Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[F:12])#[N:2].Cl.[CH3:14]N(C)CCCN=C=NCC>CO.CN(C)C1C=CN=CC=1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:14])=[O:8])=[CH:5][C:4]=1[F:12])#[N:2]
Reactant: N#Cc1ccc(C(=O)O)cc1F
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
4-Cyano-3-fluorobenzoic acid (Carbocore, 1 g; 6.06 mmol) was dissolved in MeOH (12.50 mL) to which 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.39 g; 7.27 mmol) followed by 4-dimethylaminopyridine (0.07 g; 0.61 mmol) were added. The mixture was stirred at RT overnight after which it was concentrated, taken up in EtOAc and washed with 0.1N HCl, 0.1 N NaOH and brine (2×50 mL each) and dried over MgSO4 to give the title compound as an off-white solid (0.95 g; 87%). 1H NMR: (DMSO-d6, 300 MHz) δ 8.16 (dd, J=6.40 Hz, J=7.91 Hz, 1H), 8.02 (dd, J=1.50 Hz, J=9.80 Hz, 1H), 7.97 (dd. J=1.50 Hz, J=7.91, 1H), 3.95 (s, 3H). GC/MS (M+·): 179 (EI). HPLC (Method A) Rt 3.17 min (Purity: 87.3%).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:11](=[O:19])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[CH3:26][Si]([N-][Si](C)(C)C)(C)C.[K+].S(OC)(OC)(=O)=O>C1(C)C=CC=CC=1>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=[O:18])[C:14]([CH3:16])([CH3:17])[CH3:15])[C:11](=[O:19])[C@H:10]([CH3:26])[CH2:9]2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
10 g of (S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1-a, R1=pivaloyl) were dissolved in 150 ml toluene. The mixture was cooled to about 0° C. and 71.5 ml potassium bis(trimethylsilyl)amide solution (0.5 M in toluene) were added. After 15 min, 11 ml dimethyl sulphate were added and the mixture was stirred for a further hour. The reaction was quenched with ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were concentrated to dryness to obtain 15.3 g of crude (3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one. According to HNMR analysis, on the crude, the ratio of diastereoisomers is 83:17 [(3R,5S):(3S,5S)]. Spectroscopic data for (2-a, R1=Pivaloyl) is reported in Example 5-1, Method 1. Spectroscopic data for (2-b, R1=Pivaloyl) is reported in Example 5-2.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([CH3:17])[C:9]([N+:14]([O-:16])=[O:15])=[C:10]([CH3:13])[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.Cl>CO>[CH3:17][C:8]1[C:9]([N+:14]([O-:16])=[O:15])=[C:10]([CH3:13])[CH:11]=[C:12]2[C:7]=1[CH2:6][CH2:5][NH:4]2
Reactant: CC(=O)N1CCc2c1cc(C)c([N+](=O)[O-])c2C
Agent: Cl
Solvent: CO
Product: Cc1cc2c(c(C)c1[N+](=O)[O-])CCN2
Yield: 91.4 %

Procedure:
1-Acetyl-4,6-dimethyl-5-nitroindoline (2.4 g) was dissolved in methanol (25 ml). Hydrochloric acid 6N (20 ml) was added, followed by reflux for 15 hours. After the completion of the reaction, the solvent was evaporated under reduced pressure. The residue was dissolved in chloroform, and the mixture was washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was chromatographed (ISCO, hexane/EtOAc, 0-40%, 40 min) to give 1.8 g of 4,6-dimethyl-5-nitroindoline as yellow solids. 1H NMR (DMSO-d6, 400 MHz): δ 6.36 (brs, 1H, exchangeable with D2O, NH), 6.20 (s, 1H), 3.54 (t, J=8.0 Hz, 2H), 2.91 (t, J=8.0 Hz, 2H), 2.17 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[CH2:23][CH:22]3[O:24][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[CH:3]=1.[H-].[Na+].[H][H]>CC(O)C>[CH:22]([O:24][C:2]1[CH:3]=[C:4]([N:17]2[CH2:23][CH:22]3[O:24][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[N:7]=1)([CH3:23])[CH3:21]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(N3CC4CCC(C3)O4)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Oc1cc(N2CC3CCC(C2)O3)nc(-c2ccc(N)cc2)n1
Temperature: 140 °C

