Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].[C:2]([O-:5])(=O)[CH3:3]>>[O:1]=[CH:3][C@@H:2]([C@H:3]([C@@H:2]([C@@H:3]([CH2:2][OH:5])[OH:1])[OH:5])[OH:1])[OH:5]
Reactant: CC(=O)[O-]
Reactant: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.08 h

Procedure:
The end 15 of the electrode is placed into a solution of water soluble DCC (25 mg/ml) in acetate buffer, pH 4.5 for 1 hour. It is then rinsed, in buffer only, for 5 minutes and thereafter placed in a solution of glucose oxidase (10 mg/ml) in acetate buffer, ph 5.5, for 11/2 hours before again rinsing in buffer. The tip of the electrode 15, with the layers of dimethyl ferrocene and immobilised enzyme is then dipped into a solution of cellulose acetate dissolved in acetone and formamide and put into ice water for several minutes, to give a protected and stable electrode.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([N:10]1[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=[C:2]1[Br:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1
Reaction time: 12 h
Yield: 89 %

Procedure:
To a stirring suspension of 8-bromo-3-methylxanthine (prepared as described for CT12440) (12.25 g, 50.0 mmol) and potassium carbonate (6.91 g, 50.0 mmol) in dimethylformamide (400 ml) was added benzyl bromide (9.20 g, 54.0 mmol). After stirring for 12 hours, the mixture was poured into cold water (680 ml). The precipitate was filtered, washed with water (3x 50 ml), ether (3x 50 ml) and dried under vacuum to provide 7-benzyl-8-bromo-3-methylxanthine (14.92 g, 89% yield) as a white powder.
Reaction SMILES: [OH:1][C:2]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.[O:19]([CH2:26][C:27](O)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][S:15]([C:12]1[CH:13]=[CH:14][C:9]([C:7]2[C:2]3([CH2:6][CH2:5][CH2:4][CH2:3]3)[O:1][C:27](=[O:28])[C:26]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)c1ccc(C(=O)C2(O)CCCC2)cc1
Reactant: O=C(O)COc1ccccc1
Product: CS(=O)(=O)c1ccc(C2=C(Oc3ccccc3)C(=O)OC23CCCC3)cc1

Procedure:
Using a procedure similar to the one used in example 1 but using (1-hydroxycyclopentyl)-(4-(methylsulfonyl)phenyl)methanone from example 21, Step 3 and phenoxyacetic acid the title compound was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:10]2[CH2:13][C:12](=[C:14]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11]2)=[CH:5][CH:4]=1.[CH3:34][C:35]1([CH3:41])[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]1>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C@@H:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:37]3[CH2:38][CH2:39][CH2:40][C:35]([CH3:41])([CH3:34])[CH2:36]3)=[CH:4][CH:5]=2)[N:10]2[CH2:13][C:12](=[C:14]([C:19]3[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11]2)=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CCl)cc2)C1)c1cc(F)cc(F)c1
Reactant: CC1(C)CCCNC1
Solvent: ClCCl
Product: CC1(C)CCCN(Cc2ccc([C@H](c3ccc(Cl)cc3)N3CC(=C(c4cc(F)cc(F)c4)S(C)(=O)=O)C3)cc2)C1
Yield: 69.5 %

