Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:21][N:22](C)[C:23](=O)OC(C)(C)C)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.[ClH:37]>C(OCC)(=O)C.C(O)C>[ClH:37].[F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:21][NH:22][CH3:23])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2nccs2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2nccs2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
tert-Butyl {[5-(2-fluoropyridin-3-yl)-1-(1,3-thiazol-2-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (168 mg) was dissolved in ethyl acetate (2 mL) and ethanol (2 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (4 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol=1:3 to give the title compound as colorless crystals (yield 101 mg, 70%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:30]2[CH2:31][CH2:32][N:27]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)[CH2:28][CH2:29]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2b from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(piperazin-1-yl-quinoline.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][CH:8]=1.Cl.Cl.[NH2:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:33][CH:34]1[CH2:37][N:36]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][CH:8]=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:35]1
Reactant: Nc1ccc(F)c(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)n1
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1ccc(F)c(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)n1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
To 190 mg of N,N-dimethylformamide were added 57 mg of 1-(6-amino-3-fluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 37 mg of 3-aminoazetidine dihydrochloride, and 100 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 30 minutes. After adding 0.2 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 40 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([F:11])=[CH:6][C:5]=1[C:12]#[N:13].[Br:15]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5]([C:12]#[N:13])=[CH:6][C:7]([F:11])=[CH:8][C:9]=1[CH2:10][Br:15]
Reactant: NC(=O)CCC(=O)NBr
Reactant: COC(=O)c1c(C)cc(F)cc1C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(C#N)cc(F)cc1CBr

Procedure:
A mixture of 4-fluoro-2-cyano-6-methyl-benzoic acid methyl ester (1.04 g, 5.38 mmol), N-bromosuccinamide (1.25 g, 7.0 mmol), and benzoyl peroxide (0.024 g, 0.146 mmol) in carbon tetrachloride (50 mL) was heated at reflux until majority of ester was consumed (as analyzed by GC/MS). The resulting mixture was filtered, the filtrate was concentrated to afford 2-bromomethyl-4-fluoro-6-cyano-benzoic acid methyl ester. The material was used without further purification.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][N:5]([CH:14]([CH3:16])[CH3:15])[C:4]=2[N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21]([OH:23])=[O:22].Cl>O.O1CCOCC1>[CH:14]([N:5]1[C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=3)[C:21]([OH:23])=[O:22])[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Cl)nc21
Reactant: Nc1cc(C(=O)O)cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(C(=O)O)cc(C(F)(F)F)c3)nc21
Temperature: 25 °C
Yield: 80 %

Procedure:
2-Chloro-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (3.5 g; 14.54 mmol) and 3-amino-5-(trifluoromethyl)-benzoic acid (2.98 g; 14.54 mmol) were diluted in 15 ml of water and 15 ml of 1,4-dioxane, 2 ml of HCl 37% were added. The reaction mixture was refluxed 24 h, then cooled to room temperature. The desired product precipitated from the reaction mixture, it was filtered, washed with water and dried in vacuo. 4.77 g (0.012 mol; 80% yield) were obtained as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]2[O:15][C:16]([CH:18]=[O:19])=[CH:17][C:7]1=2.C1COCC1.[BH4-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]2[O:15][C:16]([CH2:18][OH:19])=[CH:17][C:7]1=2
Reactant: COC(=O)c1cc2oc(C=O)cc2n1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc2oc(CO)cc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 114.3 %

Procedure:
Methyl 4-(3,4-dichlorobenzyl)-2-formylfuro[3,2-b]pyrrole-5-carboxylate (0.2 g) was dissolved in methanol (10 mL) and THF (10 mL) and cooled to 0° C. Sodium borohydride (26 mg) was added and the reaction stirred for 2 hours. The mixture was acidified with 2M HCl, partially evaporated, and extracted with ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated in vacuo to give a white solid (0.23 g), NMR d(CDCl3) 3.8 (3H, s), 4.65 (2H, d), 5.6 (2H, s), 6.2 (1H, s), 6.85 (1H, s), 7.0 (1H, dd), 7.2 (1H, d), 7.35 (1H, d); M/z (+) 340 (MH+), 332, 278.
Reaction SMILES: [H-].[Na+].[S:3]1[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[Br:10][CH:11](Br)[CH3:12]>CN(C=O)C>[Br:10][CH2:11][CH2:12][N:5]1[C:6](=[O:8])[CH2:7][S:3][C:4]1=[O:9]
Reactant: O=C1CSC(=O)N1
Reactant: CC(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CSC(=O)N1CCBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 392.2 %

