Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:39]([C:41]1[N:42]=[C:43]([C:54]([O-])=[O:55])[N:44]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:45]=1)#[N:40].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]1([C:7]2[C:12]([NH:13][C:54]([C:43]3[N:44]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:45]=[C:41]([C:39]#[N:40])[N:42]=3)=[O:55])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Nc1cccnc1C1=CCCCC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1cccnc1C1=CCCCC1
Yield: 69.1 %

Procedure:
A solution of 365 mg (2.10 mmol) of 2-cyclohex-1-enyl-pyridin-3-ylamine (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 1.46 g (3.14 mmol) of PyBroP, 704 mg (2.30 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 11, step (d)), and 1.09 mL (6.28 mmol) of DIEA at RT for 3 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with saturated aqueous NaHCO3 (1×15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 1% MeOH—CH2Cl2 afforded 615 mg (69%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 9.86 (br s, 1H), 8.69 (dd, 1H, J=8.0, 1.6 Hz), 8.37-8.34 (m, 1H), 7.78 (s, 1H), 7.22-7.17 (m, 1H), 6.05 (sept, 1H, J=1.6 Hz), 5.93 (s, 2H), 3.68-3.63 (m, 2H), 2.45-2.39 (m, 2H), 2.37-2.30 (m, 2H), 1.91-1.77 (m, 4H), 1.00-0.95 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13].Cl>C1COCC1>[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH:4][CH2:1][CH2:2][CH3:3])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCC(Cc2ccc(S(=O)(=O)Cl)cc2)CC1
Reactant: CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCNS(=O)(=O)c1ccc(CC2CCN(C(C)=O)CC2)cc1
Yield: 71.5 %

Procedure:
1-Propylamine (0.586 ml, 7.13 mmol) and triethylamine (0.993 ml, 7.13 mmol) were added to a solution of 4-(1-acetylpiperidin-4-ylmethyl)benzenesulfonylchloride (1.5 g, 4.75 mmol) in THF (20 ml) and this mixture was refluxed for 5 h. After having been cooled, 1N hydrochloric acid (20 ml) was added. The resulting mixture was extracted with ethyl acetate (20 ml×2). The combined organic layers were washed with saturated sodium chloride solution (40 ml), and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel 25 g, ethyl acetate to ethyl acetate/methanol=10/1) to give the title compound (1.15 g, 71%) as pale yellow oil.
Reaction SMILES: C(O[K])(C)(C)C.[CH3:7][N:8]([CH2:10][CH2:11][C@@H:12]([O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)C>CS(C)=O>[CH3:7][NH:8][CH2:10][CH2:11][CH:12]([O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)CC[C@@H](Oc1cccc2ccccc12)c1cccs1
Agent: CC(C)(C)O[K]
Solvent: CS(C)=O
Product: CNCCC(Oc1cccc2ccccc12)c1cccs1
Temperature: 110 °C
Yield: 84.4 %

Procedure:
tBuOK (16.8 g) is added to a solution of (R)-N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine (31 g) in DMSO (100 ml), bubbled with a moderate stream of nitrogen, and the mixture is stirred and heated at 110° C. for 2 hours. After cooling down to lab temperature, the mixture is diluted with water (300 ml) and the racemic product is extracted with toluene. After evaporation, 25 g (84%) of (RS)-N-methyl-3-(naphthyloxy)-3-(2-thienyl)propylamine is obtained.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:7]=1[C:8](O)=[O:9])([CH3:4])[CH3:3].N1C=CC=CC=1.C(Cl)(=O)C([Cl:25])=O>C(#N)C>[CH3:1][C:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:7]=1[C:8]([Cl:25])=[O:9])([CH3:4])[CH3:3]
Reactant: CC(C)(C)Oc1cccc(Cl)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)Oc1cccc(Cl)c1C(=O)Cl
Reaction time: 0.5 h

