Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].S(O[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(C1C=CC(C)=CC=1)(=O)=O>[Na]>[O:26]([CH2:25][CH2:24][O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccccc2)cc1
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: [Na]
Product: CN1C(C)(C)CC(OCCOc2ccccc2)CC1(C)C

Procedure:
30 parts of 1,2,2,6,6,-pentamethylpiperidin-4-ol were dissolved in 250 parts of sodium added. The solution was heated overnight at reflux temperature and then cooled. 38 parts of 2-phenoxyethanol tosylate were added dropwise and the solution heated at reflux for 5 hours. On cooling the precipitate was filtered off and the filtrate evaporated in vacuo Treatment of the residue with dilute hydrochloric acid and then basification with dilute sodium hydroxide to a pH 10 was followed by extraction with ether. Evaporation afforded a pale yellow oil which was chromatographed on aluminum to give 4-(2'-phenoxyethoxy)-1,2,2,6,6-pentamethylpiperidine as a colourless oil which gave the following elemental analysis by weight:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@H:18]([CH2:22][CH2:23][CH2:24][N:25]3[C:33](=[O:34])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]3=[O:35])[C:19]([OH:21])=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.ClC1(S(N[C@H](CCCN2C(=O)C3C(=CC=CC=3)C2=O)C(O)=O)(=O)=[O:50])C=CC(C2C=CC=CC=2)=CC1.[OH-].[Li+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@@H:18]([C:19]([OH:21])=[O:20])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]([OH:50])=[O:34])(=[O:15])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: O=C(O)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)C1(Cl)C=CC(c2ccccc2)=CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C(=O)NCCC[C@@H](NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of the title compound of Example 1, (2R)-(4-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid (20.0 mg, 0.039 mmol), in 2 mL of tetrahydrofuran is treated with 1M aqueous lithium hydroxide. After 2 h, the solution is acidified with 0.2 mL of 1N aqueous HCl, and the mixture is concentrated to an oil. Chomatography on LiChoprep DIOL (eluant; ethyl acetate) affords 12.8 mg (62%) of (4R)-N-[4-(4′-chlorobiphenyl-4-sulfonylamino)-4-carboxybutyl]phthalamic acid as a white solid: m.p. 119-121° C. (dec); IR 1737, 1701, 1649, 1344, 1168; ESI-MS 529 (M−−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH:21]=1)=[N:8][C:9]1[C:10]([C:18]([OH:20])=O)=[CH:11][N:12]([CH3:17])[C:13](=[O:16])[C:14]=1[CH:15]=2.[CH:22]1[N:26]=[CH:25][N:24]([C:27](N2C=NC=C2)=O)[CH:23]=1>C(#N)C>[CH3:25][N:24]([CH3:27])[CH2:23][CH2:22][NH:26][C:18]([C:10]1[C:9]2[N:8]=[C:7]3[CH:21]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]3=[CH:15][C:14]=2[C:13](=[O:16])[N:12]([CH3:17])[CH:11]=1)=[O:20]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2cc3c(=O)n(C)cc(C(=O)O)c3nc2c1
Solvent: CC#N
Product: COc1ccc2cc3c(=O)n(C)cc(C(=O)NCCN(C)C)c3nc2c1
Yield: 80 %

Procedure:
From acid 18w, with a reflux time of 96 h and a recharge with an equal amount of CDI after 48 h, and obtained as a yellow solid (80%), mp 213-215° C. (from acetonitrile). 1H NMR (CDCl3): δ 2.50 [s, 6H, N(CH3)2], 2.78 (t, J=6.0 Hz, 2H, CH2CH2NMe2), 3.67 (s, 3H, NCH3), 3.77 (q, J=5.8 Hz, 2H, CH2CH2NMe2), 4.02 (s, 3H, ArOCH3), 7.22 (dd, J=9.1, 2.2 Hz, 1H, H-8), 7.43 (d, J=2.2 Hz, 1H, H-6), 7.85 (d, J=9.1 Hz, 1H, H-9), 8.53 (s, 1H, H-3), 9.14 (s, 1H, H-10), 11.36 (br s, 1H, CONH). 13C NMR (CDCl3): δ 36.8 (CH2CH2NMe2 and NCH3), 45.0 [N(CH3)2], 55.6 (ArOCH3), 57.7 (CH2CH2NMe2), 105.3 (CH, C-6), 108.8 (C-4), 117.3 (C-10a), 120.9 (CH, C-8), 121.4 (C-9a), 130.0 (CH, C-9), 138.3 (CH, C-10), 143.1 (CH, C-3), 149.7 (C-4a), 150.9 (C-5a), 162.5 (C-1), 163.4 (C-7), 164.4 (CONH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N+:11]([O-])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(OC(=O)C)(=[O:17])C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:17])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: [O-][n+]1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(=O)OC(C)=O
Product: O=c1cc(-c2ccc(Cl)cc2)cc[nH]1
Yield: 48 %

