Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][S:40]([N:43]1[C:47]2=[N:48][CH:49]=[CH:50][C:51](B3OC(C)(C)C(C)(C)O3)=[C:46]2[CH:45]=[CH:44]1)(=[O:42])=[O:41].C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:51]4[CH:50]=[CH:49][N:48]=[C:47]5[N:43]([S:40]([CH3:39])(=[O:41])=[O:42])[CH:44]=[CH:45][C:46]=45)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2ccnc3c2ccn3S(C)(=O)=O)OC1(C)C
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: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccnc5c3ccn5S(C)(=O)=O)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (150 mg, 0.25 mmol) was treated with 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.31 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) and aqueous solution 2M of sodium carbonate (200 μl, 0.4 mmol) in N,N-dimethylformide (5 ml) according to the method described in Preparation 186 but stirring at 100° C. overnight. The crude was purified using SP1® Purification System (hexane-ethyl acetate) to obtain 90 mg (50% yield) of the title compound as a oil. Purity 99%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([NH:11][C:12]([CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:38]=[CH:39][CH:40]=1)[C:19]([C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[C:24]([C:35]([OH:37])=[O:36])=[CH:23][N:22]=1)=[O:20])=[O:13])([CH3:10])C.[C:41]1([N:47]2CCN[CH2:49][CH2:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:34][O:33][C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][C:28]=1[O:31][CH3:32])[C:21]([C:19](=[O:20])[C:18]1[CH:38]=[CH:39][CH:40]=[C:16]([O:15][CH2:14][C:12](=[O:13])[N:11]3[CH2:49][CH2:48][N:47]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH2:10][CH2:8]3)[CH:17]=1)=[N:22][CH:23]=[C:24]2[C:35]([OH:37])=[O:36]
Reactant: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)NC(C)C)c3)c2cc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)N4CCN(c5ccccc5)CC4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The resin bound activated ester (intermediate in the preparation of 1-[3-(Isopropylcarbamoyl-methoxy)-benzoyl]-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 37)) (225 mg, 0.19 mmol) was combined with 3 ml of methylene chloride and 0.060 ml of N-phenylpiperazine (0.388 mmol). The mixture was shaken for 15 minutes under argon at room temperature. The mixture was filtered and the filter cake was washed with methylene chloride. The filtrate was evaporated to dryness. The residue was saponified by dissolving in 1 ml of methanol containing 0.5 ml of 1N sodium hydroxide solution and several drops of tetrahydrofuran. The mixture was stirred at room temperature for 4 hrs and then evaporated to dryness. The residue was purified through a reverse phase preparative HPLC to give 6,7-Dimethoxy-1-{3-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethoxy]-benzoyl}-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid, as a fluffy solid (30 mg).
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:36][CH:37]1[CH2:40][CH2:39][CH2:38]1>CN(C=O)C.C(OCC)(=O)C>[CH:37]1([CH2:36][O:1][C:2]2[CH:28]=[CH:27][C:5]3[N:6]=[C:7]([N:9]4[CH2:10][CH2:11][CH:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH3:18])[CH2:13][CH2:14]4)[O:8][C:4]=3[CH:3]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: ICC1CCC1
Reactant: C[C@@H](COC1CCN(c2nc3ccc(O)cc3o2)CC1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](COC1CCN(c2nc3ccc(OCC4CCC4)cc3o2)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.4 %

Procedure:
To a solution of tert-butyl [(1S)-2-{[1-(6-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]oxy}-1-methylethyl]carbamate (200 mg) in DMF (5 mL) were added potassium carbonate (210 mg) and (iodomethyl)cyclobutane (150 mg), and the mixture was stirred at room temperature for 15 hr. Potassium carbonate (210 mg) and (iodomethyl)cyclobutane (150 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (130 mg).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=3)[N:10]=2)[CH:5]([CH2:22][CH2:23][CH2:24]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:4]1)=[O:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-:53]>C1COCC1>[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=3)[N:10]=2)[CH:5]([CH2:22][CH2:23][CH2:24][F:53])[CH2:4]1)=[O:2]
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OCCCC2CN(C=O)CCN2c2ccc3cc([N+](=O)[O-])ccc3n2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: O=CN1CCN(c2ccc3cc([N+](=O)[O-])ccc3n2)C(CCCF)C1
Temperature: 55 °C

