Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=O)[NH:14][C:15]=2[CH:16]=1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=[S:30])[NH:14][C:15]=2[CH:16]=1)=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)CCc1ccc2c(c1)NC(=O)C1CCCC21
Product: COC(=O)CCc1ccc2c(c1)NC(=S)C1CCCC21
Yield: 117.8 %

Procedure:
Analogously to Example 4, 7-(methoxycarbonylethyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (120 mg, 0.44 mmol) is reacted with Lawesson's reagent (195 mg, 0.48 mmol) to form 150 mg of product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.C(OCC)(=O)C>[CH3:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-hydroxyphenyl)cyclohexanone (1 g, 5.26 mmol) in DMF (50 ml) was added cesium carbonate (3.00 g, 9.20 mmol) followed by methyl iodide (0.411 ml, 6.57 mmol). The reaction was stirred at room temperature for 1 hour and then diluted with ethyl acetate (100 mL), washed with water (3×50 mL), and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 0 to 100% EtOAc/hexanes afforded 4-(4-methoxyphenyl)cyclohexanone. 1H NMR (CDCl3, 500 MHz) δ 7.16 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 3.80 (s, 3H), 2.99 (m, 1H), 2.45-2.55 (m, 4H), 2.16-2.23 (m, 2H), 1.86-1.96 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C)=O.O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1ccccc1-c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
2-Bromobenzaldehyde a (19 mmol), 4-chlorophenyl boronic acid b (19 mmol), tetrabutylammonium iodide (0.19 mmol), potassium carbonate (57 mmol) and palladium acetate (0.12 mmol) in mixture of acetone/water (25 ml/25 ml) was stirred at 40° C. for 30 mins. The mixture was partitioned between ethyl acetate and water and the layers were separated. The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting residue was applied to silica chromatography gradient eluting with 100% petroleum ether to 5% ethyl acetate/petroleum ether to yield intermediate c 4′-chloro-biphenyl-2-carbaldehyde as a colourless oil (76%). 1H NMR (300 MHz, CDCl3) δ 9.96 (1H, s), 8.02 (1H, dd, J 7.8 and 1.0 Hz), 7.64-7.30 (7H, m, ArH).
Reaction SMILES: [C:1]([C:3]([C:18]1[S:22][C:21]([C:23]#[N:24])=[CH:20][CH:19]=1)([CH:15]([CH3:17])[CH3:16])[CH2:4][CH2:5][CH2:6][O:7][Si](C(C)(C)C)(C)C)#[N:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1.[Cl-].[Na+].O>[C:1]([C:3]([C:18]1[S:22][C:21]([C:23]#[N:24])=[CH:20][CH:19]=1)([CH:15]([CH3:17])[CH3:16])[CH2:4][CH2:5][CH2:6][OH:7])#[N:2]
Reactant: CC(C)C(C#N)(CCCO[Si](C)(C)C(C)(C)C)c1ccc(C#N)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(C#N)(CCCO)c1ccc(C#N)s1
Temperature: 0 °C

Procedure:
[4-Cyano-5-methyl-4-(2-cyano-5-thienyl)hexyloxy]-t-butyldimethylsilane, 452 mg 1.25 mmol, was dissolved in 10 ml tetrahydrofuran and cooled at 0° C. A solution of 1 M tetrabutylammonium fluoride in tetrahydrofuran 1.38 ml was added dropwise thereto, and then the temperature was raised to room temperature. Aqueous saturated ammonium chloride and brine were added to the reaction mixture which was then extracted with ether. The organic layer was washed with brine, dried over magnesium sulfate anhydride, and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane system), whereby the title compound, 273 mg 1.10 mmol, 87.9%, was obtained as a yellow syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH3:20][C:21]1([CH3:27])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][C:21]1([CH3:27])[CH2:26][CH2:25][N:24]([C:10]2[N:11]=[C:6]([CH2:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:8](=[O:16])[C:9]=2[C:14]#[N:15])[CH2:23][CH2:22]1
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Reactant: CC1(C)CCNCC1
Product: CC1(C)CCN(c2nc(Cc3cccc(Cl)c3)[nH]c(=O)c2C#N)CC1

Procedure:
In analogy to the preparation of Example 1, 150 mg (0.51 mmol) of 2-(3-chlorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 582 mg (5.14 mmol) of 4,4-dimethylpiperidine to give 96 mg (52% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[F:10][C:11]1[CH:24]=[CH:23][C:14]([C:15]([CH2:17]C(OCC)=O)=O)=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:10][C:11]1[CH:24]=[CH:23][C:14]([C:15]2[N:1]=[C:2]3[CH:6]=[CH:5][S:4][C:3]3=[C:7]([OH:9])[CH:17]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccsc1C(=O)O
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1cc(-c2ccc(F)cc2)nc2ccsc12
Temperature: 25 °C