Procedure:
4-(4-Chlorophenyl)pyridine 1-oxide (1.04 g, 5.07 mmol) and acetic anhydride (25 mL) were heated to reflux for 24 h. The mixture was then concentrated, and 1 N NaOH (10 mL) in MeOH (10 mL) was added. The reaction mixture was heated to reflux for 1 h, then cooled, concentrated, and purified by flash column chromatography (silica gel, methylene chloride/MeOH 100:0 to 98:2 to 95:5 then 90:10) providing the title compound (500 mg, 48%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 11.64 (s, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.54 (d, J=8.6 Hz, 2H), 7.46 (d, J=6.8 Hz, 1H), 6.60 (d, J=1.4 Hz, 1H), 6.50 (dd, J=6.9, 1.8 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]([CH3:18])[C:13]([O:15]CC)=[O:14])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].Cl>C(O)C>[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]([CH3:18])[C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(C)c1cccc(OCc2c(C)cccc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1COc1cccc(C(C)C(=O)O)c1
Reaction time: 3 h

Procedure:
To a stirred solution of Ethyl 2-(3-(2,6-dimethylbenzyloxy)phenyl)-2-methylacetate (Step C, 3 g, 9.6 mmol) in absolute ethanol (60 ml) was added 1N NaOH (20 ml) at room temperature. The reaction mixture was stirred for 3 hours, acidified to pH 3.5-4.0 by 1N HCl, and concentrated. The residue was taken into chloroform and washed with 0.1N HCl, brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol 95:5 spiked with acetic acid) to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:10][NH:9][CH2:8][CH:7]1[CH2:6]C[CH2:4]2.C([OH:13])C>[Pd]>[NH2:1][CH2:2][C:3]12[CH2:10][NH:9][CH2:8][CH:7]1[CH2:6][O:13][CH2:4]2
Reactant: NCC12CCCC1CNC2
Reactant: CCO
Agent: [Pd]
Product: NCC12CNCC1COC2

Procedure:
2.8 g (12.1 mmol) of 1-aminomethyl-7-azabicyclo[3.3.0]octane are dissolved in 50 ml of ethanol and hydrogenated on 0.3 g of palladium-active charcoal at 100° C. and 100 bar. The catalyst is filtered off with suction and the filtrate is concentrated and distilled. Yield: 1.5 g (87% of theory) Boiling point: 70°-72° C./0.03 mbar.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[N:21]([CH3:23])[C:20](=[O:24])[C:19]2([CH3:26])[CH3:25].[CH3:27][Si:28](Cl)([CH3:30])[CH3:29]>O1CCCC1>[F:13][C:14]1[C:15]([Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH:16][CH:17]=[C:18]2[C:22]=1[N:21]([CH3:23])[C:20](=[O:24])[C:19]2([CH3:26])[CH3:25]
Reactant: C[Si](C)(C)Cl
Reactant: CN1C(=O)C(C)(C)c2cccc(F)c21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CN1C(=O)C(C)(C)c2ccc([Si](C)(C)C)c(F)c21
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (5.4 g, 7.6 ml, 52.8 mmol) in dry tetrahydrofuran (23 ml) under an argon atmosphere was cooled to −40° C. and a solution of n-BuLi (1.6 M in hexane, 31.6 ml, 50.5 mmol) was added dropwise. The mixture was stirred at −40° C. for 30 minutes and then added to a solution of 7-fluoro-1,3,3-trimethylindolin-2-one (8.875 g, 45.9 mmol) and trimethylsilyl chloride (5.49 g, 6.46 ml, 50.5 mmol) in dry tetrahydrofuran (69 ml) at −75° C. The reaction mixture was warmed to room temperature within 16 hours. The reaction mixture was carefully quenched with water (2 ml) and diluted with ethyl acetate and water. The aqueous phase was extracted ethyl acetate, the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as light yellow oil (8.55 g).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[F:2].[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[F:2][CH2:1][CH:3]([OH:5])[CH2:4][N:13]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH:3]([OH:5])[CH2:1][F:2]
Reactant: FCC1CO1
Reactant: NCc1ccccc1
Solvent: CCO
Product: OC(CF)CN(Cc1ccccc1)CC(O)CF
Yield: 100.1 %

