Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:11])([F:10])[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[C:13]1[CH:45]=[CH:44][C:16]([CH2:17][N:18]2[C:22]3[CH:23]=[C:24]([O:27][CH2:28][C:29]4[CH:33]=[CH:32][N:31]([CH3:34])[N:30]=4)[CH:25]=[CH:26][C:21]=3[N:20]=[C:19]2[CH2:35][C:36]([CH2:42][CH3:43])([CH2:40][CH3:41])[C:37]([OH:39])=[O:38])=[CH:15][CH:14]=1.FC(F)(F)C1CCNCC1>>[CH2:40]([C:36]([CH2:35][C:19]1[N:18]([CH2:17][C:16]2[CH:44]=[CH:45][C:13]([N:7]3[CH2:8][CH2:9][CH:4]([C:3]([F:11])([F:10])[F:2])[CH2:5][CH2:6]3)=[CH:14][CH:15]=2)[C:22]2[CH:23]=[C:24]([O:27][CH2:28][C:29]3[CH:33]=[CH:32][N:31]([CH3:34])[N:30]=3)[CH:25]=[CH:26][C:21]=2[N:20]=1)([CH2:42][CH3:43])[C:37]([OH:39])=[O:38])[CH3:41]
Reactant: FC(F)(F)C1CCNCC1
Reactant: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(Br)cc1)C(=O)O
Agent: Cl
Product: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(N2CCC(C(F)(F)F)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared in a manner analogous to that in Example 152 substituting 4-(trifluoromethyl)piperidine hydrochloride and 2-((1-(4-bromobenzyl)-6-((1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)methyl)-2-ethylbutanoic acid and 4-(trifluoromethyl)piperidine. MS (ESI): mass calcd. for C32H38F3N5O3, 597.29; m/z found, 598.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 7.70 (d, J=9.1, 1H), 7.55 (d, J=2.3, 1H), 7.35 (d, J=2.3, 1H), 7.26 (dd, J=9.0, 2.3, 1H), 7.20-7.15 (m, 2H), 7.10-7.02 (m, 2H), 6.31 (d, J=2.3, 1H), 5.68 (s, 2H), 5.07 (s, 2H), 3.85 (s, 3H), 3.83-3.77 (m, 2H), 3.41 (s, 2H), 2.85 (td, J=12.6, 2.6, 2H), 2.46-2.29 (m, 1H), 2.00-1.95 (m, 2H), 1.86-1.60 (m, 6H), 0.87 (t, J=7.4, 6H).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=O)[CH:13]=[CH:12][NH:11][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:14]1[CH:13]=[CH:12][N:11]=[C:10]2[S:9][CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:15]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc[nH]c2scc(-c3ccccc3)c12
Product: Clc1ccnc2scc(-c3ccccc3)c12

Procedure:
3-Phenyl-7H-thieno[2,3-b]pyridine-4-one (0.7 g, 4.29 mmol) was added to phosphorous oxychloride (10 ml) and heated to reflux for 4 hr. The solvent was removed to near dryness and the residue dissolved in DCM. The solution was washed with water followed by saturated sodium hydrogen carbonate and dried over magnesium sulfate. The solution was filtered through a pad of silica and solvents removed in vacuo to give 4-chloro-3-phenyl-thieno[2,3-b]pyridine. Yield=0.261 g (25%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1.[CH:11](O)=[O:12].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>ClCCl>[CH:11]([NH:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1)=[O:12]
Reactant: NCc1csc2cncn12
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=CNCc1csc2cncn12
Yield: 87 %

Procedure:
0.33 g of the above-obtained 3-aminomethylimidazo[5,1-b]-thiazole was dissolved in 10 ml of dichloromethane. To this solution, a mixture which had been prepared in advance by reacting 0.5 ml of formic acid with 0.5 ml of acetic anhydride at 50° C. for 10 minutes was added with stirring, and the resulting mixture was stirred at room temperature for an additional one hour. To the reaction solution was added 20 ml of a saturated aqueous solution of sodium hydrogencarbonate, and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 ml×2). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 0.338 g (yield 87%) of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[CH3:8][C:9]([S:14][CH3:15])([CH3:13])[C:10](Cl)=[O:11].Cl>C(=O)([O-])[O-].[K+].[K+]>[CH3:8][C:9]([S:14][CH3:15])([CH3:13])[C:10]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4])=[O:11]
Reactant: CSC(C)(C)C(=O)Cl
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CSC(C)(C)C(=O)N[C@@H](CS)C(=O)O
Temperature: 0 °C
Yield: 89.2 %

