Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1N=C2C(N=C(C(O)(C)C)N2)=C(N2CCOCC2)N=1.[Si]([O:28][CH2:29][CH2:30][CH2:31][N:32]1[C:40]([C:41]([OH:44])([CH3:43])[CH3:42])=[N:39][C:38]2[C:33]1=[N:34][C:35](Cl)=[N:36][C:37]=2[N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1)(C(C)(C)C)(C)C.[NH2:52][C:53]1[N:58]=[CH:57][C:56](B(O)O)=[CH:55][N:54]=1>>[NH2:52][C:53]1[N:58]=[CH:57][C:56]([C:35]2[N:34]=[C:33]3[C:38]([N:39]=[C:40]([C:41]([OH:44])([CH3:43])[CH3:42])[N:32]3[CH2:31][CH2:30][CH2:29][OH:28])=[C:37]([N:45]3[CH2:46][CH2:47][O:48][CH2:49][CH2:50]3)[N:36]=2)=[CH:55][N:54]=1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2n1CCCO[Si](C)(C)C(C)(C)C
Agent: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Product: CC(C)(O)c1nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc2n1CCCO

Procedure:
100 mg of 2-(2-chloro-6-morpholino-9H-purin-8-yl)propan-2-ol was treated with TBDMS-protected bromopropanol via General Procedure C. Crude intermediate 2-(9-(3-(tert-butyldimethylsilyloxy)propyl)-2-chloro-6-morpholino-9H-purin-8-yl)propan-2-ol was treated with 2-aminopyrimidine-5-boronic acid, pinacol ester via General Procedure A and was purified via reverse phase HPLC to give 36 mg of 105 as a white solid. MS (Q1) 415.2 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]=[N+:12]=[N-:13])[CH:5]=1.[C:15]([O:19][Si](C)(C)C)(=[O:18])[C:16]#[CH:17].CO>O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH:17]=[C:16]([C:15]([OH:19])=[O:18])[N:13]=[N:12]2)[CH:5]=1)=[O:14]
Reactant: C#CC(=O)O[Si](C)(C)C
Reactant: COC(=O)c1ccc(C)c(N=[N+]=[N-])c1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C)c(-n2cc(C(=O)O)nn2)c1
Reaction time: 2 h
Yield: 68.5 %

