Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:4]1[C:3]([C:1]#[N:2])=[C:8]([CH3:9])[CH:7]=[C:6]([CH3:10])[N:5]=1
Reactant: Cc1cc(C)c(C#N)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(C)c(C#N)c(Cl)n1

Procedure:
2-Chloro-3-cyano-4,6-dimethylpyridine was prepared from 3-cyano-4,6-dimethylpyrid-2-one and phosphorus oxychloride following the procedure of Kametani and Sato (Yakugaka Kenyu 34, 117, 1962).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+].O>C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)Cc1cccc(Oc2cccc(Cl)c2Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: Nc1c(CC(=O)O)cccc1Oc1cccc(Cl)c1Cl
Yield: 78.1 %

Procedure:
A mixture of ethyl 2-[2-amino-3-(2,3-dichlorophenoxy)phenyl]acetate (3.7 g.), sodium hydroxide (880 mg.) and water (50 ml.) was treated in a similar manner to that of Example 5-(2). The resultant residue was pulverized with benzene, and the precipitates were collected by filtration and dried to give 2-[2-amino-3-(2,3-dichlorophenoxy)phenyl]acetic acid (2.65 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:14]([CH3:13])(=[O:16])=[O:15])[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a solution of 3-Amino-5-bromobenzotrifluoride (200 mg) in pyridine (2 mL) was added methane sulphonyl chloride (115 mg) and one crystal of 4-(dimethyl-amino)pyridine. The mixture was stirred at room temperature for four hours then diluted with ethyl acetate (50 mL) and washed with HCl (2M, 50 mL) and saturated sodium chloride solution (50 mL). Organics were separated, dried over sodium sulphate, filtered, and solvent was removed under reduced pressure to yield N-(3-bromo-5-trifluoromethyl-phenyl)-methanesulfonamide (264 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([O:13][CH2:14][C@@H:15]([N:22]([CH3:35])[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[Cl:34])=[O:24])[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[O:12].[Li+].[OH-].Cl.C(OCC)(=O)C>O1CCOCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([O:13][CH2:14][C@@H:15]([N:22]([CH3:35])[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[Cl:34])=[O:24])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:12]
Reactant: COC(=O)CC[C@@H](COC(=O)Nc1nc2ccccc2s1)N(C)C(=O)NCc1cccc(F)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)O)COC(=O)Nc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.4 %

Procedure:
To a solution of (S)-methyl 5-(benzo[d]thiazol-2-ylcarbamoyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoate (2.3 g, 4.4 mmol) in 1,4-dioxane (15 mL) was added LiOH (2 N, 4.4 mL, 2 equiv.). The reaction mixture was stirred at RT for 2 h. The mixture was acidified to pH ˜3 with HCl (1 N, ˜10 mL), and ethyl acetate (50 mL) was added. The organic layer was extracted with EtOAc (3×20 mL), dried over Na2SO4 and concentrated. A small sample (30 mg) was purified by RP-HPLC (20-100% ACN in H2O) to give (S)-5-(benzo[d]thiazol-2-ylcarbamoyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoic acid as a white solid (8 mg). The remainder was used without further purification. LRMS (M−H+)=507.4.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10]C(C)=O>>[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])[CH3:10]
Reactant: CC(C)=O
Reactant: O=C(O)c1ccccc1
Product: CC(=O)c1ccccc1

Procedure:
A method according to claim 1 wherein the ketone is acetone and the carboxylic acid is benzoic acid to yield acetophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:4]([CH2:17][OH:18])[CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:9])=[C:4]([CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH:3]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1COS(C)(=O)=O
Reaction time: 3 h

Procedure:
A solution of the product of part (d) (1 g) and triethylamine (0.51 ml) in dichloromethane (10 ml) was cooled to 0° C. Methanesulfonyl chloride (0.29 ml) was then added dropwise and the reaction was allowed to reach room temperature. After stirring for 3 hours the reaction was diluted with dichloromethane, washed with water, NaHCO3 (aq), brine, dried (MgSO4) and concentrated in vacuo to give the subtitle compound as an oil (1.13 g).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([S:9][CH2:10][C:11]1[N:12]([CH2:38][CH2:39][CH3:40])[C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:37])(=[O:36])[NH:30][CH2:31][CH2:32][O:33][CH2:34][CH3:35])=[CH:25][CH:24]=3)[N:17]=2)=[CH:14][N:15]=1)[CH3:8]>O.CO>[CH2:7]([S:9]([CH2:10][C:11]1[N:12]([CH2:38][CH2:39][CH3:40])[C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([S:29](=[O:37])(=[O:36])[NH:30][CH2:31][CH2:32][O:33][CH2:34][CH3:35])=[CH:27][CH:28]=3)[N:17]=2)=[CH:14][N:15]=1)=[O:2])[CH3:8]
Reactant: CCCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOCC)cc3)n2)cnc1CSCC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOCC)cc3)n2)cnc1CS(=O)CC
Reaction time: 18 h
Yield: 50.8 %

