Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12](C(OCCCC)=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.IC1C=C(C=CC=1)[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29]>>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29])[CH:14]=2)=[CH:7][CH:8]=1
Reactant: CCCCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CCCCOC(=O)c1cccc(I)c1
Product: CCCCOC(=O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 40 %

Procedure:
This compound was prepared by the procedure for butyl 4′-(trifluoromethyl)biphenyl-4-carboxylate (CS-16), except using butyl 3-iodobenzoate instead of butyl 4-iodobenzoate. The product was purified by column chromatography followed by vacuum distillation, collecting fraction bp 127-131° C./0.12 mm. The product was a colorless oil, and obtained in 40% yield. 1H NMR (CDCl3): δ 0.99 (t, 3H), 1.5 (m, 2H), 1.8 (m, 2H), 4.37 (t, 2H), 7.54 (d, 2H), 7.72 (s, 4H), 7.77 (d, 2H), 8.09 (d, 2H), 8.28 (s, 2H).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]=[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=1[O:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:6].[OH-].[Na+]>CO.O1CCOCC1.Cl>[CH2:30]([O:29][C:18]1[C:19]([CH:26]([CH3:28])[CH3:27])=[CH:20][C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:17]=1[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:5]([CH3:6])=[CH:4][C:3]([OH:34])=[O:2])[CH:8]=2)[N:12]([CH3:16])[CH:11]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOc1c(-c2cn(C)c3ccc(C(C)=CC(=O)OC)cc23)cc(C(C)C)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1c(-c2cn(C)c3ccc(C(C)=CC(=O)O)cc23)cc(C(C)C)cc1C(C)C
Yield: 115.1 %

Procedure:
3-[3-(2-Butoxy-3,5-diisopropylphenyl)-1-methyl-1H-indol-5-yl]-but-2-enoic acid methyl ester (119 mg, 0.26 mmol) was dissolved in methanol (2.5 mL)/dioxane (2.5 mL) and treated with 1N NaOH (2.5 mL) at 60° C. for 3 h. The reaction was diluted with 1N HCl (3 mL) and extracted with ethyl acetate (3×10 mL). The combined organic portions were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to provide 134 mg of residue. The material was purified using radial chromatography by elution with hexane:ethyl acetate gradient to provide 60 mg (52%) of a light yellow solid. 1H NMR (250 MHz, CDCl3): δ 8.05 (d, 1H, J=1.4), 7.49 (dd, 1H, J=1.6, 8.7), 7.44 (s, 1H), 7.38 (d, 1H, J=8.7), 7.07 (d, J=2.3), 7.30 (d, 1H, J=2.2), 7.10 (d, 1H, J=2.2), 3.89 (s, 3H), 3.47 (m, 3H), 2.97 (sep, 2H, J=6.9), 2.73 (s, 3H), 1.46 (m, 2H), 1.34-1.22 (m, 14H), 0.78 (t, 3H, J=7.3). MS [EI+] 448 (M+H)+[EI−] 446. Anal. Calcd for C29H37NO3: C, 77.82; H, 8.33; N, 3.13. Found: C, 77.50; H, 8.28; N, 3.15.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:11]([OH:13])=O)[C:7](=[O:20])[CH:6]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:46][C:47]1([CH3:59])[O:51][C@H:50]([CH2:52][N:53]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54]2)[CH2:49][O:48]1>ClCCl>[CH3:46][C:47]1([CH3:59])[O:51][C@H:50]([CH2:52][N:53]2[CH:57]=[CH:56][C:55]([NH:58][C:11](=[O:13])[CH:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=4[Cl:1])=[CH:6][C:7]3=[O:20])[CH2:14][CH2:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[N:54]2)[CH2:49][O:48]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC(C)(C)CCC(C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)CCC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
In a round bottom flask under argon was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5-dimethyl-hexanoic acid (32 mg, 0.091 mmol) in dichloromethane (3 mL). To this mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (20 μL, 0.10 mmol) and 1-hydoxybenzotriazole (13 mg, 0.096 mmol) and stirred at 25° C. for 2 h. After this time period, 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 21 mg, 0.109 mmol) was added and stirred for 16 h at 25° C. After this time, the mixture was diluted with dichloromethane (10 mL) and washed with a 1N aqueous hydrochloric acid solution (10 mL), water (10 mL) and a saturated aqueous sodium bicarbonate solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography (4 g column, 30% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5-dimethyl-hexanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (14 mg, 29%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]([CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7])=[CH:3]1.[C:17](=[O:20])([O-])O.[Na+].O>O1CCOCC1>[CH3:1][N:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]([CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH:7][C:17](=[O:20])[CH:3]=[CH:4][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3]1
Reactant: O=C([O-])O
Reactant: Cn1cc(C[C@H](N)C(=O)O)c2ccccc21
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(C[C@H](NC(=O)C=Cc2ccccc2)C(=O)O)c2ccccc21
Yield: 68.9 %

