Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:16]=[C:10]2[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[CH:16]=[C:10]3[CH2:9][NH:8][CH2:13][CH2:12][N:11]3[N:14]=2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(-c2cc3n(n2)CCN(Cc2ccccc2)C3)cc1
Agent: [Pd]
Solvent: CO
Product: Fc1ccc(-c2cc3n(n2)CCNC3)cc1
Reaction time: 3 h
Yield: 74.9 %

Procedure:
To a degassed solution of Intermediate 1E (17 g, 55.3 mmol) in methanol (170 mL) was added 10% palladium on carbon (2.94 g, 2.77 mmol) and stirred under H2 atmospheric pressure for 3 h. The reaction mixture was filtered through CELITE® pad, washed with methanol (500 mL) and concentrated. The residue was triturated with diethyl ether (2×100 mL) and the resulting solid was filtered, rinsed with diethyl ether (200 mL) and dried under vacuum to afford Intermediate 1F (9 g, 75%). MS(ES): m/z=218 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 7.73-7.87 (m, 2H), 7.13-7.28 (m, 2H), 6.43 (s, 1H), 4.02 (t, J=5.57 Hz, 2H), 3.94 (s, 2H), 3.16 (t, J=5.57 Hz, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[N:5][C:4]=1[C:14]([N:16]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@@H:17]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][C@H:19]([C:30]([O:32]C)=[O:31])[CH2:18]1)=[O:15].[Cl-].[NH4+].Cl>C1COCC1.CO.O.[OH-].[Na+]>[C:26]([O:25][C:23]([N:21]1[CH2:22][C@@H:17]([N:16]([C:14]([C:4]2[N:5]=[N:6][N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:3]=2[CH2:2][OH:1])=[O:15])[CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:18][C@@H:19]([C:30]([OH:32])=[O:31])[CH2:20]1)=[O:24])([CH3:28])([CH3:29])[CH3:27]
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nnn(-c3ccccc3)c2CO)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CN(C(=O)c1nnn(-c2ccccc2)c1CO)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
1-tert-Butyl 3-methyl(3R,5S)-5-[{[5-(hydroxymethyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (2.25 g) was dissolved in THF (10 ml)-methanol (10 ml)-water (8 ml), 8M aqueous sodium hydroxide solution (1.5 ml) was added and the reaction mixture was stirred at room temperature for 3 hr. The reaction mixture was neutralized with saturated aqueous ammonium chloride solution, acidified with 1M hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (2.18 g).
Reaction SMILES: NC1N=C(C2C(Cl)=CC3COCC4C=3C=2C=CC=4)N=C(SCCC(O)=O)N=1.Cl.[NH2:29][CH2:30][C:31]#[N:32].[NH2:33][C:34]1[N:39]=[C:38]([C:40]2[C:41]([Cl:53])=[CH:42][C:43]3[CH2:44][O:45][CH2:46][C:47]4[C:52]=3[C:51]=2[CH:50]=[CH:49][CH:48]=4)[N:37]=[C:36]([S:54][CH2:55][C:56]([OH:58])=[O:57])[N:35]=1>>[NH2:33][C:34]1[N:39]=[C:38]([C:40]2[C:41]([Cl:53])=[CH:42][C:43]3[CH2:44][O:45][CH2:46][C:47]4[C:52]=3[C:51]=2[CH:50]=[CH:49][CH:48]=4)[N:37]=[C:36]([S:54][CH2:55][C:56]([NH:32][CH2:31][C:30]#[N:29])=[O:57])[N:35]=1.[NH2:33][C:34]1[N:39]=[C:38]([C:40]2[C:41]([Cl:53])=[CH:42][C:43]3[CH2:44][O:45][CH2:46][C:47]4[C:52]=3[C:51]=2[CH:50]=[CH:49][CH:48]=4)[N:37]=[C:36]([S:54][CH2:55][C:56]([OH:58])=[O:57])[N:35]=1
Reactant: N#CCN
Agent: Cl
Agent: Nc1nc(SCC(=O)O)nc(-c2c(Cl)cc3c4c(cccc24)COC3)n1
Agent: Nc1nc(SCCC(=O)O)nc(-c2c(Cl)cc3c4c(cccc24)COC3)n1
Product: N#CCNC(=O)CSc1nc(N)nc(-c2c(Cl)cc3c4c(cccc24)COC3)n1
Yield: 55 %

