Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH:28]([C@@H:31]1[C:35]([CH3:37])([CH3:36])[O:34][C:33](=[O:38])[NH:32]1)([CH3:30])[CH3:29]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:32]3[C@H:31]([CH:28]([CH3:29])[CH3:30])[C:35]([CH3:36])([CH3:37])[O:34][C:33]3=[O:38])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: CC(C)[C@H]1NC(=O)OC1(C)C
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC(C)(C)[C@H]4C(C)C)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 42.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (722 mg) described in Preparation Example 9 and (R)-(+)-4-isopropyl-5,5-dimethyloxazolidin-2-one (250 mg), the title compound (359 mg) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([I:13])[C:4]=1[OH:14].[S:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>C1C=CC=CC=1>[CH3:12][C:9]([C:7]1[CH:6]=[C:5]([I:13])[C:4]2[O:14][C:18]3([CH2:19][CH2:20][S:15][CH2:16][CH2:17]3)[NH:1][CH2:2][C:3]=2[CH:8]=1)([CH3:11])[CH3:10]
Reactant: O=C1CCSCC1
Reactant: CC(C)(C)c1cc(I)c(O)c(CN)c1
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(I)c2c(c1)CNC1(CCSCC1)O2
Yield: 62 %

Procedure:
A mixture of 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol (3.0 g., 0.01 mole), tetrahydrothiopyran-4-one (1.18 g., 0.01 mole), and benzene (100 ml.), is refluxed under a Dean-Stark trap for 4 hr. The solvent is evaporated, and the residue is crystallized from ethanol to obtain 3,4-dihydro-6-(1,1-dimethylethyl)-8-iodospiro[2H-1,3-benzoxazine-2,4'-tetrahydrothiopyran], (2.5 g.), m.p. 123°-124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[SH:11][CH2:12][CH2:13][CH2:14][OH:15]>>[Cl:1][C:2]1[CH:9]=[C:8]([S:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: OCCCS
Product: N#Cc1ccc(SCCCO)cc1Cl

Procedure:
4 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with 3-mercapto-1-propanol to afford 2-chloro-4-(3-hydroxypropylthio)benzonitrile. 1 g of 2-chloro-4-(3-hydroxypropylthio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(3-hydroxypropylthio)benzoic acid. 1.2 g of 2-chloro-4-(3-hydroxypropylthio)benzoic acid was reacted via Procedure R to yield 2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-hydroxypropylsulfonyl)benzamide. MS (Q1) 465.0 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC=CC=1>O>[CH:10](=[N:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc(N=Cc2ccccc2)c(F)c1
Yield: 95.2 %

