Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:31]=[CH:30][C:19]([CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)=[CH:18][CH:17]=2)=[C:4]([O:32]C)[CH:3]=1.B(Br)(Br)[Br:35]>>[ClH:1].[NH2:22][CH2:21][CH2:20][C:19]1[CH:30]=[CH:31][C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([Br:35])=[CH:3][C:4]=2[OH:32])=[CH:17][CH:18]=1
Reactant: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Reactant: BrB(Br)Br
Product: Cl
Product: NCCc1ccc(-c2c(O)cc(Br)c3[nH]c(=O)c4sccc4c23)cc1
Yield: 16.9 %

Procedure:
Following General Procedure F, tert-butyl 4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenethylcarbamate (410 mg, 0.76 mmol) was treated with BBr3 (1.0 M in CH2Cl2, 10 mL, 10 mmol) to afford the desired product as an off-white solid (58 mg, 18%): 1H NMR (500 MHz, CD3OD) δ 7.62 (d, J=5.4 Hz, 1H), 7.53-7.45 (m, 3H), 7.31 (d, J=8.1 Hz, 2H), 6.10 (d, J=5.4 Hz, 1H), 3.31-3.28 (m, 2H), 3.11 (t, J=7.6 Hz, 2H); ESI MS m/z 415 [C19H15BrN2O2S+H]+; HPLC 94.9% (AUC), tR=9.02 min.
Reaction SMILES: C(O)C.CS[C:6](SC)=[CH:7][N+:8]([O-:10])=[O:9].[CH2:13]([NH:20][CH2:21][CH2:22][NH2:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO>C(Cl)(Cl)Cl>[CH2:13]([N:20]1[CH2:21][CH2:22][NH:23][C:6]1=[CH:7][N+:8]([O-:10])=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCNCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCO
Product: O=[N+]([O-])C=C1NCCN1Cc1ccccc1
Yield: 74.1 %

Procedure:
Ethanol (200 mL) was added to a solution of 1,1-bis-methylsulfanyl-2-nitro-ethene (14.5 g, 0.0878 mol) and N1-benzyl-ethane-1,2-diamine (12 g, 0.080 mol). The resulting mixture was heated to reflux for 2 hours. The reaction mixture was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was concentrated and the concentrate was dissolved in ethylacetate. The precipitate formed was collected and washed with ethylacetate to afford 13 g of the product (74.7% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:6]([CH3:7])[S:5][CH2:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].S(Cl)([Cl:15])(=O)=O>C(Cl)Cl>[ClH:15].[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][S:5][C:6]=1[CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)C1=C(N)C(C)SC1
Solvent: ClCCl
Product: COC(=O)c1csc(C)c1N
Product: Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 118 %

Procedure:
11.5 g of methyl 4-amino-5-methyl-2,5-dihydrothiophene-3-carboxylate (2) (60 mmol, content: 90%) were dissolved in 25 ml of CH2Cl2 and cooled to −10° C. A solution of 8.9 g of sulfuryl chloride (66 mmol) in 10 ml of CH2Cl2 in the temperature range of −10-0° C. was added dropwise to this solution over a period of 2 h. The reaction mixture was subsequently stirred at −10-0° C. for another 1 h and then warmed to room temperature. For workup, the reaction mixture was concentrated under reduced pressure. 14.7 g of methyl 4-amino-5-methylthiophene-3-carboxylate hydrochloride (5) were obtained (89% of theory, content: 62.5%, determined as the free amine).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](=[O:13])[CH2:11][Cl:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[BH4-].[Na+]>C(O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@H:10]([OH:13])[CH2:11][Cl:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 72.6 %

Procedure:
To (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (2.08 g) were added toluene (4.2 ml) and ethanol (16.7 ml). Sodium borohydride (133 mg) was added by portions at −10° C. and the mixture was stirred for 1 hr and 40 min. The reaction was quenched by adding acetic acid (0.40 ml). The reaction mixture was warmed to 60° C. over 1 hr and further stirred 60° C. for 30 min. The reaction mixture was then cooled to −10° C. over 1 hr and 50 min and further stirred at −10° C. for 6 hr. The obtained crystals were collected by filtration, washed with toluene (10.4 ml) and water of 0° C., and dried under reduced pressure to give the objective (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (1.52 g, yield 83%). The obtained dry crystals were analyzed by HPLC and found to be (2S,3S):(2R,3S)=99.2:0.8 crystals.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2([CH2:14][O:15][CH:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)[CH2:17]O)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([Zn]CC)C.ICI>CCOCC.C(OCC)(=O)C.Cl.CCOCC>[ClH:1].[C:2]1([C:8]2([CH2:14][O:15][C:16]3([C:19]4[CH:20]=[C:21]([C:29]([F:31])([F:30])[F:32])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=4)[CH2:17][CH2:33]3)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Zn]CC
Reactant: OCC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCOCC
Solvent: ICI
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(C(F)(F)F)cc(C2(OCC3(c4ccccc4)CCNCC3)CC2)c1
Temperature: 0 °C

