Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.[Mg]>>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([C:7]2([OH:10])[CH2:6][CH2:5][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:9][CH2:8]2)=[CH:14][CH:15]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Mg]
Product: OC1(c2ccc(C(F)(F)F)cc2)CCC2(CC1)OCCO2
Yield: 94.5 %

Procedure:
This compound was prepared from 1,4-cyclohexanedione monoethylene ketal (10.9 g, 70 mmole) and the Grignard reagent prepared from 4-bromobenzotrifluoride (25.0 g, 110 mmole) and magnesium (2.7 g, 110 mmole) in a manner similar to example 3. The crude product was crystallized from petroleum ether to give the product (20 g, 94.8% ).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.N1C=CC=CC=1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([Cl:28])(=[O:27])=[O:26])[CH:20]=1.Cl>ClC(Cl)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:29]([C:19]2[CH:20]=[C:21]([S:25]([Cl:28])(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=2)(=[O:31])=[O:30])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(F)cc1C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: O=S(=O)(Cl)c1cccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
8.78 g (30 mmol) of 4-fluoro-2-(trifluoromethyl)-aniline is dissolved in 88 ml of dichloroethane with exclusion of moisture, 5.55 g (70 mmol) of pyridine is added and the solution is cooled to 0° C. With this temperature being maintained, a solution of 9.9 g (36 mmol) of 1,3-benzenedisulfonic acid dichloride in 50 ml of dichloroethane is instilled, it is stirred for 30 more minutes at 0° C. and for 5 hours more at room temperature. The suspension is shaken out three times with 2N hydrochloric acid and twice with water, the organic phase is dried on sodium sulfate, filtered, concentrated by evaporation and the residue is chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane 1:1. The fractions of the corresponding polarity, concentrated by evaporation, yield 9.7 g (23.22 mmol)=77.4% of the theoretical yield is obtained of a partially crystalline product.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)C=C(c2ccccn2)c2ccccc2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(c2ccccn2)c2ccccc2O1
Yield: 72.3 %

Procedure:
6.95 g of 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 100 ml of ethanol and shaken at room temperature with 10% palladium-on-charcoal under a hydrogen atmosphere. After the required volume of hydrogen had been taken up the catalyst was filtered off, the filtrate was evaporated and the residue was recrystallized from n-hexane to give 5.07 g of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran of melting point 99-101° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[C:38]([F:39])=[CH:37][C:36]([F:40])=[CH:35][C:34]=1B(O)O>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:34]3[CH:35]=[C:36]([F:40])[CH:37]=[C:38]([F:39])[C:33]=3[F:32])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: OB(O)c1cc(F)cc(F)c1F
Product: Cn1ncc(NC(=O)c2csc(-c3cc(F)cc(F)c3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3,5-trifluorophenyl)boronic acid gave 236. 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.63 (s, 1H), 8.14-8.04 (m, 1H), 7.83-7.71 (m, 2H), 4.85 (dd, J=10.7, 3.5 Hz, 1H), 4.71-4.46 (m, 1H), 4.36-4.22 (m, 1H), 4.20-3.94 (m, 1H), 3.81 (s, 3H), 3.45-3.31 (m, 1H), 2.16-2.07 (m, 1H), 1.98-1.76 (m, 3H). LCMS (ES+) m/z 470 (M+1).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:16](OC)(=[O:27])[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.C[O-].[Na+].Cl>O.CN(C)C=O>[CH3:24][O:23][C:21]([C:20]1[CH:25]=[CH:26][C:17]([C:16](=[O:27])[CH2:14][C:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:11]=2)=[O:15])=[CH:18][CH:19]=1)=[O:22]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: CCCCCOc1ccc(C(C)=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.6 %

