Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([O:10][CH3:11])=[N:8][C:7]([Br:12])=[CH:6][N:5]=1.[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([S:29](OC3C=CC([N+]([O-])=O)=CC=3)(=[O:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15].Cl>C(COC)OC.O>[Br:12][C:7]1[N:8]=[C:9]([O:10][CH3:11])[C:4]([NH:3][S:29]([C:24]2[C:23]([C:20]3[CH:19]=[CH:18][C:17]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:22][CH:21]=3)=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:31])=[O:30])=[N:5][CH:6]=1
Reactant: CC(C)Cc1ccc(-c2ccccc2S(=O)(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: COc1nc(Br)cnc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccccc1-c1ccc(CC(C)C)cc1
Reaction time: 0.17 h
Yield: 24.2 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.094 g) was added to a solution of 2-amino-5-bromo-3-methoxypyrazine (0.159 g) in dimethoxyethane (4 ml). The solution was stirred for 10 minutes and then 4-nitrophenyl 4'-isobutyl-2-biphenylsulphonate (0.321 g) was added. The solution was allowed to stand for 5 hours and then water (20 ml) was added. 2M Hydrochloric acid (2 ml) was added and the mixture was extracted with ethyl acetate (2×30 ml). The extracts were dried (MgSO4) and volatile material was removed by evaporation. The residue was purified by elution with ethyl acetate/hexane (1:3 v/v) through a silica gel Mega Bond Elut column. The resulting solid was recrystallised from a mixture of ether and hexane to give N-(5-bromo-3-methoxy-2-pyrazinyl)-4'-isobutyl-2-biphenylsulphonamide (0.09 g), m.p. 154-156° C.; 1H NMR (d6 -DMSO): 0.9 (d,6H), 1.8-2.0 (m,1H), 2.5 (d,2H), 3.85 (s,3H), 7.1 (s,4H), 7.3 (d,1H), 7.5-7.7 (m,2H), 7.8 (br s,1H), 8.05 (d,1H), 10.2-10.3 (br, 1H); mass spectrum (+ve FAB, methanol/NBA): 478 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[N:15][C:6]2[N:7]=[CH:8][C:9](=[O:14])[N:10]([CH2:11][CH:12]=C)[C:5]=2[CH:4]=1.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:16]=[N:15][C:6]2[N:7]=[CH:8][C:9](=[O:14])[N:10]([CH2:11][CH:12]=[O:18])[C:5]=2[CH:4]=1
Reactant: C=CCn1c(=O)cnc2ncc(OC)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cnc2ncc(=O)n(CC=O)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7-(Methyloxy)-1-(2-propen-1-yl)pyrido[2,3-b]pyrazin-2(1H)-one (846 mg, 3.900 mmol) was dissolved in 1,4-dioxane (20 ml) and water (10 ml). Sodium periodate (20.09 g, 9.75 mmol) was added, followed by osmium tetroxide (0.83 ml of 4% aqueous solution). The mixture stirred at rt for 4 h, and then extracted with 20% MeOH/DCM (3×200 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give [7-(methyloxy)-2-oxopyrido[2,3-b]pyrazin-1(2H)-yl]acetaldehyde (existing mostly as the methyl hemiacetal) as an impure brown solid (969 mg, 113%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2(O)[CH2:15][CH:14]3[N:16]([CH3:17])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].O=S(Cl)Cl.[OH-].[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH:11]3[N:16]([CH3:17])[CH:14]([CH2:13][CH2:12]3)[CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C2CCC1CC(O)(c1ccc(Cl)c(Cl)c1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: CN1C2C=C(c3ccc(Cl)c(Cl)c3)CC1CC2
Reaction time: 17 h
Yield: 53 %

