Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=3[C:8]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:7][C:6]=12.O1CCOCC1.[NH:38]1[CH:42]=[C:41](B(O)O)[CH:40]=[N:39]1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[Br:1][C:2]1[N:3]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([C:41]4[CH:42]=[N:38][NH:39][CH:40]=4)=[CH:10][C:9]=3[C:8]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:7][C:6]=12
Reactant: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(I)ccc32)c1Br
Reactant: OB(O)c1cn[nH]c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(-c4cn[nH]c4)ccc32)c1Br
Yield: 44 %

Procedure:
342 mg of 3-bromo-5-(2,6-difluorophenyl)-2-(2-trimethylsilanylethoxymethyl)-7-iodo-2H-pyrazolo[4,3-c]isoquinoline are introduced into 13 ml of 1,4-dioxane. 74 mg of 4-pyrazoleboronic acid, 77 mg of Pd(PPh3)4 and 165 mg of sodium carbonate are added. The mixture is heated at reflux for 4 h 30 min. After cooling, the mixture is poured into water, extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a DCM/methanol mixture (95/05 by vol.), to give 136 mg of 3-bromo-5-(2,6-difluorophenyl)-7-(1H-pyrazol-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinoline (white foam), which is used as it is in the following step.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:19][CH:20]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-n-Butyl-4-chloroimidazole-5-carboxaldehyde (6.34 g, 34.0 mmol), 1 eq.), 4-bromomethyl-2'-cyanobiphenyl (9.25 g, 34.0 mmol, 1 eq.), potassium carbonate (5.17 g, 37.4 mmol., 1.1 eq.) and DMF (100 mL) were mixed and stirred at 25° C. overnight. The solids were filtered and the filtrate evaporated. The residue wash chromatography over silica gel in 9:1 to 1:1 hexane/ethyl acetate and crystallized from methylcylcohexane/n-butyl chloride yielding 9.70 g of a solid; m.p. 96.0°-97.0° C. NMR (CDCl3): δ 9.78 (s, 1H); 7.83-7.40 (m, 6H); 7.19 (d, 2H, J=9Hz); 5.63 (s, 2H); 2.71 (t, 2H, J=7Hz); 1.72 (t of t, 2H, J=7,7Hz); 1.38 (t of q, 2H, J=7,7Hz); 0.90 (t, 3H, J= 7Hz). Anal. calcd. for C22H20ClN3O: C, 69.93; H, 5.34; N, 11.12. Found: C, 69.64; H, 5.37; N, 11.21.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:5]2.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(N1C2C(=CC(C3C=CC=CC=3)=CC=2)C[C@H](NS(C2C=CC=CC=2)(=O)=O)C1)C1C=CC=CC=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][CH2:7][CH:6]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:5]3)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=S(=O)(NC1CNc2ccc(Br)cc2C1)c1ccccc1
Agent: O=S(=O)(N[C@H]1Cc2cc(-c3ccccc3)ccc2N(Cc2ccccc2)C1)c1ccccc1
Product: O=S(=O)(NC1CNc2ccc(-c3ccc(F)cc3)cc2C1)c1ccccc1

Procedure:
Compound 113A was prepared from 87A and 4-fluorophenylboronic acid by procedures analogous to those described in 89E.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.FC(F)(F)C1C=C(Cl)C=CC=1C(O)C1C=CC=CC=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]([OH:19])[C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: FC(F)(F)c1ccccc1[Mg]Br
Agent: OC(c1ccccc1)c1ccc(Cl)cc1C(F)(F)F
Product: OC(c1ccc(F)cc1)c1ccccc1C(F)(F)F

Procedure:
This material was prepared from 2-(trifluoromethyl)phenylmagnesium bromide (16 mmol) and 4-fluorobenzaldehyde (1.64 mL, 15 mmol) using the procedure described for compound (96) (4.27 g, 100%).
Reaction SMILES: ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[CH:24]1[CH:29]=[C:28]([CH2:30][C:31](O)=[O:32])[C:27]([NH:34][C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:42])=[CH:26][CH:25]=1.CCOC(C)=O>ClCCl>[CH2:30]1[C:31](=[O:32])[N:34]([C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:42])[C:27]2[C:28]1=[CH:29][CH:24]=[CH:25][CH:26]=2
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1Cc2ccccc2N1c1c(Cl)cccc1Cl
Reaction time: 1 h