Procedure:
A solution of sodium periodate (43 mg, 0.2 mmol) in water (0.5 ml) was added to a stirred solution of 4-[2-(ethylthiomethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine (Example 82; 70 mg, 0.14 mmol) in MeOH (2 ml) and the solution was stirred for 18 hours. The MeOH was removed by evaporation and the aqueous residue was extracted with EtOAc. The extracts were combined, washed with brine, dried and the volatiles removed by evaporation. The residue was purified by chromatography on silica gel eluting with DCM/MeOH (95:5 increasing in polarity to 90:10) and the purified product triturated with ether to give the title compound (37 mg, 51%). NMR: 0.68 (t, 3H), 1.05 (t, 3H), 1.22 (t, 3H), 1.52 (m, 2H), 2.85 (m, 4H), 3.33 (m, 4H), 4.31 (d of d, 2H), 4.63 (m, 2H), 7.23 (d, 1H), 7.46 (t, 1H), 7.70 (d, 2H), 7.78 (s, 1H), 7.86 (d, 2H), 8.48 (d, 1H), 9.90 (s, 1H); m/z 521.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH:12]([CH3:26])[CH2:13][C:14]1[C:22]2[C:17](=[C:18]([O:23][CH2:24][CH3:25])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1>>[CH2:24]([O:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:13][CH:12]([NH:11][CH2:10][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:9])[CH3:26])[CH3:25]
Reactant: CCOc1cccc2c(CC(C)N)c[nH]c12
Reactant: Clc1cccc(C2CO2)c1
Product: CCOc1cccc2c(CC(C)NCC(O)c3cccc(Cl)c3)c[nH]c12
Yield: 52.3 %

Procedure:
(3-Chlorophenyl)oxirane (0.92 g) and 3-(2-aminopropyl)-7-ethoxyindole (2.18 g) are treated in the same manner as in Example 1, Process (a) to give the desired compound (1.16 g) as an oily product.
Reaction SMILES: [C:1]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:27]([CH2:28][CH2:29][C@:7]12[CH3:8])[C@:20]1([CH2:21][O:22]C(=O)CC)[C:15](=[CH:16][CH2:17][CH2:18][C@@H:19]1[CH3:30])[CH2:14][CH2:13]3)(=[O:4])[CH2:2][CH3:3].C(=O)(O)[O-].[Na+]>CO>[C:1]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:27]([CH2:28][CH2:29][C@:7]12[CH3:8])[C@:20]1([CH2:21][OH:22])[C:15](=[CH:16][CH2:17][CH2:18][C@@H:19]1[CH3:30])[CH2:14][CH2:13]3)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)OC[C@@]12C(=CCC[C@@H]1C)CC[C@H]1[C@@H]3CC[C@H](OC(=O)CC)[C@@]3(C)CC[C@@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CCC[C@H](C)[C@]4(CO)[C@H]3CC[C@]12C

Procedure:
To a solution of 1α-methyl-4-androstene-17β,19-diol dipropionate in 10% aqueous methanol is added 1 equivalent sodium bicarbonate and the solution is heated under reflux for one hour. Methanol is removed under vacuum to half volume and the concentrate is poured onto water. The solid is filtered, air dried and crystallized from hexane to give 1α-methyl-4-androstene-17β,19-diol 17-propionate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:16])([CH:13]([F:15])[F:14])[CH2:11]I.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:9][C:10]([F:16])([CH:13]([F:15])[F:14])[CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)C(F)(F)CI
Reactant: Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(OCC(F)(F)C(F)F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a solution of 3-hydroxytoluene (5.0 g, 46.2 mmol) in N,N-dimethylformamide (50 ml) were added 2,2,3,3-tetrafluoro-1-iodopropane (12.3 g, 50.9 mmol) and potassium carbonate (12.8 g, 92.5 mmol) and the mixture was stirred overnight at 80° C. The reaction solution was diluted with water (200 ml) and extracted with diethyl ether (300 ml×2). The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 3-(2,2,3,3-tetrafluoropropyloxy)toluene (10.0 g, 97%) as a colorless oil.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([OH:34])(=O)=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:17]>CN(C=O)C>[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([Cl:4])(=[O:34])=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(Nc1ccc(-c2ccc(S(=O)(=O)O)cc2)cc1)c1cc2ccccc2o1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
To 75 ml of DMF cooled to −20° C., oxalyl chloride (6.7 ml, 76 mmol) was carefully added dropwise. A white suspension was formed and the fumes generated were removed by blowing N2 through the flask. A solution of 4′-[(benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonic acid (15 g, 38 mmol) in 100 ml DMF was added slowly and the temperature was maintained <0° C. After the addition was complete, the reaction mixture was warmed to room temperature and was stirred at room temperature for 3 h. The reaction mixture was poured into 4L ice/water, and the suspension was filtered. The solid was collected and dried under vacuum to provide 7.3 g of 4′-[(benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonyl chloride, obtained as off-white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[OH-].[K+].S(O[CH:20]([CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:21])(C1C=CC(C)=CC=1)(=O)=O.O>O1CCOCC1>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH:20]([CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:21]
Reactant: OCCCCO
Reactant: Cc1ccc(S(=O)(=O)OC(C)COCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(COCc1ccccc1)OCCCCO
Temperature: 102 °C
Reaction time: 4 h
Yield: 58.3 %

