Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([C@H:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:13][N:12]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]2)=[O:24])[CH2:11]1)[CH2:8][CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:22][C:17]1[CH:16]=[C:15]([C@H:14]2[C@H:10]([NH:7][CH2:8][CH3:9])[CH2:11][N:12]([C:23]([N:25]3[CH2:26][CH2:27][N:28]([S:31]([CH3:34])(=[O:32])=[O:33])[CH2:29][CH2:30]3)=[O:24])[CH2:13]2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 84.3 %

Procedure:
To a solution of rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid tert-butyl ester (0.36 g, 0.66 mmol) in CH2Cl2 (10 ml) was added TFA (2 ml) at RT. Stirring was continued over night. The reaction mixture was then concentrated under vacuo, the crude dissolved in CH2Cl2, washed with aq.NaHCO3 and the organic phase was dried over Na2SO4. Purification by flash chromatography (SiO2, CH2Cl2/MeOH 95:5) yielded 0.25 g (84%) of the title compound as light yellow oil. ES-MS m/e: 449.8 (M+H+).
Reaction SMILES: C[O-].[Na+].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([CH3:14])=[C:7]([CH3:15])[N:6]=1.[CH2:16]([O:18]CC)C.O>CO>[CH3:14][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]([O:18][CH3:16])=[N:6][C:7]=1[CH3:15]
Reactant: CCOCC
Reactant: Cc1cc([N+](=O)[O-])c(Cl)nc1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(C)c(C)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 7 h
Yield: 82.6 %

Procedure:
To a solution of 28% sodium methoxide (1.11 mL) and methanol (5.5 mL) was added dropwise a solution of 2-chloro-5,6-dimethyl-3-nitropyridine (1-013-05) (837 mg) in methanol (6.6 mL) for 5 min at room temperature under nitrogen atmosphere, and the reaction mixture was heated with stirring in oil-bath at 50° C. for 7 h. To the reaction mixture was added diethyl ether and the reaction mixture was poured into water, extracted with twice with diethyl ether, washed once with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5,6-dimethyl-2-methoxy-3-nitropyridine (1-013-06) (675 mg, 82.6%, m.p.: 71-73° C.) as an orange crystal.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30]([CH2:37][C:38](O)=[O:39])=[N:29]1>>[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30]([CH2:37][C:38]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[C:7]5[CH2:6][CH2:5][O:4][C:12]=5[CH:11]=[CH:10][N:9]=4)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:39])=[N:29]1
Reactant: O=C(O)Cc1noc2ccccc12
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(Cc1noc2ccccc12)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (114 mg, 93%), MS (ISP) m/z=490.4 [(M+H)+], mp 217.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 2-benzo[d]isoxazol-3-yl-acetic acid.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C@H:6]([CH3:18])[CH2:5][CH2:4]1)#[CH:2].Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1.C(N(CC)CC)C>CCOC(C)=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:2]#[C:1][C@@H:3]2[CH2:4][CH2:5][C@@H:6]([CH3:18])[N:7]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[CH2:8]2)=[N:21][CH:22]=1
Reactant: C#C[C@@H]1CC[C@@H](C)N(Cc2ccc(OC)cc2)C1
Reactant: Fc1ccc(Br)nc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C[C@H](C#Cc3ccc(F)cn3)CC[C@H]2C)cc1
Temperature: 90 °C

Procedure:
A solution of (2R,55)-5-ethynyl-1-(4-methoxybenzyl)-2-methylpiperidine (284 mg, 1.17 mmol), 2-bromo-5-fluoropyridine (226 mg, 1.28 mmol), copper (I) iodide (67 mg, 0.35 mmol), and triethylamine (2.12 mL, 15.2 mmol) was purged subsurface with nitrogen. Palladium tetrakis (135 mg, 0.117 mmol) was added and the reaction was capped and heated at 90° C. overnight. The reaction was diluted with EtOAc and washed with water and then brine. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with 0-85% EtOAc in hexanes to provide 5-fluoro-2-{[(3S,6R)-1-(4-methoxybenzyl)-6-methylpiperidin-3-yl]ethynyl}pyridine as a yellow oil, which gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 339.2 for M+H+.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[OH:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>>[CH3:33][C:8]1[CH:9]=[C:10]([O:13][C:14]2[CH:15]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][C:23]=3[O:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:3])=[O:34]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: Oc1cccnc1
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2Oc2cccnc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 3-hydroxypyridine as in Example 45 to afford 0.044 g (31%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C29H24NO5F3 524.1685, found 524.1680.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]1[CH2:18][CH:17]1[CH2:19][CH2:20][NH2:21]>>[CH2:16]1[CH2:18][CH:17]1[CH2:19][CH2:20][NH:21][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1
Reactant: NCCC1CC1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Product: O=C(NCCC1CC1)c1cccc(-c2ccccc2)c1

