Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=O.O=[C:21]([CH2:29][CH3:30])[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl[Si](C)(C)C>CN(C=O)C>[CH2:29]([C:21]1[N:1]=[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=3[C:3]2=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:22]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:30]
Reactant: Cc1ccc(C(=O)c2c(N)sc3c2CCCC3)cc1
Reactant: CCOC(=O)CCC(=O)CC
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(CC)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Temperature: 100 °C
Yield: 64.5 %

Procedure:
To a solution of (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(p-tolyl)methanone (0.542 g; 2 mmol) and ethyl 4-oxohexanoate (0.348 g; 2.2 mmol) in dry DMF (8 mL) under a nitrogen atmosphere was added chlorotrimethylsilane (1.02 mL; 8 mmol) dropwise. The mixture was stirred in a sealed tube and heated at 100° C. for 24 h. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was successively washed with a saturated solution of sodium hydrogen carbonate, water, brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using a gradient of ethyl acetate (1-30%) in heptane to afford 0.508 g (64%) of the title compound as a yellow oil.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH:10]([O:39][Si](C(C)(C)C)(C)C)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:24]=[C:23]([N:25]([CH3:32])[CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:22]=[C:21]([C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[N:20]=2)[CH:14]=1)C)(C)(C)C.Cl>CO>[CH3:6][NH:7][CH2:9][CH:10]([OH:39])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:24]=[C:23]([N:25]([CH3:32])[CH:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:22]=[C:21]([C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[N:20]=2)[CH:14]=1
Reactant: CN(CC(COc1cccc(-c2nc(-c3ccncc3)cc(N(C)C3CCOCC3)n2)c1)O[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CNCC(O)COc1cccc(-c2nc(-c3ccncc3)cc(N(C)C3CCOCC3)n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.5 %

Procedure:
A solution of [2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-[methyl-(tetrahydro-pyran-4-yl)-amino]-6-pyridin-4-yl-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic acid tert-butyl ester (135 mg, 0.20 mmol) was treated with a 2.5 N HCl solution in methanol (10 mL) and the mixture was stirred at room temperature for 4 h., concentrated under vacuum and the residue was purified by preparative HPLC to give 1-methylamino-3-(3-{4-[methyl-(tetrahydro-pyran-4-yl)-amino]-6-pyridin-4-yl-pyrimidin-2-yl}-phenoxy)-propan-2-ol as white solid (49 mg, 56% yield). 1HNMR (500 MHz, CD3OD) δ ppm: 8.72-8.70 (m, 2H), 8.23 (brs, 2H), 8.14-8.10 (m, 2H), 7.43 (t, J=8.5 Hz, 1H), 7.16-7.10 (m, 2H), 4.24-4.18 (m, 1H), 4.15-4.08 (m, 4H), 3.72-3.65 (m, 2H), 3.14 (s, 3H), 3.00-2.85 (m, 2H), 2.56 (s, 3H), 2.09-1.98 (m, 2H), 1.79-1.72 (m, 2H). ESI-LCMS: 450.5 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:14]=O>>[O:5]=[C:4]1[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:2]=2[N:1]=[CH:14][O:6]1
Reactant: Nc1c(C(=O)O)cccc1C(=O)O
Reactant: C=O
Product: O=C(O)c1cccc2c(=O)ocnc12
Temperature: 140 °C
Yield: 89 %

