Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([CH:12]=O)[C:8]=2[CH3:11])[CH2:3]1.O.[OH-].[Na+].Cl.[CH3:21][C:22]([CH3:24])=[O:23]>>[CH3:1][C:2]1([CH3:16])[CH2:3][C:4]2[C:9](=[C:8]([CH3:11])[C:7]([CH3:12])=[C:6]([CH:14]=[CH:21][C:22](=[O:23])[CH3:24])[C:5]=2[CH3:15])[CH2:10]1
Reactant: Cc1c(C)c2c(c(C)c1C=O)CC(C)(C)C2
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1c(C)c(C)c2c(c1C)CC(C)(C)C2
Yield: 79 %

Procedure:
To a solution of 26.8 g of the 2,2,4,6,7-pentamethylindan-5-carboxaldehyde in 93 ml of absolute acetone was added 46 ml of water and 50 g of 2% NaOH. After refluxing for 20 hours, the solution was acidified with 2N HCl and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 25.36 g of the title compound as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:29])[N:7]2[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]1.Cl>C(Cl)(Cl)Cl.O1CCOCC1.CO>[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:7]2[C:8]3[C:3](=[C:2]([F:1])[CH:11]=[C:10]([F:12])[CH:9]=3)[CH:4]=[CH:5][C:6]2=[O:29])[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
1,1-Dimethylethyl {1-[2-(5,7-difluoro-2-oxo-1(2H)-quinolinyl)ethyl]-4-piperidinyl}carbamate (2 g; 4.9 mmol) was dissolved in chloroform (20 ml) and 4M HCl in 1,4-dioxane added (20 ml), this was stirred at rt for 1 h. The salts were then dissolved in MeOH and all solvents removed. The residues were redissolved in MeOH and stirred with amberlyst ion exchange resin until neutral pH was reached, the resin was filtered off and solvents removed. The crude residues were purified by column chromatography on silica gel using a 0-20% 2M NH3:MeOH/DCM gradient to give the desired product (970 mg; 65%).
Reaction SMILES: [F:1][C:2]1[C:21]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:20][CH:19]=[C:18]([F:29])[C:3]=1[C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15](O)=[O:16])[CH:13]=2)[NH:8][CH:7]=1)=[O:5].[CH2:30]([NH2:32])[CH3:31].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C>O1CCCC1.O>[CH2:30]([NH:32][C:15]([C:12]1[CH:13]=[C:14]2[C:6]([C:4](=[O:5])[C:3]3[C:18]([F:29])=[CH:19][CH:20]=[C:21]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:24])=[O:25])[C:2]=3[F:1])=[CH:7][NH:8][C:9]2=[N:10][CH:11]=1)=[O:16])[CH3:31]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(C(=O)O)cc23)c1F
Reactant: CCN
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(C(=O)NCC)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To 3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (P-1559, 38.0 mg, 0.090 mmol) in tetrahydrofuran (2.3 mL) was added a solution of ethylamine (2.0 M in tetrahydrofuran, 0.20 mL), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (80.0 mg, 0.17 mmol) and triethylamine (0.30 mL, 2.2 mmol) under an atmosphere of nitrogen. The reaction mixture was stirred overnight at room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 40% ethyl acetate in hexane to give the compound as a white solid (P-1630, 13.2 mg, 33%). MS(ESI) [M−H+]−=449.0.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)[CH:16]=[CH:17][CH:18]=3)[CH:10]=[C:9]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][N:34]=4)[CH2:29][CH2:28]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:43][NH:44][CH3:45]>C1COCC1>[CH3:43][N:44]([CH3:45])[CH2:21][CH2:20][CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11]2[CH:10]=[C:9]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][N:34]=4)[CH2:29][CH2:28]3)[N:8]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:12]=2)[CH:14]=1
Reactant: CNC
Reactant: CS(=O)(=O)OCCCc1cccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(N3CCOCC3)n2)c1
Solvent: C1CCOC1
Product: CN(C)CCCc1cccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(N3CCOCC3)n2)c1

