Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([O:21][CH:22]([CH3:24])[CH3:23])[C:19]=1I)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:17]=[C:18]([O:21][CH:22]([CH3:24])[CH3:23])[C:19]=1[C:37]1[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c(I)c(OC(C)C)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(OCc2ccccc2)c(-c2ccc(F)cc2)c(OC(C)C)c1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
Palladium acetate (72 mg) was added to a mixture of ethyl 3-(benzyloxy)-4-iodo-5-isopropoxybenzoate (2.72 g), tripotassium phosphate (4.06 g), (4-fluorophenyl)boronic acid (1.78 g), tricyclohexylphosphine (20% toluene solution, 1.13 mL), toluene (20 mL), and water (10 mL), and the resultant mixture was stirred at 100° C. for 2 hours in an argon atmosphere. The reaction mixture was allowed to cool to room temperature, then diluted with ethyl acetate, and washed with water and saturated saline in this order. The organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.03 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](O)=O)=[N:6][CH:7]=1.Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1.[NH2:29][C:30]1[C:35]([NH2:36])=[CH:34][C:33]([CH:37]2[CH2:41][CH2:40][CH2:39][N:38]2C(OC(C)(C)C)=O)=[C:32]([O:49][C:50]2[CH:55]=[CH:54][C:53]([S:56]([CH3:59])(=[O:58])=[O:57])=[CH:52][CH:51]=2)[CH:31]=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:36][C:35]3[CH:34]=[C:33]([CH:37]4[CH2:41][CH2:40][CH2:39][NH:38]4)[C:32]([O:49][C:50]4[CH:55]=[CH:54][C:53]([S:56]([CH3:59])(=[O:58])=[O:57])=[CH:52][CH:51]=4)=[CH:31][C:30]=3[N:29]=2)=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cc(N)c(N)cc1Oc1ccc(S(C)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccc(Br)cn4)[nH]c3cc2C2CCCN2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
220 mg of 5-bromopyridine-2-carboxylic acid and 260 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride were added in order to a pyridine (10 ml) solution of 500 mg of t-butyl 2-(4,5-diamino-2-(4-methanesulfonyl-phenoxy)-phenyl)-pyrrolidine-1-carboxylate, and the reaction liquid was stirred at room temperature for 12 hours. The reaction liquid was diluted with chloroform, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, the resulting residue was dissolved in 10 ml of trifluoroacetic acid, and the reaction liquid was heated under reflux for 3 hours. After cooled, the reaction liquid was distilled under reduced pressure, and the resulting residue was diluted with chloroform, and then made basic with aqueous saturated sodium bicarbonate added thereto. Then, the organic layer was washed with saturated saline and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol/aqueous ammonia=50/1/0.1) to obtain the entitled compound as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:19])=[O:18])=[CH:12][CH:11]=2)[CH:3]=1.[CH3:29][N:30](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[C:29]([C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:19])=[O:18])=[CH:12][CH:11]=2)[CH:3]=1)#[N:30]
Reactant: CN(C)C=O
Reactant: Cc1nc(Cl)cc(Oc2ccc(CS(=O)(=O)N(C)C(=O)OC(C)(C)C)cc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1nc(C#N)cc(Oc2ccc(CS(=O)(=O)N(C)C(=O)OC(C)(C)C)cc2)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
Under an atmosphere of nitrogen, combine tert-butyl N-[[4-(6-chloro-2-methyl-pyrimidin-4-y)oxyphenyl]methylsulfonyl]-N-methyl-carbamate (2.24 g, 3.4 mmol), DMF (2 mL), tetrakis(triphenylphosphine)palladium (1.9 g, 1.7 mmol), and zinc cyanide (2.0 g, 16.8 mmol). Heat the mixture to 90° C. and stir for 3 hours. Quench the reaction with water and sodium hydroxide. Extract the mixture with EtOAc; wash the EtOAc extract(s) with brine; dry over magnesium sulfate; filter and concentrate the filtrate under reduced pressure to provide a residue. Purify the title compound via flash column chromatography using 80 g of silica gel, and eluting with a 0-55% gradient of EtOAc in hexanes. Evaporate the relevant fractions to provide the title compound as a yellow oil (1.2 g, 80.9%). MS (m/z): 419 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C1COCC1.CC([O-])(C)C.[K+].C1(S([C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)(=[O:39])=[O:38])=[CH:33][N:32]=2)(=O)=O)CCCCC1>O>[CH:40]1([S:37]([C:34]2[CH:35]=[CH:36][C:31]([O:1][C:2]3[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=3)=[N:32][CH:33]=2)(=[O:39])=[O:38])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: O=S(=O)(c1ccc(S(=O)(=O)C2CCCCC2)nc1)C1CCCCC1
Reactant: CC(=O)c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(Oc2ccc(S(=O)(=O)C3CCCCC3)cn2)cc1
Yield: 31 %