Procedure:
A mixture of 3-amino-2-thiophenecarboxylic acid (8 g, 49 mmol), ethyl 4-fluorobenzoylacetate (9.6 g, 49 mmol), and p-toluenesulfonic acid monohydrate (0.2 g, 1 mmol) in toluene (100 mL) is refluxed for 20 hours in a flask equipped with a Dean-Stark water trap. The mixture is cooled to room temperature and the precipitate filtered and washed with diethyl ether. The solid is dissolved in diphenyl ether (80 mL) and heated at 240° C. for 2 hours. The reaction solution is then cooled to room temperature, diethyl ether added and the precipitate filtered and washed with diethyl ether to give 5-(4-fluorophenyl)-thieno[3,2-b]pyridin-7-ol as brown crystalline needles, m.p. 316-318° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH2:9])[CH2:3][CH2:2]1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[F:20].CCN(CC)CC>CCOC(C)=O>[F:20][C:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=1[NH:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(NCCN2CCOCC2)c(F)c1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of 2-morpholinoethanamine (0.90 g, 6.91 mmol), 1,2-difluoro-4-nitrobenzene (1.10 g, 6.91 mmol) and Et3N (1.40 g, 13.82 mmol) in EtOAc (10 mL) was refluxed under N2 for 24 h, then cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as yellow oil (1.57 g, 84%).
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[C:11]([NH:14][CH:15]([C:21](=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])[CH3:12]>C1COCC1>[C:11]([NH:14][C@H:15]([C@H:21]([OH:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])[CH3:12]
Reactant: CCCCCCCCCCCCCCCC(=O)C(NC(C)=O)C(=O)OCC
Solvent: C1CCOC1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@@H](NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.5 %

Procedure:
A dehydrated THF solution (0.5 ml) of triethylamine (131.9 mg, 1.30 mmol) and a dehydrated THF solution (0.5 ml) of formic acid (64.2 mg, 1.37 mmol) were added to a dehydrated THF solution (4.0 ml) of RuCl[(R,R)-TsDPEN](p-cymene) complex (19.6 mg, 0.03 mmol) and ethyl 2-acetylamino-3-oxooctadecanoate (7.70 g, 0.20 mmol) synthesized in the same method as Example 1. After the mixture was stirred for 3 days at room temperature, the reaction solvent was removed in reduced pressure. Water was added thereto, and the mixture was extracted with ethyl acetate three times. The organic layers were combined and dried with magnesium sulfate. After the solvent was removed in reduced pressure, the obtained crude product was purified by silica gel chromatography (Kieselgel 60 manufactured by Merck, solely ethyl acetate) to obtain the title compound (71.3 mg, yield: 94%). The product was analyzed by HPLC to find that anti-form:syn-form was 93:7 and the optical purity of the anti-form was 98% ee.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25](=[O:38])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[F:39][C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1>>[F:39][C:40]1[CH:45]=[CH:44][C:43]([O:1][CH2:2][C:3]2[CH2:4][S:5][C@@H:6]3[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25](=[O:38])[N:7]3[C:8]=2[C:9]([O:11][CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:10])=[CH:42][CH:41]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COc3ccc(F)cc3)CS[C@H]12

Procedure:
The procedure described in Example 1(a) was repeated, but using 2.00 g of diphenylmethyl 3-hydroxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate and p-fluorophenol, to afford 400 mg of the title compound as a powder.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 98.9 %

Procedure:
A mixture of 4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (3.0 g), phenylboronic acid (2.1 g), copper(II) acetate (3.1 g), pyridine (3.1 mL), triethylamine (3.4 mL), molecular sieves 4 A (6.0 g) and dichloromethane (60 mL) was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (3.6 g, 100%) as a pale-yellow liquid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=2[N:7]=1.[F:22][C:23]1[CH:24]=[C:25]([NH:38][C:39]([NH:41][CH2:42][CH2:43][F:44])=[O:40])[CH:26]=[CH:27][C:28]=1B1OC(C)(C)C(C)(C)O1>>[F:22][C:23]1[CH:24]=[C:25]([NH:38][C:39]([NH:41][CH2:42][CH2:43][F:44])=[O:40])[CH:26]=[CH:27][C:28]=1[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=2[N:7]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2F)OC1(C)C
Reactant: COC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Product: COC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCF)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Yield: 5 %

Procedure:
Method as described for example 147 using (S)-methyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 26) and 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-fluoroethyl)urea (intermediate 31) as starting materials. The crude reaction mixture was purified by SCX-2 cartridge (loaded in MeOH eluted with 2M methanolic ammonia). Ammonia eluent was concentrated in vacuo. Residue was then purified by prep. HPLC at low pH to afford a brown solid (10 mg, 0.02 mmol, 5%).
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20].N12CCN(CC1)CC2.O>CN(C)C=O>[CH:11]1([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:7][CH:6]=2)=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(Nc1ccc(O)nc1)C1CCCCC1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)Oc1ccc(NC(=O)C2CCCCC2)cn1)c1ccccc1
Yield: 70.7 %

