Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]#[C:11][Si](C)(C)C)[NH:6]1)=[O:4].O[Li].O.[Cl:19][CH2:20][C:21](Cl)=[O:22]>O1CCCC1>[Cl:19][CH2:20][C:21]([N:6]1[C@H:7]([C:10]#[CH:11])[CH2:8][CH2:9][C@H:5]1[C:3]([OH:2])=[O:4])=[O:22]
Reactant: COC(=O)[C@@H]1CC[C@@H](C#C[Si](C)(C)C)N1
Reactant: O=C(Cl)CCl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: C#C[C@@H]1CC[C@@H](C(=O)O)N1C(=O)CCl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 86.3 %

Procedure:
A solution of the product from Example 19 (11.9 kg total, 308.1 g active, 1.37 mol) was concentrated to about 1240 grams and transferred to a 5-L flask. Tetrahydrofuran (1800 mL) was added and the mixture was cooled to less than 10° C. LiOH—H2O (127 g, 3.03 mol) was added over 5 minutes. After 1 hour the mixture was cooled to 0° C. and chloroacetyl chloride (339.8 g, 3.01 mol) was added over about 60 minutes. After 1.5 hours, the reaction was quenched by the addition of a 1/9 mixture of 6 M HCl and 25% aq NaCl (1.8 kg) and isopropyl acetate (1.9 L). The layers were separated and the organic layer was washed with a 1/9 mixture of 6 M HCl and 25% aq NaCl (1.1 kg). The combined aqueous layers were extracted with isopropyl acetate (2×2 L). The combined organic layers were concentrated several times from isopropyl acetate to dry and then to about 800 grams total weight. Solids had come out of solution during the concentration. Heptane (200 mL) was added slowly, causing more solid to precipitate. After stirring for 2-3 h, the mixture was filtered and the solids were washed with 1:1 isopropyl acetate/heptane (250 mL) and dried at 40° C. in a vacuum oven to give 255 g (86% yield) of white solid. The 1H NMR spectrum of the product exhibited 2 rotomers. Rotomer (a) was the major rotomer and rotomer (U) was the minor rotomer. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78-2.07 (m, 2H) 2.08-2.30 (m, 2H) rotomer b: 3.13 (d, J=2.20 Hz, 1H) rotomer a: 3.46 (d, J=2.20 Hz, 1H) rotomer b: 4.09 (d, J=14.13 Hz, 1H) rotomer a: 4.32 (d, J=14.41 Hz, 1H) 4.21 (t, J=741 Hz, 7H) rotomer b; 4.40 (d, J=14.00 Hz, 1H) rotomer a: 4.59 (d, J=14.27 Hz, 1H) rotomer b; 4.61-467 (m, 1H) rotomer a: 4.77-4.85 (m, 1H) 12.53-12.85 (m, 1H)
Reaction SMILES: [C:1]([C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])#[N:2].C1(N=[CH:17][C:18]2[O:19][CH:20]=[CH:21][C:22]=2[CH3:23])C=CC=CC=1.ClC(OCCCC)=O>C1(C)C(C)=CC=CC=1>[CH2:6]([O:5][C:3]([C:1]1[CH:23]=[C:22]2[CH:21]=[CH:20][O:19][C:18]2=[CH:17][N:2]=1)=[O:4])[CH2:7][CH2:8][CH3:9]
Reactant: Cc1ccoc1C=Nc1ccccc1
Reactant: CCCCOC(=O)C#N
Agent: CCCCOC(=O)Cl
Solvent: Cc1ccccc1C
Product: CCCCOC(=O)c1cc2ccoc2cn1
Temperature: 130 °C
Yield: 45.8 %

Procedure:
n-Butyl cyanoformate(13.7 g, 0.108 mol) and 3-methylfuran-2-carbaldehyde-N-phenylimine(5.0 g, 27.0 mmol) were mixed at room temperature in xylene (25 mL) then heated to reflux at 120 to 140° C. with stirring. A xylene (15 mL) solution of 7.40 g (54.2 mol) of n-butyl chloroformate was added dropwise for an hour to the resulting mixture. After all the solution had been added, the reaction mixture was heated to reflux for 2 hours, it was allowed to cool to room temperature, and the solvent was distilled off to give 7.10 g of crude product. This product was purified by column chromatography on silica gel, giving 2.71 g (45.8% yield) of 5-n-butoxycarbonylfuro[2,3-c]pyridine.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[F:16].[Br:17][C:18]1[CH:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=1>C1COCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:22]2[CH:23]=[C:18]([Br:17])[CH:19]=[CH:20][C:21]2=[O:24])=[C:10]([F:16])[CH:11]=1
Reactant: Fc1cc(Cl)ccc1CBr
Reactant: O=c1ccc(Br)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1F
Temperature: 60 °C
Reaction time: 17 h
Yield: 82.7 %