Procedure:
Dimethylformamide (600 ml), p-pentyloxyacetophenone (60.0 g) and dimethyl terephthalate (73.5 g) were charged in 1-liter three-necked flask and stirred. To this mixture was added 28% methanolic solution (84.2 g) of sodium methoxide and, after that, a reaction was carried out at the inner temperature of 35 to 40° C. for 48 hours. After completion of the reaction, the reaction solution was added to a mixed solution of water (3,000 ml) and 1N hydrochloric acid (600 ml) to separate the crystals. The mixture was stirred at room temperature for 1 hour, and then the separated crystals were filtered. The wet crystals and methanol (1,000 ml) were charged in a 2-liter three-necked flask, heated to reflux for 2 hours and cooled down to room temperature, and the crystals were filtered. The crystals were washed with methanol (200 ml). The crystals were dried overnight in vacuo to give 1-(4-methoxycarbonyl-phenyl)-3-(4-pentyloxyphenyl)-propane-1,3-dione (66.0 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=1[CH2:26][CH2:27][C@H:28]1[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])[N:30](C(OC(C)(C)C)=O)[CH2:29]1>>[F:42][C:39]([F:40])([F:41])[CH2:38][NH:37][C:36](=[O:43])[O:35][CH2:34][C@@H:31]1[CH2:32][O:33][C@H:28]([CH2:27][CH2:26][C:25]2[C:24]([NH:23][C:10](=[O:11])[CH2:9][C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:13]3[CH:14]=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=3)=[CH:54][CH:53]=[CH:52][C:51]=2[F:55])[CH2:29][NH:30]1
Reactant: O=C(O)C[C@@H](c1ccc(F)cc1)c1cncc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Product: O=C(C[C@@H](c1ccc(F)cc1)c1cncc(C(F)(F)F)c1)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 99 using the procedures given in steps 8 and 9 of Example 89. MS (ES) m/z=675 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:46])([CH3:45])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:44])([C@@:13]3([CH3:43])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][S:38](=[O:42])(=[O:41])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[C:49]([NH:52][C:53]1([C:68]([O:70][CH3:71])=[O:69])[CH2:58][CH2:57][C:56](B2OC(C)(C)C(C)(C)O2)=[CH:55][CH2:54]1)(=[O:51])[CH3:50]>>[C:49]([NH:52][C:53]1([C:68]([O:70][CH3:71])=[O:69])[CH2:58][CH2:57][C:56]([C:7]2[C:8]([CH3:46])([CH3:45])[C@H:9]3[C@:22]([CH3:25])([CH2:23][CH:24]=2)[C@@H:21]2[C@:12]([CH3:44])([C@@:13]4([CH3:43])[C@H:18]([CH2:19][CH2:20]2)[C@H:17]2[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]2([NH:32][CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][S:38](=[O:41])(=[O:42])[CH2:39][CH2:40]2)[CH2:15][CH2:14]4)[CH2:11][CH2:10]3)=[CH:55][CH2:54]1)(=[O:51])[CH3:50]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: COC(=O)C1(NC(C)=O)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(NC(C)=O)(C(=O)OC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 65.7 %

Procedure:
The title compound was prepared following the method described in step 1 for the preparation of Example 1, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and methyl 1-acetamido-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as the reactants. The product was obtained as a mixture of diastereomers in 65.7% yield. MS: m/e 766.8 (M+H)+, 2.72 min (method 3). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.82 (d, J=3.0 Hz, 1H), 5.26 (br. s., 1H), 5.21-5.12 (m, 1H), 4.70 (d, J=2.0 Hz, 1H), 4.58 (d, J=1.3 Hz, 1H), 3.78-3.68 (m, 3H), 3.14-2.90 (m, 7H), 2.75-2.42 (m, 6H), 2.40-2.19 (m, 3H), 2.13-2.05 (m, 1H), 1.98 (d, J=2.0 Hz, 3H), 1.95-1.69 (m, 6H), 1.68 (s, 3H), 1.65-1.30 (m, 7H), 1.25 (m, 11H), 1.10-1.01 (m, 6H), 0.98-0.87 (m, 6H), 0.87-0.83 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([NH:5][C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1)=[O:4].C([O-])(=O)C.[Na+].C(O)(=O)C.[Br:25]Br>C(Cl)Cl>[CH3:1][N:2]([CH3:15])[C:3]([NH:5][C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:12])([CH3:14])[CH3:13])[C:7]=1[Br:25])=[O:4]
Reactant: BrBr
Reactant: CN(C)C(=O)Nc1cc(C(C)(C)C)no1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)C(=O)Nc1onc(C(C)(C)C)c1Br
Temperature: 0 °C
Yield: 99.9 %

