Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.[Na].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccccc1-c1ccc(CO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1-c1ccc(COS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
10.0 g (41 mmol) of methyl 2-(4'-hydroxymethylphenyl)benzoate was dissolved in tetrahydrofuran (200 ml). 2.0 g (50 mmol) of a 60% sodium hydrode was added thereto under cooling with ice, followed by stirring for one hour. A solution of 8.65 g (45.4 mmol) of p-toluenesulfonyl chloride in tetrahydrofuran (50 ml) was dropwise added thereto. Then, the reaction was effected at room temperature for 2 hours and further reflux by heating was effected for 4 hours. The reaction liquid was cooled and added to a saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with chloroform (200 ml). After the organic phase was washed with water and dried, it was subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 13.4 g of the title compound as a was (yield 82%).
Reaction SMILES: N#N.Cl[C:4]1[N:5]=[N+:6]([O-:20])[C:7]2[CH:16]=[C:15]3[C:11]([CH2:12][CH:13]([N:17]([CH3:19])[CH3:18])[CH2:14]3)=[CH:10][C:8]=2[N:9]=1.[Sn](CC)(CC)(CC)[CH2:22][CH3:23]>COCCOC.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>[CH3:18][N:17]([CH3:19])[CH:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:7]3[N+:6]([O-:20])=[N:5][C:4]([CH2:22][CH3:23])=[N:9][C:8]=3[CH:10]=2)[CH2:14]1
Reactant: CC[Sn](CC)(CC)CC
Reactant: CN(C)C1Cc2cc3nc(Cl)n[n+]([O-])c3cc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: COCCOC
Product: CCc1nc2cc3c(cc2[n+]([O-])n1)CC(N(C)C)C3
Temperature: 85 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
Pd(PPh3)4 (240 mg, 0.21 mmol) was added to a N2-purged, stirred solution of chloride 112 (550 mg, 1.9 mmol) and SnEt4 (800 mg, 3.4 mmol) in DME (55 mL), and the mixture stirred at 85° C. under N2 for 16 h. The mixture was cooled, the solvent evaporated and the residue purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 115 (250 mg, 47%) as an unstable brown solid: 1H NMR δ 8.23 (s, 1H, H-9), 7.73 (s, 1H, H-5), 3.04-3.33 (m, 5H, H-6, H-7, H-8) 3.02 (q, J=7.6 Hz, 2H, CH2), 2.35 [s, 6H, N(CH3)2], 1.43 (t, J=7.6 Hz, 3H, CH3); 13C NMR δ 167.2, 152.2, 147.6, 146.3, 132.4, 122.9, 114.6, 67.6, 43.8 (2), 38.0, 37.6, 30.6, 12.3; HRMS calcd for C14H18N4O (M+) m/z 258.1481, found 258.1473.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][CH2:31][C:32](O)=[O:33])[C:25]=1[CH3:35])(=[O:12])=[O:11].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:57]1([NH:60][CH:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH2:59][CH2:58]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH:57]1([NH:60][CH:61]2[CH2:66][CH2:65][N:64]([C:32](=[O:33])[CH2:31][CH2:30][C:26]3[C:25]([CH3:35])=[C:24](/[CH:23]=[C:16]4\[C:17](=[O:22])[NH:18][C:19]5[C:15]\4=[CH:14][C:13]([S:10]([CH2:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=5)[NH:28][C:27]=3[CH3:29])[CH2:63][CH2:62]2)[CH2:59][CH2:58]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)O
Reactant: C1CC(NC2CC2)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)N1CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 3-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-propionic acid (178 mg, 0.33 mmol), EDAC (135 mg, 0.7 mmol) and HOBt (45 mg, 0.33 mmol) in DMF (4 mL) was added cyclopropyl-piperidin-4-yl-amine (100 mg, 0.7 mmol) and TEA (0.14 mL). The mixture was stirred at rt for 2 days. The reaction was diluted with and NaHCO3, extracted with DCM. The combined extracts were concentrated and the residue was purified on a silica gel column to give the titled compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[CH3:8][O:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([CH2:21]Cl)[CH:19]=[CH:20][C:15]=2[S:14][C:13]2[N:23]=[CH:24][CH:25]=[N:26][C:12]1=2.O>CN(C)C=O.C(OCC)(=O)C>[CH3:8][O:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([CH2:21][N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)[CH:19]=[CH:20][C:15]=2[S:14][C:13]2[N:23]=[CH:24][CH:25]=[N:26][C:12]1=2
Reactant: COCN1c2cc(CCl)ccc2Sc2nccnc21