Procedure:
A solution of 3-(4-formyl-1-(6-nitroquinolin-2-yl)piperazin-2-yl)propyl4-methylbenzene-sulfonate 30 (0.056 g, 0.11 mmol) in dry THF (0.30 mL) was treated with a solution of TBAF (0.16 mL, 1 M in THF, 0.16 mmol) to give a dark orange solution. The reaction mixture was heated at 55° C. for 2 h, and then was concentrated in vacuo and diluted with CHCl3. The crude material was purified by column chromatography to give N-Formyl-3-(3-fluoropropyl)-4-(6-nitroquinolin-2-yl)piperazine, 31 as a yellow foam (0.025 g, 64%). 1H NMR (CDCl3, 400 MHz) δ1.60-2.00 (m, 4H), 2.90 (dt, J=3.6 and 12.3 Hz, 0.5H), 3.00 (dd, J=4.2 and 13.3 Hz, 0.5H), 3.20-3.40 (2 m, 2H), 3.44-3.62 (m, 1.5H), 3.72 (bd, 0.5H), 4.32-4.60 (m, 3H), 4.83 (bs, 0.5H), 5.07 (bs, 0.5H), 7.07 (dd, J=3.2 and 9.4 Hz, 1H), 7.69 (m, 1H), 8.03 (d, J=9.1 Hz, 1H), 8.10 (s, 0.5H), 8.25 (s, 0.5H), 8.32 (dd, J=2.6 and 9.1 Hz, 1H), 8.56 (d, J=2.3 Hz, 1H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[OH:16][C@@H:17]([C@H:19]1[CH2:23][N:22]([C@@H:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:25])[C:21](=[O:34])[CH2:20]1)[CH3:18].[Cl:35][C:36]1[N:41]=[C:40](S(C)(=O)=O)[C:39]2[N:46]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH:47]=[N:48][C:38]=2[CH:37]=1>CN(C=O)C>[Cl:35][C:36]1[N:41]=[C:40]([O:16][C@@H:17]([C@H:19]2[CH2:23][N:22]([C@@H:24]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[CH3:25])[C:21](=[O:34])[CH2:20]2)[CH3:18])[C:39]2[N:46]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH:47]=[N:48][C:38]=2[CH:37]=1
Reactant: C[Si](C)(C)CCOCn1cnc2cc(Cl)nc(S(C)(=O)=O)c21
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)O)CC2=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cc4ncn(COCC[Si](C)(C)C)c34)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of NaHMDS in THF (1M, 0.85 ml, 0.85 mmol) was added to a solution of (R)-4-((R)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.04 (205 mg, 0.78 mmol) in DMF (10 mL) at room temperature. After 5 minutes, a solution of 6-chloro-4-(methylsulfonyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridine 2.09 (256 mg, 0.707 mmol) in DMF (2 mL) was added and mixture stirred at room temperature. After 10 minutes, LC/MS indicated full conversion to desired product. Reaction mixture was quenched with 15 mL of water, poured into 30 mL of water, and extracted with ethyl acetate (100 mL). Organics were washed with Brine (2×50 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to yield (R)-4-((R)-1-(6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.11, which was used in the next step without further purification.
Reaction SMILES: [Si]([O:8][C@H:9]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[CH2:10][CH2:11][C@@H:12]1[C@@H:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)=[CH:18][C:17]=2[OH:29])[N:14]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:13]1=[O:36])(C(C)(C)C)(C)C.F>C(#N)C>[OH:29][C:17]1[CH:18]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[CH:20]=[CH:21][C:16]=1[C@H:15]1[N:14]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:13](=[O:36])[C@@H:12]1[CH2:11][CH2:10][C@@H:9]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[OH:8]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CC[C@H]1C(=O)N(c2ccccc2)[C@@H]1c1ccc(-c2cccc(O)c2)cc1O)c1ccc(F)cc1
Agent: *CC(*)C
Agent: F
Solvent: CC#N
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc(O)c3)cc2O)N1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
(3R,4S)-3-[(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-(3,3′-dihydroxybiphenyl-4-yl)-1-phenylazetidin-2-one (73 mg, 0.122 mmol) was dissolved in acetonitrile (5 mL) and transferred to a polypropylene conical vial. 48% Hydrofluoric acid (1 mL) was added dropwise and the reaction stirred at room temperature for 1 h. The reaction was quenched with 1 N sodium hydroxide (24 mL) and transferred to a flask containing pH 7.4 phosphate buffer (24 mL). The pH of the solution was adjusted to 7.5-8.0 with saturated sodium bicarbonate solution then extracted with ethyl acetate (3×). The combined organic layers were washed with saturated sodium bicarbonate solution (2×), water, brine, dried over sodium sulfate, filtered, concentrated and purified by chromatography (12 g silica gel, 40% to 100% ethyl acetate-hexane) to afford (3R,4S)-4-(3,3′-dihydroxybiphenyl-4-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one (53 mg, 69% yield)); 1H NMR (300 MHz, CDCl3) δ 7.30-7.13 (m, 7H), 7.08-6.85 (m, 8H), 6.78 (ddd, J=8.1, 2.3, 0.9 Hz, 1H), 5.04 (d, J=2.3 Hz, 1H), 4.61 (t, J=5.9 Hz, 1H), 3.07 (ddd, J=5.7, 1.8, 1.5 Hz, 1H), 2.08-1.80 (m, 4H) ppm; MS [M+H]+ 584.0 [M−H]− 582.0.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:13][O:14][CH2:15][CH2:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:6]([O:5][C:3](=[O:4])[C:2]([C:21]1[CH:22]=[CH:23][C:18]([S:17][CH2:16][CH2:15][O:14][CH3:13])=[CH:19][CH:20]=1)=[O:8])[CH3:7]
Reactant: COCCSc1ccccc1
Reactant: CCOC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(SCCOC)cc1
Temperature: 0 °C

