Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:13])([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[O:2][CH:3](Cl)[CH3:4].[Cl:14][C:15]1[C:16]([F:55])=[C:17]([C@@H:21]2[C@:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:24]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:23][C@H:22]2[C:41]([NH:43][C:44]2[CH:52]=[CH:51][C:47]([C:48]([OH:50])=[O:49])=[CH:46][C:45]=2[O:53][CH3:54])=[O:42])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[Cl:14][C:15]1[C:16]([F:55])=[C:17]([C@@H:21]2[C@:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:24]([CH2:36][C:37]([CH3:39])([CH3:40])[CH3:38])[NH:23][C@H:22]2[C:41]([NH:43][C:44]2[CH:52]=[CH:51][C:47]([C:48]([O:50][CH:3]([O:2][C:1]([O:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)=[O:13])[CH3:4])=[O:49])=[CH:46][C:45]=2[O:53][CH3:54])=[O:42])[CH:18]=[CH:19][CH:20]=1
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
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)OC(C)OC(=O)OC2CCCCC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 70.5 %

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (Oakwood Products, 1.99 g, 1.5 mL, 13.9 mmol) was reacted with cyclohexanol (Alfa Aesar, 1.33 g, 1.4 mL, 13.3 mmol) and pyridine (1.27 g, 1.3 mL, 16.1 mmol) in methylene chloride (11 mL) at −78° C. for 3 h to give 1-chloroethyl cyclohexyl carbonate. A portion of 1-chloroethyl cyclohexyl carbonate (253 mg, 1.22 mmol) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (150.3 mg, 0.244 mmol) in the presence of cesium carbonate (487.4 mg, 1.5 mmol) in dimethylformamide (5 mL) overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 1-(cyclohexyloxycarbonyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (135.4 mg, 70% yield). MS (ES+) m/z calcd. for C40H44Cl2F2N3O7: [(M+H)+]: 786, found: 786
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[CH2:14][C@@H:15]([OH:31])[C@@H:16]([NH:24][C:25](=[O:30])[C@H:26]([CH2:28][SH:29])[NH2:27])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32](O)(=[O:43])[C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1.OC1C2N=NNC=2C=CC=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[CH2:14][C@@H:15]([OH:31])[C@@H:16]([NH:24][C:25](=[O:30])[C@H:26]([CH2:28][SH:29])[NH:27][C:32]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1)=[O:43])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CS
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CS)NC(=O)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 64 h
Yield: 41.3 %

Procedure:
A solution of 650 mg of N-tert.butyl-1-[3(S)-[(L-cysteinyl)amino]-2(R)-hydroxy-4-phenylbutyl]-2(S)-piperidinecarboxamide and 242 mg of quinaldic acid was cooled in an ice/salt mixture. 189 mg of hydroxybenzotriazole. 161 mg of N-ethylmorpholine and 317 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 64 hours. The mixture was diluted with ethyl acetate and filtered, and the filtrate was then evaporated. The residue was partitioned between dichloromethane and aqueous sodium bicarbonate solution. The organic phase was washed with sodium chloride solution and then evaporated. The residue was chromatographed on silica gel using dichloromethane/methanol (19:1) for the elution to give 350 mg of N-tert.butyl-1-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-cysteinyl]amino]butyl]-2(S)-piperidinecarboxamide as a white solid: MS: m/e 620 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[OH:9][C:10]1[CH:19]=[CH:18][C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([O:9][C:10]2[CH:19]=[CH:18][C:13]3[NH:14][C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)[CH:7]=1
Reactant: O=c1[nH]c2ccc(O)cc2o1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2ccc(Oc3cc(Cl)ncn3)cc2o1

Procedure:
0.20 g (1.34 mmol) 4,6-dichloropyrimidine, 0.21 g (1.39 mmol) 6-hydroxy-2-benzoxazolinone and 0.20. g (1.45 mmol) potassium carbonate in 2.0 mL DMF were stirred for 2 h at RT. The reaction mixture was mixed with water. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH2:23])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N)c1
Reactant: CCOC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCNc1ccc(Cl)cc1Oc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 46.6 %

