Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]Cl.O>C(OCCCC)CCC.ClCCl>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: ClCCOCCOC1CCCCO1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCCCOCCCC
Product: c1ccc2c(c1)Sc1ccccc1N2CCOCCOC1CCCCO1
Temperature: 135 °C
Yield: 55.3 %

Procedure:
Phenothiazine (3.8 g, 19 mmol) was added to a suspension of sodium hydride (0.92 g, 23 mmol, 60% oil dispersion) in dry dibutylether (25 ml) under an atmosphere of nitrogen. The mixture was heated at 135° C. for 1 h and then cooled to approximately 100° C. 2-(2-((tetrahydro-2-pyranyl)oxy)ethoxy)ethylchloride (8 g, 38 mmol) was added in one portion and the mixture was heated overnight at 110° C. The reaction mixture was poured into water (250 ml) and extracted with dichloromethane (3×50 ml) and diethyl ether (50 ml). The combined organic extracts were washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo leaving an oil, which was submitted to column chromatography using dichloromethane as eluent. Collecting the proper fractions afforded 3.9 g of crude 10-(2-(2-((tetrahydro-2-pyranyl)oxy)ethoxy)ethyl)-10H-phenothiazine. TLC: rf=0.72 (SiO2 ; dichloromethane/methanol=19:1).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](C1C=CC(B(O)O)=CC=1)([OH:23])=[O:22]>>[O:20]=[C:19]1[C:13]2[C:14]3[C:15](=[C:7]([C:1]4[CH:2]=[CH:3][C:4]([C:21]([OH:23])=[O:22])=[CH:5][CH:6]=4)[NH:8][C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:16][CH2:17][NH:18]1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C(O)c1ccc(-c2[nH]c3cccc4c3c2CCNC4=O)cc1

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (530 mg, 2.00 mmol) and 4-carboxyphenylboronic acid (365 mg, 2.20 mmol) were coupled to yield 4-(6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzoic acid, 340 mg (56%) as a pale yellow solid: m.p. 345.5-346.5° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 3.10 (m, 2H), 3.40 (m, 2H), 7.25 (t, J=7.8 Hz, 1H), 7.59 (dd, J=8.1, 0.9 Hz, 1H), 7.70 (dd, J=7.5, 0.6 Hz, 1H), 7.78 (m, 2H), 8.10 (m, 3H), 11.73 (br S, 1H), 13.00 (br s, 1H). MS (electrospray, MH+) 307. Anal. (C18H14N2O3.0.9 H2O) C, H, N.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH:28]1[CH2:32][CH2:31][N:30]([C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])[CH2:29]1)(C(C)(C)C)(C)C>C1COCC1>[F:37][C:34]([F:35])([F:36])[C:33]([N:30]1[CH2:31][CH2:32][CH:28]([CH2:27][OH:26])[CH2:29]1)=[O:38]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCN(C(=O)C(F)(F)F)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(N1CCC(CO)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TBAF was added to a THF solution of 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-(trifluoroacetyl)pyrrolidine and stirred overnight at room temperature. Thereafter, its work-up and purification were carried out in the standard method to obtain [1-(trifluoroacetyl)pyrrolidin-3-yl]methanol. EP: 198.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:41][C:42]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:43])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3cccc(F)c3)n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3cccc(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3.000 g 4-((S)-4-tert-Butoxycarbonyl-2-{[1-(3-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 20 ml DMF were added 0.908 ml benzyl bromoacetate and 3.571 g cesium carbonate. After stirring at RT for 12 h the solution was reduced to a volume of 50 ml, diluted with 200 ml ethyl acetate and extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent reaction.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.C(N(C(C)C)CC)(C)C.[CH3:26][N:27]([CH3:32])[CH2:28][C:29](Cl)=[O:30]>ClCCl>[CH3:26][N:27]([CH3:32])[CH2:28][C:29]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)=[O:30]
Reactant: CN(C)CC(=O)Cl
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a 100 mL round bottom flask was placed 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine 65 (438 mg, 2 mmol), dichloromethane (30 mL), diisopropylethylamine (517 mg, 4 mmol), and 2-(dimethylamino)acetyl chloride (267 mg, 2.2 mmol). The reaction was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure. Saturated aqueous sodium bicarbonate was added (20 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified on a silica-gel column using 0 to 20% methanol in dichloromethane as the solvent gradient. The product fractions were collected and concentrated to afford the title compound 66 as an orange oil. Mass found by LC-MS(+): 305 (M+H); calc. for C16H25BN2O3: 304.19.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17].P(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[F:12][C:13]([F:25])([F:26])[C:14]1[CH:15]=[C:16]([NH:17][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Reaction time: 6 h
Yield: 56.8 %