Procedure:
The compound of Example 1 (c) (0.500 g, 0.922 mmol) was dissolved in anhydrous ether (10 ml) and diethylzinc (1.0M solution in hexanes, 1.84 ml, 1.84 mmol) was added. The solution was cooled to 0° C. and diiodomethane (0.15 ml 1.84 mmol) was added. The reaction was diluted with ethyl acetate (50 ml) and washed with saturated aqueous ammonium chloride solution. The organic layer was dried over (MgSO4) and evaporated. The residue was purified by chromatography on silica eluting with 5% ethyl acetate/hexanes→10% ethyl acetate/hexanes. The product obtained was left standing in HCl/ether for 16 h. The solvent was removed in vacuo and the title compound suspended in ether and filtered. 1H NMR (DMSO-d6) δ 7.90 (1H, s), 7.50 (2H, s), 7.29-7.40 (5H, m), 3.36 (2H, s), 3.17 (2H, m), 2.74 (2H, m), 2.30 (2H, m), 2.01 (2H, m), 1.13 (4H, m). MS (Cl+) 444 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][CH:3]1[NH:19]C(=O)OCC1C=CC=CC=1.[Cl:30][C:31]1[CH:32]=[CH:33][C:34](I)=[N:35][CH:36]=1.C(O)(C(F)(F)F)=O>O.CO>[NH2:19][C@@H:3]1[C:2](=[O:1])[N:8]([C:34]2[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][N:35]=2)[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:4]1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: Clc1ccc(I)nc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N[C@H]1N=C(c2ccccc2)c2ccccc2N(c2ccc(Cl)cn2)C1=O

Procedure:
Intermediate B-16 was prepared from benzyl 2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate and 5-chloro-2-iodopyridine according to the procedure described for Intermediate B-15. RT=2.430 min (H2O/CH3OH with TFA, CHROMOLITH® ODS S5 4.6×50 mm, gradient=3 min, wavelength=220 and 254 nm); MS(ES):m/z=363.12 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](Cl)=[O:14])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[CH3:26][NH2:27].O1CCCC1.O>C(OCC)(=O)C>[CH3:26][NH:27][C:13]([C:11]1[S:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:10]=1)=[O:14]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(=O)Cl)sc2-c2ccc(F)cc2)cc1
Reactant: CN
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(4-Fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carbonyl chloride (1.4 g) was added to a stirred mixture of methylamine (25% in water, 2 ml), tetrahydrofuran (15 ml) and water (5 ml) at 5° C. The mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with water, and concentrated to dryness. The residue was purified by column chromatography on silica gel (20 g) eluting with a mixture of chloroform and ethyl acetate (1:1). The purified powder (1.1 g) was crystallized from diethyl ether to give colorless crystals of N-methyl-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxamide (1.0 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)[CH:14]=2)[NH:9][CH:8]=1.C(Cl)Cl.B(Br)(Br)Br>O>[S:18]1[CH:19]=[CH:20][C:16]([C:13]2[CH:14]=[C:15]3[C:7]([CH2:6][C:5]4[CH:4]=[C:3]([OH:2])[CH:23]=[CH:22][CH:21]=4)=[CH:8][NH:9][C:10]3=[N:11][CH:12]=2)=[CH:17]1
Reactant: COc1cccc(Cc2c[nH]c3ncc(-c4ccsc4)cc23)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1cccc(Cc2c[nH]c3ncc(-c4ccsc4)cc23)c1
Reaction time: 5 h
Yield: 26.2 %