Procedure:
In a 2-5 mL microwave vial was placed 3-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (13, 70 mg, 0.202 mmol) in 2-propanol (4 mL) to give a yellow suspension. Sodium hydride (60% in oil, 32.3 mg, 0.807 mmol) was added and the mixture was stirred until no further formation of hydrogen gas was observed. The reaction was heated under microwave irradiation at 140° C. for 30 min to give a bright orange suspension. Work-up: the solvents were evaporated. The residue was dissolved in dichloromethane and washed with sat NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated to give the title compound in a quantitative yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[C:5]([CH3:9])([CH3:8])[CH2:6][NH2:7])[CH3:2].C[O:12][C:13]([C:15]1[N:16]=[CH:17][C:18]2[C:23]([C:24]=1[OH:25])=[CH:22][CH:21]=[C:20]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:19]=2)=O>CCO>[CH2:1]([O:3][C:4](=[O:10])[C:5]([CH3:9])([CH3:8])[CH2:6][NH:7][C:13]([C:15]1[N:16]=[CH:17][C:18]2[C:23]([C:24]=1[OH:25])=[CH:22][CH:21]=[C:20]([O:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH:19]=2)=[O:12])[CH3:2]
Reactant: CCOC(=O)C(C)(C)CN
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 26.7 %

Procedure:
To a solution of the 3-amino-2,2-dimethyl-propionic acid ethyl ester (598 mg, 4.12 mmol) in EtOH (9.1 mL) at r.t. were added 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (811 mg, 2.75 mmol) to give suspension solution, the reaction mixture was allowed to reflux for 18 h. After cooled to rt, the solvent was evaporated in vacuo, the crude was purified by silica gel chromatography to give 300 mg of title compound as a yellow oil: MS (m/z) 409.0 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[C:3]1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:25][C:26]([CH3:31])([CH3:30])[C:27]([O:17][CH2:16][CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:3]2[C:2](=[O:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:14][CH2:13]1)=[O:28]
Reactant: O=c1cccccc1N1CCN(CCO)CC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCCN1CCN(c2cccccc2=O)CC1
Reaction time: 72 h

Procedure:
To a solution of 4-(2-oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine-ethanol (7.04 g, described in Example 7) in methylene chloride (100 ml), triethylamine (4.3 g) was added followed by the dropwise addition of 2,2-dimethylpropanoyl chloride. The resulting solution was allowed to stay at room temperature for 3 days, then washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed twice on 250 g of silica gel with ethyl acetate to yield 3.5 g of the title compound. The title compound (3.0 g) was dissolved in acetone (15 ml) and a solution of maleic acid (1.16 g) in acetone (15 ml) was added. Diethyl ether (100 ml) was added to give the (Z)-2-butenedioate salt (2.5 g) of the title compound; mp 101°-102° C.; ir(mull) 2350, 1723, 1700 and 1545 cm-1 ; uv max(MeOH) 343 (ε=8040) and 251 nm(ε=12645); nmr(DMSO-d6 ) δ1.2 (m, 9H), 3.3 (m, 10H), 4.3 (m, 2H), 6.1 (s, 2H) and 6.95 (m, 5H); and Anal. Calcd for C18H26N2O3.C4H4O4 : C, 60.82% H, 6.96% N, 6.45% and Found: C, 60.74% H, 7.01% N, 6.16%.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][N:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=2)[CH:17]=[CH:16][N:15]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Product: COc1cc(-c2ccc(C(F)(F)F)nn2)ccn1
Yield: 60.2 %

Procedure:
3-Chloro-6-(trifluoromethyl)pyridazine (137 mg, 0.751 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (176 mg, 0.749 mmol) were reacted according to Example 31 (step a) to provide the title compound (115 mg, 60%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.39 (d, J=5.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.62 (dd, J=5.4, 1.5 Hz, 1H), 7.45 (s, 1H), 4.03 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C@@H:7]([C:9]([OH:11])=O)[NH2:8].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>O1CCCC1.O>[OH:11][CH2:9][CH:7]([NH:8][C:21](=[O:22])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](Cc1cccs1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC(CO)Cc1cccs1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
24.8 g of 3-(2-thienyl)alanine (144.8 mmol) were added in portions to 11.0 g of LiAlH4 in 550 ml of tetrahydrofuran, heated to reflux. The mixture was then heated under reflux for 8 hours and subsequently stirred at room temperature overnight. 17.6 ml of 10% NaOH solution were added and then 22 ml of H2O were slowly added dropwise, and the mixture was stirred for 5 minutes. Then, first 391 ml of 10% NaOH solution and subsequently, at −5° C., 22.2 g of benzyl chloroformate (130.32 mmol) were added, and the mixture was stirred at room temperature for 3 hours. For workup, the mixture was extracted with dichloromethane, the organic phase was dried, the solvent was evaporated and the remaining residue was filtered through silica gel (eluent: CH2Cl2/methanol 2.5%). 36.8 g of the title compound were obtained as a yellowish oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][NH:37][C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:25][CH2:26][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][N:37]([C:20]([C:17]5[CH:18]=[CH:19][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[O:9][C:10]([CH3:13])=[CH:11][N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:15][CH:16]=5)=[O:22])[C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:28][CH2:29]1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: Cc1cnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Product: Cc1cnc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)o1