Procedure:
Proceeding in the same manner as in Step 2 of Example 205 and replacing N-methylamine hydrochloride and 3-[4-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-[1,3,5]triazin-2-ylsulfanyl]-propionic acid by aminoacetonitrile hydrochloride (1.91 g, 20.6 mmol) and [4-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-[1,3,5]triazin-2-ylsulfanyl]-acetic acid (2.0 g, 5.16 mmol) respectively, there was obtained 2-[4-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-[1,3,5]triazin-2-ylsulfanyl]-N-cyano methyl-acetamide (1.22 g, 55%) as a white solid from [4-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-[1,3,5]triazin-2-ylsulfanyl]-acetic acid (2.0 g).
Reaction SMILES: CS[CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[NH:5][C:4]1=[O:21].[Cl-].[NH4+]>C1COCC1.[Zn]>[Si:14]([O:13][CH2:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:3][C:4](=[O:21])[NH:5]2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CSC1C(=O)Nc2cccc(CO[Si](C)(C)C(C)(C)C)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 60 h
Yield: 113 %

Procedure:
A solution of 1.2 g (3.7 mmol) of 3-methylsulfanyl-4-(t-butyidimethylsilyloxy)methyl-1,3-dihydro-indol-2-one in THF (25 mL) was stirred with saturated ammonium chloride solution (20 mL), and activated zinc dust (5 g) was added. The mixture was stirred for 60 h at rt. The organic phase was separated, dried over MgSO4 and concentrated to give 1,16 g of impure 4-(t-butyidimethylsilyloxy)methyl-1,3dihydro-indol-2-one as an off-white solid: 1H NMR (DMSO-d6): δ 0.11 (s, 6H), 0.86 (s, 9H), 3.42 (s, 2H), 4.67 (s, 2H), 6.74 (d, J=7.7 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 7.18 (t J=7.7 Hz, 1H), 10.40 (s, 1H). A solution of 0.64 g (2.3 mmol) of 4-(t-butyldimethylsilyloxy)methyl-1,3-dihydro-indol-2-one in DMF dimethylacetal (5 mL) was heated to 100° C. for 1 h. The excesss DMF dimethylacetal was removed under high vacuum, and the resulting dark oil was chromatographed on silica gel, eluting with EtOAc, to give 0.34 g (44%) of 3-dimethylaminomethylene-4-(t-butyidimethyl-silyloxy)methyl-1,3-dihydro-indol-2one as a white solid: 1H NMR (DMSO-d6): δ −0.03 (s, 6H), 0.81 (s, 9H), 3.29 (s, 6H), 4.64 (s, 2H), 6.66 (d, J=7.3 Hz, 1H), 6.73 (d, J=7.3 Hz, 1H), 6.79 (t, J=7.3 Hz, 1H), 7.76 (s, 1H), 9.97 (s, 1H)); APCI−MS m/z 333 (M+1)+. A solution of 0.115 g (0.34 mmol) of 3-dimethylaminomethylene-4-(t-butyidimethylsilyloxy)methyl-1,3dihydro-indol-2-one in ethanol (10 mL) was treated with 0.076 g (0.34 mmol) N-methylsulfanilamide hydrochloride. The solution was refluxed for 0.5 h and cooled to rt. The resulting yellow precipitate was isolated by filtration, washed with ethanol and dried to yield 0.048 g (38%) of the title compound: 1H NMR (DMSO-d6): δ 2.37 (d, J=5.0 Hz, 3H), 4.67 (s, 2H), 5.3 (bs, 1H), 6.78 (d, J=7.5 Hz, 1H), 6.93 (d, J=7.5 Hz, 1H), 6.99 (t, J=7.5 Hz, 1H), 7.33 (q, J=5.0 Hz, 1H), 7.44 (d, J=8.6 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 8.32 (d, J=12.2 Hz, 1H), 10.67 (s, 1H), 11.26 (d, J=12.2 Hz, 1H); APCI−MS m/z 358 (M−1)−. Anal. Calcd for C17H17N3O4S: C, 56.81, H, 4.77; N, 11.69, S, 8.92. Found C, 56.89, H, 4.81; N, 11.70; S, 8.84.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[N:7][CH:8]([Cl:11])[CH2:9][Cl:10])[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2Cl)[C:3]1=[O:20].[Cl:21][C:22]1C=[CH:26][CH:25]=[CH:24][C:23]=1N1C(=NC(Cl)CCl)CN(C)C1>>[Cl:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:1]=1[N:2]1[C:6](=[N:7][CH:8]([Cl:11])[CH2:9][Cl:10])[C:5](=[O:12])[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:3]1=[O:20]
Reactant: CN1CC(=NC(Cl)CCl)N(c2ccccc2Cl)C1
Reactant: CN1C(=O)N(c2ccccc2Cl)C(=O)C1=NC(Cl)CCl
Product: O=C1C(=NC(Cl)CCl)N(c2ccccc2Cl)C(=O)N1C1CCCCC1

