Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][C:10]1([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=O)C1C=CC=CC=1.O.[OH-].[K+].C(O)(=O)C>CO>[CH2:20]([N:12]1[C:13]2[C:18](=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:10]([OH:9])([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)[C:11]1=[O:22])[CH3:21]
Reactant: CCN1C(=O)C(Cc2cc(OC)c(OC)c(OC)c2)(OC(=O)c2ccccc2)c2cc(C)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCN1C(=O)C(O)(Cc2cc(OC)c(OC)c(OC)c2)c2cc(C)ccc21
Temperature: 130 °C
Yield: 85 %

Procedure:
Alternative route: To an oven dried Biotage microwave vial cooled under argon was added 1-ethyl-5-methyl-2-oxo-3-(3,4,5-trimethoxybenzyl)indolin-3-yl benzoate (0.053 grams, 0.11 mmol). This was taken up in 0.6 mL of methanol, 0.6 mL of deionized water. A solution of KOH (223 μl, 2.0M in water) was added and the sealed vial was placed in the microwave and heated to 130° C. for 12 minutes, and 18 minutes at 140° C. Upon cooling the solution was neutralized with a stoichiometric amount of glacial acetic acid (Fisher scientific), and concentrated. Purification on a Teledyne ISCO using a C18 reverse phase column (water with 0.1% formic acid/acetonitrile gradient) afforded the desired compound. 85% yield. 1H NMR 7.22 (s, 1H), 7.08 (d, 1H), 6.55 (d, 1H), 6.06 (s, 2H), 4.38 (bs, OH), 3.72 (s, 3H), 3.66 (m, 1H), 3.61 (s, 6H), 3.34 (m, 1H), 3.23 (d, 1H), 3.17 (d, 1H), 2.35 (s, 3H), 0.87 (t, 3H). Calculated mass for C21H25NO5, 371.43. Observed 394.1 (M+Na)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH2:28][CH3:29])([CH3:27])[CH3:26])=[CH:21][C:20]=1[C:30]([CH2:33][CH3:34])([CH3:32])[CH3:31])=[O:13].[N+:35]([O-])([OH:37])=[O:36].CO>C(O)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:35]([O-:37])=[O:36])=[CH:4][C:3]=1[C:12]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH2:28][CH3:29])([CH3:26])[CH3:27])=[CH:21][C:20]=1[C:30]([CH2:33][CH3:34])([CH3:32])[CH3:31])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CCC(C)(C)c1ccc(OCCCNC(=O)c2ccc3ccccc3c2O)c(C(C)(C)CC)c1
Solvent: CO
Solvent: CC(=O)O
Product: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc([N+](=O)[O-])c3ccccc3c2O)c(C(C)(C)CC)c1

Procedure:
100 g of 1-hydroxy-N-[γ-(2,4-di-tert-amylphenoxy)propyl]-2-naphthamide was dissolved in 1 liter of acetic acid and nitrated at 15°-18° C. using 23 g of a 60% nitric acid aqueous solution. After the completion of the reaction, 1 liter of methanol was added thereto and precipitated crystals were separated by filtration. After recrystallization from a 2:1 by volume solvent mixture composed of ethyl acetate and methanol, 70 g of the titled compound was obtained. The melting point was 209°-210° C.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16](=[O:19])[CH2:17][CH3:18].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>O1CCCC1.O>[CH3:12][O:13][C:14](=[O:20])[CH:15]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=1)[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: CCC(=O)CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: CCC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)OC
Temperature: 70 °C

Procedure:
A suspension of potassium tert-butoxide (2.7 g) in anhydrous tetrahydrofuran (35 mL) at 0° C. was treated with a mixture of tert-butanol (0.1 mL) and 3-oxopentanoic acid methyl ester (3.2 g). After stirring at room temperature for 15 minutes a solution of 1-chloromethyl-4-methanesulfonylbenzene (5.0 g) in tetrahydrofuran (15 mL) was added and the resulting mixture heated at 70° C. for 16 hours. The mixture was cooled to room temperature, diluted with water and the tetrahydrofuran removed under reduced pressure. The residue was partitioned between ethyl acetate and dilute aqueous ammonium chloride solution. The aqueous phase was extracted with ethyl acetate and the combined organic phases dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of toluene, dichloromethane and ethyl acetate (1:1:0 to 0:1:0 to 0:4:1 by volume) to afford title compound as a waxy white solid, 3.0 g.
Reaction SMILES: SC1C(=O)C=CC=CC=1.SC1C2C=CC=CC=2C=CC(=O)C=1.[NH2:23][C:24]1[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:29]=2[CH:28]=[CH:27][C:26](=[O:35])[CH:25]=1.[CH2:36]([O:38][C:39](=[O:55])[C:40](SC1C2C=CC=CC=2C=CC(=O)C=1)=[O:41])[CH3:37]>>[CH2:36]([O:38][C:39](=[O:55])[C:40]([NH:23][C:24]1[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:29]=2[CH:28]=[CH:27][C:26](=[O:35])[CH:25]=1)=[O:41])[CH3:37]
Reactant: CCOC(=O)C(=O)Sc1cc(=O)ccc2ccccc12
Reactant: Nc1cc(=O)ccc2ccncc12
Agent: O=c1ccc2ccccc2c(S)c1
Agent: O=c1cccccc1S
Product: CCOC(=O)C(=O)Nc1cc(=O)ccc2ccncc12

