Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([C:23]2[S:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][C:29]=3Cl)[CH:24]=2)=[O:22])=[CH:14][CH:13]=1>>[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([C:23]2[S:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][C:29]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:24]=2)=[O:22])=[CH:14][CH:13]=1
Reactant: O=C(NCCc1ccncc1)c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)NCCc5ccncc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid (2-pyridin-4-yl-ethyl)-amide by a procedure analogous to Example 1C. MS: 428 (MH+); HPLC Rf: 4.09 min.; HPLC purity 99%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.N1C=CN=C1.[Si:63](Cl)([C:76]([CH3:79])([CH3:78])[CH3:77])([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>ClCCl.[Cl-].[NH4+]>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([O:50][Si:63]([C:76]([CH3:79])([CH3:78])[CH3:77])([C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH:46]([O:48][CH3:49])[CH2:47]2)[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the FR-900506 substance (89.7 mg) in dichloromethane (3 ml) were added imidazole (118 mg) and tert-butyl-diphenylsilyl chloride (52.2 mg). After the mixture was stirred at room temperature for 2 hours, the reaction mixture was diluted with a saturated aqueous ammonium chloride and extracted three times with diethyl ether. The extract was washed with water and an aqueous sodium chloride, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified on silica gel column chromatography (developing solvent: ethyl acetate and hexane, 1:3 v/v) to give 17-allyl-12-[2-(4-tert-butyl-diphenylsilyloxy-3-methoxycyclohexyl)-1-methylvinyl]-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (107 mg).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH3:27])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.C1CCCCC=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:11]([CH3:27])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1
Reactant: COc1cccc(S(=O)(=O)N2c3ccc(F)cc3-c3ccccc3C2C)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC1c2ccccc2-c2cc(F)ccc2N1S(=O)(=O)c1cccc(O)c1
Yield: 89.5 %

Procedure:
The title compound was prepared from 2-fluoro-5-[(3-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (100 mg, 0.26 mmol), cyclohexene (528 μL, 5.2 mmol), and 1.0 M solution of boron tribromide in dichloromethane (1.6 mL) according to the procedure and in the same manner as described in Example 105, step e. The volatile components were removed in vacuo, and the crude residue was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 5%-30% methyl tert-butyl ether in hexane, to afford the desired compound (86 mg, 89%) as a solid, m.p. 195-196° C.;
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1[O:19][CH3:20].[CH2:21]([C:23]([CH2:28][CH2:29][CH2:30][CH3:31])(CO)[CH2:24][OH:25])[CH3:22].[OH-].[K+]>>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1[O:19][CH2:20][C:23]([CH2:21][CH3:22])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][OH:25]
Reactant: COc1cc(O)c2c(c1N)C(=O)c1ccccc1C2=O
Reactant: CCCCC(CC)(CO)CO
Agent: [K+]
Agent: [OH-]
Product: CCCCC(CC)(CO)COc1cc(O)c2c(c1N)C(=O)c1ccccc1C2=O

Procedure:
15 parts of 1-amino-2-methoxy-4-hydroxyanthraquinone, 50 parts of 2-ethyl-2-butyl-1,3-propanediol, 2.5 parts of a polyethylene oxide of average moleclar weight 200 and 1.5 parts of potassium hydroxide are heated for 3.5 hours at 160°C under nitrogen. After working up, 13.5 parts of 1-amino-2-(2'-ethyl-2'-butyl-3'-hydroxypropanoxy)-4-hydroxyanthraquinone are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([N:6]([CH3:15])[C:7](=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([NH2:18])[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH3:15])[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[N:18][C:4]=2[CH:3]=1
Reactant: CN(C(=O)c1ccccc1)c1ccc(Br)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: Cn1c(-c2ccccc2)nc2cc(Br)ccc21
Yield: 87.1 %