Procedure:
N-Hydroxysuccinimide (0.76 mmol) and DCC (0.76 mmol) are added to a solution of the corresponding diclofenac acid derivative (0.506 mmol) dissolved in 10 ml of dichloromethane. The mixture is stirred for 1 hour and monitored by TLC (EtOAc:He, 1:1). When completion of the reaction is detected, the mixture is filtered and the solvent is evaporated under reduced pressure. The crude product is purified by column chromatography to afford the pure diclofenac amide derivative.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.N1C=CN=C1.[CH3:25][C:26]([Si:29](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:28])[CH3:27].COC1C=CC(C=O)=CC=1>CCOC(C)=O.CN(C=O)C>[Si:29]([O:1][CH2:2][C@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)([C:26]([CH3:28])([CH3:27])[CH3:25])([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)COC1CCCCO1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: COc1ccc(C=O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](COC1CCCCO1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 18 h
Yield: 18.5 %

Procedure:
To a 5 L three neck flask fitted with a thermometer, mechanical stirrer, under argon was added 3 (108 g, 0.39 mol) and DMF (700 mL). To the light yellow solution was added imidazole (53 g, 0.78 mol) and TBDPSCl (tert-butyldiphenylchlorosilane) (150 mL, 0.58 mol). The solution turned cloudy and colorless. After stirring 18 hours the reaction was shown to be complete by TLC (EtOAc:hexanes; 3:7, anisaldehyde dip reagent). The clear yellow solution was concentrated under reduced pressure to a yellow residue (415 g). The residue was dissolved in diethyl ether (2 L) in a 4 L flask with a mechanical stirrer. To this solution was added 1.2M HCl (300 mL) to pH 3-4. The solution was stirred for 10 min. The layers were separated and the organic layer was washed with sat. NaHCO3 (300 mL) to pH 7 and brine (400 mL). The organic layer was dried over MgSO4 (60 g), filtered and concentrated under reduced pressure to 248 g of an oil. The oil was flashed chromatographed in portions over flash silica as follows. The oil (60 g) was flash chromatographed over flash silica gel (440 g) with anhydrous Na2SO4 (100 g) on top of the column packed with hexanes. Fractions of 500 mL were collected. Fractions 1-2 were eluted with hexanes, 3-10 with 4% ethyl acetate in hexanes, 11-18 with 10% ethyl acetate in hexanes. Fractions were monitored by TLC (EtOAc:hexanes; 2:8, anisaldehyde dip reagent) and HPLC. Fractions 9-18 were combined and concentrated under reduced pressure to give 37 g (18%) of product 4 as a viscous colorless oil. HPLC analysis showed a purity of 98%. The total weight of product 4 after purifications was 164 g (82%). 1H NMR (60 MHz, CDCl3) δ 7.0-7.7 (m, 10H), 3.2-5.2 (m, 9H), 1.0-2.0 (m, 24H).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O1CCCC1.CCOCC>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8.5 g 5-hexen-1-ol in 100 mL tetrahydrofuran is added 14 mL dihydropyran followed by 0.5 g p-toluenesulfonyl chloride. The mixture is stirred at room temperature for 18 hours and then diluted with ether. The mixture is then washed with saturated aqueous sodium bicarbonate, dried, filtered and evaporated. The resulting oil is chromatographed over silica gel using hexane/ether (18:1) as eluent to give 6-(2-tetrahydropyranyloxy)-hex-1-ene; NMR (CDCl3): delta 5.85 (m,1H), 4.6 (brs,1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:13]=[N:14][C:15]([N:19]([CH3:21])[CH3:20])=[CH:16][C:17]=3[CH3:18])[N:7]([CH2:22][CH2:23][CH2:24][C:25](OCC)=[O:26])[C:6]=2[C:5]([CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:4][CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:13]=[N:14][C:15]([N:19]([CH3:21])[CH3:20])=[CH:16][C:17]=3[CH3:18])[N:7]([CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:6]=2[C:5]([CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2cnc(N(C)C)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3cnc(N(C)C)cc3C)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.2 %