Procedure:
To 30 ml of toluene were added 5-chlorosalicylic acid (862 mg, 5 mmol), 3,5-bis(trifluoromethyl)aniline (1.37 g, 6 mmol), and phosphoroustrichloride (755 mg, 5.5 mmol) in the presence of argon gas, followed by stirring for 6 hours through heat-reflux. Sodium hydrogen carbonate was added to the mixture to adjust pH to 7, followed by concentration under reduced pressure. The mixture was dissolved in 60 ml of ethylacetate, which was washed with water (40 ml×2). The organic layer was concentrated under reduced pressure, followed by column chromatography to give 1.09 g of the target compound (yield: 57%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][N:34]([CH:36]3[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]3)[CH:35]=2)O1.Cl>CO>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:31]3[CH:32]=[N:33][N:34]([CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH:35]=3)[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Agent: Cl
Solvent: CO
Product: CC(On1ccc2ncc(-c3cnn(C4CCNCC4)c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate according to the procedure described in example 4. The resulting compound (BOC protected compound) was dissolved in methanol and was treated with HCl (4.0M solution in dioxane,) at room temperature for 30 min. Solvents were evaporated and the residue was dissolved in DCM and treated with Na2CO3/NaHCO3 and drops of water. The solution was then purified to give the entitled compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:13][NH:14][C:15]([C:17]3[S:21][C:20](Br)=[N:19][C:18]=3[C:23]([F:26])([F:25])[F:24])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:2]=1.[CH3:27][N:28]([CH3:34])[C@@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:13][NH:14][C:15]([C:17]3[S:21][C:20]([N:31]4[CH2:32][CH2:33][C@@H:29]([N:28]([CH3:34])[CH3:27])[CH2:30]4)=[N:19][C:18]=3[C:23]([F:26])([F:25])[F:24])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:2]=1
Reactant: O=C(NCC1(c2cccnc2)CCCCC1)c1sc(Br)nc1C(F)(F)F
Reactant: CN(C)[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(C)[C@@H]1CCN(c2nc(C(F)(F)F)c(C(=O)NCC3(c4cccnc4)CCCCC3)s2)C1
Temperature: 80 °C

Procedure:
A mixture of 2-bromo-4-trifluoromethyl-thiazole-5-carboxylic acid (1-pyridin-3-yl-cyclohexylmethyl)-amide (44.8 mg), dimethyl-(R)-pyrrolidin-3-yl-amine (12.6 mg), and potassium carbonate (15.2 mg) in ACN (1 mL) is heated at 80° C. for 1 h. The mixture is cooled, poured into water and extracted with EtOAc. The extract is concentrated in vacuo and the residue is purified by PTLC (silica gel, 5% MeOH in methylene chloride) to give the title compound. MS (M+1)=482.24; RT=1.03 min. *IC50.
Reaction SMILES: [C:1]1([C:7]2([C:13]([OH:15])=[O:14])[CH2:9][CH:8]2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[N+:16]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2([C:13]([OH:15])=[O:14])[CH2:9][CH:8]2[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:18])=[O:17]
Reactant: O=C(O)C1CC1(C(=O)O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)C1CC1(C(=O)O)c1ccc([N+](=O)[O-])cc1

