Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.CN(C=O)C.[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C@@H:15]([OH:21])[CH2:14]2.CC([O:26][C:27]([N:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@@H:30]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=O)(C)C>CC(C)([O-])C.[Na+]>[CH:42]1[CH:43]=[CH:44][C:39]([C@@H:30]2[N:29]([C:27]([O:21][C@@H:15]3[CH:16]4[CH2:19][CH2:20][N:13]([CH2:18][CH2:17]4)[CH2:14]3)=[O:26])[CH2:38][CH2:37][C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]2=3)=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc2[C@@H]1c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1
Yield: 3.9 %

Procedure:
In a mixture of 0.38 g of sodium tert-butoxide, 60 ml of toluene and 3 ml of DMF, 2.96 g of (R)-quinuclidin-3-ol was allowed to react with 6.00 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid 2-methylpropan-2-yl ester for 8 hours while evaporating the solvent, thereby obtaining 0.274 g of a solifenacin-containing composition.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Cl:10][C:11]1[CH:12]=[C:13]([N:18]=[C:19]=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17]>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:19](=[O:20])[NH:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([Cl:10])[CH:12]=1)[CH2:2]2
Reactant: OC1CN2CCC1CC2
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)OC1CN2CCC1CC2
Yield: 60 %

Procedure:
3-Quinuclidinol and 3,4-dichlorophenyl isocyanate were used. Filtration of the precipitated solid from the cooled reaction mixture afforded the title compound (60%) as a white solid: mp 181.0-184.0° C.; FAB LRMS m /z (relative intensity, %) 319 ([MH+ with two Cl37 ], 13), 318 (11), 317 ([MH+ with one Cl37 ], 71), 316 (18), 315 ([MH+ with two Cl35 ], 100).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]1[CH3:13])(=[O:3])[CH3:2].[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:8]([CH3:13])=[CH:9][C:10]([C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([Cl:14])=[CH:16][CH:17]=2)=[C:11]1[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCn1c(C)ccc1C
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)OCCn1c(C)cc(C(=O)c2ccc(Cl)cc2)c1C
Yield: 34 %

Procedure:
In 1,2-dichloroethane, 2-(2,5-dimethylpyrrol-1-yl)ethyl acetate was reacted with p-chlorobenzoyl chloride in the presence of aluminum chloride at room temperature for 18 hours to afford compound (340) in a yield of 34.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.B(Cl)(Cl)Cl.[CH2:18]1[CH2:29][O:28][C:27]2[C:20](=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH:22]=[O:23])[O:19]1.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH:22]([C:21]2[CH:24]=[CH:25][CH:26]=[C:27]3[O:28][CH2:29][CH2:18][O:19][C:20]=23)[OH:23])[CH:3]=1
Reactant: O=Cc1cccc2c1OCCO2
Reactant: CC(C)(C)CNc1ccc(Cl)cc1
Agent: ClB(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)CNc1ccc(Cl)cc1C(O)c1cccc2c1OCCO2
Reaction time: 3.5 h
Yield: 88.5 %

Procedure:
A solution of (4-chloro-phenyl)-(neopentyl)-amine (2.24 g, 11.3 mmol) in benzene (6 mL) was added to a solution of boron trichloride (1.0 M in xylenes; 12.5 mL, 12.5 mmol) in benzene (13 mL) at 0° C. under a nitrogen atmosphere. Once the addition was complete, the resulting mixture was heated at reflux for 3 hours, under a steady stream of nitrogen exiting into an aqueous 5N sodium hydroxide trap, and then recooled to 0° C. A solution of 2,3-ethylenedioxybenzaldehyde (1.86 g, 11.3 mmol), triethylamine (2.29 g, 22.7 mmol, 3.2 mL) and benzene (6 mL) was then added and the resulting mixture stirred 3.5 hours before quenching with aqueous 1N hydrochloric acid. After 1 hour, ethyl acetate was added and the resulting mixture was shaken vigorously. The aqueous layer was alkalized with aqueous 5N sodium hydroxide and the layers separated. The aqueous layer was extracted with ethyl acetate (2×). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography (4:1 hexanes/ethyl acetate) to produce 3.62 g (88%) of the title compound as an off-white foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9](Br)[C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13].[CH:15]1(B(O)O)[CH2:17][CH2:16]1>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>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([CH:15]2[CH2:17][CH2:16]2)[C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13]
Reactant: OB(O)C1CC1
Reactant: COC(=O)Cc1cc(Br)c(C)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(C2CC2)c(C)cc1C
Reaction time: 0.08 h
Yield: 49.1 %