Procedure:
L-Cysteine (7.1 g) is dissolved in 88 ml of 2 M potassium carbonate and 7.5 g of 2-methyl-2-(methylthio)propanoyl chloride [b.p. 78° C. (37 mmHg)] is added dropwise while stirring under a nitrogen atmosphere at 0° C. After the addition, the mixture is stirred overnight at room temperature. The mixture is acidified with hydrochloric acid and the obtained crystals are separated by filtration and dried to yield 10.4 g (89.8%) of the titled compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([NH2:26])=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.[Cl:27][C:28]1[C:29](I)=[C:30]([C:34]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:35])[CH:31]=[CH:32][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:26][C:8]1[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:29]3[C:28]([Cl:27])=[CH:33][CH:32]=[CH:31][C:30]=3[C:34]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[O:35])[CH:14]=2)[N:9]=1
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Reactant: O=C(c1cccc(Cl)c1I)N1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: Nc1nc2ccc(-c3c(Cl)cccc3C(=O)N3CCCC3)cc2cc1N1CCOCC1
Temperature: 60 °C

Procedure:
A vial was charged with 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (710 mg, 2.000 mmol, prepared as in Example 2, Step 1-2), (3-chloro-2-iodophenyl)(pyrrolidin-1-yl)methanone (671 mg, 2 mmol), Pd(OAc)2 (22.45 mg, 0.100 mmol), triphenylphosphine (52.5 mg, 0.200 mmol) and potassium phosphate (0.331 mL, 4.00 mmol). The vial was evacuated and backfilled with nitrogen gas 3×. ACN (8 mL) and water (2 mL) were added and the reaction mixture was heated to 60° C. overnight in an oil bath. The product precipitated out of solution and was filtered off, dissolved in DCM/MeOH, washed with water and dried over MgSO4. The solvent was removed and the solid was dried under vacuum at 50° C. This material was further purified by preparative HPLC (10-100%; water with 0.1% TFA/CH3CN, 11 min). The obtained product was eluted on an SCX cartridge with MeOH followed by 2M NH3 in MeOH. The basic fraction was concentrated to afford the titled compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 437 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[N:11]=[C:12]([CH2:22]O)[C:13]=2[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[N:6][CH:7]=1.C(P(CCCC)CCCC)CCC.[O:42]1[CH2:46][CH2:45][NH:44][C:43]1=[O:47].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[N:11]=[C:12]([CH2:22][N:44]3[CH2:45][CH2:46][O:42][C:43]3=[O:47])[C:13]=2[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[N:6][CH:7]=1
Reactant: O=C1NCCO1
Reactant: CCOC(=O)CCCc1c(CO)nn2c(CC)ccc2c1-c1cncc(Br)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCc1c(CN2CCOC2=O)nn2c(CC)ccc2c1-c1cncc(Br)c1
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
To a solution of ethyl 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate (70.0 mg) in toluene (1 mL) was added tributylphosphine (0.098 mL), 1,3-oxazolidin-2-one (34.1 mg) in that order in an ice bath. After stirring for 5 minutes, to the mixture was added 1,1′-(azodicarbonyl)dipiperidine (98.9 mg). The mixture was stirred for 10 minutes in the bath, and 8 hours at room temperature. Hexane (5 mL) was added, and the mixture was filtered. The filtrate was evaporated. Preparative thin layer chromatography (ethyl acetate-hexane=1-1) afforded ethyl 4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-oxo-1,3-oxazolidin-3-yl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate as an yellow gum (25.0 mg).
Reaction SMILES: C1C2C(COC(=O)N[C@H](C([N:25]3[C:29]4=[N:30][CH:31]=[C:32](Br)[CH:33]=[C:28]4[C:27]([C@@H:35]([C:37]4[C:42]([Cl:43])=[CH:41][CH:40]=[C:39]([F:44])[C:38]=4[Cl:45])[CH3:36])=[CH:26]3)=O)CC(C)C)C3C(=CC=CC=3)C=2C=CC=1.C(OC([N:54]1[CH2:59][CH2:58][N:57]([C:60](=[O:76])[C:61]2[CH:66]=[CH:65][C:64](B3OC(C)(C)C(C)(C)O3)=[CH:63][CH:62]=2)[CH2:56][CH2:55]1)=O)(C)(C)C>>[Cl:45][C:38]1[C:39]([F:44])=[CH:40][CH:41]=[C:42]([Cl:43])[C:37]=1[C@H:35]([C:27]1[C:28]2[C:29](=[N:30][CH:31]=[C:32]([C:64]3[CH:63]=[CH:62][C:61]([C:60]([N:57]4[CH2:58][CH2:59][NH:54][CH2:55][CH2:56]4)=[O:76])=[CH:66][CH:65]=3)[CH:33]=2)[NH:25][CH:26]=1)[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)n1cc([C@H](C)c2c(Cl)ccc(F)c2Cl)c2cc(Br)cnc21
Product: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3ccc(C(=O)N4CCNCC4)cc3)cc12