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCN1c2cc(Cn3cccn3)ccc2Sc2nccnc21
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
To a solution of 100 mg of pyrazole in N,N-dimethylformamide was added in a nitrogen atmosphere 60 mg of sodium hydride (oily 60%) under ice cooling and the resulting mixture was stirred for 10 minutes. Subsequently, 240 mg of 10-methoxymethyl-8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine was added to the reaction mixture, which was then heated to 80° C. for 10 minutes. Then the reaction mixture was brought back to room temperature and distributed into water and ethyl acetate. The organic layer was extracted, washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue thus obtained was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane) to thereby give 150 mg of the title compound as a yellow powder.
Reaction SMILES: [Mg].Br[C:3]1[C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=2[S:6][CH:7]=1.[F:12][C:13]([F:30])([F:29])[CH:14]1[CH2:16][N:15]1[S:17]([C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=1[CH3:28])(=[O:19])=[O:18]>C1COCC1.[Cu]I>[S:6]1[CH:7]=[C:3]([CH2:16][CH:14]([NH:15][S:17]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])(=[O:19])=[O:18])[C:13]([F:29])([F:12])[F:30])[C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][C:5]1=2
Reactant: Brc1csc2ccccc12
Reactant: Cc1cc(C)c(S(=O)(=O)N2CC2C(F)(F)F)c(C)c1
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)NC(Cc2csc3ccccc23)C(F)(F)F)c(C)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 23.4 %

Procedure:
A mixture of 9 mg (2.20 mmol) of magnesium powder, 79 mg (0.37 mmol) of 3-bromobenzo[b]thiophene, 8 mg (0.04 mmol) of copper (I) iodide, and 50 mg (0.17 mmol) of 2-trifluoromethyl-1-(2,4,6-trimethylbenzenesulfonyl)aziridine in 1 mL of THF was warmed at 80° C. in a sealed tube. After 30 minutes, the reaction was quenched with 7 mL of saturated aqueous ammonium chloride solution and extracted with three 7 mL portions of ethyl acetate. The combined organic layers were washed with two 5 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was chromatographed on silica gel using dichloromethane-hexanes (1:1) to load the sample and then eluting with dichloromethane-hexanes (1:1, then 75:25). The material from the column was triturated with ether-hexanes to afford 17 mg (23%) of the title compound as a white solid which is consistent with the desired product. MS: m/z 428.51 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11].C(O)C>C1(C)C=CC=CC=1>[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20][NH:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cn1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.5 %

Procedure:
A solution of 3-amino-6-methoxy-pyridine (200.0 g, 1611.05 mmol, 1.0 eq) and 2-ethoxymethylene-malonic acid diethyl ester (348.4 g, 1611.05 mmol, 1.0 eq) in toluene (650 mL) is heated to reflux and the ethanol formed is removed by azeotropic distillation. After 2.5 hours at 115° C., the reaction mixture is cooled to room temperature, the solvent is removed and the resulting solid is washed with 500 mL of hexane then dried under vacuum to afford 2-[(6-methoxy-pyridin-3-ylamino)-methylene]malonic acid diethyl ester as a red solid (434.0 g, 90% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH3:11][NH:12][CH3:13].C1COCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([N:12]([CH3:13])[CH3:11])=[O:8]
Reactant: O=C(Cl)c1cncc(Br)c1
Reactant: CNC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
Into a 100 mL round bottomed flask were added 5-bromonicotinoyl chloride (0.531 g, 2.41 mmol) and anhydrous pyridine (5 mL). A 2M solution of dimethylamine in THF (5 mL, 10.0 mmol) was added dropwise, and the reaction mixture was stirred at rt under N2 for 6 h after which it was concentrated under vacuum. The crude residue was partitioned between EtOAc and water. The layers were separated, and the organic phase was washed 3× with water, then treated with brine, dried (Na2SO4), filtered and concentrated to afford 5-Bromo-N,N-dimethyl-nicotinamide as a brown oil (0.4951 g, 89%). MS: m/z 229/231 [MH+].