Procedure:
A solution of 27.28 g (0.359 mole) of epifluorohydrin and 19.20 g (0.1795 mole) of benzylamine dissolved in 200 ml of ethanol was heated under reflux for 4 hours. The reaction mixture was then concentrated by evaporation under reduced pressure, to give 46.6 g of N,N-bis(3-fluoro-2-hydroxypropyl)benzylamine as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([NH:9][C:6]([C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc[nH]1
Product: O=C(Nc1ccccc1)c1ccc[nH]1
Yield: 77.6 %

Procedure:
Prepared following the experimental method described in Preparation 4b starting from 10.0 g (90.0 mmol) of 1H-pyrrole-2-carboxylic acid (purchased from Aldrich®, cat. no. P7,360-9) and 9.22 g (99.0 mmol) of aniline. 13.0 g (78% yield) of the title compound were obtained as a brownish solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5]([O:10][CH:11]([F:13])[F:12])=[C:6]([O:8][CH3:9])[CH:7]=1.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1B(O)O>>[F:12][CH:11]([F:13])[O:10][C:5]1[C:4]([O:14][CH3:15])=[CH:3][C:2]([C:17]2[O:16][CH:20]=[CH:19][CH:18]=2)=[CH:7][C:6]=1[O:8][CH3:9]
Reactant: OB(O)c1ccco1
Reactant: COc1cc(Br)cc(OC)c1OC(F)F
Product: COc1cc(-c2ccco2)cc(OC)c1OC(F)F

Procedure:
5-Bromo-2-(difluoromethoxy)-1,3-dimethoxybenzene was coupled with 2-furylboronic acid following the procedure for the synthesis of Example 21. Purification by chromatography (0-30% EtOAc-hexanes) provided 2-(4-(difluoromethoxy)-3,5-dimethoxyphenyl)furan as a white crystalline material (0.555 g, 67% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>O.C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)CCC2
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1C(=O)c1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.6 %

Procedure:
To a solution of 5-acetamidoindane (1.0 g, 5.7 mmol) and benzoyl chloride (732 mL, 6.3 mmol) in 15 mL, of CH2Cl2 at 0° C. was added AlCl3 (1.52 g, 11.4 mmol) as a solid. The mixture was stirred to rt overnight. A spatula full of AlCl3 was added and the mixture heated to reflux for 3 days. The solution was then poured into a mixture of concentrated HCl and ice, and stirred. The mixture was then diluted with water and extracted with 2×50 mL of CH2Cl2. The extract was washed with brine, then dried over MgSO4 and concentrated in vacuo. The crude residue was subjected to flash column chromatography eluting with EtOAc/hexane to give the title compound (200 mg. 13%). 1H NMR (CDCl3): 10.95 (s, 1H), 8.50 (s, 1H), 7.68 (d, 2H), 7.59 (t, 1H), 7.49 (t, 2H), 7.37 (s, 1H), 2.99 (t, 2H), 2.83 (t, 2H), 2.22 (s, 3H), 2.10 (p, 2H).
Reaction SMILES: [CH:1]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:14]=[O:15]>C1(C)C=CC=CC=1>[CH:1]([C:7]1[C:8]([OH:13])=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH:14]=[O:15])=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC=Cc1ccccc1O
Reactant: C=O
Solvent: Cc1ccccc1
Product: CCCCC=Cc1cccc(C=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a stirred solution of Mg(OMe)2 (8% by weight in methanol 16.88 ml, 12.76 mM) was added 2-(1-hexenyl)phenol (3.44 g, 19.5 mmol) in toluene (18 ml). The reaction mixture was warmed to reflux and held at reflux for 2 hours. Toluene (18 ml) was added and the solvent distilled off until the reaction temperature rose to 93° C. A slurry of paraformaldehyde (1.8 g, 60 mmol) in toluene (18 ml) was added and the reaction heated at reflux for 3 hours. The reaction was allowed to cool to ambient temperature and stirred overnight. The reaction was diluted with toluene (20 ml) and washed with 2M aqueous H2SO4 (20 ml). The organic phase was washed with water until the aqueous phase was neutral in pH, dried (MgSO4) and evaporated. The residue was purified by chromatography (eluant: ethyl ether/hexane) to give 3-(1-hexenyl)-2-hydroxybenzaldehyde (2.32 g, 58%).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17]([F:22])[CH:18]=[CH:19][CH:20]=5)[NH:15][CH2:14][C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.CN(C1C=CC=CN=1)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[N:12]2[CH:11]=[N:10][C:9]([C:6]3[N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[O:8][N:7]=3)=[C:13]2[CH2:14]1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: Fc1cccc2c1NCc1c(-c3noc(C4CC4)n3)ncn1-2
Agent: CN(C)c1ccccn1
Product: CC(=O)N1Cc2c(-c3noc(C4CC4)n3)ncn2-c2cccc(F)c21

