Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:16]([OH:18])=O)[CH2:11][C@H:10]1[CH2:12][CH:13]([F:15])[F:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:31]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH2:33][CH2:32]1.C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O>[CH:31]1([S:34]([NH:37][C:16]([C@@:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:11][C@H:10]2[CH2:12][CH:13]([F:14])[F:15])=[O:18])(=[O:36])=[O:35])[CH2:33][CH2:32]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)O)C[C@H]1CC(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1CC(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a solution of (1R,2S)-1-(tert-butoxycarbonylamino)-2-(2,2-difluoroethyl)cyclopropanecarboxylic acid (665 mg, 2.507 mmol) in THF (20 mL) was added CDI (528 mg, 3.26 mmol) and the formed solution was stirred at rt for 3 h. Cyclopropanesulfonamide (395 mg, 3.26 mmol) and DBU (0.756 mL, 5.01 mmol) were added and the mixture was stirred at rt overnight. The reaction was diluted with EtOAc and washed with 1.0M HCl solution. The aqueous layer was extracted with EtOAc and the combined organics were washed with 5% citric acid, brine, dried over MgSO4, filtered and evaporated to give crude material. The crude product was purified on the Biotage (acetone/hexanes 5-30%) to give the pure product tert-butyl (1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-(2,2-difluoroethyl)cyclopropylcarbamate (783 mg, 1.913 mmol, 76% yield) as a white solid. 1H NMR (500 MHz, MeOD) δ 1.01-1.15 (m, 2H), 1.16-1.35 (m, 2H), 1.49 (s, 10H), 1.58-1.77 (m, 2H), 1.92-2.19 (m, 2H), 2.90-2.99 (m, 1H), 5.80-6.10 (m, 1H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)=O.[CH2:18]([NH:25][CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>>[CH2:18]([N:25]([CH2:1][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=CC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CNCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(Cc1ccccc1)CC1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
4.0 g (17.1 mmol) of 4-formyl-1-(4-nitrophenyl)piperidine, 2.1 g (17.1 mmol) of N-benzyl-N-methylamine, 1.0 g (17.1 mmol) of acetic acid and 1.1 g (17.1 mmol) of sodium cyanoborohydride were reacted as in Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([Cl:19])=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([Cl:19])=[CH:12][C:10]=1[NH:11][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cc(Cl)c([N+](=O)[O-])cc1OCc1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
2-Benzyloxy-5-chloro-4-nitroaniline (31.63 g, 0.0828 mmol) was dissolved in 300 mL of dry methylene chloride in a dry 250 mL round bottom and sealed with a septum. Triethylamine (13.2 mL, 0.0947 mol, 1.1 equiv) was then added. Benzoyl chloride (31.1 mL, 0.268 mol, 3 equiv) was then added to dry methylene chloride (100 mL) in a self-equalizing dropping funnel and covered with a drying tube. The benzoyl chloride solution was added dropwise to the round bottom. The reaction mixture was allowed to stir for 15 minutes after addition of the benzoyl chloride solution. The solution was then refluxed overnight under a drying tube. The solution was diluted with chloroform (100 mL) and washed with 5% sodium bicarbonate (100 mL) and water (100 mL). The organic layer was dried with anhydrous sodium sulfate, gravity filtered and concentrated on a rotovap. Ethyl ether (150 mL) was added to the solid forming a suspension which was then suction filtered to yield N-(2-benzyloxy-5-chloro-4-nitrophenyl)benzamide as a peach solid (31.63 g, 0.0828 mol, 85%). Mp 158-160° C.; TLC (chloroform) Rf=0.62; 500 MHz 1H-NMR (CDCl3) 8.89 (s, 1H), 8.74 (s br, 1H), 7.80 (d, 8.0, 2H), 7.68 (s, 1H), 7.58 (t, 8.0, 1H), 7.48 (t, 8.0, 2H), 7.44 (m, 5H), 5.25 (s, 2H); IR (nujol) 3416, 3378, 1670, 1586, 1529, 1517, 1499, 1335, 1259, 1194. EI-MS m/z (relative intensity) 382 (M+, 7). Accurate mass for C20H15N2O4Cl: calcd. 382.0720, obsd. 382.0712.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[C:32]2[N:31]=[C:30]3[N:33]([C:37]4[C:38]([CH3:46])=[N:39][C:40]([O:44][CH3:45])=[N:41][C:42]=4[CH3:43])[CH2:34][CH2:35][CH2:36][N:29]3[C:28]=2[C:27]([CH2:47][OH:48])=[CH:26][CH:25]=1>CS(C)=O.C(#N)C.C(=O)([O-])O.[Na+]>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH:47]=[O:48])=[C:28]2[C:32]=1[N:31]=[C:30]1[N:33]([C:37]3[C:38]([CH3:46])=[N:39][C:40]([O:44][CH3:45])=[N:41][C:42]=3[CH3:43])[CH2:34][CH2:35][CH2:36][N:29]21
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(CO)c23)c(C)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CS(C)=O
Product: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C)n1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 79.2 %