Procedure:
Ethyl chloroglyoxylate (8.76 mL) was added dropwise to a suspension of aluminum chloride (13.2 g, crushed) in methylene chloride (127 mL) under stirring and cooling with ice, and (2-methoxyethyl)phenylsulfide (12.0 g) was added dropwise thereto. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water (200 mL), and the mixture was stirred for 10 minutes. The organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution (40 mL×3), and washed with saturated brine (60 mL). The washed organic layer was dried over anhydrous sodium sulfate, filtrated, and evaporated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane:ethyl acetate=4:1) to give 2-[4-(2-methoxyethylthio)phenyl]-2-oxoacetic acid ethyl ester (1.98 g).
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31]O)[CH2:25]3)[CH2:19][CH2:18]2)=[O:16])[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C.[N-:40]=[N+:41]=[N-:42].[Na+]>ClCCl.O>[N:40]([CH2:31][CH2:30][N:26]1[CH2:27][CH2:28][CH2:29][C@@H:24]([CH2:23][N:20]2[CH2:21][CH2:22][N:17]([C:15]([NH:14][C:9]3[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=3)=[O:16])[CH2:18][CH2:19]2)[CH2:25]1)=[N+:41]=[N-:42]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCN(CCO)C2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: [N-]=[N+]=NCCN1CCC[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 1 h
Yield: 5.4 %