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]1.[H-].[Na+]>CN(C=O)C>[CH3:7][N:6]1[C:2]([O:18][CH2:17][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: OCC1CCOCC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc([N+](=O)[O-])c1OCC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To a solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole (0.2 g, 1.24 mmol) and tetrahydro-2H-pyran-4-yl-methanol (0.223 g, 1.92 mmol) in DMF (20 mL) cooled to 0° C. was added sodium hydride (60% dispersion in mineral oil, 0.128 g, 3.2 mmol) portionwise. The mixture was warmed to room temperature and stirred for 1 hr. The mixture was concentrated under reduced pressure and the residue dissolved in EtOAc. The organic layer was washed with water, separated and passed through a phase separator cartridge. The solvent was removed under reduced pressure and the crude product was purified via silica gel column chromatography (0-80% EtOAc/isohexane) to give 1-methyl-4-nitro-5-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-pyrazole as a clear oil (143 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 4.28 (d, J=6.3 Hz, 2H), 4.07-3.96 (m, 4H), 3.71 (s, 3H), 2.22-2.09 (m, 1H), 1.82-1.62 (m, 4H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[N:7]=[C:6]2[C:27]([OH:29])=O.Cl.[OH:31][C:32]1[C:41]([O:42][CH3:43])=[CH:40][CH:39]=[C:38]2[C:33]=1[CH2:34][CH2:35][NH:36][CH2:37]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[N:7]=[C:6]2[C:27]([N:36]1[CH2:35][CH2:34][C:33]2[C:38](=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:32]=2[OH:31])[CH2:37]1)=[O:29]
Reactant: COc1ccc2c(c1O)CCNC2
Reactant: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(C(=O)O)c2cc1OC
Agent: Cl
Product: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(C(=O)N3CCc4c(ccc(OC)c4O)C3)c2cc1OC
Yield: 13.6 %

Procedure:
Reaction of 6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 115 (13.6% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.83 and 2.90 (2t, 2H), 3.49-4.05 (m, 20H), 4.37 and 4.90 (2s, 2H), 6.27-7.16 (m, 3H), 7.46 and 7.50 (2s, 1H), 7.78 and 7.84 (2s, 2H), 8.70 and 8.73 (2s, 1H); MS (ESI) m/z 562 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[N+:16]([O-])([O-:18])=[O:17].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:16]([C:15]1[C:2]([OH:1])=[C:3]([CH:12]=[CH:13][CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])([O-:18])=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(c1ccccc1)c1ccccc1O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cccc([N+](=O)[O-])c1O
Reaction time: 24 h
Yield: 43.6 %

Procedure:
2-Hydroxybenzophenone (3.00 g, 15.1 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.42 g, 16.7 mmol). The addition of sulfuric acid (25 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.60 g, 44%). 1H NMR (CD3COCD3): d 8.30 (d,1H), 7.86 (m,3H), 7.71 (m, 1H), 7.78 (d, 1H), 7.56 (dd 2H), 7.24 (t, 1H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH:43]=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH:43]=[N:42][N:41]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CC(C)C)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CC(C)C)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.45 g) was dissolved in dichloromethane (20 ml). The solution was cooled to −78° C., and a solution of 3-chloroperbenzoic acid (0.45 g) in dichloromethane (5 ml) was added dropwise to the solution. The mixture was stirred for 1 hour at −78° C., sodium thiosulfate solution was added to the mixture, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl)methylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 29) (0.3 g) as yellow amorphous.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[C:24]=1[NH2:25]>CN(C=O)C.CCOC(C)=O>[CH2:1]([NH:8][C:9](=[O:12])[CH2:10][NH:25][C:24]1[C:23]([F:22])=[CH:29][C:28]([F:30])=[CH:27][C:26]=1[F:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1c(F)cc(F)cc1F