Procedure:
To 2.35 g (8.76 mmol) of 3-(3,4-dichloro-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octan-3-ol in 50 mL of Cl(CH2)2Cl is added 1.92 mL (3.13 g, 26.67 mmol) SOCl2. After stirring at 23 C for 17 h, the reaction mixture is poured into 5 N NaOH, extracted with 1×100 mL H2O, 1×100 mL brine, dried over MgSO4, filtered and extracted to give a brown oil. Flash chromatography on SiO2, eluting with CHCl3/MeOH (40/1 to 10/1) gives 1.24 g (4.62 mmol, a 53% yield) of the title compound as an orange oil. MS (ES) m/z 269 (MH)+.
Reaction SMILES: C([O:8][CH:9]1[CH2:14][CH2:13][C:12]([C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([C:27]4[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=4)[N:25]=3)[NH:20][CH:19]=2)=[O:17])([CH3:15])[CH2:11][CH2:10]1)C1C=CC=CC=1>C1COCC1.CCO.[Pd]>[OH:8][CH:9]1[CH2:10][CH2:11][C:12]([C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([C:27]4[CH:28]=[C:29]([O:37][CH3:38])[C:30]([O:35][CH3:36])=[C:31]([O:33][CH3:34])[CH:32]=4)[N:25]=3)[NH:20][CH:19]=2)=[O:17])([CH3:15])[CH2:13][CH2:14]1
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCC(OCc5ccccc5)CC4)c3n2)cc(OC)c1OC
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCC(O)CC4)c3n2)cc(OC)c1OC
Yield: 130.9 %

Procedure:
A solution of (4-benzyloxy-1-methyl-cyclohexyl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone (36 mg, 0.070 mmol) and 10% Pd/C (10 mg), in THF (10 ml) and EtOH (8 ml), was hydrogenated for 5 days under a 60 psi H2 atmosphere. The reaction mixture was vacuum purged with argon (3×), and filtered through a plug of celite using THF and DCM. The filtrate was concentrated giving an opaque oil which was purified by silica gel chromatography using 0-10% MeOH in EtOAc as eluant provided 39 mg (36%) of (4-hydroxy-1-methyl-cyclohexyl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone as a pale yellow solid. MP 242-244° C. M+H=426.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][C:3]=1[NH:4][CH2:5][CH:6]([OH:13])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:13][CH:6]([CH2:5][NH:4][C:3]2[CH:14]=[C:15]([Cl:19])[C:16]([Cl:18])=[CH:17][C:2]=2[Cl:1])[CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:23][CH:22]=1
Reactant: OC(CNc1cc(Cl)c(Cl)cc1Cl)Cn1ccnc1
Reactant: ClCc1ccc(Br)cc1
Product: Clc1cc(Cl)c(NCC(Cn2ccnc2)OCc2ccc(Br)cc2)cc1Cl

Procedure:
Reaction of 1-[3-(2,4,5-trichloroanilino)-2-hydroxypropyl]-imidazole with p-bromobenzyl chloride yields 1-[2-(4-bromobenzyloxy)-3-(2,4,5-trichloroanilino)-propyl]-imidazole.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][C:6]([C:9]#N)=[CH:5][CH:4]=1.CC(C[Al]CC(C)C)C.CO.[OH:22]S(O)(=O)=O>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:22])=[CH:5][CH:4]=1
Reactant: CNc1ccc(C#N)cn1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al]CC(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: CNc1ccc(C=O)cn1
Temperature: -78 °C