Procedure:
322.8 g (2.5 mol) of 2,4-difluoroaniline, 265.3 g (2.5 mol) of benzaldehyde and 1000 ml of toluene are heated to reflux, and the water formed is removed for 5 hours at 90°-105° C. using a water separator. The toluene is removed by distillation on a vacuum rotary evaporator, and the product is recrystallized from hexane, to give 516.9 g (92.5 % of theory) of N-benzal-2,4-difluoroaniline, which melts at 51°-52° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)=[O:12])=[CH:4][CH:3]=1.[N:20]1([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([N:23]3[CH2:24][CH2:25][N:20]([C:26](=[O:27])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])[CH2:21][CH2:22]3)=[CH:17][CH:18]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(NCCc1ccc(F)cc1)c1ccc(Cl)nn1
Product: O=C(NCCc1ccc(F)cc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (59.8% yield). 1H NMR (400 MHz, CDCl3) δ 8.05, 7.92, 7.72-7.76, 7.66-7.54, 7.38-7.34, 7.20-7.14, 7.0-6.94, 4.10-4.02, 3.92-3.84, 3.80-3.68, 3.37-3.36, 2.90.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:27])[C:5]2[N:10]([CH2:11][CH2:12][CH2:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([O:20]C(C)(C)C)=[O:19])=[CH:16][CH:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.Cl>O1CCOCC1>[NH2:1][C:2]1[N:3]=[C:4]([NH2:27])[C:5]2[N:10]([CH2:11][CH2:12][CH2:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCCn2ccc3nc(N)nc(N)c32)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(N)c2c(ccn2CCCc2ccc(C(=O)O)cc2)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
The t-butyl 4-[3-(2,4-diaminopyrrolo[3,2-d]-pyrimidin-5-yl)propyl]benzoate (1 g. 2.7 mmol) prepared in the Example 1 was added to a mixture comprising dioxane (50 ml) and 1N aqueous hydrochloric acid (50 ml). The obtained mixture was stirred at 90° C. for one hour. After the completion of the reaction, the reaction mixture was concentrated, subjected to silica gel column chromatography and eluted with a solvent (ethyl acetate/methanol/acetic acid=7:1:1) to give 0.81 g of 4-[3-(2,4-diaminopyrrolo[3,2-d]pyrimidin-5-yl)propyl]benzoic acid. This acid, diethyl L-glutamate hydrochloride (1.61 g) and diphenylphosphoryl azide (DPPA) (1.65 ml) were added to DMF (35 ml), followed by the dropwise addition of triethylamine (2.2 ml) under cooling with ice. The obtained mixture was stirred under cooling with ice and thereafter at room temperature for 4 hours. After the completion of the reaction, the reaction mixture was concentrated, subjected to silica gel column chromatography and eluted with a solvent (ethyl acetate/methanol/acetic acid=8:1:1) to give an amide compound. This amide compound was dissolved in methanol (15 ml), followed by the dropwise addition of 1N aqueous sodium hydroxide (30 ml). The obtained mixture was stirred at room temperature for 5 hours and neutralized with 1N aqueous hydrochloric acid. The resulting reaction mixture was concentrated, subjected to silica gel column chromatography and eluted with a solvent (ethyl acetate/methanol/acetic acid=5:1:1), The obtained solid was washed with ethanol and a small amount of methanol to give a pale-yellow crystalline product (0.72 g). This product was recrystallized to give 0.35 g of the title compound (28%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:14][CH:12]=[N:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: NC=O
Product: O=c1[nH]cnc2cc(F)ccc12
Temperature: 0 °C
Yield: 82 %