Procedure:
7.8 g (26 mmol) of 4′-bromo-N-methyl-2′-aminobenzanilide was suspended in 50 mL of xylene. After the addition of 1.5 g (7.7 mmol) of p-toluenesulfonic acid monohydrate, the mixture was heat refluxed for 7 hours. After completion of the reaction, the mixture was filtered. The resulting solid was dissolved in methylene chloride, washed with a 10% potassium carbonate aqueous solution and a saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was then evaporated under reduced pressure. An organic substance was also collected from the filtrate by the same washing method. The solid and the organic substance were purified by silica gel column chromatography to obtain 6.5 g of 5-bromo-1-methyl-2-phenyl-1H-benzimidazole as a white crystal (yield: 89%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][NH:16][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.[Br:17][C:18]1[C:23](OC)=[CH:22][CH:21]=[C:20](I)[N:19]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I>[Br:17][C:18]1[N:19]=[C:20]([N:16]2[C:10]3[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[N:13]=[CH:12][C:11]=3[CH:14]=[N:15]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cncc(-c2cc3[nH]ncc3cn2)n1
Reactant: COc1ccc(I)nc1Br
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(Br)n2)n1
Temperature: 85 °C
Yield: 64.6 %

Procedure:
A solution containing 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (250 mg, 1.18 mmol), 2-bromo-6-iodo-3-methoxypyridine (570 mg, 1.78 mmol), Copper(I) iodide (225 mg, 1.18 mmol), Potassium carbonate (196 mg, 1.42 mmol) and N,N′-Dimethylethylenediamine (0.25 mL, 2.37 mmol) was stirred at 85° C. 4 h. The reaction was filtered through celite and concentrated. The crude product purified by isco column (EtOAc/Hep eluted at 100% EtOAc) to give the desired product 280 mg 59% yield. MS (ESI) m/z: 397.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:24]=[C:25]([NH2:32])[C:26]=2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.Cl[CH2:34][CH2:35][CH2:36][CH2:37]Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:24]=[C:25]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:26]=2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=1
Reactant: ClCCCCCl
Reactant: CCOC(=O)c1c(N)nn2c(-c3ccc(C(F)(F)F)cc3)c(-c3ccccc3Cl)cnc12
Product: CCOC(=O)c1c(N2CCCC2)nn2c(-c3ccc(C(F)(F)F)cc3)c(-c3ccccc3Cl)cnc12
Yield: 26 %

Procedure:
The compound obtained in Example 484 (2.1 g) and 1,4-dichlorobutane (2.9 g) were treated in the same manner as described in Example 43 to give 6-(2-chlorophenyl)-7-(4-trifluoromethylphenyl)-3-ethoxycarbonyl-2-(pyrrolidin-1-yl)pyrazolo[1,5-a]-pyrimidine (0.61 g, yield: 26%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:12]1[C:17]([NH2:20])=[N:18][OH:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]([C:25]#[C:26][C:27]([O:29][CH3:30])=[O:28])=[O:24]>C(Cl)(Cl)Cl>[CH3:21][O:22][C:23](=[O:24])[C:25]([O:19][N:18]=[C:17]([NH2:20])[C@@H:12]1[CH2:13][C@H:14]([F:16])[CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[CH:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)C#CC(=O)OC
Reactant: NC(=NO)[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C=C(ON=C(N)[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1)C(=O)OC

Procedure:
Benzyl-(2S,4S)-2-[amino(hydroxyimino)methyl]-4-fluoropyrrolidine-1-carboxylate in chloroform was treated with dimethylacetylene dicarboxylate for 3 hours at 60° C. The chloroform was then concentrated to give the title compound as a 8:2 mixture of isomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2I.[CH3:25][O:26][C:27]1[CH:48]=[CH:47][C:30]([CH2:31][O:32][C:33]2[CH:38]=[C:37]([Sn](C)(C)C)[N:36]=[C:35]([S:43]([CH3:46])(=[O:45])=[O:44])[N:34]=2)=[CH:29][CH:28]=1>CN(C=O)C.C(Cl)Cl.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.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[C:37]1[CH:38]=[C:33]([O:32][CH2:31][C:30]2[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:48][CH:47]=2)[N:34]=[C:35]([S:43]([CH3:46])(=[O:45])=[O:44])[N:36]=1
Reactant: COc1ccc(COc2cc([Sn](C)(C)C)nc(S(C)(=O)=O)n2)cc1
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(I)nn2C1CCCCO1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)nc(S(C)(=O)=O)n2)cc1
Temperature: 100 °C
Yield: 88.3 %