Procedure:
2-[(1,1-dimethylethyl)oxy]-6-chlorobenzoic acid (68.6 mg, 0.3 mmol) was weighed into a 1 dram septum-capped vial containing a micro stir bar under nitrogen. Dry acetonitrile (300 microliter), dry pyridine (24 microliter, 0.3 mmol) and oxalyl chloride (26 microliter, 0.3 mmol) were added in order to the vial using microliter syringes. The yellow homogeneous solution was stirred for 30 minutes to afford a solution of 2-[(1,1-dimethylethyl)oxy]-6-chlorobenzoyl chloride.
Reaction SMILES: [F:1][CH2:2][C:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O1CCOCC1.O>[F:1][CH2:2][C:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][N:5]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:4]1
Reactant: CCOC(=O)C1(CF)CCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1(CF)CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a solution of ethyl 3-(fluoromethyl)pyrrolidine-3-carboxylate (1.86 g, 10.62 mmol) in a 1:1 mixture of 1,4-dioxane/water (18 mL) was added sodium carbonate (1.35 g, 12.74 mmol) and the mixture cooled to 0° C. in an ice bath. Benzyl chloroformate (1.79 mL, 12.74 mmol) was added dropwise and the resulting mixture was stirred at 0° C. for 30 minutes, then at ambient temperature for 18 hours. The mixture was partitioned between water and ether, and the layers separated. The organic layer was washed sequentially with water, saturated sodium bicarbonate solution and brine, then dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography (Biotage 25M; 15% ethyl acetate/hexanes) to afford 1-benzyl 3-ethyl 3-(fluoromethyl)pyrrolidine-1,3-dicarboxylate (3.3 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:18])[CH3:17])=[CH:4][CH:3]=1.Br[CH2:21][C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)(O)[O-].[Na+]>C(O)(C)C>[CH2:26]([O:25][C:23]([C:22]1[N:19]=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:17])[CH3:18])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:21]=1)=[O:24])[CH3:27]
Reactant: CC(C)c1ccccc1C(=N)Nc1ccc(Br)cc1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2ccc(Br)cc2)c(-c2ccccc2C(C)C)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a 250 mL round bottom flask attached with condenser was added N-(4-Bromo-phenyl)-2-isopropyl-benzamidine (1.94 g, 6.11 mmol), ethyl bromopyruvate (1.54 mL, 12.2 mmol), sodium bicarbonate (1.02 g, 12.2 mmol), and iso-propanol (45 mL). The reaction slurry was allowed to stir at 80° C. for approximately 2 hrs. The reaction solution was decanted into a clean round bottom flask and concentrated in vacuo. The resulting residue was dissolved in acetic acid (25 mL), and the solution was allowed to stir at reflux for approximately 2 hrs. The solution was concentrated in vacuo, and the product residue was taken into EtOAc (200 mL) and washed with aq NaCl (200 mL×2) and aq NaHCO3 (100 mL). The organic phase was partitioned, dried over Na2SO4, filtered, concentrated, and chromatographed through a 40 g SiO2 column using a mobile gradient of 100% Fix to 70% EtOAc to afford 1.90 g (75% yield) of title compound. MS (ES): 414.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[O:6][CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=1.CN(C)C1C=CC=CC=1.Cl[C:30]([N:32]=[C:33]=[O:34])=[O:31]>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]1[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:9]2[CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:7][O:6][C:5]=12
Reactant: Fc1ccccc1CC1=NC(c2ccccc2)CO1
Reactant: O=C=NC(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: O=c1[nH]c(=O)n2c(c1-c1ccccc1F)OCC2c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.4 %