Procedure:
To a slurry of 20.6 g. of 1-phenylcyclopropane-1,2-dicarboxylic acid in 25 ml of concentrated sulfuric acid at 0° C. is added 15 ml of concentrated nitric acid over 30 minutes. The resultant solution is then stirred at ambient temperature for 30 minutes and then poured onto ice. The crystalline product is recrystallized from hexane-ethyl acetate to give 1-(p-nitrophenyl)-cyclopropane-1,2-dicarboxylic acid as colorless crystals, m.p. 138°-144° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[N:8][C:9]3[C:10]([C:32]([OH:34])=O)=[CH:11][N:12]([C:17]4[CH:22]=[CH:21][C:20]([B:23]5[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]5)=[CH:19][CH:18]=4)[C:13](=[O:16])[C:14]=3[CH:15]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:35]1[N:39]=[CH:38][N:37]([C:40](N2C=NC=C2)=O)[CH:36]=1>>[CH3:38][N:37]([CH3:40])[CH2:36][CH2:35][NH:39][C:32]([C:10]1[C:9]2[N:8]=[C:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[CH:15][C:14]=2[C:13](=[O:16])[N:12]([C:17]2[CH:22]=[CH:21][C:20]([B:23]3[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]3)=[CH:19][CH:18]=2)[CH:11]=1)=[O:34]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cccc2cc3c(=O)n(-c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)cc(C(=O)O)c3nc12
Product: Cc1cccc2cc3c(=O)n(-c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)cc(C(=O)NCCN(C)C)c3nc12
Temperature: 100 °C
Yield: 74 %

Procedure:
From acid 18p, carried out under nitrogen, with a reflux time of 48 h and a recharge with an equal amount of CDI after 24 h. When the amination reaction was complete, the volatiles were removed at reduced pressure with heat (−0.3 mmHg, 100° C., 20 min) and residual N,N-dimethylethylenediamine was removed by azeotropic distillation with toluene (×3). The residue was then boiled in toluene and, while hot, decanted from a brown oil. The toluene was removed at reduced pressure, and the residue was recrystallized from acetonitrile to give the intermediate N-[2-(dimethylamino)ethyl]-6-methyl-1-oxo-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxamide as a yellow solid (74%), mp 139-141° C. 1H NMR (CDCl3): δ 1.34 (s, 12H, 4×CH3), 2.31 [s, 6H, N(CH3)2], 2.64 (t, J=6.5 Hz, 2H, CH2CH2NMe2), 2.81 (s, 3H, ArCH3), 3.72 (q, J=6.1 Hz, 2H, CH2CH2NMe2), 7.42-7.48 (m, 3H, H-8,2′,6′), 7.69 (d, J=6.9 Hz, 1H, H-7), 7.80 (d, J=8.1 Hz, 1H, H-9), 7.95 (d, J=8.3 Hz, 2H, H-3′, 5′), 8.68 (s, 1H, H-3), 9.23 (s, 1H, H-10), 10.98 (br t, J=5.4 Hz, 1H, CONH). 13C NMR (CDCl3): δ 18.2 (ArCH3), 24.5 (4×CH3)1 37.2 (CH2CH2NMe2), 45.0 [N(CH3) 2], 58.3 (CH2CH2NMe2), 83.8 (2×C), 109.7 (C-4), 119.4 (C-10a), 125.5 (2×CH, C-2′, 6′), 125.7 (C-9a), 126.4 (CH, C-8), 127.0 (CH, C-9), 132.7 (CH, C-7), 135.6 (2×CH, C-3′, 5′), 140.1 (CH, C-10), 142.0 (C-1′), 142.8 (CH, C-3), 147.8 (C-5a), 148.4 (C-4a), 161.7 (C-1), 164.1 (CONH). C-6 and C-4′ were not observed.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>Cl>[CH3:19][O:18][C:17]1[CH:16]=[CH:15][C:4]([C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])=[CH:3][C:2]=1[NH:1][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: COc1ccc(C(=O)OCc2ccccc2)cc1N
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: COc1ccc(C(=O)OCc2ccccc2)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
Benzyl 3-amino-4-methoxybenzoate (300 mg, 1.17 mmol) was dissolved in Py (5 ml). Methanesulfonyl chloride (140 mg, 1.22 mmol) was added at 0° C. and under Argon atmosphere. The mixture was stirred at RT for 1 hour, then it was diluted with HCl 1N and extracted with EtOAc. The organic phase was washed with HCl 1M, dried over Na2SO4 and concentrated under vacuum to give benzyl 4-methoxy-3-(methylsulfonamido)benzoate (247 mg, 63.2% yield).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([NH:12][C:13]([C:15]1[C:20]([I:21])=[C:19]([NH2:22])[C:18]([I:23])=[C:17]([C:24]([NH:26][CH:27]([CH2:33][O:34][C:35](=[O:37])[CH3:36])[CH2:28][O:29][C:30](=[O:32])[CH3:31])=[O:25])[C:16]=1[I:38])=[O:14])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].[Br:39][CH:40]([CH2:44][CH2:45]Br)[C:41](Br)=[O:42].C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)(=O)C>CN(C)C(=O)C.N1C=CC=CC=1>[C:30]([O:29][CH2:28][CH:27]([NH:26][C:24]([C:17]1[C:18]([I:23])=[C:19]([N:22]2[CH2:45][CH2:44][CH:40]([Br:39])[C:41]2=[O:42])[C:20]([I:21])=[C:15]([C:13]([NH:12][CH:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:7][O:8][C:9](=[O:11])[CH3:10])=[O:14])[C:16]=1[I:38])=[O:25])[CH2:33][O:34][C:35](=[O:37])[CH3:36])(=[O:32])[CH3:31]
Reactant: O=C(Br)C(Br)CCBr
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(N)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c(I)c(N2CCC(Br)C2=O)c1I
Temperature: 25 °C
Reaction time: 13 h
Yield: 45.8 %