Procedure:
3-Azido-4-methyl-benzoic acid methyl ester (878 mg, 4.60 mmol) and trimethylsilyl propiolate (777 mg, 5.05 mmol) were heated to 80° C. in a sealed tube overnight. The tube was cooled and the contents were mixed with 20 mL of MeOH. After 2 h, the mixture was poured into rapidly stirring cold water, and the resulting precipitate was filtered and dried under air to provide 823 mg of 1-(5-methoxycarbonyl-2-methyl-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaB(OAc)3H (6.6 mmol, 1.4 g) was added to a mixture of 4-nitro-benzaldehyde Compound 4a (6.0 mmol, 0.9 g), piperidine Compound 5a (9.0 mmol, 0.9 mL) and glacial acetic acid (5 drops) in CH2Cl2 (50 mL) and the resulting suspension was stirred at r.t. overnight. The reaction mixture was made basic with a 2N NaOH solution and extracted with CH2Cl2. The organic layer was washed with brine, then separated and dried over Na2SO4. The drying agent was filtered and the solvent was removed in vacuo. The product was purified by flash column chromatography (10:1 EtOAc:MeOH) to yield 1-(4-nitro-benzyl)-piperidine Compound 5b as a yellow oil (0.89 g, 67% yield). MS m/e 221 (M+H, 100%).
Reaction SMILES: [NH2:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:11]([F:23])[CH:10]=2)[C:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:3]1.C(O)(=O)C.[CH:33](N)=[NH:34].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.O>[NH2:8][C:7]1[C:6]2=[C:5]([C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:11]([F:23])[CH:10]=3)[C:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:3][N:2]2[N:1]=[CH:33][N:34]=1
Reactant: CCOC(=O)c1cn(N)c(C#N)c1-c1ccc(NC(=O)OC(C)(C)C)c(F)c1
Reactant: N=CN
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(NC(=O)OC(C)(C)C)c(F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
A mixture of ethyl 1-amino-4-{4-[(tert-butoxycarbonyl)amino]-3-fluorophenyl}-5-cyano-1H-pyrrole-3-carboxylate (18.06 g, 46.5 mmol), formamidine acetate (48.41 g, 464.9 mmol) and finely ground potassium phosphate (19.74 g, 93.0 mmol) in ethanol (350 mL) was heated at 80° C. overnight. After 16 h, the reaction mixture was cooled to rt and diluted with 1.8 L water. The resulting precipitate was filtered thru a glass frit and washed with water. Drying in a vacuum oven provided the title compound as a gray solid (15.6 g, 80.8%) 1H-NMR (DMSO-d6) δ 9.11 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.72 (t, J=8 Hz, 1H), 7.26 (dd, J=12, 2 Hz, 1H), 7.12 (dd, J=8, 2 Hz, 1H), 4.07 (q, J=7 Hz, 2H), 1.47 (s, 9H), 1.09 (t, J=7 Hz, 3H); MS [M+H]+ 415.8=;. LCMS RT=3.05.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH2:32]([O:34][C:35](=[O:45])[C@H:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[NH2:37])[CH3:33]>CN(C=O)C.O>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:37][C@@H:36]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:35]([O:34][CH2:32][CH3:33])=[O:45])=[O:6]
Reactant: Nc1ncccc1C(=O)O
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1cccnc1N
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of aminonicotinic acid (2.74 g, 20 mmol) in anhydrous DMF (100 mL) was added EDC (4.2 g, 22 mmol), HOBt (2.97 g, 22 mmol) and triethylamine (8.2 mL, 60 mmol). L-phenylalanine ethyl ester (4.97 g, 22 mmol) was added and the reaction was stirred overnight. Water (100 mL) was added and the mixture was extracted with methylene chloride (4×100 mL), dried over MgSO4 and concentrate. The compound was purified by silica gel chromatography (gradient CH2Cl2 to 10% MeOH/CH2Cl2) to afford the title compound as a yellow oil (6.2 g, 98%): 1H NMR (300 MHz, CDCl3) δ 8.78 (d, J=7.6 Hz, 1H), 8.09 (d, J=5.0 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.31-7.18 (m, 5H), 6.96 (s, 2H), 6.60 (dd, J=7.7 Hz, 4.7 Hz, 1H), 4.63-4.56 (m, 1H), 4.10 (q, J=7.0 Hz, 2H), 3.15-3.09 (m, 2H), 1.05 (t, J=7.0 Hz, 3H); ESI MS m/z 314 [C17H19N3O3+H]+
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=2)[C:35](O)=[O:36])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:35](=[O:36])[C:34]4[CH:38]=[CH:39][N:40]=[C:32]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)[CH:33]=4)[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1ccnc(N2CCOCC2)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccnc(N5CCOCC5)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-morpholin-4-ylisonicotinic acid as starting compounds. The crude product is purified by chromatography (silica gel and DCM/methanol=95:5) to yield the title compound.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH2:28][N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[CH:25]=4)[C:10]=3[N:11](COCC[Si](C)(C)C)[N:12]=2)=[CH:4][CH:3]=1.[C-:36]#[N:37].[Na+]>CN(C=O)C>[CH3:35][N:32]1[CH2:33][CH2:34][N:29]([CH2:28][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[C:10]2[NH:11][N:12]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([C:36]#[N:37])=[N:7][CH:6]=4)[C:9]=2[CH2:27]3)[CH2:30][CH2:31]1
Reactant: CN1CCN(Cc2ccc3c(c2)Cc2c(-c4ccc(F)nc4)nn(COCC[Si](C)(C)C)c2-3)CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc3c(c2)Cc2c(-c4ccc(C#N)nc4)n[nH]c2-3)CC1
Temperature: 75 °C
Yield: 14.3 %

Procedure:
A mixture of Example 123D (70.6 mg, 0.142 mmol) and NaCN (9.7 mg, 0.199 mmol) in DMF (1.2 mL) in a capped vial was heated to 210° C. for 1200 seconds in a Smith Synthesizer (300W). The reaction was cooled using 40 psi pressurized air. The mixture was extracted with EtOAc and the organic layer was washed with 50% brine, NaHCO3, dried over MgSO4, filtered, concentrated. The crude product was treated with HCl (conc., 2 drops) and EtOH (3 mL) and the mixture was heated at 75° C. for 2.5 hours. The solvent was evaporated and the residue was purified using reversed-phase HPLC to give 7.5 mg of the desired product as TFA salt.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([NH2:19])=[C:15]([CH3:18])[CH:16]=2)[C:11]([CH3:20])=[CH:10][C:9]1([CH3:22])[CH3:21])(=[O:7])[CH3:6]>C1C=CC=CC=1>[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([NH2:19])=[C:15]([CH3:18])[CH:16]=2)[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:20])[CH2:10][C:9]1([CH3:22])[CH3:21])(=[O:7])[CH3:6]
Reactant: CC(=O)N1c2cc(C)c(N)cc2C(C)=CC1(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC(=O)N1c2cc(C)c(N)cc2C(C)(c2ccccc2)CC1(C)C
Reaction time: 3 h

