Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7].[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([CH3:20])[CH:19]=1)[NH:16][N:15]=[CH:14]2.CN(C1CCCCC1)C1CCCCC1>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([CH3:20])[CH:19]=1)[N:16]([CH2:2][O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7])[N:15]=[CH:14]2
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1cc(Br)cc2cn[nH]c12
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(Br)cc2cnn(COCC[Si](C)(C)C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.95 mL (11.0 mmol) (2-chloromethoxy-ethyl)-trimethyl-silane were added to 2.11 g (10.0 mmol) 5-bromo-7-methyl-1H-indazole and 1.80 mL (12.3 mmol) N-methyldicyclohexylamine in 50 mL THF and stirred overnight at RT. The precipitate formed was filtered off and the filtrate was evaporated down. The residue was purified by flash chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[I:11][C:12]1[CH:20]=[C:16]([C:17]([OH:19])=[O:18])[C:15]([NH2:21])=[CH:14][CH:13]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:21][C:15]2[CH:14]=[CH:13][C:12]([I:11])=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Nc1ccc(I)cc1C(=O)O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)Nc1ccc(I)cc1C(=O)O
Temperature: 25 °C

Procedure:
2-(4-Chlorophenylaminocarbonylamino)-5-iodobenzoic acid was prepared by adding a solution of 4-chlorophenyl isocyanate (15.4 g) in ethyl acetate (60 ml) dropwise, at room temperature, to a stirred suspension of 5-iodoanthranilic acid (26.3 g) in ethyl acetate (150 ml). The mixture was heated at reflux for 1 hour, cooled to ambient temperature and the solid removed by filtration, to give 34 g of the substituted benzoic acid. This (34 g) was added to absolute alcohol (250 ml) saturated with hydrogen chloride gas and heated at reflux for 40 minutes. When cool the solid was filtered and washed with absolute alcohol (50 ml) to give 27.1 g of 3-(4-chlorophenyl)-6-iodoquinazoline-2,4(1H,3H)-dione, mp 324°-6° C. This product (26.9 g) was added slowly to a mixture of pyridine (25 ml) and phosphoryl chloride (250 ml). The mixture was heated at reflux for 6 hours, when a solution developed. When cool, excess phosphoryl chloride and pyridine were removed by distillation in vacuo. The residue was cautiously added to ice water (500 ml) and the solid filtered. This solid was extracted with dichloromethane (100 ml), the extract concentrated in vacuo and chromatographed on silica using dichloromethane to give 9.7 g of 2-chloro-3-(4-chlorophenyl)-6-iodoquinazolin-4(3H)-one, mp 178°-180° C. This was then treated with 1,2,4-triazole and potassium carbonate in a similar manner to Example 1 to give 3-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-6-iodoquinazolin-4(3H)-one, mp 206°-208° C. (Compound 2).
Reaction SMILES: [OH:1][CH:2]([C:7]1([CH2:23]O)[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1)[C:3]([OH:6])([CH3:5])[CH3:4].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C>ClCCl>[OH:1][CH:2]1[C:7]2([CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:11][CH2:12]2)[CH2:23][O:6][C:3]1([CH3:5])[CH3:4]
Reactant: CC(C)(O)C(O)C1(CO)CCN(C(=O)OCc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OCC2(CCN(C(=O)OCc3ccccc3)CC2)C1O
Reaction time: 2 h
Yield: 59 %

Procedure:
Benzyl 4-(1,2-dihydroxy-2-methylpropyl)-4-(hydroxymethyl)piperidine-1-carboxylate (from step (iii) above; 340 mg) was dissolved in dichloromethane and p-toluenesulfonyl chloride (190 mg) was added, followed by triethylamine (0.14 mL). This mixture was stirred for 2 h and a second aliquot of triethylamine was added and the mixture was stirred for 12 h. The mixture was concentrated in vacuo. The crude product was purified by chromatography on silica using 50-100% ethyl acetate in iso-hexane as eluant to afford the product (190 mg).
Reaction SMILES: [CH:1]12[CH:6]([C:7](OCC)=[O:8])[CH:5]1[CH2:4][N:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2]2.[Li+].[OH-].CC[N:23](C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-]>C1COCC1.CO.O.CN(C=O)C>[C:7]([CH:6]1[CH:5]2[CH:1]1[CH2:2][N:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]2)(=[O:8])[NH2:23]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)C1C2CN(C(=O)OC(C)(C)C)CC21
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2C(C1)C2C(N)=O
Reaction time: 2 h
Yield: 31 %