Procedure:
To 3.68 g of p-hydroxyacetophenone in a 25 ml THF/25 ml DMSO mixture was added 3.2 g of t-BuOK and then 10.03 g of 2,5-bis(cyclohexylsulfonyl)pyridine, and the resulting mixture was heated at 62° C. for 11/2 hrs. The reaction mixture was cooled overnight, then added to 4 volumes of water and the crude product which formed recovered by filtration. Recrystallization of the crude product from CH2Cl2 /ethanol gave the product, 1-(4-((5-(cyclohexylsulfonyl)-2-pyridinyl)oxy)phenyl)ethanone, (31% yield), as light yellow prisms, m.p. 116°-118° C.
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1>C(O)C>[CH:1]([C@@H:14]1[CH2:20][C@@H:19]([OH:18])[C@H:17]([NH:30][CH2:29][CH2:28][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:16][O:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@H]3O[C@H]3CO2)cc1
Reactant: NCCc1ccc(F)cc1
Solvent: CCO
Product: O[C@@H]1C[C@@H](C(c2ccccc2)c2ccccc2)OC[C@H]1NCCc1ccc(F)cc1

Procedure:
(1S,4S,6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28a (0.025 g, 0.094 mmol) was reacted with 2-(4-fluoro-phenyl)-ethylamine (0.26 g, 1.88 mmol) in ethanol (Procedure E) to yield (2S,4R,5R)-2-benzhydryl-5-[2-(4-fluorophenyl)-ethylamino]-tetrahydropyran-4-ol, (−)-29c, 0.04 g (98%, [α]D=(−)62.9, c=1, MeOH).
Reaction SMILES: [CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[S:27][C:26]([CH2:28]O)=[CH:25][CH:24]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>O1CCCC1>[Cl:22][C:23]1[S:27][C:26]([CH2:28][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:9]3[CH:8]=[CH:7][C:6]4[C:11](=[C:12]([CH3:13])[N:4]([CH:1]5[CH2:2][CH2:3]5)[N:5]=4)[CH:10]=3)[C:15](=[O:21])[CH:16]=2)=[CH:25][CH:24]=1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C1CC1
Reactant: OCc1ccc(Cl)s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c2cc(-n3ccc(OCc4ccc(Cl)s4)cc3=O)ccc2nn1C1CC1
Reaction time: 3 h
Yield: 20.5 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (70 mg) in tetrahydrofuran (5 ml) were added (5-chlorothiophen-2-yl)methanol (74 mg), 1,1′-(azodicarbonyl)dipiperidine (188 mg) and tributylphosphine (151 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (21 mg).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[N:16]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH2:23][C:24]#[N:25])[CH2:19][CH2:18]3)[C:8]3=[C:9]4[S:15][CH:14]=[CH:13][C:10]4=[N:11][CH:12]=[C:7]3[N:6]=2)[CH2:2]1.O1CCC[CH2:27]1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(#N)C>[CH3:27][N:1]1[CH2:4][CH:3]([C:5]2[N:16]([C@H:17]3[CH2:18][CH2:19][C@H:20]([CH2:23][C:24]#[N:25])[CH2:21][CH2:22]3)[C:8]3=[C:9]4[S:15][CH:14]=[CH:13][C:10]4=[N:11][CH:12]=[C:7]3[N:6]=2)[CH2:2]1
Reactant: N#CC[C@H]1CC[C@H](n2c(C3CNC3)nc3cnc4ccsc4c32)CC1
Reactant: C1CCOC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CN1CC(c2nc3cnc4ccsc4c3n2[C@H]2CC[C@H](CC#N)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [trans-4-(2-azetidin-3-yl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)cyclohexyl]acetonitrile (14 mg, 0.038 mmol) in methanol (0.5 mL)/tetrahydrofuran (0.5 mL)/acetonitrile (0.5 mL) was added 37% aq. formaldehyde solution (12 μL, 0.16 mmol). The resulting mixture was stirred at room temperature for 10 min before sodium triacetoxyborohydride (16 mg, 0.077 mmol) was added. The mixture was stirred at room temperature for 1 h and then diluted with MeOH and purified by prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.8 mg, 6%). LCMS calculated for C20H24N5S (M+H)+: m/z=366.2. Found: 366.1.
Reaction SMILES: N1C=CC=C1C(OCC)=O.C(Br)C1C=CC=CC=1.[CH2:19]([N:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]([OH:33])=[O:32])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:34][C:35]1[S:36][CH:37]=[CH:38][N:39]=1>>[CH2:19]([N:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]([OH:33])=[O:32])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1.[S:36]1[CH:37]=[CH:38][N:39]=[C:35]1[NH:34][C:31]([C:27]1[N:26]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:30]=[CH:29][CH:28]=1)=[O:33]
Reactant: Nc1nccs1
Agent: BrCc1ccccc1
Agent: CCOC(=O)c1ccc[nH]1
Agent: O=C(O)c1cccn1Cc1ccccc1
Product: O=C(Nc1nccs1)c1cccn1Cc1ccccc1

