Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]([CH:15]([CH3:17])[CH3:16])[C:12](O)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].CN(C)C=O.S(Cl)([Cl:25])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([Cl:25])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccc(C(C(=O)O)C(C)C)cc1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccc(C(C(=O)Cl)C(C)C)cc1F
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Into a solution of 0.15 g (0.62 mM) of 2-(3-fluoro-4-ethoxyphenyl)isovaleric acid in 3.0 ml of anhydrous methylene chloride, a catalytic amount of dimethylformamide and 0.16 g (1.37 mM) of thionyl chloride were added, and the mixture was stirred for 2 hours in an oil bath at 40° C. Thereafter, an excess of thionyl chloride and methylene chloride were distilled off from the reaction mixture under a reduced pressure to obtain 2-(3-fluoro-4-ethoxyphenyl)isovaleric chloride as an oily substance.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=[C:21]([C:22]([OH:24])=O)[C:4]=2[N:3]=1.C(Cl)CCl.[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37]>CN(C)C=O.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=[C:21]([C:22]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:24])[C:4]=2[N:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1nc2c(C(=O)O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1nc2c(C(=O)NS(C)(=O)=O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 60 °C
Yield: 39 %

Procedure:
To the mixture of 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carboxylic acid, prepared as described in Example 20 (100 mg, 0.249 mmol) in N,N-Dimethylformamide (DMF) (2 mL) in a 20 mL vial was added EDC (57.3 mg, 0.299 mmol), methane sulfonamide (47.4 mg, 0.498 mmol) and DMAP (21.30 mg, 0.174 mmol). The mixture was stirred at 60° C. and monitored by LC/MS. After stirring for 5 days the DMF was removed in-vacuo and the remaining residue was dissolved in 2 mL of DMSO and purified by reverse phase chromatography with 2 injections eluting with a 27% to 57% AcCN/H2O gradient over 12 minutes. The fractions containing the desired compound, as determined by LC/MS, were combined and concentrated in-vacuo to provide the desired compound (47 mg, 0.097 mmol, 39.0% yield) as bright yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52 (s, 3H), 3.12 (t, 4H), 3.50 (s, 3H), 3.73 (t, 4H), 6.15 (s, 2H), 6.38 (d, 1H), 7.35 (t, aH), 7.50 (s. 1H), 7.51-7.75 (m, 2H), 7.88 (d, 1H), 8.05 (d, 1H), 8.25 (2, 1H), 8.35 (s, 1H), 12.8 (br. s, 1H); LC-MS: m/e=480 [M+1]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[C:13](O)(=[O:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[OH:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[NH:1][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccncc1
Temperature: 80 °C
Yield: 37.4 %

Procedure:
A mixture of 2.84 g of 2-amino-4-trifluoromethylphenol, 1.97 g of isonicotinic acid, 3.69 g of WSC [1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride] and 20 ml of pyridine was stirred while heating at 80° C. for four hours. The reaction mixture was cooled to room temperature, and then water was poured, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was washed with an ethyl acetate-hexane mixture solvent to give 1.69 g of N-(2-hydroxy-5-trifluoromethylphenyl)isonicotinamide.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[F:9])[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccccc1-c1cncc(Br)c1
Yield: 47 %

Procedure:
3,5-Dibromopyridine (ABCR Product List AB115322) (250 mg; 2.1 mmol), 2-fluorophenylboronic acid (Sigma-Aldrich, order number 445223)(147 mg; (2.1 mmol), Pd(PPh3)2Cl2 (148 mg; 0.4 mmol) are combined in DMF (8 ml) and 2N Na2CO3 (1.3 ml) and heated to 160° C. in an oil bath for 20 minutes. The reaction mixture is evaporated to dryness, taken up in TBME/CH2Cl2 (30 ml/10 ml), diluted with hexanes (50 ml), filtered and evaporated to dryness. The solid white residue is dissolved in TBME (10 ml), diluted with hexanes, filtered, and purified via chromatography (SiO2, TBME/hexanes 5:95) to yield the title compound as white crystals (125 mg; 47%). MS (m/z) ES+: 252, 254 (MH+). Retention time: 2.79 minutes (LC-MS method 3).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:33])([CH3:32])[C:30]#[N:31])[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:35].C(=O)([O-])[O-].[Na+].[Na+]>>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:33])([CH3:32])[C:30]([NH2:31])=[O:35])[CH2:25][CH2:24]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(C(C)(C)C#N)CC3)cc1OCC2
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(C(C)(C)C(N)=O)CC3)cc1OCC2
Yield: 60 %