Procedure:
Methane sulphonyl chloride (0.4 ml) was added to a solution of N-(3,4-dichlorophenyl)-4-{[(3S)-1-(2-hydroxyethyl)piperidin-3-yl]methyl}piperazine-1-carboxamide (1.85 g, 4.45 mmol) in triethylamine (0.75 ml, 5.3 mmol) and dichloromethane (50 ml) at 0° C. under an atmosphere of argon. The reaction mixture was stirred at this temperature for one hour then water (100 ml) was added. The organic layer was separated, dried over magnesium carbonate, filtered then concentrated in vacuo. This material was then dissolved in anhydrous DMF (10 ml). Sodium azide (435 mg, 6.7 mmol) was added and the reaction mixture stirred overnight at 60° C. The reaction mixture was concentrated in vacuo and the residue separated between ethyl acetate (150 ml) and water (150 ml). The organic layer was separated, dried over magnesium carbonate, filtered then concentrated in vacuo onto silica gel (3 g). The resulting powder was subjected to chromatography (SiO2, 20 g) and the product eluted with a gradient of dichloromethane through to 10% methanolic ammonia/dichloromethane to yield the title compound as a white solid (105 mg)
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16](S(C2C=CC(C)=CC=2)(=O)=O)[CH:15]=[C:14]3[C:30]2[N:35]=[C:34]([NH:36][C@@H:37]3[CH2:42][CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]3)[CH:33]=[N:32][CH:31]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]>O1CCOCC1.[OH-].[Na+]>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:30]2[N:35]=[C:34]([NH:36][C@@H:37]3[CH2:42][CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH2:38]3)[CH:33]=[N:32][CH:31]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(N[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c3cc(-c4cncc(OC(C)C)n4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Oc1cncc(-c2ccc3[nH]cc(-c4cncc(N[C@@H]5CCCN(C(=O)OC(C)(C)C)C5)n4)c3c2)n1
Temperature: 100 °C
Yield: 93.1 %

Procedure:
To a solution of (R)-tert-butyl 3-(6-(5-(6-isopropoxy-pyrazin-2-yl)-1-tosyl-1H-indol-3-yl)pyrazin-2-ylamino)piperidine-1-carboxylate (0.250 g, 0.365 mmol) in 1-4-dioxane (3.6 mL), 1N NaOH (3.6 mL) was added and heated at 100° C. for 2 h. The reaction mixture was quenched with ice cold water and precipitate was formed. The precipitate was collected by filtration, washed with ice cold water and dried to give pure (R)-tert-butyl 3-(6-(5-(6-isopropoxypyrazin-2-yl)-1H-indol-3-yl)pyrazin-2-ylamino)piperidine-1-carboxylate (180 mg, 93%). MS (ESI, pos. ion) m/z: 530.0 (M+1). To a solution of (R)-tert-butyl 3-(6-(5-(6-isopropoxypyrazin-2-yl)-1H-indol-3-yl)pyrazin-2-ylamino)piperidine-1-carboxylate (180 mg, 1.25 mmol) in EtOAc (5.0 mL) was treated with HCl in EtOAc (5.0 mL) and stirred at RT for 3 h. The reaction mixture was quenched with water, neutralized with NaHCO3, extracted with EtOAc. The organic layer was separated, dried over Na2SO4 and evaporated to dryness. The crude solid was re-crystallized in acetone to obtain (R)-6-(5-(6-isopropoxypyrazin-2-yl)-1H-indol-3-yl)-N-(piperidin-3-yl)pyrazin-2-amine. MS (ESI, pos. ion) m/z: 430.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[CH:19]=[CH2:20]>[C].[Pd]>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:6]=2[CH2:19][CH3:20])=[C:2]([F:1])[CH:24]=1
Reactant: C=Cc1c(Oc2ccc([N+](=O)[O-])cc2F)ccnc1NC(=O)OC(C)(C)C
Agent: [Pd]
Product: CCc1c(Oc2ccc(N)cc2F)ccnc1NC(=O)OC(C)(C)C
Yield: 88.6 %