Procedure:
Similarly the reverse 1-position-3-position isomers of each of the above prepared compounds are prepared by using the corresponding position isomer of formula A as the starting material. For example, by using 1-methyl-3-(2-chlorophenyl)-5-(1,2-dichloroethyl)imino-1,3-diazolidine-2,4-dione in place of 1-(2-chlorophenyl-3-methyl-5-(1,2-dichloroethyl)imino-1,3-diazolidine the following compounds (as well as the other 1-3 positions isomers of each of the above products are prepared:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[CH2:16][CH:15]([C:27]([OH:29])=O)[CH2:14]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].O[N:31]=[C:32]([CH:34]1[CH2:36][CH2:35]1)[NH2:33]>>[CH:34]1([C:32]2[N:33]=[C:27]([CH:15]3[CH2:14][CH:13]([C:4]4[CH:5]=[CH:6][C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[C:2]([CH3:1])[CH:3]=4)[CH2:18][N:17]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])[CH2:16]3)[O:29][N:31]=2)[CH2:36][CH2:35]1
Reactant: Cc1cc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)ccc1OC(F)(F)F
Reactant: NC(=NO)C1CC1
Product: Cc1cc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCOCC3)C2)ccc1OC(F)(F)F

Procedure:
100 mg (0.24 mmol) of the compound from Example 167A and 36 mg (0.36 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Yield: 72 mg (62% of theory).
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)=[C:2]=[O:3].[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]1.CCN(CC)CC.N>C1COCC1.CO>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([NH:1][C:2](=[O:3])[NH:12][C@@H:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]2)=[CH:5][CH:6]=1)#[N:9]
Reactant: COC(=O)[C@H]1C[C@H](N)CCN1C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(N=C=O)cc1
Agent: N
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@H](NC(=O)Nc2ccc(C#N)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.6 %

Procedure:
4-isocyanatobenzonitrile (1.17 g, 8.13 mmol) was added to a solution of (2R,4R)-1-tert-butyl 2-methyl 4-aminopiperidine-1,2-dicarboxylate (2.0 g, 7.7 mmol) and NEt3 (1.3 mL, 9.3 mmol) in THF (30 mL), and the resulting solution was stirred at room temperature for 6 hours. 1M ammonia in methanol (5 mL) was then added to the reaction mixture to quench excess isocyanine. Water (100 mL) and ethyl acetate (200 mL) were added to the mixture. The organic layer was separated and dried over MgSO4 and concentrated to give a solid. Purification by Companion (ReadySep, 80 g, silica gel packed) using ethyl acetate/heptane from 40-70% as eluent provided the title compound as a white solid 2.9 g (90%). LC-MS: 403.2, 401.3 (t=2.6 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:12]2[S:13][C:14](Br)=[CH:15][CH:16]=2)[N:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:7]=1)=[O:5])[CH3:2].[CH3:26][C:27]([CH3:32])([CH3:31])[CH2:28][C:29]#C.C(N)CO.O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(OCC)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:12]2[S:13][C:14]([C:29]#[C:28][C:27]([CH3:32])([CH3:31])[CH3:26])=[CH:15][CH:16]=2)[N:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:7]=1)=[O:5])[CH3:2]
Reactant: C#CCC(C)(C)C
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Br)s2)c1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: C1CCOC1
Solvent: NCCO
Product: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(C#CC(C)(C)C)s2)c1C
Temperature: 60 °C
Yield: 79.9 %

