[CH:6]=[C:7]([CH:12]=[C:3]([N:2]([CH3:1])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:4]=1)[C:8]([OH:10])=[O:9])=[O:14]
Reactant: COC(=O)c1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(C(=O)O)cc(N(C)S(C)(=O)=O)c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A mixture of dimethyl 5-[methyl(methylsulfonyl)amino]isophthalate obtained in Reference Example 5 36.0 g (119 mmol), potassium hydroxide 8.71 g (155 mmol), methanol (360 mL) and tetrahydrofuran (240 mL) was stirred at 90° C. for 1.5 hours. To a mixture of 1N hydrochloric acid (200 mL) and ice water (500 mL) was added the reaction mixture dropwise, and the precipitated solid was collected by filtering, and dried under vacuum to give 32.4 g (113 mmol) of the title compound (yield: 95%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:24]1([NH:27][CH3:28])[CH2:26][CH2:25]1.CCN(CC)CC>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:27]([CH:24]2[CH2:26][CH2:25]2)[CH3:28])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC1CC1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN(c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F)C1CC1

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example B5) (3.40 g, 10 mmol) and cyclopropyl-methyl-amine hydrochloride (3.22 g, 30 mmol) and Et3N (6.97 mL, 50 mmol) in DMSO (50 mL) at 23° C. according to the general procedure C. Obtained as a yellow solid (3.74 g).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[CH:10]([OH:14])[C:11]#[C:12][CH3:13].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[CH:10]([OH:14])/[CH:11]=[CH:12]/[CH3:13]
Reactant: C=C1CCCC(C)(C)C1C(O)C#CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C=C1CCCC(C)(C)C1C(O)/C=C/C

Procedure:
Thus, e.g., if 2-methylene-6,6-dimethyl-1-[1-hydroxy-but-2-ynyl]-cyclohexane is reduced by means of LiAlH4, trans-2-methylene-6,6-dimethyl-1-[1-hydroxy-but-2-enyl]-cyclohexane is obtained.
Reaction SMILES: C(N)CC.[F:5][C:6]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:7]=1[C:8]([N:10](C=O)[CH:11]=[CH2:12])=[O:9]>ClCCl>[F:5][C:6]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:7]=1[C:8]([NH:10][CH:11]=[CH2:12])=[O:9]
Reactant: C=CN(C=O)C(=O)c1c(F)cccc1F
Solvent: CCCN
Solvent: ClCCl
Product: C=CNC(=O)c1c(F)cccc1F
Yield: 75 %

Procedure:
n-Propylamine (36.7 ml, 26.33 g, 444 mmol) was added to a solution of crude 2,6-difluoro-N-formyl-N-vinyl-benzamide from step a (47 g, 222 mmol) in dichloromethane (200 ml). There was a weak exotherm. The reaction mixture was kept at room temperature with a cold water bath. The solution was then concentrated on the rotovap to give a brown oil, which was crystallised from ethanol/water to yield 30 g (75%) of pure 2,6-difluoro-N-vinyl-benzamide as beige crystals. A further 5.7 g was crystallised from concentration of the mother liquors. M.p. 103-107° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[CH2:15][CH2:16][CH2:17][O:18][C:19]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].FC1C2OCCOC=2C=C2OCC3(C4C(=CC=CC=4)NC3=O)C=12.Cl.Cl[CH2:48][C:49]1[C:54]([C:55]([F:58])([F:57])[F:56])=[CH:53][CH:52]=[CH:51][N:50]=1.Br.BrCC1C=CC=CN=1>>[F:58][C:55]([F:56])([F:57])[C:54]1[C:49]([CH2:48][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[CH2:15][CH2:16][CH2:17][O:18][C:19]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[N:50][CH:51]=[CH:52][CH:53]=1
Reactant: FC(F)(F)c1cccnc1CCl
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCC3
Agent: Br
Agent: BrCc1ccccn1
Agent: Cl
Product: O=C1N(Cc2ncccc2C(F)(F)F)c2ccccc2C12COc1cc3c(cc12)OCCC3