Procedure:
Dissolve the crude methanesulfonic acid 3-(3-{2-morpholin-4-yl-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-4-yl}-phenyl)-propyl ester obtained above in THF and heat with an excess of dimethylamine in a sealed tube at 55° C. Concentrate under reduced pressure and partition the residue between aqueous NaHCO3 and EtOAc. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the residue using preparative plate TLC (MeOH/DCM eluent) to afford the title compound. 1H NMR (CDCl3): δ 1.17 (m, 2H), 2.27 (s, 6H), 2.37 (t, 2H), 2.72 (t, 2H), 3.40 (m, 4H), 3.80 (m, 8H), 3.87 (m, 4H), 6.37 (s, 1H), 7.03 (m, 1H), 7.25 (d, 1H, J=7.1 Hz), 7.35 (dd, 1H), 7.79 (m, 2H), 7.89 (d, 1H, J=7.87 Hz), 8.46 (d, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4].[C:9](O)(=O)C(O)=[O:11].C(OCC)(OCC)OCC.[ClH:25]>O.CC(O)C>[OH2:4].[OH2:11].[ClH:25].[OH:4][C:3]1[NH:5][CH:9]=[N:1][C:2]=1[C:6]([NH2:8])=[O:7]
Reactant: O=C(O)C(=O)O
Reactant: NC(=O)C(N)C(N)=O
Agent: Cl
Solvent: CCOC(OCC)OCC
Solvent: CC(C)O
Solvent: O
Product: NC(=O)c1nc[nH]c1O
Temperature: 82 °C
Reaction time: 0.5 h

Procedure:
Under the nitrogen atmosphere, 30 g of 2-aminomalonamide and 115 mg of oxalic acid were added to 600 mL of 2-propanol. After heating to 82° C., 106 mL of triethyl orthoformate was added dropwise to the mixture over 10 minutes. Subsequently, the reaction mixture was stirred for 7 hours and 30 minutes at 84° C. Subsequently, after cooling to 57° C., the reaction mixture was added with 30 mL of water followed by 24 mL of conc. hydrochloric acid. After cooling the reaction mixture to 5° C., the crystal was collected by filtration and then washed with 120 mL of acetone to give 49 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloric acid salt dihydrate as a pale yellow crystal.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Br[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1)[CH3:19]>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:18]([C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=2)[CH3:19])[C:10](=[O:14])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(Br)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1ccc(I)cc1)N1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
To a solution of Boc-3-oxopiperazine (67 mg, 0.328 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 13 mg, 0.328 mmol). After cooling to 0° C., 1-(1-Bromo-ethyl)-4-iodo-benzene (100 mg, 0.273 mmol) was added. The ice bath was removed and the mixture stirred at RT for 2 h and then partitioned between EtOAc and a solution of NH4Cl. After separation, the aqueous phase was re-extracted twice with DCM and the combined organic extracts were washed with H2O, saturated brine, dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, DCM/EtOac] 1:0→0:1)) to yield the title intermediate (90 mg, 0.188 mmol, 68%) as a colorless solid. HPLC: FtRet=1.276.
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].[CH2:6]([N:8]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:25][CH:24]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:20])[CH:16]=2)[N:11]=1)[CH3:7]>N1C=CC=CC=1>[ClH:5].[CH2:6]([N:8]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][S:30]([CH3:33])(=[O:31])=[O:32])=[CH:25][CH:24]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:20][S:2]([CH3:1])(=[O:4])=[O:3])[CH:16]=2)[N:11]=1)[CH3:7]
Reactant: CCN(CCc1ccc(NS(C)(=O)=O)cc1)Cc1ccc2cc(N)ccc2n1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCN(CCc1ccc(NS(C)(=O)=O)cc1)Cc1ccc2cc(NS(C)(=O)=O)ccc2n1
Product: Cl

