Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:38]=[CH:37][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[NH:15][C@@H:16]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:17]([NH:19][CH2:20][CH2:21][N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[O:18])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl.O1CCOCC1.C(N(CC)CC)C.O(C1C=CC(N=C=O)=CC=1)C1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[CH:26]([N:22]([CH:23]([CH3:25])[CH3:24])[CH2:21][CH2:20][NH:19][C:17](=[O:18])[C@@H:16]([NH:15][C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:37]=[CH:38][CH:2]=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:27])[CH3:28]
Reactant: CC(C)N(CCNC(=O)[C@H](Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1)C(C)C
Agent: Cl
Agent: O=C=Nc1ccc(Oc2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)N(CCNC(=O)[C@H](Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccccc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
To a solution of [(S)-1-(2-diisopropylamino-ethylcarbamoyl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester (Example 3, step B) (0.1 g, 0.258 mmol) in CH2Cl2 (3 mL), a 4 M solution of HCl in dioxane (0.64 mL, 2.56 mmol) was added, and the mixture was stirred for 3 h at rt. The solvents were removed, the residue was treated with CH2Cl2, and the solvent was removed again. The crude product was dissolved in CH2Cl2 (3 mL), and triethylamine (0.037 g, 0.365 mmol) was added at 0° C. followed by 4-phenoxyphenylisocyanate (0.059 g, 0.28 mmol). The mixture was warmed to rt over a period of 2 h and was then diluted with EtOAc (100 mL). The organic layer was washed with saturated NaHCO3 (25 mL) and brine (25 mL), and dried (Na2SO4). The solvent was removed, and the residue was purified by flash column chromatography using 0–20% MeOH (1% NH4OH)/CH2Cl2 to afford 0.07 g (55%) of the desired product. MS (electrospray): mass calculated for C30H38N4O3, 502.29; m/z found, 503.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.3–7.19 (m, 9H), 7.04 (m, 1H), 6.91–6.85 (m, 4H), 4.47 (t, J=7.4 Hz, 1H), 3.19–2.95 (m, 6H), 2.42 (br s, 2H), 1.02 (d, J=6.4 Hz, 12H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:21])(=O)C.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1.[OH-].[Na+]>ClCCl.CO>[CH3:29][C:25]1[CH:24]=[C:23]([NH:22]/[C:13](=[C:6]2\[C:5](=[O:21])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cccc(N)c1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and m-toluidine in dichloromethane and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13].[H-].[Na+].Cl[S:19]([C:22]1[S:26][C:25]2[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:24]=2[C:23]=1[CH3:32])(=[O:21])=[O:20]>C1COCC1>[CH3:31][C:29]1[CH:28]=[CH:27][C:25]2[S:26][C:22]([S:19]([NH:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[S:12]([CH3:15])(=[O:14])=[O:13])(=[O:21])=[O:20])=[C:23]([CH3:32])[C:24]=2[CH:30]=1
Reactant: COC(=O)c1ccc(N)c(S(C)(=O)=O)c1
Reactant: Cc1ccc2sc(S(=O)(=O)Cl)c(C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(C)cc3c2C)c(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
Into 8.0 mL of THF was dissolved 183 mg of methyl 4-amino-3-methanesulfonylbenzoate, followed by addition of 96 mg of sodium hydride (oily, 60%) at 0° C. After 20 minutes of stirring at the same temperature, 250 mg of 2-chlorosulfonyl-5-methyl-3-methylbenzo[b]thiophene was added at 0° C., followed by 6 hours of stirring at room temperature. After confirmation of disappearance of the starting material, the reaction was terminated by adding 1 mol/L hydrochloric acid at 0° C., followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation and then the residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1 to 1/1) to obtain 181 mg of the title compound as colorless powder.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=4)[CH2:21][CH2:20]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][NH:75][C:76](=[O:82])[O:77][C:78]([CH3:81])([CH3:80])[CH3:79]>CN(C=O)C>[C:78]([O:77][C:76]([NH:75][CH2:74][CH2:73][O:72][CH2:71][CH2:70][O:69][CH2:68][CH2:67][NH:66][C:30]([C:29]1[CH:33]=[CH:34][C:26]([CH2:25][N:22]2[CH2:23][CH2:24][CH:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]3[C:13]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:20][CH2:21]2)=[CH:27][CH:28]=1)=[O:31])=[O:82])([CH3:79])([CH3:81])[CH3:80]
Reactant: CC(C)(C)OC(=O)NCCOCCOCCN
Reactant: O=C(NC1CCN(Cc2ccc(C(=O)O)cc2)CC1)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOCCOCCNC(=O)c1ccc(CN2CCC(NC(=O)OCC3c4ccccc4-c4ccccc43)CC2)cc1
Reaction time: 8 h