Procedure:
To a solution of 6.0 g of (5-bromo-2,4-dimethyl-phenyl)-acetic acid methyl ester (WO99/48869) in 100 ml of toluene is added 2.2 g of cyclopropylboronic acid and 20 g of potassium phosphate tribasic trihydrate at room temperature. The reaction mixture is stirred for 5 minutes under nitrogen atmosphere, followed by further addition of 1.2 g of tetrakis(triphenylphosphine)palladium(0). After heating and stirring for 16 hours at 110° C., the reaction mixture is filtered, the solvent removed in vacuo and the residue is subjected to silica gel chromatography (isohexane/diethyl ether 2:1) to yield 2.5 g of (5-cyclopropyl-2,4-dimethyl-phenyl)-acetic acid methyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[NH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9]([NH:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: NN1CCOCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)NN2CCOCC2)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (50 mg, 101 μmol) was dissolved in absolute THF (2.5 ml), N-aminomorpholine (29 μl, 303 μmol; 3 eq.) and triethylamine (10.2 mg, 101 μmol; 1 eq.) were added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Kromasil C-18, 5 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (38 mg, 67% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([NH2:36])[CH2:35][CH2:34][CH2:33]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:5]2=[N:6][CH:7]=1.C[Si]([N:41]=[C:42]=[O:43])(C)C>O1CCCC1.O>[Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([NH:36][C:42]([NH2:41])=[O:43])[CH2:33][CH2:34][CH2:35]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(-c4cnc(C5(N)CCC5)s4)c(Cl)cnc32)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(-c4cnc(C5(NC(N)=O)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 70 °C