Procedure:
According to Scheme 1 Step 2: K2CO3 (10 eq, 0.11 mmol, 16.0 g) and 1-(bromomethyl)-4-chloro-2-fluorobenzene (1.5 eq, 17.0 mmol, 3.90 g) was added to a solution of 5-bromopyridin-2(1H)-one (1 eq, 11.0 mmol, 2.00 g), in THF (100 mL). The suspension was stirred for 2 hours at room temperature and 17 hours at 60° C. The reaction mixture was filtered and the mother liquor was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 70 g SiO2) using CH2Cl2/AcOEt 80/20 as eluent to afford the title compound 1-(4-chloro-2-fluorobenzyl)-5-bromopyridin-2(1H)-one (9.10 mmol, 2.87 g, 79%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:10]=2[N:11]=1)=O.Cl.[S:21]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)(=[O:24])(=[O:23])[NH2:22]>>[Cl:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([C:5]3[N:31]([C:28]4[CH:27]=[CH:26][C:25]([S:21]([NH2:22])(=[O:24])=[O:23])=[CH:30][CH:29]=4)[N:32]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=3)[S:8][C:9]=2[CH:15]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1nc2ccc(Cl)cc2s1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2nc3ccc(Cl)cc3s2)cc1

Procedure:
The procedure of Example 9 was repeated using 4,4,4-trifluoro-1-(6-chlorobenzothiazol-2-yl)butane-1,3-dione and 4-sulfamoylphenylhydrazine hydrochloride as the starting materials to obtain 4-[5-(6-chlorobenzothiazol-2-yl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide. NMR(CDCl3 -DMSO-d6) δ: 6.91 (2H, bs), 7.30-7.49 (2H, m), 7.63 (2H, d, J=8.9 Hz), 7.88-7.91 (2H, m), 8.05 (2H, d, J=8.9 Hz); mp 254-255° C. (ethanol)
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5](Br)[CH:6]=1.[Li]CCCC.[CH3:13][C:14]1[S:15][CH:16]=[C:17]([CH:19]=O)[CH:18]=1.[NH4+].[Cl-].[H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-]>CCOCC.O>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:19][C:17]2[CH:18]=[C:14]([CH3:13])[S:15][CH:16]=2)[CH:6]=1
Reactant: Cc1cc(Br)cs1
Reactant: Cc1cc(C=O)cs1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(Cc2csc(C)c2)cs1
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
31.3 g of 2-methyl-4-bromo-thiophene (0.177 mol) was dissolved in 150 ml ether and treated dropwise with 113 ml 1.6M BuLi (0.1 mol) at −70° C. The resulting solution kept under stirring at −60 to −70° C. for 30 min and then was treated with 22.3 g 2-methyl-4-thiophene-aldehyd (0.177 mol) in 100 ml ether. The mixture was allowed to warm to r.t., then neutralized by 10% aq. NH4Cl and washed with water. The organic phase was collected and evaporated off. The suspension of 10 g LiAlH4 (0.266 mol) in 100 ml ether was treated dropwise with the solution of 35.5 g AlCl3 (0.266 mol) in 100 ml ether. The resulting mixture was treated with the solution of the compound obtained in the previous reaction in 100 ml ether. The mixture refluxed for additional 1 h, cooled up to r.t. and treated with 100 ml ethyl acetic ester. Then the mixture was treated with 300 ml H2O and 300 ml ether. Organic phase was collected, washed with water, dried over MgSO4 and evaporated off. The residue was distilled at 90-110/0.5 mmHg. Yield 23.2 g (63%). The title compound was analyzed by 1H-NMR spectroscopy.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:29])[CH3:28])[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:28])[CH3:29])[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:11]1
Reactant: CC(C)c1cc2c(cc1NC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@@H]1C)CO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cc2c(cc1NC1CNC1)N1C(=NNC(=O)[C@@H]1C)CO2