Procedure:
To a 50 ml 3-neck flask, NaH (60% in mineral oil) (0.614 g, 25.6 mmole) was taken in DMF (20 mL) under N2 atmosphere and cooled to 0° C. To this, thiazolidine-2,4-dione (2.0 g, 1.707 mmole) followed by dibromoethane (1.61 mL, 18.78 mmole) were added at 0° C. and the reaction mixture was stirred at room temperature for 2 hrs. After completion of the reaction, ice was added to the reaction mixture and product was extracted with EtOAc. The combined organic layer was washed with water, dried over Na2SO4 and evaporated to get the crude product which was subjected for the column purification. The crude compound was purified using column purification using 60-120 mesh size neutral silica by eluting the compound with 20-25% EtOAc in hexanes to yield 1.5 g of 3-(2-bromoethyl)thiazolidine-2,4-dione.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:17])[CH:8]=[C:9]([C:13]([O:15]C)=[O:14])[NH:10]2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+]>>[CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:17])[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[NH:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(=O)cc(C(=O)OC)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc2c(=O)cc(C(=O)O)[nH]c2c1
Yield: 87.8 %

Procedure:
Treatment of methyl 7-ethyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.8 g, Example 3a) with sodium hydroxide (0.58 g) as described in Example 1c, gave 7-ethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (0.66g), m.p. 271° C., δ (360 MHz, NaOD) 1.30 (3H, t, CH3), 2.81 (2H, q, CH2), 6.66 (1H, s, 3-H), 7.36 (1H, d, 6-H), 7.66 (1H, s, 8-H) and 8.11 (1H, d, 5-H), (Found: C, 66.46: H, 5.01; N, 6.59%, C12H11NO3 requires C, 66.35; H, 5.10: N, 6.45%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[I:11]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[C:6]([I:11])[CH:7]=1
Reactant: II
Reactant: COc1cc(Cl)ccc1N
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COc1cc(Cl)cc(I)c1N
Temperature: 50 °C
Reaction time: 4 h
Yield: 14.8 %

Procedure:
To a solution of 4-chloro-2-methoxy-phenylamine (600 mg, 3.81 mmol) in ethanol (12 ml) at 50° C. was added a solution of silver sulphate (2.14 g, 6.85 mmol) and iodine (967 mg, 3.81 mmol) in ethanol (8 ml). The resulting reaction mixture was stirred at 50° C. for 4 h. After cooling at 25° C., reaction mixture was filtered through a bed of celite and the filtrate was diluted with EtOAc (30 ml). The organic phase was washed with aqueous Na2S2O3 solution (2×15 ml), and brine (10 ml), dried over anhydrous Na2SO4, filtered, and evaporated off in vacuo. The crude residue was purified by flash column chromatography (2% EtOAc in hexane) to afford 4-chloro-2-iodo-6-methoxy-phenylamine (160 mg, 15%) as brown sticky liquid. GC-MS: 283 (M).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[NH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:32][CH2:31][C:30]([NH:29][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:27][CH:26]=1)([CH3:34])[CH3:33]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: CC(C)(N)CO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC(C)(C)CO)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with 2-amino-2-methylpropan-1-ol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=447.3 [M+H]+.
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[CH3:13][CH2:14][O:15][C:16]([CH3:18])=[O:17].[F:19][C:20]([F:30])([F:29])[C:21]([C:23]1[S:27][C:26]([SH:28])=[N:25][CH:24]=1)=[O:22]>C1COCC1>[CH2:14]([O:15][C:16](=[O:17])[CH2:18][C:21]([OH:22])([C:23]1[S:27][C:26]([SH:28])=[N:25][CH:24]=1)[C:20]([F:29])([F:19])[F:30])[CH3:13]
Reactant: O=C(c1cnc(S)s1)C(F)(F)F
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC(O)(c1cnc(S)s1)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
iPr2NH (205 mg, 2.0 mmol) was dissolved in THF (3.5 mL) and cooled to −10° C. n-Butyllithium (2.5M, 0.81 mL, 2.0 mmol) was added dropwise, and the reaction was cooled to −78° C. EtOAc (179 mg, 2.0 μmmol) in THF (0.5 mL) was added, followed by 10a (188 mg, 0.9 mmol) in THF (10.5 mL), and the reaction was stirred at −78° C. for 1 hour. The reaction was warmed to −10° C. and quenched with 5% aqueous NH4Cl (10 mL). The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with 1N HCl and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (50% Et2O in hexanes) to give the desired product, 10b.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(O)[CH3:8])(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([NH:4][CH2:5][CH:6]=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCC(C)(O)c1ccccc1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)NCC=C(C)c1ccccc1-c1ccccc1
Reaction time: 2 h

