Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[C:13]([C:20]3[NH:28][C:27]4[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=4[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[N:11]=1.CCOC(C)=O>CN(C=O)C>[CH:1]1([O:6][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([C:20]4[NH:28][C:27]5[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=5[CH:21]=4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(OC5CCCC5)nc34)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
Similar to the method described in Example 103, cyclopentanol (0.18 mL, 2.02 mmol) was added to a suspension of NaH (60% w/w in mineral oil) (81 mg, 2.02 mmol) in DMF (2.0 mL) and the resulting light-yellow solution was stirred at RT for 10 min. 2-(2-Chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 75 mg, 0.25 mmol) was then added and the resulting dark red solution was stirred at RT for 5 min, then heated at 70° C. for 3 h. The mixture was cooled to RT and partitioned between EtOAc (70 mL) and saturated aq. NH4Cl (50 mL). The organic layer was separated, sequentially washed with water (20 mL) and brine (20 mL), and then dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography silica gel column, 10-100% EtOAc in hexanes over 25 min. then 100% EtOAc for 10 min.) to give 2-(2-(cyclopentyloxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (30 mg, 0.09 mmol, 33.8% yield) as an amorphous yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 12.70 (br. s., 1H), 7.95-8.10 (m, 2H), 7.51-7.59 (m, 1H), 7.36-7.45 (m, 1H), 7.17 (d, J=2.0 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 5.57 (br. s., 1H), 5.44 (quin, J=4.4 Hz, 1H), 3.68 (t, J=6.7 Hz, 2H), 2.98 (t, J=6.8 Hz, 2H), 2.02-2.16 (m, 4H), 1.84-1.98 (m, 2H), 1.67-1.80 (m, 2H). m/z (ESI, +ve ion) 348.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1Cl.[CH:15]1([CH2:18][O-:19])[CH2:17][CH2:16]1.[Na+]>CS(C)=O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1[O:19][CH2:18][CH:15]1[CH2:17][CH2:16]1
Reactant: [O-]CC1CC1
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OCC2CC2)c(C(F)(F)F)c1
Temperature: 10 °C
Yield: 42.1 %

Procedure:
To a cooled (10° C.) solution containing 22.5 g (0.1 mole) of 3-(trifluoromethyl)-4-chloronitrobenzene in 100 ml of DMSO was added with stirring at ambient temperature a solution containing 0.11 mole of sodium cyclopropylmethoxide (prepared by dissolving 4.9 g of 57% sodium hydride in 7.9 g of cyclopropylmethanol and 50 ml of tetrahydrofuran) in 100 ml of DMSO. The reaction mixture was heated at 50° C. for one hour, poured into ice water and filtered. Recrystallization of the filter cake from hexane gave 11.0 g (42%) of product as a white crystalline solid, m.p. 41°-44° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O-])=O>[Pd].CO.C1COCC1>[NH2:1][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccc([N+](=O)[O-])c(NCCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(N)c(NCCc2ccccc2)c1
Yield: 100 %

Procedure:
A mixture comprising 3-methoxy-4-nitrobenzonitrile (1 g, 5.6 mmol), phenethylamine hydrochloride (1.8 g, 11.2 mmol), 50% sodium hydroxide (0.9 g, 11.2 mmol) and DMSO (3 mL) was heated at 100° C. for 3.5 hours, cooled and poured into a solution of 1N hydrochloric acid (200 mL, 0° C.). The mixture was stirred for 20 minutes to give a precipitate. The precipitate was collected and recrystallized from hot ethanol to provide 4-nitro-3-phenethylaminobenzonitrile (0.78 g, 2.9 mmol) as orange crystals. MS (CI), Calculated for C15H13N3O2, 267.3, Found (MH+): 282. A mixture comprising 4-nitro-3-phenethylaminobenzonitrile (0.75 g, 2.8 mmol), palladium on carbon (100 mg) and 1:1 methanol/THF (100 mL) was hydrogenated under 1 atm for 3 hours, filtered and concentrated under reduced pressure to provide 4-amino-3-phenethylaminobenzonitrile (0.68 g, 2.8 mmol) as a tan solid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1)([OH:21])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1.[H-].[Na+].[CH3:35]N(C)C=O>>[F:32][C:2]([F:1])([F:31])[C:3]([O:21][CH3:35])([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH3:30])=[CH:26][CH:27]=1)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1
Reactant: CCOc1ccc(C(O)(COCc2ccc(F)c(Oc3ccccc3)c2)C(F)(F)F)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCOc1ccc(C(COCc2ccc(F)c(Oc3ccccc3)c2)(OC)C(F)(F)F)cc1
Reaction time: 0.33 h

