Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=[N:27]C=2C=1.N.CO>CN(C=O)C.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:10]([NH2:27])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CC1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: N
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CC1CC1)C(N)=O
Reaction time: 0.5 h

Procedure:
To a solution of above mentioned (R)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoic acid (1.0 g, 4.36 mmol) in DMF (10 ml) was added EDC (1.0 g, 5.24 mmol) and HOBt.H2O (367 mg, 2.4 mmol) at room temperature, 20 min later, it was added ammonia in MeOH (7N, 0.6 mL, 4 mmol) at room temperature. After stirring for 30 min, it was diluted with water and EtOAc, organic layer was separated and washed with Sat. NaHCO3, brine, dried and concentrated to give (R)-tert-butyl-1-amino-3-cyclopropyl-1-oxopropan-2-ylcarbamate (750 mg) as crude oil, which was treated with 4N HCl in Dioxane (5 mL). 30 min later, it was concentrated to give (R)-2-amino-2-cyclopropylacetamide hydrochloride salt.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([C:11]2[C:12]3[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=3[S:14][C:15]=2[CH2:16]OS(C)(=O)=O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CN(C=O)C.O>[N:1]([CH2:16][C:15]1[S:14][C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[C:11]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1sc2ccccc2c1-c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1sc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
Sodium azide (179 mg, 2.76 mmol) was added to a solution of methanesulfonic acid 3-phenylbenzo[b]thiophen-2-ylmethyl ester (828 mg, 1.84 mmol) in DMF (10 mL) and the mixture was stirred at RT for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, then dried (Na2SO4) and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-35% DCM in cyclohexane) affording 2-azidomethyl-3-phenylbenzo[b]thiophene as a clear oil (244 mg, 50%). LCMS: RT 4.46 min [M+H-N2]+ 237.8.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[NH:16][C:15]4[CH:17]=[C:18]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=O)[O:27]C(C)(C)C)[CH3:24])[CH:19]=[CH:20][C:14]=4[N:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl.[C:34](OCC)(=O)C>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[NH:16][C:15]4[CH:17]=[C:18]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:27])[CH3:34])[CH3:24])[CH:19]=[CH:20][C:14]=4[N:13]=3)=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)cc3)[nH]c2c1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC4CC4)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)phenyl)-1H-benzimidazol-6-yl)oxy)propan-2-yl)carbamate (901 mg) was added 4 M hydrogen chloride/ethyl acetate (10 mL), and the mixture was stirred at room temperature for 20 min, and concentrated. To the residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 15 min, and concentrated. The residue was dissolved in methanol (10 mL) and THF (10 mL), and saturated aqueous sodium hydrogen carbonate solution (10 mL) was added thereto, and the mixture was stirred at room temperature for 30 min. The reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (490 mg).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[NH:21][C:20](=[O:27])[CH2:19]2.N1CCCCC1>C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[NH:21][C:20](=[O:27])[C:19]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: COc1cc2c(cc1OC)NC(=O)C2
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc2c(cc1OC)C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Yield: 58.8 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 97 mg 5,6-dimethoxy-2-oxindole, and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 104 mg (58%) of the title compound as a brown solid.
Reaction SMILES: [CH:1]([N:4]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:5](=[O:21])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2].C(OC([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[C:38]1[CH2:46][C:47]([O:54][CH3:55])([C:51](Cl)=[O:52])[C:48](Cl)=[O:49])=O)(C)(C)C>C1COCC1>[NH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[C:38]1[CH2:46][C:47]1([O:54][CH3:55])[C:48](=[O:49])[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:51]1=[O:52]
Reactant: COc1ccc(N(C(=O)CNc2ccccc2Nc2ccccc2)C(C)C)cc1
Reactant: COC(Cc1cc2ccccc2n1C(=O)OC(C)(C)C)(C(=O)Cl)C(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3cc4ccccc4[nH]3)(OC)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Yield: 12.2 %

Procedure:
A solution of 0.76 g (2.0 mmol) of N-isopropyl-N-(4-methoxy-phenyl)-2-(2-phenylamino-phenylamino) acetamide, prepared as in Intermediate 43, in 10 mL of THF is added dropwise to a solution of 1.0 g (2.4 mmol) of 2-(N-tert-butoxycarbonyl-1H-indol-2-ylmethyl)-2-methoxy-malonyl dichloride in 35 mL of THF. The brown solution is heated at reflux for 1 d. After removal of THF in vacuo the residue is diluted with 100 mL of 1N HCl and extracted with EtOAc (×2). the organic extract is washed with 1N HCl, brine, sat. NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo to a brown foam. Purification by silica gel flash chromatography (30-50% EtOAc/petroleum ether) followed by reverse phase C-18 MPLC (70-80% methanol/H2O) gave 0.15 g of the title compound as a white powder: 1H NMR (d6 -DMSO 300 MHz) δ10.78 (s,1H), 7.57 (d, 1H, J=6), 7.5-6.9 (m, 16H), 6.69 (d, 1H, J=8), 4.82 (m, 1H), 4.26 (m, 2H), 3.79 (s, 3H), 3.56 (q, 2H, J=16), 0.99 (t, 6H, J=7); low resolution MS (FAB) m/e 617 (MH+).