Procedure:
By following serially the procedures of Examples 1 and 2 but replacing 2-mercapto-2,4,6-cycloheptatrien-1-one with an equivalent amount of 5-mercapto-7H-benzocyclohepten-7-one, 9-amino-7H-cyclohepta[c]pyridin-7-one, 5-mercapto-3H-6,7-dihydrocyclobutacyclohepten-3-one, 1-ethylamino-3H-6,7,8,9,10,11-hexahydrocycloheptacycloocten-3-one and 5-mercapto-3H-6,7,8,9,10,11,12,13-octahydrocycloheptacycodecen-3-one, the following compounds are obtained respectively: [(7-oxo-7H-benzocyclohepten-5-yl)thio]oxoacetic acid ethyl ester (I: R1, R5, and R6 = H; R2 = S-CO-COOC2H5 ; and R3 and R4 together form a --CH=CH--CH=CH-- chain), [(7-oxo-7H-cyclohepta[c]pyridin-9-yl)-amino]oxo-acetic acid ethyl ester (I: R1, R5 and R6 = H; R2 = NC2H5 -CO-COOC2H5 ; and R3 and R4 together form a --CH=CH--N=CH-- chain). [(3-oxo-3H-6,7-dihydrocyclobutacyclohepten-5-yl)thio]oxo-acetic acid ethyl ester (I; R1, R5 and R6 = H; R2 = S-CO-COOC2H5 ; and R3 and R4 together form a -CH2CH2 - chain), [N-(3-oxo-3H-6,7,8,9,10,11-hexahydrocycloheptacycloocten-1-yl)ethylamino]-oxo-acetic acid ethyl ester (I; R1, R2 and R6 = H; R3 and R4 together form a -(CH2)6 chain; and R5 = NC2H5 -CO-COOC2H5) and [(3-oxo-3H-6,7,8,9,10,11,12,13-octahydrocycloheptacyclodecen-5-yl)thio]oxoacetic acid ethyl ester (I; R1, R5 and R6 = H; R2 = S-CO-COOC2H5 ; and R3 and R4 together form a --(CH2)8 -- chain).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:12][CH2:13][O:14][C:15]2[N:16]([CH3:27])[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[CH:19]=2)[CH3:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].Cl>ClCCl.C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:12][CH2:13][O:14][C:15]2[N:16]([CH3:27])[N:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([O:26][C:34](=[O:36])[CH3:35])=[CH:24][CH:25]=3)[CH:19]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(CCOc1cc(-c2ccc(O)cc2)nn1C)CCc1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2cc(OCCN(C)CCc3ccc(Cl)cc3)n(C)n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
100 mg of 3-{2-[N-(2-(4-chlorophenyl)-ethyl)-N-methylamino]-ethyloxy}-5-(4-hydroxyphenyl)-2-methylpyrazole (preparation see Example 9) were dissolved in 2 ml of dichloromethane. 0.15 ml of pyridine and 1 ml of acetic anhydride were added to the solution and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was subsequently evaporated under reduced pressure, and the residue was taken up in aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was separated, dried and concentrated. The crude title compound which remained as a residue was taken up in tert-butyl methyl ether. To form a salt, a 2N solution of hydrochloric acid in isopropanol was added. The precipitated salt was separated. 80 mg of the hydrochloride of the title compound were obtained having a melting point of from 160° to 175° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[C:11]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]([CH3:17])=[CH:13][C:14]=2[CH3:16])[NH:9][CH2:8]1)=[O:4].I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH2:26]([N:9]1[C:10]2[C:15](=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=2[NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[CH:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:8]1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCI
Reactant: COC(=O)CCC1CNc2c(NC(=O)C(C)(C)C)c(C)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCN1CC(CCC(=O)OC)c2c(C)cc(C)c(NC(=O)C(C)(C)C)c21
Temperature: 40 °C
Reaction time: 10 h
Yield: 82.2 %