Procedure:
A mixture of 1-(5-(5-chloro-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanamine (40 mg, 0.074 mmol) (Example 121A) in anhydrous tetrahydrofuran (1 mL) was treated with trimethylsilyl isocyanate (0.049 ml, 0.371 mmol), and the reaction mixture was heated to 70° C. for 5 hours. Additional trimethylsilyl isocyanate (0.025 ml, 0.185 mmol) was added, and the reaction solution was heated for 16 hours at 70° C. The reaction was cooled, diluted with water, and extracted with dichloromethane. The organic extracts were combined and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 5% methanol in dichloromethane, to provide the title compound. MS ESI(+) m/z 582.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([N:39]2[CH2:38][CH2:37][N:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[F:29])[CH2:41][CH2:40]2)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=1
Reactant: Cc1onc(-c2ccccc2F)c1C(=O)O
Reactant: Fc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccccc2F)CC1
Yield: 82.1 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(2-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (578 mg, 1.51 mmol, 82%) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.Cl.[CH3:28][NH:29][CH2:30][C:31]#[N:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:31]([CH2:30][N:29]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1)[CH3:28])#[N:32]
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: CNCC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN(C)CC#N)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 59 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4—(chloromethyl)phenyl]-3—(4-methylphenyl)cinnamamide (200 mg). and to the solution were added methylaminoacetonitrile hydrochloride (77 mg) and potassium carbonate (382 mg). The mixture was stirred at room temperature for 14 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[N-(cyanomethyl)-N-methylaminomethyl]phenyl]-3—(4-methylphenyl)cinnamamide (Compound 64) (129 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=4[O:15][N:14]=3)=[C:9]([CH2:23][CH2:24][CH3:25])[CH:8]=2)=[CH:4][CH:3]=1.C(NCC(C)C)C(C)C.S(Cl)([Cl:40])(=O)=O>C1(C)C=CC=CC=1>[Cl:40][C:18]1[C:17]2[C:13]([C:10]3[CH:11]=[CH:12][C:7]([O:6][C:5]4[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:8][C:9]=3[CH2:23][CH2:24][CH3:25])=[N:14][O:15][C:16]=2[CH:21]=[CH:20][C:19]=1[OH:22]
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2ccc(O)cc12
Reactant: O=S(=O)(Cl)Cl
Agent: CC(C)CNCC(C)C
Solvent: Cc1ccccc1
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2ccc(O)c(Cl)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the phenol product obtained from step 6 of Example 3 (0.38 g, 1.0 mmol) and diisobutylamine (18 μL, 0.10 mmol) in toluene (5 mL) was added dropwise sulfuryl chloride (80 μL, 1.0 mmol) over 10 min. The resulting solution was stirred at 25° C. for 1 h and then quenched with a saturated solution of aqueous sodium bicarbonate. The organic layer was extracted with ethyl acetate and the combined organic layer was washed with 2 N solution of sodium sulfite. After removal of the solvent, the crude product was purified by chromatography on silica gel eluting with 7:3 hexane:ethyl acetate to give the title product as a solid.
Reaction SMILES: [C:1]([CH:3]([NH:13][C:14]([CH:16]1[CH2:18][CH2:17]1)=O)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:39]>C(#N)C>[Cl:39][C:1]1[N:2]=[C:14]([CH:16]2[CH2:18][CH2:17]2)[NH:13][C:3]=1[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CC(COCc1ccccc1)NC(=O)C1CC1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Clc1nc(C2CC2)[nH]c1COCc1ccccc1
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
A solution of N-{1-cyano-2-[(phenylmethyl)oxy]ethyl}cyclopropanecarboxamide (1.84 g, 7.5 mmol), triphenylphosphine (4.8 g, 18.3 mmol), and carbon tetrachloride (1.9 mL, 19.7 mmol) in acetonitrile (74 mL) was heated at 45° C. for 6 h. The reaction was concentrated and the residue was stirred in CH2Cl2 (80 mL) and 0.5 N NaOH (70 mL) for 10 min. The organic layer was isolated, dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash column chromatography (5-50% EtOAc:hexanes) to give the title compound (1.02 g, 52%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 10.90 (br. s., 1H), 7.26-7.36 (m, 5H), 4.50 (s, 2H), 4.47 (s, 2H), 1.74-1.84 (m, 1H), 0.81-0.95 (m, 4H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=1)[C:8]([NH:10][C:11]1[S:12][C:13](Br)=[CH:14][N:15]=1)=[O:9])([CH3:3])[CH3:2].[SH:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29](=[O:30])[CH2:28][S:27][C:13]1[S:12][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:17]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:19]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=2)=[N:15][CH:14]=1
Reactant: CC(C)Oc1cc(Oc2ccccc2)cc(C(=O)Nc2ncc(Br)s2)c1
Reactant: COC(=O)CS
Product: COC(=O)CSc1cnc(NC(=O)c2cc(Oc3ccccc3)cc(OC(C)C)c2)s1
Yield: 25.7 %

