Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30][S:31][CH2:32][CH2:33][OH:34])[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.ClC1C=CC=C(C(OO)=[O:43])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30][S:31]([CH2:32][CH2:33][OH:34])=[O:43])[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1
Reactant: OCCSCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=S(CCO)CCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a solution of 2-({2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}thio)ethanol (100 mg) in dichloromethane (10 mL) was added dropwise a 70% solution of 3-chloroperbenzoic acid (58 mg) in dichloromethane (5.0 mL) at −78° C. The mixture was stirred at −78° C. for 1 hr, and aqueous sodium thiosulfate solution was added. After stirring at room temperature for 0.5 hr, the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate→ethyl acetate:methanol=4:1) to give the title compound (87 mg) as colorless crystals.
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40]OC3C=CC(C4C(C#N)=CSC=4)=CC=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19].[OH:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[C:63]([C:68]#[N:69])=[N:64][CH:65]=[CH:66][N:67]=2)=[CH:58][CH:57]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:55][C:56]3[CH:57]=[CH:58][C:59]([C:62]4[C:63]([C:68]#[N:69])=[N:64][CH:65]=[CH:66][N:67]=4)=[CH:60][CH:61]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19]
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Reactant: N#Cc1nccnc1-c1ccc(O)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nccnc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1

Procedure:
The title compound 86 was prepared as a TFA salt in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 86A: 1H NMR (DMSO-d6): δ 8.96 (d, J=2.45 Hz, 1H), 8.76 (d, J=2.45 Hz, 1H), 8.02 (d, J=7.98 Hz, 2H), 7.90-7.93 (d, J=7.98 Hz, 2H), 7.78 (d, J=7.98 Hz, 1H), 7.67 (d J=7.67 Hz, 1H), 7.33-7.49 (m, 4H), 7.11-7.15 (m, 2H), 4.84 (s, 2H), 4.1 (t, J=6.29 Hz, 2H), 3.70-3.74 (m, 2H), 3.19-3.23 (m, 2H), 3.03 (t, J=5.83 Hz, 2H), 2.02-2.09 (m, 2H). ESI (+)/MS: 674 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8](=[O:9])[N:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15])[C:6](=[O:20])[NH:5][C:4]1=[O:21])[CH3:2].[C:28]1(=[O:34])[O:33][C:31](=[O:32])[CH2:30][CH2:29]1.CN(C1C=CC=CN=1)C.O>C(Cl)(Cl)Cl.ClCCl>[C:31]([CH2:30][CH2:29][C:28]([O:19][CH2:18][CH2:17][NH:16][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][N:7]1[C:8](=[O:9])[C:3]([CH2:1][CH3:2])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:4](=[O:21])[NH:5][C:6]1=[O:20])=[O:15])=[O:34])([OH:33])=[O:32]
Reactant: CCC1(c2ccccc2)C(=O)NC(=O)N(CCCCC(=O)NCCO)C1=O
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCC1(c2ccccc2)C(=O)NC(=O)N(CCCCC(=O)NCCOC(=O)CCC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of the product from step 1 (2.9 g, 0.007 mole), succinic anhydride (0.7 g, 0.007 mole), and dimethylaminopyridine (0.9 g, 0.007 mole) in chloroform (100 mL) was heated with hot water (50°-60° C.) for 30 min and then stirred at room temperature for 3 days. Dichloromethane (300 mL) was added, and the mixture was washed with 10% hydrochloric acid solution (2×100 mL), washed with saturated sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, filtered, and solvent removed to give an oil which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:4]1.Br[C:15]1[C:16](=[O:23])[N:17]([CH3:22])[CH:18]=[C:19]([Br:21])[CH:20]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:21][C:19]1[CH:20]=[C:15]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:5]3[CH2:6][CH:3]([O:2][CH3:1])[CH2:4]3)=[CH:12][N:11]=2)[C:16](=[O:23])[N:17]([CH3:22])[CH:18]=1
Reactant: COC1CN(c2ccc(N)nc2)C1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Temperature: 100 °C
Yield: 47.4 %