Procedure:
A glass microwave reaction vessel was charged with 5-(2,6-difluorophenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (347 mg, 0.788 mmol) and 4-(4-methoxybenzyloxy)-2-(methylsulfonyl)-6-(trimethylstannyl)pyrimidine (360 mg, 0.788 mmol) in DMF (3 mL) followed by Pd(PPh3)4 (45.5 mg, 0.039 mmol) and CuI (31 mg, 0.158 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 30 min. The mixture was diluted with DCM and washed with water, brine, dried with MgSO4, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 10-30% EtOAc in Hexanes) to give 5-(2,6-difluorophenyl)-3-(6-(4-methoxybenzyloxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (422 mg, 0.696 mmol, 88% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 606.5 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:10][C:11](=[O:40])[CH:12]([CH2:35][S:36][C:37](=[O:39])[CH3:38])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([N:20](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:18][CH:19]=1)[CH3:9]>C(Cl)Cl>[CH2:8]([O:10][C:11](=[O:40])[CH:12]([CH2:35][S:36][C:37](=[O:39])[CH3:38])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=1)[CH3:9]
Reactant: CCOC(=O)C(CSC(C)=O)Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CSC(C)=O)Cc1cnc(N)nc1
Reaction time: 2 h
Yield: 132 %

Procedure:
TFA (1.5 mL) was added to a solution of 2-acetylsulfanylmethyl-3-(2-[N,N-bis(tert-butoxycarbonyl)amino]-pyrimidin-5-yl)-propionic acid ethyl ester (225 mg, 0.46 mmol) in methylene chloride (1.5 mL). The reaction was stirred for 120 min and concentrated under reduced pressure to give the title compound (172 mg, 94%) as the TFA salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:15]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9]1>CO.[Pd]>[NH2:15][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9]2)=[C:2]([F:1])[CH:3]=1
Reactant: N#Cc1ccn(-c2ccc([N+](=O)[O-])cc2F)c1
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccn(-c2ccc(N)cc2F)c1
Reaction time: 3.5 h

Procedure:
3-Fluoro-4-(3-cyano-1-pyrrolyl)nitrobenzene (5.3 g, 22.9 mmnol) was dissolved in hot MeOH (250 ml) and palladium catalyst (10% on charcoal, 700 mg) added under a nitrogen atmosphere. The mixture was cooled and hydrogenated at atmospheric pressure for 3.5 hours. After filtration through celite, the solution was evaporated to dryness to give title product in sufficent purity for the next stage (4.6 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23]>>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([S:14]([NH:18][C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([OH:24])=[O:23])(=[O:16])=[O:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CSc1nccc(-c2ccc(S(=O)(=O)Cl)s2)n1
Product: CSc1nccc(-c2ccc(S(=O)(=O)Nc3cccc(C(=O)O)c3)s2)n1
Yield: 78.5 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting with 5-[2-(methylthio)pyrimidin-4-yl]thiophene-2-sulfonyl chloride (16.8 mg, 0.055 mmol) and 3-aminobenzoic acid (6.9 mg, 0.05 mmol) affording 16.0 mg (78%) of the title compound. MS (ESI+) calcd for C16H13N3O4S3 407.006818, found 407.007148.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(=[O:16])=[O:15])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][S:14]([CH2:13][C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)(=[O:15])=[O:16])=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CS(=O)(=O)Cc2ccc(F)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Cc1ccc(F)cc1)C[C@@H]1CCNC1