Procedure:
To a suspension of 5-(5-bromo-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (500 mg, 1.09 mmol), PdCl2(PPh3)2 (23 mg, 0.03 mmol), and CuI (4 mg, 0.01 mmol) in THF (10 mL) was added 4,4-dimethylpent-1-yne (176 mg, 1.30 mmol) and 0.5 M aqueous solution of 2-ethanolamine (3 mL). The resulting mixture was heated at 60° C. for 6 h. After cooled to room temperature, the reaction mixture was poured into water and diethyl ether (H2O/ether=1:1 (v/v), 20 mL). The aqueous layer was extracted with diethyl ether and the combined organic layers were concentrated to give a crude oil, which was purified by flash column chromatography with n-hexane/ethyl acetate (5:1) to afford the desired product (402 mg, 80%) as a light solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][CH2:13][S:14](Cl)(=[O:16])=[O:15].Cl>N1C=CC=CC=1>[Cl:12][CH2:13][S:14]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)(=[O:16])=[O:15]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)CCl
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(NS(=O)(=O)CCl)ccc1F
Reaction time: 4 h

Procedure:
To a solution of 4-fluoro-3-nitroaniline (23.4 g, 0.15 mol) in anhydrous pyridine (120 mL) was added dropwise a solution of chloromethylsulfonyl chloride (22.35 g, 0.15 mol) at 0° C. under a nitrogen atmosphere. The mixture was then stirred at 0°-5° C. for 4 h and then the mixture was poured onto ice (1500 g) containing concentrated aqueous hydrochloric acid (300 mL). The mixture was filtered, and the residue was dissolved in methylene chloride (1200 mL). After drying (MgSO4) and concentration under reduced pressure, the crude product was dissolved in 1-chlorobutane:ether 9:1 v/v and passed through silica gel. The eluent was concentrated under reduced pressure to give the title compound of Step A.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.Cl[C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:20]=[C:19]([N:29]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N:31]=[C:30]2[S:38][CH3:39])[N:18]=1.CC(O)=O>C1COCC1.O>[CH3:39][S:38][C:30]1[N:29]([C:19]2[N:20]=[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:22]=[C:17]([NH:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[N:18]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=1
Reactant: CSc1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CSc1nc2ccccc2n1-c1nc(Nc2cccnc2)nc(N2CCOCC2)n1
Reaction time: 0.08 h
Yield: 78.5 %

Procedure:
A solution of 3-aminopyridine (2 g, 21 mmol) in 100 mL THF was treated with 10.6 mL (21 mmol) 2 M LDA in THF to give a suspension which was treated with 1.81 g (5 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(methylsulfanyl)-1H-benzimidazole at room temperature. After 5 min, the mixture was neutralized with HOAc and diluted with water to give 1.65 g (78%) of 4-[2-(methylsulfanyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(3-pyridinyl)-1,3,5-triazin-2-amine: mp (CHCl3/EtOH) 240-241° C.; 1H NMR (CDCl3) δ 8.85 (br s, 1H), 8.39 (d, J=4.0 Hz, 1H), 8.34 (d, J=7.5 Hz, 1H), 8.02 (d, J=7.3 Hz, 1H), 7.66 (dd, J=7.9, 0.5 Hz, 1H), 7.32 (dd, J=8.5, 4.9 Hz, 1H), 7.28 (dt, J=7.3, 1.1 Hz, 1H), 7.22 (t, J=7.4 Hz, 1H), 7.15 (br s, exchangeable with D2O, 1H), 4.05 (m, 2H), 3.90 (m, 2H), 3.81 (m, 4H), 2.73 (s, 3H); Anal. Calcd. for C20H20N8OS: C, 57.1; H, 4.8; N, 26.65. Found: C, 57.0; H, 4.9; N, 27.0%.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](Cl)=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH:25][C:17]([CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)=[O:18]
Reactant: COc1ccccc1CN
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Product: COc1ccccc1CNC(=O)C1CCNCC1

Procedure:
The above compound was prepared similarly to Preparation C starting from 1-benzyloxycarbonylpiperidine-4-carboxylic acid chloride and 2-methoxybenzylamine and had an m.p. of 139°-140°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:31][CH2:32][CH2:33][N:34]2[CH2:38][CH2:37][CH2:36][C:35]2=[O:39])[C:7]2[C:16]3[CH:15]=[C:14]([CH2:17][CH2:18][N:19]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20]4=[O:29])[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:30]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:52].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[NH2:52][C:9]1[C:8]2[N:30]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:31][CH2:32][CH2:33][N:34]3[CH2:38][CH2:37][CH2:36][C:35]3=[O:39])[C:7]=2[C:16]2[CH:15]=[C:14]([CH2:17][CH2:18][N:19]3[C:20](=[O:29])[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]3=[O:28])[CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2cnc3ccc(CCN4C(=O)c5ccccc5C4=O)cc3c2n1CCCN1CCCC1=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccc(CCN4C(=O)c5ccccc5C4=O)cc3c2n1CCCN1CCCC1=O
Reaction time: 18 h