Procedure:
A mixture of tert-butyl[3-(2-amino-5-chlorophenoxy)benzyl]carbamate (3.5 g, 10 mmols), ethyl 6-bromohexanoate (3.6 ml, 21 mmols), potassium carbonate (4.2 g, 10 mmols) and N,N-dimethylformamide (30 ml) was stirred at 60° C. for 24 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 6-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]aminohexanoate (2.29 g, 46.6%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([O:17][CH3:18])=[CH:15][C:14]([OH:19])=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.[OH-].[Na+].Cl.[C:28]([O-])(O)=[O:29].[Na+]>CN(C=O)C>[OH:19][C:14]1[C:13]([CH:28]=[O:29])=[C:11]2[CH:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[O:9][C:10]2=[C:16]([O:17][CH3:18])[CH:15]=1
Reactant: O=C([O-])O
Reactant: COc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(O)c(C=O)c2cc(-c3ccc(O)cc3)oc12

Procedure:
A solution of 62 (0.25 g, 1.0 mmol) in DMF (20 mL) was treated with POCl3 (1 mL, 11 mmol) and heated at 80° C.–100° C. for 15 minutes. The reaction mixture was worked up by allowing to cool and then poured into crushed ice. 2N NaOH aq was added and the solution stirred for several minutes and then the mixture was acidified with 2N HCl aq and then neutralized with NaHCO3 aq. The mixture was then extracted with EtOAc and washed with brine, dried over MgSO4, filtered, concentrated and chromatographed on silica gel (2:8 to 4:6 EtoAc/hexanes) to yield a solid which still contained some starting material, but that was purified by trituration with EtOAc to yield 47 mg the desired pdt as a white solid: Mp=254–255° C.; 1H NMR (DMSO-d6) δ 10.29 (s, 1 H), 10.0 (br s, 1 H), 7.73 (d, 2 H, J=8.7 Hz), 7.59 (s, 1 H), 6.88 (d, 2 H, J=8.7 Hz), 6.46 (s, 1 H), 4.00 (s, 3 H); MS 281 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:17][NH:18][C:19]([C:21]1[C:22]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:23]=2[O:24][C:25]=1[CH2:26][CH3:27])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([C:21]1[C:22]2[CH:31]=[CH:30][C:29]([O:32][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:28][C:23]=2[O:24][C:25]=1[CH2:26][CH3:27])=[O:20]
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: CCc1oc2cc(O)ccc2c1C(=O)NC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1oc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)NC
Yield: 30.2 %

Procedure:
This material was prepared by the reaction of 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e (114 mg, 0.46 mmole) with 6-hydroxy-2-ethylbenzofuran-3-carboxylic acid methylamide 14c (120 mg, 0.55 mmole) and Cs2CO3 (594 mg, 1.82 mmole) in a manner as previously described for example 1 to give 60 mg (30%) of a tan solid. 1H NMR (DMSO-d6) δ 8.49 (1H,d, J=5.6 Hz), 8.00 (1H, d, J=4.6 Hz), 7.89 (1H, s), 7.82 (1H, d, J=8.6 Hz), 7.67 (1H, s), 7.41 (1H, s), 7.26 (1H, d, J=8.6 Hz), 7.03 (1H, s), 6.68 (1H, d, J=5.6 Hz), 3.99 (3H, s), 3.04 (2H, q, J=7.6 Hz), 2.81 (3H, d, J=4.6 Hz), 1.28 (3H, t, J=7.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:20]=[C:19]([OH:21])[C:18]([OH:22])=[CH:17][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:14][CH:13]([CH3:15])[O:12][CH:11]([CH3:16])[CH2:10]1)=[O:8].[N+:23]([O-])([OH:25])=[O:24]>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[C:3]2[CH:20]=[C:19]([OH:21])[C:18]([OH:22])=[C:17]([N+:23]([O-:25])=[O:24])[C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:10][CH:11]([CH3:16])[O:12][CH:13]([CH3:15])[CH2:14]1)=[O:8]
Reactant: CC1CN(C(=O)c2sc3cc(O)c(O)cc3c2Cl)CC(C)O1
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1CN(C(=O)c2sc3c([N+](=O)[O-])c(O)c(O)cc3c2Cl)CC(C)O1
Reaction time: 4 h