Procedure:
Using a similar method to that described in Example 93, step 2, (3R)-1-(tert-butoxycarbonyl)-3-[(4-fluorobenzylsulphonyl)-methyl]pyrrolidine (0.6465 g, 1.81 mmol) was reacted with trifluoroacetic acid (2ml) in dichloromethane (6 ml) to give, after work up, 0.4755 g of the title compound as a white solid, which was used without further purification. δH (360 MHz, CDCl3) 1.55 (1H, m), 2.15 (1H, m), 2.60-2.73 (2H, m), 2.90-3.00 (4H, m), 3.30 (1H, m), 4.21 (2H, s), 7.11 (2H, t, J=8.6 Hz), 7.37-7.41 (2H, m).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:53])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4].[C:54]([O:58][C:59]([NH:61][C@H:62]([C:64]([NH:66][C@H:67]([C:69](O)=[O:70])[CH3:68])=[O:65])[CH3:63])=[O:60])([CH3:57])([CH3:56])[CH3:55]>ClCCl>[C:54]([O:58][C:59]([NH:61][C@H:62]([C:64]([NH:66][C@H:67]([C:69]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:53])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4])=[O:70])[CH3:68])=[O:65])[CH3:63])=[O:60])([CH3:57])([CH3:56])[CH3:55]
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 55 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-oleamide and N-tert-butyloxycarbonyl-L-alanyl-L-alanine. Yield 55%. [α]D =+10.3° (c=0.85, dichloromethane).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8])[CH3:3].Cl>CO.[Pd]>[CH:2]([C:4]1[CH:5]=[C:6]([CH2:7][NH2:8])[CH:9]=[CH:10][N:11]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)c1cc(C#N)ccn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)c1cc(CN)ccn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 59.2 %

Procedure:
A mixture of 154 mg (1.07 mmol) of 2-(prop-1-en-2-yl)isonicotinonitrile and 19.2 mg of 10% Pd/C with 1.7 mL of 1.25 N HCl in 10 mL of MeOH was stirred at r.t. under H2 balloon for 14 h. The mixture was filtered through Celite and concentrated. Saturated NaHCO3 was added, and the mixture concentrated with methanol, filtered through a sintered funnel, and reconcentrated to give 95.1 mg of crude (2-isopropylpyridin-4-yl)methanamine which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([OH:13])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CC(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH2:23][CH:22]=[CH2:21])[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Yield: 98.7 %