Procedure:
A solution of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-6-fluoro-4,5-dihydroimidazo[1,5-a]quinoxaline (XXXIII, EXAMPLE 103, 0.504 g), dimethylaminopyridine (0.03 g) and acetic anhydride (12 ml) is stirred at 100° for 1 hr. After cooling, excess acetic anhydride is removed under reduced pressure and the residue is partitioned between dichloromethane and aqueous sodium bicarbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated. Chromatography on silica gel (320 ml) eluting with methanol/dichloromethane (2/98) gives a poor separation of the product from the imine byproduct. The imine impurily is successfully removed by taking up the mixture in dichloromethane and allowing the imine to precipitate out. The filtrate is collected, concentrated and the product crystallized from dichloromethane and hexane to give the title compound, mp 208.5°-210.0°; MS m/z at 339; IR (mineral oil) 1671, 1503, 1254, 879 and 1204 cm-1 ; NMR (CDCl3) 1.28, 2.38, 2.13, 2.29, 7.16, 7.41 and 8.13 δ.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C(F)=NC(F)=NC=1[F:19].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10]([F:19])=[O:11])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)F)C(C)(C)C
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
To an oven-dried, septaed 25 mL round-bottom flask, cooled under an argon atmosphere, and charged with 24h (170.3 mg, 0.74 mmol) was added 2.0 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15 C and to the flask was added cyanuric fluoride (335 μL, 3.7 mmol). The reaction was stirred at −15 C for 15 minutes then anhydrous pyridine (60 μL, 0.74 mmol) was added. Stirring was maintained at −15 C for 60 minutes. Without warming, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 112.6 mg of a mixture of 24h and 25h as an off-white solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[N:9]12CCN(CC1)C[CH2:10]2>>[C:10]([C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3])#[N:9]
Reactant: CC(C)COC(=O)Cl
Reactant: C1CN2CCN1CC2
Product: CC(C)COC(=O)C#N
Yield: 53746 %

Procedure:
Isobutyl chloroformate (68.3 g; 0.5 mol), trimethylsilyl nitrile (49.5 g; 0.5 mol) and 1,4-diazabicyclo[2.2.2]octane (0.10 g; 0.9 mmol) was reacted to produce 61.5 g of isobutyl cyanoformate as a clear, colorless liquid (bp 52°-53° C./20 mmHg) Yield: 97% (theoretical); 98% purity 1H-NMR: δ4.1,d(2H), J=7 Hz; δ2.1, m(1H), δ1.00,d(6 H), J=7 Hz; IR 2250 cm-1 (CN), 1750 cm-1 (CO).
Reaction SMILES: C(O)(=O)C.S(=O)(=O)(O)O.[CH:10]1([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:28])=[C:20]([F:27])[C:21]=3[O:23][CH:24]([F:26])[F:25])[C:16](=[O:29])[C:15]([C:30]([O:32]CC)=[O:31])=[CH:14]2)[CH2:12][CH2:11]1>O>[CH:10]1([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:28])=[C:20]([F:27])[C:21]=3[O:23][CH:24]([F:25])[F:26])[C:16](=[O:29])[C:15]([C:30]([OH:32])=[O:31])=[CH:14]2)[CH2:11][CH2:12]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)cc2c1=O
Temperature: 25 °C
Yield: 84.4 %