Procedure:
A mixture of 4-[(4-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}piperidin-1-yl)methyl]benzoic acid (1.20 g; 2.63 mmol), TBTU (1.01 g; 3.15 mmol) and DIPEA (1.8 ml; 3.15 mmol) in DMF (10 ml) is stirred for 5 min. tert-Butyl N-{2-[2-(2-aminoethoxy)ethoxy]ethyl}carbamate (783 mg; 3.15 mmol) is added and the mixture is stirred overnight. Volatiles are evaporated and the product is purified by RP-HPLC (modifier: TFA) to yield 9H-fluoren-9-ylmethyl N-(1-{[4-({2-[2-(2-{[(tertbutoxy)carbonyl]amino}ethoxy)ethoxy]ethyl}carbamoyl)phenyl]methyl}piperidin-4-yl)carbamate.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17].[Br:18][CH:19](Br)[CH3:20]>C(OCC)(=O)C.O>[Br:18][CH2:19][CH2:20][O:17][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=1[F:8])[CH:13]=[O:14]
Reactant: CC(Br)Br
Reactant: O=Cc1ccc(F)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(F)c(OCCBr)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
Sodium hydride (1.14 g) was added to a DMF (30 mL) solution of 4-fluoro-3-hydroxybenzaldehyde (2.00 g) at room temperature, and the reaction solution was agitated for 30 minutes. Then, dibromoethane (2.46 mL) was added dropwise to the reaction solution, and the reaction solution was heated at 140° C. for 3 hours after the dropping ended. Water and ethyl acetate were added to the reaction solution under ice-cooling, and the organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride solution, and the solvent was evaporated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 6:1), and 606 mg (20%) 3-(2-bromoethoxy)-4-fluoro benzaldehyde was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[O:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].CCOCC>CN(C=O)C>[Si:24]([O:23][CH2:22][CH2:21][CH2:20][N:6]1[C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[O:3][C:2]1=[O:1])([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:26])[CH3:25]
Reactant: O=Cc1ccc2[nH]c(=O)oc2c1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCCn1c(=O)oc2cc(C=O)ccc21
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 89.1 %

Procedure:
To a solution of 2-oxo-2,3-dihydro-1,3-benzoxazole-6-carbaldehyde (Intermediate 7, 300 mg, 1.84 mmol) in DMF (10 mL) were added potassium carbonate (633 mg, 4.58 mmol) and (3-bromopropoxy)(tert-butyl)dimethylsilane (0.47 mL, 2.03 mmol), and the resulting mixture was heated to 75° C. Upon complete disappearance of starting material (ca 16 hours), the solvent was removed under reduced pressure and the solid residue was treated with CH2Cl2 and stirred for 5 min. The suspension was filtered through Celite® and the solid residue washed with additional CH2Cl2. The filtrate was concentrated to dryness and the crude was purified by column chromatography over silica gel, eluting with Hexane:Et2O (from 0 to 32% of Et2O) to give the title compound as a white solid (550 mg, 89% yield).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C([O:7][C:8](=O)[C:9]([C:11]1[CH:19]=[CH:18][C:14]2[O:15][CH2:16][O:17][C:13]=2[CH:12]=1)=[O:10])C>C(O)C>[O:15]1[C:14]2[CH:18]=[CH:19][C:11]([C:9](=[O:10])[C:8]([NH:4][CH2:3][CH2:1][OH:2])=[O:7])=[CH:12][C:13]=2[O:17][CH2:16]1
Reactant: NCCO
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)OCO2
Solvent: CCO
Product: O=C(NCCO)C(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
Ethanolamine (3.5 g, 49 mmol) was added to a stirred solution of benzo[1,3]dioxol-5-yl-oxo-acetic acid ethyl ester (2.5 g, 11 mmol)) in ethanol (40 ml)) at room temperature. The resulting reaction mixture was heated to reflux for 2 hours. Then ethanol was distilled off and stirring was continued at 120° C. for 1 hour. The reaction mixture was cooled to room temperature and then 50 ml of THF and 100 ml of aqueous HCl solution were added and stirred for 30 minutes. The mixture was extracted twice with DCM (50 ml). The organic layer was washed twice with water (50 ml) and evaporated to provide a dark sticky product. The product was further crystallized in pentane/ethyl acetate. Red crystals of the title compound (0.9 g, 34.5% yield) were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17]>C1COCC1.CN(C)C1C=CN=CC=1>[CH2:14]([NH:18][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 86.3 %