Procedure:
To 6-(methylamino)-3-pyridinecarbonitrile (D94) (0.1 g, 0.752 mmol) in toluene (10 mL) cooled to −78 C under argon was added Dibal-H (1.88 mL, 1M solution in toluene, 11.2 mmol) dropwise. The reaction was stirred at −78° C. and then allowed to warm to room temperature overnight. MeOH (0.47 mL) and 2 M H2SO4 (1.42 mL) were added and mixture was stirred for 1.5 h then concentrated in vacuo. The residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were dried and concentrated to give the title compound (0.067 g). δH (CDCl3, 400 MHz) 9.78 (1H, s), 8.52 (1H, d), 7.92 (1H, dd), 6.45 (1H, d), 5.38 (1H, br.s), 3.04 (3H, d). MS (ES): MH+ 137.1.
Reaction SMILES: F[C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:22]=[C:21]([C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[CH:20]=[CH:19][C:6]=1[C:7]([NH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)=[O:8].F[C:36]1C=CC(O)=C(C)C=1>>[F:34][C:32]1[CH:31]=[CH:30][C:3]([O:4][C:5]2[CH:22]=[C:21]([C:23]([F:29])([F:28])[C:24]([F:26])([F:27])[F:25])[CH:20]=[CH:19][C:6]=2[C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:17][CH:18]=2)=[O:8])=[C:2]([CH3:36])[CH:33]=1
Reactant: O=C(O)c1ccc(NC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2Oc2ccc(F)cc2F)cc1
Reactant: Cc1cc(F)ccc1O
Product: Cc1cc(F)ccc1Oc1cc(C(F)(F)C(F)(F)F)ccc1C(=O)Nc1ccc(C(=O)O)cc1

Procedure:
4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamido)benzoic acid (3) was prepared following a procedure similar to the one reported above for compound 2 from 4-fluoro-2-methylphenol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[C:6]([NH:8][C:9](=[O:20])[NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=[O:18])[N:15]=2)[CH:7]=1.[O:31]([CH2:33][CH2:34][NH2:35])[CH3:32]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[C:6]([NH:8][C:9](=[O:20])[NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:35][CH2:34][CH2:33][O:31][CH3:32])=[O:18])[N:15]=2)[CH:7]=1
Reactant: COc1ccccc1C(=O)c1ccc(F)cc1NC(=O)Nc1nc(CC(=O)O)cs1
Reactant: COCCN
Product: COCCNC(=O)Cc1csc(NC(=O)Nc2cc(F)ccc2C(=O)c2ccccc2OC)n1
Yield: 65 %

Procedure:
2-(2-{3-[5-Fluoro-2-(2-methoxy-benzoyl)-phenyl]-ureido}-thiazol-4-yl)-N-(2-methoxy-ethyl)-acetamide (158 mg, 65%) was prepared from (2-{3-[5-fluoro-2-(2-methoxy-benzoyl)-phenyl]-ureido}-thiazol-4-yl)-acetic acid (215 mg, 0.5 mmol) and 2-methoxylethylamine (38 mg, 0.5 mmol) following the general procedure K.
Reaction SMILES: [F:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[CH2:12]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17])[CH3:13]>>[CH2:12]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH:17][C:3](=[O:5])[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[F:1])[CH3:13]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(O)C(F)c1ccccc1
Product: CCOC(=O)[C@H](C)NC(=O)C(F)c1ccccc1

Procedure:
Following General Procedure BF above, and using a-fluorophenyl acetic acid (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared. The reaction was monitored by tlc on silica gel (Rf=0.75 in 1:1 EtOAc:hexane) and purification was by chromatography on silica gel using 1:2 ethyl acetate/hexanes as the eluent.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][O:17][C:18](=[O:24])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN1CCN(CCO)CC1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NN1CCN(CCOC(=O)CCC(=O)O)CC1
Reaction time: 12 h