Procedure:
1,1,1-Trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxy-4-fluorobenzyloxy)propan-2-ol (0.2 g) in dry N,N-dimethylformamide (2 cm3) was added to a suspension of sodium hydride (0.1 g of a 50% dispersion in oil--washed free of oil with n -hexane) in N,N-dimethylformamide (2 cm3) at the ambient temperature (ca. 22° C.) under an atmosphere of nitrogen. After stirring for 20 minutes a solution of methyl iodide (0.1 g) in N,N-dimethylformamide (3 cm3) was added in one portion. After 20 minutes no starting material could be detected by gas liquid chromatographic analysis. The mixture was carefully diluted with water (30 cm3) then solid sodium chloride was added and the mixture shaken with diethyl ether. The layers were separated and the aqueous layer extracted with a further three portions of diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulphate and the solvent removed by evaporation under reduced pressure. The resulting pale yellow oil was purified by chromatography on silica gel, eluting with n-hexane containing 10% by volume ethyl acetate to give 1,1,1-trifluoro-2-methoxy-2-(4-ethoxyphenyl)-3-(3-phenoxy-4-fluorobenzyloxy)propane as a colourless oil (0.2 g).
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1.Cl>N1C=CC=CC=1>[O:1]([C:8]1[N:13]=[CH:12][C:11]([CH:14]=[CH:17][C:18]([OH:20])=[O:19])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(Oc2ccccc2)nc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(Oc2ccccc2)nc1
Temperature: 25 °C

Procedure:
5 g (25.1 mmol) of 6-phenoxy-pyridine-3-carbaldehyde were dissolved in 50 ml of pyridine, and 3.134 g (30.1 mmol) of malonic acid and 213 mg (2.5 mmol) of piperidine were added. The reaction mixture was boiled under reflux for 6 h. After cooling to room temperature, it was poured into a mixture of ice and concentrated hydrochloric acid. The precipitated product was isolated by filtration. Yield: 5.66 g.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:32])[C@@H:8]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][NH:24]C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([O:6][C:7](=[O:32])[C@@H:8]([NH:15][CH2:16][CH:17]2[CH2:18][CH2:19][CH:20]([CH2:23][NH2:24])[CH2:21][CH2:22]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(CN[C@H](C(=O)OC2CCCC2)c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1CCC(CN[C@H](C(=O)OC2CCCC2)c2ccccc2)CC1
Reaction time: 2 h
Yield: 75.5 %

Procedure:
(S)-{[4-(tert-Butoxycarbonylamino-methyl)-cyclohexylmethyl]-amino}-phenyl-acetic acid cyclopentyl ester (223 mg, 0.5 mmol) was stirred in DCM (4 ml), TFA (1 ml) was added and the mixture was stirred at r.t, for 2 h. The solution was concentrated in vacuo, taken up in DCM, washed twice with a saturated solution of NaHCO3 and once with a saturated solution of brine. The organic phase was dried over magnesium sulfate, filtered and evaporated to yield the expected amine as a yellow oil (130 mg, 75% yield). LCMS purity 100%, m/z 345 [M++H]+.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[C:8]2[C:14]3[CH:15]=[CH:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:13]=3[O:12][CH2:11][CH2:10][N:9]2[CH:23]=1)CCC.N[C:33]1[N:37]([CH:38]([CH3:40])[CH3:39])[N:36]=[CH:35][C:34]=1[C:41]#[N:42].C1(C)C=CC=CC=1>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>[C:41]([C:34]1[CH:35]=[N:36][N:37]([CH:38]([CH3:40])[CH3:39])[C:33]=1[C:6]1[N:7]=[C:8]2[C:14]3[CH:15]=[CH:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:13]=3[O:12][CH2:11][CH2:10][N:9]2[CH:23]=1)#[N:42]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2c(n1)-c1ccc(C(=O)OC)cc1OCC2
Reactant: CC(C)n1ncc(C#N)c1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)OCCn1cc(-c3c(C#N)cnn3C(C)C)nc1-2

