Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1.[CH2:30]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([C:42]4[CH:41]=[CH:40][C:39]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:44][CH:43]=4)[CH:29]=[CH:28][C:5]=3[N:6]=2)=[CH:10][CH:11]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCc1ccc(B(O)O)cc1
Reactant: CCCCCCCCCCCCOc1ccc(-c2nc3ccc(Br)cc3s2)cc1
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
Product: CCCCCCCCCCCCOc1ccc(-c2nc3ccc(-c4ccc(CCCCCCCCC)cc4)cc3s2)cc1
Yield: 74.6 %

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium(0) (0.30 g, 0.26×10−3 mol), 6-bromo-2-(4-dodecyloxyphenyl)benzothiazole (2.50 g, 5.27×10−3 mol), 4-nonylbenzene boronic acid (1.57 g, 6.33×10−3 mol), 2M sodium carbonate solution (25 cm3) and 1,2-dimethoxyethane (100 cm3). The reaction mixture was heated under reflux overnight. The cooled reaction mixture was extracted with dichloromethane (2×100 cm3) and the combined organic layers were washed with brine (2×100 cm3) and dried (MgSO4). After filtration the solvent was removed under reduced pressure and the residue was purified by column chromatography [silica gel, dichloromethane: hexane 1:1] followed by recrystallisation from ethanol to yield 2.35 g (74.5%) of the desired product.
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16](C)[C:17](=O)OC(C)(C)C)[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]#[N:44])[N:29]=2)[C:6]2[CH:45]=[CH:46][CH:47]=[CH:48][C:5]1=2)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([NH:16][CH3:17])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]#[N:44])[N:29]=2)[C:6]2[CH:45]=[CH:46][CH:47]=[CH:48][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2N(Cc2nn(-c3ccccc3C#N)c3ccccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2nn(-c3ccccc3C#N)c3ccccc23)c2ccccc2N(C(C)=O)[C@H]1C
Reaction time: 1.5 h

Procedure:
To a rt solution of tert-butyl(S)-1-((2S,3S)-1-acetyl-5-((1-(2-cyanophenyl)-1H-indazol-3-yl)methyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (79 mg, 122 μmol) in CH2Cl2 (486 μl) was added TFA (122 μl). The reaction was stirred for 1.5 h, then concentrated and purified by reverse phase preparative HPLC to provide, after extraction from sat. aq. NaHCO3, (S)-N-((2S,3S)-1-acetyl-5-((1-(2-cyanophenyl)-1H-indazol-3-yl)methyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide (57.0 mg, 85%) as a white solid. MS m/z 550 (MH)+.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([NH:14][CH3:15])[CH:6]=1)[CH3:2]>C(O)C.[C].[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([NH:3][CH2:1][CH3:2])=[O:16])=[CH:6][C:7]=1[NH:14][CH3:15]
Reactant: CCNC(=O)c1ccc([N+](=O)[O-])c(NC)c1
Agent: [Pd]
Solvent: CCO
Product: CCNC(=O)c1ccc(N)c(NC)c1
Reaction time: 15 h
Yield: 112 %

Procedure:
10% palladium-carbon (containing 50% water, 500 mg) was added to a solution of N-ethyl-3-(methylamino)-4-nitrobenzamide (1.99 g) in ethanol (50 ml), followed by stirring at ambient pressure under a hydrogen atmosphere for 15 hours. The reaction solution was filtered with celite and the solvent was evaporated under reduced pressure to obtain 4-amino-N-ethyl-3-(methylamino)benzamide (1.93 g) as a light red-purple oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][C:21](=O)[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:26][O:27][NH2:28]>CO.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][C:21](=[N:28][O:27][CH3:26])[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCC(CC(C(=O)Nc2nccs2)c2ccc(Cl)c(Cl)c2)C1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C1CCC(CC(C(=O)Nc2nccs2)c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A solution of the 2-(3,4-dichloro-phenyl)-3-(3-oxo-cyclopentyl)-N-thiazol-2-yl-propionamide (prepared as in Example 43, 159.9 mg, 0.41 mmol) and methoxyamine hydrochloride (52.3 mg, 0.62 mmol) in methanol (1.2 mL) and pyridine (1.2 mL) was heated under reflux for 3.5 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The resulting residue was diluted with ethyl acetate (75 mL), washed with a 1N aqueous hydrochloric acid solution (75 mL) and a saturated aqueous sodium chloride solution (75 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50% ethyl acetate/hexanes) afforded 2-(3,4-dichloro-phenyl)-3-(3-methoxyimino-cyclopentyl)-N-thiazol-2-yl-propionamide (168.2 mg, 98%) as a white foam: mp 69-72° C. (foam to gel); (ES)+-HRMS m/e calcd for C18H19Cl2N3O2S (M+H)+ 412.0648. found 412.0652.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[O:23][C:22](=O)[NH:21][N:20]=4)[CH:17]=3)[NH:12][CH:11]=2)[N:5]=1)([CH3:3])[CH3:2].Cl.[NH2:26][CH2:27][C:28]#[N:29].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[O:23][C:22]([NH:29][CH2:28][C:27]#[N:26])=[N:21][N:20]=4)[CH:17]=3)[NH:12][CH:11]=2)[N:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1ccnc(-c2c[nH]c3ccc(-c4n[nH]c(=O)o4)cc23)n1
Reactant: N#CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1ccnc(-c2c[nH]c3ccc(-c4nnc(NCC#N)o4)cc23)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.5 %