Procedure:
Compound 4 (250 mg, 1.0 mmol), succinic anhydride (105 mg, 1.05 mmol) and 4-DMAP (cat.) were dissolved in CHCl3 (600 μL) and stirred for 12 hours. The solution was concentrated in vacuo and used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 2.60 (s, 4H), 2.76 (m, 6H), 2.86 (m, 4H), 4.23 (t, J=5.5 Hz, 2H), 5.71 (br s, 1H), 10.82 (br s, 1H).
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[S:33][CH:34]=[C:35]([C:37](O)=[O:38])[N:36]=1>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:37]([C:35]2[N:36]=[C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)[S:33][CH:34]=2)=[O:38])[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: O=C(O)c1csc(-c2ccccn2)n1
Product: Cn1ncc(NC(=O)c2csc(-c3ccccn3)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 2-(pyridin-2-yl)thiazole-4-carboxylic acid (see Tetrahedron 2011, 67, 267) gave 326. 1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.70-8.65 (m, 1H), 8.50 (s, 1H), 8.35-8.30 (m, 1H), 8.04-7.97 (m, 1H), 7.87 (s, 1H), 7.59-7.53 (m, 1H), 4.94-4.88 (m, 1H), 4.84-4.67 (m, 1H), 4.48-4.34 (m, 1H), 4.24-4.07 (m, 1H), 3.80 (s, 3H), 3.60-3.47 (m, 1H), 2.17-2.09 (m, 1H), 1.96-1.78 (m, 3H). LCMS (ES+) m/z 417 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2=[N:6][C:7]3[CH2:8][CH2:9][N:10]([CH3:15])[CH2:11][C:12]=3[C:13](Cl)=[C:4]2[CH:3]=1.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2=[N:6][C:7]3[CH2:8][CH2:9][N:10]([CH3:15])[CH2:11][C:12]=3[C:13]([O:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:4]2[CH:3]=1
Reactant: CN1CCc2nc3ccc(Cl)cc3c(Cl)c2C1
Reactant: Oc1ccccc1
Product: CN1CCc2nc3ccc(Cl)cc3c(Oc3ccccc3)c2C1

Procedure:
A mixture of the compound of Example 6 (5.0 g, 0.018 mol) and phenol (3.38 g, 0.036 mol) is reacted as described for Example 14 to obtain the free base which is recrystallized three times from hexane to afford the title compound as a crystalline solid, m.p. 182°-184° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:6][C@@H:5]1[CH3:21])(=[O:3])[CH3:2].[C:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([OH:24])=[O:23].C1(C(N2C3C(=CC(C4C=NNC=4)=CC=3)N(C(OC(C)C)=O)C[C@@H]2C)=O)CC1>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:28]3[CH:29]=[CH:30][C:25]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=3)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:6][C@@H:5]1[CH3:21])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Agent: CC(C)OC(=O)N1C[C@H](C)N(C(=O)C2CC2)c2ccc(-c3cn[nH]c3)cc21
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2N(C(=O)OC(C)C)C[C@@H]1C

Procedure:
(S)-4-(1-acetyl-4-(isopropoxycarbonyl)-2-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)benzoic acid was synthesized from (S)-isopropyl 4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate and 4-carboxyphenylboronic acid according to the procedure outlined above for (S)-isopropyl 4-(cyclopropanecarbonyl)-3-methyl-7-(1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 419 [M+Na]+
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Br.[NH2:21][C@H:22]1[CH2:27][CH2:26][O:25][C:23]1=[O:24].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=N.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C.O>[CH2:4]([O:3][C:1]([NH:11][C@H:12]([C:17]([NH:21][C@H:22]1[CH2:27][CH2:26][O:25][C:23]1=[O:24])=[O:19])[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@H]1CCOC1=O
Agent: Br
Agent: CN(C)CCCN=C=N
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1CCOC1=O
Temperature: 20 °C
Reaction time: 15 h
Yield: 68 %

Procedure:
3.51 g (13.25 mmol) of Cbz-L-Leucine, 2.41 g (1 eq.) of (S)-2-amino-4-butyrolactone hydrobromide, 1.97 g of HOBT (1.1 eq.) and 5.59 g (2.2 eq.) of 1-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) are dissolved in 60 ml of anhydrous DMF, then 7.64 ml of (3.3 eq.) of N,N-diisopropylethylamine is added. The reaction mixture is stirred for 15 hours at 20° C. before being poured into 200 ml of a 1/1 mixture of ethyl acetate/water. After stirring and decantation, the organic solution is washed successively with 100 ml of a saturated solution of NaHCO3, 50 ml of water, 100 ml of a 1M solution of citric acid and finally 100 ml of a solution of salt water. The organic phase is dried over sodium sulphate, filtered and concentrated to dryness under vacuum. The oil obtained is washed using isopentane and then crystallized from a dichloromethane/isopentane mixture. A white solid is obtained with a yield of 68%. Melting point: 130-131° C.
Reaction SMILES: ClC1C=CC(C2[C:9]([CH:14]=[O:15])=[CH:10][CH:11]=[CH:12]C=2)=CC=1.[NH:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17]1.N1(C(OC(C)(C)C)=O)CCNCC1>>[O:15]1[CH2:14][CH2:9][CH:10]([N:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:17]2)[CH2:11][CH2:12]1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C2CCOCC2)C1