Procedure:
HO(CH2)4OH (37 g), potassium hydroxide (23 g) and dioxane (200 ml) were charged into a four necked flask and heated to an internal temperature of 102° C. to dissolve potassium hydroxide. A solution of TsOCH(CH3)CH2OCH2Ph (63.7 g) obtained in Example 2-1 in dioxane (65 ml), was dropwise added over a period of 1 hour and stirred for 4 hours. The mixture was left to cool, then added to water (350 ml) and extracted three times with dichloromethane (100 ml). The organic layer was washed with water (20 ml). It was dried over magnesium sulfate, filtered and then concentrated by an evaporator to obtain a crude product (52 g). It was purified by silica gel column chromatography to obtain the above-identified compound (27.6 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](F)[N:3]=1.[NH2:13][C@H:14]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:15][OH:16]>C1COCC1>[F:8][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([NH:13][C@@H:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:15][OH:16])=[N:3][C:2]=1[F:1]
Reactant: N[C@@H](CO)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc(F)c(F)nc1F
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c(F)nc1N[C@H](CO)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
A solution of 2,3,6-trifluoro-5-nitropyridine (1.2 g, 6.7 mmol) in THF (40 ml) was cooled to 0° C. (R)-2-amino-2-(4-fluorophenyl)ethanol (1.0 g, 6.7 mmol) was then added and the reaction was stirred at 0° C. for 30 minutes. The reaction was quenched with water (50 ml) and then extracted with DCM (2×75 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (1.2 g, 57%). The product was carried over to the next step without characterization.
Reaction SMILES: [BrH:1].C1(O[CH2:9][C:10]2[CH:17]=[C:16]([C@:18]3([O:36][C@H:35]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]3[O:21][C:22](=[O:24])[CH3:23])[OH:19])[CH:15]=[CH:14][C:11]=2[C:12]#[N:13])C=CC=CC=1.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Br:1][CH2:9][C:10]1[CH:17]=[C:16]([C@:18]2([O:36][C@H:35]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]2[O:21][C:22](=[O:24])[CH3:23])[OH:19])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(C#N)c(COc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC[C@H]1O[C@](O)(c2ccc(C#N)c(CBr)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 55 °C
Reaction time: 6 h

Procedure:
A 33% solution of hydrobromic acid in acetic acid (15 mL) is added to a solution of 2-phenyloxymethyl-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzonitrile (0.71 g) and acetic anhydride (0.12 mL) in acetic acid (10 ml). The resulting solution is stirred at 55° C. for 6 h and then cooled in an ice-bath. The reaction mixture is neutralized with chilled aqueous potassium carbonate solution, and the resultant mixture is extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate/cyclohexane (1:5), and the precipitate is separated by filtration and dried at 50° C. to give the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[OH:25].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=1[F:17]
Reactant: O=S(=O)(c1ccc(F)c(Br)c1)N1CCCC1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=S(=O)(c1ccc(Oc2ccc(F)cc2F)c(Br)c1)N1CCCC1
Yield: 82 %

