Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=O)[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O>N1C=CC=CC=1>[Cl:24][C:10]1[O:11][C:12]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CCOC(=O)CCCc1oc(=O)[nH]c1-c1ccc(F)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)CCCc1oc(Cl)nc1-c1ccc(F)cc1
Temperature: 125 °C
Reaction time: 0.75 h

Procedure:
A mixture of ethyl 4-[4-(4-fluorophenyl)-2-oxo-4-oxazolin-5-yl]butanoate (7.00 g), phosphorus oxychloride (14.7 g) and pyridine (1.89 g) was heated to 120-130° C. and stirred for 45 minutes. The reaction mixture was poured into ice water (200 ml) and extracted with ethyl acetate (150 ml×2). The organic layer was washed in sequence with a 10% aqueous solution of sodium hydrogen carbonate (100 ml) and a saturated aqueous solution of sodium chloride (100 ml), and then dried over anhydrous magnesium sulfate. The organic layer was concentrated, the residue was subjected to silica gel column chromatography, and ethyl 2-chloro-4-(4-fluorophenyl)-5-oxazolebutanoate was obtained as a yellow oil (4.23 g, 57%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22](O)=[O:23])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:37]1[C:42](C)=CC=C[C:38]=1C.Cl.CNC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22](=[O:23])[N:37]([CH3:42])[CH3:38])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cc1cccc(C)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Agent: CNC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN(C)C(=O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution containing {3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid (prepared in example 3, 100 mg, 0.22 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (121 μL, 0.24 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (28 μL, 0.24 mmol) was added to the solution. After 1 h, dimethylamine hydrochloride (20 mg, 0.24 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with saturated aqueous ammonium chloride solution, the organic phase was concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-dimethylcarbamoylmethyl-1H-pyrazol-3-yl)-propionamide (64 mg, 60%) as a white solid: ESI-LRMS m/e calcd for C22H29ClN4O4S [M+] 480.2, found 481.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.02-1.22 (m, 2H, CH2), 1.41-1.93 (m, 8H, 4×CH2), 2.18-2.27 (m, 1H, CH), 2.97 (s, 3H, NCH3), 3.03 (s, 3H, NCH3), 3.26 (s, 3H, SO2CH3), 3.54 (t, J=7.5 Hz, 1H, CH), 4.81 (s, 2H, NCH2), 6.71 (d, J=2.3 Hz, 1H, Ar), 7.34 (d, J=2.3 Hz, 1H, Ar), 7.43 (dd, Jo=8.2, Jm=1.8 Hz, 1H, Ar), 7.57 (d, Jm=1.8 Hz, 1H, Ar), 7.96 (s, 1H, NH), 8.06 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[O:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([OH:14])=[O:13].[CH:16](NC(=NC(C)C)OC(C)C)([CH3:18])[CH3:17]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[O:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([O:14][CH:16]([CH3:18])[CH3:17])=[O:13]
Reactant: CC(C)N=C(NC(C)C)OC(C)C
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C1\CCOC1=O
Solvent: c1ccccc1
Product: CC(C)OC(=O)[C@@H]1[C@H](/C=C2\CCOC2=O)C1(C)C
Yield: 49.2 %

Procedure:
Using the procedure of Example 17, 8.4 g of (1R,cis) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-furanylidene)-methyl]-cyclopropane-1-carboxylic acid and 7.45 g of isopropyl N,N'-diisopropylcarbamimidate were reacted to obtain 4.96 g of isopropyl (1R,cis) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-furanylidene)-methyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+41°±2.5° (c=0.5% in benzene).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-:26])=O)=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].Cl.[F:29][C:30]1([F:35])[CH2:33][CH:32]([NH2:34])[CH2:31]1>>[F:29][C:30]1([F:35])[CH2:33][CH:32]([NH:34][C:24]([C:21]2[O:22][C:23]3[C:15]([N:12]4[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:10][CH2:11]4)=[CH:16][CH:17]=[CH:18][C:19]=3[CH:20]=2)=[O:26])[CH2:31]1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reactant: NC1CC(F)(F)C1
Agent: Cl
Agent: [Li+]
Product: O=C(NC1CC(F)(F)C1)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and 3,3-difluorocyclobutanamine hydrochloride (48 mg, 0.34 mmol). Yield: 63 mg (64%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[S:18][C:17]2[C:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)=[N:15][CH:14]=[N:13][C:12]=2[CH:11]=1>>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:16]3[C:17]4[S:18][C:10]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)=[CH:11][C:12]=4[N:13]=[CH:14][N:15]=3)=[CH:21][CH:22]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(Nc2ccc(Nc3ncnc4cc(Br)sc34)cc2)cc1
Reactant: OB(O)c1cccs1
Product: COc1ccc(Nc2ccc(Nc3ncnc4cc(-c5cccs5)sc34)cc2)cc1

