Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:13]1[N:18]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)[C:17](=[O:27])[C:16]2=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][N:15]2[N:14]=1)[CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:34]1[N:39]=[CH:38][N:37]=[C:36]([NH2:40])[C:35]=1[I:41].[F-].[Cs+].C(N(CC)C(C)C)(C)C>>[NH2:40][C:36]1[N:37]=[CH:38][N:39]=[C:34]([NH:1][C@H:2]([C:13]2[N:18]([C:19]3[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=3)[C:17](=[O:27])[C:16]3=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][N:15]3[N:14]=2)[CH2:3][CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:35]=1[I:41]
Reactant: N#Cc1ccn2nc([C@@H](N)CCOCc3ccccc3)n(-c3cc(F)cc(F)c3)c(=O)c12
Reactant: Nc1ncnc(Cl)c1I
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccn2nc([C@H](CCOCc3ccccc3)Nc3ncnc(N)c3I)n(-c3cc(F)cc(F)c3)c(=O)c12
Yield: 15.3 %

Procedure:
(S)-2-(1-Amino-3-(benzyloxy)propyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-5-carbonitrile (51 mg, 0.12 mmol) was treated with 6-chloro-5-iodopyrimidin-4-amine (50 mg, 0.2 mmol), cesium fluoride (55 mg, 0.36 mmol) and N,N-diisopropylethylamine (170 μl, 0.98 mmol) according to the method of Preparation 13. The residue was purified by reverse phase using SP1® Purification System to give 12 mg (16% yield) of the title compound.
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:2][N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:15]([O:19][C:20](ON=C(C1C=CC=CC=1)C#N)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCOCC1.O>[C:15]([O:19][C:20]([N:6]1[CH2:7][CH2:8][N:3]([CH2:2][CH2:1][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH2:4][CH2:5]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: C1CN(CCN2CCNCC2)CCN1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCN2CCNCC2)CC1

Procedure:
1,1'-ethylenedipiperazine (1.98 g, 10 mmol) is dissolved in 20 mL of dioxane: water (1:1) mixture and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (2.46 g, 10 mmol) is added. The mixture is then stirred until no starting material is detected on thin layer chromatography. The obtained mixture is fractionally separated by silica gel chromatography, followed by RP-HPLC to obtain N-[4-tert-butoxycarbonylpiperazino]ethyl-piperazine. Following the procedure of Example 6, but replacing 1-benzylpiperazine with N-[4-tert-butoxycarbonylpiperazino]ethyl-piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), N-[4-tert-butoxycarbonylpiperazino]ethyl-piperazine (1.817 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5, followed by a carefully deprotection of N-tert-butoxycarbonyl group with 10% trifiuoroacetic acid to obtain the pure title compound.
Reaction SMILES: [C:1]1([C:7](=O)[CH:8](Br)[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C([O-])(O)=O.[Na+]>CCO>[CH3:18][S:15]([C:12]1[CH:13]=[CH:14][C:9]([C:8]2[N:26]3[C:22]([S:23][CH:24]=[CH:25]3)=[N:21][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccccc3)nc3sccn23)cc1
Yield: 44.1 %

Procedure:
A mixture of the bromoketone of step 3 (2.26 g, 6.4 mmol) and 2-aminothiazole (964 mg, 9.6 mmol) in EtOH (45 mL) was heated to reflux for 18 h. Aqueous NaHCO3 was added to the cooled mixture and the mixture was extracted with Et2O. The Et2O extracts were washed with brine, dried over MgSO4, filtered and concentrated to an oil. Chromatography of the oil on silica gel (eluted with 60 % EtOAc/hexane) gave 1 g (44%) of the title compound: m.p. 190°-192° C. Anal. calcd for C18H14N2O2S2 : C, 61.00; H, 3.98; N, 7.90. Found: C, 60.31; H, 3.96; N, 7.68. 1H NMR (CD3COCD3): δ3.20 (s, 3H), 7.20-7.34 (m, 4H), 7.58-7.61 (m, 2H), 7.77-7.83 (m, 3H), 8.03-8.06 (m, 2H).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[NH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:14][CH2:13]1.C(Cl)Cl>CCOCC>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][N:12]([NH:11][C:8]([NH:7][C:3]3[CH:2]=[C:1]([CH3:10])[CH:6]=[CH:5][CH:4]=3)=[O:9])[CH2:13][CH2:14]2)=[CH:21]1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NN1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cccc(NC(=O)NN2CCN(CCc3c[nH]c4ccccc34)CC2)c1
Reaction time: 2 h