Procedure:
Dess-Martin reagent (10.1 g, 23.8 mmol) was added to a stirred solution of [9-chloro-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (8.08 g, 21.6 mmol) in dimethyl sulfoxide (5.0 mL) and acetonitrile (100 mL) at 0° C., and the mixture was stirred at 0° C. for 50 min. Additional Dess-Martin reagent (4.00 g, 9.43 mmol) was added to the stirred mixture, and the mixture was stirred at 0° C. for 60 min. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, filtrated and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow solid (6.35 g, 17.1 mmol, 79%).
Reaction SMILES: [BH4-].[Na+].[C:3]1(=[O:23])[N:7]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:6](=[O:18])[C:5]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:4]12>C(O)C>[OH:23][CH2:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)=[O:18]
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(NCCCOc1ccncc1)c1ccccc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
Sodium borohydride [3.78 g (100 mmol)] was added to a solution of 2.82 g (10.0 mmol) of 4-(3-phthalimidopropyloxy)pyridine in 150 ml of ethanol. The mixture was stirred at room temperature for 3 hours. After the solvent was distilled off, brine was added to the residue. The mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was distilled off and then the residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10) to obtain 1.488 g of the desired compound (yield: 52.0% colorless crystals).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=[O:14])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)=[O:6].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC>[F:1][C:2]([F:16])([F:15])[C:3](=[O:14])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:18]2[O:17][CH:21]=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)=[O:6]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)cc1
Reactant: OB(O)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-c2ccco2)cc1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
To a stirred solution of 4,4,4-trifluoro-1-(4-bromophenyl)butane-1,3-dione (1 g, 3.39 mmol, J.Med.Chem., 1997, 40, 1347) in DME.(40 mL) was added furan-2-boronic acid (0.455 g, 4.07 mmol), bis(triphenylphosphine) palladium(.)chloride (0.271 g, 0.386 mmol) and saturated NaHCO3 solution (12 mL) at room temperature under nitrogen. The mixture was heated at reflux temperature for 5 hours, and cooled down to room temperature. The reaction mixture was filtered through celite, the filtrate was poured into water and the whole was extracted with ethyl acetate (30 mL×3). The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (3/1) to give the subtitle compound (0.586 g, 61.2% yield). MS (EI): m/z 282 (M+).
Reaction SMILES: [ClH:1].[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.O=[C:12]([CH3:28])[CH2:13][S:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.Cl>C(O)(C)C>[ClH:1].[CH3:28][C:12]1[NH:8][C:5]2[C:6]([C:13]=1[S:14][CH:15]1[CH2:16][CH2:17][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:19][CH2:20]1)=[CH:7][C:2]([CH3:10])=[CH:3][CH:4]=2
Reactant: Cc1ccc(NN)cc1
Reactant: CC(=O)CSC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccc2[nH]c(C)c(SC3CCN(Cc4ccccc4)CC3)c2c1
Reaction time: 0.5 h