Procedure:
AlCl3 (266 mg) was added to a heated (70° C.) solution of 1-acetyl-6-amino-1,2-dihydro-2,2,4,7-tetramethylquinoline (100 mg) in benzene (10 ml). After 3 h, the mixture was cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/0=>3/1 (v/v) as eluent.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[C:13]([O:14][CH3:15])=[CH:12][C:10]([NH2:11])=[C:9]([Cl:16])[CH:8]=1.C([Li])CCC.CN(C)[CH:24]=[O:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[NH2:11][C:10]1[C:9]([Cl:16])=[CH:8][C:7]([CH:24]=[O:25])=[C:13]([O:14][CH3:15])[CH:12]=1
Reactant: CN(C)C=O
Reactant: COc1cc(N)c(Cl)cc1Br
Agent: CC(C)[Mg]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N)c(Cl)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
Isopropylmagnesium chloride (2M in tetrahydrofuran, 23 ml, 46 mmol) (commercially available, for example, from Aldrich) was added over 5 minutes to a stirred solution of 4-bromo-2-chloro-5-methoxyaniline (Step A) (10 g, 42 mmol) in tetrahydrofuran (70 ml) at −10° C. The resulting solution was allowed to warm to 0° C. over 50 minutes to give a thick slurry, then cooled to −25° C. and n-butyllithium (1.6M in hexanes, 90 ml, 144 mmol) was added over 20 minutes followed by tetrahydrofuran (20 ml). The solution was warmed to −10° C. over 30 minutes and then N,N-dimethylformamide (16 ml, 207 mmol) was added over 5 minutes and the resulting thick slurry was warmed to 0° C. over 20 minutes. A solution of citric acid (22 g, 105 mmol) in water (50 ml) was added cautiously over 15 minutes keeping reaction at <10° C. The slurry was aged at 20° C. for 30 minutes then filtered under vacuum. The cake was washed with water (100 ml) and then dried under vacuum at 40° C. for 16 hours to give 4-amino-5-chloro-2-methoxybenzaldehyde (6.1 g, 80% th) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][C:12]=1[C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][N:32]=1)[C:26]([O:28]C)=[O:27])=[O:9])=[O:4].O.[OH-].[Li+]>O1CCOCC1.O>[CH3:1][N:2]([CH2:36][CH2:37][N:38]1[CH2:39][CH2:40][O:41][CH2:42][CH2:43]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[CH:13][C:12]=1[C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][N:32]=1)[C:26]([OH:28])=[O:27])=[O:9])=[O:4]
Reactant: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)O)ccn2)c1
Reaction time: 1 h
Yield: 124.2 %

Procedure:
A solution of 231 mg of methyl 2-(2-(3-(methyl(2-morpholinoethyl)carbamoyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinate in 9 mL of 2:1 dioxane/water was treated with 33 mg of lithium hydroxide hydrate. After stirring for 1 h the solvent was evaporated and the residue was partitioned between dichloromethane and 3 N hydrochloric acid. The aqueous phase was evaporated to give the product as 280 mg of a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][Cl:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCCCN1Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCC1CCCCN1Cc1ccccc1

Procedure:
To a stirred solution of compound 13 (3.6 g, 15.00 mmol) in chloroform (50 mL) was added thionyl chloride (1.34 mL) at 0° C. The reaction mixture was heated at reflux for 2 hours and then concentrated. The residue was dissolved in EtOAc and washed with saturated sodium bicarbonate solution, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by chromatography on 230-400 mesh silica gel eluting with 10% EtOAc-hexane to provide compound 14 as an oil.
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:14])([O:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S([O-])([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[CH:15](=[N:1][CH2:2][P:3](=[O:14])([O:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCCOP(=O)(CN)OCCCC
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: CCCCOP(=O)(CN=Cc1ccccc1)OCCCC