Procedure:
To a solution of 1 (6.65 g, 26.2 mmol) in THF (100 mL) and MeOH (40 mL) was added a solution of LiOH (4.40 g, 104 mmol) in H2O (40 mL) and stirred for 2 h. The reaction was quenched upon addition of 0.5 N HCl (150 mL) and extracted with EtOAc (2×200 ml). The combined organic extracts were dried over MgSO4 and concentrated under vacuum to afford the intermediate acid. Dissolved in DMF (90 mL), added DIPEA (18.8 mL, 104 mmol), EDC (5.84 g, 31.4 mmol), HOBt (4.24 g, 31.4 mmol) and NH4Cl (4.16 g, 78.5 mmol). The reaction was sealed and stirred for 48 h. Diluted the reaction with water (350 mL) and extracted with EtOAc (2×250 mL). The combined organic extracts were washed with water (2×300 mL), brine (300 mL), dried over MgSO4 and concentrated under vacuum to afford 2 (1.84 g, 31%) as a white solid; 1H-nmr (400 MHz, CDCl3) δ 5.75 (s, 1H), 5.45 (s, 1H), 3.68 (d, J=7.0 Hz, 1H), 3.58 (d, J=11.0 Hz, 1H), 3.43 (d, J=11.0 Hz, 2H), 2.07 (s, 2H), 1.44 (s, 9H), 1.31-1.26 (m, 1H); LC-MS (214 nM) 2.15 min (>98%), m/z 171 [M-tBu].
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:58])=[N:14][C:15]2[N:16]([N:50]=[C:51]([C:53]([O:55]CC)=[O:54])[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:58])=[N:14][C:15]2[N:16]([N:50]=[C:51]([C:53]([OH:55])=[O:54])[CH:52]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:33]([C:46]([CH3:48])([CH3:47])[CH3:49])([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH3:31])([CH3:24])[CH2:22][CH2:23]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCCCC[C@@H](C)O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC3)n2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.5 %

Procedure:
To a solution of ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (6.8 g, 8.34 mmol) in Ethanol (70 mL) was added 1N NaOH (9.18 mL, 9.18 mmol) and the resulting mixture was stirred at room temp for 5 h. Mixture was then concentrated and the residue was diluted with water (50 mL) acidified with 1N HCl and extracted with ether (200 mL), washed with brine (50 mL), dried (Na2SO4), filtered and concentrated to afford 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (6.4 g, 8.13 mmol, 97% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.73-7.68 (m, 4H), 7.47-7.35 (m, 6H), 7.13 (s, 1H), 5.85 (br.s, 1H), 4.30-4.16 (m, 2H), 3.94-3.84 (m, 1H), 3.35 (q, J=6.3 Hz, 2H), 2.65 (s, 3H), 1.92 (d, J=10.7 Hz, 2H), 1.67-1.39 (m, 12H), 1.30 (s, 3H), 1.28-1.25 (m, 3H), 1.24 (s, 9H), 1.11-1.08 (m, 3H), 1.07 (s, 9H). LCMS (M+H)=787.4.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][O:20]C1C=CC(N)=CC=1.N1C=CC=CC=1C=O>>[CH3:19][O:20][C:7]1[CH:6]=[CH:5][C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)=[CH:3][CH:2]=1
Reactant: COc1ccc(N)cc1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: O=Cc1ccccn1
Product: COc1ccc(-n2nnc(-c3ccccn3)n2)cc1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 4-methoxyaniline (41.8 mg, 0.3 mmol) and 2-pyridinecarboxaldehyde (32.1 mg, 0.3 mmol) were employed to obtain 2-[2-(4-methoxyphenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([C:57]1[CH:64]=[CH:63][C:60]([C:61]#[N:62])=[CH:59][CH:58]=1)=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][C:57]2[CH:64]=[CH:63][C:60]([C:61]#[N:62])=[CH:59][CH:58]=2)=[O:56])[CH2:51][CH2:52]1
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NC(=O)N2CCC(CCOc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cc1
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 4-isocyanatobenzonitrile as the starting materials in 40% yield. LCMS for C32H32ClN8O2 (M+H)+: m/z=595.0.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]2[CH2:6][CH2:7][CH2:8][C:2]=12.[CH2:9]=[O:10]>>[OH:10][CH2:9][C:4]1[N:3]2[CH2:6][CH2:7][CH2:8][C:2]2=[CH:1][N:5]=1
Reactant: c1ncn2c1CCC2
Reactant: C=O
Product: OCc1ncc2n1CCC2
Temperature: 160 °C
Yield: 38 %