Procedure:
Paratolylhydrazine hydrochloride (20 g) is added to a solution of 4-[(2-oxopropyl)thio]-1-(phenylmethyl)piperidine (33.2 g, prepared in Example 9) in isopropanol (150 ml) under nitrogen. After 30 minutes, the solution is cooled to 0° C. and saturated with gaseous hydrogen chloride. After 4 hours at room temperature, the precipitate formed is filtered off, washed with water and then taken up in hot ethanol. After cooling, the white crystals of 2,5-dimethyl-3-[[1-(phenylmethyl)piperidin-4-yl]thio]-1H-indole hydrochloride (28.3 g) are filtered off.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:19]3[CH2:21][CH2:20]3)[C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:23]C(OC(Cl)C)=O>C1(C)C=CC=CC=1>[ClH:23].[CH:19]1([C:18]2[C:12]3[O:11][CH2:10][CH2:9][NH:8][CH2:14][C:13]=3[CH:15]=[CH:16][C:17]=2[F:22])[CH2:21][CH2:20]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: Fc1ccc2c(c1C1CC1)OCCN(Cc1ccccc1)C2
Solvent: Cc1ccccc1
Product: Cl
Product: Fc1ccc2c(c1C1CC1)OCCNC2
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
A solution of 4-benzyl-9-cyclopropyl-8-fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepine (408 mg, 1.37 mmol) and 1-chloroethyl chloroformate (0.178 ml, 1.65 mmol) in toluene (10 ml) was stirred at 90° C. for 2 hr, and the solvent was evaporated under reduced pressure. Methanol (10 ml) was added to the residue, the mixture was stirred at 80° C. for 1 hr, and diisopropyl ether (10 ml) was added. The precipitate was collected by filtration and recrystallized from a mixed solvent of ethanol and diisopropyl ether to give the desired product (295 mg, 88.5%) as a solid.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.I[C:21]1[C:26]([NH2:27])=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[N:22]=1.[CH2:30]([O:32][C:33](=[O:40])[C:34]([CH3:39])([CH3:38])[CH2:35][C:36]#[CH:37])[CH3:31]>CCN(CC)CC.Cl[Pd]Cl.[Cu]I>[CH2:30]([O:32][C:33](=[O:40])[C:34]([CH3:39])([CH3:38])[CH2:35][C:36]#[C:37][C:21]1[C:26]([NH2:27])=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[N:22]=1)[CH3:31]
Reactant: C#CCC(C)(C)C(=O)OCC
Reactant: COc1ccc(N)c(I)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)CC#Cc1nc(OC)ccc1N

Procedure:
PdCl2 (0.059 g, 0.33 mmol), CuI (0.063 g, 0.33 mmol), and PPh3 (0.173 g, 0.66 mmol) were suspended in NEt3 (40 mL) and stirred under N2. 2-Iodo-6-methoxy-pyridin-3-ylamine (1.65 g, 6.60 mmol) was added, followed by 2,2-dimethyl-pent-4-ynoic acid ethyl ester (Example 4, Step 1; 1.22 g, 7.91 mmol), and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated and purified on silica gel (0-50% EtOAc in hexanes) to give the desired product.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH:8]([N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19](OCC)=[O:20])[CH2:7]2.C([O-])(=O)C.[NH4+:30]>C(O)(=O)C>[F:25][C:2]([F:1])([F:24])[O:3][C:4]1[CH:12]=[CH:11][C:10]2[C:9]3[NH:30][C:19](=[O:20])[C:15]4[N:14]([CH:18]=[CH:17][N:16]=4)[C:8]=3[CH2:7][C:6]=2[CH:5]=1
Reactant: CCOC(=O)c1nccn1C1Cc2cc(OC(F)(F)F)ccc2C1=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=c1[nH]c2c(n3ccnc13)Cc1cc(OC(F)(F)F)ccc1-2
Temperature: 20 °C
Yield: 75.9 %

Procedure:
0.76 g of 5-trifluoromethoxy-2-(2-ethoxycarbonyl-1H-imidazol-1-yl)indanone and 19 g of ammonium acetate in 30 ml of acetic acid are heated at reflux for 45 minutes. After cooling to a temperature in the region of 20° C., the precipitate formed is filtered, washed with water and dried under reduced pressure (1 mm Hg, 0.13 kPa) at 40° C. There is obtained 0.5 g of 8-trifluoromethoxy-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one in the form of a beige powder, the melting point of which is greater than 260° C. (Analysis C14H8F3N3O2.0.9AcOH, % calculated C: 54.73, H: 2.62, F: 18.55, N: 13.68, % found C: 55.0, H: 2.6, F: 18.3, N: 13.8).
Reaction SMILES: S(Cl)(Cl)=O.CN(C=O)C.[CH3:10][C:11]1[N:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:13]=[C:14]2[C:23]=1[C:22]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:16][C:15]2=O.[Cl:31]CCl>C(#N)C>[Cl:31][C:15]1[C:14]2=[N:13][N:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:11]([CH3:10])=[C:23]2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: ClCCl
Reactant: Cc1c2c(nn1-c1ccccc1)c(=O)[nH]c1ccccc12
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: Cc1c2c(nn1-c1ccccc1)c(Cl)nc1ccccc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Thionyl chloride (17 mL) and DMF (17 mL) were combined and added dropwise to a mixture of 1-methyl-2-phenyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (9.78 g, 35.5 mmol) and dichloromethane (500 mL) at 0° C. The resulting suspension was stirred 5 minutes at 0° C. before warming to ambient temperature and stirring 2 hours. The suspension was concentrated under reduced pressure to afford a tan solid that was stirred in acetonitrile and filtered to obtain 8.8 g of 4-chloro-1-methyl-2-phenyl-2H-pyrazolo[3,4-c]quinoline as a tan solid, mp 208-209° C. MS (APCI) m/z 294 (M+H)+; Anal. calcd for C17H12ClN3.0.05 CH2Cl2: C, 68.72; H, 4.09; N, 14.10. Found: C, 68.85; H, 3.95; N, 14.09.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[O:21])=[CH:16][CH:15]=1.I[CH3:32]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]([CH3:32])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccccc4C)cc3)c2)o1
Reactant: CI
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)Cc4ccccc4C)cc3)c2)o1