Procedure:
Following the procedure as described in EXAMPLE 5.25 and making non-critical variations using 7,8-dihydro-6H-spiro[furo[2,3-g]chromene-3,3′-indol]-2′(1H)-one to replace 9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 2-(chloromethyl)-3-(trifluoromethyl)pyridine hydrochloride to replace 2-(bromomethyl)pyridine hydrobromide, 1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-7,8-dihydro-6H-spiro[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-one was obtained (2%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 8.65 (d, J=4.4 Hz, 1H), 8.25 (d, J=7.8 Hz, 1H), 7.56 (dd, J=7.8, 5.0 Hz, 1H), 7.20-7.26 (m, 1H), 7.15 (d, J=6.9 Hz, 1H), 7.01 (t, J=7.4 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.65 (s, 1H), 6.31 (s, 1H), 5.22 (ABq, J=39.2 Hz, 2H), 4.72 (ABq, J=18.8 Hz, 2H), 4.04-3.95 (m, 2H), 2.70 (t, J=6.4 Hz, 2H), 1.89-1.77 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.1, 155.7, 154.3, 149.7, 149.4, 143.0, 137.5, 132.3, 129.1, 128.6, 123.9, 123.6, 123.4, 123.1, 122.0, 111.5, 110.4, 109.8, 79.3, 66.2, 58.0, 45.2, 25.2, 22.1; MS (ES+) m/z 453.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:15])[C:6]([OH:14])=[N:7]2.[CH:16](O)=O>O>[Cl:13][C:10]1[CH:9]=[C:8]2[C:3]([N:4]=[C:5]([OH:15])[C:6]([OH:14])=[N:7]2)=[C:2]2[NH:1][CH:16]=[N:12][C:11]=12
Reactant: O=CO
Reactant: Nc1c(Cl)cc2nc(O)c(O)nc2c1N
Solvent: O
Product: Oc1nc2cc(Cl)c3nc[nH]c3c2nc1O
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of 0,3 g (1,35 mmol) 5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline and 8 ml formic acid was refluxed for 2 h. After cooling to 25° C., the reaction mixture was poured into 30 ml water to give 0,21 g (67%) 4-chloro-7,8-dihydroxy-1H-imidazo(4,5-f)quinoxaline, m.p.>300° C. NMR (DMSO-d6): 7.37 (1H,s), 6.70 (1H,s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:30])([CH2:28][OH:29])[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:18][CH:17]=2)[C:12]1=[O:27])[CH3:10].[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(OCC)(=O)C.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:30])([CH2:28][O:29][S:32]([CH3:31])(=[O:34])=[O:33])[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:18][CH:17]=2)[C:12]1=[O:27])[CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@](O)(CO)c1ccccc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2,3-dihydroxy-1-methyl propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (440 mg) was dissolved in a mixture of ethyl acetate and tetrahydrofuran (1:2, 30 ml), to which methanesulfonyl chloride (0.18 g) and triethylamine (0.16 g) were added dropwise at ice-bath temperature. The reaction solution was stirred at 0° C. for 30 minutes and washed with water (15 ml×2) and a saturated aqueous solution of sodium chloride (15 ml) successively. The organic layer was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1/4) to give 1-[(1R,2S)-2-(2-fluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (330 mg) as a colorless crystalline powder.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:20]([O:26][CH2:27]Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>CC(C)=O>[C:20]([O:26][CH2:27][N:10]1[C:11]2[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=2[N:8]=[CH:9]1)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1c(=O)c2c(ncn2COC(=O)C(C)(C)C)n(C)c1=O
Yield: 25.5 %

Procedure:
A suspension of 3.60 g (0.02 mole) of theophylline and 1.38 g (0.01 mole) of K2CO3 in 75 ml of acetone was refluxed overnight and then allowed to react at reflux with 3.00 g (0.02 mole) of pivaloxymethyl chloride for 2 days. The suspension was filtered and the residue was washed with acetone (200 ml). The combined filtrate and wash was concentrated in vacuo and the residue was extracted with boiling heptane (200 ml). The heptane solution was cooled in the refrigerator for 0.5 hr then filtered. The residue was dried in vacuo to give 1.50 g (mp 108°-109.5°) of 7-pivaloxymethyl theophylline.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[NH:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([F:17])=[CH:11][N:10]=2)=[O:5])[CH3:2].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[NH:8][C:9]2[C:14]([C:15]=1[N:29]1[CH2:30][CH2:31][N:26]([C:24]([C:20]3[O:19][CH:23]=[CH:22][CH:21]=3)=[O:25])[CH2:27][CH2:28]1)=[CH:13][C:12]([F:17])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cc(F)cnc2[nH]c1=O
Reactant: O=C(c1ccco1)N1CCNCC1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2[nH]c1=O