Procedure:
To 2-(2-fluorobenzyl)-4-phenyloxazoline (0.250 g, 0.980 mmol) and N,N-dimethylaniline (0.134 g, 1.09 mmol) in dichloromethane (1.5 mL) at 0° C. was added dropwise chlorocarbonyl isocyanate (0.103 g, 0.980 mmol). The mixture was allowed to warm to room temperature and was stirred for 24 h. The solution was concentrated, dissolved in ethyl acetate (1 mL) and filtered through a short pad of silica gel, eluating with ethyl acetate (150 mL). Concentration gave green-yellow crystals (0.300 g) which were used immediately in the next step due. MS=325.1 ((M+H)+).
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[CH3:11][O:12][C:13](=[O:31])[CH2:14][C:15]1[CH:20]=[C:19]([Br:21])[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[C:17]([Br:30])[CH:16]=1.FC(F)(F)[C:34](O)=[O:35].Cl>>[CH3:11][O:12][C:13](=[O:31])[CH2:14][C:15]1[CH:20]=[C:19]([Br:21])[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([CH:34]=[O:35])[CH:24]=2)=[C:17]([Br:30])[CH:16]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(O)cc2)c(Br)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: COC(=O)Cc1cc(Br)c(Oc2ccc(O)c(C=O)c2)c(Br)c1
Temperature: 95 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
Hexamethylenetetramine (262 mg, 1.87 mmol) was added to a solution of methyl[3,5-dibromo-4-(4-hydroxyphenoxy)phenyl]acetate (370 mg, 0.89 mmol) and trifluoroacetic acid (1.5 mL). The reaction mixture was stirred for 16 hours at 95° C. before cooling to room temperature. Hydrochloric acid (3 mL, 2 N) was added and the reaction mixture was stirred for one hour and extracted with chloroform. The organic phase was concentrated in vacuo and dissolved in ethyl acetate. The organic phase was washed with hydrochloric acid (2 N), water and brine, dried over Na2SO4 and concentrated. The residue was purified on a column (MPLC, silica, gradient eluent: n-heptane/ethyl acetate from 1:0 to 4:1) to give yielded methyl[3,5-dibromo-4-(3-formyl-4-hydroxyphenoxy)phenyl]acetate as a white solid (150 mg, 38%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.C([Li])CCC.I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:22]([NH:14][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:15])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCI
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCNc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: -20 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) (1.0 g, 4.93 mmole) in 12 mL tetrahydrofuran (THF) was cooled to −78° C. and treated dropwise with 2.5 M n-butyllithium solution (2.2 mL) and allowed to warm to −20° C. over a one hour period. Iodopentane (1.28 mL) was introduced at −20° C., the mixture stirred at room temperature for three hours, poured into 50 mL of a saturated aqueous sodium bicarbonate solution and extracted with three portions of 50 mL of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a brown oil. The product was purified by flash chromatography (SiO2, 5% ethyl acetate/hexanes) providing 1.1 g (82%) of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (51) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[N:2]=1.[Cl:9][C:10]1[S:14][C:13]([S:15]([NH:18][C:19]2[C:24](Br)=[N:23][C:22]([CH3:26])=[CH:21][N:20]=2)(=[O:17])=[O:16])=[CH:12][CH:11]=1>>[Cl:9][C:10]1[S:14][C:13]([S:15]([NH:18][C:19]2[C:24]([O:8][CH2:7][C:3]3[N:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:23][C:22]([CH3:26])=[CH:21][N:20]=2)(=[O:16])=[O:17])=[CH:12][CH:11]=1
Reactant: OCc1cccnn1
Reactant: Cc1cnc(NS(=O)(=O)c2ccc(Cl)s2)c(Br)n1
Product: Cc1cnc(NS(=O)(=O)c2ccc(Cl)s2)c(OCc2cccnn2)n1

Procedure:
Prepared by the method of Example 20b using pyridazine-3-methanol and 5-chloro-N-(3-bromo-5-methyl-2-pyrazinyl)-2-thiophenesulphonamide (Example 23a).
Reaction SMILES: [CH:1]1([N:7]([CH3:30])[C:8](=[O:29])[CH2:9][CH2:10][CH:11]([C:27]#[N:28])[CH2:12][C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=[CH:15][C:14]=2[NH2:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[NH2:28][C:27]1[CH:11]([CH2:10][CH2:9][C:8]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:30])=[O:29])[CH2:12][C:13]2[C:14](=[CH:15][CH:16]=[C:17]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:18]=2)[N:26]=1
Reactant: CN(C(=O)CCC(C#N)Cc1cc(Oc2ccccc2)ccc1N)C1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CN(C(=O)CCC1Cc2cc(Oc3ccccc3)ccc2N=C1N)C1CCCCC1
Temperature: 25 °C