Procedure:
4-Nitrophenylsulfonyl chloride (3.0 g, 13.5 mmol) was dissolved in THF and a catalytic amount of 4-dimethylaminopyridine and 1-butylamine (4.0 mL, 41 mmol) was added and the mixture was refluxed for 16 hours. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (100 mL) and washed with water (50 mL) and a 10% aqueous solution of sodium hydrogen carbonate (50 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to afford 3.01 g (86%) of N-butyl-4-nitrobenzenesulfonamide as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]3=[O:30])=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C(O)(C(F)(F)F)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C:18]3=[O:30])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)C(=O)C1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(N2CCNCC2=O)cc1

Procedure:
A mixture of 1 g of methyl 4-iodobenzoate, 920 mg of 4-Boc-piperazinone, 1.1 g of potassium carbonate, 32 mg of N,N′-dimethylethylenediamine and 70 mg of copper iodide in 10 mL of toluene was heated to 150° C. in a sealed microwave reactor for 3 h. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatography (20-80% ethyl acetate/hexane) to afford tert-butyl 4-(4-(methoxycarbonyl)phenyl)-3-oxopiperazine-1-carboxylate. 500 mg of tert-butyl 4-(4-(methoxycarbonyl)phenyl)-3-oxopiperazine-1-carboxylate was hydrolyzed via Procedure M to give 4-(4-(tert-buthoxycarbonyl)-2-oxopiperazin-1-yl)benzoic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(4-(tert-buthoxycarbonyl)-2-oxopiperazin-1-yl)benzoic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N sodium hydroxide and brine, dried (MgSO4) and evaporated to afford tert-butyl 4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)phenyl)-3-oxopiperazine-1-carboxylate. 300 mg of crude tert-butyl 4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)phenyl)-3-oxopiperazine-1-carboxylate was treated with TFA (2 mL) containing trace amounts of H2O for 1 h. The reaction mixture was evaporated and the crude product was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxopiperazin-1-yl)benzamide. MS (Q1) 407.3 (M)+.
Reaction SMILES: C(OC([C:6]1[N:7]([CH2:19][CH2:20][NH:21][C:22]([O:24]C(C)(C)C)=O)[N:8]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=O)C.C([O-])([O-])=O.[Na+].[Na+]>Cl.O1CCOCC1>[O:12]([CH2:11][C:9]1[CH:10]=[C:6]2[C:22](=[O:24])[NH:21][CH2:20][CH2:19][N:7]2[N:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CCNC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1NCCn2nc(COc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
2-(2-tert-Butoxycarbonylamino-ethyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.72 g, 1.85 mmol) was dissolved in a 4M solution of HCl in 1,4-dioxane (7 mL) under N2. The mixture was stirred at room temperature for 1 hour. The mixture was basified with a saturated solution of Na2CO3 and stirred at room temperature for 72 hours. Then the mixture was extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7 M solution of ammonia in MeOH in DCM 0/100 to 5/95). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.39 g, 85% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 3.71-3.86 (m, 2H), 4.32-4.48 (m, 2H), 5.11 (s, 2H), 6.39 (br. s., 1H), 6.91-6.99 (m, 2H), 7.00 (d, J=8.1 Hz, 2H), 7.27-7.34 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12]Br)=[C:10]([O:14][CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:16][CH3:17].BrC1C([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=C(OC)C2C(C=1OC)=CC=CC=2.CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[C:11]([CH2:12][CH:34]([CH3:33])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:10]([O:14][CH3:15])[C:9]2[C:4]([C:3]=1[O:16][CH3:17])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CCOC(=O)CCc1c(Br)c(OC)c2ccccc2c1OC
Reactant: COc1c(Br)c(CBr)c(OC)c2ccccc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)Cc1c(Br)c(OC)c2ccccc2c1OC