Reactant: O=C(CCl)NCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(CNc1c(F)cc(F)cc1F)NCc1ccccc1
Temperature: 100 °C
Reaction time: 40 h
Yield: 23.7 %

Procedure:
A mixture of N-benzyl-2-chloroacetamide (700 mg—obtained as described for intermediate 1), DIPEA (0.76 mL) and 2,4,6-trifluoro-aniline (559 mg) in anhydrous DMF (5 mL) was stirred at 100° C. for 40 hours under a Nitrogen atmosphere. Then, more DIPEA (0.2 mL) was added and the mixture was heated to 100° C. for further 4 hours. After cooling to room temperature, the solution was diluted with AcOEt and washed with water and ice. The separated aqueous phase was extracted with further AcOEt (3×30 mL). The combined organic extracts were dried and concentrated in vacuo. The residue was purified by flash chromatography (CH/AcOEt from 8:2 to 6:4) to give the title compound (265 mg) as a beige solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:37])[CH2:33][CH2:34][O:35][CH3:36]>>[CH3:36][O:35][CH2:34][CH2:33][C:32]1[N:37]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:28][N:31]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1
Yield: 23.3 %

Procedure:
250 mg (0.611 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example OOA) and 106 mg (0.672 mmol, 75% pure) of N′-hydroxy-3-methoxypropanimidamide (Example 64A) were reacted according to the General Method 1. Enantiomer separation of the racemate according to Method 16D gave 77.0 mg of the title compound from Example 277 and 70.0 mg of the title compound from Example 278 (47% of theory).
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=O)=[O:21].[CH2:31]1[C:39]2[C:34](=[CH:35]C=CC=2)[CH2:33][N:32]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH3:33][CH:34]([CH3:35])[CH2:39][CH2:31][NH:32][C:28](=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:20]([N:12]1[CH2:11][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)=[O:21]
Reactant: O=C(O)CCCCCNC(=O)N1Cc2ccccc2C1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: NCCCc1ccccc1
Product: CC(C)CCNC(=O)CCCCCNC(=O)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 1C, substituting 3-methylbutan-1-amine for 3-phenylpropan-1-amine and 6-[(1,3-dihydro-2H-isoindol-2-ylcarbonyl)amino]hexanoic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.64-7.69 (m, 1H), 7.24-7.34 (m, 4H), 6.26 (t, J=5.5 Hz, 1H), 4.57 (s, 4H), 2.99-3.10 (m, 4H), 2.03 (t, J=7.3 Hz, 2H), 1.41-1.59 (m, 5H), 1.21-1.30 (m, 4H), 0.84 (d, J=6.6 Hz, 6H); MS (ESI(+)) m/e 346 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([N:11]=O)[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]2.[Cl-].[NH4+].[CH3:21][C:22]([CH3:24])=O>[Zn]>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([N:11]=[C:22]([CH3:24])[CH3:21])[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]2
Reactant: CC(C)=O