Procedure:
A mixture of 2.82 g of 1-acetamido-3-p-biphenylylbutan-3-ol, 0.1 g of p-toluenesulfonic acid and 70 ml of toluene is boiled for 2 hours under a water separator, 1-Acetamido-3-p-biphenylyl-2-butene is obtained after working up in the customary manner.
Reaction SMILES: O.[OH-].[Li+].[C:4]1(/[C:10](=[N:20]/[O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[N:35]=[C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[O:33][N:32]=3)=[CH:25][CH:24]=2)/[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>O1CCCC1.C(O)C>[C:4]1(/[C:10](=[N:20]/[O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[N:35]=[C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[O:33][N:32]=3)=[CH:25][CH:24]=2)/[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCCC/C(=N\OCc1ccc(OCc2noc(-c3ccccc3)n2)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)CCCC/C(=N\OCc1ccc(OCc2noc(-c3ccccc3)n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
Lithium hydroxide monohydrate (134 mg) was added to a solution of ethyl E-6-phenyl-6-[4-(5-phenyl-1,2,4-oxadiazol-3-ylmethoxy)benzyloxyimino]hexanoate (545 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) and stirred at room temperature for 4 hours. 1N hydrochloric acid (3.3 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6-phenyl-6-[4-(5-phenyl-1,2,4-oxadiazol-3-ylmethoxy)benzyloxyimino]hexanoic acid (465 mg, yield 90%) as colorless crystals. m.p. 88-89° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH:4]([N:15]1[C:21](=[O:22])[CH2:20][CH2:19][N:18]([C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH2:17][CH2:16]1)[CH2:5][CH2:6][O:7][Si](C(C)(C)C)(C)C.Cl>CO>[CH3:1][O:2][C:3](=[O:35])[CH:4]([N:15]1[C:21](=[O:22])[CH2:20][CH2:19][N:18]([C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH2:17][CH2:16]1)[CH2:5][CH2:6][OH:7]
Reactant: COC(=O)C(CCO[Si](C)(C)C(C)(C)C)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Agent: Cl
Solvent: CO
Product: COC(=O)C(CCO)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Reaction time: 1.5 h

Procedure:
A solution of 0.175 g (0.320 mmol) of (rac)-4-(tert-butyl-dimethyl-silanyloxy)-2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-butyric acid methyl ester in 4.9 ml of methanol was treated at 0° C. with 0.8 ml (3.22 mmol, 4 M in dioxane) of HCl and kept 1.5 h at RT. Extraction with cold sat. aq. sodium hydrogencarbonate solution and diethyl ether (2×) followed by drying (Na2SO4) and evaporation gave 0.165 g (quantitative) of the titled compound together with 50% of the lactone (1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(2-oxo-tetrahydro-furan-3-yl)-[1,4]diazepan-5-one) as a white gum. MS: 429.3 (MH+, 2Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18]N=C[CH:15]=2)[CH:13]=1)=[O:7].O=[C:27]1C(C(O)=O)=CC(C2C=NC=CC=2)=N[NH:28]1.C(Cl)(=O)C(Cl)=O.ClC1C=C(Cl)C=CC=1CN>C(N(CC)CC)C.CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:15]=[N:28][CH:27]=[CH:18][CH:19]=2)[CH:13]=1)=[O:7]
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: O=C(O)c1cc(-c2cccnc2)n[nH]c1=O
Agent: NCc1ccc(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2cccnc2)n[nH]c1=O

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-3-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 1 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.21 cm3 of 2,4-dichlorobenzylamine and 0.22 cm3 of triethylamine, and after purification by chromatography on silica gel (particle size 40-63 μm, under an argon pressure of 150 kPa), eluting with a mixture of dichloromethane and methanol (90/10 by volume), 0.204 g of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a cream-colored solid melting at a temperature in the region of 260° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](Cl)=[O:16]>O1CCCC1>[NH2:1][C:2]1[C:7]([NH:8][C:15](=[O:16])[C:14]([Cl:19])([Cl:18])[Cl:13])=[CH:6][C:5]([C:9]([F:10])([F:12])[F:11])=[CH:4][N:3]=1
Reactant: Nc1cc(C(F)(F)F)cnc1N
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Nc1ncc(C(F)(F)F)cc1NC(=O)C(Cl)(Cl)Cl
Reaction time: 0.17 h
Yield: 80.6 %