Procedure:
A 100-mL round bottomed flask was equipped with a reflux condenser was charged with 323b (1.2 g, 6.7 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (2.14 g, 8.04 mmol), Pd2(dba)3 (306.5 mg, 0.335 mmol), Xantphos (387.3 mg, 0.67 mmol), Cs2CO3 (4.37 g, 13.4 mmol), and dioxane (50 mL). After bubbling nitrogen through the reaction mixture for 20 minutes, it was heated at 100° C. under N2 protection for 3 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. It was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was washed with petroleum ether to afford 323c as a brown solid (1.16 g, 47%), which was used in next step without further purification. MS-ESI: [M+H]+ 364.8.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[N:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[C:38]([C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=3)[CH:39]=[CH:40][C:41]=2[OH:42])=[CH:32][N:31]=1>>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:11])=[O:12])[CH:6]=[CH:7][C:8]=1[O:42][C:41]1[CH:40]=[CH:39][C:38]([C:43]2[CH:44]=[CH:45][C:46]([C:49]([F:50])([F:51])[F:52])=[CH:47][CH:48]=2)=[CH:37][C:36]=1[C:33]1[CH:34]=[CH:35][N:30]=[N:31][CH:32]=1)#[N:2]
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnnc3)c(C#N)c2)c(OC)c1
Yield: 79.1 %

Procedure:
Prepared according to Preparation 22 using 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 19, 165 mg, 0.379 mmol) and 3-Pyridazin-4-yl-4′-(trifluoromethyl)biphenyl-4-ol (Preparation 8, 120 mg, 0.379 mmol) to afford the title compound as a solid (219 mg, 79%).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH3:10].[B:11](OC(C)C)([O:16]C(C)C)[O:12]C(C)C.O>O1CCCC1.BrC1C=CC=CC=1SC.II>[CH3:10][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[B:11]([OH:16])[OH:12]
Reactant: CSc1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccccc1B(O)O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Magnesium (9.52 g) was suspended in 119 mL of tetrahydrofuran, and to the suspension were added 3.00 g of 2-bromothioanisole and about 20 mg of iodine. After the reaction was started by heating employing a dryer, 72 g of 2-bromothioanisole was dropped to the mixture during 20 minutes. After being heated for 1 hour, the reaction mixture was diluted with 1000 mL of tetrahydrofuran, and cooled to 0° C. To the mixture was added 102 mL of triisopropyl borate at the same temperature, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added water, and the solvent was removed under reduced pressure. The residue was added 500 mL of 2 mol/L hydrochloric acid, and the mixture was extracted with 300 mL of diethyl ether. The organic layer was extracted with 500 mL of 2 mol/L aqueous sodium hydroxide solution, and the aqueous layer was acidified by addition of concentrated hydrochloric acid under ice-cooling. The residual diethyl ether was removed under reduced pressure, and the precipitate was collected by filtration to give 45.95 g of 2-(methylthio)phenylboronic acid.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8]C(C)C)=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]2[O:23][CH3:24])=[C:4]([F:25])[CH:3]=1.S(=O)(=O)(O)O>>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[N:14]=[C:13]2[O:23][CH3:24])=[C:4]([F:25])[CH:3]=1
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(OC(C)C)c(Br)cc1F
Agent: O=S(=O)(O)O
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Br)cc1F

Procedure:
using 1-(4-bromo-2-fluoro-5-isopropoxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone with concentrated sulphuric acid there is obtained 1-(4-bromo-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 132°-136° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=3)[C:6]=2[CH:21]=1>C1COCC1.[Pd]>[NH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][N:7]1[C:6]2[CH:21]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][C:8]1=[O:10]
Reactant: O=c1sc2ccc(Cl)cc2n1Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc(Cn2c(=O)sc3ccc(Cl)cc32)c1
Reaction time: 24 h