Procedure:
(3-Chloro-5,6-dihydroxy-benzo[b]thiophen-2-yl)-(2,6-dimethyl-morpholin-4-yl)-methanone (0.20 g) was dissolved in ethyl acetate and 1 N HNO3 solution in dichloromethane (0.64 ml) was added. Stirring was continued for 4 hours. The mixture was concentrated to smaller volume and the precipitate filtered and washed with water. The crude product was recrystallized from N,N-dimethylformamide/ethanol (25:75).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH2:18][CH2:19][CH3:20])[CH:12]=2)=[N:6][CH:7]=1.C(C1C=NC(N(CC(C)(C2C=CC(O[CH2:63][C:64]3[N:65]=[N:66][NH:67][N:68]=3)=C(CCC)C=2)C)CC2C=CC(OC(F)(F)F)=CC=2)=NC=1)C>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:63][C:64]3[N:65]=[N:66][NH:67][N:68]=3)=[C:13]([CH2:18][CH2:19][CH3:20])[CH:12]=2)[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:27]=2)=[N:6][CH:7]=1
Reactant: CCCc1cc(C(C)(C)CN(Cc2ccc(OC(F)(F)F)cc2)c2ncc(CC)cn2)ccc1OCc1nn[nH]n1
Reactant: CCCc1cc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(C)cn2)ccc1O
Product: CCCc1cc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(C)cn2)ccc1OCc1nn[nH]n1

Procedure:
The title compound was prepared from 4-(2-{(5-methylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-propylphenol via a two-step sequence similar to that described for 5-ethyl-N-{2-methyl-2-[3-propyl-4-(2H-tetraazol-5-ylmethoxy)phenyl]propyl}-N-[4-(trifluoromethoxy)benzyl]pyrimidin-2-amine.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[Na].[CH:8]([OH:11])([CH3:10])[CH3:9]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:11][CH:8]([CH3:10])[CH3:9]
Reactant: BrCCCCBr
Reactant: CC(C)O
Agent: [Na]
Product: CC(C)OCCCCBr

Procedure:
The above compound is produced in analogous manner to that described in Example 10, but using isopropanol and 1,4-dibromo butane and sodium instead of sodium hydride. B.P.: 90°-91°/34 mm Hg.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C>O>[C:7]1([S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C=CS(=O)(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
(β-chloroethylsulfonyl)benzene (4.09 g, 20 mmol) was added to 20 g of toluene, to this solution were added 3.00 g of 49% aqueous potassium carbonate solution (potassium carbonate 10.6 mmol) and 113 mg (1.0 mmol) or diisopropylethylamine, and the mixture was stirred for 4 hours at 40° C. Then, 10 g of water was added and the mixture was separated to an organic phase and aqueous phase. This aqueous phase was extracted by chloroform, and the resulted organic phase was combined with the previous organic phase, dried over magnesium sulfate, the solvents were distilled off, to obtain 2.76 g (yield 82.1%) of phenylvinylsulfone.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10](B1OC(C)(C)C(C)(C)O1)([CH3:12])=[CH2:11].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[Br:9][C:5]1[CH:6]=[C:7]([C:10]([CH3:12])=[CH2:11])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1I
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)c1cc(Br)cnc1N
Temperature: 65 °C
Reaction time: 6 h

Procedure:
A solution of 2-amino-5-bromo-3-iodopyridine B-78-1 (4.75 g, 15.9 mmol), isopropenylboronic acid pinacol ester (3.28 mL, 2.94 g, 17.5 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]-palladium(II) dichloride dichloromethane complex (1:1) (295 mg, 0.403 mmol) in dimethylformamide (48 mL) was treated with 24 mL of 2.0 M aqueous sodium carbonate solution. The resulting biphasic mixture was stirred under argon in a 65° C. oil bath for 6 hours. After cooling to room temperature, the mixture was diluted with 200 mL ethyl acetate and 75 mL deionized water, then suction-filtered to remove some insoluble black precipitate. After separation, the aqueous layer was back-extracted with 100 mL ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to 5.87 g brown oil. The crude product was purified by silica gel chromatography (eluting with a 10-50% ethyl acetate in hexanes gradient), to give B-78-2 (2.5501 g, 75.3%) as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Cl[CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:13]([OH:14])[N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccc(F)cc1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Product: Oc1nc(-c2ccc(F)cc2)sc1-c1ccccc1