Procedure:
The same procedures as in Example 121 were carried out from 1-methyl-L-tryptophan (2.0 g), sodium hydrogencarbonate (0.8 g), 2,5-dioxopyrrolidin-1-yl 3-phenyl acrylate (2.3 g), water (60 mL), and dioxane (140 mL), to give the captioned compound (1.1 g, 33%) as crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=1.[NH2:20][C@H:21]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH2:22][OH:23].CCN(C(C)C)C(C)C>CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=[C:2]([NH:20][C@H:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH2:22][OH:23])[CH:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Nc1cc(C2CC2)[nH]n1
Reactant: N[C@@H](CO)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=[N+]([O-])c1cnc(N[C@@H](CO)c2ccc(F)cc2)cc1Nc1cc(C2CC2)[nH]n1
Temperature: 195 °C
Yield: 69.7 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyridin-4-amine (Method 90, 0.15 g, 0.54 mmol), (R)-2-amino-2-(4-fluorophenyl)ethanol (0.10 g, 0.67 mmol), and DIEA (0.12 ml, 0.67 mmol) in n-BuOH (5 ml) was heated in a sealed tube at 195° C. for 52 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc) to give the title compound as a yellow solid (0.15 g, 72%). 1H NMR (400 MHz) 12.38 (s, 1H), 9.59 (b, 1H), 8.83 (s, 1H), 8.16 (b, 11H), 7.37 (m, 2H), 7.13 (m, 2H), 6.75 (b, 1H), 5.92 (b, 11H), 5.25 (b, 1H), 4.98 (m, 1H), 3.61 (t, J=6.4 Hz, 2H), 1.92 (m, 1H), 0.97 (m, 2H), 0.72 (m, 2H). MS: Calcd.: 398; Found: [M+H]+ 399.
Reaction SMILES: [CH3:1][N:2]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:3]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[C:10](O)=[O:11].Cl.CN(C)CCCN=C=NCC.[OH:46][N:47]1C2C=CC=CC=2N=N1.NO>CN(C=O)C.C(OCC)(=O)C>[OH:46][NH:47][C:10]([C@@H:4]1[C@H:3]([N:2]([CH3:1])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C@@H:8]2[CH2:9][C@H:5]1[CH2:6][CH2:7]2)=[O:11]
Reactant: CN(C1C2CCC(C2)C1C(=O)O)S(=O)(=O)c1ccc(OCc2ccc3ccccc3c2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN([C@@H]1[C@H]2CC[C@H](C2)[C@@H]1C(=O)NO)S(=O)(=O)c1ccc(OCc2ccc3ccccc3c2)cc1
Reaction time: 20 h
Yield: 50 %