Procedure:
2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionitrile (312 mg, 0.70 mmol) was added concentrated sulfuric acid (3.5 mL). The resultant mixture was stirred for 3.5 hours at RT before being poured onto ice and basified with sodium carbonate. The aqueous mixture was extracted with 10% MeOH in DCM (×5). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2, gradient 0-10% MeOH in DCM), then triturated with diethyl ether (x 3), to afford 287 (196 mg, 0.42 mmol, 60%). LCMS: RT=2.67 min, [M+H]+=464. 1H NMR δ (ppm)(DMSO-d): 8.27 (1 H, d, J=8.27 Hz), 7.86 (1 H, d, J=0.63 Hz), 7.85 (1 H, s), 7.17 (1 H, d, J=3.55 Hz), 7.03 (1 H, dd, J=8.34, 1.74 Hz), 6.91-6.89 (2 H, m), 5.89-5.79 (1 H, m), 4.48-4.41 (4 H, m), 2.80 (2 H, d, J=10.82 Hz), 2.17-2.09 (2 H, m), 1.77-1.60 (4 H, m), 1.44 (6 H, d, J=6.60 Hz), 1.05 (6 H, s). 1H obscured by solvent.
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH3:11])[C:6]([OH:8])=O)(=[O:3])[CH3:2].[F:20][C:21]([F:34])([F:33])[O:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1>ClCCl>[C:16]([O:15][C:13]([NH:12][CH:9]([CH2:10][CH3:11])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]([NH:30][NH:29][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([O:22][C:21]([F:20])([F:34])[F:33])=[CH:32][CH:31]=1)=[O:8])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCC(NC(=O)OC(C)(C)C)[C@H](OC(C)=O)C(=O)O
Reactant: NNC(=O)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Product: CCC(NC(=O)OC(C)(C)C)[C@H](OC(C)=O)C(=O)NNC(=O)c1ccc(OC(F)(F)F)cc1
Reaction time: 0.03 h
Yield: 64 %

Procedure:
(S)-2-acetoxy-3-tert-butoxycarbonylamino-pentanoic acid (1.82 mmol, 0.5 g, A) is dissolved in 30 mL dichloromethane. N-Cyclohexylcarbodiimide-N′-methylpolystyrene (3.64 mmol, 1.92 g, B) is added and the resulting reaction mixture stirred for 2 min. 4-(trifluoromethoxy)benzoic acid hydrazide (1.65 mmol, 0.363 g, C) is added and the reaction mixture stirred over night. After 16 hours LC/MS analysis still showed hydrazide. Polystyrene methyl isocyanate (1.65 mmol, 1.15 g) is added and stirring continued for eight hours. The reaction mixture is filtered under suction and the filtrate concentrated under reduced pressure. To give acetic acid (S)-2-tert-butoxycarbonylamino-1-[N′-(4-trifluoromethoxy-benzoyl)hydrazinocarbonyl]-butyl ester as a foam (0.5 g, 64%). According to LC/MS still some hydrazide present. MS: m/z=500 (M+Na+), 478 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[C:3]([CH3:12])[C:2]([Br:1])=[CH:7][CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1c(Br)ccc(O)c1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(Br)ccc(OCc2ccccc2)c1[N+](=O)[O-]