Procedure:
5-(2-amino-5-phenoxy-phenyl)-4-cyano-pentanoic acid cyclohexyl-methyl-amide (0.20 g, 0.46 mmol) was dissolved in toluene (5 mL), followed by addition of aluminum chloride (0.184 g, 1.38 mmol). The reaction mixture was heated to reflux for 10 minutes and was then allowed to cool to room temperature. The crude reaction mixture was poured into a separatory funnel and partitioned between ethyl acetate and 10% aqueous Na2CO3 solution. The organic layer was washed 2 more times with 10% aqueous Na2CO3 solution and one time with saturated brine solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield a residue which was purified by flash chromatography using chloroform:methanol:triethylamine as the mobile phase to yield the title compound as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]Cl)=[CH:7][CH:6]=[CH:5][C:4]=1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18].[I-].[Na+].[C-:21]#[N:22].[K+]>CS(C)=O>[CH3:1][O:2][C:3]1[C:4]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:5][CH:6]=[CH:7][C:8]=1[CH2:9][C:21]#[N:22]
Reactant: [C-]#N
Reactant: COc1c(CCl)cccc1Sc1ccccc1Cl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(CC#N)cccc1Sc1ccccc1Cl
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A mixture of 2-chlorophenyl 2-methoxy-3-chloromethylphenyl thioether (9.2 g) and sodium iodide (4.8 g) in dimethyl sulfoxide (50 ml) was stirred at room temperature. To the mixture was added powdered potassium cyanide (2.1 g) all at once, and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was poured into ice-water and extracted with diethyl ether. The extract was washed with water, dried and then evaporated to give oily 2-[2-methoxy-3-(2-chlorophenylthio)phenyl]acetonitrile (8.9 g). This product was purified by column chromatography (silica gel 150 g, benzene) to give purified oily product (4.1 g).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][NH:48][CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:48]([CH3:47])[CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNCCC(C)C
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)CCC(C)C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with n-methylisoamylamine (Matrix) to give the title product. LC-MS (ES+) 748 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:14])[C:5](=[O:15])[C:4]=1[C:16]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19].[C:29](OC(=O)C)(=[O:31])[CH3:30].O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:14][C:29](=[O:31])[CH3:30])[C:5](=[O:15])[C:4]=1[C:16]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(C)cc(OC)c1C1=C(OC)C(=O)c2c(O)cccc2C1=O
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1cc(C)cc(OC)c1C1=C(OC)C(=O)c2c(OC(C)=O)cccc2C1=O
Reaction time: 8 h

Procedure:
In pyridine (3 ml) was dissolved methyl 2-(3-methoxy-5-hydroxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methylbenzoate (20 mg) as obtained in Example 3, followed by addition of acetic anhydride (3 ml). The mixture was allowed to stand at room temperature overnight. After addition of water, the mixture was extracted with ethyl acetate. The solvent layer was washed with dilute HCl, water and dilute aqueous sodium hydrogen carbonate in that order, and dried over magnesium sulfate. The solvent was then distilled off and the residue was crystallized by addition of methanol. The above procedure gave methyl 2-(3-methoxy-5-acetoxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methylbenzoate (13 mg).
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:12][C@H](C)C2C=CC=CC=2)[CH3:11])=[CH:5][CH:4]=1>[Pd].CO>[ClH:1].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C@H:10]([NH2:12])[CH3:11])=[CH:7][CH:8]=1
Reactant: C[C@H](Cc1ccc(O)cc1)N[C@H](C)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C[C@@H](N)Cc1ccc(O)cc1
Temperature: 50 °C
Yield: 73.5 %

Procedure:
A hastalloy autoclave was charged with (2R)-1-(4-hydroxyphenyl)-2-(N-[(R)-a-methylbenzyl])amino propane hydrochloride (72.3 g, 248 mmol), 5% Pd/C (16.0 g, wetted with 100 mL of EtOH), and MeOH (400 mL). The autoclave was pressurized to 50 psi H2 and heated to 50° C. for 6 h with vigorous stirring. After cooling, purging with nitrogen and filtering the mixture, the filtrate was concentrated on a rotary evaporator under vacuum. The resulting oily foam was dissolved in a minimal amount of MeOH and was triturated by addition of EtOAc. The solid was filtered, and another crop of solid which precipitated from the filtrate was also collected. The combined solids were dried in a 45° C. vacuum oven overnight to yield 34.2 g (73%) of a white solid. MP 160° C. [dec]). MS(FD+) m/z 151 (92%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH3:18])[CH:16]=[N:17][C:13]=2[CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>O>[CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH3:18])[CH:16]=[N:17][C:13]=2[CH:12]=[C:11]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[C:27]([O:28][CH3:29])[CH:26]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Cn1cnc2cc(Br)cc(OCc3ccccc3)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cc(OCc3ccccc3)c3c(c2)ncn3C)cc1OC
Temperature: 110 °C