Procedure:
Using Preparation Method 1, 3-phenylbenzoic acid was reacted with (2-cyclopropyl)ethylamine. The resulting reaction mixture was purified using SiO2 with CH2Cl2 100%. A white crystalline solid was obtained (69%). NMR 1H (ppm, CDCl3): 7.97 (s, 1H), 7.69 (d, J3=7.7 Hz, 2H), 7.60 (d, J3=7.2 Hz, 2H), 7.51-7.33 (m, 4H), 6.29 (br. s., 1H), 3.60-3.53 (m, 2H), 1.54 (quart., J3=7.0 Hz, 2H), 0.78-0.67 (m, 1H), 0.52-0.46 (m, 2H), 0.14-0.06 (m, 2H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[CH:26]=2)=[CH:18][CH:17]=1.[CH3:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([CH3:41])[CH:40]=1)[C:35](Cl)=[O:36]>O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[C:26]=2[C:35](=[O:36])[C:34]2[CH:38]=[C:39]([CH3:41])[CH:40]=[C:32]([CH3:31])[CH:33]=2)=[CH:18][CH:17]=1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: COc1ccc(-c2cc3ccccc3o2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(-c2oc3ccccc3c2C(=O)c2cc(C)cc(C)c2)cc1
Reaction time: 0.2 h

Procedure:
To a cooled (0°) solution of 14.0 g. (0.105 mol.) of aluminum chloride in 100 ml. of nitrobenzene was added 11.2 g. (0.05 mol.) of 2-p-methoxyphenylbenzofuran followed immediately by 10.0 g. (0.06 mol.) of 3,5-dimethylbenzoyl chloride. The reaction mixture was stirred at 0° for 12 minutes (until the red color began to turn reddish-brown) then poured into water. The aqueous mixture was steam distilled to remove nitrobenzene and the residue was dissolved in methylene chloride. The methylene chloride solution was washed with aqueous sodium carbonate and saturated sodium chloride solution, dried (MgSO4) and concentrated at reduced pressure to give a residue which was purified by column chromatography to give 2-p-methoxyphenyl-3-(3',5'-dimethylbenzoyl)benzofuran which was then crystallized from ethanol.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([N:16]2[CH2:22][CH2:21][CH2:20][C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[CH2:17]2)[CH:7]=1)=[O:4].[N-:27]=[N+:28]=[N-:29].[Na+]>C(#N)C.C(OCC)(=O)C>[N:27]([CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([N:16]2[CH2:22][CH2:21][CH2:20][C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[CH2:17]2)[CH:7]=1)=[O:4])=[N+:28]=[N-:29]
Reactant: O=C(CCl)Nc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCC(=O)Nc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.9 %