Procedure:
To a solution of ethyl 4-[4-chloro-2-{[6-(dimethylamino)-4-methylpyridin-3-yl]amino}-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (200 mg, 0.41 mmol) in tetrahydrofuran (4 mL) was added lithium borohydride (27 mg, 1.23 mmol) portionwise at 0° C. The mixture was warmed to room temperature and stirred for 24 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate to give the title compound (95 mg, 0.214 mmol, 52%) as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.[F:19][C:20]([F:28])(S(F)(=O)=O)C(O)=O>[Cu]I.C(#N)C>[F:19][CH:20]([F:28])[O:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: COC(=O)[C@@H]1C[C@H](CO)CN1C(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@H](COC(F)F)CN1C(=O)OC(C)(C)C
Temperature: 45 °C
Yield: 60.7 %

Procedure:
A 100 mL round-bottom flask was charged with (2S,4S)-1-tert-butyl 2-methyl 4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (3.33 g, 12.84 mmol), CuI (0.489 g, 2.56 mmol), and anhydrous acetonitrile (57.1 mL). The reaction was heated to 45° C. (ext. oil bath). 2,2-difluoro-2-(fluorosulfonyl)acetic acid (2.655 mL, 25.68 mmol) was added at 45° C. over 30 minutes via syringe pump. The reaction was heated for 30 minutes. Upon completion as monitored by TLC, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was diluted in EtOAc and washed with sodium bicarbonate (aq). The bicarbonate layer was back extracted with ethyl acetate twice. Combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated. The resulting residue was further purified via silica gel chromatography (10 to 40% EtOAc/Hexanes) to afford (2S,4S)-1-tert-butyl 2-methyl 4-((difluoromethoxy)methyl)pyrrolidine-1,2-dicarboxylate (2.41 g, 61%). MS (ESI) m/z 210.21
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:10][CH3:11])[CH2:7][CH2:8][CH3:9]>CCOCC.O>[Br:1][CH2:2][C:3]([N:10]([CH2:6][CH2:7][CH2:8][CH3:9])[CH3:11])=[O:4]
Reactant: O=C(Br)CBr
Reactant: CCCCNC
Solvent: O
Solvent: CCOCC
Product: CCCCN(C)C(=O)CBr
Reaction time: 0.5 h

Procedure:
To a solution cooled to -20° C. of 11.9 ml of bromoacetyl bromide in 180 ml of ether there were added 26 g of butylmethyl amine in solution in 120 ml of ether and then the temperature returned to 20° C. The mixture was stirred for 30 minutes diluted with water and extracted with ether. The ether phase was evaporated to dryness under reduced pressure and the 27.4 g of residue were distilled under reduced pressure (0.05 mbar) at 79/83° C. to obtain. 19.36 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Si](C=[N+]=[N-])(C)(C)[CH3:22]>C1COCC1.CO>[CH3:22][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[C:3]([F:20])=[C:4]([F:19])[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a solution of 5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid (17.4 g, 48.1 mmol) in THF-MeOH (100 mL-30 mL) was added TMSCHN2 (31.0 mL, 62.0 mmol, 2M solution in hexanes) at room temperature. The resulting mixture was stirred for 2 hours, quenched with AcOH, and diluted with EtOAc. The organic layer was washed with water, saturated NaHCO3 (2×), and brine. The organic layer was dried over MgSO4, filtered, and concentrated to give the crude product (18.0 g, 99%) that was used directly without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)(=[O:12])=[O:11])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.I[CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:54]=[CH:53][C:41]2[N:42]([CH3:52])[C:43](=[O:51])[C:44]([CH3:50])([CH3:49])[C:45](=[O:48])[N:46]([CH3:47])[C:40]=2[CH:39]=1>C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:54]=[CH:53][C:41]2[N:42]([CH3:52])[C:43](=[O:51])[C:44]([CH3:49])([CH3:50])[C:45](=[O:48])[N:46]([CH3:47])[C:40]=2[CH:39]=1)(=[O:11])=[O:12])([O-:3])=[O:2]
Reactant: CN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN(CCc3cccnc3)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
2-Nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide (1.8 g, 5.8 mmol) and potassium carbonate (1.0 g, 7.2 mmol) were added to a DMF solution (30 ml) of 7-(3-iodopropoxy)-1,3,3,5-tetramethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.0 g, 4.8 mmol) and stirred at room temperature overnight. The reaction mixture was added to ice water, and extraction with ethyl acetate was performed. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2→ethyl acetate→ethyl acetate:methanol=20:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 2.29 g (yield: 80%) of 2-nitro-N-(2-pyridin-3-ylethyl)-N-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]benzenesulfonamide as a yellow amorphous solid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]([C:11]1[C:12]([F:22])=[C:13]([C:18]([F:21])=[CH:19][CH:20]=1)[C:14]([O:16]C)=[O:15])[S:6](=[O:10])(=[O:9])[NH:7][CH3:8])[CH3:4]>C1COCC1.CO>[CH2:3]([N:5]([C:11]1[C:12]([F:22])=[C:13]([C:18]([F:21])=[CH:19][CH:20]=1)[C:14]([OH:16])=[O:15])[S:6](=[O:9])(=[O:10])[NH:7][CH3:8])[CH3:4]
Reactant: CCN(c1ccc(F)c(C(=O)OC)c1F)S(=O)(=O)NC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(c1ccc(F)c(C(=O)O)c1F)S(=O)(=O)NC
Temperature: 60 °C
Yield: 83.1 %