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[C:13]1([C:19]2[CH:20]=[C:21]([C:24](O)=[O:25])[S:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:24]([C:21]3[S:22][CH:23]=[C:19]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:20]=3)=[O:25])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1cc(-c2ccccc2)cs1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc(-c2ccccc2)cs1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 4-phenylthiophene-2-carboxylic acid (Oakwood) according to methods A and C; yield 65 mg, 0.17 mmol (53%): 1H NMR (300 MHz, methanol-d4) δ 1.98 (d, J=14 Hz, 2H), 2.20 (s, 1H), 2.37 (d, J=14 Hz, 2H), 2.48 (s, 2H), 3.57 (s, 2H), 3.67 (d, J=1 Hz, 4H), 4.40 (s, 1H), 7.26-7.36 (m, 1H), 7.42 (t, J=7 Hz, 2H), 7.65-7.74 (m, 2H), 7.89 (d, J=1 Hz, 1H), 8.27 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 339 (M+H)+; Anal. C20H22N2OS.HCl.0.5H2O: C, H, N.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([O:30][CH2:31][CH3:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:15]2[C:24]([CH3:25])=[CH:23][C:22]3[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=3[CH:16]=2)[CH3:14])=[CH:8][CH:7]=1.[OH-].[Na+]>CO>[CH2:31]([O:30][CH:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH:13]([C:15]2[C:24]([CH3:25])=[CH:23][C:22]3[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=3[CH:16]=2)[CH3:14])=[CH:10][CH:11]=1)[C:3]([OH:33])=[O:2])[CH3:32]
Reactant: CCOC(Cc1ccc(OC(C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(Cc1ccc(OC(C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1)C(=O)O
Reaction time: 16 h

Procedure:
A solution of 2-ethoxy-3-(4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphtalen-2-yl)-ethoxy)-phenyl)-propionic acid methyl ester (108 mg; 0.24 mmol) in methanol (15 ml) was treated with 1 N NaOH and the reaction mixture was stirred for 16 hours. The reaction mixture was evaporated and 0.1 N HCl (20 ml) and ethyl acetate (50 ml) was added. The organic phase was separated and the water phase was further extracted with ethyl acetate (50 ml). The combined organic phases were dried and evaporated to give crude product. Purification on column chromatography using methylene chloride:methanol (15:1) as eluent gave the title compound in 105 mg (100%) yield. Compound 3.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:21][C:22]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])=[O:23])[CH2:9][N:10]([CH3:20])[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:34][NH:35][O:36][CH3:37].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.[Cl-].[Na+].O>[CH:1]1([CH2:7][C@H:8]([NH:21][C:22](=[O:23])[C:24]2[CH:32]=[CH:31][CH:30]=[C:26]([C:27]([N:35]([O:36][CH3:37])[CH3:34])=[O:28])[CH:25]=2)[CH2:9][N:10]([CH3:20])[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:17])[CH3:19])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNOC
Reactant: CN(C[C@H](CC1CCCCC1)NC(=O)c1cccc(C(=O)O)c1)C(=O)OCC[Si](C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CON(C)C(=O)c1cccc(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.5 %

Procedure:
A mixture of (S)-3-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-ylcarbamoyl)benzoic acid (0.923 g, 1.77 mmol, 1.0 equiv), obtained as described above, N,O-dimethylhydroxylamine hydrochloride (0.378 g, 2.2 equiv), EDC (0.600 g, 1.8 equiv), HOBt (0.384 g, 1.6 equiv), and DIEA (3 mL, 9.7 equiv) in CH2Cl2 (20 mL) was stirred at rt for 3 d. The reaction mixture was diluted with brine and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4. After the solvent was removed, the crude product was purified by chromatography on a 40-g silica gel cartridge eluted with a gradient from 0% to 40% EtOAc in hexanes to give (S)—N1-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-N3-methoxy-N3-methylisophthalamide (0.7388 g, 83%). TLC rf=0.38 (50% EtOAc in hexanes); LC-MS (3 min) tR=2.12 min, m/z 528 (MNa+), 506 (M+H+), 478; 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.84 (dt, J=7.9, 1.5 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 677 (d, J=8.2 Hz, 1H), 4.48-4.39 (m, 1H), 4.11-3.97 (m, 2H), 3.72 (dd, J=14.3, 10.5 Hz, 1H), 3.54 (s, 3H), 3.33 (s, 3H), 3.01 (dd, J=14.3, 4.1 Hz, 1H), 2.90 (s, 3H), 1.85-0.80 (m, 15H), −0.06 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 169.03, 166.25, 158.12, 134.41, 130.84, 128.80, 128.12, 126.89, 63.75, 61.06, 52.51, 46.78, 40.64, 34.60, 34.35, 33.53, 33.15, 26.36, 26.13, 26.06, 17.56, −1.61.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]([NH:15]C(=O)C(F)(F)F)([CH3:14])[CH2:9][S:10][CH2:11][C:12]#[N:13])[CH:7]=1.[BH4-].[Na+].[NH4+].[Cl-]>C(O)C>[NH2:15][C@@:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:22])([CH3:14])[CH2:9][S:10][CH2:11][C:12]#[N:13]
Reactant: C[C@@](CSCC#N)(NC(=O)C(F)(F)F)c1cc(Br)ccc1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: C[C@](N)(CSCC#N)c1cc(Br)ccc1F
Temperature: 23 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
To a solution of (R)—N-(2-(5-bromo-2-fluorophenyl)-1-(cyanomethylthio)propan-2-yl)-2,2,2-trifluoroacetamide (3 g, 6.76 mmol, Eq: 1.00) in ethanol (30 ml) was added sodium borohydride (1.02 g, 27.1 mmol, Eq: 4.0) and the mixture was stirred at 23° C. for 16 hours. Poured into icecold sat. NH4Cl-sol., stirred for 10 min and extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography with 0 to 50% ethyl acetate in heptane to give the (R)-2-(2-amino-2-(5-bromo-2-fluorophenyl)propylthio)acetonitrile (1.1 g, 3.63 mmol, 53.6% yield) as a light yellow oil. MS (ISP): m/z=303.0 [M+H]+ and 304.9 [M+2+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:28][C:29]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=1[C:36](=[O:40])[C:37]#[C:38][CH3:39]>>[F:28][C:29]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=1[C:36](=[O:40])/[CH:37]=[C:38](\[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])/[CH3:39]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC#CC(=O)c1cccc(F)c1F
Product: C/C(=C/C(=O)c1cccc(F)c1F)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 12) from 120 mg (0.33 mmol) of Intermediate 45 and 59 mg (0.33 mmol) of Intermediate 40 to yield 32 mg (18% yield) of Example 38: TLC (DCM/MeOH (4:1): Rf=0.72; 1H NMR (DMSO-d6, 300 MHz) δ11.43 (d, 1H, J=9.8), 7.97 (m, 2H), 7.56 (m, 5 h), 7.28 (m, 1H), 7.19 (d, 2H, J=8.0) 6.91 (d, 2H, J=8.0), 5.34 (s, 1H), 4.21 (m, 3H), 3.21 (m, 2H), 2.98 (t, 2H, J=6.6), 2.84 9 m, 1H), 2.40 (s, 3H), 1.78 (s, 3H); low resolution MS (ES+)m/e 547 (MH+).