Procedure:
The operation is carried out as described in Example 87, starting. with 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm3 of dichloromethane and 0.025 g of 3,3-dimethylpiperidine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm3 of dichloromethane and then eluting with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm3 fractions immediately after using this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.040 g of 1-{(R*)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 0.94 (s, 6H), 1.21 (mt, 2H), from 1.50 to 1.65 (mt, 2H), 1.99 (broad s, 2H), 2.27 (unresolved complex, 2H), 2.81 (s, 3H), 3.36 (s, 2H), 3.85 (mt, 2H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[C:9]2[C:10]([Cl:27])=[CH:11][C:12]([O:14][CH2:15][C:16]3[C:17]([CH3:26])=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=3)=[CH:13][C:8]=2[S:7][C:6]=1[CH3:28].C1COCC1.[OH-].[Na+].Cl>CO>[Cl:27][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:29])=[O:2])=[C:6]([CH3:28])[S:7][C:8]=2[CH:13]=[C:12]([O:14][CH2:15][C:16]2[C:17]([CH3:26])=[N:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:11]=1
Reactant: COC(=O)Cc1c(C)sc2cc(OCc3ccc(C(F)(F)F)nc3C)cc(Cl)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)ccc1COc1cc(Cl)c2c(CC(=O)O)c(C)sc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a mixture of methyl(4-chloro-2-methyl-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetate (132.1 mg), THF (dry) (1.5 mL) and MeOH (1.5 mL) was added 1N NaOH (0.893 mL) at room temperature. The mixture was stirred at 50° C. for 2 h. The mixture was neutralized with 1N HCl. The resulting precipitate was collected by filtration to give a colorless solid. The solid was crystallized from acetone-hexane to give the title compound (87 mg).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl.FC(F)(F)C([NH:48][C@H:49]1[CH2:53][CH2:52][NH:51][CH2:50]1)=O>CS(C)=O.COC(C)(C)C>[NH2:48][C@H:49]1[CH2:53][CH2:52][N:51]([C:21]2[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]3[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=3)([CH3:34])[CH3:33])=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])[CH:22]=2)[CH2:50]1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(N[C@H]1CCNC1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: Cc1cc(F)ccc1-c1cc(N2CC[C@H](N)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 130 °C
Reaction time: 52 h
Yield: 60 %

Procedure:
A mixture of 975 mg (1.83 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 1.26 g (9.15 mmol) potassium carbonate and 800 mg (3.66 mmol) (S)-3-(trifluoro-acetamido)pyrrolidine hydrochloride in 10 ml dimethyl sulfoxide was stirred at 130° C. for 52 h. After cooling to room temperature the reaction mixture was diluted with 30 ml tert-butyl methyl ether and washed with 20 ml of water and 10 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was dissolved in 25 ml of a 2 N solution of ammonia in ethanol. The solution was stirred at room temperature for 18 h. The reaction mixture was concentrated and purified by flash chromatography to give 640 mg (60%) of the title compound as a light brown foam.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([OH:17])[C:10]([OH:18])=[C:9]1[C:19]([O:21][CH3:22])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:22][O:21][C:19]([C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]2[O:17][CH2:24][CH2:25][O:18][C:10]=12)=[O:20]
Reactant: COC(=O)c1c(O)c(O)c(C(=O)OC)n1Cc1ccccc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c2c(c(C(=O)OC)n1Cc1ccccc1)OCCO2
Temperature: 107.5 °C
Reaction time: 12 h
Yield: 55 %

Procedure:
A mixture of dimethyl N-benzyl-3,4-dihydroxypyrrole-2,5-dicarboxylate (0.1 mol), 1,2-dibromoethane (0.1 mol), and potassium carbonate (0.5 mol) in dry DMF was stirred for 12 h under argon at 105-110° C. After cooling to 25° C., the reaction mixture was poured onto ice-water. The crude product was collected by suction filtration and purified by recrystallization in methanol yielding 6-benzyl-2,3-dihydro-6H-[1,4]dioxino[2,3-c]pyrrole-5,7-dicarboxylic acid dimethyl ester as colourless crystals in 55-65% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][C:10]1[C:18]2[N:17]=[CH:16][NH:15][C:14]=2[CH:13]=[C:12]([C:19]([O:21][CH3:22])=[O:20])[CH:11]=1)(=[O:8])=[O:7].CCN(CC)CC>CCO>[O:7]=[S:6]1(=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][N:9]1[C:10]1[C:18]2[N:17]=[CH:16][NH:15][C:14]=2[CH:13]=[C:12]([C:19]([O:21][CH3:22])=[O:20])[CH:11]=1
Reactant: COC(=O)c1cc(NS(=O)(=O)CCCCCl)c2nc[nH]c2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1cc(N2CCCCS2(=O)=O)c2nc[nH]c2c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 25 %