Procedure:
To a solution of 5-(3-(4-isopropylpyrimidin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2(3H)-one (350 mg, in about 60% pure) in DMF (4 mL) at RT was sequentially added 2-aminoacetonitrile hydrochloride (302 mg, 3.27 mmol) (Alfa Aesar), diisopropylethylamine (0.79 mL, 4.57 mmol) and BOP (530 mg, 1.20 mmol) (Aldrich). After the reaction was stirred at RT for 18 h, it was diluted with H2O (10 mL) and extracted with EtOAc (3×25 mL). The aqueous layer was discarded. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified on a silica gel column eluting with 25-100% EtOAc in Hex to give 2-(5-(3-(4-isopropylpyrimidin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-ylamino)-acetonitrile (45 mg) as a brown amorphous solid. MS (ESI, pos. ion) m/z: 360.0 (M+1). 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.99 (1H, br.), 9.16 (1H, s), 8.69 (1H, d, J=5.1 Hz), 8.49 (1H, t, J=5.7 Hz), 8.33 (1H, m), 7.73 (1H, d, J=8.2 Hz), 7.62 (1H, d, J=8.6 Hz), 7.16 (1H, d, J=5.1 Hz), 4.43 (2H, d, J=5.7 Hz), 3.06 (1H, dt, J=13.7, 6.8 Hz), 1.37 (6H, d, J=6.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH3:17]>O1CCOCC1>[Cl:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:17])=[O:5]
Reactant: N
Reactant: O=C(O)c1ccc(F)c(F)c1Cl
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc(F)c(F)c1Cl
Temperature: 80 °C

Procedure:
2-Chloro-3,4-difluorobenzoic acid (2 g, 10.4 mmol) was treated with thionyl chloride (3.04 ml) and the mixture was heated to 80° C. for 90 minutes. The mixture was then cooled and reduced in vacuo. The residue was dissolved in anhydrous 1,4-dioxane (10 ml) and the mixture was then cooled in an ice-water bath. 0.88 Ammonia (aqueous, 25 ml) was added dropwise to the mixture which was subsequently allowed to warm to 22° C. over a period of 2 hrs. This process was repeated using 10.8 g of 2-chloro-3,4-difluorobenzoic acid, 8.2 ml of thionyl chloride, and 45 ml of 0.88 ammonia and then both mixtures were combined and partitioned between ethyl acetate (150 ml) and water (100 ml). The aqueous layer was separated and extracted with 2×150 ml aliquots of ethyl acetate. The combined organic extracts were then washed with saturated aqueous sodium hydrogen carbonate (100 ml), dried using a hydrophobic frit, and reduced in vacuo to give 2-chloro-3,4-difluorobenzamide (11.86 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:38]=[CH:37][C:27]([CH2:28][P:29](=[O:36])([O:33]CC)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[Cl:39])[N:14]=2)=[CH:4][CH:3]=1.[I-].[Na+].N1C=CC=CC=1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:21])([F:20])[F:22])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:38]=[CH:37][C:27]([CH2:28][P:29](=[O:33])([OH:36])[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[Cl:39])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(Cl)c1)OCC
Agent: [I-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(Cl)c1