Procedure:
4.5 g (12.8 mol) of 5-chloro-3-(3-nitrobenzyl)-3H-benzothiazol-2-one [“A13a”; prepared analogously to “A12”; ESI: 321 (M+H); Rt.=3.20 min (method A)] are dissolved in 100 ml of THF and hydrogenated under a hydrogen atmosphere at room temperature using 2 g of palladium on active carbon (water-moist, 5% of Pd). After 24 h, the catalyst is filtered off with suction, rinsed with THF and evaporated, giving 3-(3-aminobenzyl)-5-chloro-3H-benzothiazol-2-one, ESI: 291 (M+H); HPLC: Rt.=2.28 min (method A).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[N:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:20]([O:22][C:23]([C@H:25]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]1)=[O:24])[CH3:21]>C1COCC1>[CH2:20]([O:22][C:23]([C@H:25]1[CH2:30][CH2:29][C@H:28]([NH:31][C:5]2[N:10]=[C:9]([N:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[N:12]3)[CH:8]=[CH:7][N:6]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21]
Reactant: CCOC(=O)[C@H]1CC[C@H](N)CC1
Reactant: CS(=O)(=O)c1nccc(-n2ncc3ccccc32)n1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](Nc2nccc(-n3ncc4ccccc43)n2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-(2-Methanesulfonylpyrimidin-4-yl)-1H-indazole (6.4 g) was suspended in THF and the mixture heated to 60° C. until complete dissolution of the solids. trans-4-Amino-cyclohexane-carboxylic acid ethyl ester (7.99 g, 46.6 mmol) was added, followed by TEA (9.7 mL, 69.9 mmol), and the resulting mixture stirred overnight. The reaction mixture was concentrated under reduced pressure until solids started to precipitate, and was then heated to 60° C. for 24 h. THF (4 mL) was added, and the reaction mixture stirred for 64 h at 60° C. The resulting mixture was extracted with EtOAc, the combined organic extracts washed with water, dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM/MeOH, 98:2) and the brown solid obtained was triturated with Et2O to give trans-4-(4-indazol-1-ylpyrimidin-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (2.883 g) as a white solid.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][C:21](=[O:25])[NH:22]3)=[CH:17][CH:16]=2)[C:10]1=[O:26])[C:6](O)=[O:7])(=[O:3])[CH3:2].[NH2:27][C:28]1[CH:47]=[CH:46][C:31]2[C:32]([N:35]3[C:43](=[O:44])[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:36]3=[O:45])=[N:33][O:34][C:30]=2[CH:29]=1>>[O:45]=[C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43](=[O:44])[N:35]1[C:32]1[C:31]2[CH:46]=[CH:47][C:28]([NH:27][C:6](=[O:7])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:9]3[O:14][CH2:13][CH2:12][N:11]([C:15]4[CH:24]=[C:23]5[C:18]([CH:19]=[CH:20][C:21](=[O:25])[NH:22]5)=[CH:17][CH:16]=4)[C:10]3=[O:26])=[CH:29][C:30]=2[O:34][N:33]=1
Reactant: CC(=O)O[C@@H](C(=O)O)[C@H]1OCCN(c2ccc3ccc(=O)[nH]c3c2)C1=O
Reactant: Nc1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1
Product: CC(=O)O[C@@H](C(=O)Nc1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1)[C@H]1OCCN(c2ccc3ccc(=O)[nH]c3c2)C1=O

Procedure:
According to the Step 15-1 in the synthetic method for Example aa15, (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-7-yl)morpholin-2-yl]acetic acid (compound aa7-4) and 6-amino-3-(1,3-dioxoisoindol-2-yl)-1,2-benzisoxazole can be used to obtain [(1R)-2-[[3-(1,3-dioxoisoindol-2-yl)-1,2-benzisoxazol-6-yl]amino]-2-oxo-1-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-7-yl)morpholin-2-yl]ethyl]acetate (compound ap2-1), then further treatment can be achieved according to the Step 15-2 to obtain the title compound ap2.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1.[CH2:14]([O:17][C:18]1[CH:34]=[CH:33][CH:32]=[CH:31][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29]Cl)[CH2:23][CH2:22]1)[CH2:15][CH3:16]>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:29][CH2:28][CH2:27][N:24]3[CH2:25][CH2:26][N:21]([CH2:20][C:19]4[CH:31]=[CH:32][CH:33]=[CH:34][C:18]=4[O:17][CH2:14][CH2:15][CH3:16])[CH2:22][CH2:23]3)[CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1
Reactant: Cc1cc(=O)[nH]c2ccc(O)cc12
Reactant: CCCOc1ccccc1CN1CCN(CCCCl)CC1
Product: CCCOc1ccccc1CN1CCN(CCCOc2ccc3[nH]c(=O)cc(C)c3c2)CC1
Yield: 53 %