Procedure:
1-Benzyl-pyrrole-2-carboxylic acid (1.12 g) was prepared from ethyl pyrrole-2-carboxylate (1.39 g, 10.0 mmol) and benzyl bromide (1.26 mL, 11.0 mmol) following general procedures A and B. 1-Benzyl-pyrrole-2-carboxylic acid thiazol-2-ylamide (45 mg) was prepared from 1-benzyl-pyrrole-2-carboxylic acid (50 mg, 0.25 mmol) and 2-aminothiazole (25 mg, 0.25 mmol) following the general procedure F.
Reaction SMILES: N#N.[Br:3][C:4]1[S:5][C:6]([CH2:9][OH:10])=[CH:7][N:8]=1.CCN(CC)CC.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:21][S:18]([O:10][CH2:9][C:6]1[S:5][C:4]([Br:3])=[N:8][CH:7]=1)(=[O:20])=[O:19]
Reactant: OCc1cnc(Br)s1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cnc(Br)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-bromo-thiazol-5-yl)-methanol (621 mg, 3.20 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.60 mL, 4.23 mmol) followed by DMAP (39 mg, 0.32 mmol) and Ms-Cl (0.33 mL, 4.15 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (2-bromothiazol-5-yl)methyl methanesulfonate as a colorless oil. The crude material was dissolved in dry DMF (15 mL) and treated with NaN3 (223 mg, 3.40 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer washed with water (2×), dried over MgSO4, filtered and concentrated under reduced pressure to give crude 5-(azidomethyl)-2-bromothiazole as a yellow oil. To a solution of the crude azide in THF (12 mL) were added polymer-supported Ph3P (1.2 eq.) and water (4 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. 1N NaOH/aq. sat. NaHCO3 and the layers separated. The aq. layer was extracted with EA and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 01: tR=0.16 min; [M+CH3CN+H]+=233.91.
Reaction SMILES: [ClH:1].N([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)C1C=CC=CC=1.[CH3:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32]>C(O)C>[ClH:1].[CH3:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: CCO
Product: Cc1cc(Nc2ccc(C)c([N+](=O)[O-])c2)c2c(ccc3nc[nH]c32)n1

Procedure:
A mixture of 10.85 g. (0.05 m.) of the compound of Example I, C., 7.6 g. (0.05 m.) of 4-methyl-3-nitroaniline and 500 ml. of ethanol was refluxed overnight. The reaction mixture was concentrated in vacuo to give 38 g. of crude product. It was then dissolved in 6000 ml. of MeOH and filtered hot. The MeOH filtrate was concentrated in vacuo to yield 27 g., m.p. 344°-345°C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(=[O:10])[CH:8]=[CH2:9].[C:26]1([CH:33]=[CH:32][C:30](O)=[CH:29][CH:28]=1)[OH:27].O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([O:23][C:30]2[CH:32]=[CH:33][C:26]([OH:27])=[CH:28][CH:29]=2)=[O:22])=[CH:19][CH:18]=1)(=[O:10])[CH:8]=[CH2:9]
Reactant: C=CC(=O)OCCCCOc1ccc(C(=O)O)cc1
Reactant: Oc1ccc(O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCCCOc1ccc(C(=O)Oc2ccc(O)cc2)cc1
Reaction time: 0.33 h
Yield: 66.5 %