Procedure:
This compound was prepared from 4-chloro-6-fluoro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (78) and 2-furoyl piperazine according to general procedure E. Yield 3.11 g (74%), MP 207° C.; 1H-NMR (DMSO-d6): δ 1.27 (t, J=6.8 Hz, 3H), 3.11 (m, 4H), 3.90 (m, 4H), 4.29 (q, J=6.8 Hz, 2H), 6.65 (dd, J=2.0, 3.6, Hz, 1H), 7.04 (d, J=3.6 Hz, 1H), 7.87 (d, J=1.6 Hz, 1H), 8.06 (dd, J=2.8, 8.0 Hz, 1H), 8.63 (d, J=2.8 Hz, 1H) 12.40 (s, 1H); EIMS: 415 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:11]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH3:25])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][NH:8][CH2:9][CH2:10][N:11]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH3:25])=[CH:17][CH:16]=1)(=[O:13])=[O:14])=[O:5])[CH3:2]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2C(=O)OCC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)N2CCNCC2C(=O)OCC)cc1
Reaction time: 8 h
Yield: 88 %

Procedure:
The product of Example 57, 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (3.8 g, 8.1 mmol), was dissolved in dichloromethane (3 mL). To this solution was added trifluoroacetic acid (3 mL) and the reaction was allowed to stir overnight. The reaction was then concentrated in vacuo and the residue triturated with dichloromethane to provide 2.64 g (88%) of 1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid ethyl ester. Electrospray Mass Spec 367.3(M+H)+.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:16]
Reactant: COc1ccccc1
Reactant: O=C(Cl)CCCCCBr
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCCCCBr)cc1
Yield: 100.4 %

Procedure:
Anisole (1.16 g), 6-bromohexanoyl chloride (2.3 g) and aluminum chloride (1.5 g) were reacted and treated in the same manner as in Preparation Example 105 to give 3.07 g of 6-bromo-1-(4-methoxyphenyl)-1-hexanone.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:2]=[CH2:3].[PH2:13]([OH:15])=[O:14].C1C(C(OOC(C)(C)C)=O)=CC=CC=1.CCCCCCC>C(O)(C)C.O>[CH2:5]([O:4][CH2:1][CH2:2][CH2:3][PH:13](=[O:14])[OH:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=CCOCCCCCCCC
Reactant: O=[PH2]O
Agent: CC(C)(C)OOC(=O)c1ccccc1
Solvent: O
Solvent: CCCCCCC
Solvent: CC(C)O
Product: CCCCCCCCOCCC[PH](=O)O
Reaction time: 0.5 h

Procedure:
Allyloxyoctane of step a) (15 g, 0.0882 mols), 50% hypophosphorous acid (15 mL, 0.0882 mols) and tert-butyl perbenzoate (1 mL) in 100 mL isopropyl alcohol are heated at 100° C. for 26 hrs. After completion of the reaction, a mixture of 200 mL n-heptane and water (1:1) is added and the mixture is stirred for 30 minutes. The organic phase is separated and is washed with water. It is dried over Na2SO4 and concentrated to give 16.2 g of oily product. The characterization of the crude material by 1H and 31P NMR shows the formation of product with 63% purity.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17](Cl)(=[O:19])=[O:18])[CH2:5][CH2:4]1)[CH3:2].[NH2:21][C:22]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]2[C:25]([CH:26]3[CH2:36][CH:27]3[CH2:28][O:29]2)=[CH:24][CH:23]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:21][C:22]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]3[C:25]([CH:26]4[CH2:36][CH:27]4[CH2:28][O:29]3)=[CH:24][CH:23]=2)(=[O:19])=[O:18])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(Cc2cc(F)ccc2S(=O)(=O)Cl)CC1
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN1CCC(Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)CC1
Yield: 77.1 %