Procedure:
A solution of N,N'-bis-[2-acetyloxy-1-(acetyloxymethyl)ethyl]-5-[amino]-2,4,6-triiodo-1,3-benzenedicarboxamide, (8.73 g, 10 mmol) in dry N,N-dimethylacetamide (100 ml) was treated with 2,4-dibromobutyroyl bromide (4.017 g, 13 mmol) under nitrogen and the mixture was stirred for 13 hours at 25° C. The dimethylacetamide was removed by distillation at 55°-60° C. under high vacuum. The resulting thick paste was dissolved in dry N,N-dimethylacetamide (160 ml) and potassium carbonate (1.80 g, 13 mmol) was added. The mixture was stirred for 60 minutes. An additional portion of potassium carbonate (1.80 g, 13.0 mmol) was added and the mixture stirred for 80 minutes. The suspended salts were filtered off and the volume of the reaction mixture was reduced to about 80 ml by vacuum distillation at 0.05-0.10 mm/Hg. The residual solution was poured slowly wink rapid stirring into ice-water (900 ml). The resulting mixture was stirred overnight at 0° C. and then filtered. The collected precipitate was dried in a vacuum desiccator (P2O5) and then crystallized from acetonitrile to give an off-white powder. This product was treated with acetic anhydride (30 ml) and pyridine (4.2 ml) for 32 hours at 25°, after which the volatile components were completely removed under high vacuum to obtain N,N'-bis-[2-acetyloxy-1-(acetyloxymethyl)ethyl]-5-[3-bromo-2-oxo-1-pyrrolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as a white powder (4.67 g, 45% yield), m.p. 232°-234°.
Reaction SMILES: [CH3:1][Si:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[O:23])=[CH:20][CH:19]=1.[OH-].[K+].C(O)C.Cl>O>[CH3:33][Si:2]([CH3:1])([CH3:32])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:23])=[CH:30][CH:31]=1
Reactant: COC(=O)CCC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 25 °C