Procedure:
2-Aminoisophthalic acid moiety (50.0 g; 276.0 mmol) and formaldehyde (250.0 ml; 5.00 V) were combined and heated to 140° C. for 4 h. The reaction mixture was cooled to room temperature and distilled under high vacuum on the rotary evaporator. The remaining formaldehyde was removed by azeotropic distillation with toluene. The residue was slurried with ethyl ether, filtered, and the solid was dried under vacuum to provide the desired intermediate (50.3 g, 89% yield).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl.[CH3:36][C@H]1CCC[C@@H](C)N1CCN1CCC(N)CC1>>[CH3:36][CH:7]1[CH2:6][CH2:5][CH2:4][CH:3]([CH3:2])[N:1]1[CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[C:25]([O:28][CH2:29][CH:30]([CH3:31])[CH3:32])[CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:14][CH2:15]1
Reactant: C[C@@H]1CCC[C@H](C)N1CCN1CCC(N)CC1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12
Agent: Cl
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4C(C)CCCC4C)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8) and amine 27.
Reaction SMILES: OC[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:25](=[C:26]([CH3:28])[CH:27]=3)[N:24]=[CH:23][C:22]([C:29]([NH2:31])=[O:30])=[C:21]4[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CC1(C)C(C)(C)OB(C2C=C[C:52]([CH:55](CC)[CH2:56][CH2:57][OH:58])=[CH:51]C=2)O1>>[OH:58][CH2:57][CH2:56][CH2:55][CH2:52][CH2:51][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:25](=[C:26]([CH3:28])[CH:27]=3)[N:24]=[CH:23][C:22]([C:29]([NH2:31])=[O:30])=[C:21]4[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4ccc(-c5ccc(CO)cc5)cc4)cc23)c1
Reactant: CCC(CCO)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4ccc(-c5ccc(CCCCCO)cc5)cc4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 65, using 3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]pentan-1-ol in place of 4-(hydroxymethyl)phenylboronic acid. ES/MS calcd. for C35H36N3O5S+ 610.2. Found m/z=610.3 (M+H)+.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=3)[C:22]([Cl:34])=[CH:21][C:20]=2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]O)[O:7][C@@H:6]1[CH2:41][O:42]C(=O)C)(=O)C.CCN(S(F)(F)[F:52])CC.O[Li].O>C(Cl)Cl.C1COCC1.CO.O>[Cl:34][C:22]1[C:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=2)=[CH:24][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:41][OH:42])[O:7]2)=[C:20]([CH2:35][CH2:36][O:37][CH2:38][CH2:39][F:52])[CH:21]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c(CCOCCO)cc2Cl)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(CCOCCF)cc2Cl)cc1
Reaction time: 2.5 h
Yield: 26.8 %