Procedure:
A mixture of 6,7-dihydro-5H-pyrrolo[1,2-c]imidazole (7 g) and paraformaldehyde (4 g) was heated at 160° C., to which was added, 20 minutes later, paraformaldehyde (2 g), and, further 20 minutes later, paraformaldehyde (1 g), followed by heating for 45 minutes. The reaction mixture was subjected to a silica gel chromatography (4.0 cm×15 cm), eluting with methanol-methylene chloride (1:9). The object fraction was concentrated. To the concentrate were added ethanol and diethyl ether to give 6,7-dihydro-3-hydroxymethyl-5H-pyrrolo[1,2-c]imidazole (3.4 g) as colorless needles, m.p. 110°-120° C.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:30][C@H:31]1[NH:36][C@@H:35]([CH3:37])[CH2:34][N:33]([C:38]2[N:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]=2)[CH2:32]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:36]3[C@H:35]([CH3:37])[CH2:34][N:33]([C:38]4[N:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[CH2:32][C@@H:31]3[CH3:30])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: C[C@@H]1CN(c2ncc3ccccc3n2)C[C@H](C)N1
Product: C[C@@H]1CN(c2ncc3ccccc3n2)C[C@H](C)N1CCCCC1(C(=O)NCc2ccc(F)cc2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-quinazoline.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][N:5]=[C:4]([C:9]([NH:11][C@@H:12]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[C:22]([F:31])[CH:21]=2)[C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:10])[CH:3]=1.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.CCOC(C)=O>C1COCC1.CCCCCC>[F:31][C:22]1[CH:21]=[C:20]([C@@H:12]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[NH:11][C:9]([C:4]2[N:5]=[CH:6][C:7]3[O:8][C:33](=[O:35])[NH:1][C:2]=3[CH:3]=2)=[O:10])[CH:25]=[CH:24][C:23]=1[O:26][C:27]([F:28])([F:29])[F:30]
Reactant: Nc1cc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)ncc1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1cc2[nH]c(=O)oc2cn1
Temperature: -78 °C

Procedure:
To a cooled (−78° C.) stirred mixture of (S)-4-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-hydroxypicolinamide (200 mg, 0.00045 mol) in THF (5 mL) were added TEA (0.31 mL, 0.002 mol, Spectrochem, India) and triphosgene (270 mg, 0.0009 mol, Spectrochem, India) in one lot and the reaction mixture was stirred for 2 h at the same temperature, warmed to rt and stirred for 12 h. After completion of the reaction (monitored by TLC, 50% EtOAc in hexane), the reaction mixture was quenched with sat'd NaHCO3 (5 mL), extracted with EtOAc (10 mL×3). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated. The product thus obtained was purified by column chromatography, silica gel (60-120 mesh) using 50-60% EtOAc in petroleum ether as the eluent, and further purified using Prep TLC plates, mobile phase 50% EtOAc in hexanes to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.76 (d, J=7.6 Hz, 1H), 8.60 (s, 1H), 8.58 (d, J=4.8 Hz, 1H), 7.82 (t, J=8.8 Hz, 1H), 7.70 (s, 1H), 7.56-7.50 (m, 3H), 7.34 (d, J=8.4 Hz, 1H), 6.53 (d, J=6.8 Hz, 1H). MS (ESI, positive ion) m/z: 468.0 (M+H).
Reaction SMILES: C([O:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[N:14][C:15]1[C:20]([Cl:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=1[Cl:24])C1C=CC=CC=1.C(O)(=O)C.C(Cl)C1C=CC=CC=1>C(O)C.[Pt]=O>[Cl:21][C:20]1[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=[C:16]([Cl:24])[C:15]=1[N:14]=[C:10]1[NH:11][CH2:12][CH2:13][N:9]1[OH:8]
Reactant: COc1cc(Cl)c(N=C2NCCN2OCc2ccccc2)c(Cl)c1
Agent: O=[Pt]
Solvent: ClCc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(Cl)c(N=C2NCCN2O)c(Cl)c1