Procedure:
In a manner analogous to that described in Example 9, 4-methyl-6-hydroxy-2-oxo-1,2-dihydroquinoline is reacted with 3-[4-(2-propoxybenzyl)-piperazin-1-yl]-propyl chloride. There is obtained 4-methyl-6-{3-[4-(2-propoxybenzyl)-piperazin-1-yl]-propoxy}-2-oxo-1,2-dihydroquinoline in a yield of 53% of theory in the form of an oily base. The corresponding hydrochloride is obtained from an acetone solution of the base, by the addition of ethereal hydrochloric acid, in amorphous fomrm with a melting point of about 140°-145° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]2[C:17](=O)[CH2:16][CH2:15][CH2:14][C:13]2=[O:19])=[CH:10][C:9]([CH3:20])=[C:8]2[C:3]=1[CH:4]([O:23][CH:24]([CH3:26])[CH3:25])[CH2:5][CH2:6][S:7]2(=[O:22])=[O:21].C(N(CC)CC)C>ClCCCl>[Cl:1][C:2]1[C:11]([C:12]2[C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH:17]=2)=[CH:10][C:9]([CH3:20])=[C:8]2[C:3]=1[CH:4]([O:23][CH:24]([CH3:26])[CH3:25])[CH2:5][CH2:6][S:7]2(=[O:22])=[O:21]
Reactant: Cc1cc(C2C(=O)CCCC2=O)c(Cl)c2c1S(=O)(=O)CCC2OC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cc(C2=CCCCC2=O)c(Cl)c2c1S(=O)(=O)CCC2OC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
0.5 Gram of 5-chloro-8-methyl-6(1,3-dioxocyclohexan-2-yl)-4-(2-propoxy)thiochroman-1,1-dioxide (Compound No. 15 in Table 38) prepared in Preparation Example 6 was dissolved in 5 ml of 1,2-dichloroethane, and 0.12 g of triethylamine was added. The mixture was stirred at room temperature for 1 hour. A formed crystal was recovered by filtration to give, as an end product, 0.3 g of Compound No. 251 shown in Table 48 (yield 65%). Table 60 shows the physical property date of the obtained compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=4)[N:15](C(OC(C)(C)C)=O)[CH:14]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[Br:38][C:39]1[S:40][C:41](Br)=[N:42][N:43]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:38][C:39]1[S:40][C:41]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[C:11]2[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:8]=[CH:9][CH:10]=2)=[N:42][N:43]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Brc1nnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Brc1nnc(-c2ccc3[nH]cc(-c4cccc(N5CCOCC5)n4)c3c2)s1
Temperature: 100 °C
Yield: 16.4 %

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 3-(6-morpholinopyridin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (250 mg, 0.495 mmol) and 2,5-dibromo-1,3,4-thiadiazole (133 mg, 0.544 mmol) in p-dioxane/H2O (4:1, 4.5 mL) followed by potassium carbonate (205 mg, 1.484 mmol) and Pd(PPh3)4 (28.6 mg, 0.025 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 75 min. The mixture was diluted with DCM, washed with H2O, dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 2-10% EtOAc in DCM) to give 4-(6-(5-(5-bromo-1,3,4-thiadiazol-2-yl)-1H-indol-3-yl)pyridin-2-yl)morpholine (36.0 mg, 0.081 mmol, 16.45%) as a yellow solid. MS (ESI, pos. ion) 442 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.85 (1H, br. s.), 9.11 (1H, d, J=1.6 Hz), 8.19 (1H, d, J=2.5 Hz), 7.80 (1H, dd, J=8.6, 1.8 Hz), 7.56-7.64 (2H, m), 7.24 (1H, d, J=7.4 Hz), 6.67 (1H, d, J=8.4 Hz), 3.79-3.86 (4H, m), 3.58-3.65 (4H, m).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([O:14][C:15](=[O:17])[CH3:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[C:18]([Si:22]([CH3:34])([CH3:33])[O:23][CH:24]([C:26]([CH3:32])([CH:30]=[CH2:31])[C:27]([OH:29])=[O:28])[CH3:25])([CH3:21])([CH3:20])[CH3:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1(CNCC2CCCCC2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:15]([O:14][C@@H:12]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2](/[CH:31]=[CH:30]/[C:26]([CH:24]([O:23][Si:22]([C:18]([CH3:19])([CH3:21])[CH3:20])([CH3:33])[CH3:34])[CH3:25])([CH3:32])[C:27]([OH:29])=[O:28])=[CH:3][CH:4]=2)[N:9]=1)[CH3:13])(=[O:17])[CH3:16]
Reactant: CC(=O)O[C@H](C)c1ccc2ccc(Br)cc2n1
Reactant: C=CC(C)(C(=O)O)C(C)O[Si](C)(C)C(C)(C)C
Agent: [Pd+2]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(=O)O[C@H](C)c1ccc2ccc(/C=C/C(C)(C(=O)O)C(C)O[Si](C)(C)C(C)(C)C)cc2n1
Yield: 28.4 %