Procedure:
3.34 g of m-tolylisocyanate are added dropwise to a stirred solution of 6.13 g of 3-[2-(4-aminopiperazin-1-yl)ethyl]indole in 100 ml. of dry methylene chloride while maintaining the reaction temperature below 35° C. After 2 hours a fine precipitate appears, 50 ml. of ether are added and stirring is continued for 3 additional hours. More ether is added and the product is filtered and washed with ether. The solid product is recrystallized from an ethanol and water mixture to give white flakes, m.p. 186°-188° C. of 1-[1-(indol-3-ylethyl)piperazin-4-yl]-3-m-tolylurea.
Reaction SMILES: N[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([Br:14])=[CH:4][N:3]=1.N([O-])=[O:16].[Na+]>>[OH:16][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([Br:14])=[CH:4][N:3]=1
Reactant: O=N[O-]
Reactant: Nc1ncc(Br)nc1N1CCOCC1
Agent: [Na+]
Product: Oc1ncc(Br)nc1N1CCOCC1

Procedure:
2-Amino-3-morpholino-5-bromopyrazine (see Preparation 92, Step A) is treated with sodium nitrite by the method described in Preparation 91, Step C, to give 2-hydroxy-3-morpholino-5-bromopyrazine.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.C1C=CC2N([OH:25])N=NC=2C=1.O.CN1CCOCC1>CN(C=O)C>[CH:10]1([NH:9][C:8](=[O:25])[NH:7][CH:4]2[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: On1nnc2ccccc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
DCys(O3Bu4N)-Pro-DThg-Leu-resin prepared in the same manner described in Example 5, was acylated with Boc-DTrp(CHO) by the standard protocol described in Example 5. The resulting resin was washed successively with DMF, methanol, and dichloromethane and dried in vacuo to give Boc-DTrp(CHO)-DCys(O3Bu4N)-Pro-nThg-Leu-resin. The resin was added to TFA/water(95/5, 20 ml) and the mixture was stirred at room temperature for 1.5 h and filtered. The collected resin was washed with TFA and the combined filtrate and washings were concentrated under reduced pressure. The residue was precipitated with ether to give DTrp(CHO)-DCys(O3Bu4N)-Pro-DThg-Leu. A solution of the pentapeptide(28 mg) in DMF(1.4 ml) was added dropwise to a solution of DCC(9 mg), HOBT H2O(7 mg) and N-methylmorpholine(1.6 μl) in DMF(1.4 ml) under ice cooling over a period of 1 h. The reaction mixture was stirred under ice cooling for 1 h and at room temperature for 17 h. Acetic acid(10 μl) was added to the reaction mixture. The resulting mixture was stirred and concentrated under reduced pressure. The residue was triturated with water to give colorless dicyclohexyl urea which was collected by filtration and thoroughly washed with water. The combined filtrate and washings were lyophilized to give a colorless solid which was purified by thin layer chromatography on silica gel (Analtichem International, Empore sheet) with butanol/acetic acid/water(8/1/1) for development to give an ammonium salt of the title compound. A water solution of the ammonium salt was passed through a column of ion exchange resin(AMBERLITE IR-120B, H+ -form) and lyophilized. The resulting solid(12.93 mg) was dissolved in water(0.6 ml) and the equimolar amount of NaHCO3 was added. The solution was directly purified by reverse-phase short column chromatography(Waters, SEP-PAK C18 cartridge) with water and methanol for elution. The combined methanolic layers were concentrated under reduced pressure to give the title compound(10.74 mg) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(ccn2Cc2ccccc2)c1