Reaction SMILES: C[Al](C)C.[CH2:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][NH:6]1.[C:15]1([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28](OCC)=[O:29])[CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC.C1(C)C=CC=CC=1>[C:15]1([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]([N:6]3[CH2:7][CH2:8][C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH2:5]3)=[O:29])[CH2:24][CH2:23]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C(C1CCN(Cc2ccccc2)CC1)N1CCc2ccccc2C1
Temperature: 50 °C
Yield: 90.8 %

Procedure:
251 ml (594 mmol) of trimethylaluminium (at a concentration of 25% in hexane) are introduced under an argon atmosphere into 400 ml of tolune. The solution is cooled in an ice bath and 81.5 g (612 mmol) of 1,2,3,4-tetrahydroisoquinoline, dissolved in 200 ml of toluene, are added. The mixture is heated to approximately 50° C. and 95 g (384 mmol) of ethyl 1phenylmethyl-4-piperidinecarboxylate, dissolved in 400 ml of toluene, are added. The mixture is heated under reflux for 2 h, approximately 250 ml of solvent being removed by means of a Dean and Stark apparatus. The mixture is cooled in an ice bath and hydrolysed by slowly adding 250 ml of water, and the insoluble material is filtered off, it being rinsed with ethyl acetate. The filtrate is washed three times with water, the organic phase dried over sodium sulphate, the solvent evaporated off and the residue recrystallized in cyclohexane. 116.6 g of product are obtained. Melting point: 98°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][CH:13]=2)[CH:5]=[N:6][C:7]=1[C:8]#[N:9].[H][H]>C(OCC)(=O)C.CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][CH:13]=2)[CH:5]=[N:6][C:7]=1[C:8]#[N:9]
Reactant: [H][H]
Reactant: CC(=O)Nc1ccc(C#Cc2cnc(C#N)c(Cl)c2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(CCc2cnc(C#N)c(Cl)c2)cc1
Reaction time: 3 h

Procedure:
To a solution of N-(4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)phenyl)acetamide (from the previous step) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 3 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vaccuo and purified by a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give N-(4-(2-(5-chloro-6-cyanopyridin-3-yl)ethyl)phenyl)acetamide.
Reaction SMILES: CCN(CC)CC.[CH3:8][C:9](OC(C)=O)=[O:10].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[NH:28][C:27]4[N:35]=[CH:36][CH:37]=[CH:38][C:26]=4[N:25]3[C:39]=2[C:40]2[CH:45]=[CH:44][C:43]([C:46]3([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:49][CH2:48][CH2:47]3)=[CH:42][CH:41]=2)=[CH:18][CH:17]=1>C(Cl)Cl>[C:9]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[C:24]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[NH:28][C:27]4[N:35]=[CH:36][CH:37]=[CH:38][C:26]=4[N:25]3[C:39]=2[C:40]2[CH:45]=[CH:44][C:43]([C:46]3([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:54])([CH3:56])[CH3:55])[CH2:47][CH2:48][CH2:49]3)=[CH:42][CH:41]=2)=[CH:20][CH:21]=1)(=[O:10])[CH3:8]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(N)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Yield: 59.5 %

Procedure:
Et3N (25.9 μL, 0.186 mmol) and Ac2O (6.45 μL, 0.0682 mmol) were added to a solution of tert-butyl (1-{4-[2-(4-aminophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (35.4 mg, 0.0620 mmol) in DCM (1 mL) at 0° C. After stiffing the mixture for 17.5 hours at room temperature, the mixture was concentrated. The residue was diluted with sat. NaHCO3 aq. and extracted with CHCl3 (3×). The combined organic layers were dried over anhydrous Na2SO4, and concentrated. The residue was purified by PTLC (CHCl3/MeOH=9:1) to afford desired product (22.6 mg, 59.5%) as a white solid. 1HNMR (CDCl3) 400 MHz δ: 8.18-8.13 (m, 1H), 8.03-7.97 (m, 1H), 7.60-7.49 (m, 2H), 7.45-7.25 (m, 8H), 7.19-7.10 (m, 3H), 6.95 (d, J=7.8 Hz, 1H), 6.85-6.73 (m, 1H), 6.59 (dd, J=8.0, 4.8 Hz, 1H), 6.46-6.37 (m, 1H), 5.27-5.17 (m, 1H), 2.64-2.25 (m, 4H), 2.20-2.01 (m, 1H), 2.14 (s, 3H), 1.98-1.83 (m, 1H), 1.38 (br s, 9H); LCMS: 613 [M+H].