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyloxazol-2-yl)biphenyl-4-carboxylic acid (D76) and 2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8) following the procedure of Example 1 (58%). This was converted to its oxalate salt and crystallised from acetone/methanol as a white solid m.p. 230-233° C.
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]([C@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]1)([CH3:7])[CH3:6])C.[OH-].[Li+].Cl>CO>[OH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:15])=[O:3])[CH2:9]1
Reactant: CCOC(=O)C(C)(C)[C@H]1CCC[C@@H](O)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C(=O)O)[C@@H]1CCC[C@H](O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.00 g of 2-(cis-3-hydroxy-cyclohexyl)-2-methyl-propionic acid ethyl ester are dissolved in 30 ml of methanol. 30 ml of a 1M aqueous lithium hydroxide solution are added and the mixture is stirred for 16 hours at room temperature. The reaction mixture is neutralised with 1M HCl and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60 F) based on its Rf value.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:13]1[N:18]=[C:17]([NH2:19])[C:16]([F:20])=[CH:15][N:14]=1>O1CCOCC1>[F:20][C:16]1[C:17]([NH2:19])=[N:18][C:13]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)=[N:14][CH:15]=1
Reactant: Nc1nc(Cl)ncc1F
Reactant: OCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1nc(OCc2ccc(F)cc2)ncc1F
Temperature: 25 °C
Yield: 52 %

Procedure:
To a solution of 4-fluorobenzyl alcohol (2.56 g, 20.3 mmol) in 1,4-dioxane (20 mL) was added 60% NaH (0.813 g, 20.3 mmol) in several portions over a period of 10 min. To the magnetically stirred solution was added 2-Chloro-5-fluoropyrimidin-4-amine* (2.00 g, 13.6 mmol) and the mixture was stirred at room temperature until gas evolution subsided. The reaction mixture was then heated in a CEM Discover microwave reactor at 120° C. for 90 min. The cooled reaction mixture was partitioned between ethyl acetate and water, the organic phase was concentrated, and the product was purified by column chromatography (hexane/ethyl acetate gradient) to yield 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-amine (1.66 g, 52% yield) as a white solid: mp 129-131° C.; 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J=2.6 Hz, 1H), 7.42 (m, 2H), 7.03 (m, 2H), 5.27 (s, 2H), 5.05 (br s, 2H); MS (ESI) m/z 238 (M+H)+. *4-Amino-2-chloro-5-fluoropyrimidine can be purchased commercially or can be prepared through known literature methods.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1O.C(N(CC)CC)C.CCN=C=NCCCN(C)C.[CH3:40][S:41]([OH:44])(=[O:43])=[O:42]>O1CCOCC1.O.C(Cl)(Cl)Cl>[CH3:40][S:41]([OH:44])(=[O:43])=[O:42].[O:13]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:11]1[C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([CH3:1])[NH:3][C:4]=2[CH:10]=1
Reactant: Cc1nc2ccc(C(=O)O)cc2[nH]1
Reactant: Nc1ccccc1O
Agent: CCN=C=NCCCN(C)C
Agent: CS(=O)(=O)O
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1nc2ccc(-c3nc4ccccc4o3)cc2[nH]1
Yield: 42 %

Procedure:
2-Methylbenzimidazole-5-carboxylic acid (1.00 g, 5.7 mmol), 2-aminophenol (0.68 g, 6.2 mmol), chloroform (20 mL), triethylamine (0.69 g, 6.8 mmol), and WSC (1.20 g, 6.2 mmol) were stirred overnight at room temperature. After the reaction was complete, water (50 mL) was added to the residue from concentration, and this was extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, filtration and concentration gave crystals that were dissolved in dioxane (30 mL), to which methanesulfonic acid (0.48 mL) was added and this was stirred at reflux for 10 hours. After cooling a precipitated solid was filtered off, and washing with THF and drying under reduced pressure at 50° C. yielded the title compound (0.82 g, 42% yield) as a white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([F:15])([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5].[F:18][C:19](I)([F:24])[C:20]([F:23])([F:22])[F:21]>>[F:18][C:19]([F:24])([C:13]1[CH:14]=[C:8]([C:3]([F:15])([C:4]([F:7])([F:6])[F:5])[C:2]([F:16])([F:17])[F:1])[CH:9]=[CH:10][C:11]=1[NH2:12])[C:20]([F:23])([F:22])[F:21]
Reactant: FC(F)(F)C(F)(F)I
Reactant: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1
Product: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)C(F)(F)F