Procedure:
Example 69 was synthesized according to Suzuki coupling method described above for synthesis of example 66, using ((S)-1-{5-Bromo-3-[(S)-1-(2,6-dichloro-3-fluorophenyl)ethyl]pyrrolo[2,3-b]pyridine-1-carbonyl}-3-methylbutyl)carbamic acid 9H-fluoren-9-ylmethyl ester and 4-[4-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)benzoyl]piperazine-1-carboxylic acid tert-butyl ester. The crude material was purified by HPLC. MS (ES+): m/z=497.24, 499.25 (100, 69) [MH+]. HPLC: tR=0.72 min (HPLC-ACQUITY, Purity).
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].Br[CH2:25][C:26]1[CH:44]=[CH:43][C:29]([CH2:30][P:31](=[O:42])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][CH:27]=1>CN(C=O)C>[C:38]([O:37][P:31]([CH2:30][C:29]1[CH:43]=[CH:44][C:26]([CH2:25][CH:2]([C:1]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])=[CH:27][CH:28]=1)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:42])([CH3:39])([CH3:40])[CH3:41]
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CC(C)(C)OP(=O)(Cc1ccc(CBr)cc1)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OP(=O)(Cc1ccc(CC(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
To a solution of dibenzyl malonate (0.5 g) in DMF (8 mL), was added sequentially NaH (0.06 g, 80% in mineral oil), di(tert-butyl) [4-(bromomethyl)benzyl]phosphonate(0.66 g). The reaction mixture was stirred at room temperature for 1 h, then quenched with 20 mL of saturated aqueous NH4OAc solution and extracted with 50 mL EtOAc. The extract was dried over Na2SO4 and concentrated. The sesidue was purified by silica gel chromatography eluted with to give the title compound (0.2 g).
Reaction SMILES: Cl[C:2]1[C:3]([NH:8][CH3:9])=[N:4][CH:5]=[CH:6][N:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][NH:8][C:3]1[C:2]([NH:10][C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1cccc(N)c1
Reactant: CNc1nccnc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CNc1nccnc1Nc1cccc(C)c1
Yield: 30.1 %

Procedure:
3-chloro-N-methylpyrazin-2-amine (6 g, 41.8 mmol), m-toluidine (6.72 g, 62.7 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.520 g, 0.836 mmol), Pd2(dba)3 (0.383 g, 0.418 mmol), and sodium t-butoxide (6.02 g, 62.7 mmol) were mixed in 200 mL of toluene and degassed for 20 minutes. The mixture was heated to reflux overnight. TLC indicated the reaction did not go to completion. 0.3 g of Pd2(dba)3 and 0.56 g of BINAP was added and heated up to reflux again for 24 h. The reaction was filtered through Celite® and concentrated. The residue was purified by column using 10% ethyl acetate and dichloromethane as solvent to give N2-methyl-N3-(m-tolyl)pyrazine-2,3-diamine (2.7 g, 30.2%).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:30])[C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Ni]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:31])[CH2:15][CH2:16]2)=[O:30])=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)cc3)CC2)c1
Reaction time: 0.02 h
Yield: 67.7 %