Procedure:
A mixture of dibutyl aminomethylphosphonate (69.7 g) and benzaldehyde (33.0 g) in benzene (600 ml) is stirred with magnesium sulfate (150 g) for 3 hours. The mixture is filtered and the salts washed with benzene. Concentration of the filtrate in vacuo leaves dibutyl N-benzylideneaminomethylphosphonate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:35]OC1C=CC(C)=CC=1S(Cl)(=O)=O>>[CH3:35][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:24])=[O:25])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(C(=O)O)c(Cl)c3)cc21
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)ccc2OC)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 501.26 (M+H+.), was prepared in analogy to example 1, steps 1 to 5. Step 4 was performed using 2-methoxy-5-methyl-benzenesulfonyl chloride and yielded 2-chloro-4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([N+]([O-])=O)=[CH:15][CH:14]=3)=[O:10])=[C:6]([F:23])[C:5]([F:24])=[C:4]([F:25])[C:3]=1[F:26].[N+:27](C1C=C2C(=CC=1)NC(C(O)=O)=C2)([O-:29])=[O:28]>>[F:1][C:2]1[C:7]([O:8][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[C:15]([N+:27]([O-:29])=[O:28])[CH:14]=3)=[O:10])=[C:6]([F:23])[C:5]([F:24])=[C:4]([F:25])[C:3]=1[F:26]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc2ccc([N+](=O)[O-])cc2[nH]1

Procedure:
Compound 192 was synthesized as described for Compound 105 in Example 93, except instead of 104, 191 was used. It was used without isolation.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1(=[O:14])=[O:13].[C:15](=O)([O-:17])[O-:16].C[Mg+2].Cl.C(OCC)C>CN(C)C=O>[CH3:1][N:2]1[CH:7]([C:15]([OH:17])=[O:16])[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1(=[O:13])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: CN1CC(=O)c2ccccc2S1(=O)=O
Agent: C[Mg+2]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1C(C(=O)O)C(=O)c2ccccc2S1(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To 6.34 g (0.03 mole) 3,4-dihydro-2-methyl-4-oxo-1,2-benzothiazine 1,1-dioxide, 19.5 g (0.15 mole) methylmagnesiumcarbonate in 150 ml N,N-dimethyl formamide were added. The mixture was stirred at 140°-150° C. for 2 hours. The resulting solution was poured quickly into a mixture of 200 ml conc-hydrochloric acid, 200 g ice chips and 500 ml diethyl ether. After stirring the mixture for 10 minutes, the diethylether layer was separated and the separated diethyl ether solution was evaporated in vacuo. The precipitated pale yellow crystals were filtered and recrystallized in dilute methanol solution to obtain 7.21 g of the title compound as white crystals. Yield: 94%
Reaction SMILES: [CH3:1][NH:2][C@@:3]12[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][CH2:4]2.C=O.[C:19]([BH3-])#N.[Na+]>CO>[CH3:1][N:2]([CH3:19])[C:3]12[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][CH:8]1[CH2:7][CH2:6][CH2:5][CH2:4]2
Reactant: [BH3-]C#N
Reactant: CN[C@]12CCCC[C@H]1CCc1ccccc12
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN(C)C12CCCCC1CCc1ccccc12
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of the compound obtained in Example 4 (1.0 g) in methanol (15 ml) was added aqueous formaldehyde (5 ml, 35%) and in one batch sodium cyanoborohydride (1 g). The reaction was stirred overnight then the solvent removed in vacuo. The residue was taken up in ether and washed with dilute sodium hydroxide, water and finally 2N HCl. The aqueous acid solution was layered with fresh ether and basified with sodium hydroxide solution. The ether layer was washed with water and brine then dried (NaSO4). The ether layer was reduced in volume then to was added slowly anisopropanolic solution of HCl. The white solid obtained was dried in vacuo to give the title compound (0.81 g, 76%), mp 181°-182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:12]=2)[C:7]([CH3:19])=[N:6]1.[OH-].[K+:26]>C(O)C>[Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH2:15][C:16]([O-:18])=[O:17])[CH:12]=2)[C:7]([CH3:19])=[N:6]1.[K+:26]
Reactant: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(CCC(=O)O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(CCC(=O)[O-])ccc12