Procedure:
To a solution of 2-chloro-N-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]acetamide (70 mg, 0.19 mmol) in acetonitrile (2 mL) was added sodium azide (62 mg, 0.95 mmol). The resulting mixture was stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate (20 mL), and then washed with water (10 mL). The ethyl acetate fraction was dried over sodium sulfate, and then concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 1:4) to give 65 mg of product as a white powder (yield was 91.8%). MS obsd. (ESI+) [(M+H)+] 373.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8](Cl)(=O)=O)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([SH:8])[CH:7]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1S
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
5-Chloro-2-methoxy-benzenesulfonyl chloride (1.0 g, 4.1 mmol) and triphenylphosphine (3.81 g, 14.5 mmol) were dissolved in THF (10 ml). Water (1.3 ml) was added and the mixture was stirred for 2 h at room temperature. The mixture was partitioned between 2N aqueous NaOH and diethylether. The aqueous phase was acidified to pH 1 with concentrated HCl and then extracted twice with methylene chloride. The combined organic layers were dried over MgSO4 and the solvent was evaporated to afford the desired product (690 mg), which was used in the next reaction step without further purification. MS m/z: 175 [M+H]+
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13]C)=O)(C(C)(C)C)(C)C.CC(C)C(=O)[CH2:20][C:21]#[N:22]>>[OH:8][CH2:9][C:10]([CH3:15])([CH3:16])[C:11](=[O:13])[CH2:20][C:21]#[N:22]
Reactant: CC(C)C(=O)CC#N
Reactant: COC(=O)C(C)(C)CO[Si](C)(C)C(C)(C)C
Product: CC(C)(CO)C(=O)CC#N
Yield: 29 %

Procedure:
Prepared from methyl 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate (6 g, 24.39 mmol) according to the method described for 4-methyl-3-oxopentanenitrile Example XA Step 1. Purification via silica gel chromatography eluting with 33% ethyl acetate in petroleum ether afforded 5-hydroxy-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (1 g, 29%). 1H NMR (300 MHz, CDCl3) δ 3.76 (s, 2H), 3.61 (s, 2H), 1.19 (s, 6H).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([CH:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.[CH2:19](O)[CH:20]=[CH2:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[C:14]1([CH3:17])[CH:13]=[CH:12][C:11]([CH:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:18])=[CH:2][CH:3]=2)[C:8]([O:10][CH2:21][CH:20]=[CH2:19])=[O:9])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(C(=O)O)c2ccc(C)cc2)cc1
Reactant: C=CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C(c1ccc(C)cc1)c1ccc(C)cc1

Procedure:
A mixture of 2,2-bis(p-tolyl)acetic acid (8.52 g), allyl alcohol (6.6 ml) and p-toluenesulfonic acid monohydrate (0.34 g) in toluene (25 ml) was refluxed for 20 hours with continuous removal of water with Dean-Stark apparatus. After being cooled, the mixture was poured into 1N Sodium hydroxide aqueous solution and extracted with ethyl acetate. The extract was washed with 1N sodium hydroxide aqueous solution, 1N hydrochloric acid and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with methylene chloride as an eluent to give allyl 2,2-bis(p-tolyl)acetate (8.09 g).
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:8][CH2:9][C:10]([N:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](OC)=[O:24])=[CH:19][CH:18]=2)[CH3:14])([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:33]>>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][N:13]([C:10]([CH3:12])([CH3:11])[CH2:9][O:8][CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:14])=[CH:18][CH:19]=1)(=[O:24])[NH2:33]
Reactant: N
Reactant: COC(=O)c1ccc(CCN(C)C(C)(C)COC(c2ccccc2)c2ccccc2)cc1
Product: CN(CCc1ccc(C(N)=O)cc1)C(C)(C)COC(c1ccccc1)c1ccccc1
Yield: 62 %

Procedure:
A solution of 1-diphenylmethoxy-2-[N-(4-methoxycarbonylphenethyl)-N-methylamino]-2-methylpropane (800 mg -- see Example 13) in saturated methanolic ammonia (80 ml) was heated in a steel bomb at 100° for 80 hours and evaporated. The residue was purified by chromatography on silica (40 g) using methylene chloride:methanol:saturated methanolic ammonia (96:4:1) as the eluant. Appropriate fractions were combined and evaporated to give the title compound as a colourless oil (480 mg, 62%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][N:14]=[C:15]=[O:16].O>CS(C)=O>[CH3:13][NH:14][C:15](=[O:16])[NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CN=C=O
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1csc(NC(=O)NC)n1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a solution of ethyl 2-aminothiazol-4-ylacetate (27.4 g.) in dimethylsulfoxide (135 ml.) was dropwise added methylisocyanate (13.05 g.) with stirring at room temperature, and the mixture was stirred for 3 hours at 40° C. After the reaction, the reaction mixture was poured into water (500 ml.), and then extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride in turn and then dried over magnesium sulfate. After distillation of the solvent from the extract, the residue was pulverized in diethyl ether, collected by filtration and then dried to give colorless crystals of ethyl 2-(3-methylureido)thiazol-4-ylacetate (25.7 g.), mp 158° to 159° C.
Reaction SMILES: I[C:2]1[C:10]([N+]([O-])=O)=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])/[C:5](=[O:14])[NH:6]2.[OH:23][CH2:24][CH2:25][CH:26]=[CH:27]B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.O.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>[OH:23][CH2:24][CH2:25][CH:26]=[CH:27][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[CH:15][C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:5](=[O:14])[NH:6]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Reactant: OCCC=CB(O)O
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc[nH]c1C=C1C(=O)Nc2cccc(C=CCCO)c21