Procedure:
To a solution of 3-hydroxy-4-nitro-benzoic acid methyl ester (50.0 g, 253.6 mmol) in acetone (1 L) was added potassium carbonate (105.0 gram, 759.7 mmol) and allyl bromide (44.0 mL, 508.4 mmol). The reaction mixture was heated to reflux overnight and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure to give 3-allyloxy-4-nitro-benzoic acid methyl ester as solid (59.4 g, 98.8%). 1H NMR (CDCl3) δ3.96 (s, 3H), 4.75 (dt, 2H, J=5.0 Hz, 1.6 Hz), 5.36 (ddt, 1H, J=10.6 Hz, 1.4 Hz, 1.4 Hz), 5.50 (ddt, 1H, J=17.2 Hz, 1.6 Hz, 1.6 Hz), 6.05 (ddt, 1H, J=17.3 Hz, 10.6 Hz, 5.0 Hz), 7.69 (dd, 1H, J=8.33 Hz, 1.58 Hz), 7.75 (d, 1H, J=1.55 Hz), 7.83 (d, 1H, J=8.34 Hz).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.O1[C:31]2[C:30](=[O:32])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:23][C:22]1=2>C(#N)C.CN(C)C=O>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:31]1[C:30](=[O:32])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:23][CH:22]=1
Reactant: O=c1c2c(oc3ccccc13)O2
Reactant: c1ccc2[nH]cnc2c1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1c(-c2nc3ccccc3[nH]2)coc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
Benzimidazole (472 mg) and DBU (608 mg) were dissolved in acetonitrile (20 ml), and stirred at room temperature for 1 hour. To the resulting solution, a solution of 2,3-epoxychromone (162 mg) in dimethylformamide (5 ml) was added dropwise, and the whole was stirred for 5 minutes. After ice water was added, the reaction mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was fractionatedby silica gel column chromatography (ethyl acetate/hexane=1:3) to give the titled compound (122 mg; yield=93%). Melting point: 154° C. Mass spectrum (M+): 262. 1H-NMR(CDCl3, δ ppm): 8.21 (s, 1H, H2), 8.33 (dd, 1H, H5), 7.52 (t, 1H, H6), 7.80 (t, 1H, H7), 7.61 (d, 1H, H8), 8.35 (s, 1H, H2'), 7.33 (m, 3H, H4', 5', 6'), 7.86 (d, 1H, H7').
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:23]=[CH:22][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.C([O-])(=O)C.[Na+].[Br:35]Br.ClCCl>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:23]=[CH:22][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=3)=[CH:11][CH:10]=2)[C:5]([Br:35])=[C:4]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:3]=1
Reactant: N#Cc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc(Oc2ccc(Nc3nc(N)nc(-c4ccccc4)c3Br)cc2)ccn1
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a solution of 4-[4-(2-amino-6-phenyl-pyrimidin-4-ylamino)-phenoxy]-pyridine-2-carbonitrile (Example 8, 200 mg, 0.53 mmol) and sodium acetate (146.6 mg, 459.8 mmol) in acetic acid (4 mL) at rt was added bromine (84 mg, 0.53 mmol). The reaction was allowed to stand for 2 h after which time dichloromethane (20 mL) was added followed by water (20 mL). The phases were separated and the organic layer was washed with a saturated aqueous bicarbonate solution. The combined organic extracts were dried over MgSO4 and then evaporated under vacuum. The crude material was purified by column chromatography eluting with a gradient of 0 to 60% AcOEt/Hexanes to give 4-[4-(2-Amino-5-bromo-6-phenyl-pyrimidin-4-ylamino)-phenoxy]-pyridine-2-carbonitrile as an orange solid (200 mg, 83%). 1H NMR (DMSO d6) δ 8.58 (d, J=5 Hz, 1H, 8.50 (Br, 1H), 7.90-7.86 (m, 2H), 7.67 (d, J=2 Hz, 1H), 7.54-7.51 (m, 2H), 7.47-7.41 (m, 3H), 7.20-7.16 (m, 3H), 6.57 (Br, 2H). MS ES 459 (M+H)+, calcd 459, RT=2.85 min.
Reaction SMILES: [C:1]([CH:3]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[C:5]=1[O:14][CH3:15])#[N:2].N1C=CC=CC=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(OCC)C>[C:1]([CH:3]([N:16]1[CH2:21][CH2:20][N:19]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:18][CH2:17]1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[C:5]=1[O:14][CH3:15])#[N:2]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(C(C#N)N2CCNCC2)c(OC)c1OC
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)N1CCN(C(C#N)c2ccc(OC)c(OC)c2OC)CC1
Temperature: 25 °C

Procedure:
14.5 g. of N-(α-cyano-2,3,4-trimethoxybenzyl)piperazine was dissolved in 50 ml. of anhydrous diethyl ether and to the resultant solution was added 4 g. of pyridine. To the mixture was added dropwise 6 g. of ethyl chloroformate dissolved in 10 ml. of anhydrous diethyl ether over a period of about 30 minutes with ice cooling while the internal temperature was kept at 10°-15° C. The mixture was further stirred at room temperature and filtered off to separate an insoluble matter. The filtrate was evaporated to give crude N-(α-cyano-2,3,4-trimethoxybenzyl)-N'-ethoxycarbonylpiperazine as an oily substance. This product was dissolved in toluene and the resultant solution was saturated with dry hydrochloric gas to separate crystal which was collected by filtration. Recrystallization from tetrahydrofuran-methanol afforded 14 g. of crystal having a melting point of 137.5°-139.0° C.