Procedure:
To a mixture of 1,1-dimethyl-(3-t-butyl-5-isoxazolyl)-urea (0.70 g), anhydrous sodium acetate (0.30 g) and glacial acetic acid (3.3 ml), bromine (0.53 g) is added dropwise in 10 minutes with ice cooling and stirring and the resultant mixture is stirred for 15 minutes. The reaction mixture is poured into ice water (30 ml) and shaken with methylene chloride. The organic layer is washed with saturated aqueous sodium bicarbonate solution and then water and evaporated to remove the solvent. The residue is recrystallized from benzene to give 1,1-dimethyl-3-(3-t-butyl-4-bromo-5-isoxazolyl)urea (0.96 g) as crystals melting at 175.5° to 176.5° C. (decomp.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:18][C:19]1[C:36]([CH3:37])=[CH:35][C:22]2[NH:23][C:24]([C:26]3[NH:27][N:28]=[C:29]4[C:34]=3[CH2:33][CH2:32][NH:31][CH2:30]4)=[N:25][C:21]=2[CH:20]=1.O>CN(C)C=O>[CH3:37][C:36]1[C:19]([CH3:18])=[CH:20][C:21]2[NH:25][C:24]([C:26]3[NH:27][N:28]=[C:29]4[C:34]=3[CH2:33][CH2:32][N:31]([C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=3)[CH2:30]4)=[N:23][C:22]=2[CH:35]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1cc2nc(-c3[nH]nc4c3CCNC4)[nH]c2cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2nc(-c3[nH]nc4c3CCN(c3ccc([N+](=O)[O-])cn3)C4)[nH]c2cc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.5 %

Procedure:
287 mg of 2-chloro-5-nitropyridine and 500 mg of potassium carbonate are added to a solution of 500 mg of 3-(5,6-dimethyl-1H-benzimidazol-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine hydrochloride in 5 ml of dimethylformamide. After stirring for 20 hours at ambient temperature, the reaction medium is added to 50 ml of water. The precipitate formed is recovered by filtration through sintered glass, washed with 3 times 15 ml of water and then dried under reduced pressure. 548 mg of 3-(5,6-dimethyl-1H-benzimidazol-2-yl)-6-(5-nitropyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo-[3,4-c]pyridine are thus obtained in the form of a yellow powder, the characteristics of which are as follows:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:35][C:36]3[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[C:39]([NH2:46])=[C:38]([Cl:47])[CH:37]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[C:32]([OH:34])=[O:33])[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1.[N:52]1([CH2:58][CH2:59]O)[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:35][C:36]3[CH:41]=[C:40]([C:42]([F:43])([F:45])[F:44])[C:39]([NH2:46])=[C:38]([Cl:47])[CH:37]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[C:32]([O:34][CH2:59][CH2:58][N:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)=[O:33])[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1
Reactant: OCCN1CCOCC1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@@H]3C(=O)O)CC2)cc1C(F)(F)F
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@@H]3C(=O)OCCN3CCOCC3)CC2)cc1C(F)(F)F

Procedure:
Prepared analogously to Example 9.2 from 50 mg (0.07 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((R)-2-carboxy-pyrrolidin-1-yl) -piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 10.3 mg (0.08 mmol) 2-morpholin-4-yl-ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:38][CH:39]([CH3:41])[CH3:40])=[C:34]([CH:37]=1)[C:35]#[N:36].O>CN(C=O)C>[C:35]([C:34]1[CH:37]=[C:30]([CH:31]=[CH:32][C:33]=1[O:38][CH:39]([CH3:41])[CH3:40])[CH2:29][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1)#[N:36]
Reactant: CC(C)Oc1ccc(CCl)cc1C#N
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1C#N
Temperature: 60 °C
Yield: 65.4 %

Procedure:
tert-Butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.287 g, 1.000 mmol), cesium carbonate (0.489 g, 1.500 mmol) and 5-(chloromethyl)-2-isopropoxybenzonitrile (0.315 g, 1.500 mmol) were taken up in DMF (2.0 mL) and heated to 60° C. for 16 h in a 20 mL sealed scintillation vial. The reaction was cooled down to room temperature and poured into water and extracted into ether (2×5 mL). The organic layers were combined and washed with water (3×5 mL), saturated NaCl (1×5 mL), dried over MgSO4, and filtered by vacuum filtration through a glass fiber paper. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.301 g) as a light yellow solid. LCMS m/z=461.5 [M+H]+.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:17]2[C:16]([NH2:18])=[N:15][S:14](=[O:20])(=[O:19])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C1C=C(Cl)C=C(C(OO)=[O:29])C=1>C(Cl)Cl.CC(O)=O>[CH3:1][S:2]([CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:17]2[C:16]([NH2:18])=[N:15][S:14](=[O:19])(=[O:20])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:29]
Reactant: CSCCCCOc1cccc2c1C(N)=NS(=O)(=O)N2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CS(=O)CCCCOc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 5-(4-(methylthio)butoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide (Example 244) (79 mg, 0.25 mmol) in DCM/CH3CO2H (20:1, 20 mL) was added MCPBA (1.0 equiv.) at room temperature. The reaction mixture was then stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel eluting with 15% MeOH in dichloromethane to give the title compound (74 mg, 90%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.74-1.77 (m, 2H), 1.88-1.95 (m, 2H), 2.50 (s, 3H), 2.68-2.73 (m, 1H), 2.77-2.83 (m, 1H), 4.19 (t, 2H), 6.58-6.60 (d, J=8.4 Hz, 1H), 6.73-6.75 (d, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.79 (s, 1H), 8.33 (s, 1H), 10.92 (s, 1H). MS 332 (MH+).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH3:35])[C:17]2[NH:18][C:19](=[O:34])[C:20]3[CH:30]=[C:29]([CH2:31][CH2:32][OH:33])[CH:28]=[N:27][C:21]=3[N:22]([CH2:25][CH3:26])[C:23]=2[N:24]=1.O[C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=[CH:39][CH:38]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH3:35])[C:17]2[NH:18][C:19](=[O:34])[C:20]3[CH:30]=[C:29]([CH2:31][CH2:32][O:33][C:37]4[C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[N:40]=[CH:39][CH:38]=4)[CH:28]=[N:27][C:21]=3[N:22]([CH2:25][CH3:26])[C:23]=2[N:24]=1
Reactant: CCN1c2ncc(CCO)cc2C(=O)Nc2c(C)cc(Cl)nc21
Reactant: Oc1ccnc2ccccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3ccnc4ccccc34)cc2C(=O)Nc2c(C)cc(Cl)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.8 %