Procedure:
Methanesulphonyl chloride (0.1 g, 1.29 mmole) was reacted with N-ethyl-N-(6-aminoquinol-2-ylmethyl)-4-methanesulphonamidophenethylamine (see Preparation 11B--0.51 g, 1.23 mmole) in pyridine similarly to the procedure of Example 2, giving the free base of the title compound as a gum. The gum was dissolved in ethyl acetate and the solution was diluted with ethereal hydrogen chloride and evaporated to dryness. The residue was triturated with ether to give the title compound as a foam, yield 0.06 g, m.p. 96°.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].I[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH:25]1([CH2:24][CH:19]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([O:10][CH3:9])[CH:12]=2)[C:20]([OH:22])=[O:21])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(C(CC2CCCC2)C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (58.5 mL of a 0.91M stock solution, 53.2 mmol) cooled to −78° C. was treated with (3,4-dimethoxy-phenyl)-acetic acid (4.97 g, 25.3 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (25.3 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min and at 25° C. for 15 min. At this time, the reaction was cooled to 0° C. and was treated with a solution of iodomethylcyclopentane (5.87 g, 27.8 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The reaction mixture was stirred at 0° C. for 30 min. The reaction was then warmed to 25° C. and was stirred at 25° C. for 18 h. The reaction mixture was then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (10 mL). The resulting mixture was concentrated in vacuo. The residue was diluted with water (100 mL) and acidified to pH=1 with a 1N aqueous hydrochloric acid solution. This solution was extracted with ethyl acetate (3×50 mL). The organics were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-propionic acid (4.5 g, 63.8%) as a yellow solid: mp 111-112° C.; EI-HRMS m/e calcd for C16H22O4 (M+) 278.1518 found 278.1517.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17].C(N(CC)CC)C.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].[Cl-].[Na+]>CN(C)C=O>[Si:9]([O:8][C@H:6]1[CH2:5][N:4]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[C@H:3]([CH2:2][NH:1][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:7]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 6 h

Procedure:
To a solution of (2S,4R)-2-aminomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (5 g) and triethylamine (1.87 ml) in N,N-dimethylformamide (50 ml) was dropwise added ethyl bromoacetate (1.49 ml) at ambient temperature with stirring. The mixture was stirred at 40° C. for 30 minutes and then allowed to stand at ambient temperature for 6 hours. The reaction mixture was poured into saturated aqueous sodium chloride (100 ml) and extracted twice with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was subjected to a column chromatography on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (20:1 v/v). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-t-butyldimethylsilyloxy-2-[(ethoxycarbonylmethyl)aminomethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3.52 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:13][C:6]1[N:2]([CH3:1])[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:5]=1[CH3:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(C)cn1C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(C)c(Br)n1C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 1,4-dimethyl-1H-pyrrole-2-carboxylate (63 mg, 0.377 mmol) in CHCl3 (3.5 mL) at 0° C. was added N-bromosuccinimide (67.1 mg, 0.377 mmol). The reaction was stirred at 0° C. for 15 min. The reaction was warmed to room temperature and stirred overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (1000 μm, hexanes/EtOAc (9:1)) to give ethyl 5-bromo-1,4-dimethyl-1H-pyrrole-2-carboxylate. LCMS calc.=245.0. found=245.9 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 6.83 (s, 1H); 4.27 (q, J=7.1 Hz, 2H); 3.91 (s, 3H); 2.05-2.02 (m, 3H); 1.34 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH2:9])=[O:8])[CH:2]=1.Cl[C:12]([S:14]Cl)=[O:13]>C1(C)C=CC=CC=1.CC1CCCCC1>[C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:12](=[O:13])[S:14][N:9]=2)[CH:2]=1
Reactant: Cc1cccc(C(N)=O)c1
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Solvent: CC1CCCCC1
Product: Cc1cccc(-c2nsc(=O)o2)c1
Reaction time: 5.5 h
Yield: 45.8 %