Procedure:
A mixture of methyl 2-(tributylstannyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (155 mg, 0.291 mmol), 5-amino-1-isopropyl-1H-pyrazole-4-carbonitrile (133 mg, 0.509 mmol) and Tetrakis(triphenylphosphine)palladium(0) (16.8 mg, 0.0145 mmol) in Toluene (6.0 mL, 56 mmol) was heated for 18 hours. The mixture was concentrated in vacuum, the residue purified on 4 g silica column eluting with 30% ethyl acetate in heptane. Yield 65 mg (59%). MS (ESI+): 378.2
Reaction SMILES: [CH:1]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=[O:34].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH:1]1([CH2:8][O:9][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[CH:33]=[O:34])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCCCC1
Reactant: O=Cc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1cccc(OCC2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cold solution of cycloheptylmethanol (5.244 g, 40.9 mmol), triphenylphosphine (10.73 g, 40.9 mmol) and 3-hydroxybenzaldehyde (11) (5.0 g, 40.9 mmol) in THF (50 mL) was added diethyl azodicarboxylate (9.097 g, 44.99 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated under reduced pressure, and the residue was suspended in 20% diethyl ether-hexanes. Solids were removed by filtration then the mixture was concentrated under reduced pressure. Purification by flash chromatography (5% EtOAc-hexanes) gave 3-(cycloheptylmethoxy)benzaldehyde as a colorless oil. Yield (3.9 g, 41%): 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.46-7.51 (m, 2H), 7.39-7.40 (m, 1H), 7.25, (dt, J=6.8, 2.6 Hz, 1H), 3.81 (d, J=6.8 Hz, 2H), 1.88-1.93 (m, 1H), 1.76-1.82 (m, 2H), 1.22-1.68 (m, 10H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:11])=[O:7].[CH2:23]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26].[BH3-]C#N.[Na+].CO>C(O)(=O)C>[CH2:23]([C:27]1[CH:28]=[CH:29][C:30]([CH2:31][N:15]2[CH2:16][CH2:17][C@@H:13]([NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=3)[CH2:14]2)=[CH:33][CH:34]=1)[CH2:24][CH2:25][CH3:26]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Reactant: CCCCc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCc1ccc(CN2CC[C@@H](NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a mixture of (R)-3-[N-{3-(trifluoromethyl)benzoyl}glycyl]aminopyrrolidine (0.050 mmol), 4-butylbenzaldehyde (0.18 mmol), NaBH3CN (0.23 mmol), and methanol (1.85 mL) was added acetic acid (0.060 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (15 mL). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated to afford (R)-1-(4-butylbenzyl)-3-[{N-(3-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (Compound No. 1648) (20.6 mg, 89%): The purity was determined by RPLC/MS (91%); ESI/MS m/e 462.2 (M++H, C25H30F3N3O2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=O.C[Si](Cl)(C)C.C([BH3-])#N.[Na+]>C(#N)C.ClCCl>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)c2ccccc2O)cc1
Agent: C[Si](C)(C)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc(Cc2ccccc2O)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
0.78 g of (2-hydroxyphenyl)(4-methoxyphenyl)methanone is dissolved in acetonitrile and cooled to 0° C. 2 ml of TMSCl are added dropwise to the mixture, and then 1 g of sodium cyanoborohydride is added. The mixture is stirred at room temperature for 3 h. The reaction solution is diluted with dichloromethane and filtered through Celite.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:16]([CH:17]=O)=[N:15][N:14]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[C:11]2=[N:12][CH:13]=1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[NH2:32].[S]>CN(C=O)C>[N:32]1[C:31]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[NH:25][C:17]=1[C:16]1[C:10]2[C:11](=[N:12][CH:13]=[C:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[CH:9]=2)[N:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:15]=1
Reactant: Nc1ccncc1N
Reactant: Cc1ccncc1-c1cnc2c(c1)c(C=O)nn2C1CCCCO1
Agent: [S]
Solvent: CN(C)C=O
Product: Cc1ccncc1-c1cnc2c(c1)c(-c1nc3ccncc3[nH]1)nn2C1CCCCO1
Temperature: 25 °C