Procedure:
5-Methoxy-1H-indole (5.6 g, 21.5 mmol) was reacted with 1.0 g (25 mmol) of 60% sodium hydride and then 3.0 mL (25 mmol) of benzyl bromide by the method described in Example 12, Part D to give crude 5-methoxy-1-(phenylmethyl)-1H-indole. This material was dissolved in 250 mL of methylene chloride, cooled to −5° C., 50 mL of 1M BBr3/CH2Cl2 added, the cooling bath removed and the mixture stirred for 1.75 hours. Ice water was added and the mixture stirred. The organic layer was separated, washed with saturated NaCl, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted with 20% ether/hexaneØether to give 870 mg (19% overall yield) of crude 5-hydroxy-1-(phenylmethyl)-1H-indole.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Br:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[S:13][C:14]=1[Br:15]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:16]([C:12]1[S:13][C:14]([Br:15])=[C:10]([Br:9])[CH:11]=1)(=[O:18])=[O:17]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cc(Br)c(Br)s1
Product: Cc1noc(NS(=O)(=O)c2cc(Br)c(Br)s2)c1Br
Yield: 45 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-4,5-dibromothiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 4,5-dibromothiophene-2-sulphonyl chloride in 45% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 153-155° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[C:35]1(CO)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccccc4)cc3)c2cc1OC
Yield: 68.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, phenylmethanol (55 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (100 mg, yield 58%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2.CCN(C(C)C)C(C)C>C(O)CCC.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:24]=2[CH:25]=[N:26][NH:27]3)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Nc1cccc2[nH]ncc12
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc5[nH]ncc45)nc(Cl)nc32)cc1
Temperature: 90 °C
Yield: 93.4 %

Procedure:
To a solution of 2,4-dichloro-7-tosyl-pyrrolo[2,3-d]pyrimidine (0.68 g, 2 mmol) in nBuOH (5 ml) was added 4-aminoindazole (0.293 g, 2.2 mmol) and DIPEA (0.534 mL, 3 mmol) at room temperature. After heating at 90° C. for 15 h, it was diluted with EtOAc, the organic layer was washed with 1N HCl, Sat NaHCO3, brine, dried and concentrated to give crude 2-chloro-N-(1H-indazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.82 g).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][C:18]([F:24])([F:23])[CH2:19][CH:20]1[CH2:22][CH2:21]1)[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1.[ClH:25]>O1CCOCC1>[ClH:25].[NH2:11][C@@H:12]([CH2:17][C:18]([F:23])([F:24])[CH2:19][CH:20]1[CH2:22][CH2:21]1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)[C@H](CC(F)(F)CC1CC1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)CC(F)(F)CC1CC1
Yield: 98.8 %

Procedure:
A solution of (S)-methyl 2-(benzyloxycarbonylamino)-5-cyclopropyl-4,4-difluoropentanoate (570 mg, 1.87 mmol) in dioxane/4N—HCl (9 mL, 37 mmol) was stirred at RT for two hr, after which the solvent was removed by rotoevaporation to give 450 mg of (S)-methyl 2-amino-5-cyclopropyl-4,4-difluoropentanoate hydrochloride as a beige solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:28])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([O:35][C:36]([NH:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]1[CH:51]=[CH:50][C:49]([CH2:52]O)=[CH:48][CH:47]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:19]=2[N:18]([CH2:52][C:49]2[CH:48]=[CH:47][C:46]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[CH2:39][NH:38][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])=[CH:51][CH:50]=2)[C:17]1=[O:28])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2cc(F)ccc2NC1=O
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3cc(F)ccc32)cc1