Procedure:
A solution of 3-(7-isopropyl-4(S)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 2, SFC (Table 1, Method 11) Rt=4.715 min, 0.32 g, 0.75 mmol) in DCM (8 mL) and TFA (2 mL) was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give 6-(azetidin-3-ylamino)-7-isopropyl-4(S)-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoacetic acid as a pale yellow solid (Example #57-2, Enantiomer 2, SFC (Table 1, Method 11) Rt=4.92 min, 0.31 g, 92%). LC/MS (Table 1, Method 5) Rt=1.688 min.; MS m/z: 330 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.C(OC([N:19]1[CH2:26][CH:25]2[CH:21]([CH2:22][NH:23][CH2:24]2)[CH2:20]1)=O)(C)(C)C>>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([N:19]2[CH2:26][CH:25]3[CH:21]([CH2:22][NH:23][CH2:24]3)[CH2:20]2)[N:3]=1
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Product: COc1cc(OC)nc(N2CC3CNCC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 23 utilizing 2-chloro-4,6-dimethoxypyrimidine and hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester as starting materials.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+]([O-])=O.FC1C=C(F)C=CC=1[N+:25]([O-:27])=[O:26].N1CCOCC1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:25]([O-:27])=[O:26])=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1F
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: O=[N+]([O-])c1ccc(F)cc1N1CCOCC1

Procedure:
4-(3-Fluoro-4-nitrophenyl)morpholine: A solution of 2,4-difluoronitrobenzene (10.0 mL, 91 mmol) and morpholine (17.4 mL, 200 mmol) in THF (100 mL) was stirred at RT under nitrogen for 2 h. The solvent was removed and the residue was partitioned between EtOAc and water. The organic layer was washed brine, dried over MgSO4, and concentrated. The resulting solid was purified by SiO2 chromatography with 20-50% EtOAc in hexane to give 4-fluoro-2-morpholinonitrobenzene (18.1 g) and 55a (1.81 g, 8% yield); [M+H]+=227.10.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH:19]([CH2:21][NH:22][C:23]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[O:24])[O:18][C:17]2=[O:31])=[CH:12][CH:11]=1.CCOCC>ClCCl>[NH2:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH:19]([CH2:21][NH:22][C:23]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[O:24])[O:18][C:17]2=[O:31])=[CH:12][CH:11]=1)=[O:7]
Reactant: C[Si](C)(C)N=C=O
Reactant: NCc1ccc(N2CC(CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: NC(=O)NCc1ccc(N2CC(CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Reaction time: 8 h

Procedure:
At room temperature, 0.19 ml (0.82 mmol) of trimethylsilylisocyanate are added dropwise to a mixture of 30 mg (0.082 mmol) of N-({3-[4-(aminomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophene-carboxamide (from Example 148) in 1.0 ml of dichloromethane. The mixture is stirred overnight and, after addition of ether, the product is then obtained by filtration. Yield: 21.1 mg (52% of theory),
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]3[S:20][C:19]4[N:21]=[CH:22][CH:23]=[N:24][C:18]=4[N:17]([CH2:25][O:26][CH3:27])[C:16]=3[CH:28]=1)[CH:5]=[N:6]2.[CH:29]([Sn](CCCC)(CCCC)CCCC)=[CH2:30]>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:27][O:26][CH2:25][N:17]1[C:16]2[CH:28]=[C:12]([CH2:11][N:4]3[C:3]4[C:7](=[N:8][CH:9]=[N:10][C:2]=4[CH:29]=[CH2:30])[N:6]=[CH:5]3)[CH:13]=[CH:14][C:15]=2[S:20][C:19]2[N:21]=[CH:22][CH:23]=[N:24][C:18]1=2
Reactant: COCN1c2cc(Cn3cnc4ncnc(Cl)c43)ccc2Sc2nccnc21
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1ncnc2ncn(Cc3ccc4c(c3)N(COC)c3nccnc3S4)c12
Temperature: 80 °C