Procedure:
9 ml of acetic acid, 1.2 ml of concentrated sulfuric acid and 7 ml of water were added to 1.40 g (0.0039 moles) of ethyl 1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate [(XX), R1 =--OCHF2, R3' =H, R17 =, C2H5, X=F] (prepared as described in Preparation 6), and the mixture was heated under reflux for 1 hour. At the end of this time, it was cooled to room temperature and poured into ice-water. The precipitated crystals were collected by filtration and washed with water and with diethyl ether, in that order, to give 1.09 g of 1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as colorless needles, melting at 202°-207° C.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].O>CO>[CH:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3](=[O:28])[NH:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:5][CH:6]=3)=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[CH:21][CH:22]=1)([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Reactant: COCCN
Solvent: O
Solvent: CO
Product: COCCNC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid methyl ester (1.6 g) was dissolved in methanol (35 ml) and then, 2-methoxyethylamine (0.68 g) was added. And then, the reaction mixture was heated to reflux for 10 hours. The mixture was cooled, and after excess of water was added slowly to the solution at 35~40° C. to precipitate the crystals, the solution was slowly cooled again, stirred at 10° C. for 1 hour and filtered. The filtered solid was washed with a co-solvent (water:methanol=4:1, v/v) and was recrystallized using isopropanol and ether, filtered and dried to give 1.39 g (yield: 78%) of the desired compound. m.p.: 120~121° C.; 1H-NMR(CDCl3), ppm: δ 1.23(d, 6H), 3.15(m, 4H), 3.38(s, 3H), 3.55(m, 5H), 3.64(m, 2H), 3.91(m, 2H), 6.55(m, 1H), 6.90(m, 1H), 6.99(m, 1H), 7.49(m, 2H), 7.70(m, 1H), 7.81(m, 2H)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH3:25][O:26][C:27](=[O:37])[C:28]1[C:33](CO)=[C:32]([Cl:36])[CH:31]=[N:30][CH:29]=1>C(Cl)Cl>[CH3:25][O:26][C:27](=[O:37])[C:28]1[C:33]([CH2:32][Cl:36])=[C:20]([Cl:24])[CH:31]=[N:30][CH:29]=1
Reactant: COC(=O)c1cncc(Cl)c1CO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cncc(Cl)c1CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Polymer bound triphenylphosphine (3 mmol/g, 234 mg, 0.702 mmol) and CCl4 (400 μL) were added to a stirred solution of 5-chloro-4-hydroxymethyl-nicotinic acid methyl ester (14.2 mg, 0.070 mmol) in DCM (4 mL). After stirring for 2 h at room temperature, the reaction mixture was filtered and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 220.1 [M+H+].
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[OH-].[K+].[CH2:14](Br)[CH3:15]>CS(C)=O.O>[CH2:14]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:15]
Reactant: CCBr
Reactant: CN(CCO)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOCCN(C)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.5 %

Procedure:
To a solution of the product from step 1 (850 mg, 506 mmol) in DMSO (4 mL) and KOH (1.2 g, 22.0 mmol) was added ethyl bromide (0.85 mL, 11.4 mmol). After stirring 1.5 hours at ambient temperature, the reaction mixture was diluted with water and the product extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered and concentrated to afford the title compound as a yellow oil (950 mg, 95%). MS (ES+) m/z 180 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.CC(C)=O>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[O:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:27])[C:3]([OH:28])=[O:2])=[CH:10][CH:9]=1
Reactant: COC(=O)C(=O)c1ccc(OCCCCOc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: O=C(O)C(=O)c1ccc(OCCCCOc2ccc3ccccc3c2)cc1
Yield: 49.6 %

Procedure:
A mixture of 4-[[4-(2-naphthalenyloxy)butyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.9 g) in methanol (15 mL), acetone (5 mL), and 0.5N sodium hydroxide (10 mL) was treated as in Example 19. Extraction with dichloromethane provided material which was crystallized from diethyl ether-hexane to give 0.43 g of colorless 4-[[4-(2naphthalenyloxy) butyl]oxy]-alpha-oxobenzeneacetic acid, mp 133°-135°C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[S:25][C:26]4[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:27]=4[N:28]=3)=[CH:19][CH:18]=2)=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])C.[OH-].[Na+]>C1COCC1>[F:33][C:31]1[CH:30]=[CH:29][C:27]2[N:28]=[C:24]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([C:7]4[C:6]([C:4]([OH:5])=[O:3])=[C:10]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[O:9][N:8]=4)=[CH:18][CH:19]=3)[S:25][C:26]=2[CH:32]=1
Reactant: CCOC(=O)c1c(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)noc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1c(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)noc1-c1ccccc1
Reaction time: 2 h
Yield: 78.2 %

Procedure:
The compound 3-[4-(6-fluoro-benzothiazol-2-ylamino)-phenyl]-5-phenyl-isoxazole-4-carboxylic acid ethyl ester (10.9 g; 23.7 mmol) was dissolved in 100 ml THF by heating at reflux to get a clear solution. To the solution, 1N NaOH (47.4 ml; 44.7 mmol) was added and the reaction mixture was stirred for 2 h. The solvent was removed. The residue was taken up in water and acidified with 2N HCl to pH 2. The solid was filtered and dried to provide 8 g of the title compound in 78.2% yield. 1H NMR (DMSO-d6) δ: 7.18 (m, 1H), 7.54-7.59 (m, 3H), 7.62-7.69 (m 3H), 7.76 (2×d, 1H), 7.84-7.92 (m, 4H), 10.76 (s, 1H); Mass (ES+), 432 (M++1).