Procedure:
m-Toluamide (116 g, 0.86 mol) and chlorocarbonylsulfenyl chloride (144 g, 1.1 mol, 28% excess) was heated to 100° C. in 400 ml of toluene, with stirring, for 5.5 hours. Cooling resulted in an orange solid. The solid, isolated by filtration, was dissolved in hot methylcyclohexane and decolorized. The light yellow product was recrystallized once from methylcyclohexane to give 76.05 g (45.8%) of white solid, m.p. 82.5°-84°.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].N1C=CC=CC=1.C(Cl)Cl.[C:20]([O:24][C:25](=[O:34])[NH:26][CH:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl>[C:5]1([O:4][C:2](=[O:3])[NH:33][CH:30]2[CH2:31][CH2:32][CH:27]([NH:26][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:34])[CH2:28][CH2:29]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)Oc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phenyl chloroformate (1 eq.) is added dropwise to a solution of pyridine/DCM. The reaction mixture is cooled to 0° C. and a solution of (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (1 eq.) in DCM is added dropwise. The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is partitioned between (0.2 M) HCl(aq) and DCM. The organics are washed with water, saturated sodium hydrogen carbonate solution and brine. The combined organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH:11]([C:13]#[N:14])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][C:44](=[CH2:46])[CH2:43][N:42]6[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])=[N:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7])(C)(C)C.Cl.[CH3:59][O:60][C:61]([NH:63][CH:64]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)C(O)=O)=[O:62].CCN(C(C)C)C(C)C.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O1CCOCC1>[CH3:56][O:55][C:53](=[O:54])[NH:52][CH:48]([C:47]([N:42]1[CH2:43][C:44](=[CH2:46])[CH2:45][CH:41]1[C:38]1[NH:37][C:36]([C:31]2[CH:30]=[CH:29][C:28]3[C:33](=[CH:34][CH:35]=[C:26]([C:23]4[CH:22]=[CH:21][C:20]([C:17]5[NH:16][C:15]([CH:9]6[CH2:10][CH:11]([C:13]#[N:14])[CH2:12][N:8]6[C:6](=[O:7])[CH:64]([NH:63][C:61]([O:60][CH3:59])=[O:62])[C:68]6[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=6)=[N:19][CH:18]=5)=[CH:25][CH:24]=4)[CH:27]=3)[CH:32]=2)=[CH:40][N:39]=1)=[O:57])[CH:49]([CH3:51])[CH3:50]
Reactant: COC(=O)NC(C(=O)O)c1ccccc1
Reactant: C=C1CC(c2ncc(-c3ccc4cc(-c5ccc(-c6cnc(C7CC(C#N)CN7C(=O)OC(C)(C)C)[nH]6)cc5)ccc4c3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C=C1CC(c2ncc(-c3ccc4cc(-c5ccc(-c6cnc(C7CC(C#N)CN7C(=O)C(NC(=O)OC)c7ccccc7)[nH]6)cc5)ccc4c3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Cyano-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-4-methylene-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (102.0 mg, 0.134 mmol) was stirred in DCM (2.0 mL)/HCl in dioxane (4M, 2.0 mL). After 40 minutes all volatiles were removed in vacuo. The crude material was dissolved in DMF (1.5 mL) and methoxycarbonylamino-phenyl-acetic acid (28.2 mg, 0.134 mmol), DIEA (52.2 mg, 0.4 mmol), and COMU (57.7 mg, 0.134 mmol) was added and stirring at room temperature was continued. After 15 minutes, the reaction was quenched with aqueous HCl (1N, 0.1 mL). The crude reaction mixture was purified via RP-HPLC (eluent: water/MeCN w/0.1% TFA). The product containing fractions were lyophilized to give the final compound (59.3.0 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=[O:14])([O-])=O.CO>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=[O:14]
Reactant: O=c1[nH]cnc2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Nc1ccc2nc[nH]c(=O)c2c1

Procedure:
Hydrogenation of 6-nitro-3H-quinazolin-4-one (2 g) in EtOH (200 mL) was catalyzed by Pd/c (10%, 200 mg) under a H2 balloon for 1 h. MeOH (200 mL) was added to the mixture. The suspension was filtered through a layer of Celite® and the filtrate was concentrated in vacuum to give the desired compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.CCN(CC)CC.[Si:19](OS(C(F)(F)F)(=O)=O)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>ClCCl>[Si:19]([NH:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Nc1nc(Cl)c2cc[nH]c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Nc1nc(Cl)c2cc[nH]c2n1
Temperature: -30 °C
Yield: 77.5 %