Procedure:
NaOH (0.908 mL, 1.82 mmol) was added to methyl 3-(N-ethyl-N-methylsulfamoylamino)-2,6-difluorobenzoate (0.280 g, 0.908 mmol) in THF:MeOH (3:2; 5 mL). The mixture was warmed to 60° C. for 16 hours. The cooled mixture was concentrated under reduced pressure, and the residue was taken up in 1M NaOH (4 mL) and washed with EtOAc. The aqueous pH was lowered to below 3, and the mixture was extracted with EtOAc (3×6 mL) to provide crude 3-(N-ethyl-N-methylsulfamoylamino)-2,6-difluorobenzoic acid (222 mg, 83% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].C1C(=O)N([Br:16])C(=O)C1.O>CN(C=O)C>[Br:16][C:5]1[S:1][C:2]([CH2:6][C:7]#[N:8])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CCc1cccs1
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
To a solution of 2-(thiophen-2-yl)acetonitrile (1.23 g, 10 mmol, 1.0 eq) in DMF (10 mL), NBS (1.96 g, 11 mmol, 1.1 eq) was added. The mixture was stirred at room temperature for 2 h. Water was added to the reaction mixture. After extraction with EtOAc (3×), the organic layers were washed with water, brine, dried (Na2SO4) and filtered. The filtrate was concentrated and the resulting residue was purified by silica gel chromatography (petroleum/EtOAc from 100:1 to 10:1) to affords 2-(5-bromothiophen-2-yl)acetonitrile (738 mg, 60%). LC-MS (m/z)=202 [M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])[CH3:9])=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[O:12][C:11](=[O:31])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:37]4[CH:38]=[N:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CCCNS(C)(=O)=O)(c4ccc(F)cc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamide and 6-methoxypyridine-3-boronic acid following a procedure analogous to that described in Example 75 Step 1. LC-MS Method 2 tR=1.327 min, m/z=542.1; 1H NMR (CD3OD) 1.33 (m, 1H), 1.58 (d, 3H), 1.66 (m, 1H), 1.98 (m, 2H), 2.20-2.39 (m, 2H), 2.47 (m, 1H), 2.87 (s, 3H), 2.99 (m, 2H), 3.15 (m, 1H), 3.96 (s, 3H), 5.60 (m, 1H), 6.87 (d, 1H), 7.12 (m, 4H), 7.36 (m, 4H), 7.87 (d, 1H), 8.29 (s, 1H).
Reaction SMILES: CC1C=CC=C(C)C=1C(O)=O.[CH3:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:18][O:17][C:15](=[O:16])[C:14]1[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=1[CH2:12][Br:23]
Reactant: COC(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cc1cccc(C)c1C(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1CBr
Yield: 73 %