Procedure:
The title compound was prepared by substituting dihydro-2H-pyran-4(3H)-one for 4′-chlorobiphenyl-2-carboxaldehyde and (R)-tert-butyl pyrrolidin-3-ylcarbamate for tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH:8][CH2:9][CH2:10][SH:11].N1CCCCC1.C(NC(C)C)(C)C>>[O:5]=[C:4]1[CH:3]([CH2:2][C:1]([OH:6])=[O:7])[S:11][CH2:10][CH2:9][O:8]1
Reactant: O=C1C=CC(=O)O1
Reactant: OCCS
Solvent: CC(C)NC(C)C
Solvent: C1CCNCC1
Product: O=C(O)CC1SCCOC1=O

Procedure:
Analogously to Example 1, by reaction of maleic acid anhydride with 2-hydroxyethanethiol in the presence of piperidine (instead of diisopropylamine) and the usual working up, 2-oxo-1,4-oxathiane-3-acetic acid, m.p. = 96°-98° is obtained.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].F[C:10](F)(F)C(F)=C(F)F>>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][CH:10]=1
Reactant: Nc1ccccc1N
Reactant: FC(F)=C(F)C(F)(F)F
Product: c1ccc2[nH]cnc2c1

Procedure:
The first step (a) illustrated on FIG. 15 is a reaction between ortho phenylene diamine 23 and hexafluoropropene 24 in autoclave for 24 hours and the resulting derived product is obtained with a good output (75%). This reaction does not make it possible to obtain a fluorinated vinyl monomer with benzimidazole functionality 21b, but to obtain 2-(1,1,1,2-tetrafluoroethyl)benzimidazole 10, after recrystallization in a water/ethanol mixture and with an output of 75%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][NH:13][C:12](=[O:16])[CH:11]=2)=[N:6][CH:7]=1.[C:17]([O:21][C:22]([N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][C:28]([CH2:34][CH2:35]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:29][CH:30]=2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][C:28]([CH2:34][CH2:35][N:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=4)=[CH:11][C:12]3=[O:16])=[CH:29][CH:30]=2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=c1cc(OCc2ccc(Br)cn2)cc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)cc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(CCn3ccc(OCc4ccc(Br)cn4)cc3=O)cc2C1

Procedure:
7-{2-[4-(5-Bromo-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester is prepared following example 24.1 from 562 mg (2.00 mmol) 4-(5-bromo-pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 22.2) and 863 mg (2.00 mmol) 7-[2-(toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 7).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])=[CH:8][CH:9]=2)[N:4]=1.Cl>CC(O)=O>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:9]=2)[N:4]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc2ccc(C(F)(F)F)nc2c1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc2ccc(C(F)(F)F)nc2c1

Procedure:
tert-Butyl 2-(2-(trifluoromethyl)quinolin-7-yl)acetate was dissolved in glacial AcOH (0.8 mL) and 6 N HCl (0.8 mL) and heated to 80° C. for 2 hr. The reaction mixture was concentrated in vacuo to afford the crude product, which was used without further purification. HPLC method [4], retention time=1.874 min; MS (ESI) 256.1 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[O:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[H][H]>C1(C)C=CC=CC=1.CO>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([OH:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)CCc1ccccc1