Procedure:
2-(2-{2-(2-Methoxyethyl)-1-[3-(2-oxo-pyrrolidin-1-yl)propyl]-1H-imidazo[4,5-c]quinolin-8-yl}ethyl)-1H-isoindole-1,3(2H)-dione (2.1 g, 3.8 mmol) in dichloromethane (75 mL) was combined with 3-chloroperoxybenzoic acid (60% pure, 2.0 g, 7.5 mmol) and the reaction was stirred for 18 hours. Concentrated ammonium hydroxide (40 mL) was added and the mixture was vigorously stirred for an additional 10 minutes. p-Toluenesulfonyl chloride (791 mg, 4.12 mmol) was added and the mixture was stirred for an additional 1 hour. The fractions were separated and aqueous fraction was extracted with chloroform (10×35 mL). The combined organic fractions were sequentially dried (MgSO4), filtered, and concentrated to provide 2.2 g of 2-(2-{4-amino-2-(2-methoxyethyl)-1-[3-(2-oxopyrrolidin-1-yl)propyl]-1H-imidazo[4,5-c]quinolin-8-yl}ethyl)-1H-isoindole-1,3(2H)dione as an off-white foam. MS (APCI) m/z 541 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:24]=[CH:23][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:12][S:13](=[O:15])(=[O:14])[C:9]=2[CH:8]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:11]2[C:10]3[CH:23]=[CH:24][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:8][C:9]=3[S:13](=[O:15])(=[O:14])[N:12]=2)=[CH:17][CH:18]=1
Reactant: O=S1(=O)N=C(c2ccc(Cl)cc2)c2ccc(OCCCCBr)cc21
Reactant: C1CCNC1
Product: O=S1(=O)N=C(c2ccc(Cl)cc2)c2ccc(OCCCCN3CCCC3)cc21

Procedure:
According to the method in example 10, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole 1,1-dioxide and Pyrrolidine were converted to yield 3-(4-Chloro-phenyl)-6-(4-pyrrolidin-1-yl-butoxy)-benzo[d]isothiazole 1,1-dioxide, MS: 419 (MH+, 1Cl).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][N:23]5[CH2:27][C:26](=[O:28])[N:25]([CH3:29])[C:24]5=[O:30])=[CH:18][CH:17]=4)=[C:13]([CH:14]=[O:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.[BH4-].[Na+].O>CO.ClCCl>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][N:23]5[CH2:27][C:26](=[O:28])[N:25]([CH3:29])[C:24]5=[O:30])=[CH:18][CH:17]=4)=[C:13]([CH2:14][OH:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: CN1C(=O)CN(Cc2ccc(-c3ccc4c(nnn4CC4CC4)c3C=O)cc2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)CN(Cc2ccc(-c3ccc4c(nnn4CC4CC4)c3CO)cc2)C1=O
Reaction time: 1.5 h

Procedure:
To a solution of 1-(cyclopropylmethyl)-5-{4-[(3-methyl-2,4-dioxoimidazolidin-1-yl)methyl]phenyl}-1H-benzotriazole-4-carbaldehyde (Example 20, 72 mg, 0.18 mmol) in methanol (1.8 mL) was added sodium borohydride (6.8 mg, 0.18 mmol). After 1.5 hours, the mixture was treated with water, diluted with dichloromethane and washed with brine. The organic extract was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (ethyl acetate/hexane gradient), providing the titled compound: 1H NMR (400 MHz, CDCl3) 7.54 (d, 1H, J=8.8 Hz), 7.42-7.45 (m, 3H), 7.35 (d, 2H, J=8.0 Hz), 5.12 (d, 2H, J=6.4 Hz), 4.65 (s, 2H), 4.55 (d, 2H, J=7.2 Hz), 3.83 (s, 2H), 3.08 (s, 3H), 1.40-1.47 (m, 1H), 0.67-0.71 (m, 2H), 0.51-0.55 (m, 2H) ppm. LRMS m/z (M+H) 406.0 found, 406.2 required.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:15].[CH2:17]([O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH3:19]>CC#N>[CH3:16][CH:3]([CH2:2][N:24]1[CH2:25][CH2:26][CH:21]([O:20][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23]1)[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:15]
Reactant: C[C@H](CI)Cn1c(=O)ccc2ccccc21
Reactant: CCCOC1CCNCC1
Solvent: CC#N
Product: CCCOC1CCN(CC(C)Cn2c(=O)ccc3ccccc32)CC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 25.6 %