Procedure:
To a mixture 7-(benzyloxy)-5-bromo-1-methyl-1H-benzo[d]imidazole 2.51 (105 mg, 0.33 mmol), 3,4-dimethoxy phenyl boronic acid (72 mg, 0.39 mmol), Cs2CO3 (294 mg, 0.90 mmol) and PEPPSI″-IPr catalyst (10.2 mg, 0.015 mmol) was added DME and water (1:1, 3 mL) and the reaction was heated to 110° C. for 1 hr. The reaction mixture was concentrated and purified by flash chromatography (SiO2, 0% MeOH/EtOAc to 20% MeOHEtOAc/MeOH) to afford 7-(benzyloxy)-5-(3,4-dimethoxyphenyl)-1-methyl-1H-benzo[d]imidazole 2.52.
Reaction SMILES: [C:1]([O:6]C)(=O)[C:2]([CH3:4])=[CH2:3].[CH:8]([NH2:11])([CH3:10])[CH3:9]>>[CH:8]([NH:11][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3])([CH3:10])[CH3:9]
Reactant: C=C(C)C(=O)OC
Reactant: CC(C)N
Product: C=C(C)C(=O)NC(C)C
Yield: 32 %

Procedure:
200 g of methyl methacrylate and 142 g of isopropylamine were heated at 190° C. for 21/2 hours in a 0.5-liter stirred autoclave (pmax =15 atmospheres). N-isopropyl-methacrylic acid amide was formed in this way in a 32% yield.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1>>[Br:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7]([CH2:9][O:21][C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:22])[F:23])=[CH:20][CH:19]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: ClCc1nc2cc(Br)ccc2[nH]1
Product: FC(F)(F)c1ccc(OCc2nc3cc(Br)ccc3[nH]2)cc1

Procedure:
Using the procedure for Step E in Example 1, the title compound was prepared from 5-bromo-2-chloromethyl-1H-benzimidazole (200 mg, 0.816 mmol) and α,α,α-trifluoro-p-cresol (132 mg, 0.816 mmol) and was obtained as an off-white solid (76.2 mg, 25% yield). Calcd. For C21H16F3N3O3S: 371.15 (M+H), Found 371.0.
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.C(OC([NH:29][CH:30]([C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]([NH2:43])=[O:42])=[CH:36][CH:35]=1)[C:31](O)=[O:32])=O)(C)(C)C>>[CH3:10][CH:9]([S:11][C:12]1[NH:13][N:14]=[N:15][N:16]=1)[C:6]1[CH2:7][S:8][C@@H:3]2[CH:2]([NH:1][C:31](=[O:32])[CH:30]([C:34]3[CH:35]=[CH:36][C:37]([NH:40][C:41]([NH2:43])=[O:42])=[CH:38][CH:39]=3)[NH2:29])[C:20](=[O:21])[N:4]2[C:5]=1[C:17]([OH:19])=[O:18]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(NC(N)=O)cc1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccc(NC(N)=O)cc3)[C@H]2SC1

Procedure:
When 7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (3.28 g, 0.01 mol) was acylated with the product of Example 1 (3.1 g, 0.01 mol) according to the procedure of Example 2, the title compound was obtained: mp > 300°.
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=2[C:28]([F:31])([F:30])[F:29])[N:14]=[CH:13]3)[C:6](=[O:8])[N:7]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:3]2[S:4][C:5](=[CH:9][C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[N:15]([CH2:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[C:28]([F:30])([F:31])[F:29])[N:14]=[CH:13]4)[C:6](=[O:8])[N:7]=2)[CH2:35][CH2:34]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C#N)cc3C(F)(F)F)c2)S1
Reactant: CN1CCNCC1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C#N)cc4C(F)(F)F)c3)S2)CC1

Procedure:
4-{5-[2-(4-Methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-indazol-1-ylmethyl}-3-trifluoromethyl-benzonitrile was prepared from 4-[5-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-indazol-1-ylmethyl]-3-trifluoromethyl-benzonitrile and 1-methyl-piperazine following General Procedure C.