Procedure:
2′-Methyl-N-methyl-N-(2-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-N-(2-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, m), 7.77,(1H, m), 7.59-7.43,(5H, m), 7.22,(4H, m), 4.71-4.53,(2H, m), 2.93-2.87,(3H, m), 2.55,(3H, s), 2.32-2.29,(3H, m). LCMS; retention time 3.48 min, MH+ 412.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#N.S(=O)(=O)(O)[OH:13].[OH2:17]>>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]([OH:13])=[O:17]
Reactant: O
Reactant: N#Cc1cc(F)c(F)cc1Cl
Reactant: O=S(=O)(O)O
Product: O=C(O)c1cc(F)c(F)cc1Cl
Yield: 94.8 %

Procedure:
2.10 g of the 2-chloro-4,5-difluorobenzonitrile obtained as above and 12 ml of 60% sulfuric acid were reacted under reflux for 10 hour. After cooling, the mixture was diluted with 20 ml of water and then extracted with chloroform (10ml×2 times). The extract was washed with water and dried, and then the the solvent was distilled off to obtain 2.20 g (yield: 94.8%) of 2 -chloro-4,5-difluorobenzoic acid. Melting point: 103°-105° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10][CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C@@:8]([CH2:28][O:29]C(=O)C)([CH2:22][O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[O:7][C@@:6]1([SiH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[N:33]1[CH:40]=[CH:39][C:37](=[O:38])[NH:36][C:34]1=[O:35])(=O)C.C(N)(C)(C)C>CO>[C:24]([O:23][CH2:22][C@@:8]1([CH2:28][OH:29])[O:7][C@@:6]([SiH:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)([N:33]2[CH:40]=[CH:39][C:37](=[O:38])[NH:36][C:34]2=[O:35])[C@H:5]([OH:4])[C@@H:9]1[O:10][CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(=O)OC[C@]1(COC(C)(C)C)O[C@](n2ccc(=O)[nH]c2=O)([SiH](c2ccccc2)c2ccccc2)[C@H](OC(C)=O)[C@@H]1OCc1cccc2ccccc12
Solvent: CO
Solvent: CC(C)(C)N
Product: CC(C)(C)OC[C@@]1(CO)O[C@](n2ccc(=O)[nH]c2=O)([SiH](c2ccccc2)c2ccccc2)[C@H](O)[C@@H]1OCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.6 %