Procedure:
The reaction was carried out in a manner similar to Reference Example 12 a) except for using 5.11 g (29.9 mmol) of 4-bromo-3-methyl-2-nitrophenol, 6.30 g (27.2 mmol) of benzyl bromide, 8.26 g (59.7 mmol) of potassium carbonate and 150 ml of acetone. 3-Benzyloxy-6-bromo-2-nitrotoluene was thus obtained in the yield of 5.10 g (58.3%).
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH2:10][CH2:9][N:8]2[CH:17]=[O:18])=[CH:4][CH:3]=1.N1C=CC=CC=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.[Cu]>[O:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH2:10][CH2:9][N:8]2[CH:17]=[O:18])=[CH:19][CH:20]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Brc1ccccc1
Reactant: O=CN1CCC2=C(CCCC2)C1Cc1ccc(O)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=CN1CCC2=C(CCCC2)C1Cc1ccc(Oc2ccccc2)cc1
Yield: 69 %

Procedure:
A solution of 29.0 g (0.106 mol) of (±)-1-(p-hydroxybenzyl)-2-formyl-1,2,3,4,5,6,7,8-octahydroisoquinoline in 530 ml of freshly distilled pyridine was refluxed with stirring under nitrogen with 12.88 ml of bromobenzene, 51.5 g of copper (granular) and 22.55 g of potassium carbonate for 14 days. The reaction mixture after cooling was diluted with ether 1 l. and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in ether (300 ml). The ether solution was washed with 4 N aqueous sodium hydroxide (200 ml) then with water and dried. Removal of the solvent under reduced pressure gave 25.8 g (69%) of crude (±)-1-(p-phenoxybenzyl)-2-formyl-1,2,3,4,5,6,7,8-octahydroisoquinoline. For analysis, a sample of this compound was distilled, bp 220°-230° (0.05 mm Hq).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[CH2:18][CH2:19][CH3:20].C1CCC(N=C=NC2CCCCC2)CC1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[CH2:17]([NH:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][C:14](=[O:16])[C@H:9]([CH2:10][CH2:11][CH2:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCNC(=O)[C@H](C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCNC(=O)[C@H](C)NC(=O)[C@H](CCCC)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 58.4 %