Procedure:
N-[3-(2-Methoxycarbonylethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide (1.0 g) was dissolved in DMF (10 ml) and 1-iodooctane (1.44 g) and K2CO3 (830 mg) were added, which was followed by stirring at 40° C. for 10 hr. AcOEt (100 ml) was added, and after washing with water, the mixture was dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene/AcOEt=20/1-5/1) to give 1.1 g of the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH:16]([C:20]5[O:21][CH:22]=[CH:23][CH:24]=5)[CH2:15]4)[CH:12]=3)[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:30]=O>C(O)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH3:30])[CH:16]([C:20]5[O:21][CH:22]=[CH:23][CH:24]=5)[CH2:15]4)[CH:12]=3)[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C=O
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(c4ccco4)C3)c(F)cc2c1=O
Solvent: O=CO
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1c1ccco1

Procedure:
A mixture of 200 mg of 1-cyclopropyl-6-fluoro-7-[3-(2-furanyl)-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.3 ml of 90% formic acid and 0.24 ml of 37% formalin was heated for 2 hours, then evaporated. The residue was diluted with water, neutralized to pH 7 with 1N sodium hydroxide, the solid collected and washed with water, methanol and ether and dried in vacuo, giving 145 mg of the desired product, mp 122°-124° C.
Reaction SMILES: C1C=CC=CC=1.[F:7][C:8]1[C:9](=[O:42])[NH:10][C:11](=[O:41])[N:12]([CH:40]=1)[C@@H:13]1[O:39][C@H:17]([CH2:18][O:19]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:15]([OH:16])[CH2:14]1.[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[OH-].[K+]>O1CCOCC1>[CH2:43]([O:16][C@@H:15]1[C@@H:17]([CH2:18][OH:19])[O:39][C@@H:13]([N:12]2[CH:40]=[C:8]([F:7])[C:9](=[O:42])[NH:10][C:11]2=[O:41])[CH2:14]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Reaction time: 2 h
Yield: 20 %

Procedure:
To a mixture of 50 ml of benzene and 50 ml of dioxane were added 1.00 g of 2'-deoxy-5-fluoro-5'-O-trityluridine, 0.30 ml of benzyl bromide and 0.23 g of potassium hydroxide powder, and the mixture was refluxed for 25 hours. The insolubles were removed by filtration and the filtrate was concentrated and the concentrate was dissolved in 5 ml of 80% acetic acid. The solution was left to stand at 80° C. for 2 hours. The solvent was distilled off and the residue was placed on a silica gel column to conduct a gradient elution using chloroform and mixtures of methanol (up to 2%) and chloroform. The fractions corresponding to 3'-O-benzyl-2'-deoxy-5-fluorouridine were collected and concentrated. The concentrate was recrystallized from ethanol, giving 0.14 g of the title compound in a yield of 20%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:28])[CH2:14][C:15]2[O:16][C:17]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])=[N:18][N:19]=2)(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1.[CH3:30][C:31]1[CH:36]=[C:35]([CH:37]=O)[CH:34]=[CH:33][N:32]=1.ClCCCl>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:28])[CH2:14][C:15]2[O:16][C:17]([C:20]([N:22]3[CH2:23][CH2:24][N:25]([CH2:37][C:35]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:30])[CH:36]=4)[CH2:26][CH2:27]3)=[O:21])=[N:18][N:19]=2)(=[O:11])=[O:12])=[C:5]([CH3:29])[CH:4]=1
Reactant: Cc1cc(C=O)ccn1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCNCC3)o2)c(C)c1
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(Cc4ccnc(C)c4)CC3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure CD using 4-methoxy-N,2,6-trimethyl-N-{[5-(piperazin-1-ylcarbonyl)-1,3,4-oxadiazol-2-yl]methyl}benzenesulfonamide (42 mg, 0.10 mmol), 2-methylpyridine-4-carbaldehyde (15 mg, 0.12 mmol), STAB (42 mg, 0.2 mmol) DCE (0.8 mL) and a few 4 Å molecular sieves. The crude product was purified using prep method D.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20]4[N:21]([N:32]=[CH:33][C:34]=4[C:35](O)=[O:36])[C:22]=3[NH:23][C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[F:31])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20]4[N:21]([N:32]=[CH:33][C:34]=4[C:35]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:36])[C:22]=3[NH:23][C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[F:31])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccc(F)c(F)c4)CC3)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccc(F)c(F)c4)CC3)cnc12
Yield: 59 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-[4-(3,4-difluorophenyl)piperidine-1-carbonyl]-7-(2-fluoro-5-methylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (57 mg, 0.11 mmol) obtained in step 4 and ethanesulfonamide (58 mg, 0.55 mmol), the title compound (39 mg, 59%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C([N:19]1[CH:23]=[CH:22]N=C1)(N1C=CN=C1)=O.[C:24]12(CCN)[CH2:33][CH:28]3[CH2:29]C([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:23][C:22]12[CH2:32][CH:26]3[CH2:27][CH:28]([CH2:33][CH:24]([CH2:25]3)[CH2:31]1)[CH2:29]2)=[O:6]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1ccc(O)cc1Cl
Solvent: CN(C)C=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1ccc(O)cc1Cl
Reaction time: 2.5 h