Procedure:
To a stirred solution of (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.14 mmol) (Starting Material 2) in dimethoxyethane (5 mL) was added 4-hydroxy-1-butenyl-boronic acid (48 mg, 0.418 mmol) (from Example 68 above), tetrakis(triphenylphosphine)palladium(0) (39 mg, 0.034 mmol) (Aldrich) and 2M Na2CO3 solution in H2O (0.34 mL). The reaction mixture was stirred at 850C overnight in a pressure tube. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (Hex:EtOAc=5:1) to provide 1,3-dihydro-4-(4-hydroxy-but-1-enyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-indol-2-one as a yellow solid. (Yield 21 mg, 50%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].O=[C:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([N:33]3[CH2:38][CH2:37][N:36]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:35][CH2:34]3)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.C(C(O)=O)(F)(F)F>C(Cl)Cl>[OH:4][C@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[CH2:2][NH:1][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[CH:26][C:27]([S:30]([N:33]3[CH2:34][CH2:35][N:36]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][CH2:38]3)(=[O:32])=[O:31])=[CH:28][CH:29]=2)[CH2:22][CH2:23]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCOC(=O)CN1CCN(S(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CN1CCN(S(=O)(=O)c2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)CC1

Procedure:
The title compound was prepared from N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide and ethyl 2-(4-{[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}-1-piperazinyl)acetate in substantially the same manner, as described in Example 50. The product was obtained as a light yellow solid; mp: 91-92° C.; 1H NMR (400 MHz, DMSO-d6): δ 1.08-1.17 (t, 3H), 1.49-1.56 (m, 2H), 2.02-2.07 (m, 2H), 2.45-2.50 (m, 4H), 2.52-56 (m, 2H), 2.74-80 (m, 2H), 2.86-3.01 (m, 5H), 3.20 (s, 2H), 3.24-3.36 (m, 4H), 3.96-3.99 (d, 2H), 4.01-4.07 (q, 2H), 4.69-4.71 (m, 1H), 6.86-6.88 (d, 2H), 7.05-7.09 (m, 3H), 7.23-7.24 (m, 1), 7.47-7.50 (d, 2H), 8.20 (brs, 4H); MS m/z 640 (M+H)+; Analysis for C28H41N5O8S2×1.0 F3CCO2H×0.18 CH2Cl2 Calc'd: C, 47.13; H, 5.55; N, 9.11; Found: C, 47.02; H, 5.75; N, 8.67.
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH:13](O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)([CH3:3])[CH3:2].[SH:21][CH2:22][C:23]([OH:25])=[O:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:1]([C:4]1[C:5]([CH:13]([S:21][CH2:22][C:23]([OH:25])=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc2c(cc1C(O)c1ccccc1)OCO2
Reactant: O=C(O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)c1cc2c(cc1C(SCC(=O)O)c1ccccc1)OCO2
Yield: 92.9 %