Procedure:
The title compound was prepared according to the method of Scheme II in a manner analogous to Example 31 except 4-fluorothiobenzamide was used instead of thiobenzamide and 2-chloro-2-phenylacetyl chloride was used instead of 2-bromopropionate.
Reaction SMILES: [CH2:1]([C@H:3]1[O:5][CH2:4]1)[Cl:2].[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12>>[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][N:10]1[C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]2[C:6]1=[O:16]
Reactant: ClC[C@@H]1CO1
Reactant: O=C1NC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1CC(O)CCl

Procedure:
reacting (S)-(+)-epichlorohydrin with phthalimide to form a stereoisomer of 1-chloro-3-phthalimido-2-propanol;
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4][N:16]1[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]1
Reactant: COc1ccc(C=O)c(F)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc(CN2CCN(C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
2-Fluoro-4-methoxybenzaldehyde (6.0 g, 39 mmol) was dissolved in dichloroethane (100 mL) and 1-methylpiperazine (4.5 g, 45 mmol) was added and the solution was stirred at rt for 30 minutes. Sodium triacetoxyborohydride (10 g, 47 mmol) was added in portions and the reaction mixture was stirred at rt over night. Aqueous Na2CO3 (sat.) was added to the reaction and the phases were separated. The aqueous phase were extracted twice with DCM and the combined organic phases were filtered through a phase separator and the solvent was removed by evaporation. There was obtained 9.3 g (100%) of 29A as a brown oil. 1H NMR (500 MHz, CDCl3): δ 2.28 (s, 3H), 2.30-2.70 (bm, 8H), 3.53 (s, 2H), 3.78 (s, 3H), 6.53-6.71 (m, 2H), 7.17-7.27 (m, 1H).
Reaction SMILES: [C:1]([O:10]CC)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CC(=O)CC.CCO>[CH2:15]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: CCOC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CCC(C)=O
Product: C=CCOc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under N2, the mixture of ethyl salicylate (16.62 g, 100 mmol), allyl bromide (18.15 g, 12.7 ml, 150 mmol) and potassium carbonate (17.97 g, 130 mmol) in dry 2-butanone (400 ml) was heated to reflux for 48 h. After the reaction mixture cooled down to 25° C., the suspended inorganic salt was removed by filtration. The concentration of the resulting solution by rotary evaporation yielded pale yellowish syrup, which was then mixed with 2N NaOH (80 ml, 160 mmol) and EtOH (150 ml). After this mixture was stirred for 2 h at 50° C., ethanol was removed at reduced pressure. The aqueous solution was acidified by 6N HCl to pH 2 at 5° C. to generate white precipitate, which was then collected by filtration. The recrystallization of this crude product from hexane/ether yielded pure 2-Allyloxy-benzoic acid as colorless crystal (14.87 g, 83.5%). Microanalysis Calc. for C10H10O3 (178.19): C 67.41, H 5.66; found: C 67.35, H 5.39. 1H-NMR (400 MHz, d6-DMSO): 12.51 (s, —CO2H); 7.55 (m, 1 arom. H); 7.38 (m, 1 arom. H); 7.01 (m, 1 arom. H); 6.90 (m, 1 arom. H); 5.93 (m, —CH═CH2); 5.40, 5.15 (2 d-like, —CH═CH2); 4.57 (d-like, CH2—CH═CH2). 13C-NMR (100 MHz, d6-DMSO): 167.35 (—C═O); 156.88; 133.36; 132.81; 130.62; 121.68; 120.16; 116.91; 113.64; 68.52.
Reaction SMILES: [C:1]([NH:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:2].C1COCC1.Br[CH2:19][C:20]([N:22]([CH2:27][C:28]([N:30]1[CH2:39][CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31]1)=[O:29])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21]>CN(C=O)C.CC(C)([O-])C.[K+]>[CH2:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:38][CH2:39][N:30]1[C:28](=[O:29])[CH2:27][N:22]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:20]([CH2:19][N:3]([C:1]#[N:2])[C:4](=[O:12])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:21]
Reactant: N#CNC(=O)Cc1ccccc1
Reactant: CC(C)CN(CC(=O)N1CCc2ccccc2C1)C(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)CN(CC(=O)N1CCc2ccccc2C1)C(=O)CN(C#N)C(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 12.2 %