Procedure:
The title compound was prepared from 2-thiophene boronic acid and N-(6-bromo-thieno[3,2-d]pyrimidin-4-yl)-N′-(4-methoxy-phenyl)-benzene-1,4-diamine by a procedure analogous to example 2. M.P. 231-40° C. ; LC-MS: 431 (MH+); HPLC RT: 6.740 minutes.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)C>[CH3:1][NH:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: CNN
Solvent: CCOCC
Product: CNN=Cc1ccccc1

Procedure:
18.4 g (0.4 mol) of methylhydrazine were initially charged in 248.7 g of diethyl ether. At 22-26° C., 42.4 g (0.4 mol) of benzaldehyde were added dropwise within 1.75 hours. The reaction mixture was then stirred at reflux temperature for 5 hours. The residue obtained after the solvent had been distilled off was taken up in diethyl ether and the solution was dried over sodium sulfate. After drying, the solution was concentrated under reduced pressure and the residue obtained was distilled at 78° C./0.5-1 mbar.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][S:7][C:8]([F:21])([F:20])[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])[O:11][CH2:10]1)(=[O:3])[CH3:2].[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[C:1]([O:4][CH2:5][CH2:6][S:7][C:8]([F:21])([F:20])[C:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19])([OH:11])[CH2:10][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCSC(F)(F)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)OCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.3 %

Procedure:
To a solution of 1-(2-acetoxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-2,3-epoxypropane (24.0 g, 0.07 mol) in DMF (250 ml), 1,2,4-triazole (16.6 g, 0.24 mol) and potassium carbonate (33.2 g, 0.24 mol) were added, followed by stirring at room temperature for 12 hours and then at an external temperature of 50° C. for one hour. After the completion of the reaction, the reaction mixture was diluted with ethyl ether and an insoluble matter was filtered off. The ether solution was washed with water, dried over magnesium sulfate and then distilled off under reduced pressure. The residue so obtained was recrystallized from isopropyl ether-ethyl acetate, whereby 1-(2-acetoxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (12.2 g, yield: 37.8%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH3:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:37]1[CH:38]=[C:33]([CH3:32])[CH:34]=[CH:35][CH:36]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: Cc1cccc(B(O)O)c1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Product: COC(=O)c1c(-c2cccc(C)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and 3-methylphenylboronic acid. A colorless powder (63 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:14])=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH2:25](O)[CH3:26]>>[F:1][C:2]1[C:3]([OH:14])=[C:4]([CH2:10][C:11]([O:13][CH2:25][CH3:26])=[O:12])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: O=C(O)Cc1cc(F)c(F)c(F)c1O
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1cc(F)c(F)c(F)c1O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of (3,4,5-trifluoro-2-hydroxyphenyl)acetic acid (6.0 g), sulfuric acid (0.016 mL) and ethanol (50 mL) was stirred at 80° C. overnight, neutralized with saturated aqueous sodium hydrogen carbonate solution, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9](I)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:17]([Sn](CCCC)(CCCC)C=C)[CH2:18]CC>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([CH:17]=[CH2:18])[C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:2]=1[NH2:1]
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 25 °C
Yield: 71.2 %

Procedure:
Add tetrakis palladium(triphenylphosphine)(0) (5.00 g, 4.33 mmol) to a mixture of 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (Example 3, Step 3) (17.25 g, 49.99 mmol) and tributyl(vinyl)tin (16.10 mL, 55.14 mmol) in toluene (500 mL) and heat at reflux for 14 h. Allow the reaction to cool to room temperature dilute the mixture with ethyl acetate (1 L). Wash the mixture with saturated aqueous potassium fluoride solution (3×300 mL), then water (300 mL), followed by brine (500 mL). Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvents under reduced pressure. Purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0 to 15%), to provide the title compound as a pale yellow solid (8.73 g, 71%): TLC Rf 0.52 (3:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 3.89 (s, 3H), 5.21-5.30 (m, 1H), 5.60-5.71 (m, 1H), 5.98 (bs, 2H), 6.83-7.02 (m, 2H), 8.19 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)=[O:13])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].Br[CH2:27][C:28]([OH:30])=[O:29]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12](=[O:13])[C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)[CH:5]=[C:6]([CH3:9])[C:7]=1[O:8][CH2:27][C:28]([OH:30])=[O:29]
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Reactant: O=C(O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCC(=O)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 14.7 %