Procedure:
To a solution of methyl 4-{[(4-chlorobutyl)sulfonyl]amino}-1H-benzimidazole-6-carboxylate (D252) (1 g, 3.23 mmol, 1 equiv) in EtOH (50 ml) was added NEt3 (2 ml, excess) and the resulting solution was stirred at 70° C. for 2 days. then cooled to room temperature and concentrated in vacuo. The residue was dissolved in AcOEt and the organic phase was washed with a 5% aqueous citric acid solution. The aqueous phase was saturated with NaCl and extracted twice with AcOEt. The combined organic phases were dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (CH2Cl2/MeOH: 96/4 to 90/10) gave methyl 4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-1H-benzimidazole-6-carboxylate (D253) (250 mg, 25%) as a pale yellow solid. [M+H]+=310.3, RT=2.11 min.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].[C:16](O)([CH3:19])([CH3:18])[CH3:17]>C(O)(C(F)(F)F)=O.O>[C:16]([C:13]1[CH:14]=[C:9]([C:1]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:2])[CH3:3])[CH:10]=[CH:11][C:12]=1[OH:15])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Reactant: CC(C)(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Yield: 54 %

Procedure:
4-t-octylphenol (160 g, 0.78 mole) was dissolved in 400 ml anhydrous TFA. T-butyl alcohol (94.3 g, 1.27 mole) was added with stirring. The mixture was stoppered and stirred for 24 hours at ambient (~22° C.) temperature. This solution was diluted with 600 ml water, and the resulting upper organic layer was isolated in a separatory funnel. The crude product, 2-t-butyl-4-t-octylphenol, was dried over anhydrous magnesium sulfate and purified by eluting 35 g of the mixture with 70:30 hexanes:dichloromethane (v/v) in a 5×20 cm silica column, then eluted with 300 to 700 ml of solvent and collected in aliquots of 50 ml. Aliquots showing a single spot by TLC on silica eluted with 70:30 hexanes:dichloromethane (v/v) were combined and rotoevaporated to a thick syrup for a yield of 54%.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12](I)[S:13][C:6]=12.Br[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][N:24]=1.[Sn].CO>O1CCOCC1.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>[F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:23]3[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][N:24]=3)[S:13][C:6]=12
Reactant: O=Cc1ccc(Br)nc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Sn]
Solvent: C1COCCO1
Solvent: CO
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Yield: 52.1 %

Procedure:
A solution of 408 (1 g, 2.40 mmol) and 6-bromonicotinaldehyde (450 mg, 2.40 mmol) in dioxane (10 mL) was treated sequentially with bistirmethyl tin (500 μL, 787 mg, 2.40 mmol) and Pd(PPh3)4 (270 mg, 0.24 mmol). The reaction mixture was heated to reflux under nitrogen overnight and concentrated. The residue was purified by flash chromatography using the gradient 5%-10% MeOH in DCM as an eluent and subsequent trituration with MeOH, yielding pure 438 (494 mg, 52% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.11 (s, 1H), 9.10 (m, 1H), 8.65 (d, 1H, J=5.2 Hz), 8.62 (s, 1H), 8.51 (d, 1H, J=8.8 Hz), 8.48 (dd, 1H, J=2.8 Hz, J=10.4 Hz), 8.38 (dd, 1H, J=2.1 Hz, J=8.2 Hz), 8.20 (m, 1H), 7.73 (t, 1H, J=9.0 Hz), 7.01 (d, 1H, J=5.5 Hz). LCMS: (M+H) 395.9.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8].[ClH:25]>CO.O1CCOCC1>[NH2:1][C@H:2]([C:10]([NH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8].[ClH:25]
Reactant: COC(=O)CNC(=O)[C@H](CSCNC(C)=O)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CNC(=O)[C@@H](N)CSCNC(C)=O
Reaction time: 0.17 h