Procedure:
[2-(3-Isopropoxy-5-phenoxy-benzoylamino)-thiazol-5-yl-sulfanyl]-acetic acid methyl ester (100 mg) was prepared from 3-isopropyloxy-5-phenoxy-N-(5-bromothiazol-2-yl)-benzamide (370 mg, 0.85 mmol) and methyl mercaptoacetate (0.4 mL, 4.0 mmol) in 26% yield following the general procedure F.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:8]/[CH:9]=[CH:10]/[CH2:11][C@H:12]([NH2:16])[C:13]([OH:15])=[O:14])[C:5]([OH:7])=[O:6].C[Si](Cl)(C)C.[C:22](Cl)([O:24][CH2:25][CH:26]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23]>C[Si](N[Si](C)(C)C)(C)C.ClCCl>[CH:37]1[C:38]2[CH:26]([CH2:25][O:24][C:22]([NH:3][C@@H:4]([CH2:8]/[CH:9]=[CH:10]/[CH2:11][C@H:12]([NH:16][C:22]([O:24][CH2:25][CH:26]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=4[C:33]4[C:38]3=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:23])[C:13]([OH:15])=[O:14])[C:5]([OH:7])=[O:6])=[O:23])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: N[C@@H](C/C=C/C[C@H](N)C(=O)O)C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(N[C@@H](C/C=C/C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(S,S)-2,7-Diamino-E-oct-4-enedioic acid dihydrochloride (1.59 g, 5.8 mmol) was suspended in HMDS (20 ml) and TMSCl and refluxed overnight. The solvents were removed, and the residue was dissolved in anhydrous dichloromethane. This solution was cooled to 0° C. and a solution of FmocCl (3.10 g, 12 mmol) in dichloromethane was added. The solution was stirred for 1 hour at this temperature and overnight at ambient temperature. The solvent was evaporated and the residue dissolved in THF. After addition of 1N aqueous HCl the solution was stirred for two hours, extracted with chloroform and dried (MgSO4). The residue was dissolved in dichloromethane and crystallized by the addition of diethylether.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[C:16]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C:23](=O)[CH2:22][CH2:21]4)[N:17]=2)=[CH:9][CH:8]=1.[NH2:35][OH:36]>C(O)C>[CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[C:16]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C:23](=[N:35][OH:36])[CH2:22][CH2:21]4)[N:17]=2)=[CH:9][CH:8]=1
Reactant: NO
Reactant: CN(C)CCCOc1ccc(-c2nc(-c3ccc4c(c3)CCC4=O)c(-c3ccncc3)[nH]2)cc1
Solvent: CCO
Product: CN(C)CCCOc1ccc(-c2nc(-c3ccc4c(c3)CCC4=NO)c(-c3ccncc3)[nH]2)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of the product of Example 14, Step 6 (0.07 g, 0.155 mmol) in ethanol (3 ml) at 80° C. was added aqueous hydroxylamine (1.5 ml, 50% in water). After 30 minutes the mixture was cooled to room temperature and concentrated in vacuo to give the title compound, (0.072 g, 100%) as a yellow solid; MS(AP+) m/e 468 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[C:17]([CH:20]=1)[CH:18]=O.N1CCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:18]/[C:17]3[CH:20]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=3[O:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: COc1ccc(Oc2ccc(Cl)cc2C=O)cc1
Solvent: C1CCNC1
Solvent: CO
Product: COc1ccc(Oc2ccc(Cl)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: 70 °C
Yield: 75.6 %

Procedure:
To the mixture of 6-chlorooxindole (8.3 g, 49.7 mmol) and 5-chloro-2-(4-methoxy-phenoxy)-benzaldehyde (13 g, 49.7 mmol) in methanol (100 mL) was added pyrrolidine (4.1 mL, 49.5 mmol) dropwise. The mixture was then heated at 70° C. for 3 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give the title compound as a yellow solid (15.5 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:12][CH2:11]2)=[O:9])[N:6]=1.[C:24](O)(=[O:34])[C:25]1[CH:33]=[CH:32][C:31]2[O:30][CH2:29][O:28][C:27]=2[CH:26]=1>>[O:9]=[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:12][CH2:11]1)[CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:24]([C:25]2[CH:33]=[CH:32][C:31]3[O:30][CH2:29][O:28][C:27]=3[CH:26]=2)=[O:34])[S:3][CH:4]=1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1
Product: O=C(Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1)c1ccc2c(c1)OCO2

Procedure:
In analogy to example 37.5, 2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone (example 37.4) was coupled with piperonylic acid, using general method D, to give benzo[1,3]dioxole-5-carboxylic acid (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide. Off-white solid. MS 486.4 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:19][S:20](O)(=[O:22])=[O:21]>>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:20]([Cl:19])(=[O:22])=[O:21])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)(F)c1cnc(-c2ccc(Cl)cc2)c(Cl)c1
Product: O=S(=O)(Cl)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Temperature: 0 °C