Procedure:
A solution of 5-(4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (LVII) (0.120 g, 0.37 mmol), 3,4-diaminopyridine (LVIII) (42 mg, 0.39 mmol) and sulfur (13 mg, 0.39 mmol) in dry DMF (5 mL) was heated at 140° C. under nitrogen for 12 h. The solution was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in DCM and washed with water (1×20 mL). The organic layer was dried over MgSO4, filtered and concentrated to yield 3-(3H-imidazo[4,5-c]pyridin-2-yl)-5-(4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (LIX). The crude product was used directly for step 3 without further purification. ESIMS found for C23H21N7O m/z 412.7 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([OH:17])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=O)[CH:7]=1.C[O-].[Na+].[NH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].C1(C)C=CC=CC=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([OH:17])=[C:6]([C:8](=[N:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Cc1cc(Cl)cc(C(=O)c2ccc(Cl)cc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(Cl)cc(C(=NCCC(=O)O)c2ccc(Cl)cc2)c1O

Procedure:
(5-Chloro-2-hydroxy-3-methylphenyl)-(4-chlorophenyl)-methanone (98.4 g, 0.35 mol), sodium methoxide (19 g, 0.35 mol) and β-alanine (31.2 g, 0.35 mol) are added to 2 liters of toluene and 0.5 liters of methanol. The mixture is heated gradually and the ternary azeotrope (62° C.) is distilled. After a Dean-Stark apparatus has been fitted, the residue is heated at the reflux temperature of toluene for 6 hours. The mixture is then evaporated to dryness in vacuo. The solid residue is triturated with diethyl ether and filtered off. The solid is dissolved in 1.5 liters of water. The aqueous solution is acidified by the addition of citric acid to pH 4. The solid obtained is filtered off and then dissolved in CHCl3. The chloroform solution is dried (MgSO4) and then evaporated in vacuo. The solid obtained is triturated in petroleum ether, filtered off and dried. This gives the desired acid product, melting at 137.5°-138° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[NH:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:23][C:24]([CH3:26])=O.[OH-].[K+].C(Br)C=C>O>[N+:1]([C:4]1[CH:5]=[C:6]2[N:12]([CH2:26][CH:24]=[CH2:23])[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)=O
Reactant: O=c1[nH]c2cc([N+](=O)[O-])cnc2n1-c1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C=CCBr
Product: C=CCn1c(=O)n(-c2ccc3c(c2)OCO3)c2ncc([N+](=O)[O-])cc21
Reaction time: 1.5 h

Procedure:
To a mixture of 1.1 g. (0.0036 mole) of the nitro product of Step C in 175 ml. of refluxing acetone, was added 400 mg. (0.0068 mole) of powdered potassium hydroxide. The mixture was stirred and heated for 15 minutes, 1 ml. of allyl bromide was added and reflux was continued for 1.5 hours. About 50 ml. of water was then added and the resulting solution was concentrated to about 75 ml. The product, 1.2 g. crystallized and melted at 152°-153° C.
Reaction SMILES: [S:1]([N:11]1[CH2:13][C@H:12]1[C:14]([O:16]C)=[O:15])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[OH-].[Na+].[NH2:20][C@H:21]([C:28]([OH:30])=[O:29])[CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1>CO>[C:28]([C@@H:21]([NH:20][CH2:13][C@H:12]([NH:11][S:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3])[C:14]([OH:16])=[O:15])[CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1)([OH:30])=[O:29]
Reactant: COC(=O)[C@@H]1CN1S(=O)(=O)c1ccc(C)cc1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N[C@@H](CN[C@@H](Cc2c[nH]cn2)C(=O)O)C(=O)O)cc1
Reaction time: 0.83 h
Yield: 30 %

Procedure:
A solution of methyl (2S)-1-tosyl-2-aziridinecarboxylate (1.04 g) in methanol was added to 1N aqueous sodium hydroxide (4.1 ml) in an ice bath and the mixture was stirred for 50 minutes at the same temperature. To the resulting solution were added L-histidine (2.11 g) and sodium hydroxide (730 mg) and the mixture was refluxed for 1.5 hours. After removal of the solvent in vacuo, the residue was dissolved in water and adjusted to pH 4 with 2N sulfuric acid. The solution was subjected to a column of "Diaion HP-20" (150 ml) and the column was washed with water. The elution was carried out with a mixture of water and methanol (1:1 400 ml). The eluate was evaporated in vacuo and the residue was chromatographed on a silica gel (100 g) column with a mixutre of chloroform, methanol and 28% aqueous ammonia (5:3:1) as an eluent to give (2S)-3-[[(1S)-1-carboxy-2 -(4-imidazolyl)ethyl]amino]-2-tosylaminopropionic acid (485 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.COCCOC.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1>O>[Cl:18][C:19]1[CH:24]=[C:23]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:22]=[CH:21][N:20]=1
Reactant: OB(O)c1cccc(F)c1F
Reactant: Clc1cc(Cl)ncn1
Solvent: COCCOC
Solvent: O
Product: Fc1cccc(-c2cc(Cl)ncn2)c1F
Temperature: 80 °C
Reaction time: 12 h
Yield: 42 %