Procedure:
According to the method of 1-1 of Example 1, a target compound was prepared from 4-(perfluoropropan-2-yl)aniline obtained in Example 2-1 and 1,1,2,2,2-pentafluoroethyliodide.
Reaction SMILES: [CH2:1]([S:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])(=[O:6])=[O:5])[CH2:2][CH3:3].S(Cl)([Cl:19])=O>>[CH2:1]([S:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([Cl:19])=[O:12])(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCCS(=O)(=O)Nc1cccc(C(=O)O)c1
Product: CCCS(=O)(=O)Nc1cccc(C(=O)Cl)c1

Procedure:
A solution of 3-(propane-1-sulfonylamino)-benzoic acid (76, 1.20 g, 4.93 mmol) in thionyl chloride was heated to reflux for 3.0 hours. Evaporation of the solvent gave compound 77 as white solid that was used for the next step.
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.C(=O)([O-])[O-].[Cs+].[Cs+].[C:49](=[O:72])([O:54][C@H:55]1[C@@H:59]2[O:60][C:61]([CH3:64])([CH3:63])[O:62][C@@H:58]2[O:57][C@H:56]1[C@@H:65]1[CH2:69][O:68][C:67]([CH3:71])([CH3:70])[O:66]1)[O:50][CH:51](Cl)[CH3:52]>CN(C)C=O.C(OCC)(=O)C>[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]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH:51]([O:50][C:49]([O:54][C@@H:55]3[C@H:59]4[O:60][C:61]([CH3:64])([CH3:63])[O:62][C@H:58]4[O:57][C@@H:56]3[C@H:65]3[CH2:69][O:68][C:67]([CH3:70])([CH3:71])[O:66]3)=[O:72])[CH3:52])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cl)OC(=O)O[C@H]1[C@@H]2OC(C)(C)O[C@@H]2O[C@H]1[C@@H]1COC(C)(C)O1
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
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)OC(C)OC(=O)O[C@@H]2[C@H]3OC(C)(C)O[C@H]3O[C@@H]2[C@H]2COC(C)(C)O2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
To a solution of 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, 100 mg, 162 μmol) in dry dimethyl formamide (4 mL) was added cesium carbonate (185 mg, 568 μmol). The mixture was stirred for 10 min at room temperature. The freshly made solution of 1-chloroethyl (3aS,5S,6R,6aS)-5-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-6-yl carbonate (178 mg, 487 μmol) in 4 mL of dry dimethyl formamide was added to the above mixture and stirred at room temperature overnight. It was diluted with ethyl acetate and washed with water (2×) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude, which was purified with flash chromatography (0-50% ethyl acetate in hexane over 25 min) to give an off-white solid (127 mg, 82% yield). LCMS (ES+) m/z calcd. for C46H51Cl2F2N3O12 [(M+H)+]: 946, found: 946.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:4]=[CH:5][C:6](Br)=[C:7]([CH:11]=1)[C:8]([O-:10])=[O:9]>Cl[Cu]>[F:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([NH2:1])=[CH:5][CH:4]=1
Reactant: N
Reactant: O=C([O-])c1cc(F)ccc1Br
Agent: Cl[Cu]
Product: Nc1ccc(F)cc1C(=O)O
Yield: 85.4 %

Procedure:
Example 9 is repeated precisely, the only difference being that one part of CuCl is added to the initial ammonia solution charge. After the 5-fluoro-2-bromobenzoate solution has been metered in and the batch worked up, 144 parts of 5-fluoroanthranilic acid of m.p. 176.5°-177.5° C. are obtained with a purity of 91.9% (HPLC), corresponding to a yield of 85.4% of theory, based on the 5-fluoro-2-bromobenzoic acid employed.
Reaction SMILES: N[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C@@H:7]([C:9]([NH2:11])=[O:10])[NH2:8])=[CH:4][CH:3]=1.C[C@@H](O)[C@H]([NH2:20])C(O)=O.C(O)CCCO.N[C@H](C(O)=O)CS.[OH-].[Na+].ICC(O)=O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[NH2:20][CH:6]([C:5]1[CH:12]=[CH:13][CH:2]=[CH:3][CH:4]=1)[C@@H:7]([C:9]([NH2:11])=[O:10])[NH2:8]
Reactant: NC(=O)[C@@H](N)Cc1ccc(N)cc1
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Agent: N[C@@H](CS)C(=O)O
Agent: O=C(O)CI
Agent: O=C([O-])O
Solvent: OCCCCO
Solvent: CC(=O)O
Product: NC(=O)[C@@H](N)C(N)c1ccccc1