Procedure:
44.3 g of 1-(benzyloxy)-2-[(2,6-dichloro-4-methoxyphenyl)imino]imidazoline are dissolved in 350 ml of ethanol and 350 ml of acetic acid and treated with 13.8 ml of benzyl chloride. The mixture is hydrogenated in the presence of 1 g of platinum oxide under normal pressure. After completion of the hydrogen uptake, the catalyst is removed by filtration and the solution is evaporated. The residue is treated with water and washed with ether. The aqueous phase is made alkaline and extracted with ethyl acetate. After drying and evaporating the organic extracts and recrystallization of the residue from ethyl acetate/methanol, there is obtained 2-[(2,6-dichloro-4-methoxyphenyl)imino]-1-hydroxyimidazolidine of melting point 199°-201°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([OH:14])=O)[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27]>ClCCl>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([C:12](=[O:14])[CH2:11][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]3[CH2:18][N:17]([CH3:19])[CH2:16][CH2:15][C:6]2=3)[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNCC1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)CC1
Reaction time: 3 h
Yield: 12 %

Procedure:
A mixture of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetic acid (125 mg, 0.45 mmol) and oxalyl chloride (2 ml) in dichloromethane (6.0 ml) was stirred at 25 deg C. for 3 h. The reaction mixture was concentrated to dryness. The resulting crude was dissolved in dichloromethane (6.0 ml) and DMAP (64 mg, 052 mmol) was added followed by addition of acetyl piperazine (56 mg, 0.43 mmol). The resulting mixture was stirred at 25 deg C. for 14 h. The solvent was removed in vacuo and purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 20 mg of 1-(4-Acetyl-piperazin-1-yl)-2-(8-chloro-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethanone as trifluoroacetic acid salt.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:13][CH2:12]3)[CH:10]=[C:6]2[N:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH:3]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CN1C(=O)CCC1>CN(C=O)C>[CH:11]1([C:9]2[CH:10]=[C:6]3[N:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]4[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=4)[CH:3]=[C:2]([N:31]4[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]4)[N:7]3[N:8]=2)[CH2:13][CH2:12]1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nc(C4CC4)cc3n2)cc1
Reactant: OC1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC(O)CC3)n3nc(C4CC4)cc3n2)cc1
Temperature: 25 °C

Procedure:
In a 2 mL microwave vial was placed N-(7-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2J, 100 mg, 0.27 mmol) and 4-hydroxypiperidine (55.0 mg, 0.54 mmol). To the sealed vial was then added NMP (2 ml) and the mixture was then heated in the microwave at 120° C. for 15 minutes. After cooling to room temperature, DMF (1 ml) was added. The crude product mixture was filtered by syringe filter and purified by preparatory HPLC (20-40% ACN/water, TFA mode). Lyophilization of the collected fractions gave the titled compound product (30 mg, 26% yield) as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ=10.78 (s, 1 H), 7.98 (d, J=8.6 Hz, 2 H), 7.59 (d, J=8.6 Hz, 2 H), 7.34 (s, 1 H), 6.02 (s, 1 H), 5.18 (s, 1 H), 4.84 (d, J=4.3 Hz, 1 H), 4.12 (d, J=12.6 Hz, 2 H), 3.79 (dd, J=4.2, 8.5 Hz, 1 H), 3.41-3.36 (m, 1 H), 2.11-2.00 (m, 1 H), 1.91 (br. s., 2 H), 1.65-1.51 (m, 2 H), 1.45 (s, 6 H), 1.04-0.94 (m, 2 H), 0.88-0.75 (m, 2 H); ESI-MS: m/z 436.3 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:34]([O:36]C)=[O:35])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][C@H:23]4[CH2:27][CH2:26][CH2:25][N:24]4[CH3:28])[CH2:18][C:17]4[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[K+]>O1CCOCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:34]([OH:36])=[O:35])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][C@H:23]4[CH2:27][CH2:26][CH2:25][N:24]4[CH3:28])[CH2:18][C:17]4[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C[C@H]1CCCN1C)Cc1cc(F)ccc1-3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCC[C@@H]1CN1CCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccc(F)cc2C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 18 %

