Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH2:25]([O:32][C:33]1[C:40]([Br:41])=[CH:39][C:36]([CH:37]=[O:38])=[C:35]([CH3:42])[CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:25]([O:32][C:33]1[C:40]([Br:41])=[CH:39][C:36]([CH:37]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=2)[OH:38])=[C:35]([CH3:42])[CH:34]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cc(OCc2ccccc2)c(Br)cc1C=O
Reactant: COCOCCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOCCc1ccc(C(O)c2cc(Br)c(OCc3ccccc3)cc2C)cc1
Reaction time: 0.25 h

Procedure:
To a tetrahydrofuran solution (1 L) of 1-bromo-4-[2-(methoxymethoxy)ethyl]benzene (50.2 g, 0.205 mol) was added dropwise under nitrogen atmosphere at −78° C. a 2.6 M n-butyllithium solution in hexane (78.8 mL, 0.205 mol), and the mixture was stirred for 15 minutes at the same temperature. Then a tetrahydrofuran solution (150 mL) of 4-benzyloxy-5-bromo-2-methyl benzaldehyde (56.9 g, 0.195 mol) was added dropwise over an hour, and the mixture was stirred for 30 minutes at the same temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure to obtain [4-(benzyloxy)-5-bromo-2-methylphenyl][4-[2-(methoxymethoxy)ethyl]phenyl]methanol.
Reaction SMILES: [I:1]Cl.[CH3:3][C:4]1[CH:5]=[C:6]([N:15]2[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]2[CH3:21])[CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=[O:14])[CH:10]=[CH:9]2.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:3][C:4]1[CH:5]=[C:6]([N:15]2[C:19]([I:1])=[C:18]([CH3:20])[N:17]=[C:16]2[CH3:21])[CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=[O:14])[CH:10]=[CH:9]2
Reactant: Cc1cn(-c2cc(C)c3[nH]c(=O)ccc3c2)c(C)n1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nc(C)n(-c2cc(C)c3[nH]c(=O)ccc3c2)c1I
Reaction time: 16 h

Procedure:
Iodine monochloride (0.406 g) was added at room temperature to a stirred solution of 8-methyl-6-(2,4-dimethylimidazol-1-yl)-2-(1H)-quinolone (0.506 g) and sodium acetate (0.328 g) in acetic acid (10 cm3). After 16 hours, volatile material was removed in vacuo and the residue partitioned between aqueous 2M sodium carbonate solution (50 cm3) and dichloromethane (50 cm3). The aqueous phase was further extracted with dichloromethane (2×50 cm3) and the combined and dried (MgSO4) organic extracts were filtered and evaporated in vacuo. The residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate. Combination and evaporation of the appropriate fractions afforded a solid which was recrystallised from ethyl acetatemethanol to give the title compound, m.p. 242°-245° (0.38 g).
Reaction SMILES: [CH3:1][S-:2].[Na+].[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:55]OS(C)(=O)=O)[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)C=1C(OCC)=O)([CH3:7])[CH3:6].[C:61]([O:64][CH2:65][CH3:66])(=[O:63])[CH3:62].O>CN(C)C=O>[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:55][S:2][CH3:1])[N:11]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:62]=1[C:61]([O:64][CH2:65][CH3:66])=[O:63])([CH3:7])[CH3:6]
Reactant: CCOC(=O)c1c(C(C)(C)O)nc(COS(C)(=O)=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: C[S-]
Reactant: CCOC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C(C)(C)O)nc(CSC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
50.3 mg of sodium methanethiolate were added to a solution of 610 mg of ethyl 4-(1-hydroxy-1-methylethyl)-2-methanesulfonyloxymethyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (c) above] in 6 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 45 minutes, after which it was mixed with ethyl acetate and water. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure, after which the residue was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and ethyl acetate as the eluent, to give 338 mg of the title compound as crystals, melting at 174.5°-176.5° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:14][C:11]([C:12]#[N:13])=[C:10]([O:23][CH2:24][CH2:25][N:26]2C(=O)C3C(=CC=CC=3)C2=O)[N:9]=1.O.NN>>[NH2:26][CH2:25][CH2:24][O:23][C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:15]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCCN

Procedure:
Using the procedure described in Example 26, the product of Example 134 was reacted with hydrazine hydrate to afford the title compound. MS (electrospray) m/e 384.1 MH+ (Rt=2.8 min LC/MS).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:25][CH:26]=1>CCCCCC.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:25]3[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=3)[NH2:20])[N:3]=2)[CH2:15][CH2:16]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1cccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)c1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 3-aminophenylboronic acid pinacol ester with reaction time of 15 h. Column chromatography (hexane/ethyl acetate 1:1) gave the title compound as an colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25](Br)[CH:26]=[CH2:27].O>C1COCC1.C(OCC)(=O)C>[CH2:27]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:6][CH:7]=1)[CH:26]=[CH2:25]
Reactant: CCOC(=O)c1c(-c2ccc(O)cc2)noc1C
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=CCOc1ccc(-c2noc(C)c2C(=O)OCC)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 119.6 %

Procedure:
The mixture of ethyl 3-(4-hydroxyphenyl)-5-methylisoxazole-4-carboxylate (Preparation C) (0.474 g, 1.92 mmol), Cs2CO3 (0.937 g, 2.88 mmol) and allyl bromide (0.27 mL, 3.12 mmol) in 10 mL of THF was sealed in a 150-mL pressure vessel and stirred at 90° C. overnight. The reaction mixture was cooled to room temperature. Water (150 mL) and ethyl acetate (150 mL) were added to the reaction mixture. Layers were separated and the aqueous layer was extracted with ethyl acetate (150 mL). The combined organic extract was dried over anhydrous sodium sulfate. Solvent was evaporated in vacuo to give 0.66 g of crude product, which was used in the next step without purification. LCMS (method B) RT 3.34 min., MH+288. 1H NMR (500 MHz, CDCl3) δ 7.58 (d, J=8.5Hz, 2H), 6.96 (d, J=8.5Hz, 2H), 6.12-6.00 (m, 1H), 5.46-5.26 (m, 2H), 4.58 (d, J=5.2Hz, 2H), 4.25 (q, J=7.2Hz, 2H), 2.71 (s, 3H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: C1(C[N:5]([C:15]2[C:16]([S:34][CH3:35])=[N:17][N:18]3[C:23]([C:24]4[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:22][CH:21]=[CH:20][C:19]=23)[CH2:6][C:7]2[C:8]([O:13]C)=[N:9][CH:10]=[CH:11][CH:12]=2)CC1.Cl.C(O[CH2:41][CH3:42])(=O)C.C(=O)([O-])O.[Na+].[C:48](OCC)(=O)[CH3:49]>C(O)C>[CH:41]1([CH2:42][CH:6]([NH:5][C:15]2[C:16]([S:34][CH3:35])=[N:17][N:18]3[C:23]([C:24]4[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:22][CH:21]=[CH:20][C:19]=23)[C:7]2[C:8]([OH:13])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:49][CH2:48]1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(N(Cc3cccnc3OC)CC3CC3)c(SC)nn12
Reactant: CCOC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C)cc(C)c1-c1cccc2c(NC(CC3CC3)c3cccnc3O)c(SC)nn12

Procedure:
After dissolving N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-((2-methoxy-3-pyridyl)methyl]amine (63 mg) in ethanol (1 mL), a 4 N hydrochloric acid/ethyl acetate solution (1 mL) was added at room temperature and the mixture was heated to reflux for 3 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture for neutralization while cooling on ice, and extraction was performed with ethyl acetate. The obtained organic layer was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (49 mg) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][C:13](I)=[N:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.[CH3:32][NH:33][CH2:34][CH2:35][OH:36]>CC(C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][C:13]([N:33]([CH2:34][CH2:35][OH:36])[CH3:32])=[N:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cnc(I)s1
Reactant: CNCCO
Solvent: CC(C)=O
Product: CN(CCO)c1ncc(-c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)s1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
130 mg (0.219 mmol) of 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-(2-iodo-1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile were initially charged in 2.5 ml of acetone, 0.885 ml (10.963 mmol) of 2-(methylamino)ethanol was added and the mixture was stirred at 80° C. overnight. The reaction mixture was concentrated and the product was isolated by preparative HPLC. This gave 74 mg (63% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:17]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)N3CCCCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(C(=O)N2CCCCC2)c1
Yield: 58.4 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(piperidine-1-carbonyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (68 mg, 0.24 mmol) in methanol (6 mL) and 1N sodium hydroxide aqueous solution (2.5 mL, 2.5 mmol) was heated to reflux for 1 h. LC-MS showed the reaction was complete. The solvent was removed in vacuo to give white solid, which was dissolved in water and acidified with 1N hydrochloric acid solution to pH=2. The precipitated white solid was collected by filtration and back-dissolved in aqueous sodium hydroxide solution, then was acidified with 1 M hydrochloric acid solution again to pH=7. The white precipitated solid was collected by filtration and dried in vacuo to afford 55 mg of 3,3-dimethyl-2-(3-(piperidine-1-carbonyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 83.8%. LC-MS (M+1)=393.2.
Reaction SMILES: [CH:1](=[C:5]1[S:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][S:15][C:16]2[N:21]3[CH:22]=[CH:23][N:24]=[C:20]3[CH:19]=[CH:18][CH:17]=2)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].[Br:26]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)(Cl)Cl>[CH:1](=[C:5]1[S:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][S:15][C:16]2[N:21]3[C:22]([Br:26])=[CH:23][N:24]=[C:20]3[CH:19]=[CH:18][CH:17]=2)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC=C1SC(=O)N(CCCCSc2cccc3ncc(Br)n23)C1=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1.13 g (3.0 mmol) of 5-butylidene-3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione in 15 ml of carbon tetrachloride, 0.59 g (3.3 mmol) of N-bromosuccinimide was added at room temperature, followed by stirring at 80° C. for 90 minutes. After the reaction mixture was cooled, saturated aqueous sodium hydrogen carbonate was added. The organic layer was separated and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=2/1→1/4) to yield 1.11 g (81.4%, yellow oily substance) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:35][CH2:36][CH2:37][O:38][CH3:39])=[C:24]([NH:27][C:28]([C@@H:30]4[CH2:34][CH2:33][CH2:32][NH:31]4)=[O:29])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:40](O)(=[O:43])[CH:41]=[CH2:42].N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:35][CH2:36][CH2:37][O:38][CH3:39])=[C:24]([NH:27][C:28]([C@@H:30]4[CH2:34][CH2:33][CH2:32][N:31]4[C:40](=[O:43])[CH:41]=[CH2:42])=[O:29])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COCCOc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)[C@@H]1CCCN1
Reactant: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CC(=O)N1CCC[C@H]1C(=O)Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cc1OCCOC
Temperature: 0 °C
Yield: 9 %