Procedure:
A solution of 3-(3,5-dimethyl-4-hydroxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (350 mg, 0.988 mmol, Intermediate 10) in isopropanol (5 mL) and 3 N aq. NaOH (1.5 mL) is treated with bromoacetic acid (274 mg, 1.98 mmol). The dark red reaction mixture is stirred at 70° C. After 1, 2, 3 and 18 h an additional portion of bromoacetic acid (274 mg, 1.98 mmol) and 3N aq. NaOH (1.5 mL) is added and stirring is continued for 2 h after the last addition. The reaction mixture is diluted with EA, and washed with 1 N aq. HCl. The aq. phase is extracted with EA. The combined organic extracts are dried over MgSO4 and evaporated. The crude product is purified by chromatography on prep. TLC plates with DCM containing 10% of methanol to give {2,6-dimethyl-4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenoxy}-acetic acid (60 mg) as a pale yellow oil; LC-MS: tR=1.07 min, [M+1]+=413.23.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([NH:1][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7][CH:6]=1)([O-:10])=[O:9]
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncc([N+](=O)[O-])cn1
Solvent: c1ccncc1
Product: O=C(Nc1ncc([N+](=O)[O-])cn1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a solution of 2-amino-5-nitropyrimidine (6.34 g, 45.3 mmol) in pyridine (100 ml) was added benzoyl chloride (5.8 ml, 49.8 mmol, 1.1 eq) dropwise over 10 minutes. The reaction mixture was refluxed for 6 hours, poured into ice (800 ml) and allowed to stand overnight. A brown solid was collected by filtration, washed with water and taken up in DCM (500 ml). The solution was washed with brine (3×200 ml), dried (MgSO4), filtered and concentrated under reduced pressure to leave a brown solid. Purification by column chromatography (1% methanol in DCM), afforded the title compound as a thick yellow oil (5.14 g, 47% yield).
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([OH:20])=O)(=[O:14])=[O:13])[CH2:8][CH2:7]1)[CH:2]([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH:50]1[C:54]2([CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:53][NH:52]/[C:51]/1=[N:60]\[C:61]([C:63]1[C:68]([NH2:69])=[N:67][C:66]([NH2:70])=[C:65]([Cl:71])[N:64]=1)=[O:62].CN1CCOCC1>CN(C=O)C>[CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([N:57]2[CH2:58][CH2:59][C:54]3([NH:50]/[C:51](=[N:60]/[C:61]([C:63]4[C:68]([NH2:69])=[N:67][C:66]([NH2:70])=[C:65]([Cl:71])[N:64]=4)=[O:62])/[NH:52][CH2:53]3)[CH2:55][CH2:56]2)=[O:20])(=[O:14])=[O:13])[CH2:8][CH2:7]1)[CH:2]([CH3:4])[CH3:3]
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Reactant: CC(C)COC1CCN(S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)COC1CCN(S(=O)(=O)c2cccc(C(=O)N3CCC4(CC3)CN/C(=N\C(=O)c3nc(Cl)c(N)nc3N)N4)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-Isobutoxy-piperidine-1-sulfonyl)-benzoic acid (0.03 mmol, 10.2 mg) is treated with a solution of HATU (11.4 mg, 0.03 mmol) in DMF (1 ml) followed by a solution of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide dihydrochloride (Ex. 38) (11.9 mg, 0.03 mmol) and N-methyl morpholine (0.010 ml, 0.03 mmol) in DMF (1 ml) and shaken at room temperature overnight. The solution is evaporated under vacuum, redissolved in DMSO (0.5 ml) and purified by mass-directed preparative HPLC. The purified fractions are evaporated under vacuum to afford the title compound; [M+H]+ 648.4
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[S:10](=[O:13])(=[O:12])[NH2:11].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C)C=O>O>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[S:10](=[O:13])(=[O:12])[NH2:11])[CH2:17][CH2:16]1
Reactant: CN1CCNCC1
Reactant: N#Cc1ccc(Cl)c(S(N)(=O)=O)c1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(C#N)cc2S(N)(=O)=O)CC1