Procedure:
Into a Round bottom flask was added compound 14 (20.0 mg, 0.0000624 mol) and Methylene chloride (4.0 mL, 0.062 mol) at room temperature. Into the reaction mixture, was added 0.1 mL BBr3 (1.0M in). The reaction mixture was allowed to room temperature for 5 hours. TLC indicated the reaction was not complete. The reaction mixture was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with preparative TLC to give product 15 (5 mg).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[C:5]([O:22][CH3:23])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[ClH:1].[CH3:23][O:22][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[N:11]=[C:10]2[N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1
Reactant: Nc1ccccc1
Reactant: COc1cccc2c(N3CCc4ccccc4C3)nc(Cl)nc12
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CCc4ccccc4C3)nc(Nc3ccccc3)nc12
Product: Cl
Yield: 73 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 1.5 g of the compound (4.6 mM) prepared in Example 4 and 15 ml of dimethylform-amide, 0.65 ml of aniline(6.9 mM) was added, 1.40 g of the title compound was prepared.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CC[N:27](C(C)C)C(C)C.[CH:34]([CH:37]1[CH2:41][CH2:40][N:39](N)[CH:38]1[CH3:43])([CH3:36])[CH3:35]>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][CH:37]([CH:34]([CH3:36])[CH3:35])[C:38]4([CH3:43])[NH2:27])=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: CC(C)C1CCN(N)C1C
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CCN(C(C)C)C(C)C
Product: CC(C)C1CCN(c2ccc3c(C(=O)NC[C@@]4(O)CCC[C@@H](C)C4)c(Cl)ccc3n2)C1(C)N

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-isopropyl-methyl-amino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 3H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 4H), 0.83 (d, 3H). m/z: 474 [M+H]
Reaction SMILES: [CH3:1][C@:2]12[C:8]([CH3:10])([CH3:9])[C@H:5]([CH2:6][CH2:7]1)[CH:4]([C:11](Cl)=[O:12])[C:3]2=O.C(N(CC)CC)C.C(O[C:27]([N:29](C)[NH:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[C:38]([F:41])([F:40])[F:39])=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[F:37][C:35]1[CH:34]=[CH:33][C:32]([C:38]([F:39])([F:40])[F:41])=[C:31]([N:30]2[C:11](=[O:12])[C:4]3[C@@H:5]4[C:8]([CH3:10])([CH3:9])[C@@:2]([CH3:1])([CH2:7][CH2:6]4)[C:3]=3[N:29]2[CH3:27])[CH:36]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CN(Nc1cc(F)ccc1C(F)(F)F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cn1c2c(c(=O)n1-c1cc(F)ccc1C(F)(F)F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.5 %

Procedure:
A solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 349 mg, 1.62 mmol) in 1,2-dichloroethane (9 mL) was added to a cooled (0° C.) solution of triethylamine (320 μL, 2.30 mmol) and N′-(5-fluoro-2-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (348 mg, 1.13 mmol) in 1,2-dichloroethane (6 mL) over a period of 1 min. The reaction mixture was stirred for 10 min at room temperature and then in an oil bath at 50° C. for 1 h. A solution of HCl in dioxane (4 M; 8 mL, 32 mmol) was added and the mixture was heated at reflux for 1 h and then allowed to cool to room temperature. Silica gel was added and the solvent was evaporated. The residue was purified using an ISCO40 g column, eluting with 50-100% ethyl acetate/hexanes and then with 10% methanol/ethyl acetate. Fractions homogeneous for the product were evaporated, and the residue was dissolved in dichloromethane (75 mL), and washed with 1:1 water/saturated aqueous sodium thiosulfate (20 mL) and brine (20 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and dried under high vacuum at 95° C. to give (4S,7R)-2-(5-fluoro-2-trifluoromethyl-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (127 mg, 31%) as a white solid. ES(+)-MS (M+H) 369.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@:10]1([CH:50]1[CH2:52][O:51]1)[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:53][NH2:54]>CO.O1CCCC1>[CH3:53][NH:54][CH2:52][CH:50]([C@:10]12[O:32][C@:13]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=4)[CH:34]=3)([O:12][CH2:11]1)[C@H:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:15]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@@H:9]2[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:51]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@@](C5CO5)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(O)CNC)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(oxiran-2-yl)-6,8-dioxabicyclo[3.2.1]octane 10a (50 mg, 0.56 mmol, obtained from the synthetic method described in step 1 of example 10) in a methanol/tetrahydrofuran mixture (v/v=2/1, 9 mL) was added methylamine solution (1 mL, 1.25 mmol). The mixture was heated to 55° C. and stirred for 16 h. The resulting mixture was extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with water (10 mL×2) and saturated brine (10 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with EtOAc to give the title compound 11a as a white solid (37.4 mg, 71.6%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.41 (m, 2H), 7.40 (m, 1H), 7.32 (m, 3H), 7.26 (m, 6H), 7.17 (m, 3H), 7.04 (d, 2H), 6.85 (m, 2H), 6.73 (m, 2H), 4.87 (m, 1H), 4.75 (m, 3H), 4.26 (m, 1H), 4.11 (m, 2H), 3.97 (m, 2H), 3.92 (m, 3H), 3.82 (m, 2H), 3.72 (m, 3H), 2.65 (m, 1H), 2.55 (m, 1H), 2.22 (s, 3H), 1.27 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[C:13]2[C:3]1=[CH:4][C:5]1[C:10](=[O:11])[CH:9]=[CH:8][O:7][C:6]=1[CH:12]=2.CO>[Pd].C(OCC)(=O)C>[CH3:1][C:2]1([CH3:19])[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[C:13]2[C:3]1=[CH:4][C:5]1[C:10](=[O:11])[CH2:9][CH2:8][O:7][C:6]=1[CH:12]=2
Reactant: CC1(C)CCC(C)(C)c2cc3c(=O)ccoc3cc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)OCCC3=O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The synthesis process is as set forth in the chemical reaction formula below. To 6,7,8,9-tetrahydro-6,6,9,9-tetramethyl-4H-naphtho[2,3-b]pyran-4-one (the above named compound N) (124 mg, 0.48 mmol) were added methanol (4.0 mL), ethyl acetate (4.0 mL) and 10% palladium on carbon (40 mg), followed by stirring under a hydrogen atmosphere at room temperature for 10 hours. The reaction solution was filtrated by celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography using hexane/ethyl acetate (4/1 to 2/1) as an elution solvent. The yield was 80.0 mg (64%).
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:10]=[CH:9]2.C(OCC)C.O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:10]=[CH:9]2
Reactant: COc1ccc(S(=O)(=O)c2ccc3cc(Br)ccc3c2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: O=S(=O)(c1ccc(O)cc1)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.4 %