Procedure:
Oxalyl chloride (10 ml) is added at 0° C. to (2) (5 g; 19 mmol), and the mixture is stirred until the evolution of gas subsides (20 min). The excess oxalyl chloride is removed by distillation in a water-pump vacuum, the acid chloride is taken up in toluene (10 ml), the toluene solution is added at 0° C. to a solution of hydroquinone (10.5 g; 95 mmol) in pyridine (10 ml) and toluene (5 ml), and the mixture is subsequently stirred at room temperature for 24 hours. The reaction mixture is then transferred into water (200 ml), and the mixture is extracted twice with dichloromethane (50 ml each time). The organic extracts are dried using calcium chloride, hydroquinone (50 mg) is added to the filtrate, and the mixture is evaporated in a water-pump vacuum. The residue is chromatographed on silica gel (toluene/ethyl acetate (5:1), giving 4.5 g (66%) of (3).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:4]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.[C:30](#[N:32])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:8][N:7]1[C:3]([CH2:2][C:30]#[N:32])=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:6]1
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CCl
Reactant: CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
Tetrabutylammonium cyanide (1.96 g, 7 mmol) was added to a solution of 5-chloromethyl-1-methyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole (1.54 g, 6 mmol) in acetonitrile (35 ml). The solution was stirred at ambient temperature for 16 h, saturated aqueous sodium bicarbonate solution/ice water 1/1 and ethyl acetate were added and the layers were separated. The aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent was evaporated in vacuo to give an orange oil which was purified by column chromatography (silica gel, n-heptane/AcOEt) to yield 267 mg (1 mmol, 18%) of the title compound as yellow crystals.
Reaction SMILES: [N:1]1([C@@H:8]([CH:13]([CH3:15])[CH3:14])[C:9]([O:11]C)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[OH-].[Na+]>CO>[N:1]1([C@@H:8]([CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7]
Reactant: COC(=O)[C@H](C(C)C)N1CCCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@@H](C(=O)O)N1CCCCC1=O
Reaction time: 8 h

Procedure:
The product of Step B was dissolved in 4 mL of methanol and 0.85 mL of 1N NaOH was added. The mixture was stirred overnight and the solvent was evaporated. The residue was dissolved in water, filtered and acidified. Ethyl acetate extraction and standard workup gave 30 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([S:26][C:27]1[C:35]([Br:36])=[CH:34][C:30]3[O:31][CH2:32][O:33][C:29]=3[CH:28]=1)[N:6]2[CH2:11][CH2:12][CH:13]([NH:18]C(=O)OC(C)(C)C)[CH:14]1[CH2:17][CH2:16][CH2:15]1.Cl>CCOC(C)=O>[NH2:18][CH:13]([CH:14]1[CH2:17][CH2:16][CH2:15]1)[CH2:12][CH2:11][N:6]1[C:5]([S:26][C:27]2[C:35]([Br:36])=[CH:34][C:30]3[O:31][CH2:32][O:33][C:29]=3[CH:28]=2)=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH2:1]
Reactant: CC(C)(C)OC(=O)NC(CCn1c(Sc2cc3c(cc2Br)OCO3)nc2c(N)ncnc21)C1CCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ncnc2c1nc(Sc1cc3c(cc1Br)OCO3)n2CCC(N)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To a solution of tert-Butyl (3-{6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)thio]-9H-purin-9-yl}-1-cyclobutylpropyl)carbamate (0.015 g, 0.026 mmol) in EtOAc (2 mL) was added dropwise conc. HCl (1 mL) and the resulting mixture was stirred for overnight at room temperature. After concentration under reduced pressure, the residual HCl was removed by co-evaporation with toluene afford title product (0.005 g) as a hydrochloride salt. 1H MNR (CD3OD) δ 8.33 (s, 1H), 7.29 (s, 1H), 7.19 (s, 1H), 6.09 (s, 2H), 4.40-4.28 (m, 2H), 3.49-3.40 (m, 4H), 2.50-1.70 (m, 6H); LC-MS [M+23]+ 477.9.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[CH2:12]1[O:23][C:22]2[CH:21]=[CH:20][C:16]([CH2:17][NH:18][NH2:19])=[CH:15][C:14]=2[O:13]1>>[NH2:10][C:6]1[NH:19][N:18]([CH2:17][C:16]2[CH:20]=[CH:21][C:22]3[O:23][CH2:12][O:13][C:14]=3[CH:15]=2)[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1ccc2c(c1)OCO2
Product: Nc1cc(=O)n(Cc2ccc3c(c2)OCO3)[nH]1