Procedure:
2-(1-Ethylpiperidine-4-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate 178, 0.165 g) was added to a solution of methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 42, 0.290 g) in DCM (5 mL) and pyridine (1 mL) and the resultant mixture was stirred at room temperature for 21 hours. The mixture was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of 2M NH3 in methanol and DCM with a gradient of 0-20% to give methyl (1aRS,7bSR)-5-[2-(1-ethyl-piperidin-4-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.200 g) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.F[C:11]1[CH:19]=[N:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:16]2[CH:17]=[N:18][CH:19]=[CH:11][C:12]=2[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccncc1F
Reactant: NCc1ccc(Br)cc1
Product: O=C(O)c1ccncc1NCc1ccc(Br)cc1
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield from 4-bromobenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.55 (br s, 1H), 8.08 (s, 1H), 7.82 (d, 1H, J=5.0 Hz), 7.52-7.58 (m, 3H), 7.32 (d, 2H, J=8.3 Hz), 4.55 (s, 2H). [M+H] calc'd for C13H11BrN2O2, 307, 309. Found 307, 309.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:39]=[CH:38][C:17]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][C:27]([P:30](=[O:37])([O:34]CC)[O:31]CC)([F:29])[F:28])=[CH:22][CH:21]=4)=[CH:16][C:15]=3[CH3:40])=[CH:7][C:6]=2[C:5]2[CH:41]=[CH:42][C:43]([CH3:45])=[CH:44][C:4]=2[N:3]=1.C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:39]=[CH:38][C:17]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([CH2:26][C:27]([P:30](=[O:31])([OH:34])[OH:37])([F:28])[F:29])=[CH:24][CH:25]=4)=[CH:16][C:15]=3[CH3:40])=[CH:7][C:6]=2[C:5]2[CH:41]=[CH:42][C:43]([CH3:45])=[CH:44][C:4]=2[N:3]=1
Reactant: CCOP(=O)(OCC)C(F)(F)Cc1ccc(COc2ccc(CCc3cnc4c(N)nc5cc(C)ccc5c4c3)c(C)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCc4ccc(CC(F)(F)P(=O)(O)O)cc4)cc3C)cc12

Procedure:
2-(4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenyl)-1,1-difluoroethylphosphonic acid (8) was prepared according to the procedure described in Example 1—Step 3, but using diethyl 2-(4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenyl)-1,1-difluoroethylphosphonate from the previous step 3. TFA was added to the 1H NMR sample to solubilize the compound for analysis. The 1H NMR (Dimethylsulfoxide-d6) obtained for 2-(4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenyl)-1,1-difluoroethylphosphonic acid (8) was: δ 9.71 (br, 1H), 9.35 (br, 1H), 9.01 (s, 1H), 8.86 (s, 1H), 8.54 (d, 1H, J=8.4 Hz), 7.53 (s, 1H), 7.44 (d, 1H), 7.40 (s, 1H), 7.38 (s, 1H), 7.29 (d, 1H, J=8.0 Hz), 7.24 (s, 1H), 7.11 (s, 1H), 7.09 (s, 1H), 6.99 (s, 1H), 6.85 (s, 1H), 6.76 (d, 1H, J=8.3 Hz), 5.04 (s, 2H), 3.84-3.73 (m, 2H), 3.15 (t, 2H, J=8.5 Hz), 2.99 (t, 2H, J=8.5 Hz), 2.50 (s, 3H), 2.29 (s, 3H). LRMS [M+H]=578.2
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH:11]=[C:12]([C:18]([O:20]CC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].CCOC(C)=O>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[CH3:1][C:2]1([CH3:23])[N:3]2[C:4]3[C:5]([C:18](=[O:20])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11]2)=[CH:6][CH:7]=[CH:8][C:9]=3[CH2:10]1
Reactant: CCOC(=O)C(=CN1c2ccccc2CC1(C)C)C(=O)OCC
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn2c3c(cccc3c1=O)CC2(C)C
Temperature: 100 °C
Yield: 85.7 %

Procedure:
Diethyl 2-((2,2-dimethyl-2,3-dihydro-1H-indol-1-yl)methylene)malonate (Preparation 11, 3.14 g) is dissolved in Eaton's Reagent (3.5 mL) and slowly heated to 100° C. The reaction is cooled and poured into EtOAc (350 mL). The separated organic layer is washed with water (2×200 mL). The aqueous extracts are extracted further with CH2Cl2 (2×100 mL). The organic extracts are washed with brine and dried over MgSO4, filtered and concentrated to a brown oil which is purified by chromatography over silica gel, eluting with 5% methanol in CH2Cl2 to give 2.3 g (85%) of the title compound as a pale yellow oil that slowly crystallizes. Physical characteristics: M.p. 117-119° C.; 1H NMR (DMSO-d6) δ8.73, 7.83, 7.61, 7.41, 4.22, 3.41, 1.63, 1.29; IR (diffuse reflectance) 1933, 1677, 1640, 1624, 1601, 1544, 1459, 1367, 1310, 1213, 1176, 1144, 1032, 773, 757 cm−1; MS (EI) m/z 271 (M+). Anal. Found: C, 70.48; H, 6.36; N, 5.12.
Reaction SMILES: [Br:1][C:2]1[C:3](C)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Br[C:11]1C=C(C)C(N)=NC=1>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:11])[C:5]([Cl:8])=[N:4][CH:3]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: Cc1nc(Cl)ccc1Br
Product: Cc1cc(Br)cnc1Cl
Yield: 67 %