Procedure:
To a solution of 2.3 g (15.3 mmol) of methyl o-methylbenzoate (methyl o-toluate) in 20 mL of refluxing CCl4 was added 3 g of N-bromosuccinimide and 0.10 g AIBN. After 2.5 hours the mixture was cooled, diluted with 500 mL of CH2Cl2 and washed with 200 mL of H2O and 200 mL of brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resultant oil was flash chromatographed with 5:1 hexane/ethyl acetate to yield the titled compound (2.56 g, 73%).
Reaction SMILES: C(Cl)CCl.[C:5](=[N:8][OH:9])([NH2:7])[CH3:6].[C:10]([O:14][C:15]([N:17]([C@@H:22]1[CH2:24][C@H:23]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:18][C:19](O)=O)=[O:16])([CH3:13])([CH3:12])[CH3:11]>COCCOCCOC>[CH3:6][C:5]1[N:7]=[C:19]([CH2:18][N:17]([C@H:22]2[CH2:24][C@H:23]2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:15](=[O:16])[O:14][C:10]([CH3:13])([CH3:11])[CH3:12])[O:9][N:8]=1
Reactant: CC(N)=NO
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)[C@@H]1C[C@H]1c1ccccc1
Solvent: COCCOCCOC
Solvent: ClCCCl
Product: Cc1noc(CN(C(=O)OC(C)(C)C)[C@H]2C[C@H]2c2ccccc2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
EDC (107 μL, 0.585 mmol) and acetoamidoxime (41 mg, 0.532 mmol) was added to a stirred solution of 2-(tert-butoxycarbonyl((trans)-2-phenylcyclopropyl)amino)acetic acid (163 mg, 0.532 mmol) in diglyme (2 mL) under argon atmosphere. The mixture was stirred at 50° C. overnight and then at 110° C. for 14 hours. After removal of solvent under vacuum, the reaction mixture was purified by flash chromatography eluting with hexane/MTBE (80:20 to 0:100) to afford tert-butyl (3-methyl-1,2,4-oxadiazol-5-yl)methyl((1S,2S)-2-phenylcyclopropyl)carbamate as a colourless oil (35 mg. Yield=20%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:32][CH3:33])=[C:19]([CH2:23][N:24]4[CH2:27][CH:26]([C:28]([O:30]C)=[O:29])[CH2:25]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:32][CH3:33])=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:23][N:24]3[CH2:25][CH:26]([C:28]([OH:30])=[O:29])[CH2:27]3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCc1c(CN2CC(C(=O)OC)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.85 h

Procedure:
To a solution of methyl 1-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylate (2.78 g, 5.32 mmol) in Isopropanol (20.00 mL) and Water (10 mL) was added sodium hydroxide (0.638 g, 15.96 mmol). The mixture was stirred at rt for 51 mins. Stirring was stopped and the solution was concentrated under the reduced pressure. The residue was adjusted to pH value around 6 with HCl (1.0 M) solution, 1-(3-(5-(3-chloro-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2-ethylbenzyl)azetidine-3-carboxylic acid (2.33 g) was collected by filtering and dried in vacuum as yellow solid.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][C:6]1[C:7]([N+:16]([O-:18])=[O:17])=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1.O>ClCCl>[CH3:5][C:6]1[C:7]([N+:16]([O-:18])=[O:17])=[C:8]([S:12]([NH:4][CH:1]([CH3:3])[CH3:2])(=[O:13])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1[N+](=O)[O-]
Reactant: CC(C)N
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(S(=O)(=O)NC(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of isopropylamine (13 mL, 155 mmol) in 60 mL of dichloromethane at 0° C. was added a solution of 5.3 g of 3-methyl-2-nitrobenzenesulfonyl chloride (prepared according to Courtin, A. Helv. Chim. Acta, 1976, 59, 379-387) in 60 mL of dichloromethane dropwise. The reaction mixture was stirred 2 hours at room temperature. Water was added and the layers were separated. The organic layer was dried (sodium sulfate) and the volatiles were removed with a rotary evaporator. The residue was purified by medium pressure liquid chromatography (MPLC), using 20-40% ethyl acetate in hexanes as eluant, to afford 4.3 g of the title compound as a yellow solid.