Procedure:
Tertiarybutoxycarbonyl-L-norleucine (13.2 g) in CH2Cl2 (200 ml) was treated at 0° with L-alanine N-butylamide (5.25 g), DCC (7.77 g) and 1-hydroxybenzotriazole (5 g). The pH of the reaction mixture was adjusted to 7 with N-methyl morpholine and allowed to warm to room temperature overnight. The precipitated urea was filtered off and the filtrate washed successively with saturated aqueous sodium hydrogen carbonate, water and 1M citric acid. The organic phase was dried over sodium sulphate and the solvent evaporated in vacuo. The residue was chromatographed on silica in a gradient of 30-70% ethyl acetate in dichloromethane. Elution with 50% ethyl acetate in dichloromethane afforded the title compound (7.6 g) which crystallised from ethyl acetate as needles m.p. 108°-112°; (Found: C,60.8; H,9.8; N,11.8. C18H35N3O4 requires C,60.5; H,9.9; N,11.75%); νmax (Nujol) 3280, 3340 1675 and 1640 cms-1 δ (CDCl3) 0.9 and 0.91 (each 3H, each t, each J=5 Hz,2xCH3); 1.1-1.9 (10H,m,(CH 2)3 and (CH2)2); 1.38 (3H,d,J=5 Hz,6H2CHCH3); 1.44 (9H,s, C(CH3)3); 3.24 (2H,tt,J=5 Hz NHCH2) and 4.1 and 4.48 (each 1H, each m, 2x CH).
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([N:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)=[C:17]([F:35])[CH:16]=2)=[N:6][C:7]([S:12][CH3:13])=[N:8][C:9]=1[NH:10][NH2:11])(=[O:3])[NH2:2].[CH:36]([O-])([O-])OC>CC(N(C)C)=O>[C:1]([C:4]1[C:9]2[N:8]([CH:36]=[N:11][N:10]=2)[C:7]([S:12][CH3:13])=[N:6][C:5]=1[NH:14][C:15]1[C:20]([F:21])=[CH:19][C:18]([N:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:26][CH2:27]2)=[C:17]([F:35])[CH:16]=1)(=[O:3])[NH2:2]
Reactant: COC([O-])[O-]
Reactant: CSc1nc(NN)c(C(N)=O)c(Nc2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Solvent: CC(=O)N(C)C
Product: CSc1nc(Nc2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)c(C(N)=O)c2nncn12
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of the product of Example 15E (281 mg, 0.55 mmol) in dimethylacetamide (5 mL) was added methyl orthoformate (2 mL). The mixture was stirred at ambient temperature for 1 hour and at 60° C. for 4 hours. After cooling to ambient temperature, 9/1 petroleum ether/ethyl acetate (50 mL) was added and the precipitate was filtered. The solid was washed with petroleum ether and dried under vacuum to give the title compound. MS: 521 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].CS(O[CH2:20][CH2:21][O:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)(=O)=O>CN(C)C=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:20][CH2:21][O:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH:11]=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(NC=O)cc1
Reactant: CS(=O)(=O)OCCOc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(N(C=O)CCOc2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
A stirred mixture of N-(4-acetylphenyl)formamide (4.9 g) in dimethylformamide (50 mL) under argon was treated with 55% sodium hydride (1.31 g), stireed for 15 minutes and treated with 2-(2-naphthalenyloxy)ethyl methanesulfonate (7.6 g). The mixture was heated at 60° C. overnight and worked upas in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-ethyl acetate; 20:1 ) and crystallized from dichloromethane-hexane to provide 5.9 g of N-(4-acetylphenyl)-N[2-(2-naphthalenyloxy)ethyl]formamide as a colorless solid, mp 115°-116° C.
Reaction SMILES: C(O[C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:17])C.[C:20]([NH2:25])([CH2:23][CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[C:20]([NH:25][C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:17])([CH2:23][CH3:24])([CH3:22])[CH3:21]
Reactant: CCC(C)(C)N
Reactant: CCOc1c(Nc2c(O)cccc2C#N)c(=O)c1=O
Solvent: ClCCl
Product: CCC(C)(C)Nc1c(Nc2c(O)cccc2C#N)c(=O)c1=O

Procedure:
A mixture of 3-ethoxy-4-(2-hydroxy-6-cyanophenyl)amino-3-cyclobutene-1,2-dione (0.250 g, 0.00097 mol) and tert-amylamine (1.13 ml, 0.0097 mol) was stirred in enough CH2Cl2 to form a solution at room temperature for two days. During this time a precipitate forms. The reaction solvent is evaporated on a rotary evaporator, the residue is taken up in ethyl acetate and extracted well with 0.25N HCl. The organic layer is washed once with distilled water, dried (Na2SO4), and evaporated to a solid. The solid is collected and gives 3-(tert-amylamino)-4-(2-hydroxy-6-cyanophenyl)amino-3-cyclobutene-1,2-dione, 0.135 g (0.00045 mol, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.Cl.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([C:13]3[C:12]4[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=4[O:10][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:32])=[CH:34][CH:35]=2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COc1ccc(-c2cc3ccccc3o2)cc1
Reactant: O=C(O)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Product: COc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1
Yield: 79 %