Procedure:
To one volume of a solution of an Fab fragment (the same solution conditions as that used in (a) above) were added two volumes of a solution of 1M p-aminophenylalanine amide (pH adjusted to pH 6.7 with acetic acid). Thre volumes of butane-1,4-diol were added, followed by 0.06 volumes of cysteine (1M). A 50:50 mixture of papain suspension and butane-1,4-diol was prepared (final papain content 18 mg/ml) and 0.28 volumes of the mixture were added at once to the Fab solution. The apparent pH was checked with pH paper: if the apparent value was lower than pH 6.2 it was raised to 6.2–6.7 with 0.01M NaOH (with careful, rapid mixing). After 18 hours at room temperature the papain was inactivated by addition of the appropriate volume of iodoacetic acid, 0.5M, brought to pH 7.0 with 1% NaHCO3 solution. After incubation for 10 minutes at room temperature the protein conjugate was isolated on Sephadex G50 as described above.
Reaction SMILES: CN1CCN2CCN(C)P1N(C)CC2.C(#N)C.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:26][C:27]([CH3:33])=[C:28]([CH2:30][CH2:31]I)[N:29]=2)=[CH:21][CH:20]=1>C1COCC1>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[O:26][C:27]([CH3:33])=[C:28]([CH:30]=[CH2:31])[N:29]=2)=[CH:23][CH:24]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCI
Agent: CN1CCN2CCN(C)P1N(C)CC2
Solvent: C1CCOC1
Solvent: CC#N
Product: C=Cc1nc(-c2ccc(Br)cc2)oc1C
Reaction time: 4 h
Yield: 78.8 %

Procedure:
Add 2,8,9-trimethyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (3.17 g, 14.7 mmol) as a solution using acetonitrile (10 mL) to a solution of 2-(4-bromo-phenyl)-4-(2-iodo-ethyl)-5-methyl-oxazole (See Intermediate 30) (4.38 g, 11.1 mmol) in 2.8:1 acetonitrile:THF (190 mL). After 4 hrs, concentrate under reduced pressure and add EtOAc and water to the residue. Separate the layers and extract the aqueous material with EtOAc. Wash the crude organic extract with water, dry over MgSO4, filter and concentrate. Purify on silica gel eluting with 7% EtOAc to give 2-(4-bromo-phenyl)-5-methyl-4-vinyl-oxazole (2.31 g, 83%): 1H NMR (400 Hz): (CDCl3) δ 7.89 (d, 2H, J=8 Hz), 7.57 (d, 2H, J=8 Hz), 6.54 (dd, 1H, J=17, 11 Hz), 5.93 (dd, 1H, J=17, 2 Hz), 5.29 (dd, 1H, J=11, 2 Hz), 2.40 (s, 3H).
Reaction SMILES: [CH2:1]([CH:8]([NH:23][C:24]([C:26]1[CH:35]=[N:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1)=[O:25])[CH:9]([OH:22])[CH2:10][CH:11]([C:18]([NH:20][NH2:21])=[O:19])[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:43](N1C=CN=C1)(N1C=CN=C1)=[O:44]>O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH2:1]([CH:8]([NH:23][C:24]([C:26]1[CH:35]=[N:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1)=[O:25])[CH:9]([OH:22])[CH2:10][CH:11]([C:18]1[O:19][C:43](=[O:44])[NH:21][N:20]=1)[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)NN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)c1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.5 %

Procedure:
To a solution of quinoxaline-2-carboxylic acid (1-benzyl-7-fluoro-4-hydrazinocarbonyl-2-hydroxy-7-methyl-octyl)-amide (62 mg, 0.129 mmol) in tetrahydrofuran (2 mL) was added triethylamine (0.018, 0.129 mmol) at 0° C. was added carbonyldiimidazole (23 mg, 0.142 mmol). The reaction was allowed to warm to ambient temperature and stirred a total of 20 hours before diluting with ethyl acetate (10 mL) and hexane (2 mL). The mixture was washed with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated. Chromatography on silica gel gave the title compound (54 mg, 82%).