Procedure:
302 mg of (2S)-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-(2-methoxyethoxy)-quinazolin-6-yl}-amide as a starting material was dissolved in 10 ml of THF, and cooled to 0° C. The solution was reacted with 0.15 ml of acrylic acid, 0.18 ml of pyridine and 0.53 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at 0° C. for 30 mins and at room temperature for 2 hours. The reacted solution was extracted with a mixture of chloroform and isopropanol after adding water, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate:methanol=30:1) to obtain the title compound (31 mg, 9%).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C1(C)C=CC=CC=1.[CH3:26][N:27]([CH3:37])[C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>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.C(O)C>[C:1]([C:3]1[CH:17]=[C:16]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([N:27]([CH3:37])[CH3:26])[CH:33]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: CN(C)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)c1cccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)c1
Yield: 37.8 %

Procedure:
5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), 3-dimethylaminophenylboronic acid (82 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) were combined and the mixture was stirred at reflux overnight. The solvent was removed under reduced pressure and crude product was purified on a 2 g silica Isolute® SPE column, eluting with dichloromethane/methanol (95:5). The eluent was concentrated under reduced pressure and the crude product was suspended in acetonitrile then treated with diethyl ether to precipitate the product Recrystallisation from diethyl ether afforded the title compound (64 mg, 38%) m/z, 339.0 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH:9]=O)[CH2:7][S:8][C@H:3]12.[C:16]1([CH:22]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[NH2:1][CH:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH:9]=[CH:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:7][S:8][C@H:3]12
Reactant: C(c1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC1C(=O)N2C(C(=O)O)=C(C=O)CS[C@H]12
Solvent: C1CCOC1
Product: NC1C(=O)N2C(C(=O)O)=C(C=Cc3ccccc3)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of 0.3 g of 7-amino-3-formyl-3-cephem-4-carboxylic acid in 3 ml of THF is treated at room temperature with 1.4 ml of BSA. The reaction mixture is stirred at room temperature for 10 minutes . A clear solution is obtained containing N,O-bistrimethylsilyle 7-amino-3-formyl-3-cephem-4-carboxylic acid. The solution is cooled to 0° and treated with a solution of 0.53 g of phenylmethylene triphenylphosphorane in 4 ml of THF. After 24 hours stirring at 0° the reaction mixture is worked up as described in example 23). A mixture of the isomers (6 parts Z-isomer and 11 parts E-isomer) is obtained.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)([CH3:40])[CH3:39]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:44]3[CH2:45][CH2:46][N:41]([CH:38]([CH3:40])[CH3:39])[CH2:42][CH2:43]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(C)C)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-isopropyl-piperazine (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C36H46Cl2N5O2 [(M+H)+] 650.3023, observed 650.3022.
Reaction SMILES: [Na+].[Cl-].C(O)[C@H:4]1[O:9][C@H:8]([O:10][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:7](O)[C@@H:6](O)[C@@H:5]1O.[OH-].[Na+].C[N+:29]([O-])([CH3:31])C.C1N(CCO)CC[N:35](CCS(O)(=O)=O)C1>>[NH2:35][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:31][NH2:29]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: C[N+](C)(C)[O-]
Reactant: O=S(=O)(O)CCN1CCN(CCO)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: NCCCC[C@H](N)C(=O)O