Procedure:
To a solution of 3-{methyl-[4-(naphthalen-2-ylmethoxy)-benzenesulfonyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid (125 mg, 0.268 mmol) in DMF (1 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (103 mg, 0.536 mmol), 1-hydroxybenzotriazole (72.5 mg, 0.536 mmol) and hydroxylamine (50% in water, 82 μL, 1.34 mmol) at room temperature. The mixture was stirred for 20 h, diluted with ethyl acetate (5 mL), and washed with water (3×3 mL) and brine (3 mL). The organic layer was concentrated and the residue was purified by RP-HPLC to give (1R,2S,3R,4S)-N-hydroxy-3-(methyl{[4-(2-naphthylmethoxy)phenyl]sulfonyl}amino)bicyclo[2.2.1]heptane-2-carboxamide (50% yield). MS (ESI) [M+H] 481.2
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([CH3:36])[CH:23]=1)=[O:9])=[O:4].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[CH3:36][C:24]1[CH:23]=[C:22]([NH:21][C:14]2[C:13]3[C:18](=[CH:19][CH:20]=[C:11]([NH:10][C:8](=[O:9])[CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)[CH:12]=3)[N:17]=[CH:16][N:15]=2)[CH:27]=[CH:26][C:25]=1[O:28][C:29]1[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCNC(=O)CCl)cc34)cc2C)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCNC(=O)CN5CCN(C)CC5)cc34)cc2C)cn1
Yield: 51 %

Procedure:
The procedure of Example 62 was repeated except for using 0.07 g of the compound obtained in Example 67 and 0.05 ml of 1-methylpiperazine instead of the compound obtained in Example 61 to obtain the title compound (0.04 g, 51%).
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16]C(=O)[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]4[CH:30]=[C:31]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1>C1COCC1>[CH3:1][C:2]1([CH3:39])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:16])[CH2:13][NH:14][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[C:31]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCc4cccc(S(N)(=O)=O)c4)C(=O)O3)ccc2O1
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3cccc(S(N)(=O)=O)c3)ccc2O1
Reaction time: 2.5 h
Yield: 69.7 %

Procedure:
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide (0.43 g) was stirred in THF (10 ml) while purging with a vigorous stream of nitrogen for 5 min. Potassium trimethylsilanoate (0.43 g) was added and the mixture was stirred at 70° under nitrogen for 2.5 h. The mixture was partitioned between dichloromethane and pH 6.4 phosphate buffer and the aqueous layer was extracted with more dichloromethane. The combined organic layers were washed with water, dried (MgSO4) and concentrated. The residue was purified on silica gel (60 g), eluting successively with ethyl acetate:petroleum ether (bp 40-60°) (1:1), ethyl acetate, 10% then 20% methanol in ethyl acetate to give the title compound (0.286 g), LCMS RT=2.56 min.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[CH:5][N:4]2[CH:7]=[CH:8][N:9]=[C:3]12.[H-].[Na+].Br[CH2:13][CH2:14][Cl:15]>CN(C=O)C>[Cl:15][CH2:14][CH2:13][N:2]1[CH:6]=[CH:5][N:4]2[CH:7]=[CH:8][N:9]=[C:3]12
Reactant: c1cn2cc[nH]c2n1
Reactant: ClCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCCn1ccn2ccnc12
Yield: 37.8 %

Procedure:
Under an argon atmosphere, to a solution of 1H-imidazo[1,2-a]imidazole.hydrochloride (85 mg) in DMF (3 mL) was added 60% sodium hydride (52.1 mg), and the mixture was stirred under ice-cooling for 1 hr. Then, a solution of 1-bromo-2-chloroethane (170 mg) in DMF (0.5 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (38 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:12]1[CH:13]=[CH:14][N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[NH:18][CH2:17][C:16]=12.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[CH2:21][N:15]2[CH:14]=[CH:13][CH:12]=[C:16]2[CH2:17]1)=[O:5]
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reaction time: 18 h
Yield: 75.4 %

Procedure:
The crude 2-chloro-4-fluorobenzoyl chloride (3.68 g) in dichloromethane (25 ml) was added portionwise to a stirred, ice cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (2.76 g), diisopropylethylamine (2.47 g) and dichloromethane (50 ml). After 18 hours at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried with anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (3.85 g), m.p. 110-112° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:12]2[C:7](=[C:8]([N+:18]([O-])=O)[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[NH:6][CH:5]=1)[CH3:3]>CO.O.[Pd]>[NH2:18][C:8]1[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=[C:12]2[C:7]=1[NH:6][CH:5]=[C:4]2[CH:2]([CH3:3])[CH3:1]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c2[nH]cc(C(C)C)c2c1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1cc(N)c2[nH]cc(C(C)C)c2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 20.9 %