Procedure:
A solution of acetic acid (R)-1-(7-bromo-quinolin-2-yl)-ethyl ester (555.4 mg, 1.888 mmol), 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-methyl-but-3-enoic acid (488.0 mg, 1.888 mmol), palladium(II)acetate (85 mg, 0.378 mmol), tri(o-tolyl)phosphine (115 mg, 0.378 mmol) and N,N-dicyclohexylmethylamine (1.0 mL, 4.720 mmol) in anhydrous 1,4-dioxane (15 mL) was heated at reflux for 2 h. After cooling to warm temperature the reaction was quenched with hydrochloric acid (1 M, 30 mL). The aqueous layer was extracted with ethyl acetate (2×). The combined organics were dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:1 to afford the title compound (252.7 mg, 28%) as a yellow solid along with a 1:3 mixture of 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-methyl-but-3-enoic acid and acetic acid (R)-1-(7-bromo-quinolin-2-yl)-ethyl ester (474.6 mg) which was dissolved in anhydrous 1,4-dioxane (10 mL), treated with palladium(II)acetate (85 mg, 0.378 mmol), tri(o-tolyl)phosphine (115 mg, 0.378 mmol) and N,N-dicyclohexylmethylamine (1.0 mL, 4.720 mmol) and heated at reflux for 5 h. After cooling to room temperature the mixture was quenched with hydrochloric acid (1 M, 20 mL). The aqueous layer was extracted with ethyl acetate (2×). The combined organics were dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:1 to afford the title compound (149.6 mg, 17%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 0.12 (s, 3H), 0.15 (s, 3H), 0.93 (s, 9H), 1.25 (d, J=6.0 Hz, 3H), 1.69 (d, J=6.7 Hz, 3H), 2.18 (s, 3H), 2.51 (s, 3H), 4.14 (q, J=6.2 Hz, 1H), 6.08 (q, J=6.7 Hz, 1H), 6.74 (ABq, ΔδAB=0.12, JAB=16.7 Hz, 2H), 7.44 (d, J=8.5 Hz, 1H), 7.64-7.70 (m, 1H), 7.76 (d, J=8.7 Hz, 1H), 8.03 (s, 1H), 8.12 (d, J=8.5 Hz, 1H). LCMS (m/z) 472.2 [M+H], Tr=3.61 min.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([CH2:38][S:39][C:40]5[S:41][CH:42]=[N:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([CH2:38][S:39]([C:40]5[S:41][CH:42]=[N:43][N:44]=5)=[O:54])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4nncs4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)c4nncs4)cc2)CCN3CC(C)C)cc1
Temperature: -10 °C
Reaction time: 4 h
Yield: 6.7 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(1,3,4-thiadiazol-2-ylthiomethyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (480 mg) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.28 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred at −10° C. for 4 hours, and to the reaction solution was added sodium thiosulfate solution and the mixture was further stirred at room temperature for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate:hexane 1:2→1:1) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(1,3,4-thiadiazol-2-ylsulfinylmethyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 119) (33 mg) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([OH:14])[C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH:22](Br)[CH3:23].Cl>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]2[O:14][CH2:23][CH2:22][O:13][C:12]=12)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(O)c(O)c(OC)c1
Reactant: CC(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(OC)c2c(c1)OCCO2
Reaction time: 24 h

Procedure:
Combine methyl 3-methoxy-4,5-dihydroxybenzoate (0.5 g, 2.5 mmol) and potassium carbonate (1.74 g, 12.65 mmol) in acetone (25 mL). Add dibromoethane (2.37 g, 12.65 mmol). Heat to reflux. After 24 hours, cool in an ice bath, acidify with a 1 M aqueous hydrochloric acid solution (35 mL), add water (25 mL), and extract three times with ethyl acetate. Combine the organic layers and extract with brine. Dry over-MgSO4, filter, and concentrate in vacuo to give methyl 3-methoxy-4,5-ethylenedioxybenzoate.