Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=O)[C:4]=2[CH:3]=[CH:2]1.Cl.[NH2:14][C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27](=[O:40])[C@@H:28]([CH2:30][CH2:31][CH2:32][NH:33][C:34]([NH2:39])=[N:35][N+:36]([O-:38])=[O:37])[NH2:29])=[CH:21][CH:20]=1)=[O:16].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:14][C:15]([NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][NH:26][C:27](=[O:40])[C@@H:28]([CH2:30][CH2:31][CH2:32][NH:33][C:34]([NH2:39])=[N:35][N+:36]([O-:38])=[O:37])[NH:29][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][NH:1]3)=[O:12])=[CH:23][CH:24]=1)=[O:16]
Reactant: O=C(O)c1cccc2[nH]ccc12
Reactant: NC(=O)NCc1ccc(CNC(=O)[C@H](N)CCCNC(N)=N[N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Product: NC(=O)NCc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)c2cccc3[nH]ccc23)cc1
Yield: 82 %

Procedure:
Prepared analogously to Example 69a) from 1H-indole-4-carboxylic acid, (R)-N-[[4-(aminocarbonylaminomethyl)phenyl]methyl]-N5 -[amino(nitroimino)methyl]-ornithinamide-hydrochloride and TBTU in a yield of 82% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][C@@H:10]3[C@H:14]([CH2:15][C:7]=2[CH:6]=[CH:5][CH:4]=1)[NH:13][CH2:12][CH2:11]3.[C:16]1([C:22]2[CH:35]=[CH:34][C:25]([C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH:32]=O)=[O:27])=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:50]C(Cl)C>>[ClH:50].[CH3:1][O:2][C:3]1[C:8]2[CH2:9][C@@H:10]3[C@H:14]([CH2:15][C:7]=2[CH:6]=[CH:5][CH:4]=1)[N:13]([CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:26](=[O:27])[C:25]1[CH:34]=[CH:35][C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:23][CH:24]=1)[CH2:12][CH2:11]3
Reactant: O=CCCCNC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CC(Cl)Cl
Reactant: COc1cccc2c1C[C@H]1CCN[C@H]1C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1cccc2c1C[C@H]1CCN(CCCCNC(=O)c3ccc(-c4ccccc4)cc3)[C@H]1C2
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
A mixture of cis-2,3,3a,4,9,9a-hexahydro-5-methoxy-1H-benz[f]indole (D17, 0.08 g, 0.39 mmol), 4-(4-phenylbenzoylamino)butyraldehyde (0.11 g, 0.40 mmol), and sodium triacetoxyborohydride (0.13 g, 0.61 mmol) in dichioroethane (20 ml), was stirred at room temperature for 18 h. Resulting mixture was partitioned between saturated aqueous NaHCO3 (20 ml) and dichloromethane (3×10 ml). The combined extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on silica using 0-4% methanol-dichloromethane gradient elution gave the free base of the title compound as a colourless solid (0.07 g, 38%). The free base was treated with 1M ethereal HCl (0.31 ml, 0.3 mmol) in dry dichloromethane to afford after evaporation the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[NH2:12])[N:8]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:7][CH2:6]2.Cl[C:24]1[N:25]=[C:26]([NH:43][C:44]2[CH:52]=[CH:51][CH:50]=[C:49]([F:53])[C:45]=2[C:46]([NH2:48])=[O:47])[C:27]2[CH:32]=[CH:31][N:30]([S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[C:28]=2[N:29]=1.Cl.O1CCOCC1>FC(F)(F)CO.C([O-])(O)=O.[Na+]>[F:53][C:49]1[CH:50]=[CH:51][CH:52]=[C:44]([NH:43][C:26]2[C:27]3[CH:32]=[CH:31][N:30]([S:33]([C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=4)(=[O:35])=[O:34])[C:28]=3[N:29]=[C:24]([NH:12][C:11]3[CH:10]=[C:9]4[C:5]([CH2:6][CH2:7][N:8]4[S:13]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)(=[O:14])=[O:15])=[CH:4][C:3]=3[O:2][CH3:1])[N:25]=2)[C:45]=1[C:46]([NH2:48])=[O:47]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Cl)nc32)cc1
Reactant: COc1cc2c(cc1N)N(S(=O)(=O)c1ccc(C)cc1)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: OCC(F)(F)F
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(S(=O)(=O)c1ccc(C)cc1)CC2
Reaction time: 8 h

Procedure:
A mixture of 5-(methyloxy)-1-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1H-indol-6-amine (4.0 g, 12.5 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (8.6 g, 18.79 mmol) and a 4 N solution of HCl in dioxane (16 mL, 62.5 mmol) in 2,2,2-trifluoroethanol (250 mL) was heated overnight in a sealed vessel at 80° C. The reaction mixture was diluted with a saturated NaHCO3 solution, and the resulting slurry was filtered and the solids were taken up into THF (1L). The resulting slurry was filtered and the filtrate was concentrated. The resulting orange solid was dissolved in THF (250 mL), and a 27% aqueous NH4OH solution (250 mL) was added and the reaction mixture was stirred overnight. The organic volatiles were evaporated, and the residue was extracted with CH2Cl2 (3×200 mL). The organic layers were combined, dried (Na2SO4), concentrated onto Celite and purified by silica gel chromatography using 0-2%THF/CH2Cl2 to obtain 2-fluoro-6-({2-({5-(methyloxy)-1-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1H-indol-6-yl}amino)-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide as a yellow solid (2.8 g, 30% for 2 steps). ESIMS (M+H)+=742.17.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([OH:21])=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24][S:25][CH2:26]Cl.O>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:24][S:25][CH3:26])=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2ccc(O)cc2C1
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCOc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
To a solution of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (2.5 g) in dimethylformamide (25 ml) was added 60% sodium hydride (390 mg) with ice-cooling and under an argon atmosphere, and the mixture was stirred at the same temperature for 30 min. Then, chloromethyl methyl sulfide (0.96 ml) was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained oil was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) and dried under reduced pressure to give the title compound (2.7 g).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C@@H:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][B:21]1OB(C)OB(C)O1>C1(C)C=CC=CC=1>[C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:8][B:21]([CH3:20])[N:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Solvent: Cc1ccccc1
Product: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Under argon stream, to a solution of (S)-α,α-diphenyl-2-pyrrolidine methanol (3 g, 11.8 mmol) in dry toluene (90 ml) was added trimethyl boroxine (1.13 ml, 8.0 mmol), followed by stirring for 1.5 hours. After the argon stream was stopped and the toluene (22.5 ml) was recovered under normal pressures on an oil bath at 140° C., dry toluene (22.5 ml) was added. Furthermore, after this recovery operation was repeated twice, the resultant product was concentrated under normal pressures, and subsequently under a reduced pressure, to thereby obtain the titled compound as a colorless crystalline.
Reaction SMILES: CC([N:5]([C@H:9]([CH3:29])[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26](C)C)[CH:21]=2)=[CH:17][CH:18]=1)=[O:11])[C:6](=[O:8])[O-:7])(C)C.[CH3:30][CH:31]([C:33]1C=C(OC2N=CC(N)=CC=2)C=CC=1)[CH3:32].[CH3:47]C1C=CC(C)=CC=1OC1N=CC(N)=CC=1>>[CH3:47][C:25]1[CH:24]=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=1[O:19][C:16]1[N:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C@H:9]([NH:5][C:6](=[O:8])[O:7][C:31]([CH3:33])([CH3:32])[CH3:30])[CH3:29])=[CH:18][CH:17]=1
Reactant: CC(C)c1cccc(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cn2)c1
Reactant: Cc1ccc(C)c(Oc2ccc(N)cn2)c1
Reactant: CC(C)c1cccc(Oc2ccc(N)cn2)c1
Product: Cc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cn2)c1

Procedure:
The title compound was made in a similar fashion to the preparation of Intermediate 25 replacing 6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinamine with 6-[(2,5-dimethylphenyl)oxy]-3-pyridinamine (Intermediate 34) and using the following conditions for the silica gel chromatography: Companion instrument, 12 g cartridge, a gradient cHex/EtOAc as eluent from 100/0 to 70/30. This afforded the title compound as a light brown oil (63 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([O:14][CH2:15][CH2:16]Br)[CH2:12]Br.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:16][CH2:15][O:14][CH2:11][CH2:12]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: BrCCOCCBr
Reactant: C[C@@H](N)c1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](c1ccc(Br)cc1)N1CCOCC1
Temperature: 25 °C
Yield: 65 %

Procedure:
(R)-(+)-1-(4-Bromophenyl)ethylamine (0.98 g), 2,2′-dibromodiethyl ether (1.36 g) and diisopropylethylamine (2.5 ml) were stirred in dimethylformamide (20 ml) under argon at 100° C. for 18 h. The reaction mixture was allowed to cool to room temperature, then partitioned between diethyl ether (50 ml) and water (50 ml). The aqueous phase was extracted further with diethyl ether (50 ml) and the combined organic phases were washed with water (100 ml), dried (MgSO4), concentrated in vacuo, redissolved in toluene and purified by Bondelute® chromatography, eluting with 0-50% ethyl acetate/iso-hexane to give the product as a yellow oil (0.86 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]#[N:17])[C:13]([NH2:18])=[N:12]2)=[CH:7][CH:6]=1)[CH3:2].[C:20](Cl)(=[O:22])[CH3:21].N1C=CC=CC=1.O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]#[N:17])[C:13]([NH:18][C:20](=[O:22])[CH3:21])=[N:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(N)n2)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(NC(C)=O)n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.6 %

Procedure:
To a solution of 4-(3-amino-4-cyanopyrazole-1-yl)benzoic acid ethyl ester (0.1 g) in tetrahydrofuran (4 mL) were added acetyl chloride (0.12 g) and pyridine (0.15 g), and this mixture was stirred at room temperature for 12 hours. This reaction mixture was poured into water, and the precipitated solid was collected by filtration. This obtained solid was washed with ethyl acetate, dried under reduced pressure at 50° C. to give the title compound (0.088 g).
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].N[C:6]1[CH:31]=[CH:30][C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:20][C:21]4[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=4[N:23]=3)=[CH:15][CH:14]=2)=[O:11])=[CH:8][CH:7]=1.[CH2:32]=O>CC(O)=O>[CH3:32][N:2]([CH3:1])[C:6]1[CH:31]=[CH:30][C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:20][C:21]4[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=4[N:23]=3)=[CH:15][CH:14]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: [BH3-]C#N
Reactant: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(N)cc4)cc3)sc2c1
Reactant: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(N(C)C)cc4)cc3)sc2c1
Yield: 57 %

Procedure:
Prepared as described in the Amination section using sodium cyanoborohydride (67 mg, 1.06 mmol), 4-amino-N-[4-(6-methoxybenzothiazol-2-yl)-phenyl]-benzamide (80 mg, 0.213 mmol) and paraformaldehyde (64 mg, 2.13 mmol) in AcOH (2 ml) to give the title compound (49 mg, 57%) as colourless needles after recrystallisation from EtOH.
Reaction SMILES: FC1C=CC(COC2C(=O)N([CH:16]3[CH2:39][C:21]4[N:22]([S:29]([C:32]5[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=5)(=[O:31])=[O:30])[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=5[C:20]=4[CH2:19][CH2:18][N:17]3[C:40]([O-:42])=[O:41])C=CC=2)=NC=1.[F:44][C:45]1[CH:46]=[CH:47][C:48]([CH2:51][O:52][C:53]2[CH:58]=[CH:57][NH:56][C:55](=[O:59])[CH:54]=2)=[N:49][CH:50]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=C[CH:70]=[C:71]2[C:76]=1N=CC=[CH:72]2>CS(C)=O.[Cu](I)I>[C:71]([O:42][C:40]([N:17]1[CH2:18][CH2:19][C:20]2[C:28]3[CH:27]=[CH:26][C:25]([N:56]4[CH:57]=[CH:58][C:53]([O:52][CH2:51][C:48]5[CH:47]=[CH:46][C:45]([F:44])=[CH:50][N:49]=5)=[CH:54][C:55]4=[O:59])=[CH:24][C:23]=3[N:22]([S:29]([C:32]3[CH:33]=[CH:34][C:35]([CH3:36])=[CH:37][CH:38]=3)(=[O:30])=[O:31])[C:21]=2[CH2:39][CH2:16]1)=[O:41])([CH3:76])([CH3:72])[CH3:70]
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccccc42)CCN(C(=O)[O-])C(n2cccc(OCc4ccc(F)cn4)c2=O)C3)cc1
Reactant: Oc1cccc2cccnc12
Reactant: O=c1cc(OCc2ccc(F)cn2)cc[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(-n5ccc(OCc6ccc(F)cn6)cc5=O)cc42)CCN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 162.6 %

Procedure:
tert-Butyl-8-(4-((5-fluoropyridin-2-yl)methoxy-2-oxopyridin-1(2H)-yl)-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (0.31 g, 0.82 mmol), 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (0.15 g, 0.68 mmol), and Cs2CO3 (0.24 g, 0.75 mmol) were suspended in DMSO (5.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar and 8-hydroxyquinoline (20 mg, 0.14 mmol) and copper iodide (0.16 g, 0.82 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (40 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2(50 mL) and washed with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (40 mL) (2×30 mL). The resulting organic solution was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (40 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes, increased to 50:50 over 12 column volumes and held for 5 column volumes; increased to 0:100 over 10 column volumes and held for 5 column volumes) provided the title compound (0.15 g, 34%) as a yellow film: 1H NMR (500 MHz, CDCl3) δ 8.48 (d, J=2.5 Hz, 1H), 8.24 (s, 1H), 7.66-7.63 (m, 2H), 7.52-7.45 (m, 2H), 7.42 (d, J=8.0 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.26-7.22 (m, 3H), 6.12 (dd, J=7.5, 2.5 Hz, 1H), 6.06 (d, J=3.0 Hz, 1H), 5.18 (s, 2H), 3.67-3.62 (m, 4H), 3.36-3.34 (m, 2H), 2.94-2.90 (m, 2H), 2.34 (s, 3H), 1.46-1.44 (m, 9H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][CH2:22][NH2:23])#[N:11].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O1CCCC1>[C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][CH2:22][NH:23][C:25](=[O:26])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)#[N:11]
Reactant: N#Cc1ccc2[nH]cc(CCN)c2c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Reaction time: 1.5 h
Yield: 75.2 %

Procedure:
A solution of diisopropylethylamine (6.11 g), in dry tetrahydrofuran (20 ml) was added to a stirred solution of 5-cyano-1H-indole-3-ethanamine (7.3 g) in dry tetrahydrofuran (250 ml). A solution of benzyl chloroformate (7.73 g) in dry tetrahydroguran (20 ml) was then added at room temperature. After stirring for 1.5 h the reaction mixture was partitioned between water (100 ml). The aqueous layer was separated and extracted with ethyl acetate (4×50 ml). The combined organic solutions were washed with water (100 ml), dried (MgSO4) filtered and evaporated to afford an oily solid which was washed with petroleum spirit (b.p. 60°-80°, 100 ml) and then recrystallised from a mixture of ethyl acetate (50 ml) and petroleum spirit (b.p. 60°-80°, 35 ml) to afford the title compound (9.46 g), m.p. 127.5°-129°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][CH:12]=[C:11]([C:14]3[CH:25]=[CH:24][C:17]4[C:18]5([CH2:23][NH:22][CH2:21]5)[O:19][CH2:20][C:16]=4[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:39][S:40]([CH2:43][C:44](O)=[O:45])(=[O:42])=[O:41].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:28])([F:27])[F:29])[O:13][CH:12]=[C:11]([C:14]3[CH:25]=[CH:24][C:17]4[C:18]5([CH2:23][N:22]([C:44](=[O:45])[CH2:43][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:21]5)[O:19][CH2:20][C:16]=4[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc3c(c2)COC32CNC2)=CO1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CC(=O)N1CC2(C1)OCc1cc(C3=COC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
To a stirred solution of hydrochloride salt of 5′-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrofuran-3-yl]-3′H-spiro[azetidine-3,1′-[2]benzofuran](Preparation 16, 0.5 g, 1.04 mmol) in THF (6 mL) was added DIPEA (1.82 mL, 10.45 mmol) at room temperature and stirred for 10 minutes at room temperature. Methane sulfonyl acetic acid (0.289 g, 2.09 mmol) and T3P (50% solution in ethyl acetate, 3.1 mL, 5.22 mmol) were added at room temperature. Resulting reaction mixture was stirred for 16 hours at room temperature under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (5×25 mL). Combined organic layer was washed with saturated solution of NaHCO3 (2×100 mL), dried over sodium sulphate and concentrated in vacuo to get pale yellow oil (0.62 g, crude). Crude was purified by column chromatography using 100-200 mesh silica gel. Desired product gets eluted in 0.7% MeOH in DCM to afford white semisolid (0.36 g), which was triturated with DCM: n-pentane (1:10; 2×5 mL) to afford off white solid (0.295 g, 50.18%). 1H NMR (400 MHz, CDCl3) δ: 3.17 (s, 3H), 3.21 (d, J=8.4 Hz, 1H), 3.31 (d, J=17.32 Hz, 1H), 3.84 (s, 2H), 4.31 (d, J=10.96 Hz, 1H), 4.41 (d, J=11.24 Hz, 1H), 4.58-4.64 (m, 2H), 5.08 (s, 2H), 7.15 (s, 1H), 7.33 (d, J=7.76 Hz, 1H), 7.40-7.43 (m, 2H), 7.51 (d, J=1.12 Hz, 2H). LC-MS (m/z): 559.7 (M−H).