Reactant: Cc1ccc2c(c1)CC(c1ccccc1)N2N=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: CC(C)=NN1c2ccc(C)cc2CC1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Methyl-1-nitroso-2-phenylindoline (0.8 g, 0.00336 mol) was dissolved in acetone (30 mL), and to this saturated ammonium chloride solution (4.4 mL) was added. The reaction mixture was cooled to 0° C., and zinc dust (1.31 g, 0.0201 mol) was added portionwise over 30 min. at 0° C. The reaction was stirred for 1 h at RT, and after completion of reaction (monitored by TLC), the solvent was removed under reduced pressure. Water (100 mL) was added and the mixture extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain product as a yellow colored oil (0.6 g).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:15])[CH:4]=[C:5]([CH:9]([OH:14])[C:10]([F:13])([F:12])[F:11])[N:6]([CH3:8])[CH:7]=1.[CH2:16]=[O:17].[OH-].[Na+].Cl>CO>[OH:1][C:2]1[C:3](=[O:15])[CH:4]=[C:5]([CH:9]([OH:14])[C:10]([F:11])([F:12])[F:13])[N:6]([CH3:8])[C:7]=1[CH2:16][OH:17]
Reactant: C=O
Reactant: Cn1cc(O)c(=O)cc1C(O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(C(O)C(F)(F)F)cc(=O)c(O)c1CO
Temperature: 40 °C
Reaction time: 1 h
Yield: 146.4 %

Procedure:
In each of three parallel synthesis tubes equipped with a magnetic stir bar was placed 5-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (0.50 g, 2.24 mmol), a 36.5% by wt formaldehyde solution (6 mL, 80.4 mmol), and a 6.00 N sodium hydroxide solution (0.45 mL, 2.7 mmol). The resulting solution was heated to about 40° C. for overnight. Analysis by HPLC Method 1 (Example 24) indicated consumption of the starting material. The contents of the three tubes were combined, and the resulting solution was cooled in an ice-water bath. A 6.00 N hydrochloric acid solution (1.1 mL, 6.6 mmol) was added to adjust the pH of the solution to about 6. The mixture was concentrated in vacuo to remove most of the solvent to give a solid/liquid mixture. To the mixture was added methanol (100 mL), and the mixture was stirred for 1 h. The first crop of the solid was collected by suction filtration and washed with de-ionized water thoroughly to give 3-hydroxy-2-hydroxymethyl-1-methyl-6-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (0.83 g, 48% yield, HPLC Method 1 (Example 24), RT=7.7 min, HPLC purity (peak percent area): 99.2% at λ=280 nm). 1H NMR (DMSO-d6+D2O) δ ppm: 6.53 (s, 1H), 5.54 (q, J=6.5 Hz, 1H), 4.67 (s, 2H), 3.76 (s, 3H); MS-ESI (m/z) 254.1 [M+1]+, 236.1, 208.1 (100%), 139.2.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10]CC)=[O:9])(=[O:3])[CH3:2].[OH-].[Na+].O>C1COCC1>[C:1]([C:4]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Br)cc1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(Br)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of ethyl 2-(2-acetyl-4-bromophenoxy)acetate (8.9 g, 29.56 mmol) in THF (60 mL) was added sodium hydroxide (1.43 g, 35.75 mmol) and water (10 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (30 mL) and adjusted to pH 2 with HCl (3N). The solids were collected by filtration to afford 2-(2-acetyl-4-bromophenoxy)acetic acid as a light yellow solid (6.3 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH3:12][N:13]([CH:15](OC)OC)[CH3:14]>>[CH3:12][N:13]([CH3:15])/[CH:14]=[CH:10]/[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:11]
Reactant: COC(OC)N(C)C
Reactant: COc1cccc(C(C)=O)c1
Product: COc1cccc(C(=O)/C=C/N(C)C)c1
Yield: 89 %

Procedure:
The title compound was prepared in 89% yield from 1-(3-methoxyphenyl)ethanone and DMF-DMA according to the procedure for the preparation of Example 12, part A. 1H NMR (400 MHz, CDCl3): δ 2.94 (3H, s), 3.13 (3H, s), 3.85 (3H, s), 7.69 (1H, d, J=12.4 Hz), 6.98-7.01 (1H, m), 7.29-7.46 (3H, m), 7.79 (1H, d, J=12.4 Hz).