Procedure:
To a solution of 0.30 g of 8-(6-chloropurin-7-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine in N,N-dimethylformamide (10 ml) were added in a nitrogen atmosphere 0.312 g of vinyl-tri-n-butyltin (IV) and 0.050 g of bis(triphenylphosphine) palladium (II) chloride. After degassing, the mixture was heated to 80° C. for 20 hours. Then the insoluble matters were removed by filtering through celite. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.19 g of 10-methoxymethyl-8-(6-vinylpurin-7-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine as a yellow solid. To a solution of 190 mg of the obtained compound in methanol (20 ml) was added 0.018 g of palladium/carbon and hydrogenation was effected in a hydrogengas stream for 2 hours. Thus, 0.10 g of the title compound was obtained as a yellow solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:18][CH2:19][O:20]CC1C=CC(OC)=CC=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C([O-])(O)=O.[Na+]>ClCCl.O>[Si:1]([O:8][C@@H:9]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:18][CH2:19][OH:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(COCC[C@H](CCc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H](CCO)CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
(S)-3-(t-butyl dimethylsilyloxy)-5-(4-methoxy-benzyloxy)-1-phenyl pentane (15 g, 36.2 mmol) was dissolved in a solvent mixture of dichloromethane-water (20:1) (252 ml). DDQ (8.2 g, 36.2 mmol) was added thereto and the mixture was stirred for 30 minutes at room temperature. After completion of the reaction, saturated aqueous NaHCO3 solution (100 ml) was added to the reaction solution to stop the reaction. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to give (S)-3-(t-butyldimethylsilyloxy)-5-phenyl-pentan-1-ol (10.6 g, Yield 99%) of a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[F:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20]Cl)=[CH:17][CH:16]=1.[Cl-].[NH4+]>O1CCCC1>[F:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]2([C:2]3[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=3)[CH2:20][O:22]2)=[CH:17][CH:16]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: Brc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1ccc(C2(c3ccc(Br)cc3)CO2)cc1
Reaction time: 1 h
Yield: 44.8 %

Procedure:
Part A. A solution of 1,4-dibromobenzene (20.0 g, 0.08 mole) in tetrahydrofuran (200 mL) was cooled to -70+ and treated dropwise with n-butyllithium (1.6 M in hexane; 50 mL, 0.08 mole). The solution was stirred at this temperature for 60 minutes, then was treated dropwise with 4-fluorophenacyl chloride (13.8 g, 0.08 mole). The reaction was stirred at -70° overnight, then warmed to 0° for 3 hours. Saturated aqueous ammonium chloride was added, and the aqueous phase was separated. The aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with saturated brine, then dried (Na2SO4) and concentrated under reduced pressure. The crude product was chromatographed on silica gel with 9:1 hexane/ethyl acetate to provide 2-(4-fluorophenyl)-2-(4-bromophenyl)-oxirane as an oil (10.5 g, 45% yield). NMR (CDCl3) 7.5-6.9(8H), 3.3-3.1(2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[N:43]1([CH2:52][CH2:53]O)[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][OH:51])[CH2:45][CH2:44]1>>[OH:51][CH2:50][CH2:49][N:46]1[CH2:45][CH2:44][N:43]([CH2:52][CH2:53][O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH2:48][CH2:47]1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: OCCN1CCN(CCO)CC1
Product: COc1cc(C(=O)OCCN2CCN(CCO)CC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2,2′-(piperazine-1,4-diyl)diethanol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-ethyl ester, dimer. MS (ES+) m/z calcd. for C70H73Cl4F4N8O8: [(M+H)+]1369. found: 1369.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2
Reactant: CN1CCNCC1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(N3CCN(C)CC3)c1)C(C)(C)C2
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A mixture solution of 2-(3-bromo-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (1.5 g, 3.7 mmol), 1-methyl-piperazine (2.5 g, 14.7 mmol), copper(I) iodide (282 mg, 1.48 mmol), N,N-dimethylglycine hydrochloride (413 mg, 2.96 mmol) and potassium carbonate (5.6 g, 40.7 mmol) in dimethyl sulfoxide (8.0 mL) was stirred at 120° C. for 16 hours. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×200 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 6-chloro-3,3-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (1.3 g, 80%) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C24H30ClN3O2 (M+H)+: 428.98, observed: 428.1.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[C:4]([C:11]#[N:12])[CH:3]=1.[N+:13]([CH:16]([CH:19]=O)[CH:17]=O)([O-:15])=[O:14].[Na].Cl>C(O)CC>[C:7]([N:6]1[C:2]2=[N:1][CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:19]=[C:3]2[C:4]([C:11]#[N:12])=[CH:5]1)([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)n1cc(C#N)cc1N
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: CCCO
Product: CC(C)(C)n1cc(C#N)c2cc([N+](=O)[O-])cnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
To a solution of 5.85 g (35.8 mmol) of 5-amino-1-tert-butyl-1H-pyrrole-3-carbonitrile, being prepared as disclosed in Org. Proc. Res. Dev., 7(2), 209-213, 2003, in 120 mL of n-propanol, it was added sodium nitromalonaldehyde (6.02 g, 43.0 mmol) portionwise under stirring at room temperature. The resulting mixture was treated dropwise with 37% hydrochloric acid (4.6 mL, 55.2 mmol) and heated at 100° C. for 2 hours. The reaction mass was concentrated under vacuum to ⅓ of the initial volume and kept at 4° C. for 18 hours. The precipitate was filtered off, washed thoroughly with 15% aqueous ethanol (35 mL), water (5 mL) and finally dried to afford 7.14 g of the title compound as a light brown solid.
Reaction SMILES: C1(C)C=CC(S(N2C[C@H](O)C[C@H]2CO)(=O)=O)=CC=1.C[O:20][C:21](=O)[C@:22]1([OH:37])[CH2:26][CH2:25][CH2:24][N:23]1[S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28].[Li+].[BH4-].Cl>C1COCC1>[S:27]([N:23]1[CH2:24][CH2:25][CH2:26][C@@:22]1([OH:37])[CH2:21][OH:20])([C:30]1[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=1)(=[O:28])=[O:29]
Reactant: COC(=O)[C@]1(O)CCCN1S(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)N2C[C@H](O)C[C@H]2CO)cc1
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@@]2(O)CO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
(2S,4R)-1-(4-toluenesulfonyl)-2-hydroxymethyl-4-hydroxy pyrrolidine. To a solution of N-tosylhydroxy-L-proline methyl ester (62.20 g, 0.21 mole) in THF (600 mL) at 0° C. was added LiBH4 (15.8 g, 0.73 mole) in small portions. The reaction mixture was stirred at 0° C. for 1 h and allowed to stand at 23° C. for 18 h. The reaction mixture was cooled to -20° C., made neutral with 6N HCl and concentrated under reduced pressure. The residue was treated with water (550 ml) and extracted with EtOAc (4×300 mL). The combined organic extracts were washed with H2O, dried over MgSO4, filtered and concentrated under reduced pressure to give N-tosylhydroxy-L-prolinol as a white solid (50.56 g, 88.8%) which was used in the next step without further purification.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Cl:11][C:12]1[CH:37]=[CH:36][C:15]([CH:16]=[CH:17][CH2:18][NH:19][CH2:20][CH2:21][NH:22][S:23]([C:26]2[C:27]3[CH:28]=[CH:29][N:30]=[CH:31][C:32]=3[CH:33]=[CH:34][CH:35]=2)(=[O:25])=[O:24])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH:16]=[CH:17][CH2:18][N:19]([CH2:20][CH2:21][NH:22][S:23]([C:26]2[C:27]3[CH:28]=[CH:29][N:30]=[CH:31][C:32]=3[CH:33]=[CH:34][CH:35]=2)(=[O:24])=[O:25])[CH:1]=[O:3])=[CH:36][CH:37]=1
Reactant: O=CO
Reactant: O=S(=O)(NCCNCC=Cc1ccc(Cl)cc1)c1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: O=CN(CC=Cc1ccc(Cl)cc1)CCNS(=O)(=O)c1cccc2cnccc12
Temperature: 25 °C