Procedure:
A mixture of Example 299a (250 mg, 0.811 mmol), 2,4-difluorophenol (106 mg, 0.811 mmol) and cesium carbonate (317 mg, 0.973 mmol) in 5 mL dimethylsulfoxide was heated at 110° C. for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water (2×), saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to give the title compound (278 mg, 82% yield), which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:21]([NH2:31])[C:22]1[CH:30]=[CH:29][C:28]2[O:27][CH2:26][O:25][C:24]=2[CH:23]=1>C(#N)C.C(N(CC)C(C)C)(C)C>[O:27]1[C:28]2[CH:29]=[CH:30][C:22]([CH2:21][NH:31][C:2]3[C:3]4[CH2:11][N:10]([C:12]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=5[C:14]#[N:15])[CH2:9][CH2:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:23][C:24]=2[O:25][CH2:26]1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NCc4ccc5c(c4)OCO5)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (100 mg, 0.35 mmol) and piperonylamine (120 mg, 0.79 mmol) in acetonitrile (1 mL) and N,N-diisopropylethylamine (400 μL) was subjected to microwave irradiation at 185° C. for 3 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to afford a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[N:23]1([CH2:28][CH2:29]O)[CH:27]=[CH:26][N:25]=[CH:24]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:29][CH2:28][N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: OCCn1ccnc1
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCn1ccnc1

Procedure:
Compound IIc was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and 2-(1H-imidazol-1-yl)ethanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:31][CH:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH3:33])[C:27](O)=[O:28])=[CH:22][CH:21]=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C.[CH:80]([C:83]1[CH:89]=[CH:88][C:86]([NH2:87])=[CH:85][CH:84]=1)([CH3:82])[CH3:81]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:17])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:31][CH:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH3:33])[C:27](=[O:28])[NH:87][C:86]2[CH:88]=[CH:89][C:83]([CH:80]([CH3:82])[CH3:81])=[CH:84][CH:85]=2)=[CH:22][CH:21]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(CN(C(=O)OC(C)(C)C)C(C(=O)O)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1)N1CCOCC1
Reactant: CC(C)c1ccc(N)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)c1ccc(NC(=O)C(c2ccc(/C=C/C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)N(CC(C)N2CCOCC2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-{4-[2-(2-tert-Butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-[tert-butoxycarbonyl-(2-morpholin-4-yl-propyl)-amino]-acetic acid (306 mg, 0.480 mmol) and bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (447 mg, 0.960 mmol) in anhydrous dichloromethane (5 mL) was added diisopropylethylamine (0.167 mL, 0.960 mmol) followed by 4-isopropylaniline (0.131 mL, 0.960 mmol). After stirring at room temperature overnight, the reaction was diluted to 15 mL with dichloromethane, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford crude product. This material was used without further purification. MS: calc'd 756 (MH+), exp 756 (MH+).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[OH:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[C:1][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: C#CC(O)CCCCC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, rac-1-octyn-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdC[2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield rac-(Z)-1,3-dihydro-4-(3-hydroxy-1-octynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 88 mg, 60%).
Reaction SMILES: Cl.C([NH:6][S:7]([C:10]1[C:11]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]3[CH:25]=[N:26][C:27](C)=[C:28]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]#[N:41])[CH:35]=4)[C:29]=3[CH2:30][OH:31])=[CH:18][CH:17]=2)=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8])(C)(C)C.[NH3:43].CO>C(O)C>[OH:31][CH2:30][C:29]1[C:24]([CH2:23][NH:22][C:19]2[CH:20]=[CH:21][C:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:7](=[O:9])(=[O:8])[NH2:6])=[CH:17][CH:18]=2)=[CH:25][N:26]=[CH:27][C:28]=1[O:32][CH2:33][C:34]1[CH:35]=[C:36]([CH:37]=[CH:38][CH:39]=1)[C:40]([NH2:41])=[NH:43]
Reactant: Cc1ncc(CNc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c(CO)c1OCc1cccc(C#N)c1
Reactant: N
Agent: Cl
Solvent: CCO
Solvent: CO
Product: N=C(N)c1cccc(COc2cncc(CNc3ccc(-c4ccccc4S(N)(=O)=O)cc3)c2CO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Hydrogen chloride gas was bubbled into a suspension of 4′-{[5-(3-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-amino}-biphenyl-2-sulfonic acid tert-butylamide (13) (100 mg, 0.17 mmol) in absolute ethyl alcohol (30 mL) at 0° C. for 30 minutes. The septum was replaced and the reaction mixture was stirred at room temperature overnight. Hydrogen chloride gas was purged with nitrogen gas for 2 hours and the solvent evaporated to give the crude amide ester as a solid. Ammonia in methyl alcohol (30 mL, 7 M, 350 mmol) was added to the crude amide ester and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the product purified on a silica gel column using a mixture of dichloromethane:methyl alcohol (4:1) as eluant to give the corresponding 3-{4-hydroxymethyl-5-[(2′-sulfamoyl-biphenyl-4-ylamino)-methyl]-pyridin-3-yloxymethyl}-benzamidine (14) (90 mg, 97% yield) as a colorless powder.