Procedure:
A 1M solution of boron tribromide in methylene chloride (9.65 ml) was slowly added to a stirred, cooled (−78° C.), methylene chloride (25 ml) solution of a portion (1.21 g) of the anisole derivative so obtained. The mixture was stirred for 20 hours at ambient temperature, then cooled to −10° C., diethyl ether (4 ml) slowly added, and stirring continued for 10 minutes. Water (25 ml) was added and the mixture extracted with ethyl acetate (2×25 ml). The combined organic extracts were washed with water, dried (MgSO4) and evaporated. Trituration of the residue under ether gave 4-(6-bromonaphth-2-ylsulphonyl)phenol (1.03 g), m.p. 178-180° C.;
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:10][C:11](N)=[O:12].O>C(OCCOCCO)C>[NH2:9][C:8]1[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:11](=[O:12])[N:10]=1
Reactant: N#Cc1ncccc1N
Reactant: NC(N)=O
Solvent: CCOCCOCCO
Solvent: O
Product: Nc1nc(=O)[nH]c2cccnc12
Temperature: 205 °C

Procedure:
A slurry of 3-Amino-2-cyanopyridine (200 mg) and urea (400 mg) in 2-(2-ethoxyethoxy)ethanol (0.5 mL) was gradually heated to about 205° C., and maintained at 205° C. for 10 min. Heating was ceased and 6 mL of hot water was carefully added while shaking the mixture. The mixture was vacuum filtered to collect the precipitate. The precipitate was washed with water and ethyl acetate and allowed to dry to yield 4-Amino-pyrido[2,3-e]pyrimidin-2-one as a light yellow solid, m.p. >300° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:45][C:46]1[CH:62]=[CH:61][C:49]([O:50][CH2:51][CH2:52][NH:53]C(=O)OC(C)(C)C)=[C:48]([C:63]2[N:67]([CH3:68])[N:66]=[CH:65][CH:64]=2)[CH:47]=1.[C:69]([OH:75])([C:71]([F:74])([F:73])[F:72])=[O:70]>C(Cl)Cl>[F:72][C:71]([F:74])([F:73])[C:69]([OH:75])=[O:70].[NH2:53][CH2:52][CH2:51][O:50][C:49]1[CH:61]=[CH:62][C:46]([NH:45][C:4](=[O:6])[C:3]2[C:7]([F:13])=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=2[F:1])=[CH:47][C:48]=1[C:63]1[N:67]([CH3:68])[N:66]=[CH:65][CH:64]=1
Reactant: COc1cc(F)c(C(=O)O)c(F)c1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(F)c(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c(F)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
2,6-difluoro-4-methoxybenzoic acid (22.6 mg, 120 μmol) was weighed into a microwave vial and CH2Cl2 (1 mL) was added followed by HATU (34.3 mg, 90.3 pimp and Et3N (20 μl, 144 μmol). After stirring 10 minutes, tert-butyl 2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (20 mg, 60 μmol) was added to the solution. The reaction mixture was heated at 60° C. for one hour. Then, TFA (1 mL) was added and heated for one hour at 90° C. in order to remove the Boc-protecting group from the amine. The solvent was evaporated. The resulting oil was dissolved in DMSO (1 mL) and purified by Prep LC/MS to give N-[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2,6-difluoro-4-methoxy-benzamide trifluoroacetate (8.2 mg, 0.02 mmol, 34%) as a white solid. LCMS m/z (%)=403 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.16 (s, 2 H), 3.70 (s, 3 H), 3.84 (s, 3 H), 4.17 (t, J=5.56 Hz, 2 H), 6.36 (d, J=1.77 Hz, 1 H), 6.89 (d, J=9.85 Hz, 1 H), 7.24 (d, J=9.09 Hz, 1 H), 7.49 (d, J=1.77 Hz, 1 H), 7.63 (d, J=2.78 Hz, 1 H), 7.77 (dd, J=9.09, 2.53 Hz, 1 H), 7.89 (br. s., 3 H), 10.69 (s, 1 H), 13.46 (s, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29]I>>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:29])=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:25])[CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCc1cc(O)c(OCc2ccccc2)c(OCCCCCC(C)(C)C#N)c1
Product: CCc1cc(OC)c(OCc2ccccc2)c(OCCCCCC(C)(C)C#N)c1
Yield: 75 %