Procedure:
A solution of cyclohexanecarboxylic acid (6-hydroxy-pyridin-3-yl)-amide (0.66 g, 3.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (20 ml) was stirred at room temperature for 18 hours. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was crystallised from ethyl acetate:heptane yielding the title compound (0.75 g, 71% yield) as a slightly coloured solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[C:3]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc(N2CCCNCC2)cc1NS(=O)(=O)c1ccccc1

Procedure:
N-{5-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide (0.075 g, 0.16 mmol) and, methanesulfonyl chloride (0.017 mL, 0.22 mmole) to give 41.6 mg of a light purple solid; Anal. (C24H27ClN4O3S×1.3H2O) C, H, N, S.; M+425.4 Calcd 425.12.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:5]([OH:7])=O)[CH3:3].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:33][C@H:34]([C:38]([N:40]([CH3:56])[C@H:41]([C:45]([N:47]1[CH2:55][CH2:54][CH2:53][C@H:48]1[C:49]([O:51][CH3:52])=[O:50])=[O:46])[CH:42]([CH3:44])[CH3:43])=[O:39])[CH:35]([CH3:37])[CH3:36]>C(Cl)Cl.O>[NH:8]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:4]([C:5]([NH:33][C@H:34]([C:38]([N:40]([CH3:56])[C@H:41]([C:45]([N:47]1[CH2:55][CH2:54][CH2:53][C@H:48]1[C:49]([O:51][CH3:52])=[O:50])=[O:46])[CH:42]([CH3:44])[CH3:43])=[O:39])[CH:35]([CH3:36])[CH3:37])=[O:7])[CH:2]([CH3:1])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](N)C(C)C
Agent: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(C)C
Temperature: 20 °C
Reaction time: 2 h

Procedure:
17.84 kg (70.88 mol) of Z-valine and 4.59 kg (74.42 mol) of triethylamine were dissolved in 170 l of methylene chloride in a 400 l vessel. To this solution were added at -5° to -10° C. 8.58 kg (70.88 mol) of pivaloyl chloride. After a reaction time of 2 h at -5° C., a solution of 24.2 kg of Val-MeVal-Pro-OMe in 86 l of methylene chloride was run in at -5° C. After a further 2 h at -5° C., the mixture was heated to 20° C. and stirred at this temperature for 12 h. 50 l of water were added for working up. After removal of the aqueous phase, the organic phase was extracted once with 40 l of 2N hydrochloric acid and twice with 40 l of 2N sodium hydroxide solution each time. The organic phase was washed until neutral and then the methylene chloride solvent was removed by distillation and replaced by 300 l of diisopropyl ether. The product was crystallized by heating the emulsion of the oily product to 60° C., adding seed crystals and keeping at 60° C. for 7 h. To complete the crystallization, the mixture was stirred further at 50° C. for 5 h and then at 40° C. for 5 h and subsequently cooled to 20° C. The suspension of crystals was discharged through a 120 l pressure filter.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C=O.[C:18]([O-])([O-])=O.[K+].[K+]>S([O-])(O)(=O)=O.C([N+](C)(C)C)CCCCCCCCCCCCCCC.C1(C)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=[CH2:18])[C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1ccc2ncccc2c1
Agent: C=O
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: C=C(C(=O)OC)c1ccc2ncccc2c1
Yield: 86.3 %

Procedure:
As shown in step ii of Scheme 1, methyl 2-(quinolin-6-yl)acetate (82 g, 407.5 mmol), paraformaldehyde (25.89 g, 862.1 mmol), K2CO3 (101.4 g, 733.5 mmol), and hexadecyl(trimethyl)ammonium hydrogen sulfate (15.55 g, 40.75 mmol) were taken up in toluene (1.6 liters) and refluxed for 2 hours until the starting material was completely consumed, as monitored by HPLC. The reaction mixture was cooled down using an ice-water bath and filtered through diatomaceous earth. The filtrate was washed with 1 liter of water and the organic layer dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford methyl 2-(quinolin-6-yl)acrylate as a clear colorless oil (75.0 g). This material was used immediately without further purification in the next reaction.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[F:12][C:13]1[N:18]=[C:17]([F:19])[C:16]([F:20])=[C:15](F)[C:14]=1[F:22].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:11][O:10][C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[S:4][C:15]1[C:14]([F:22])=[C:13]([F:12])[N:18]=[C:17]([F:19])[C:16]=1[F:20])=[O:9]
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: COC(=O)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1Sc1c(F)c(F)nc(F)c1F
Yield: 96.2 %