Procedure:
To a solution of crude ethyl 3-(1-methylethyl)-7-nitro-1H-indole-5-carboxylate (D218) (10.1 g, 28.5 mmol, 1 equiv) in MeOH (250 ml) and H2O (25 ml) was added 10% palladium on charcoal (50% wet, 1.5 g, 8% w/w) and NH4COOH (17 g, 280 mmol, 10 equiv) and the resulting mixture was stirred at 70° C. for 3 h then cooled to room temperature. The catalyst was filtered off through a pad of celite and most of the MeOH was removed in vacuo. The residue was diluted with AcOEt and the organic layer was washed with a saturated NaHCO3 aqueous solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 3/1 to 1/1) gave methyl 7-amino-3-(1-methylethyl)-1H-indole-5-carboxylate (D221) (1.47 g, 21%) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[S:14][CH2:13][CH2:12][CH2:11]2.[NH2:16][CH:17]1[CH2:22][O:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:19]=2[CH2:18]1.C(N(CC)CC)C>CN(C)C=O>[CH3:28][O:27][C:26]1[C:19]2[CH2:18][CH:17]([NH:16][CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:15]=3[S:14][CH2:13][CH2:12][CH2:11]4)[CH2:22][O:21][C:20]=2[CH:23]=[CH:24][CH:25]=1
Reactant: BrCCCOc1cccc2c1SCCC2
Reactant: COc1cccc2c1CC(N)CO2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc2c1CC(NCCCOc1cccc3c1SCCC3)CO2
Reaction time: 24 h

Procedure:
Under argon, 1.6 g (5.58 mmol) of 8-[(3-bromopropyl)oxy]thiochroman, 1 g (5.58 mmol) of 3-amino-5-methoxy-dihydro-[2H]-benzo[b]pyran and 1.69 g (16.74 mmol) of triethylamine are dissolved in 20 cm3 of dimethylformamide. The mixture is kept at room temperature for 24 hours. The solvent is evaporated off. The residue is taken up in H2O and extracted with methylene chloride. The product is dried over MgSO4. After evaporation, the product is purified over a flash silica column. Eluant: methanol/CH2Cl2 5: 95. The title compound is obtained (yellow oil).
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[CH2:29][C:30]1([NH2:33])[CH2:32][CH2:31]1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:33][C:30]2([CH2:29][C:28]3[CH:34]=[CH:35][CH:36]=[C:26]([CH3:25])[CH:27]=3)[CH2:32][CH2:31]2)=[CH:11][CH:10]=1
Reactant: Cc1cccc(CC2(N)CC2)c1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: Cc1cccc(CC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)c1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 161 mg (1 mmol) 1-(3-methyl-benzyl)-cyclopropylamine. Yield: 179 mg (37%, trifluoroacetate); mass spectroscopy: [M+H]+=369.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][N:18]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]C)=[O:13])=[CH:8]2.[OH-].[Na+]>O1CCCC1.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][N:18]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cn3)cc(OC)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(=O)O)[nH]c12
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 81.5 %

Procedure:
To a solution of methyl 7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate (2.78 g) in a mixture of tetrahydrofuran (25 mL) and ethanol (20 mL) was added 1M aqueous sodium hydroxide solution (11 mL), and the mixture was stirred at 50° C. for 40 min. The mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1M hydrochloric acid (11 mL) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual oil was solidified with diethyl ether to give the title compound (2.18 g, 81%) as a pale orange solid. MS 363 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH2:7])[NH:4][N:3]=1.CN(C)C=O.[CH3:13][N:14]=[C:15]=[S:16]>C(OCC)(=O)C>[NH2:1][C:2]1[N:6]=[C:5]([NH2:7])[N:4]([C:15]([NH:14][CH3:13])=[S:16])[N:3]=1
Reactant: CN=C=S
Reactant: Nc1n[nH]c(N)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=S)n1nc(N)nc1N
Yield: 68 %