Procedure:
To a cooled (−78° C.) solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-5-(4-ethylbenzyl)-2-(2-(2-hydroxyethoxy)ethyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (28.7 mg, 0.044 mmol) in CH2Cl2 (1 mL) was added DAST (0.04 mL, 0.3 mmol) dropwise. After being stirred for 2.5 h at the same temperature, the reaction was quenched by addition of saturated Na2CO3. The mixture was extracted 3× with CH2Cl2, and the combined organic layers were washed 1× with brine and dried over Na2SO4. Concentration gave the crude product, which was used for the next step without further purification. To a solution of the crude product in THF:MeOH:H2O (2:3:1, 0.8 mL), was added LiOH—H2O (3.7 mg, 0.088 mmol). After being stirred overnight at room temperature, the reaction mixture was concentrated. The residue was dissolved in EtOAc, washed 1× with brine, 1× with brine containing 1% NaHSO4 and 1× with brine prior to drying over Na2SO4. Concentration gave the crude product, which was purified by preparative HPLC to yield 5.7 mg of title compound. 1H-NMR (CD3OD, 300 MHz) δ 7.38 (s, 1H), 7.26 (s, 1H), 7.08 (s, 4H), 4.59-4.56 (m, 1H), 4.46-4.40 (m, 2H), 4.05 (d, J=15.1 Hz, 1H), 3.99 (d, J=15.1 Hz, 1H), 3.84 (d, J=12.0 Hz, 1H), 3.75-3.61 (m, 5H), 3.48-3.36 (m, 4H), 3.13-3.03 (m, 1H), 2.96-2.87 (m, 1H), 2.57 (q, J=7.6 Hz, 2H), 1.18 (t, J=7.6 Hz, 3H); MS ESI (m/z) 483 (M+1)+, calc. 482.
Reaction SMILES: C[O-].[Na+].[N+:4](C)([O-:6])=[O:5].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][S:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:18])=[CH:11][CH:10]=1>CS(C)=O>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([N+:4]([O-:6])=[O:5])[CH2:16][S:17]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:18])=[O:19])=[CH:13][CH:14]=1
Reactant: O=S(=O)(C=Cc1ccc(F)cc1)Oc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])C(CS(=O)(=O)Oc1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
56.3 g of sodium methanolate were taken up in 1 l of DMSO and, at RT, 56.3 ml of nitromethane were added dropwise. The internal temperature rose to 40° C. during this. Then, at a temperature between 26° C. and 30° C., a solution of 145.0 g of phenyl 2-(4-fluorophenyl)ethenesulfonate in 1 l of DMSO was added dropwise. Stirring at RT for 1 hour was followed by leaving to stand at RT for 16 hours and then stirring at RT for a further 6 hours and 30 minutes. The reaction mixture was then poured into 8 kg of ice and extracted 5 times with 2 l of EA each time. After drying over Na2SO4, the solvent was removed in vacuo. Chromatography on silica gel with EA/HEP 1:5 afforded 77.35 g of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH2:30][CH3:31])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25]CC)=[O:24])[C:3]=1[O:32][CH2:33][CH3:34].[OH-].[Na+]>>[Cl:1][C:2]1[C:11]2[C:10]([CH3:12])([CH3:13])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:15])[CH3:16])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH2:30][CH3:31])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([OH:25])=[O:24])[C:3]=1[O:32][CH2:33][CH3:34]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(c(Cl)c1OCC)C(C)(C)CC=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Product: CCOc1c(/C(CC)=C(F)\C=C\C(C)=C\C(=O)O)cc2c(c1Cl)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure J-1, ethyl (2E,4E,6E)-7-(4-chloro-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)-6-fluoro-3-methyl-nona-2,4,6-trienoate (Compound A-167, 30 mg, 0.06 mmol) was hydrolyzed with 1 N NaOH to produce the title compound as a solid after recrystallization from acetonitrile.
Reaction SMILES: [CH3:1][N:2]([CH:12]1[CH:17]([CH3:18])[CH2:16][CH2:15][NH:14][CH2:13]1)[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl.N1C=CC=CC=1>[CH3:18][CH:17]1[CH2:16][CH2:15][N:14]([C:19](=[O:21])[CH3:20])[CH2:13][CH:12]1[N:2]([CH3:1])[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CC(=O)Cl
Reactant: CC1CCNCC1N(C)c1ncnc2[nH]ccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCC(C)C(N(C)c2ncnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0 %