Procedure:
To a solution of 2-chloro-4-hydroxybenzoic acid (3.30 g) in dimethylformamide (20 ml) was added 1,1′-carbonyldiimidazole (3.30 g). The reaction mixture was stirred for 2.5 h and then 1-adamantanethylamine (3.4 ml) was added. After 14 h the reaction mixture was partitioned between ethyl acetate and 2N aqueous hydrochloric acid and the organic layer was separated, washed with water then brine and dried (MgSO4). The organic layer was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (eluting with 10-70% ethyl acetate in dichloromethane) to yield a white solid which was triturated with ethyl acetate to yield the subtitle compound as a white solid (3.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[C:10]([C:15]#[N:16])[C:11]([NH:13][CH3:14])=[O:12].[Cl-:17].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[ClH:17].[NH2:16][C:15]1[C:4]2[C:3](=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)[N:8]=[N:9][C:10]=1[C:11]([NH:13][CH3:14])=[O:12]
Reactant: [Cl-]
Reactant: CNC(=O)C(C#N)=NNc1ccccc1Br
Agent: Cl
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: CNC(=O)c1nnc2c(Br)cccc2c1N
Temperature: 25 °C
Yield: 89.3 %

Procedure:
A 250 mL round-bottomed flask was charged with 2-[(2-bromophenyl)-hydrazono]-N-methyl-2-cyanoacetamide (2.00 g, 7.12 mmol), aluminum chloride (3.46 g, 25.97 mmol), and anhydrous toluene (68 mL). The reaction was gently refluxed for 45 minutes, cooled to room temperature, and slowly treated with 2N HCl (68 mL). A precipitate formed. The mixture was heated to 90° C. for 10minutes, cooled to room temperature, and filtered. The solids were dried under high vacuum at 50° C. to afford the title compound (2.02 g, 90%). 1H NMR (300.132 MHz, DMSO) δ 9.08 (d, J=4.7 Hz, 1H), 8.56 (dd, J=8.4, 0.8 Hz, 1H), 8.28 (dd, J=7.6, 0.7 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 2.89 (d, J=4.7 Hz, 3H). MS APCI, m/z=281/283 (M+H). HPLC 1.61 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1>C1COCC1.CN(C=O)C>[CH3:28][O:27][CH2:26][CH2:25][O:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([CH:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]3=[O:10])=[N:15][CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: COCCOc1ccc2c(Cl)ncnc2c1
Reactant: O=C1Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOc1ccc2c(C3C(=O)Nc4ccccc43)ncnc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.5 %