Procedure:
To a solution of Compound 45 (34.9 g, 47.08 mmol) in anhydrous methanol (250 mL) was added tertbutylamine (26.3 mL, 250 mmol). After stirring at room temperature for 24 hours, the mixture was concentrated in vacuo, redissolved in EtOAc (0.8 L), washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, filtered, evaporated and dried under high vacuum to yield Compound 46 (30.6 g, 99%) as a pale yellow foam.
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][NH:4][C@H:5]([CH3:22])[CH2:6][C:7]1[C:15]2[C:10](=[C:11]([O:16][C@@H:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.Cl.[C:30](OCC)(=O)[CH3:31].C(OC(C)C)(C)C>C(O)C.O1CCOCC1>[OH:1][C@H:2]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][NH:4][C@H:5]([CH3:22])[CH2:6][C:7]1[C:15]2[C:10](=[C:11]([O:16][C@@H:17]([CH3:21])[C:18]([O:20][CH2:30][CH3:31])=[O:19])[CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1
Reactant: CCOC(C)=O
Reactant: C[C@H](Cc1c[nH]c2c(O[C@@H](C)C(=O)O)cccc12)NC[C@H](O)c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CCOC(=O)[C@H](C)Oc1cccc2c(C[C@@H](C)NC[C@H](O)c3cccnc3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a suspension of (2S)-2-((3-((2R)-2-(((2R)-2-hydroxy-2-pyridin-3-ylethyl)amino)propyl)-1H-indol-7-yl)oxy)propanoic acid (6.72 g, 17.53 mmol) in ethanol (135 mL) is added a 4N solution of hydrogen chloride in dioxane (55 mL), and the mixture is stirred at room temperature for 2 hours. The reaction solution is evaporated to remove the solvent, and the residue is separated into a saturated aqueous sodium hydrogen carbonate solution and chloroform. The organic layer is washed with a saturated brine, and dried over anhydrous sodium sulfate. The mixture is evaporated to remove the solvent, and to the obtained crude product are added ethyl acetate (50 mL) and diisopropyl ether (50 mL). The product is crystallized and collected by filtration. The product on the filter is washed with diisopropyl ether, and dried to give the title compound (6.26 g, yield: 87%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[S:9]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10]1>>[S:9]1[CH2:14][CH2:13][CH2:12][CH:11]([O:15][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:10]1
Reactant: Brc1ccc(Br)nc1
Reactant: OC1CCCSC1
Product: Brc1ccc(OC2CCCSC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and tetrahyrothiopyran-3-ol by the method of Example 10 (b).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59])[CH2:5][C:4]1=[O:65])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:75]([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][C:79]=1[S:84](Cl)(=[O:86])=[O:85])([O-:77])=[O:76]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][S:84]([C:79]3[CH:80]=[CH:81][CH:82]=[CH:83][C:78]=3[N+:75]([O-:77])=[O:76])(=[O:85])=[O:86])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([O:57][Si:58]([C:61]([CH3:62])([CH3:63])[CH3:64])([CH3:59])[CH3:60])[CH2:5][C:4]1=[O:65])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CCC1O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CCC1OS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.3 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (65 mg) in dry methylene chloride (1 ml) was added an excess of diisopropylethyl amine (29 μl) and o-nitrobenzenesulfonyl chloride (31 mg) followed by addition of 4-dimethylaminopyridine (20 mg). The mixture was stirred at room temperature for 4 hours at which time it was diluted with ethyl acetate, extracted from saturated sodium bicarbonate solution and washed with brine. The combined organics were dried over magnesium sulfate and the concentrate purified by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol to give the title compound (68 mg).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C(OC(=O)C)(=[O:15])C.C[N:21]([C:23]1[CH:28]=[CH:27]C=CN=1)C>C1COCC1>[N:7]1([CH2:27][CH2:28][C:23]([NH2:21])=[O:15])[C:8]2[C:4](=[CH:3][CH:2]=[CH:10][CH:9]=2)[C:5](=[O:12])[C:6]1=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)c1ccccn1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Solvent: C1CCOC1
Product: NC(=O)CCN1C(=O)C(=O)c2ccccc21
Reaction time: 1.25 h

Procedure:
A mixture of 5-fluoroisatin (III, 0.803 g), acetic anhydride (0.546 g), dimethylaminopyridine (0.0059 g) and THF (25 ml) is stirred at 20°-25° for 1.25 hr. THF is then removed and dichloromethane is added. After standing, the crystals are collected and dried to give 5-fluoroisatin acetamide (IV).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[Cl-:4].[CH2:5]([Al+:9]CC(C)C)[CH:6]([CH3:8])[CH3:7]>CCCCCC>[Cl:4][Al:9]([O:3][CH2:1][CH3:2])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: [Cl-]
Reactant: CCO
Reactant: CC(C)C[Al+]CC(C)C
Solvent: CCCCCC
Product: CCO[Al](Cl)CC(C)C
Temperature: 50 °C

Procedure:
A solution of 4.75 g (103.2 mmol) of absolute ethanol in 150 ml of absolute n-hexane is added dropwise at 0° C. and while stirring during about half an hour to a solution of 18.24 g (103.2 mmol) of diisobutylaluminum chloride in 150 ml of absolute n-hexane at 0° C. and under a protective gas atmosphere (argon). Thereafter, the temperature of the mixture is allowed to rise to room temperature and the mixture is warmed at about 50° C. for about a further 1 hour to yield the chloro-ethoxy-isobutyl-aluminum starting material.