Procedure:
From 17.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 16.6 g of 3,4-methylenedioxybenzylhydrazine, analogously to the procedure described in Example 1. 12.1 g of the compound identified above, as colorless crystals of melting point 218°, corresponding to 52% of theory, are obtained.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)(=O)C([Cl:24])=O>C(Cl)CCl>[C:1]([Cl:24])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Solvent: ClCCCl
Product: CCCCCCCCCCCCCCCCCC(=O)Cl
Temperature: 45 °C

Procedure:
1420g (5 moles) of stearic acid and 6 liters of ethylene dichloride are placed in a 12-liter flask and warmed to 45° C. 1270 g (10 moles) of oxalyl chloride is added dropwise over a 2.5 hour time period. After 1 hour of refluxing, the flask is blanketed with argon and cooled overnight. The solvent is removed and the stearoyl chloride is used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH2:23])[C:17]=3[C:16]([C:24](=[O:43])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([C:35]4[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=4)(=[O:34])=[O:33])[CH:26]=3)=[CH:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.NC1C2C(C(C3C=C(NC(NC4C=C(Cl)C=C(Cl)C=4)=O)C=CC=3)=O)=CN(C3CCNCC3)C=2N=CN=1>>[NH2:23][C:22]1[C:17]2[C:16]([C:24]([C:25]3[CH:26]=[C:27]([NH:31][S:32]([C:35]4[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=4)(=[O:34])=[O:33])[CH:28]=[CH:29][CH:30]=3)=[O:43])=[CH:15][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)c3cccc(NS(=O)(=O)c4cc(Cl)cc(Cl)c4)c3)c3c(N)ncnc32)CC1
Agent: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)Nc3cc(Cl)cc(Cl)c3)c1)cn2C1CCNCC1
Product: Nc1ncnc2c1c(C(=O)c1cccc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)c1)cn2C1CCNCC1

Procedure:
The title compound was prepared from 4-{4-Amino-5-[3-(3,5-dichloro-benzenesulfonylamino)-benzoyl]-pyrrolo[2,3-d]pyrimidin-7-yl}-piperidine-1-carboxylic acid tert-butyl ester by procedures analogous to those described for the preparation of 1-[3-(4-Amino-7-piperidin-4-yl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-3-(3,5-dichloro-phenyl)-urea. MS: 546.5 (MH+); HPLC Rf: 4.91 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si](C(C)C)(C(C)C)C(C)C)[CH:6]=[CH:5]2.C([Li])(C)(C)C.[C:26]1([S:32](F)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[C:26]1([S:32]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(F)c1ccccc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1ccc2[nH]ccc2c1

Procedure:
Cool a solution of 5-bromo-1-triisopropylsilanyl-1H-indole (9 g, 25.5 mmol) in 550 mL anhydrous THF to −75° C. under argon and treat with 1.7 M t-butyl lithium (33 mL, 56.2 mmol) while keeping the temperature below −60° C. After the addition, recool the reaction mixture to about −73° C. before adding a solution of phenylsulfonyl fluoride (4.6 g, 28.7 mmol) in 30 mL THF. Stir the reaction at −78° C. for 1 hour then quench with saturated NaHCO3 followed by brine. Separate the layers and extract the aqueous layer with EtOAc. Treat the combined organic layers with 1 M tetrabutylammonium fluoride (35 mL) in THF for 1 hour at ambient temperature, then concentrate to dryness. Combine the residue with EtOAc, wash twice with 1 N HCl, dry over MgSO4, and concentrate to an oil. Chromatograph the oil on silica get eluting stepwise with 50% CHCl3 in hexanes followed by 50% CHC13 in MeOH give an oily solid. Triturate the oily solid with CHCl3 to give the title compound as a solid: Analysis for C14H11NO2S H2O: calcd: C, 64.89; H, 4.36; N, 5.41; found: C, 64.76; H, 4.45; N, 5.33; ISMS 257 (M+).