Procedure:
43.5 Grams of 4-Chloro-3-sulfamoylbenzonitrile (0.2 mole) were stirred with 45 g of N-methylpiperazine and 50 ml of dimethylformamide for 1 hour at a temperature of from 115° to 120° C., and the reaction solution was subsequently introduced into 0.5 l of water. The crystalline precipitate was suction-filtered, and the moist crude product which had been washed with water, was recrystallized from ethanol.
Reaction SMILES: [N:1]1[NH:2][C:3]2[C:12]3[C:11]=1[CH2:10][CH2:9][S:8][C:7]=3[N:6]=[C:5]([NH2:13])[N:4]=2.Cl.Cl[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[CH2:16][N:2]1[C:3]2[C:12]3[C:11]([CH2:10][CH2:9][S:8][C:7]=3[N:6]=[C:5]([NH2:13])[N:4]=2)=[N:1]1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Nc1nc2c3c(n[nH]c3n1)CCS2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc2c3c(nn(Cc4ccc5ccccc5n4)c3n1)CCS2
Temperature: 60 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
A mixture composed of the above 7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylen-4-amine (30 mg), 2-(chloromethyl)quinoline hydrochloride (51 mg), potassium carbonate (98 mg) and dimethylformamide (1 mL) was stirred at 60° C. overnight. The insoluble matter was separated off by filtration, and then the solvent was evaporated in a nitrogen stream. The residue was purified by reversed phase liquid chromatography (acetonitrile-formic acid) to obtain the title compound (19 mg, 35%) as an amorphous.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[Cl:40])=[O:12])=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C@@:15]2([C:23]#[N:24])[C@H:16]([CH2:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:17][N:13]([C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:41])=[O:2])=[CH:5][CH:6]=3)=[O:12])[C@@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[Cl:40])=[C:26]([F:32])[CH:27]=1
Reactant: COC(=O)c1ccc(NC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1CN(C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2Cl)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a mixture of rac-4-{[(2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,3-dichloro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid methyl ester (85.0 mg, 0.14 mmol) in THF/MeOH (0.6 mL/0.2 mL) was added 4 N LiOH (0.2 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 NH2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-4-{[(2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,3-dichloro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid (54.3 mg, 65.4%). LC-MS (ES+) m/z Calcd for C30H27Cl3FN3O3+H [(M+H): 604; Found: 604.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:19]([CH3:20])[C:18]3[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:17]=3[N:16]=2)=[CH:9][CH:8]=1)[NH2:5].[C:28]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][C:37]1=O)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(OC)C=CC=CC=1>[Pd]>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[N:19]([CH3:20])[C:18]3[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:17]=3[N:16]=2)=[CH:11][CH:12]=1)[NH:5][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28](=[O:35])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2nc3ccc(OC)cc3n2C)cc1
Agent: [Pd]
Solvent: COc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(OCc2nc3ccc(OC)cc3n2C)cc1)Nc1ccccc1C(=O)c1ccccc1

Procedure:
A mixture of 4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine methyl ester (1.1 g), 2-benzoylcyclohexanone (0.7 g), palladium on carbon (10%, 0.2 g) and anisole (15 ml) was heated at reflux for 21 hours. Insoluble material of the reaction mixture was removed by filtration and the anisole of the filtrate was evaporated under reduced pressure. The residue was chromatographed on a silica gel column using hexane:ethyl acetate=1:2 as the eluant to afford the title compound (0.95 g, Rf=0.51 (thin layer chromatography on silica gel using hexane:ethyl acetate=1:3 as the eluant)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:18][C:19]1[N:23]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[N:22]=[N:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:15]3[CH2:17][CH2:16]3)[C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([N:23]4[C:19]([CH3:18])=[N:20][N:21]=[N:22]4)=[CH:25][CH:26]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Reactant: Cc1nnnn1-c1ccc(C(=O)O)cc1
Product: Cc1nnnn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(Cl)cn3)CC2)cc1

Procedure:
The title compound is prepared from [1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-cyclopropyl-amine and 4-(5-methyl-tetrazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.02 min; Mass spectrum (ESI+): m/z=439 [M+H]+.
Reaction SMILES: [CH:1]1C=CC(C(OC2C=CC(C(F)(F)F)=CC=2)CCN)=CC=1.[C:22]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])(=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([CH2:30][CH2:31][C:32]([O:34][CH3:1])=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCC(Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Reactant: O=C(O)CCC(=O)c1ccccc1
Product: COC(=O)CCCc1ccccc1

Procedure:
A preferred method of preparing enantiomerically pure enantiomers of norfluoxetine comprises the asymmetric synthesis of the compound from 3-benzoylpropionic acid. According to this method, 3-benzoylpropionic acid is methylated to provide methyl 3-benzylpropionate, which is then contacted with (+)-B-chlorodiisopinocamphenylborane chloride ((+)-DIP-Cl) to provide (R)-χ-phenyl-χ-butrolactone if R-norfluoxetine is being prepared, or with (−)-DIP-Cl to provide (S)-χ-phenyl-χ-butrolactone if S-norfluoxetine is being prepared. The lactone is subsequently contacted with ammonia to provide the corresponding chiral 4-hydroxy-4-phenylbutanamide (i.e., (R)- or (S)-4-hydroxy-4-phenylbutanamide). A cyclic carbamate is then prepared from the amide by contacting the chiral 4-hydroxy-4-phenylbutanamide with iodobenzene diacetate. The carbamate is then contacted with base to provide chiral 3-amino-(1R)-phenyl-propanol-1-ol, which is subsequently converted to the corresponding enantiomer of norfluoxetine free base by contacting it with sodium hydride and 4-chlorobenzotrifluoride. This free base can then be converted into a salt by known methods. For example, (D)-tartaric acid can be contacted with (R)-norfluoxetine free base to provide (R)-norfluoxetine.(D)-tartarate. Similarly, (L)-tartaric acid can be contacted with (S)-norfluoxetine free base to provide (S)-norfluoxetine.(L)-tartarate.