Procedure:
A solution of oxindole (319 mg, 2.4 mmol) in THF (3 ml) was added dropwise under nitrogen to sodium hydride (58 mg, 2.4 mmol, pre-washed with hexane) and the mixture stirred for 20 minutes at ambient temperature. A solution of 4-chloro-7-(2-methoxyethoxy)quinazoline (191 mg, 0.8 mmol) in DMF (3 ml) was added and the mixture then heated at 70° C. for 1 hour. The mixture was allowed to cool and the solvent removed by evaporation. The mixture was partitioned between water and ether. The aqueous phase was separated and adjusted to pH7 with 2M hydrochloric acid. The resulting solid was collected by filtration and washed with water and ethanol. This solid was then suspended in ether, recollected by filtration, washed with ether and dried under vacuum to give 7(2-methoxyethoxy)-4-(oxindol-3-yl)quinazoline (200 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[C:28]([C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1)#[N:29].N1C=CC=CC=1>O1CCCC1>[C:28]([C:30]1[CH:31]=[C:32]([S:36]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]3[NH:13][C:12](=[O:14])[C:11]4=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[N:10]4[N:9]=3)[CH:7]=2)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1)#[N:29]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CCCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCOc1ccc(NS(=O)(=O)c2cccc(C#N)c2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
200 mg (0.566 mmol) of the compound from example 44A are reaccted with 342 mg (1.70 mmol) of 3-cyanobenzenesulfonyl chloride and 0.46 ml (5.66 mmol) of pyridine in 15 ml of tetrahydrofuran overnight.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C(OC(=O)C[C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=1)C.C1C[O:40][CH2:39]C1>C(OCC)(=O)C>[CH2:29]([O:28][C:16]1[CH:15]=[C:14]([C:39](=[O:40])[CH2:2][C:1]#[N:3])[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC#N
Reactant: CCOC(=O)Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Product: N#CCC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (0.83 mL) in 25 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then treated in dropwise fashion with 6.32 mL of a 2.5 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 1 h and subsequently treated in dropwise fashion with a solution of 5 gms. of (3,5-bis-benzyloxy-phenyl)-acetic acid ethyl ester in 25 mL of anhydrous THF. The resulting solution is then stirred overnight at room temperature. Subsequently, the reaction mixture is diluted with ethyl acetate and then extracted with 10% NaOH(aq). The aqueous layer is acidified (pH 6-7) with a 1 M HCl(aq) solution affording a white precipitate. The precipitate is filtered and washed with water. The filtrate was then extracted ethyl acetate. The organic layer is concentrated in vacuo. The organic extraction yielded very little of the 3-(3,5-bis-benzyloxy-phenyl)-3-oxo-propionitrile, however, the precipitate isolated from the acidification of the original aqueous layer is indeed the desired 3-(3,5-bis-benzyloxy-phenyl)-3-oxo-propionitrile. Upon drying the precipitate in vacuo the desired 3-(3,5-bis-benzyloxy-phenyl)-3-oxo-propionitrile is isolated as a brownish white solid in the amount of 3.43 gms. (67% yield).
Reaction SMILES: C([O:4][CH2:5][C:6]([CH3:19])([CH3:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[C:16]#[N:17])(=O)C.O=[C:21]([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[NH2:17][C:16]1[C:10]2[C:11](=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]([CH3:18])([CH3:19])[CH2:5][OH:4])[N:15]=[C:21]([CH3:28])[C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=O)OCC(C)(C)COc1cccc(N)c1C#N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)CO)c2c1N

Procedure:
Prepared as in Example 2a from 3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropyl acetate (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as a pale yellow solid (26%). MS 333 (MH+).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH:25]([NH2:27])[CH3:26])=[N:23][CH:24]=3)[C:11]=2[F:28])[CH:7]=[CH:8][CH:9]=1.O.[O-:30][C:31]#[N:32].[Na+].Cl>C(OCC)C.C(O)(=O)C>[ClH:3].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH:25]([NH:27][C:31]([NH2:32])=[O:30])[CH3:26])=[N:23][CH:24]=3)[C:11]=2[F:28])[CH:7]=[CH:8][CH:9]=1
Reactant: N#C[O-]
Reactant: COc1ccc(Cc2ccc(C(C)N)nc2)c(F)c1-c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Cc2ccc(C(C)NC(N)=O)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
In an 8 mL vial equipped with a stir bar was placed 1-[5-(3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-ethylamine dihydrochloride (P-606, 55 mg, 0.124 mmol), water (800 uL), glacial acetic acid (400 uL) followed by sodium cyanate (32.2 mg, 0.496 mmol). The mixture was stirred at room temperature for 18 hours and then slowly quenched with a saturated solution of sodium bicarbonate (3 mL) and extracted with dichloromethane (3×4 mL). The organic portions were combined, dried (MgSO4), concentrated and purified by a 10 gram silica gel SNAP cartridge (Biotage SP4 Flash Chromatography instrument) utilizing gradient elution of 2-20% MeOH/dichloromethane to produce 13 mg of P-613 (free base) as an off-white solid in 25% yield. To P-613 (free base) (13 mg, 0.0314 mmol) was added diethyl ether (1 mL) and 2M HCl in diethyl ether (300 uL). The mixture was allowed to stir at room temperature for 10 minutes, concentrated and dried to produce 14 mg of P-613HCl salt as an off-white solid in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ 1.36 (d, J=7 Hz, 3H), 3.73 (s, 3H), 4.06 (s, 2H), 4.82 (m, 1H), 5.53 (br s, 2H), 6.69 (br s, 1H), 6.97 (d, J=9 Hz, 1H), 7.29 (br d, J=6 Hz, 1H), 7.38-7.47 (m, 4H), 7.60 (br d, J=8 Hz, 1H), 8.02 (br d, J=8 Hz, 1H), 8.58 (s, 1H) ppm.