Procedure:
To a dichloromethane solution (100 mL) of 2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (8.7 g, 52 mmol) was added Et3N (26 g, 260 mmol) and the mixture was stirred at −30° C. After this time, TBDMSOTf (15.1 g, 57.2 mmol) was added in a slow dropwise manner and the resultant reaction was stirred at ambient temperature for 1.5 h. The observed solid material completely dissolved to form a light brown solution. The mixture was then quenched with 1 N NaOH (100 mL) and extracted with DCM (250 mL). The organic layer was washed with H2O (150 mL) and then with a brine solution (150 mL) and dried over Na2SO4. The solvents were removed in vacuo and the residue was purified by flash column chromatography (PE/EtOAc=10/1 to 5/1) to afford 2-(t-butyl-dimethylsilyl)amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (CXXII, 11.4 g, 79%) as a light yellow solid. LCMS: (ESI) m/z=283 (M+H)+.
Reaction SMILES: C[O-].[Na+].C1(C)C=CC=CC=1.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:14]=[C:15]([CH2:19][C:20]([O:22]C)=O)[CH:16]=[CH:17][CH:18]=1.[C:26]1([CH2:32][C:33]#[N:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[C:33]([CH:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20](=[O:22])[CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:25])[F:24])[CH:14]=1)#[N:34]
Reactant: N#CCc1ccccc1
Reactant: COC(=O)Cc1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#CC(C(=O)Cc1cccc(C(F)(F)F)c1)c1ccccc1

Procedure:
To a flame-dried flask was added 8.1 g. of sodium methoxide, 125 ml. of toluene and 21 ml. of methanol. The mixture was brought to reflux at 85°-87°, and to it was added dropwise a mixture of 22.8 g. of methyl (3-trifluoromethylphenyl)acetate and 12.9 g. of phenylacetonitrile. The apparatus was then set up for distillation, and the mixture was heated to 110°, removing about 46 ml. of distillate. The mixture was then cooled to about 12°, and to it was added 50 ml. of ice-water. The aqueous layer was removed and washed with 20 ml. of cold toluene. The organics were combined and washed with cold water. The aqueous layers were combined, and the pH was adjusted to 3.5 with cold hydrochloric acid. The oily product was collected by extracting the aqueous portion with three 40 ml. portions of dichloromethane, drying the organic layer over sodium sulfate and evaporating it under vacuum to obtain 30.5 g. of oil, which was 89% pure product by vapor phase chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([CH3:26])[N:25]=1.[OH:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[OH:27][CH:28]1[CH2:29][CH2:30][N:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]3[CH:19]=[CH:18][C:14]([C:15](=[O:16])[NH:20][C:21]5[S:22][CH:23]=[C:24]([CH3:26])[N:25]=5)=[CH:13][CH:12]=3)[CH:6]=[CH:5]4)=[O:39])=[CH:36][CH:35]=2)[CH2:32][CH2:33]1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Reactant: Nc1ccc2c(ccn2-c2ccc(C(=O)O)cc2)c1
Reactant: Cc1csc(N)n1
Product: Cc1csc(NC(=O)c2ccc(-n3ccc4cc(NC(=O)c5ccc(N6CCC(O)CC6)cc5)ccc43)cc2)n1

Procedure:
Compound 954 was prepared according to the procedure described in Scheme IV from 4-(5-amino-1H-indol-1-yl)benzoic acid, 2-amino-4-methylthiazole, and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C31H29N5O3S: 552.10; found: 552.05.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[N:21]([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[N:22]=[CH:23][CH:24]=1>>[N:20]1[N:21]([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[N:22]=[CH:23][CH:24]=1
Reactant: COC(=O)CCCC(N)c1c(OC)cncc1OC
Reactant: O=Cc1cccc(-n2nccn2)c1
Product: COc1cncc(OC)c1C1CCCC(=O)N1Cc1cccc(-n2nccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(3,5-dimethoxypyridin-4-yl)pentanoate with 3-(2H-1,2,3-triazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.52 min.; [M+H]+: 393.71 g/mol.