Reaction SMILES: CO[C:3]1(C2C=CC=CC=2)[O:7][C:6](=[O:8])[CH:5]([CH:9]([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:15])[CH2:10][CH2:11][CH2:12][CH3:13])[O:4]1.C[O-].[Na+]>CO>[CH2:10]([C@@H:9]([C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])=[O:15])[C@H:5]([OH:4])[C:6]([O:7][CH3:3])=[O:8])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C1OC(OC)(c2ccccc2)OC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)[C@H](O)C(=O)OC
Reaction time: 1 h

Procedure:
To 1-(2-methoxy-2-phenyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S)-tert-butoxycarbonylpyrrolidin-1-ylcarbonyl)pentane 1-2 (5 mmol, 50%) (5 mmol) in methanol (20 mL) was added sodium methoxide (catalytic; pH adjusted to 10) and the solution stirred for 1 hour. Amberlite IR-120 resin (H+ form) was added, then the solution was filtered and concentrated to afford methyl 3-(R)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-1-yl-carbonyl)-2-(S)-hydroxypropionate G-3 (quant.).
Reaction SMILES: [H-].[Na+].[S:3](Cl)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18]2[CH:24]=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1>C1COCC1>[F:26][C:15]([F:14])([F:25])[C:16]1[CH:17]=[C:18]2[CH:24]=[CH:23][N:22]([S:3]([C:6]3[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=3)(=[O:5])=[O:4])[C:19]2=[N:20][CH:21]=1
Reactant: FC(F)(F)c1cnc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C(F)(F)F)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a stirred solution of sodium hydride (6.2 g, 156 mmol, 60% dispersion), tosyl chloride (27 g, 141.8 mmol), in anhydrous THF (200 mL) under a nitrogen atmosphere was added a solution of 5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (26.38 g, 141.8 mmol) in THF (150 mL) dropwise at a rate which maintained the internal temperature of the reaction below 40° C. The reaction mixture was stirred overnight at room temperature and analysis by LCMS showed no starting material remained after this time. The reaction mixture was concentrated to remove most of THF and diluted with DCM and water. The organic layer was separated and the aqueous layer further extracted with DCM. The organic layers are combined and washed with brine, dried over magnesium sulphate and concentrated to a volume which was appropriate to load onto the top of a silica plug (300 mL) pre-wet with DCM, and the silica was washed with 2.5 L DCM. The filtrate was concentrated to give the product as a slightly brown solid (44.1 g, 92% yield).
Reaction SMILES: CN(C=O)C.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[O:16])=[CH:7]1.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][O:23][CH3:24]>CCOCC>[CH3:24][O:23][CH2:22][CH2:21][CH2:20][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[O:16])=[CH:7]1
Reactant: COCCCBr
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCCn1cc(C=O)c2ccccc21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a DMF (0.1 M) solution of indole-3-carbaldehyde (1 eq) was added sodium hydride (60% (w/w) dispersion in oil, 1.1 eq.) at 0° C. followed by 1-bromo-3-methoxypropane (1.5 eq.). The reaction mixture was stirred at 50° C. for 4 h. The mixture was then diluted with ether, washed with water and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 1:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:28]([N+:29]([O-])=O)=[CH:27][C:10]([O:11][CH2:12][C:13]2([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:14]2)=[C:9]([O:32][CH3:33])[CH:8]=1)=[O:6]>CC(O)=O.CCOC(C)=O.[Fe]>[OH:6][C:5]1[C:7]2[C:28](=[CH:27][C:10]([O:11][CH2:12][C:13]3([NH:16][C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:14][CH2:15]3)=[C:9]([O:32][CH3:33])[CH:8]=2)[N:29]=[CH:3][CH:4]=1
Reactant: COc1cc(C(=O)C=CN(C)C)c([N+](=O)[O-])cc1OCC1(NC(=O)OCc2ccccc2)CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc2c(O)ccnc2cc1OCC1(NC(=O)OCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A mixture of the compound of Example 3 (1.5 g, 3.2 mmol) and powder iron (1.8 g, 32 mmol) in AcOH (15 mL) was stirred a 80° C. for 2 h. The reaction mixture was cooled at room temperature, diluted with AcOEt (150 mL), filtered and washed with 50 ml of AcOEt. The filtration liquors were combined, washed with water (2×100 mL) and an NaHCO3 saturated solution (2×100 mL), dried and evaporated to give 1-[(4-hydroxy-6-methoxyquinolin-7-yloxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane (1.2 g, yield: 95%) as a yellow solid.