Procedure:
Compound 67b was prepared from 36 (0.244 g, 0.678 mmol) as described above for 67a to give 0.258 g (0.678 mmol, 100%) of the product as a EtOAc following flash chromatography (1:1 to 3:1 CH2Cl2:hexanes).
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH2:13][C:12]([CH2:14][CH3:15])=[C:11]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.C(O)(=O)C>[CH2:1]([O:8][N:9]1[CH2:13][C@H:12]([CH2:14][CH3:15])[C@H:11]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1=C(NCc2ccc(OC)cc2)C(=O)N(OCc2ccccc2)C1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC[C@H]1CN(OCc2ccccc2)C(=O)[C@H]1NCc1ccc(OC)cc1
Yield: 99.1 %

Procedure:
1-Benzyloxy-4-ethyl-3-(4-methoxybenzylamino)-2-oxo-2,5-dihydropyrrole (72 mg, 205 μmol) was hydrogenated on platinum (IV) oxide (9.6 mg) in ethyl acetate (10 ml) and acetic acid (100 μl) at atmospheric pressure for 20 h. The mixture was filtered, washed with sodium hydrogen carbonate solution and brine, dried (MgSO4), and evaporated in bacuo to give cis-1-benzyloxy-4-ethyl-3-(4-methoxybenzylamino)pyrrolidin-2-one (72 mg, 100%) as an oil. 1H NMR (250 MHz, CDCl3) δ7.3-7.5 (5 H, m, Ph), 7.26 (2 H, d, J=9 Hz, MeOCCH), 6.84 (2 H, d, J=9 Hz MeOCCHCH), 4.98 (2 H, s, OCH2), 3.80 (2 H, s, CH2NH), 3.78 (3 H, s, OMe), 3.30 (1 H, d, J=8.5 Hz, NCH), 3.25 (1 H, dd, J=6 and 10 Hz, CHAHBNO), 2.95 (1 H, dd, J=3 and 10 Hz, CHAHBNO), 2.0-2.1 (1 H, m, CHCH2), 1.5-1.6 and 1.0-1.1 (2 H, m, CH2CH3), 0.74 (3 H, t, J=7.5 Hz, CH3), m/z (CI, NH3) 249 (M-MeOC6H4 +H).
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[Cl:15][S:16](O)(=[O:18])=[O:17]>C(Cl)(Cl)Cl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[C:9]([S:16]([Cl:15])(=[O:18])=[O:17])[CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)N1CCc2ccc(Cl)cc2C1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCc2cc(S(=O)(=O)Cl)c(Cl)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2.0 g. (0.01 mole) 2-acetyl-7-chloro-1,2,3,4-tetrahydroisoquinoline in 15 ml. dry chloroform is added dropwise to 20 ml. chlorosulfonic acid at ambient temperature. The reaction mixture is stirred at ambient temperature for 24 hours and then refluxed at 60° C. for 2 hours. The reaction mixture is then cooled, poured onto a liter of ice and extracted with methylene chloride. The organic phase is dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated to dryness under reduced pressure to yield the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4]C=1C.OS(O)(=O)=O.[OH-].[Na+].[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20]>>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:20]=1[C:19]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-fluoro-4-nitrotoluene (1.0 g, 6.4 mmol, Aldrich) and Na2Cr2O7 (2.74 g, 8.4 mmol) in 13.7 ml of HOAC was added slowly 6.83 ml of H2SO4. This mixture was slowly heated to 90° C. for 1 hour to give a greenish heterogeneous solution. The mixture was cooled to room temperature and diluted with ethyl acetate. The pH of the solution was adjusted to 4 with aqueous NaOH. The mixture was extracted with more ethyl acetate. The combined organic layers were washed with NaHCO3 (sat.), then brine and dried over Na2SO4. After filtration, the solution was concentrated to dryness which then was dissolved in 6 ml of SOCl2, and heated at 80° C. for 1 hour. The excess of SOCl2 was removed under reduced pressure and the residue was dissolved in 5 ml of CH2Cl2, 2 ml of EtOH and 2 ml of pyridine. The mixture was stirred at room temperature for 2 hours and concentrated to dryness. Ethyl 2-fluoro-4-nitrobenzoate was obtained as a white solid after column chromatography of the residue with ethyl acetate/hexane (1/9). This solid was then dissolved in 10 ml of ethyl acetate, and Pd/C (50 mg) was added. Hydrogenation converted ethyl 2-fluoro-4-nitrobenzoate into the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[CH2:16][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:14][CH:13]1[CH2:12][S:11][C:10]([NH2:24])=[N:9]2>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:16][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH2:24])=[N:9]2
Reactant: NC1=NC2(c3ccccc3F)CN(c3ncc(F)cn3)CC2CS1
Solvent: CO
Product: NC1=N[C@@]2(c3ccccc3F)CN(c3ncc(F)cn3)C[C@H]2CS1
Yield: 31.6 %