Procedure:
To a solution of the compound [122] (24 mg) in ethanol (2.0 mL) was added an aqueous solution of 1N-potassium hydroxide (65 μL) at room temperature, and the solution was concentrated under reduced pressure to give the titled compound (27 mg) as a yellow solid.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].S(O[CH:22](OS(C1C=CC(C)=CC=1)(=O)=O)[C:23]([CH3:26])([CH3:25])[CH3:24])(C1C=CC(C)=CC=1)(=O)=O>CS(C)=O>[CH3:22][C:23]1([CH3:26])[CH2:25][S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[S:1][CH2:24]1
Reactant: Sc1ccccc1S
Reactant: Cc1ccc(S(=O)(=O)OC(OS(=O)(=O)c2ccc(C)cc2)C(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)CSc2ccccc2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
15 g of dimercaptobenzene were slowly added dropwise while cooling to 5.55 g of sodium hydride (50% in mineral oil) in 150 ml of dimethyl sulfoxide, whereby the internal temperature was held between 15° and 23° C. Subsequently, the reaction mixture was stirred at room temperature for 1 hour and cooled with ice/methanol. Thereafter, 50 g of 2,2-dimethylpropanediol ditosylate in solid form were added in one portion and the reaction mixture was heated to 80° C. for 3 hours. Thereafter, the reaction mixture was cooled, poured on to ice, extracted with ether, the extract was washed with water and dried. After evaporation of the solvent, there was obtained a yellow oil which was chromatographed on silica gel (petroleum ether/ethyl acetate 99:1). There were obtained 14 g of 3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepine as a colorless oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][C:23]=2[F:32])[C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[CH2:15][CH2:14]1.[I:33]I>O1CCCC1.C(OCC)(=O)C.O>[N:13]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]([I:33])[C:23]=2[F:32])[C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[CH2:15][CH2:14]1
Reactant: Fc1cnc2ccccc2c1N1CCc2cnccc21
Reactant: II
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: Fc1c(I)nc2ccccc2c1N1CCc2cnccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 670.2 %

Procedure:
Diisopropylamine (0.052 ml, 0.5 mmol) was added to a 50 ml round bottomed flask containing tetrahydrofuran 15. (5 ml) and magnetically stirred. The flask was cooled to 0° C. and butyllithium (0.146 ml, 2.5M solution in hexane, 0.5 mmol) was added drop wise. After 10 mins the contents were cooled to −78° C. and 4-(2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl)-3-fluoro-quinoline from Step A (0.100 g, 0.37 mmol) in 20 ml of tetrahydrofuran was added over 15 mins. The stirring was continued for an additional 2 hrs, after which iodine (0.086 g, 0.38 mmol) in 10 ml tetrahydrofuran was added. The reaction mixture was maintained at −78° C. for 2 hrs. Water and tetrahydrofuran (5 ml, 1:9) were added. The reaction mixture was diluted with ethyl acetate, washed with water and brine. Purification by column over silica gel gave pure title compound (0.97 g, 65%). MS (ES) 393.1 (M+H)+
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[C:17](=[O:33])[N:18]([C:29]([CH3:32])([CH3:31])[CH3:30])[S:19](=[O:28])(=[O:27])[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=O)=O)=CC=1.[OH:34][CH2:35][C:36]1[CH:37]=[C:38](O)[CH:39]=[CH:40][CH:41]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:29]([N:18]1[C:17](=[O:33])[C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:35][OH:34])[CH:41]=2)=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:19]1(=[O:27])=[O:28])([CH3:30])([CH3:32])[CH3:31]
Reactant: OCc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCCCOc2cccc(CO)c2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 0 %

Procedure:
A mixture of 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate (0.120 g, 0.244 mmol), 3-(hydroxymethyl)phenol (0.030 mg, 0.244 mmol) and K2CO3 (0.168 mg, 1.218 mmol) in MeCN (2 ml) was heated in the microwave reactor at 120° C. for 25 mins. The reaction mixture was filtered, evaporated and the residue was purified twice by silica gel column chromatography (Horizons Biotage) using 50% EtOAc in hexane and then 0-10% EtOAc in DCM as eluent to give the title compound (0.049 mg, 45%). 1H NMR (500 MHz CDCl3): δ 7.54-7.7.46 (m, 2H), 7.45-7.40 (m, 3H), 7.30-7.24 (m, 1H), 6.96 (d, 1H), 6.91 (s, 1H), 6.78 (d, 1H), 5.73 (t, 1H), 4.69 (s, 2H), 3.92 (t, 2H), 3.11-3.06 (m, 2H), 1.88-1.80 (m, 2H), 1.74 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.8, 158.8, 142.9, 135.4, 131.8, 129.9, 129.8, 128.8, 125.3, 119.8, 113.9, 112.9, 107.2, 66.0, 65.4, 61.7, 42.4, 28.9, 27.8; Mass Spectrum M+H+ 445.