Procedure:
A 4 mL vial was charged with crude (S)-1-(3-iodo-2-methylpropyl)-1H-quinolin-2-one (0.190 g), 4-propyloxypiperidine (0.137 g, 0.96 mmol) and dry CH3CN (2.5 mL). The mixture was shaken at 50° C. for 24 h and then purified by cation-exchange CC followed by flash CC (SiO2; EtOAc/MeOH 1:4) to give the title compound (0.051 g, 17%). 1H NMR (CD3OD) δ 7.85 (d, J=9.6 Hz), 7.70-7.63 (m, 2H), 7.60 (brt, J=7.8 Hz, 1H), 7.26 (brt, 7.6 Hz), 6.63 (d, J=9.6 Hz, 1H), 4.39-4.23 (m, 2H), 3.37 (t, J=6.6 Hz), 3.28-3.18 (m, 1H), 2.77-2.69 (m, 1H), 2.64-2.58 (m, 1H), 2.35 (dd, J=8.4, 12.0 Hz), 2.51-2.21 (m, 1H), 2.18 (dd, J=4.8, 12.0 Hz), 2.13-2.04 (m, 1H), 2.00-1.92 (m, 1H), 1.84-1.75 (m, 2H), 1.58-1.32 (m, 4H), 0.95-0.85 (m, 6H); 13C NMR (CD3OD) δ 163.7, 140.2, 139.5, 130.8, 129.2, 12.5, 121.4, 120.4, 115.2, 75.3, 69.5, 63.6, 52.3, 51.5, 46.8, 31.4, 31.3, 30.0, 23.1, 16.1, 9.8.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:14])([F:13])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[CH3:15][C:16]([CH3:18])=[O:17].Cl>CCCCCCC.C(O)(C)C>[F:3][C:4]([F:14])([F:13])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:15][C:16](=[O:17])[CH:18]=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([C:4]([F:3])([F:13])[F:14])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCCCCCC
Product: O=C(C=Cc1ccc(C(F)(F)F)cc1)C=Cc1ccc(C(F)(F)F)cc1
Temperature: 20 °C
Yield: 74.6 %

Procedure:
A solution of sodium hydroxide (15 g of 10% aqueous) is added with stirring, and under a nitrogen atmosphere to a solution of 4-trifluoromethylbenzaldehyde (6.42 g; 0.369 mol) in heptane (70 ml). Next, a solution of acetone (10.7 g; 0.184 mol) in heptane (30 ml) is added to the above two phase system at a temperature range of from 25° C. to 30° C. over a period of two hours. The reaction mixture is then stirred for two hours at 25° C. to 30° C. Concentrated hydrochloric acid (9.4 ml) and isopropyl alcohol (48 ml) are then added, the mixture heated at reflux for 1.5 hours, and is then cooled to 20° C. The precipitated solid is filtered, washed with heptane (40 ml), and water and dried under vacuum to afford 50.8 g of title product, 98.8% pure, mp 154° C. to 156° C. (yield: 73.7%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].C(N(CC)CC)C.[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>ClCCl>[CH:21]1([NH:27][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.2 %

Procedure:
To a solution of 2-nitrobenzene-1-sulfonyl chloride (22.1 g, 100 mol) in dichloromethane (500 mL) at 0° C. was added triethylamine (14 g, 138.6 mol) and cyclohexanamine (11.9 g, 120.2 mmol) in several portions over 10-15 minutes. The reaction mixture was stirred at room temperature for 4 hours, concentrated and purified by silica gel chromatography to afford the product N-cyclohexyl-2-nitrobenzenesulfonamide (25.7 g, yield 90.5%). 1H NMR (400 MHz, CDCl3) δ ppm 8.16-8.19 (m, 1H), 7.85-7.87 (m, 1H), 7.72-7.78 (m, 2H), 5.24-5.26 (d, 1H, J=7.6 Hz), 3.34-3.36 (m, 1H), 1.77-1.81 (m, 2H), 1.63-1.69 (m, 2H), 1.52-1.56 (m, 1H), 1.17-1.30 (m, 5H).