Procedure:
To a stirred solution of the product from Method C (0.03 grams, 0.114 mmol) dissolved in 5 mL of 10:1 dichloromethane/pyridine was added (0.018 grams, 0.228 mmol) of acetylchloride and the resulting mixture stirred at room temperature for 18 hours. The reaction mixture was then partitioned between dichloromethane and saturated sodium bicarbonate (NaHCO3). The organic layer was washed again with saturated NaHCO3, dried-over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by preparative thin layer chromatography (PTLC) (silica; 4% methanol in dichloromethane) affording 0.005 mg (15%) of the title compound as a colorless oil. LRMS: 288.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[N+:15]([C:11]1[C:2]([Cl:1])=[C:3]2[C:8](=[CH:9][C:10]=1[Cl:12])[NH:7][C:6](=[O:13])[C:5](=[O:14])[NH:4]2)([O-:17])=[O:16]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(Cl)cc(Cl)c2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])c(Cl)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
The method of Cheeseman, supra. was adapted. 5,7-Dichloro-1,4-dihydroquinoxaline-2,3-dione (239 mg, 1.03 mMol) was dissolved in concentrated H2SO4 (3 mL) at 0° C. for 30 min, and KNO3 (125.3 mg, 1.24 mMol, Baker) was added to this solution. The mixture was stirred at 0° C. for 3 h and then was stirred at room temperature for 30 h. It was then poured into ice water (15 g). A precipitate came out and was collected by filtration, was dissolved in 1N KOH (10 mL) and the red precipitate was removed by filtration. The solution then was acidified to pH=2 with 4N HCl to give a cream precipitate, which was collected by filtration, then was dried in the air at 50° C. for 4 h to afford the pure 6-nitro-5,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (231 mg, 80%), as yellow microcrystals. mp: 320°-25° C. (dec. from 290° C.). IR (KBr, cm-1): 3467, 3140, 3055, 2946, 1717, 1693, 1541. NMR (1H, DMSO-d6): δ7.221 (s, 1H), 11.932 (s, 1H), 12.312 (s, 1H). HRMS: calcd. for C8H3N3O4Cl2 (M+) m/z: 274.9499, found: 274.9509.
Reaction SMILES: N1C=CC=C1[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[C:14]3[CH:21]=[C:20]([C:22]4[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH:27]=4)[NH:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:9]=[CH:10][CH:11]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[N:45][NH:46][CH:47]=2)O1>>[NH:45]1[CH:44]=[C:43]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[C:14]4[CH:21]=[C:20]([C:22]5[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:26][CH:27]=5)[NH:19][C:15]=4[N:16]=[CH:17][N:18]=3)[CH:9]=[CH:10][CH:11]=2)[CH:47]=[N:46]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5ccc[nH]5)c4)ncnc3[nH]2)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5cn[nH]c5)c4)ncnc3[nH]2)CC1

Procedure:
The title compound was prepared following the procedure for tert-butyl 4-{4-[3-(1H-pyrrol-2-yl)phenylamino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylate, but using 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole. 1H-NMR (CD3OD, 400 MHz): δ=1.50 (s, 9H), 2.57 (m, 2H), 3.67 (m, 2H), 4.14 (m, 2H), 6.29 (s, br, 1H), 6.66 (s, 1H), 7.33-7.39 (m, 2H), 7.58 (dt, J=2.0, 7.2 Hz, 1H), 7.92 (d, J=1.2 Hz, 1H), 7.93-8.00 (m, 2H), 8.23 (s, 1H). MS (ES+): m/z 458.03 [MH+]. HPLC: tR=2.70 min (ZQ2000, polar—5 min).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[CH:11]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[NH2:23][C:14]1[C:13]2[N:12]=[CH:11][N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:25]([CH3:24])(=[O:27])=[O:26])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCCCCCCCn1cnc2c(N)nc3ccccc3c21
Product: CS(=O)(=O)NCCCCCCCCn1cnc2c(N)nc3ccccc3c21

Procedure:
Using the general method of Example 242, 1-(8-aminooctyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.85 mmol) was reacted with methanesulfonyl chloride (310 μL, 3.85 nmmol) to provide 0.43 g of N-{8-[4-amino-1H-imidazo[4,5-c]quinolin-1-yl]octyl}methanesulfonamide as an off white powder, m.p. 153-155° C. Analysis: Calculated for C19H27N5O2S: %C, 58.59; %H, 6.99; %N, 17.98; %S, 8.23; Found: %C, 58.40; %H, 6.99; %N, 17.71; %S, 8.14.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:6][C:7]=1[NH:8]CC1C=CC(OC)=CC=1OC)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:7]1[S:6][C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[C:3]=1[C:1]#[N:2]
Reactant: CCOC(=O)c1sc(NCc2ccc(OC)cc2OC)c(C#N)c1-c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 89.5 %