Procedure:
A solution of 2-amino-4-fluorobenzoic acid (3 g, 19.3 mmol) in formamide (30 ml) was heated at 150° C. for 6 hours. The reaction mixture was poured onto ice/water 1/1 (250 ml). The precipitated solid was collected by filtration, washed with water and dried to give 7-fluoro-3,4-dihydroquinazolin-4-one (2.6 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11]O)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([NH:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:14])=[O:15])[C:6](=[CH2:11])[C:7]([O:9][CH3:10])=[O:8])(=[O:37])[CH3:36]
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C(=O)OC)N(Cc1ccccc1NC(C)=O)S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
A mixture of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate (8.0 g, 20.28 mmol) in methylene chloride (60 ml) was cooled to 0° C. and triethylamine (12.69 ml, 91.1 mmol) in methylene chloride (25 ml)was added, followed by the addition of acetyl chloride (4.34 ml, 60.84 mmol). The mixture was stirred at room temperature overnight and diluted with methylene chloride. The mixture was washed with water, 2N citric acid, saturated sodium chloride and then dried with anhydrous sodium sulfate. The solvent was removed in vacuo to give 8.6 g of a yellow oil.
Reaction SMILES: [C:1]([OH:26])(=[O:25])[CH2:2][CH2:3][C@H:4]([C@@H:6]1[C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[CH3:5].[CH2:27](O)[CH3:28]>>[CH2:27]([O:25][C:1](=[O:26])[CH2:2][CH2:3][C@H:4]([C@@H:6]1[C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[CH3:5])[CH3:28]
Reactant: CCO
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C
Product: CCOC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
25 m mol of 5β-cholanic acid was heated in ethanol in the presence of sulfic acid, forming 23 m mol of 5β-cholanic acid ethyl ester. This product was reduced by using lithium aluminum hydride, into 20 m mol of 5β-cholane alcohol. This alcohol, 19 m mol, was subjected to tosylation and then treated with thiourea. The resultant product was treated with bromine water, whereby 10 m mol of 5β-cholanesulfonylbromide was obtained. This compound, 8 m mol, was made to react with 8.5 m mol of nitroaniline. The product of this reaction was subjected to hydrogenation, thus 6.1 m mol of preparing p-amino-5β-cholanesulfonylanilide. This anilide was reacted with cyanogen bromide, and the resultant product was treated with dichloro-dicyanobenzoquinone, thereby obtaining 1.2 m mol of N-5β-cholanesulfonyl-N'-cyano-p-quinonediimine, which is represented by the following formula: ##STR52##
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[OH-].[K+]>C(O)C.O>[CH:14]1([O:13][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=2)[C:3]([OH:19])=[O:2])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
A solution of rac-cyclopentyloxy-(3,4-dichloro-phenyl)-acetic acid methyl ester (266 mg, 0.877 mmol) in ethanol (10 mL) was treated with a solution of potassium hydroxide (123 mg, 2.19 mmol) in water (1 mL) and the mixture was stirred at 25° C. After 3 h, the reaction was diluted with water (5 mL) and the ethanol was removed in vacuo. The aqueous layer was then acidified to pH 2 with 1 N hydrochloric acid and extracted with dichloromethane (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 chloroform/methanol plus 1% acetic acid) to afford rac-cyclopentyloxy-(3,4-dichloro-phenyl)-acetic acid (223 mg, 88% yield) as a white solid, mp 87.5-89.9 IC; EI-HRMS m/e calcd for C13H14Cl2O3 (M+) 288.0320, found 288.0332.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:48]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:47])[CH2:39][CH2:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.[CH3:49][C:50]1[O:54][N:53]=[C:52]([C:55](Cl)=[O:56])[CH:51]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:48]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:47])[CH2:39][CH2:40][CH:41]1[CH2:42][CH2:43][N:44]([C:55]([C:52]2[CH:51]=[C:50]([CH3:49])[O:54][N:53]=2)=[O:56])[CH2:45][CH2:46]1
Reactant: O=C(CCC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC(CCC(=O)Nc3ccc4cc3CCc3cccc(c3)Nc3ncc(Cl)c(n3)N4)CC2)no1
Yield: 54 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3piperidin-4-ylpropanamide bis(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as starting materials in 54% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.34 (m, 2H), 8.12 (s, 1H), 7.98 (s, 1H), 7.73 (s, 1H), 7.21 (d, 1H), 7.04 (m, 2H), 6.87 (d, 1H), 6.78 (d, 1H), 6.40 (s, 1H), 4.42 (m, 2H), 3.88 (m, 2H), 3.03 (m, 2H), 2.83 (m, 4H), 2.45 (s, 3H), 2.27 (m, 2H), 1.80 (m, 2H), 1.60 (m, 2H), 1.10 (m, 1H). LCMS for C31H33ClN7O3 (M+H)+: m/z=586.2.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])[CH:3]=1.[NH2:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([CH3:27])[N:20]=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([NH:15][C:16]([NH:18][C:19]2[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([CH3:27])[N:20]=2)=[O:17])(=[O:14])=[O:13])[CH:3]=1
Reactant: COC(=O)c1ccc(I)cc1S(=O)(=O)N=C=O
Reactant: COc1nc(C)nc(N)n1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: COC(=O)c1ccc(I)cc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Reaction time: 4 h
Yield: 99.2 %