Procedure:
N-tert-Butyl-3((4-(4-nitrobenzoyl)piperazin-1-yl)methyl)benzamide (0.56 g, 1.31 mmol) was dissolved In methanol (10 mL) at room temperature. Raney 2800 nickel (−1mL of an aqueous suspension) was added and the grey suspension was stirred vigorously. A balloon of hydrogen was attached to the flask via a three-way stopcock and hydrogen was allowed to slowly flow through the system for 1 minute. The flask was sealed under 1 atmosphere of hydrogen and vigorous stirring continued for 1 hour. The balloon was removed and the flask was flushed with argon. The suspension was gravity-filtered over fluted paper and washed with methanol. The filtrate was concentrated to a crude foam/glass and silica chromatography (70-90% ethyl acetate in n-hexanes with 1-3% methanol, followed by 1-6% methanol in dichloromethane) gave the title compound (0.35 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:21][C:22]([F:25])([F:24])[F:23])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.[N:26]1[CH:31]=[CH:30][C:29]([C:32]#[CH:33])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.[Cu]I>[N:26]1[CH:31]=[CH:30][C:29]([C:32]#[C:33][C:2]2[CH:3]=[C:4]([O:21][C:22]([F:24])([F:23])[F:25])[CH:5]=[C:6]3[C:11]=2[O:10][CH:9]([C:12]([F:14])([F:15])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]3)=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(I)c2OC1C(F)(F)F
Reactant: C#Cc1ccncc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(C#Cc3ccncc3)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 120 h
Yield: 36 %

Procedure:
A mixture of ethyl 8-iodo-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 21a, Step 2 (1.00 g, 2.07 mmole), 4-pyridylacetylene (419 uL, 4.15 mmole), CuI (39 mg, 0.207 mmole), PdCI2(dppf)2-CH2Cl2 (169 mg, 0.207 mmole) and TEA (0.866 mL, 6.21 mmole) in anhydrous toluene (10 mL) was stirred at room temperature for 5 days under a N2 atmosphere. The mixture was then diluted with hexanes and purified by silica chromatography (0% to 75% EtOAc:hexanes gradient) to give 0.34 g (36% yield) of the product as a pale yellow crystalline solid: ESHRMS m/z 458.0822 (M+H, C21H14F6NO4, Calc'd 458.0822).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(O)CC.C([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[N:31]([CH2:38][CH3:39])[N:32]=[C:33]([C:36]#[N:37])[C:34]=1Br)(=O)C>[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[NH2:37][C:36]1[C:33]2=[N:32][N:31]([CH2:38][CH3:39])[C:30]([CH2:29][CH2:28][CH2:27][CH2:26][OH:25])=[C:34]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[N:2]=1
Reactant: CCn1nc(C#N)c(Br)c1CCCCOC(C)=O
Reactant: Nc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCCO
Product: CCn1nc2c(N)nc3ccccc3c2c1CCCCO
Temperature: 100 °C
Yield: 32.6 %