Procedure:
1.2 g of α-(6-isopropyl-1,3-benzodioxol-5-yl)benzyl alcohol was dissolved in 10 ml of benzene, followed by the addition of 490 mg of mercaptoacetic acid and a catalytic amount of p-toluenesulfonic acid monohydrate. The obtained mixture was heated under reflux for one hour and cooled, followed by the addition of benzene. The mixture was washed with water, followed by the addition of a 1N aqueous solution of sodium hydroxide. The alkaline layer was separated, acidified with concentrated hydrochloric acid and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography (hexane/chloroform=3:7) to obtain 1.42 g of the title compound as a colorless prismatic crystal.
Reaction SMILES: [CH3:1]I.[H-].[Na+].[OH:5][CH2:6][CH2:7][O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([I:17])=[CH:11][C:10]=1[O:18][CH3:19].O>O1CCCC1>[I:17][C:12]1[CH:11]=[C:10]([O:18][CH3:19])[C:9]([O:8][CH2:7][CH2:6][O:5][CH3:1])=[C:14]([O:15][CH3:16])[CH:13]=1
Reactant: CI
Reactant: COc1cc(I)cc(OC)c1OCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1c(OC)cc(I)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
Methyl iodide (0.010 mL, 0.16 mmol) and a 50% dispersion of sodium hydride in mineral oil (12.0 mg, 0.24 mmol) were added to a solution of 4-(2-hydroxyethoxy)-1-iodo-3,5-dimethoxybenzene (39.0 mg, 0.120 mmol) in anhydrous tetrahydrofuran (1.0 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with 3.0 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield 1-iodo-3,5-dimethoxy-4-(2-methoxyethoxy)benzene as a colorless oil (40.0 mg, yield: 98%).
Reaction SMILES: C(N(C(C)C)/[CH:5]=[C:6](\[F:9])/[CH:7]=O)(C)C.NC1C(C(ON2C3C=CC=CC=3N=N2)=O)=C2N=CC(CC#N)=CN2N=1.[NH2:38][C:39]1[C:43]([C:44]([NH:46][C:47]2[CH:48]=[N:49][CH:50]=[CH:51][C:52]=2[N:53]2[CH2:58][CH2:57][N:56]([CH3:59])[CH2:55][CH2:54]2)=[O:45])=[C:42]([NH2:60])[NH:41][N:40]=1.O>CS(C)=O>[NH2:60][C:42]1[C:43]([C:44]([NH:46][C:47]2[CH:48]=[N:49][CH:50]=[CH:51][C:52]=2[N:53]2[CH2:58][CH2:57][N:56]([CH3:59])[CH2:55][CH2:54]2)=[O:45])=[C:39]2[N:38]=[CH:5][C:6]([F:9])=[CH:7][N:40]2[N:41]=1
Reactant: CN1CCN(c2ccncc2NC(=O)c2c(N)n[nH]c2N)CC1
Reactant: CC(C)N(/C=C(\F)C=O)C(C)C
Agent: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(c2ccncc2NC(=O)c2c(N)nn3cc(F)cnc23)CC1
Temperature: 140 °C
Reaction time: 0.42 h

Procedure:
A mixture of (Z)-3-(diisopropylamino)-2-fluoro-prop-2-enal (Tetrahedron Letters (1992), 33(3), 357-60) (22.81 mg, 0.1317 mmol), 4-methylbenzenesulfonic acid (Water (1)) (30.05 mg, 0.1580 mmol), 3,5-diamino-N-[4-(4-methylpiperazin-1-yl)-3-pyridyl]-1H-pyrazole-4-carboxamide (50 mg, 0.1580 mmol) in DMSO (1 mL)/H2O (0.5 mL) was stirred at 140° C. for 25 min. The crude mixture was purified by Fractionlynx HPLC. The aqueous fractions were combined and lyophilised to yield 2-amino-6-fluoro-N-(4-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. (10 mg, 21%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.[NH2:13][NH2:14].O>CO>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:13][NH2:14])=[O:2])=[CH:5][CH:6]=1)#[N:11]
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: N#Cc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-cyano-benzoic acid methyl ester (1.0 g, 13 mmol) in 30 mL of MeOH was added 3 mL of H2NNH2.H2O. The mixture was stirred at ambient temperature for 16 h. The solid was collected and washed with CH3OH to give 4-cyano-benzoic acid hydrazide 9 as a solid. Yield: 0.8 g, 80%.