Procedure:
Into 38 ml of dry tetrahydrofuran, 1.5 g of 2,3-diamino-5-trifluoromethylpyridine was dissolved, and a solution mixture comprising 1.54 g of trichloroacetyl chloride and 3.8 ml of dry tetrahydrofuran was dropwise added thereto over a period of 10 minutes. Then, the mixture was reacted at room temperature for 3 hours. After completion of the reaction, precipitated crystals were collected by filtration and washed with tetrahydrofuran to obtain 2.2 g of N-(2-amino-5-trifluoromethyl-3-pyridyl)trichloroacetamide having a melting point of from 210° to 223° C.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH2:14]([C@H:21]1[CH2:26][CH2:25][NH:24][CH2:23][C@H:22]1[OH:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C@H:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][S:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:23][C@H:22]1[OH:27])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O[C@@H]1CNCC[C@@H]1Cc1ccccc1
Reactant: O=S(=O)(CCCl)c1ccc(O)cc1
Product: O=S(=O)(CCN1CC[C@H](Cc2ccccc2)[C@H](O)C1)c1ccc(O)cc1
Yield: 66 %

Procedure:
The title compound was prepared from 4-(2-chloro-ethanesulfonyl)-phenol and (3S,4S)-4-benzyl-piperidine-3-ol in 66% yield as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:19]([C:21]([OH:28])([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])#[CH:20]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:20]#[C:19][C:21]([OH:28])([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH:3]=1)=[O:17]
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Reactant: C#CC(O)(CCC)CCC
Product: CCCC(O)(C#Cc1cccc(C(O)CCNC(=O)C(F)(F)F)c1)CCC

Procedure:
Coupling of N-(3-(3-bromophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide (25) (55.35 g, 169.7 mmol) with 4-ethynylheptan-4-ol (20) (30.13 g, 214.9 mmol) following the method described in Example 1 gave crude 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)propyl)acetamide (26) as a brown oil which was used in the next step without additional purification. Yield (90.32 g, quant.): 1H NMR (400 MHz, DMSO-d6) δ 9.35 (m, 1H), 7.29-7.34 (m, 3H), 7.22-7.26 (m, 1H), 5.39 (d, J=4.4 Hz, 1H), 5.12 (s, 1H), 4.59 (dt, J=8.4, 4.8 Hz, 1H), 3.25 (quint, J=7.6 Hz, 2H), 1.80 (quint, J=8.0 Hz, 2H), 1.44-1.63 (m, 8H), 0.92 (t, J=7.2 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[CH3:23][C:24]1[N:25]=[CH:26][NH:27][C:28]=1[CH:29]=O>>[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH:22][C:8]2[CH:7]=[CH:6][C:5]3[C:4]([NH:1][CH2:23][C:24]4[N:25]=[CH:26][NH:27][C:28]=4[CH3:29])=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=2)=[CH:18][CH:17]=1
Reactant: Cc1nc[nH]c1C=O
Reactant: Cc1ccc(CN)o1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: Cc1ccc(CNc2ccc3c(NCc4nc[nH]c4C)cccc3n2)o1

Procedure:
The title compound, MS: m/e=348.5 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and 4-methylimidazole-5-carbaldehyde as described in example 26.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:12].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Li+].[Cl-]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:3]1[C:4]2[CH2:8][O:7][C:6](=[O:9])[C:5]=2[CH:10]=[CH:11][C:2]=1[CH2:15][CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)ccc2c1COC2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1C)COC2=O

Procedure:
A mixture of 5-bromo-4-methyl-2-benzofuran-1(3H)-one (980 mg, 4.3 mmol), allyl-tributyl-stannane (1.7 g, 5.2 mmol), LiCl (550 mg, 12.9 mmol) and Pd(PPh3)4 (0.1 g) in anhydrous toluene was stirred at reflux under N2 overnight. The solvent was removed under reduced pressure, and the residue was purified with silica gel column chromatography to give the product 4-methyl-5-prop-2-en-1-yl-2-benzofuran-1(3H)-one.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:17][O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1.Cl.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O>[CH3:17][O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:14](=[O:16])[C@@H:12]([CH3:13])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-CBZ-D-alanine (28.1 g, 0.149 mol) in DMF (250 mL) at 0° C., was added L-proline-methylester.HCl (24.6 g, 0.149 mmol), 1-hydroxybenzotriazole hydrate (22.2 g, 0.164 mmol), ethyl-3-(3-dimethylamino)-propyl carbodiimide.HCl (31.4 g, 0.164 mmol) and 4-methylmorpholine (22.6. g, 0.224 mmol). The reaction mixture was stirred for 12 h while allowing the reaction to warm to room temperature. The reaction mixture was poured in water (750 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed as follows: KHSO4 (0.25 M, 2×50 mL), water (1×50 mL), saturated aqueous NaHCO3 (2×50 mL) and saturated NaCl (1×50 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo to give the title compound, 41.16 g (92%), as an oil. MS (M+H)+ =301+.