Procedure:
Triphenylphosphine (21 mg, 0.082 mmol), 2-aminophenylboronic acid hydrochloride (710 mg, 4.1 mmol), 2 M aqueous sodium carbonate (4.1 mL), n-propanol (4.8 mL), and water (1 mL) were added to 4-(4-bromo-5-cyano-2-ethyl-2H-pyrazol-3-yl)butyl acetate (0.86 mg, 2.7 mmol), and the flask was evacuated and backfilled with nitrogen five times before the addition of palladium (II) acetate (6.0 g, 0.027 mmol). The reaction was evacuated and backfilled with nitrogen three more times and then heated overnight at 100° C. An analysis by HPLC indicated that the reaction was incomplete. Additional triphenylphosphine (10 mg, 0.038 mmol), 2-aminophenylboronic acid hydrochloride (300 mg, 1.73 mmol), solid sodium carbonate (500 mg), and palladium (II) acetate (3.0 g, 0.013 mmol) were added at ambient temperature, and the reaction was heated at reflux for three hours and allowed to cool to ambient temperature. The reaction was diluted with brine and extracted with chloroform. The combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Methanol (10 mL) and sodium methoxide (2.2 mL of a 47% solution in methanol) were added to the resulting dark oil. The reaction was heated at reflux for three hours, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was diluted with water and extracted with chloroform. The combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (40+M cartridge, eluting with chloroform/CMA in a gradient from 100:0 to 75:25) to provide an oil. The oil was crystallized from acetonitrile and recrystallized from acetonitrile to provide 250 mg of 4-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butan-1-ol as gold-colored crystals, mp 159-160° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[CH:33]=[CH:32][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])=[O:20])=[CH:17][CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.O[C:47]1[C:55]2[N:54]=N[NH:52][C:51]=2[CH:50]=[CH:49][CH:48]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:52][C:51]2[CH:50]=[CH:49][CH:48]=[CH:47][C:55]=2[NH2:54])=[O:30])=[O:20])=[CH:32][CH:33]=1
Reactant: O=C(O)CCCCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ccccc1NC(=O)CCCCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
8-(4-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)benzamido)octanoic acid (452 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzo-triazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (423 mg, 72% yield) as a brown solid. LC-MS (m/z) 543 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:17](=[O:18])[CH2:16][NH:15][C:14](=[O:19])[CH2:13][CH:7]12.NCC(N1CCC2C(=CC=C(F)C=2Br)C1CC(O)=O)=O.C(N(CC)CC)C.O>C(Cl)Cl.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCOC(C)=O>[Br:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:17](=[O:18])[CH2:16][NH:15][C:14](=[O:19])[CH:13]=[C:7]12
Reactant: O=C1CC2c3ccc(F)c(Br)c3CCN2C(=O)CN1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: NCC(=O)N1CCc2c(ccc(F)c2Br)C1CC(=O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C=C2c3ccc(F)c(Br)c3CCN2C(=O)CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9-bromo-10-fluoro-1,3,4,7,8,12b-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione. To a stirred solution of 2-(2-(2-aminoacetyl)-5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid (HCl salt) (54.6 g, 143 mmol) and triethylamine (100 mL, 715 mmol) in DCM (570 mL), T3P (125 mL, 215 mmol, 50% m/m in AcOEt) was added slowly (exotherm) and the suspension was stirred at rt for 1 h. The solvent was reduced to a small amount under reduced pressure and the thick suspension was treated with water (500 mL) and the suspension was stirred overnight. The suspension was filtered off and the solid was again treated with water (200 mL), stirred for 10 min and filtered off. The slightly yellow solid was washed with water (1×) and with diethyl ether (2×). The resulting solid was dried at rt under high vacuo overnight to yield the title compound as slightly yellow solid (40.5 g). UPLC-MS: MS 327.1/329.1 (M+H+); UPLC rt 0.73 min.
Reaction SMILES: C1(C[O:8][C:9](=[O:64])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([O:48]CC4C=CC=CC=4)[C:43]=3[O:56]CC3C=CC=CC=3)[CH:11]=2)C=CC=CC=1.[H][H].CCCCCC>[Pd].C1COCC1>[OH:56][C:43]1[C:44]([OH:48])=[CH:45][CH:46]=[CH:47][C:42]=1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][O:35][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=1)[C:9]([OH:64])=[O:8]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCCCc2cccc(O)c2O)cc(C(=O)O)c1
Reaction time: 5 h
Yield: 87.1 %

Procedure:
A mixture of 2.0 g of 3-[[6-[2,3-bis(phenylmethoxy)phenyl]hexyl]oxy]-5-(octadecyloxy)benzoic acid phenylmethyl ester and 0.5 g of 10% palladium on carbon in 100 ml of THF was stirred in a hydrogen atmosphere until uptake ceased after 5 hours. The usual workup followed by trituration of the crude product with hexane gave 1.2 g (88% yield, mp 92°-94°) of 3-[[6-(2,3-dihydroxyphenyl) hexyl]oxy]-5-(octadecyloxy)benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:26](=[O:27])[N:25]([CH3:29])[CH3:24])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CN(C)C(=O)Cl
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)N(C)C)nc3cc21

Procedure:
3-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and N,N-dimethylcarbamoyl chloride (81 μl, 0.88 mmol). The title compound was obtained as brown powder (39 mg, 12%).