Procedure:
Ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-[(2,4-dimethoxybenzyl)amino]thiophene-2-carboxylate (4.70 g, 0.00956 mol) was dissolved in dichloromethane (100 mL). Trifluoroacetic acid (25 mL) was added and the solution was stirred at room temperature for ten minutes. The reaction was concentrated in vacuo, diluted with ethyl acetate and filtered. The filtrate was washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (2.92 g, 90%) as a yellow solid. LCMS: (FA) ES+, 341. 1H NMR (400 MHz, d6-DMSO) δ: 8.17 (s, 2H) 7.75 (d, 1H, J=2.00 Hz), 7.52-7.48 (m, 1H), 7.39 (d, 1H, J=8.28 Hz), 4.05-3.92 (m, 2H), 1.02-0.96 (m, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:33]([C:34](=[O:45])[NH:35][C:36]3[CH:44]=[C:43]4[C:39]([CH:40]=[N:41][NH:42]4)=[CH:38][CH:37]=3)=[CH:32][C:17]3[N:18]=[C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:30])[F:29])[NH:20][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>CO.O1CCOCC1.CCOCC>[NH:42]1[C:43]2[C:39](=[CH:38][CH:37]=[C:36]([NH:35][C:34]([C:33]3[C:14]([N:11]4[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]4)=[CH:15][C:16]4[NH:20][C:19]([NH:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:28]([F:30])([F:31])[F:29])=[N:18][C:17]=4[CH:32]=3)=[O:45])[CH:44]=2)[CH:40]=[N:41]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc3[nH]c(Nc4ccccc4C(F)(F)F)nc3cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CO
Product: NC1CCN(c2cc3[nH]c(Nc4ccccc4C(F)(F)F)nc3cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of {1-[6-(1H-Indazol-6-ylcarbamoyl)-2-(2-trifluoromethyl-phenylamino)-3H-benzoimidazol-5-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (0.25 mmol; see Example 155) in methanol (1 mL) was 4M HCl in dioxane (0.5 mL) added. The resulting mixture was stirred at room temperature for 5-6 h. The volatiles were removed in vacuo, and the residue obtained was suspended in ether. The solid obtained was collected by filtration, washed with ether and dried in vacuo to afford 6-(4-Amino-piperidin-1-yl)-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide as a hydrochloride salt. MS: m/z 535 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])[CH2:36][CH2:35]2)=[S:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1nc2ccccc2nc1NC(=S)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(C(=S)Nc2nc3ccccc3nc2OC)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate (215 mg, 0.69 mmol) and 1-(2-methoxyphenyl)piperazine (154 mg, 0.69 mmol) were dissolved in anhydrous tetrahydrofuran (25 ml) and thereto DBU (105 mg, 0.69 mmol) was added. The mixture was stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][C@@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]1[CH:23]=[C:24]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1>CN(C=O)C.O.C1(P([Pd-4](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)C=CC=CC=1>[F:21][C:22]1[CH:23]=[C:24]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:25]=[CH:26][C:27]=1[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH2:12][C@@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: OC[C@@H]1CC(c2ccc(Br)cn2)=NO1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NO[C@H](CO)C4)nc3)c(F)c2)C(=O)O1
Temperature: 75 °C
Yield: 48.7 %

Procedure:
[(5S)-3-(5-Bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (Intermediate 11, 0.5 g, 1.95 mmol), potassium carbonate (0.622 g, 4.5 mmol), N-({(5S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (Intermediate 13, 0.736 g, 1.95 mmol) and tetrakis(triphenylphosphino)palladium(0) (0.225 g, 0.195 mmol) were combined and suspended in DMF (7 ml) and water (1 ml). The mixture was heated at 75° C. for 2 hours, then was poured into cold water (30 ml). The solids formed were collected, rinsed with water and washed with dichloromethane, dried under vaccuum and collected to give the title compound (0.407 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1>>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=[C:2]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=2)[N:7]=1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(CO)cc1
Product: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc(CO)cc2)n1
Yield: 62 %

Procedure:
The reaction of 2,4-dichloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine and 4-aminobenzyl alcohol using the method described in Example 37 provided the title compound (50 mg, 62% yield). 1H NMR (DMSO-d6) 9.52 (br s, 1H), 7.77 (s, 1H), 7.70 (s, 2H), 7.42 (d, 1H), 7.33 (d, 1H), 7.24 (m, 4H), 5.07 (m, 1H), 4.45 (d, J=5.7 Hz, 2H), 2.52 (s, 3H).