Reaction SMILES: [C:1]([O:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=3)=[CH:15][CH:14]=2)[O:10][N:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:29]([BH3-])#N.[Na+].[C:33](O)(=O)[CH3:34]>CO.CC(C)=O.[Na+].C(=O)([O-])O>[C:1]([O:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][CH:33]([CH3:34])[CH3:29])[CH:23]=3)=[CH:17][CH:18]=2)[O:10][N:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Reactant: CC(C)(C)C(=O)Oc1cc(-c2ccc(OCCc3cccc(N)c3)cc2)on1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)Nc1cccc(CCOc2ccc(-c3cc(OC(=O)C(C)(C)C)no3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(4-(2-(3-aminophenyl)ethoxy)phenyl)-3-isoxazolyl pivalate (27.6 mg) in methanol (1 ml), 0.020 ml of acetone, 19.2 mg of sodium cyanoborohydride and 0.05 ml of acetic acid were added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with saturated aqueous hydrogen carbonate sodium, extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by preparative thin layer chromatography (Kieselgel™ 60 F254, Art5744, made by Merck & Co., ethyl acetate/hexane (50:50)) to afford the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)[C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][N:8]=1)=[O:5])[CH3:2].I[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]([CH2:42][CH2:43][O:44][CH3:45])[CH:37]=[C:36]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:35]2=[O:51].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C1C=CC([P]([Pd]([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)=CC=1>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[N:8]=[CH:9][C:10]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]([CH2:42][CH2:43][O:44][CH3:45])[CH:37]=[C:36]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:35]3=[O:51])=[C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[N:17]=2)[CH:12]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)c1cn(CCOC)c2ccc(I)cc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CCOC)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
1-Ethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-2-yl)urea (0.171 g, 0.39 mmol, Intermediate 17), ethyl 6-iodo-1-(2-methoxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.155 g, 0.39 mmol, Intermediate 20), cesium carbonate (0.214 g, 0.66 mmol, Aldrich) and tris(dibenzylideneacetaone)palladium (0) (0.035 g, 0.04 mmol, Aldrich) or tetrakis(triphenylphosphine)palladium (0) (5 mol %, Strem) were combined in dioxane (2 mL)/water (0 mL) and heated to 100° C. The reaction mixture was stirred for 1 h. The reaction mixture was cooled to room temperature and then placed in an ice-bath. The resulting precipitate was collected by filtration and dried under vacuum to provide the desired product (0.090 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[O:30][CH2:31][CH2:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:36]5[CH:35]=[N:34][N:33]([CH2:32][CH2:31][O:30][CH:25]6[CH2:26][CH2:27][CH2:28][CH2:29][O:24]6)[CH:37]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnn(CCOC5CCCCO5)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 80 mg, 0.215 mmol) and 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 106.1.2, 91 mg, 0.279 mmol) to give the title compound as red sticky oil. Used for next step without further purification. (HPLC: tR 2.66 min (Method A); M+H=488 MS-ES)