Procedure:
To a solution of methyl thiosalicylate (1.0 g, 5.9 mmol) in dry DMF (15 mL) at 0° C. was added pentafluoropyridine (1.2 g, 7.1 mmol) and cesium carbonate (2.5 g, 7.7 mmol). The resultant mixture was stirred at ambient temperature for 5 hours then poured into 100 mL of 0.5 M aqueous KOH solution and 100 mL of ethyl acetate. The aqueous layer was separated and extracted with another 100 mL of ethyl acetate. The combined organic extracts were washed with 0.5 M aqueous KOH solution (100 mL) then brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford 1.8 g (98% yield) of 4-(2-methoxycarbonylphenyl)thio-2,3,5,6-tetrafluoropyridine as a crystalline solid, NMR (CDCl3) 8.1 (dd, 1), 7.4 (m, 1), 7.4 (tt, 1), 7.0 (d, 1), 4.0 (s, 3) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.C(OC([O-])=O)(OC(C)(C)C)=[O:31]>CN(C1C=CN=CC=1)C.C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:21])([CH3:22])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=[O:31])=[CH:4][CH:3]=1
Reactant: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
A mixture of compound 5 (50 mg, 0.11 mmol, 76% purity), tert-Butyl dicarbonate (48 mg, 0.22 mmol) and DMAP (27 mg, 0.22 mmol) in THF (5 mL) was stirred at ambient temperature overnight. The solvent was removed by evaporation in vacuo, the residue was purified by preparative TLC on silica gel eluting with petroleum ether:ethyl acetate=2:1 to give compound 6 (30 mg, 50%) as a white solid. LC-MS: 699-091-1B, tR=2.06 min in 3 min chromatography, MS (ESI) m/z=546.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([NH2:25])[CH:8]=[C:9]([O:23][CH3:24])[C:10]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:5]=[CH:4][CH:3]=1.I[CH:27]([CH3:42])[CH2:28][CH2:29][CH2:30][N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41].C(N(CC)CC)C.C(OCCO)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([NH:25][CH:27]([CH3:42])[CH2:28][CH2:29][CH2:30][N:31]3[C:35](=[O:36])[C:34]4=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]4[C:32]3=[O:41])[CH:8]=[C:9]([O:23][CH3:24])[C:10]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)[N:5]=[CH:4][CH:3]=1
Reactant: CC(I)CCCN1C(=O)c2ccccc2C1=O
Reactant: COc1cc(N)c2nccc(C)c2c1Oc1cccc(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Solvent: CCOCCO
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1Oc1cccc(C(F)(F)F)c1
Reaction time: 4 h
Yield: 34 %

Procedure:
A mixture of the above-8-aminoquinoline (VII 3.0 g, 8.6 mmol), 4-iodo-1-phthalimidopentane (IPP) 3.0 g, 8.7 mmol), triethylamine (TEA) (1.2 mL) and 2-ethoxyethanol (6 mL) was heated at 105° for 2.5 hours, after which time an additional quantity of IPP (3 g) and TEA (1.2 mL) was added. After an additional 4 hours at 105°, the mixture was cooled and dissolved in chloroform. The chloroform solution was washed with 10% aqueous potassium hydroxide and with water, dried and concentrated to dryness. The residue was dissolved in ether and excess ethereal HCL was added. The ether was decanted and the gum was triturated in fresh ether (×2). The gum was then shaken with ether and 10% aqueous potassium carbonate. The ether was removed and the residue was heated in ethanol (15 mL). The mixture was cooled and the solid was filtered to give 1.65 g of the title compound. The filtrate was concentrated to dryness and the residue was triturated in hot ligroin (bp 60°-80°, 50 mL). The ligroin was decanted from a little insoluble gum and concentrated to dryness to afford 1.5 g of additional crude product. The combined crops were crystallized from ethanol (75 mL) to give 2.75 g (57%) of pure title compound, mp 143°-145°.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:12](O)[CH2:13][OH:14]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[OH:1][N:2]=[C:3]([C:9]1([O:14][CH2:13][CH2:12][O:11]1)[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: OCCO
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C(=NO)C1(C)OCCO1
Yield: 55.8 %

Procedure:
A mixture of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 10 g), ethylene glycol (19.75 g) and p-toluenesulfonic acid (0.3 g) and dried benzene (150 ml) was heated for 2 hours under reflux while removing water azeotropically. The reaction mixture was washed with water (50 ml), a saturated aqueous solution of sodium bicarbonate (50 ml), water (50 ml) and a saturated aqueous solution of sodium chloride (50 ml) in turn, dried over magnesium sulfate and then filtered. The filtrate was evaporated to give an oil of ethyl 2-hydroxyimino-3,3-ethylenedioxybutyrate (syn isomer, 7.12 g). (Yield: 55.1%).