Procedure:
Under protective gas, a 14.5% strength solution (1465 g) of methyl 4-iodo-2-isocyanatosulfonylbenzoate in xylene is added over 4 hours at a constant rate at 50° C. to a suspension of 84.5 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 670 g of ethyl acetate. After the addition has ended, the mixture is stirred at the same temperature for approximately 4 hours, and the ethyl acetate is then distilled off under reduced pressure (80–60 mbar, T=50° C.). The suspension that remains is filtered off with suction and the solid is washed repeatedly with dilute hydrochloric acid and dried; if appropriate, acetone can be added to the hydrochloric acid. This gives 297 g (content>98%) of the title compound; yield 99.2% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.CCOCC>[CH2:25]([O:16][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:13]=1[N:12]([CH2:15][C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:13]=1)[S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(C)ccc2C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2cc(C)ccc2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 155 %

Procedure:
To a solution of 1.82 g (5.66 mmol) of the product of Example 4 in 20 ml DMF, was added NaH (60% suspension in oil, 498 mg, (12.5 mmol). The resulting mixture was stired for 15 minutes and benzyl bromide (4.84 g, 0.028 mol) was then added. The mixture was heated to 80-84° with stirnng for 18 hr under N2. The motion was then cooled to room temperature, diluted with ether, washed with H2O and brine, dried over MgSO4 and concentrated in vacuo. The residue was triturated with EtOAc to afford 2.2 g (77%) of the desired product as a white solid. Electrospray Mass Spec: 502 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([F:22])[CH:16]=2)[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:30][NH2:31]>CO>[F:22][C:17]1[CH:16]=[C:15](/[C:12](/[CH2:13][CH3:14])=[C:11](/[C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)\[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:31][CH3:30])=[CH:6][CH:7]=2)[CH:20]=[CH:19][C:18]=1[OH:21]
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc(O)c(F)c1
Reactant: CN
Solvent: CO
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccc(O)c(F)c1
Temperature: 85 °C

Procedure:
To a stirred solution of 4-(1-(4-(2-chloroethoxy)phenyl)-1-(4-hydroxyphenyl) but-1-en-2-yl)-2-fluorophenol (310 mg, 0.75 mmol) in 10 mL MeOH was added 2 mL CH3NH2 (30% aq). The reaction mixture was heated at 85° C. for 13 h. and extracted with EtOAc. The extract was washed with water and brine, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (CH2Cl2/MeOH(NH3 gas)=10/1) to give the (Z)-product (39 mg, white solid) and (E)-product (14 mg, black brown crystal). m/z=408[M+1]+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]#[N:11])[N:9]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]#[N:11])[N:9]=1
Reactant: N#Cc1csc(CN=[N+]=[N-])n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1csc(CN)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
To a magnetically stirred solution of 2-azidomethyl-thiazole-4-carbonitrile (1.3 g, 7.8 mmol) in a mixture of THF (40 mL) and water (4 mL) was added triphenylphosphine (3.10 g, 11.8 mmol) portionwise with ice-bath cooling. After the addition was complete, the mixture was stirred for an additional 18 h at room temperature and extracted with 3% hydrochloric acid (10 mL). The resultant aqueous solution was extracted with ether, basified to pH=12 with 3N NaOH, extracted into ethyl acetate (3×), and the combined organic layers were washed with 100 mL of brine, dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 1.0 g (91%) of the title compound as an oil which was used in next step with out further purification.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)=[CH:14][CH:15]=2)[O:10][C:9]([C:26]2[N:27]=[CH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:8]1)(C)(C)C.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44]O)[CH2:39][CH2:38]1>>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[C:26]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][CH:14]=[C:13]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:44][CH2:43][N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)[CH:20]=2)[CH:12]=3)[N:27]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#Cc3cccc(O)c3)ccc12
Reactant: CN1CCN(CCO)CC1
Product: CN1CCN(CCOc2cccc(C#Cc3ccc4c(=NO)cc(-c5cc6ccccc6cn5)oc4c3)c2)CC1