Procedure:
Diethyl azodicarboxylate (DEAD) (83 μL, 0.53 mmol) was added drop-wise to a solution of 2-chloro-5,11-dihydro-11-ethyl-8-(2-hydroxyethyl)-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (125 mg, 0.38 mmol), 4-hydroxyquinoline (76.3 mg, 0.53 mmol) and Ph3P (138 mg, 0.53 mmol) in THF (2.5 mL) at room temperature. The mixture was stirred at room temperature for 3 h then was concentrated under reduced pressure. The residue was dissolved in EtOAc (60 mL) and the solution was successively washed with 1 N aqueous NaOH (3×10 mL) and brine (15 mL) then was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc:MeOH, 9:1) to give the title compound (52 mg, 30% yield) as a white solid: MS (ESI) m/z 460/462 (MH)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[N:3]=1.[C:20](B1OC(C)(C)C(C)(C)O1)([CH3:22])=[CH2:21]>>[C:20]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[N:3]=1)([CH3:22])=[CH2:21]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(Nc2cc3cc(O)ccc3c(Br)n2)n[nH]1
Product: C=C(C)c1nc(Nc2cc(C)[nH]n2)cc2cc(O)ccc12

Procedure:
Similar procedure as described in example 131 was used, starting from 1-Bromo-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol and isopropenylboronic acid pinacol ester to give 1-Isopropenyl-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol. LC-MS m/e 281(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].C(O)(=O)C.C([O-])(=O)C.[Na+].[Br:42]Br>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[C:32]([Br:42])=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: BrBr
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1cc2c(cc1Br)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg) in THF (6 ml) were added acetic acid (3 ml) and sodium acetate (100 mg) at room temperature, and bromine (0.04 ml) was added dropwise under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr., sodium acetate (100 mg) was added, and bromine (0.04 ml) was added dropwise at room temperature. The reaction mixture was further stirred at room temperature for 1 hr., and bromine (0.04 ml) was added dropwise. The mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue and crystals were collected by filtration. The crystals were further washed with ethyl acetate to give the title compound (250 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:42][C:39]2[C:40]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]1)=[CH:41][C:36]([O:35][C:34]([F:33])([F:44])[F:45])=[CH:37][CH:38]=2
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Cl)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4Cl)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 598.2 (M+H)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]12([CH2:22][CH2:23][N:24]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:25]([NH:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)=[O:26])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.[OH-].[Na+]>C(Cl)(Cl)Cl>[C:12]12([CH2:22][CH2:23][N:24]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:25](=[O:26])[NH:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][N+:34]([O-:9])=[CH:35][CH:36]=3)[CH2:13][CH:14]3[CH2:15][CH:16]([CH2:17][CH:18]([CH2:20]3)[CH2:19]1)[CH2:21]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1cc[n+]([O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
m-Chloroperbenzoic acid (2.5 g, 15 mmol) was added to a solution of 1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-1) (3.0 g, 7.3 mmol) at room temperature under a nitrogen atmosphere, and the mixture was stirred overnight. The reaction mixture was distributed with chloroform (20 ml) and a 1 N aqueous sodium hydroxide solution (60 ml). The organic layer was washed with water (10 ml) and a saturated aqueous sodium chloride solution (10 ml) successively and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 2.92 g (94.2%) of the titled compound.