Procedure:
The general procedure described in Example B1 is repeated, with the following modifications to the reaction conditions: ethyl-4-phenyl-2-oxobutyrate (substrate): 0.352 g (1.7 mmol); solvent: 10 ml of toluene/methanol (1:1); hydrogen: 50 bar, temperature: 50° C.; reaction time: 19 hours. The conversion is 100%, ee: 44% (R).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH2:5][C:4](=[O:7])[CH:3]=1.[CH2:8](Cl)[CH:9]=[C:10]([CH3:12])[CH3:11].C1(C)C=CC=CC=1.[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(O)(=O)C.O>[CH3:1][C:2]1[CH2:6][CH2:5][C:4](=[O:7])[C:3]=1[CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11]
Reactant: CC(C)=CCCl
Reactant: CC1=CC(=O)CC1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)=CCC1=C(C)CCC1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 49.9 %

Procedure:
A mixture of 3-methyl-2-cyclopentenone 24.5 g (0.25 mole) and prenyl chloride 54 g (0.51 mole) was fed into a reaction flask containing 30 ml of toluene, sodium hydroxide 21.3 g, water 21.3 g and Aliquat 336 1 g maintaining 100° C. The reaction mass was aged for 4 hours, cooled to 25° C. and neutralized with acetic acid. The organic layer was removed and distilled to give 20.5 g of 3-methyl-2-(3-methyl-2-butenyl)-2-cyclopenten-1-one.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:12][O:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]#[C:21][Si](C)(C)C)[CH:19]=2)=[CH:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[C:20]([C:18]1[CH:19]=[C:14]([O:13][CH2:12][C@@H:11]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH:15]=[N:16][CH:17]=1)#[CH:21]
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cncc(C#C[Si](C)(C)C)c1)Cc1c[nH]c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#Cc1cncc(OC[C@H](Cc2c[nH]c3ccccc23)NC(=O)OC(C)(C)C)c1
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of Example 14A (400 mg, 0.86 mmol) in THF (6 mL) at room temperature was treated with tetrabutylammonium fluoride (1.0 M solution in THF, 1.12 mL, 1.12 mmol), stirred for 1 hour, treated with ethyl acetate (50 mL), washed with brine, dried (MgSO4), filtered, and concentrated. The residual oil was purified by flash column chromatography on silica gel with 40% ethyl acetate/hexanes to provide the desired product (290 mg, 86%). MS (APCI) m/e 392 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH:6]1[C:11]2[CH:12]=[CH:13][C:14]([Br:16])=[CH:15][C:10]=2[CH2:9][CH2:8][O:7]1)C.[OH-].[Na+].O.C1CCCCC1>C(O)C.C1(C)C=CC=CC=1>[Br:16][C:14]1[CH:13]=[CH:12][C:11]2[CH:6]([CH2:5][C:4]([OH:17])=[O:3])[O:7][CH2:8][CH2:9][C:10]=2[CH:15]=1
Reactant: CCOC(=O)CC1OCCc2cc(Br)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Solvent: O
Product: O=C(O)CC1OCCc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2-(6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl)acetic acid ethyl ester (20 g, 66.9 mmol) was dissolved in absolute ethanol (40 mL). The mixture was cooled to 0° C. and 4N NaOH (22 mL) was added over five minutes. The reaction mixture was then stirred for 1.5 h at room temperature. Water (22 mL) was added, and the solution washed with dichloromethane (70 mL). The aqueous layer was collected and acidified with 6N HCl (17 mL) and extracted with dichloromethane (70 mL). The organic layer was concentrated in vacuo to give an off-white solid. This solid was suspended in toluene (66 mL) and heated to 100° C. The resulting solution was cooled to 80° C. and cyclohexane (66 mL) added. The resulting suspension was cooled to room temperature and stirred for an hour. The solid was then filtered off, washed with cyclohexane (20 mL), and dried at 40° C. in vacuo to give the title compound as a white solid.