Procedure:
A solution of a mature rVWF (35 U VWF:Ag/ml) in 20 mM HEPES buffer, 150 mM NaCl, pH 7.4, containing 0.5% sucrose was prepared according to Example 23. Then branched mPEG succinimidyl glutarate (PE-SG/chain length: 20 kD) supplied by NOF corporation (NOF Europe, Grobbendonk, Belgium) was added to this solution under gentle stirring (5 mg PEG-SG/mg protein) and the pH value was adjusted to 7.4 by drop wise addition of 0.5 M NaOH. Then the PEGylation was carried out under gentle stirring for 1 h at room temperature. Subsequently the reaction mixture was applied onto an equilibrated ion-exchange chromatography resin (Fractogel EMD TMAE 650M) in 20 mM HEPES buffer, 150 mM NaCl, pH 7.4, containing 0.5% sucrose. Then the column was washed with 20 CV equilibration buffer to remove excess reagent and the PEGylated rVWF was eluted with elution buffer (20 mM HEPES, 0.5 M NaCl, 0.5% sucrose, pH 7.4). The eluate was concentrated by ultrafiltration/diafiltration with a membrane consisting of regenerated cellulose and with a molecular weight cut-off of 100 kD using a buffer system consisting of 20 mM HEPES, 150 mM NaCl, 0.5% sucrose, pH 7.4. The PEGylated derivative obtained showed a slightly diminished VWF:RCoNWF:Aa ratio of 0.79 as compared with the rVWF starting material (VWF:RcoNWF:Ag ratio: 0.89). In addition, the PEGylated rVWF starting material had a FVIII binding capacity of 83% as measured by the ECA test (Example 16).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH2:9][C:10](=O)[C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:16].CN([CH:22]=[O:23])C>>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][C:9]([CH:22]=[O:23])=[C:10]([Cl:16])[C:4]=2[CH:3]=1
Reactant: O=C1CCCOc2ccc(Br)cc21
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Product: O=CC1=C(Cl)c2cc(Br)ccc2OCC1
Temperature: 25 °C

Procedure:
To a stirred solution of 7-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (9.84 g; 41 mmol) in DMF (50 ml) at 0° C. was added POCl3 (10 ml; 107 mmol) dropwise over 10 min. The reaction mixture was stirred whilst allowing to warm to room temperature overnight (16 h) upon which time it was quenched by pouring into well-stirred ice/water (500 ml). The resulting solid was extracted into EtOAc (2 400 ml), the combined organics were dried (MgSO4) and concentrated to give a yellow solid (7-bromo-5-chloro-2,3-dihydro-benzo[b]oxepine-4-carbaldehyde). This solid was dissolved in DMF (50 ml) and treated successively with K2CO3 (7 g; 51 mmol) then ethyl mercaptoacetate (5.5 ml; 50 mmol). The reaction mixture was heated at 70° C. for 4 h upon which time it was cooled and poured into well-stirred ice/water (500 ml). The resulting solid was collected by filtration and dried to give 9-Bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-2-carboxylic acid ethyl ester as an off-white solid (13.69 g; 95%). δH (400 MHz, d6-DMSO) 1.31 (t, J=7.2, 3H), 3.23 (t, J=5.2, 2H), 4.27-4.35 (m, 4H), 7.03 (d, J=8.8, 1H), 7.42 (dd, J=8.8 and 2.4, 1H), 7.70 (s, 1H), 7.80 (d, J=2.4, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14]([CH3:22])=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[C:14]([CH3:22])=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(N)cccc1C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Product: Cc1c(NS(=O)(=O)c2ccc(Br)cc2)cccc1C(=O)O

Procedure:
The title compound was prepared using a method analogous to Method A, using 4-bromobenzene sulfonyl chloride, 3-amino-2-methylbenzoic acid, and a large excess of pyridine. The title compound was precipitated on partition of the reaction mixture between dilute HCl and DCM. The precipitate was collected by filtration, dissolved in ethyl acetate and dried. Evaporation of the solvent gave the title compound as a pale brown solid.