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl-N-[7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]propanamide (Step E) and 2'-[(t-butoxycarbonylamino)methyl]-1,1'-biphenyl-4-methanol, methanesulfonate ester (Example 35, Step G) according to the procedure described in Example 35, Step H. 1H NMR (200 MHz, CDCl3): δ 1.39 (s, 9H), 1.48 (s, 3H), 1.51 (s, 3H), 1.78 (m, 1H), 2.35-2.70 (m, 3H), 4.18 (d, 7 Hz, 2H), 4.42 (m, 1H), 4.58 (m, 1H), 4.75 (d, 16 Hz, 1H), 5.05 (s, 2H), 5.27 (d, 16 Hz, 1H), 5.35 (s, 1H), 6.88 (dd; 8, 6 Hz; 1H), 6.98 (m, 1H), 7.09 (d, 6 Hz,1 H), 7.14-7.35 (m, 13H), 7.40 (d, 8HZ, 1H). FAB-MS: calculated for C41H45FN4O6 708; found 709 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[I:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][OH:15])[CH:10]=[CH:11][CH:12]=1.C(N(C(C)C)CC)(C)C>ClCCl.[Cl-].[NH4+]>[CH3:1][S:2]([O:15][CH2:14][CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([I:6])[CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cccc(I)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cccc(I)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
Methanesulfonyl chloride (1.5 mL, 1.2 eq.) was added dropwise to a stirred solution of 2-(3-iodophenyl)ethanol (3.6 g) in dichloromethane (100 mL) and diisopropylethylamine (3.8 mL, 1.5 equiv.) at 0° C. The solution was warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with aqueous ammonium chloride solution and extracted with dichloromethane. The organic layers were combined, washed with aqueous sodium hydrogencarbonate solution, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude was purified using column chromatography (SiO2 cartridge) using DCM-cyclohexane (70:30) to afford the title compound (3.2 g, 45% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:21])=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[C:10]=1[CH3:11])=[O:5])[CH3:2].C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:21])=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nn(-c2ccccc2[N+](=O)[O-])c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nn(-c2ccccc2N)c1C

Procedure:
To a solution of 3,5-dimethyl-1-(2-nitrophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.4 g) in a solution of equal proportions of ethanol and ethyl acetate was added 5% Pd/C (37 mg). The solution was treated with hydrogen gas at 45 psi. Upon completion of the reaction, the mixture was filtered through Celite, then the filtrate concentrated under vacuum. The named product was collected as an oil, which then was purified by flash chromatography to provide a solid product having a melting point of 59° C.–61° C.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:19])[CH2:6][N:7]([C:13](=[O:18])[CH:14]([CH3:17])[CH2:15][SH:16])[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:3].[CH2:20](I)[CH3:21]>C(O)C>[CH2:2]([O:4][C:5](=[O:19])[CH2:6][N:7]([C:13](=[O:18])[CH:14]([CH3:17])[CH2:15][S:16][CH2:20][CH3:21])[CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12]1)[CH3:3]
Reactant: CCI
Reactant: CCOC(=O)CN(C(=O)C(C)CS)C1CCCC1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)C(C)CSCC)C1CCCC1
Reaction time: 1 h

Procedure:
To a solution of 0.45 g (0.02M) of sodium in 50 ml ethanol was dropwise added a solution of 4.8 g of N-(3-mercapto-2-methyl propanoyl)-N-cyclopentyl glycine ethyl ester in 10 ml ethanol and stirring continued for 1 hour. Then, 3.04 g (0.02M) ethyl iodide in 5 ml ethanol was added and stirring continued for 4 hours. The solution was concentrated in vacuum, diluted with ether, washed with water, dried over MgSO4 and evaporated to dryness. The oily residue was chromatographed by HPLC using EtOAc-hexane (3:17) as eluent.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:14][C:15]1[CH:23]=[CH:22][C:18]2[N:19]=[CH:20][NH:21][C:17]=2[CH:16]=1.[Si](C#N)(C)(C)C.[N:30]1([C:35](N2C=CN=C2)=[O:36])C=CN=[CH:31]1>>[NH:19]1[C:18]2[CH:22]=[CH:23][C:15]([N:14]3[CH:4]([C:3]4[CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][C:2]=4[F:1])[CH2:31][NH:30][C:35]3=[O:36])=[CH:16][C:17]=2[N:21]=[CH:20]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: C[Si](C)(C)C#N
Product: O=C1NCC(c2cc(C(F)(F)F)ccc2F)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized from 2-fluoro-5-(trifluoromethyl)benzaldehyde (0.565 mL, 4 mmol), 5-aminobenzimidazole (0.585 g, 4.4 mmol), TMSCN (0.5 g, 4 mmol), TEA (0.669 mL, 4.8 mmol), PdC (10%, 0.02 g), di(1H-imidazol-1-yl)methanone (0.778 g, 4.8 mmol) as described in method 2.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[C:5]2[C:6]([CH:10]=[CH2:11])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[Cl:1][C:2]1[N:12]=[C:5]2[C:6](/[CH:10]=[CH:11]/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: C=Cc1cccn2nc(Cl)nc12
Reactant: CN(c1ccccc1Br)S(C)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(c1ccccc1/C=C/c1cccn2nc(Cl)nc12)S(C)(=O)=O
Temperature: 100 °C