Procedure:
2-Isoquinolin-3-yl-7-{3-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylethynyl}-chromen-4-one oxime was prepared in 9% overall yield using the method described in examples 44 and 44A, starting from 7-(3-hydroxyphenyl)ethynyl-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (tert-butyl protected oxime of example 30) and 2-(4-methyl-piperazin-1-yl)-ethanol. The title compound was isolated as a yellow solid and as a 90/10 mixture of Z/E oxime isomers after Preparative HPLC purification (gradient 65-50% Water/acetonitrile+0.05% trifluoroacetic acid).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]/[C:21]1[CH:29]=[C:28]2[C:24]([C:25]([I:38])=[N:26][N:27]2[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[CH:23][CH:22]=1>CN(C=O)C>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C@:13]12[CH2:2][C@H:20]1[C:21]1[CH:29]=[C:28]2[C:24]([C:25]([I:38])=[N:26][N:27]2[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[CH:23][CH:22]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(/C=C3/C(=O)Nc4ccc(F)cc43)cc21
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(I)c2ccc([C@@H]3C[C@@]34C(=O)Nc3ccc(F)cc34)cc21
Temperature: 55 °C
Reaction time: 7 h
Yield: 45.9 %

Procedure:
Trimethylsulfoxonium iodide (164.4 mg, 0.747 mmol) was added to a suspension of sodium hydride (89.6 mg, 2.24 mmol) (60% dispersion in oil) in DMF (2.0 mL) at room temperature. The mixture was stirred for 15 min after which time a solution of (E)-5-fluoro-3-((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene)indolin-2-one (200 mg, 0.373 mmol) in DMF (1.25 ml) was added. The solution was stirred at 55° C. for 7.0 h prior to quenching reaction mass over 25% NH4Cl solution (10 mL) at room temperature. The product was extracted using ethyl acetate (15 mL×2) and the organic layer was dried over MgSO4 and evaporated in vacuo. The crude product was purified using silica gel column chromatography (hexane:acetone 80:20 as an eluent) to yield a creamy semi-solid, which was then triturated with hexanes (2.0 mL) to give the title compound as an off-white powder (94 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.46 (s, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 6.86 (s, 1H), 6.78 (m, 1H), 5.72 (s, 2H), 5.68 (d, J=8 Hz, 1H), 3.54-3.48 (m, 3H), 2.34 (br s, 1H), 2.13 (br s, 1H), 0.88 (m, 2H), 0.03 (s, 9H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[N:11][C:10]2[O:13][CH2:14][CH2:15][CH2:16][C:9]=2[CH:8]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O.[CH:26](B1OB(C=C)OB(C=C)O1)=[CH2:27]>COCCOC.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>[CH:26]([C:7]1[N:12]=[N:11][C:10]2[O:13][CH2:14][CH2:15][CH2:16][C:9]=2[CH:8]=1)=[CH2:27]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: O=S(=O)(Oc1cc2c(nn1)OCCC2)C(F)(F)F
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: O
Solvent: COCCOC
Product: C=Cc1cc2c(nn1)OCCC2
Reaction time: 0.33 h
Yield: 77 %

Procedure:
Argon was bubbled for 15 minutes through a solution of 6,7-dihydro-5H-pyrano[2,3-c]pyridazin-3-yl trifluoromethanesulfonate (228 mg, 0.8 mmol) in 1,2-dimethoxyethane (6.5 ml). Tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.0435 mmol) was added and the solution stirred for 20 minutes under argon. The mixture was then treated with potassium carbonate (111 mg, 0.8 mmol), water (1.9 ml) and 2,4,6-trivinylcyclotriboroxane:pyridine complex (180 mg, 0.75 mmol) (for a preparation of this reagent see F. Kerins and D. F. O'Shea, J. Org. Chem. 2002, 67, 4968-4971). After stirring for 2 hours at 80° C., the mixture was cooled and partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous fraction was extracted twice with 20% methanol/dichloromethane. The combined organic solution was dried, evaporated and the residue chromatographed on silica gel, eluting with ethyl acetate to give product as a white solid (100 mg, 77%).