Procedure:
Racemic 7a-(2-fluorophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine (361 mg, 1.04 mmol) is purified by chiral HPLC (Column: Chiralpak AD-H (5u), 3×25 cm; eluent: 100% methanol (0.2% isopropylamine); flow 30 mL/min at UV 225 nm. The second eluting isomer is the title compound (114 mg, 32%, 99% ee). Rt=4.887 minutes; column: Chiralpak AD-H 0.46×15 cm; eluent: 100% methanol (0.2% isopropylamine) in CO2; flow: 1 mL/min at UV 225 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[S:21][C:22]([CH2:25][CH3:26])=[N:23][N:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1.Cl.N[C@@H:31](CCN1CC(OC2C=CC(Cl)=C(C)C=2)C1)CO>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[S:21][C:22]([CH2:25][CH3:26])=[N:23][N:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][C:3]=1[CH3:31]
Reactant: Cc1cc(OC2CN(CC[C@H](N)CO)C2)ccc1Cl
Reactant: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)s1
Agent: Cl
Product: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)c(C)c3)C2)s1

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]-thiadiazol-2-yl)-urea in Example 99 except using (S)-2-amino-4-[3-(4-chloro-3-methyl-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:17]([O:19]C)=[O:18])=[N:4][C:5]([Cl:16])=[CH:6][C:7]=1[N:8]([CH3:15])[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[N:4][C:5]([Cl:16])=[CH:6][C:7]=1[N:8]([CH3:15])[CH:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: COC(=O)c1nc(Cl)cc(N(C)C2CCOCC2)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(c1cc(Cl)nc(C(=O)O)c1Br)C1CCOCC1
Yield: 73.6 %

Procedure:
To a stirred solution of methyl 3-bromo-6-chloro-4-[methyl(oxan-4-yl)amino]pyridine-2-carboxylate (102 mg, 0.28 mmol) in THF (2 ml) was added 2M aqueous NaOH (0.70 ml, 1.40 mmol) and the reaction mixture was left to stir at room temperature for 18 h after which time the THF was evaporated in vacuo. The aqueous phase was then treated with an aqueous 10% citric acid solution to 5-6 and then extracted with EtOAc (3×50 ml) followed by a solution of 1:1 IPA/CHCl3 (2×50 ml), the combined organic phases were then washed with brine (50 ml) dried with Na2SO4 and evaporated to give the title compound as a white solid (72 mg, 73%). LC-MS 100%, 1.49 min (3.5 minute LC-MS method), m/z=349.0/351.0/352.9, 1H NMR (500 MHz, Methanol-d4) δ 7.07 (s, 1H), 4.02 (dd, J=11.3, 4.3 Hz, 2H), 3.96-3.87 (m, 1H), 3.46 (t, J=11.0 Hz, 2H), 2.85 (s, 3H), 1.96 (dd, J=12.3, 4.3 Hz, 2H), 1.77 (s, 2H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[F:12][C:13]([F:17])([F:16])[CH2:14]I.O>CS(C)=O>[F:12][C:13]([F:17])([F:16])[CH2:14][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: FC(F)(F)CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(OCC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24.5 %

Procedure:
To sodium hydride (60% in oil, 240 mg, 6.0 mmol) 0° C. was added 2 mL anhydrous dimethylsulfoxide. The resulting suspension was stirred for 15 minutes at 0° C. 4-Hydroxybenzaldehyde (610 mg, 5.0 mmol) was added dropwise as a solution in 2 mL dimethylsulfoxide and the resulting mixture stirred for 30 minutes at 0° C. Trifluoroethyl iodide (1.5 mL, 15.24 mmol) was added and the reaction mixture was heated to 55° C. for 24 h. The reaction mixture was cooled to room temperature and poured into water. Organics were extracted with ether (3×50 mL), dried with magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel (20% ethyl acetate in hexanes) to give 4-(2,2,2-trifluoroethoxyl)benzaldehyde (250 mg, 24%) as an oil. Used without further characterization.