Procedure:
3 ml of formic acid and 3 ml of acetic anhydride were mixed and stirred at a room temperature, and to the mixture was added 1.41 g of the product of Example 172, and the mixture was stirred for one hour. The reaction mixture was added to 50 ml of ethyl acetate and 30 ml of saturated sodium carbonate aqueous solution with ice, and the mixture was stirred, and after foaming was terminated, the ethyl acetate layer was sequentially washed twice with water and once with a saturated sodium chloride aqueous solution, and dried over magnesium sulfate, filtered and evaporated under a reduced pressure. The resulting residue was purified on a silica gel column (silica gel 60 g, eluant: 2% methanol in chloroform), to obtain 1.49 g of the title compound as a mixture of two isomers (3:2) in a colorless amorphous form.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:7]=2[CH:6]=1.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>C(#N)C.CO>[C:19]([NH:23][CH2:18][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:7]=2[CH:6]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)N
Reactant: NS(=O)(=O)c1nc2ccc(OCC3CO3)cc2s1
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)NCC(O)COc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 50 °C

Procedure:
A solution of 6-(2,3-epoxypropoxy)benzothiazole-2-sulfonamide (1.14 gm, 4.0 mmol) in acetonitrile (16 mL) and methanol (4 mL) containing t-butylamine (0.88 mL, 0.4 mmol) was warmed at 50° C. for 15-20 hours. The solvents were evaporated and the residue (1.1 gm) was chromatographed on silica gel eluting with 20-30% methanol/chloroform (V/V). The appropriate fractions were combined and evaporated. The residue was digested in acetonitrile, cooled and the produce collected (0.62 gm), m.p. 195°-196° C.