Procedure:
5 g of Boc-Cys(Acm)-Gly-OMe are dissolved in 20 ml of methanol and 50 ml of 4.4 N HCl in dioxane are added. After 10 minutes at 25°C, the mixture is concentrated to half its volume and 100 ml of ether are added. The mother liquor is separated from the resulting amorphous precipitate and the latter is dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([C@H:18]2[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]2[F:24])[CH3:17])=[O:15])[C@:11]([CH2:31][OH:32])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=1.C(O)(=O)C.[CH3:37][C:38]([CH3:40])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([C@H:18]2[CH2:23][CH2:22][N:21]([CH:38]([CH3:40])[CH3:37])[CH2:20][C@H:19]2[F:24])[CH3:17])=[O:15])[C@:11]([CH2:31][OH:32])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=1
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=C[C@@]1(CO)c1ccccc1)[C@H]1CCNC[C@H]1F
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)N1CC[C@H](N(C)C(=O)N2CC(c3cc(F)ccc3F)=C[C@@]2(CO)c2ccccc2)[C@H](F)C1
Reaction time: 8 h

Procedure:
To a solution of 38 mg (0.085 mmol) of 10-2 in 1 mL of 1,2-dichloroethane was added 20 μL (0.34 mmol) of acetic acid, 25 μL (0.34 mmol) of acetone, and 27 mg (0.13 mmol) of Na(OAc)3BH. After stirring overnight, the reaction was partitioned between EtOAc and saturated aqueous NaHCO3, the organic phase was washed again with NaHCO3, H2O, brine, dried over Na2SO4, and concentrated by rotary evaporation. The residue was purified by reverse phase chromatography with 95:5 to 5:95 H2O/CH3CN (both with 0.1% TFA). The fractions were basified with NaHCO3 to provide 11-1 as a colorless film. Data for 11-1: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.3 (m, 1H), 4.95-4.8 (m, 2H), 4.6 (m, 1H), 4.45 (m, 1H), 4.1-4.0 (m, 2H), 3.2 (m, 1H), 3.15 (s, 3H), 3.0 (m, 1H), 2.8 (m, 1H), 2.45-2.25 (m, 3H), 1.75 (m, 1H), 1.1-1.0 (m, 6H) ppm. HRMS (ES) calc'd M+H for C27H32F3N3O2: 488.2519. Found: 488.2517.
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH2:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:14]([CH:16]=O)=O.[OH-].[NH4+]>O.C(O)(=O)C>[N+:11]([C:8]1[C:9]2[N:10]=[CH:16][CH:14]=[N:1][C:2]=2[C:3]([C:4]#[N:5])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: N#Cc1ccc([N+](=O)[O-])c(N)c1N
Reactant: O=CC=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc([N+](=O)[O-])c2nccnc12
Temperature: 0 °C
Yield: 70 %

Procedure:
2,3-Diamino-4-nitro-benzonitrile (0.050 g, 0.28 mmol, as prepared in WO98/32439) was added to solution of glyoxal (40% in water, 0.032 m]L, 0.28 mmol) in acetic acid (0.75 mL) and stirred at 22° C. for 3 h. The reaction was cooled to 0° C. and water (2.0 mL) was added and the pH was adjusted to 9.0 by addition of ammonium hydroxide which caused the product to precipitate. The mixture was then filtered and rinsed with cold water. Drying in vacuo gave 0.039 g (70%) of compound 468A as an orange solid. HPLC: 100% at 2.037 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10–90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:20][C:19]3[CH2:18][NH:17][CH2:16][C:15]=3[CH2:14]2)=[N:10][CH:9]=1)=[O:7].FC(F)(F)C([O-])=O.[Br:29][C:30]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:31]=1[C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:14][C:15]3[CH2:16][N:17]([C:32](=[O:33])[C:31]4[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:30]=4[Br:29])[CH2:18][C:19]=3[CH2:20]2)=[N:10][CH:9]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1cnc(N2CC3=C(CNC3)C2)s1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Product: COc1ccc(Br)c(C(=O)N2CC3=C(C2)CN(c2ncc(C(=O)NCCC(C)C)s2)C3)c1