Procedure:
Methyl 14-cyclohexyl-3-fluoro-6-{[(2R)-1-methylpyrrolidin-2-yl]methyl}-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate was dissolved in a solution of dioxane: H2O 2O (1:1) (0.1 M) and to that solution aqueous KOH (3 eq, 5 N) was added. The solution was stirred at 60° C. for 3 h. The solvent was evaporated in vacuo. The crude was then purified by automated RP-MS-HPLC (stationary phase: column Waters SYMMETRY prep. C18, 7 μm, 19×300 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (18%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[OH:59][C:52]1[C:51]([CH2:50][NH:49][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:10][C:2]=2[CH3:1])=[C:56]([CH3:57])[CH:55]=[C:54]([CH3:58])[N:53]=1
Reactant: Cc1cc(CN2CCCCC2)ccc1C(=O)O
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(CN3CCCCC3)cc2C)c(O)n1
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
A solution of 2-methyl-4-(piperidin-1-ylmethyl)benzoic acid (100 mg, 0.43 mmol) in dichloromethane (50 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (35 mg, 0.1 mmol), triethylamine (32 mg, 0.3 mmol). The mixture was stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (27 mg, 0.2 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was washed with water (50 mL), dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-4-(piperidin-1-ylmethyl)benzamide as white solid (35 mg, 19%). LRMS (M+H+) m/z: calcd 367.23. found 367. HPLC purity (214 nm): 96%. 1H NMR (300 MHz, CD3OD): δ 7.54-7.46 (m, 3H), 6.26 (s, 1H), 4.62 (s, 2H), 4.17 (s, 2H), 3.10 (s, 4H), 2.54 (s, 3H), 2.53 (s, 3H), 2.39 (s, 3H), 1.93-1.89 (m, 4H), 1.77-1.75 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:3].C1N2CN3CN(C2)CN1C3.C(O)(=[O:35])C.C(=O)(O)[O-].[Na+]>O>[CH3:1][N:2]([CH:4]=[N:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[O:35])=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:3]
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(C=O)cc1

Procedure:
10 g of N-[(dimethylamino) methylene]4'-bromomethyl(1,1'-biphenyl)2-sulfonamide, 8.14 g of hexamethylene-tetramine and 80 ml of 50% acetic acid are were stirred for one hour at 120° C. and after the addition of 220 ml of water, the reaction mixture was neutralized with a saturated solution of sodium bicarbonate and extracted with dichloromethane. The extracts were dried and evaporated to obtain 7.99 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:28]2[C:29](=[O:42])[N:30]([CH3:41])[C:31]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:32][CH:33]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15](CC3C=CC(OC)=CC=3)[N:16]=[C:17]([CH3:18])[C:10]=12>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:28]2[C:29](=[O:42])[N:30]([CH3:41])[C:31]([NH:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[N:32][CH:33]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][N:16]=[C:17]([CH3:18])[C:10]=12
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(-c5cnc(Nc6ccccc6)n(C)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2nccc(Oc3ccc(-c4cnc(Nc5ccccc5)n(C)c4=O)cc3F)c12
Temperature: 80 °C
Reaction time: 1 h
Yield: 15.3 %

Procedure:
To a 15 mL reaction tube was added 5-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (16 mg, 0.028 mmol) and the solids were dissolved in trifluoroacetic acid (0.5 mL, excess). The solution was stirred in a sealed tube for 1 hour at 80° C. The solvent was removed and the crude material was purified by loading onto a 0.5 mm preparative TLC plate, eluting with 8% MeOH in ethyl acetate. The product was obtained as a pale orange semi-solid (1.9 mg, 15%). LRMS (APCI pos) m/e 443.3 (M+1). 1H NMR (400 MHz, CD3OD) 8.26 (d, J=5.5 Hz, 1H), 7.94 (br s, 1H), 7.73 (m, 1H), 7.54 (br d, 1H), 7.48 (br d, 1H), 7.39 (m, J=7.4 Hz, 6H), 7.23 (t, J=7.4 Hz, 1H), 6.31 (d, J=5.5 Hz, 1H), 3.66 (s, 3H), 2.72 (s, 3H).