Procedure:
The synthesis method of Example 1-(3) was applied. 3,5-Diamino-1H-1,2,4-triazole (11.0 g), dimethylformamide (100 ml) and methyl isothiocyanate (10.0 g) were used as reagents. After the reaction, recrystallization from ethyl acetate gave 13.0 g of white powdery crystals (yield (68%).
Reaction SMILES: [Li][CH2:2]CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[F:26])[C:20]([OH:22])=[O:21].IC>O1CCCC1>[Cl:16][C:17]1[C:18]([CH3:2])=[C:19]([CH:23]=[CH:24][C:25]=1[F:26])[C:20]([OH:22])=[O:21]
Reactant: [Li]CCCC
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccc(F)c1Cl
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
BuLi (68.8 mL, 110 mmol) was diluted with tetrahydrofuran (THF) (80 mL) and cooled to −20° C. 2,2,6,6-tetramethylpiperidine (18.56 mL, 110 mmol) was added dropwise and the mixture stirred at −20° C. for 15 minutes. The solution was cooled to −50° C. whereupon 3-chloro-4-fluorobenzoic acid (8.73 g, 50 mmol, commercially available from e.g. Sigma-Aldrich, Fluorochem or Apollo) dissolved in tetrahydrofuran (THF) (20 mL) was added dropwise. The mixture was stirred at −50° C. for 4 hours before iodomethane (12.51 mL, 200 mmol) was added dropwise. The mixture was allowed to reach room temperature overnight and quenched with water (100 mL). The mixture was acidified with 5N HCl (200 mL) and extracted with tert-butyl methyl ether (3×300 mL). The combined extracts were washed with water (100 mL), brine (100 mL) dried over anhydrous magnesium sulfate and concentrated to a crude product. The solid was recrystalised from cyclohexane (note: some insolubles not satisfactorarily removed) to afford product in 5.73 g.
Reaction SMILES: [C:1]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C.S(=O)(=O)(O)O>[C:2]1([CH2:1][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: c1ccc(CCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
A mixture of dibenzoylmethane (100 g) and 5% palladium on carbon (10.0 g) in ethyl acetate (600 ml) and concentrated sulfuric acid (15 ml) was hydrogenated at a hydrogen pressure of 60 psi and at room temperature. After 2 hours, the reaction was allowed to cool to room temperature. Reaction mixture filtered through talc. The filtrate was treated with water (2×250 ml) and phases separated. The organic phase was treated with saturated aqueous sodium bicarbonate (250 ml). The organic phase was dried over sodium chloride then magnesium sulfate, filtered, concentrated vacuo to give 75.34 g of 1,3-diphenylpropane.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([CH3:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH3:17][C:12]1[CH:11]=[CH:10][C:15]([O:16][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
In an argon atmosphere, 4-fluorobenzaldehyde (0.53 mL, 5.0 mmol) and p-cresol (648 mg, 6.0 mmol) were dissolved in dimethylacetamide (8 mL), and to the solution were added potassium carbonate (828 mg, 6.0 mmol) and cupric oxide (95 mg, 0.50 mmol) and the mixture was heated under reflux for 1.5 hours. The reaction solution was cooled down to room temperature, and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with a 0.5 N aqueous sodium hydroxide solution, water and brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (6:1 hexane/ethyl acetate) to obtain 4-(4methylphenoxy)benzaldehyde (697 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([O:26]C)=O)=[CH:15][C:13]=2[N:14]=1.[F:28][C:29]([F:38])([F:37])[C:30]1[N:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:36][C:33]3[CH:34]=[N:35][C:30]([C:29]([F:38])([F:28])[F:37])=[CH:31][CH:32]=3)=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: COC(=O)c1cc2nc(Nc3c(C)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3ccc(C(F)(F)F)nc3)c3c(c2[nH]1)CC(C)(C)O3
Yield: 48.3 %

Procedure:
The title compound was prepared by following the procedure as described for Example-137 using methyl 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-35, 0.150 g, 0.301 mmol), 6-(trifluoromethyl)pyridine-3-amine (0.067 g, 0.451 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (5.0 mL) to afford 0.075 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 2.23 (s, 3H), 3.09 (s, 2H), 7.23-7.31 (m, 2H), 7.40 (d, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.87 (d, J=8.7 Hz, 1H), 8.45 (d, J=8.4 Hz, 1H), 8.98 (s, 1H), 9.10 (bs, 1H), 10.08 (s, 1H), 10.90 (bs, 1H); MS [M]+: 516.16.