Procedure:
N-(3-Methylbutyl)-2-(3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)thiazole-5-carboxamide, trifluoroacetate (43.8 mg, 0.1 mmol) was reacted with 2-bromo-5-methoxybenzoic acid after activation with HATU analogously to example 3f. M+H+: 519.15.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([OH:27])=O.Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[N:34]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:27])[NH:42][C:39]2([C:35]3[N:34]=[N:33][CH:38]=[CH:37][CH:36]=3)[CH2:41][CH2:40]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Reactant: NC1(c2cccnn2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cccnn5)CC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.095 mmol, 1 eq), 1-(pyridazin-3-yl)cyclopropanamine HCl salt (0.017, 0.095 mmol, 1 eq) and Py-Bop (0.064 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.029 g, 0.28 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.029 g (57%). 1H NMR (400 MHz, CD3OD): δ 9.14 (d, J=3.6 Hz, 1H), 7.97-7.85 (m, 6H), 7.56 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.34-7.28 (m, 3H), 2.96 (s, 3H), 2.30 (s, 3H), 1.89-1.86 (m, 2H), 1.62-1.59 (m, 2H). 19F NMR (376.57 MHz, CD3OD): δ −77.63 (TFA), −112.22, −112.77 LCMS: (ES+) m/z=539.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:8]([OH:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[OH:4].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:23](O)=[O:24]>>[F:1][C:2]1[C:3]([OH:4])=[C:5]([CH:6]=[C:7]([F:10])[C:8]=1[OH:9])[CH:23]=[O:24]
Reactant: O=C(O)C(F)(F)F
Reactant: Oc1ccc(F)c(O)c1F
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1cc(F)c(O)c(F)c1O
Yield: 59 %

Procedure:
A solution of 2,4-difluororesorcinol (0.50 g, 3.4 mmol) and hexamethylenetetraamine (0.96 g, 6.8 mmol) in 4 mL trifluoroacetic acid is heated to reflux for 24 hours. After cooling, the reaction is quenched by the addition of 2 mL 20% H2SO4, and then stirred for an additional hour. The reaction mixture is then poured into 50 mL water and extracted with EtOAc (50 mL×2), washed with brine (30 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The residue is purified by sublimation to yield 0.35 g (59%) of Compound 13 as a colorless powder. Mp. 141°-143° C. 1H-NMR (DMSO-d6) δ 9.7 (s, 1H), 7.21 (dd, J=9.8; 6.5 Hz, 1H). 19 F-NMR(DMSO-d6) Φ 143.78 (t, J=9.8 Hz, 1F), 158.31 (d, J=6.5 Hz, 1F). Anal. calcd for C7H4F3O3 : C, 48.29; H, 2.32. Found: C, 47.87, H, 2.62.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[C:4]([F:12])[CH:3]=1.[Cl:13][C:14]1[C:15]([F:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[C:15]=3[F:22])/[C:7](=[O:11])[NH:8]2)=[C:4]([F:12])[CH:3]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: O=C1Cc2c(F)cc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)cc(F)c2/C1=C/c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 74.8 %

Procedure:
To the mixture of 6-chloro-4-fluoroindolin-2-one (Natrochem, 85% purity) (1.1 g, 5.0 mmol) and 3-chloro-2-fluorobenzaldehyde (2.4 g, 15 mmol) (Oakwood) in methanol (50 mL) was added piperidine (1.7 g, 20 mmol) (Aldrich) dropwise. The mixture was then heated at 50° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, washed with cold methanol, dried to give the first batch of desired product (1.22 g). The filtrate was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (20-35% EtOAc in hexanes) to give the second batch of desired product (0.32 g). The two batches were combined to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-4-fluoro-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.54 g, 94%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:21][CH:22]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Product: Oc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 150 °C

Procedure:
A mixture of 0.384 g (1.5 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.491 g (4.5 mmol) 4-aminophenol is heated under nitrogen atmosphere for 2 h at 150° C. After processing as described in Example 18, drying under HV (8 h at 100° C. and 24 h at 145° C.), title compound is obtained with a water content of 0.68%; m.p. 239-241° C.; 1H NMR (DMSO-d6) 9.19 (s, 1H), 8.99 (brs, 1H), 8.56 (d, 1H), 8.44 (d, 2H), 8.06 (d, 1H), 7.86-7.96 (m, 2H), 7.61 (d, 2H), 7.30 (d, 2H), 6.77 (d, 2H), 4.53 (s, 2H); ESI-MS: (M+H)+=329.