Procedure:
A solution of 5.4 g. of methyl 3-[4-[14-(trimethylsilyl)tetradecylamino]benzoyl]propionate is stirred with 5.4 g. of potassium hydroxide in 100 ml. of 95% ethanol for 3 hours at reflux. The reaction mixture is cooled, diluted with 50 ml. of ethanol and 100 ml. of water, and neutralized with hydrochloric acid. The solution is cooled to room temperature and filtered. The white solid is washed with 50% aqueous ethanol and dried. The product is recrystallized to yield 3-[4-[14-(trimethylsilyl)tetradecylamino]benzoyl]propionic acid as a white crystalline solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CCCCCC.[O:19]=[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22][CH2:21]1>C(OCC)C.C1COCC1>[OH:19][C:20]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:24][CH2:25]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(OCc1ccccc1)N1CCC(O)(c2cccnc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
A solution of 3-bromopyridine (9.09 mL, 94.31 mmol) in diethyl ether (50 mL) was added dropwise to a stirred solution of 1.6M n-butyl lithium in hexane (58.9 mL, 94.31 mmol) in diethyl ether (500 mL) cooled to −78° C., over a period of 15 minutes under nitrogen. The resulting suspension was stirred at −78° C. for 1 hour. A solution of benzyl 4-oxopiperidine-1-carboxylate (20 g, 85.74 mmol) in diethyl ether (50 mL) and THF (50 mL) was added dropwise over 15 minutes. The reaction mixture was stirred at −78° C. for 1 hour, warmed to 0° C. over 2.5 hours and quenched with saturated ammonium chloride solution (500 ml). The mixture was extracted with ethyl acetate (2×500 mL) and the combined extracts were washed with brine (200 mL) then dried over MgSO4 and filtered through a short pad of silica. The silica pad was washed through with ethyl acetate (4×250 mL) and the filtrate was concentrated under vacuum. The residue was purified by flash silica chromatography eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford benzyl 4-hydroxy-4-(pyridin-3-yl)piperidine-1-carboxylate (12.8 g, 48%) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH:15]=O)=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].N1C=CC=CC=1.Cl.[NH2:36][OH:37]>CCO>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[N:36][OH:37])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C=O)c2cc(F)ccc2n1Cc1cccc2ccccc12
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C=NO)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
To a suspension of 5-fluoro-3-formyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (1.16 g) in EtOH (35 ml) was added at 22° C. pyridine (8.0 ml) and hydroxylamine hydrochloride (0.54 g) and the mixture was heated to reflux temperature for 2 h. The mixture was evaporated and the residue partitioned between 1 N HCl and t-butylmethyl ether. The organic layer was dried and evaporated to give 5-fluoro-3-(hydroxyimino-methyl)-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester as a colorless foam. MS: 391.1 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5](I)=[C:6]([CH:8]=1)[NH2:7].[CH2:11]([Si:13]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:14]#[C:15][CH2:16][CH2:17][OH:18])[CH3:12].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:6]2[C:5]([C:15]([CH2:16][CH2:17][OH:18])=[C:14]([Si:13]([CH2:19][CH3:20])([CH2:21][CH3:22])[CH2:11][CH3:12])[NH:7]2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(I)c(N)cc1Cl
Reactant: CC[Si](C#CCCO)(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(C)cc2c1CCO
Yield: 79.2 %

Procedure:
2-(6-chloro-5-methyl-2-(triethylsilyl)-1H-indol-3-yl)ethanol was prepared according to method D Step II with 5-chloro-2-iodo-4-methylaniline (1.50 g; 5.61 mmol), 4-(triethylsilyl)but-3-yn-1-ol (2.36 mL; 11.22 mmol), Bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.229 g; 0.280 mmol), lithium chloride (0.237 g; 5.61 mmol) and sodium carbonate (1.19 g; 11.22 mmol) in DMF (14 mL). The crude material was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to afford 1.44 g (79%) of 2-(6-chloro-5-methyl-2-(triethylsilyl)-1H-indol-3-yl)ethanol as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.Cl.[CH3:28][C:29]1([NH2:33])[CH2:32][CH2:31][CH2:30]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([NH:33][C:29]3([CH3:28])[CH2:32][CH2:31][CH2:30]3)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: CC1(N)CCC1
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(NC(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.9 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol) in DMF (2 mL) were added 1-methyl-cyclobutyl amine hydrochloride (37 mg, 0.30 mmol), diisopropylethylamine (DIPEA) (150 μL, 0.60 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (125 mg, 0.33 mmol). The solution obtained was stirred at room temperature for 2 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by chromatography purification (silica gel, gradient 10-20% ethyl acetate/isohexane) yielding Compound 61 as a solid (22 mg).