Procedure:
40.0 g (0.137 mol) of 3-chloro-2-(4-chlorophenyl)-5-trifluoromethylpyridine (see above for preparation) were added in portions to 75 ml of chlorosulfonic acid while stirring and cooling in ice. After the addition was complete, the mixture was stirred at 130° C. for four hours. The cooled mixture was cautiously poured into ice-water which was then extracted three times with methylene chloride. The combined organic phases were dried over sodium sulfate and concentrated. Yield: 45.0 g (84%) of a dark oil.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8]1[C:9]([Cl:22])=[C:10]([CH:15]=[CH:16][C:17]=1[S:18]([CH3:21])(=[O:20])=[O:19])[C:11]([O:13]C)=[O:12])(=O)C.CO>O>[Cl:22][C:9]1[C:8]([CH2:7][OH:6])=[C:17]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:16]=[CH:15][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(COC(C)=O)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
6 ml of an aqueous solution containing 1.3 g of sodium hydroxide (93%), was added to 3.9 g of methyl 3-acetoxymethyl-2-chloro-4-methanesulfonylbenzoate and 100 ml of methanol. The mixture was stirred for 30 minutes at room temperature. 50 ml of water was added thereto, and methanol was distilled off under reduced pressure. Then, the reaction mixture was acidified with hydrochloric acid and extracted with chloroform. The extract was concentrated to dryness to obtain 1.3 g of the desired product. Melting point: 240°-245° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([NH:11][NH2:12])=O)[CH:5]=[CH:4][N:3]=1.Cl[C:14]1[N:15]=[N:16][C:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[N:15]3[N:16]=[C:17]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH:18]=[CH:19][C:14]3=[N:12][N:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NNC(=O)Cc1ccnc(Cl)c1
Reactant: Clc1ccc(-c2cccnc2)nn1
Product: Clc1cc(Cc2nnc3ccc(-c4cccnc4)nn23)ccn1

Procedure:
The title compound was prepared as described in Example 1 as a pale orange solid from (2-Chloro-pyridin-4-yl)-acetic acid hydrazide (0.61 mmol) and 3-chloro-6-pyridin-3-yl-pyridazine (0.33 mmol). 1H NMR (CDCl3/CD3OD) δ 9.17 (1H, d, J=2.6 Hz), 8.79 (1H, dd, J=4.9 Hz, 1.6 Hz), 8.32 (1H, d, J=4.6 Hz), 8.30 (1H, d, J=9.5 Hz), 8.28 (1H, ddd, J=8.0 Hz, 2.4 Hz, 1.6 Hz), 7.70 (1H, d, J=9.6 Hz), 7.58 (1H, m), 7.47 (1H, s), 7.34 (1H, m), 4.67 (2H, s). ESI-MS (m/z): Calcd for C1-6H11N6Cl: 322.1; found 323.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH:11]([F:13])[F:12])[CH:3]=1>C(O)(=O)C.C(O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH:11]([F:12])[F:13])[CH:3]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(Br)cc(C(F)F)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc(Br)cc(C(F)F)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 107 %

Procedure:
1-Bromo-3-(difluoromethyl)-5-nitrobenzene (944 mg, 3.60 mmol) was treated with iron powder (804 mg, 23.43 mmol) in a mixture of acetic acid (1.35 ml) and ethanol (25 ml) and stirred at 80° C. for 3 h. The crude was filtered over Celite and the solvent was removed in vacuum. A mixture of a solution of sodium bicarbonate 4% and ethyl acetate was added and the resulting mixture was filtered over Celite. The organic phase was washed with water and brine, dried over magnesium sulphate and the solvent was remove to give 855 mg (100% yield) of the title compound as a dark solid, that was used in the next step without further purification. Purity 96%.