Procedure:
A solution of tert-butyl 4-(2-fluoro-4-nitrophenoxy)-3-vinylpyridin-2-ylcarbamate (48 mg, 0.13 mmol) was hydrogenated over 10% palladium-carbon (10 mg) and Pt2O (5 mg) for 1.5 h using H2 from a rubber balloon. The mixture was filtered through Celite® and the filtrate concentrated in vacuo to give the title compound (40 mg, 89%) as a pale yellow solid. 1H NMR (DMSO-d6) δ 9.04 (s, 1H), 8.03 (d, 1H, J=5.6 Hz), 6.95 (dd, 1H, J=8.6, 8.6 Hz), 6.50 (dd, 1H, J=2.5, 13.2 Hz), 6.41 (dd, 1H, J=2.5, 9.4 Hz), 6.36 (d, 1H, J=5.6 Hz), 5.44 (s, 2H), 2.67-2.62 (m, 2H), 1.43 (s, 9H), 1.11 (t, 3H, J=7.1 Hz); MS (ESI+): m/z 348.22 (M+H)+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:35][CH:36]([N:40]2[CH2:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]2=[O:49])[C:37](O)=[O:38])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[S:52][CH:53]=[CH:54][N:55]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:35][CH:36]([N:40]2[CH2:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]2=[O:49])[C:37]([NH:50][C:51]2[S:52][CH:53]=[CH:54][N:55]=2)=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: O=C(O)C(CC1CCCCCC1)N1Cc2ccccc2C1=O
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1nccs1)C(CC1CCCCCC1)N1Cc2ccccc2C1=O
Yield: 97.6 %

Procedure:
BOP coupling of 3-Cycloheptyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Step E; 173 mg; 0.58 mmol) and 2-aminothiazole (97 mg; 0.94 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as outlined in Example 1, Step B) provided after flash chromatography (Biotage 40S, eluent: 35% ethyl acetate/hexanes) 217 mg (99%) of 3-Cycloheptyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as a white foam EI-HRMS m/e calcd for C21H25N3O2S (M+) 383.1667, found 383.1660.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6](=[O:9])[CH2:7][SH:8].Cl[CH2:11][C:12](=[O:14])[CH3:13].O>CO>[CH3:4][O:5][C:6](=[O:9])[CH2:7][S:8][CH2:11][C:12](=[O:14])[CH3:13]
Reactant: COC(=O)CS
Reactant: CC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CSCC(C)=O

Procedure:
To a mixture of a 5.4 M methanolic solution of sodium methylate (185 mL, 1.00 mol) in 500 mL methanol is added mercapto-acetic acid methyl ester (97.0 g, 912 mmol) at RT. After stirring for 20 minutes at RT chloro acetone (80 mL, 1.0 mmol) is added carefully. After complete addition the reaction mixture is heated at reflux for 20 minutes. The reaction mixture is added to water and extracted with diethyl ether. The organic layer is washed with brine, dried over Na2SO4 and the solvent is evaporated under reduced pressure. The crude reaction product is distilled under reduced pressure (75° C.-90° C., 0.3 mbar) yielding the desired product as colorless liquid. Yield: 61.5 g. (M+H)+=163
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:22]([O:26][C:27](=[O:36])[NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])([CH3:25])([CH3:24])[CH3:23]>ClCCl.C(OCC)C.CCCCC>[C:22]([O:26][C:27](=[O:36])[NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[O:35])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCCCCCO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: CCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCC=O
Reaction time: 24 h
Yield: 79.9 %

Procedure:
Pyridinium dichromate (13.5 g, 0.036 mol) is added to a solution of t-butyl-(6-hydroxyhexyl)carbamate (5.88 g, 24 mmol) in dichloromethane (40 ml). After stirring for 24 hours, the reaction mixture is diluted with diethylether/pentane (1:1), filtered through Florisil and concentrated to yield t-butyl-(5-formylpentyl)carbamate (4.13 g, 80%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC(F)(F)F)N1CCN(C2CCCC2)CC1
Yield: 31 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a colorless foam (31%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:18])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1.N1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
A suspension of 11.9 g (0.0394 mol) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide in a mixture of 85 ml of dioxan and 6.8 ml of pyridine was treated dropwise at 0° with 7.1 ml (0.051 mol) of trifluoroacetic anhydride. The suspension was stirred at 50° for 3 hrs., cooled and poured on to ice-water. After stirring for 11/2 hr. the suspension was suction filtered. There were obtained 11.2 g (100%) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile as white crystals; m.p. 130° (dec.).