Procedure:
A reaction vessel was charged with 2.03 g of tetrakistriphenylphosphine palladium, 5.55 g of 2,3-difluorophenylboronic acid, and 14.9 g of tripotassium phosphate n-hydrate, to which 120 ml of 1,2-dimethoxyethane, 30 ml of water, and 5.20 g of 4,6-dichloropyrimidine were added, followed by stirring at 80° C. under an atmosphere of a nitrogen gas for 12 hours. The reaction mixture was then left for cooling to room temperature, and water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 3.32 g of 4-chloro-6-(2,3-difluorophenyl)pyrimidine.
Reaction SMILES: [CH3:1][N:2]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:3]1(=[O:5])=[O:4].Cl[CH2:15][C:16]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[O:17].[H-].[Na+]>CS(C)=O>[OH:13][C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:3](=[O:5])(=[O:4])[N:2]([CH3:1])[C:15]=1[C:16]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[O:17]
Reactant: COCCOC(=O)CCl
Reactant: CN1C(=O)c2ccccc2S1(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCCOC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reaction time: 2 h

Procedure:
To a solution of 3.0 g. (0.015 mole) of N-methylsaccharin and 2.3 g. (0.015 mole) of 2-methoxyethyl chloroacetate in 15 ml. of dimethylsulfoxide at 40° C. was added 810 mg. (0.033 mole) of sodium hydride over a 2 hour period. The resulting reaction mixture was stirred for 2 hours at 40°-50° C. and was then quenched in 5% hydrochloric acid solution. The resulting suspension was extracted with methylene chloride (2×100 ml.) and the organic layers separated, combined and washed with water (50 ml.) and a brine solution (50 ml). The organic layer was dried over magnesium sulfate and concentrated to an oil, 4.1 g. The product was purified by dissolution of the residue in 5 ml. of acetone and addition of the acetone slowly to 125 ml. of 0.25 N hydrochloric acid. The suspension was allowed to stir for several hours, and was then filtered and dried 2.6 g. (55%). The product is indistinguishable from that reported in U.S. Patent Application Ser. No. 191,716, filed Sept. 29, 1980.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([Cl:14])[CH:13]=1.Br[CH2:17][C:18](=[O:21])[CH2:19][CH3:20].O>CC(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:11]=[C:12]([Cl:14])[CH:13]=1)[O:15][CH2:17][C:18](=[O:21])[CH2:19][CH3:20]
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: CCC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: CCC(=O)COc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
Cesium carbonate (108 g, 0.33 mol) was added in one portion to a stirred solution of 3,5-dichlorophenol (49 g, 0.30 mol) in acetone (900 ml) at room temperature under nitrogen. To this suspension a solution of 1-bromo-2-butanone (30.6 ml, 0.30 mol) in acetone (300 ml) was added dropwise and the resultant suspension was heated under reflux for 2 hours. The suspension was cooled to room temperature, water (200 ml) was added and the acetone was removed under reduced pressure. The mixture was extracted with dichloromethane (2×300 ml) and the combined organic phases were dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a clear oil. The crude product was purified by flash column chromatography on silica gel eluting with dichloromethane:cyclohexane (50:50, by volume) to provide the title compound (65 g) as a yellow oil.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[O:12][C:11]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[O:12][C:11]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1ccc(CN2CCNCC2)o1
Reaction time: 2 h
Yield: 86.6 %

Procedure:
Tert-butyl 4-((5-(tert-butylcarbamoyl)furan-2-yl)methyl)piperazine-1-carboxylate (6.57 mmol, 2.4 g) was dissolved in dichloromethane (20 mL). 2,2,2-Trifluoro-acetic acid (20 mL) was added and the reaction mixture was stirred for 2 hours. The reaction was concentrated under reduced pressure and purified by SCX chromatography to give the title compound (1.51 g). MS (ESI) m/z 266.4 [M+H]+