Procedure:
196 c) A tube was charged with 2-chloro-8-vinyl-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.5568 mmol), N-(2-bromo-phenyl)-N-methyl-methanesulfonamide (140.0 mg, 0.5300 mmol), palladium acetate (4.0 mg, 0.018 mmol) and tri-o-tolylphosphine (26.0 mg, 0.0854 mmol), triethylamine (0.35 mL, 2.5 mmol) and acetonitrile (1 mL) under an atmosphere of nitrogen. The tube was sealed and the mixture was heated at 100° C. for 18 hours then cooled to room temperature, diluted with dichloromethane (30 mL) and washed with 2N Hydrochloric acid (10 mL). The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. The residue was purified via chromatography (silica gel column 24 g and 10%→90% ethyl acetate:hexane). N-{2-[(E)-2-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-vinyl]-phenyl}-N-methyl-methanesulfonamide was isolated as a tan foam (0.133 g, 69%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.52 (d, J=16.1 Hz, 1H), 8.40 (d, J=6.8 Hz, 1H), 7.86 (d, J=7.1 Hz, 1H), 7.65 (d, J=7.4 Hz, 1H), 7.46-7.30 (m, 3H), 7.20-7.05 (m, 2H), 3.36 (s, 3H), 3.19 (s, 3H). MS=363, 365 (MH)+.
Reaction SMILES: [CH2:1]([O:5][C:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])[CH3:7])[C:2](=C)[CH3:3].CC[O:16]C(C)=O>>[CH2:9]([O:8][C:6]([O:11][CH2:12][CH3:13])([O:5][CH2:1][C:2](=[O:16])[CH3:3])[CH3:7])[CH3:10]
Reactant: CCOC(C)=O
Reactant: C=C(C)COC(C)(OCC)OCC
Product: CCOC(C)(OCC)OCC(C)=O
Reaction time: 8 h
Yield: 82 %

Procedure:
To a cold (0° C.) suspension of NaH (2.68 g, 60%) in THF (150 mL) was added a solution of 1,1-diethoxyethanol [which was prepared according to the literature procedure of Zirkle, C. L. et. al. J. Org. Chem. 1961, 26, 395-407] (9.00 g) in THF (20 mL), and the reaction mixture was stirred at room temperature for 1 hour before adding methallyl chloride (8.0 mL). The reaction mixture was heated to reflux overnight, cooled and filtered through a plug of celite. Solvent was removed by rotary evaporation, and the residue purified by column chromatography (silica, 20% ether/hexane) to give 1,1-diethoxyethyl methallyl ether (11.5, 90%). ozonolysis of a chilled (−30° C.) solution of this ether (6.00 g) in EtOAc (80 mL) was carried out until no starting material was detectable by TLC (1 hour). At this time, the reaction was purged with oxygen, treated with Pd(OH)2 (150 mg) and stirred under an atmosphere of hydrogen overnight. The catalyst was filtered away, and the filtrate was concentrated by rotary evaporation. The resulting residue was purified by column chromatography (silica, 20% EtOAc/hexane) to afford the title compound (4.53 g, 82%).