Procedure:
The title compound was prepared in 79% yield from 2-(4-methoxyphenyl)benzofuran (Part A) and 4-[2-(1-pyrrolidinyl)ethoxy]benzoic acid hydrochloride by essentially following the procedure detailed in Example 1, Part C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][NH2:8].C(OC)(OC)OC.[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH:21]=O.[BH4-].[Na+]>CO>[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21][NH:8][CH2:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1
Reactant: Cn1ccnc1CN
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: Cn1ccnc1CNCc1ncc[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
The compound (201 mg) obtained in Example 14-7 was dissolved in methanol (4.0 ml) and added with trimethyl orthoformate (200 μl) and 2-imidazole carboxaldehyde (115 mg) and the whole was stirred at room temperature for 30 minutes. After having been cooled to 0° C., the solution was added with sodium borohydride (89.6 mg) and then the whole was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and washed with water, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (137 mg) as a pale-yellow oily substance.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].[Cl:9][C:10]1[CH:11]=[C:12](O)[CH:13]=[CH:14][CH:15]=1>C1COCC1>[Cl:9][C:10]1[CH:15]=[C:14]([CH:13]=[CH:12][CH:11]=1)[O:8][CH2:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][N:2]1[CH3:1]
Reactant: CN1CCC[C@H]1CO
Reactant: Oc1cccc(Cl)c1
Solvent: C1CCOC1
Product: CN1CCC[C@H]1COc1cccc(Cl)c1
Reaction time: 4 h

Procedure:
A 2 g (17.4 mmol) sample of (S)-1-methyl-2-pyrrolidinemethanol (from Aldrich) and 2.8 g (22 mmol) of 3-chlorophenol (Aldrich) were added to a complex of TPP and TBAD, (prepared as in Example 5b above, 22 mmol of each) in 150 mL of THF. The reaction was stirred for 4 hr. The solvents were removed, the residue was stirred with 15% HCl, and the mixture was extracted with ether. The aqueous solution was then adjusted to pH 12 with K2CO3 and extracted with methylene chloride. The solvent was removed, and the residue was triturated with ether, the precipitate was removed by filtration, and the solvent was removed to give the crude product. The residue was purified by chromatography on silica gel.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([C:35]([N:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38]2)=[O:36])[CH:30]=1>CN(C=O)C>[N:37]1([C:35]([C:31]2[N:32]=[CH:33][N:34]=[C:29]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:30]=2)=[O:36])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38]1
Reactant: O=C(c1cc(Cl)ncn1)n1ccc2ccccc21
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
100 mg (0.34 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one dihydrochloride and 200 μL (1.162 mmol) DIPEA were added to 100 mg (0.39 mmol) (6-chloropyrimidin-4-yl)-indol-1-yl-methanone in 30 mL DMF. The reaction mixture was stirred for 3 h at RT. The reaction mixture was evaporated down i. vac. The residue was combined with 20 mL water and stirred for 10 min. The solid was suction filtered and purified by flash chromatography. The product fractions were combined and evaporated down i. vac. The residue was triturated with diisopropylether and suction filtered. The solid was dried at 40° C. in the CAD.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([CH:63]([CH3:65])[CH3:64])([CH:60]([CH3:62])[CH3:61])[CH:57]([CH3:59])[CH3:58])[CH2:5][C:4]1=[O:66])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:76]([C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][C:80]=1[S:85](Cl)(=[O:87])=[O:86])([O-:78])=[O:77]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][S:85]([C:80]3[CH:81]=[CH:82][CH:83]=[CH:84][C:79]=3[N+:76]([O-:78])=[O:77])(=[O:86])=[O:87])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([CH:60]([CH3:62])[CH3:61])([CH:57]([CH3:59])[CH3:58])[CH:63]([CH3:65])[CH3:64])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OS(=O)(=O)c4ccccc4[N+](=O)[O-])C(OC)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
A solution of 17-ethyl-1-hydroxy-14-triisopropylsilyloxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone(1.0 g, 1.06 mmol) in MeCl2 (20 ml) containing 4-dimethylaminopyridine (312 mg, 2.55 mmol) and diisopropylethylamine (319 mg, 2.47 mmol) was treated with o-nitrobenzenesulfonyl chloride (476 mg, 2.14 mmol). After stirring at RT for 18 hr, the reaction mixture was diluted with MeCl2 (20 ml). The resultant suspension was filtered and the filtrate passed over SiO2 (90 g). Elution with n-hexane/ethyl acetate (1:1) yielded 17-ethyl-1-hydroxy-14-triisopropylsilyloxy-12-[2'-(4"-o-nitrobenzenesulfonyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (933 mg, 78%) and starting material (206 mg, 20%).