Procedure:
To a stirred solution of N-cyano-2-phenyl-acetamide (0.15 g, 0.9 mmol) (see Example 1) in DMF (5.0 mL), potassium tert-butoxide (0.9 mL of a 1.0 M THF solution, 0.9 mmol) was added dropwise at 0° C., under argon. The resulting mixture was stirred at 0° C. for 20 min, then at ambient temperature for 15 min. After this time, the resulting anion was added dropwise to a stirred solution of the 2-bromo-N-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]-N-isobutyl-acetamide (0.34 g, 0.9 mmol) from above in DMF (5.0 mL) at room temperature, under argon. Upon complete addition, the reaction was stirred at room temperature for 1.5 h, then warmed to 40° C. for 6 h. The reaction was cooled to room temperature and stirred for 48 h after which time it was concentrated to dryness. The resulting residue was dissolved in EtOAc and washed with 5% citric acid (aqueous). The layers were separated and the aqueous phase was extracted with EtOAc (2×). The combined organics were dried (MgSO4), filtered and concentrated to give the crude product which was purified via reverse phase HPLC (C18 column, 20-100% CH3CN/H2O over 20 min at a flow rate of 20 mL/min, UV detection was at 220 nm). Retention time of the product was 16 min. Product-containing fractions were concentrated to give 49 mg (12%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[NH:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([C:20]([OH:22])=O)[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:34]=[CH:33][C:28]2[NH:29][C:30](=[O:32])[O:31][C:27]=2[CH:26]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[O:32]=[C:30]1[NH:29][C:28]2[CH:33]=[CH:34][C:25]([NH:24][C:20]([C:18]3[CH:17]=[CH:16][C:14]4[N:15]=[C:11]([NH:10][C:9]([NH:8][C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)=[O:23])[S:12][C:13]=4[CH:19]=3)=[O:22])=[CH:26][C:27]=2[O:31]1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: O=C(Nc1ccc(Cl)cc1)Nc1nc2ccc(C(=O)O)cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)Nc1nc2ccc(C(=O)Nc3ccc4[nH]c(=O)oc4c3)cc2s1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
Starting material 35 (300 mg, 45% content, 0.4 mmol) and 6-Amino-3H-benzooxazol-2-one (30, 58 mg, 0.4 mmol) were dissolved in 2 ml of dry DMF. Then EDCl (96 mg, 0.5 mmol) and HOBt (76 mg, 0.5 mmol) were added. The reaction was stirred at ambient temperature over night. It was then purred into water and the resulting precipitate was filtered. The isolated precipitate was then stirred in 100 ml warm methanol and the non-soluble crystals filtered and washed with methanol. Thereby the desired product 36 (130 mg, 0.271 mmol, 70%) could be isolated.
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:21])=[C:18]([F:20])[F:19])(=O)=O.[S:22]1[C:26]([C:27](O)=[O:28])=[CH:25][C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]1=2.C(=O)([O-])O.[Na+]>O>[S:22]1[C:26]([C:27]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:21])=[C:18]([F:19])[F:20])=[O:28])=[CH:25][C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]1=2
Reactant: CC(CCCCCCOS(C)(=O)=O)=C(F)F
Reactant: O=C(O)c1cc2ccccc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CCCCCCOC(=O)c1cc2ccccc2s1)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To 10 ml of N,N-dimethylformamide were dissolved 0.29 g (1.1 mmol) of 8,8-difluoro-7-methyl-7-octenyl methanesulfonate and 0.26 g (1.5 mmol) of benzo[b]thiophene-2-carboxylic acid, followed by the addition of 0.28 g (3.3 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether:hexane=1:8) to obtain 0.27 g (yield: 71%) of 8,8-difluoro-7-methyl-7-octenyl benzo[b]thiophene-2-carboxylate.