Procedure:
Compound 76A (1.8 g, 67%) was prepared using a procedure similar to the synthesis of 55A from 5-bromo-3-methyl-pyridin-2-ylamine.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([OH:15])[C@@H:8]([CH2:16][O:17]C(=O)C)[O:7][C@H:6]1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([Cl:29])=[C:23]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][CH:32]=2)[CH:22]=1)(=O)C.C[O-].[Na+].CC(O)=O>CO>[Cl:29][C:24]1[C:25]([O:27][CH3:28])=[CH:26][C:21]([C@H:6]2[C@H:5]([OH:4])[C@@H:10]([OH:11])[C@H:9]([OH:15])[C@@H:8]([CH2:16][OH:17])[O:7]2)=[CH:22][C:23]=1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][CH:32]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(OC)c2Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc(OC)c2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of acetate 74-5 (2.5 g, 4.12 mmol) in MeOH (40 mL) was added NaOMe (25 wt % in MeOH, 0.75 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. Glacial AcOH was added to the mixture to acidify the mixture. The mixture was concentrated under reduced pressure. The residue was carried on to the next step without purification.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C@H:14]2[O:16][CH2:15]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[C:17](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:17][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C@H:14]2[O:16][CH2:15]2)=[CH:10][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Nc1ccc(OC[C@@H]2CO2)cc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN(c1ccc(OC[C@@H]2CO2)cc1)S(C)(=O)=O
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of compound 3-S (0.243 g, 1 mmol) and potassium carbonate (0.166 g, 1.2 mmol) in 20 ml acetone was stirred for 1 hour at room temperature, then methyl iodide (0.142 g, 0.062 ml, 1 mmol) was added dropwise at room temperature. After stirring for 8 hours, the reaction was filtered and the solvent evaporated to furnish a white solid that was used directly in the next step (0.2 g, 78% yield).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16](=O)[CH3:17])=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1>CCO>[N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16](=[N:2][OH:3])[CH3:17])=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: NO
Reactant: CC(=O)c1ccc2ncccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=NO)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a suspension of hydroxylamine hydrochloride in EtOH (150 mL) was added a suspension of NaOH (2.4 g, 59.7 mmol) in EtOH (25 mL). The reaction mixture was stirred at ambient temperature for 15 minutes. The precipitated sodium hydrochloride was filtered off. A solution of 1-quinolin-6-yl-ethanone (9.3 g, 54.25 mmol) in EtOH (150 mL) was added. The reaction solution was stirred for 16 hours at ambient temperature. EtOH was removed in vacuum to give 1-quinolin-6-yl-ethanone oxime (10.1 g, >99% yield).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:6]([CH3:17])[CH:5]=1)(=[O:3])[NH2:2].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:32]([S:34]Cl)=[O:33]>O1CCOCC1>[CH3:17][C:6]1[CH:5]=[C:4]([C:1]2[O:3][C:32](=[O:33])[S:34][N:2]=2)[CH:16]=[CH:15][C:7]=1[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: O=C(Cl)SCl
Reactant: Cc1cc(C(N)=O)ccc1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(-c2nsc(=O)o2)ccc1C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
To a stirring solution of tert-butyl 4-carbamoyl-2-methyl-benzoate (10 g) in mixture of Toluene and Dioxane (3:1, 240 mL) was added potassium carbonate (5.88 g) then chlorocarbonylsulfenyl chloride (5.5 mL). The mixture was heated at 100° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, filtered and the filtrate was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate) to give tert-butyl 2-methyl-4-(2-oxo-1,3,4-oxathiazol-5-yl)benzoate (11.12 g) as a solid. 1H-NMR (CDCl3, 400 MHz): δ=7.87-7.96 (m, 1 H), 7.79-7.87 (m, 2 H), 2.63 (s, 3 H), 1.56-1.64 ppm (m, 9 H).