Procedure:
1-Benzyloxy-2-(6-cyano-6-methylheptyloxy)-4-ethyl -6-methoxy benzene was prepared in 75% yield as a white solid from 1-Benzyloxy-2-(6-cyano-6-methylheptyloxy)-4-ethyl-6-hydroxy benzene and methyliodide.
Reaction SMILES: C([NH:5][S:6]([C:9]1([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7])(C)(C)C.CC1(S(N)(=O)=O)CC1>>[C:12]([C:9]1([S:6]([NH2:5])(=[O:8])=[O:7])[CH2:10][CH2:11]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)NS(=O)(=O)C1(C(=O)c2ccccc2)CC1
Agent: CC1(S(N)(=O)=O)CC1
Product: NS(=O)(=O)C1(C(=O)c2ccccc2)CC1
Yield: 87 %

Procedure:
This compound was obtained in 87% yield from N-tert-butyl(1-benzoyl)cyclopropyl-sulfonamide (from Step A.6.a) using the procedure described for the synthesis of 1-methylcyclopropylsulfonamide, followed by recrystallization from the minimum amount of ethyl acetate in hexane: 1H NMR (DMSO-d6) δ 1.39 (m, 2H), 1.61 (m, 2H), 7.22 (s, 2H), 7.53 (t, J=7.6 Hz, 2H), 7.65 (t, J=7.6 Hz, 1H), 8.06 (d, J=8.2 Hz, 2H); 13C NMR (DMSO-d6) δ 12.3, 48.4, 128.1, 130.0, 133.4, 135.3, 192.0.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[CH:7][C:8]2[C:9]([CH:28]=1)=[CH:10][CH:11]=[C:12]1[C:16]=2[NH+:15]([CH2:17]CCCS(O)(=O)=O)[CH:14]([CH3:25])[C:13]1([CH3:27])[CH3:26])([OH:4])(=[O:3])=[O:2].C(N(CC)CC)C>C(OC(=O)C)(=O)C>[C:8]1([CH3:16])[CH:9]=[CH:28][C:5]([S:1]([O-:4])(=[O:2])=[O:3])=[CH:6][CH:7]=1.[CH3:17][NH+:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]3[CH:28]=[CH:5][CH:6]=[CH:7][C:8]3=2)[C:13]([CH3:27])([CH3:26])[CH:14]1[CH3:25]
Reactant: CC1[NH+](CCCCS(=O)(=O)O)c2c(ccc3cc(S(=O)(=O)O)ccc23)C1(C)C
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC1[NH+](C)c2c(ccc3ccccc23)C1(C)C
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
N-[5-(Phenylamino)-2-hydroxy-2,5-pentadienylidene]aniline monohydrochloride (15.0 g, 0.05 mol), 7-sulfo-2,3,3-trimethyl-(4-sulfobutyl)-1H-benzindolium, inner salt [NKX-1632 from the Japanese Institute of Photosensitizing Dyes], (41.3 g, 0.1 mol) and 300 ml acetic anhydride were stirred together at ambient temperature. Triethylamine (20.2 g, 0.2 mol) was added and the mixture was stirred 80 minutes at ambient temperature. The mixture was filtered and poured into 2000 ml stirred ethyl acetate. The ethyl acetate was filtered away and the solid reslurried twice in ethyl acetate. After filtering and vacuum drying, the yield was 61.79 g of dye, mp 177°-195° C., λmax (methanol)=789 nm (ε=215,000).