Procedure:
A mixture of diethyl (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-chlorobenzyl)phosphonate (Compound 58C, 4.30 g, 6.60 mmol) and Sodium iodide (1.483 g, 9.896 mmol) in Pyridine (21.4 mL, 265 mmol) was heated to reflux for 18 hours. The pyridine was removed in vacuo and the remaining solids were taken up in water (˜50 mL). This was treated with 6N HCl, dropwise with stirring, until pH-2 was reached. A thick ppt formed. This mixture was extracted with DCM twice. The combined organic layers were dried over Na2SO4, filtered and concentrated to 3.719 g of a tan solid (90%). The material was used without further purification. 1H NMR (400 MHz, CDCl3) δ 12.57 (br. s., 1H) 8.81 (d, J=8.8 Hz, 1H) 8.33 (s, 1H) 8.08 (q, J=4.5 Hz, 1H) 7.83 (br. s., 1H) 7.35-7.44 (m, 2H) 7.19 (dt, J=8.3, 2.4 Hz, 1H) 4.06 (quin, J=7.3 Hz, 2H) 3.10 (d, J=22.0 Hz, 2H) 3.02 (d, J=5.1 Hz, 3H) 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: C1(C)C=CC=CC=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].[C:22]([O:26][C:27](=[O:58])[NH:28][CH2:29][C:30]#[C:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][N:36]=[C:35]2[NH:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]2[CH:51]=[N:52][C:53]([CH3:56])=[CH:54][CH:55]=2)=[C:45]([Cl:57])[CH:44]=1)([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[C:22]([O:26][C:27](=[O:58])[NH:28][CH2:29]/[CH:30]=[CH:31]/[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][N:36]=[C:35]2[NH:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]2[CH:51]=[N:52][C:53]([CH3:56])=[CH:54][CH:55]=2)=[C:45]([Cl:57])[CH:44]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(C#CCNC(=O)OC(C)(C)C)cc34)cc2Cl)cn1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(/C=C/CNC(=O)OC(C)(C)C)cc34)cc2Cl)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a solution of 7.53 mL of a 65% weight toluene solution of sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al, 24.2 mmol) in 90 mL of tetrahydrofuran at 0° C. was added 5.0 g of (3-{4-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester as a solid. The reaction was stirred at 0° C. for 2 hours, quenched with 10% aqueous potassium carbonate and extracted with ethyl acetate. The combined organics were dried and evaporated. The crude material was purified on 115 g of silica gel, eluting with 80% ethyl acetate/hexanes to afford 4.42 g of E-(3-{4-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-carbamic acid tert-butyl ester. 1H NMR (CDCl3): δ 8.66 (s, 1), 8.24 (m, 1), 8.03 (m, 2), 7.77-7.65 (m, 3), 7.13 (m, 2), 6.97 (d, J=8.7 Hz, 1), 6.54 (d, 1), 6.35 (m, 1), 4.9 (m, 1), 3.90 (m, 2), 2.52 (s, 3), 1.46 (s, 9).
Reaction SMILES: C([C@H:3]([S:7]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-:6])=O)C.[NH:41]1[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42]1>C1COCC1>[OH:46][CH:43]1[CH2:44][CH2:45][N:41]([C:4](=[O:6])[CH2:3][S:7](=[O:8])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[N:9][C:10](=[O:11])[C:12]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]4[O:30][CH:31]=[CH:32][C:33]=4[CH3:34])=[O:28])[CH:21]=3)[CH:15]=[N:14][CH:13]=2)[CH2:42]1
Reactant: OC1CCNC1
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CC(=O)N3CCC(O)C3)c3ccccc3)c2)c1
Temperature: 65 °C

Procedure:
To the solution of (S)-ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetate (4.03 g, 7.26 mmol) in anhydrous THF (75 mL) was added dropwise 3-pyrrolidinol (6.0 mL) and the resulting reaction solution was heated at 65° C. for 5 hours. The reaction was then concentrated under reduced pressure and the yellow oily residue was partitioned between aqueous NH4Cl and EtOAc. The organic layer was separated and washed sequentially with brine (1×), saturated aqueous NaHCO3 (1×), brine (1×), and finally dried with anhydrous sodium sulfate overnight. The clear solution was decanted and concentrated. The oily residue was subject to multiple times of column chromatography (eg. from CH2Cl2 to MeOH—CH2Cl2 1:25 or from EtOAc-Hex 3:1 to MeOH-EtOAc 1:100) the title compound as white foam (2.35 g, 54%).
Reaction SMILES: [C:1]1([CH2:11][C:12]([NH:14][C:15]2[N:16]=[CH:17][N:18]([C@H:20]3[CH2:23][C@H:22](OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:21]3)[CH:19]=2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N-:35]=[N+:36]=[N-:37].[Na+].C(Cl)(Cl)Cl>C(O)C.O>[N:35]([C@@H:22]1[CH2:23][C@H:20]([N:18]2[CH:19]=[C:15]([NH:14][C:12](=[O:13])[CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[N:16]=[CH:17]2)[CH2:21]1)=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](n3cnc(NC(=O)Cc4cccc5ccccc45)c3)C2)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=N[C@H]1C[C@@H](n2cnc(NC(=O)Cc3cccc4ccccc34)c2)C1
Reaction time: 96 h

Procedure:
trans-Toluene-4-sulfonic acid 3-[4-(2-naphthalen-i -yl-acetylamino)-imidazol-1-yl]-cyclobutyl ester (Preparation 4, Step 3; 593 mg, 1.25 mmol) was mixed with sodium azide (813 mg, 12.5 mmol) in ethanol (15 mL), water (5 mL), and chloroform (5 mL). The mixture was then heated at reflux with stirring for 96 h. The solvent was removed in vacuo and the residue was diluted with water and was extracted with methylene chloride. The organic layer was dried (MgSO4), filtered, and was concentrated in vacuo. Purification by silica gel chromatography (50:1 chloroform-methanol) afforded 340 mg (79% yield) of N-[1-(cis-3-azido-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide; 1H NMR (400 MHz, CDCl3) δ8.41 (s, 1H), 7.98 (d, J=6.4 Hz, 1H), 7.87 (m, 1H), 7.82 (m, 1H), 7.5 (m, 2H), 7.45 (m, 3H), 7.08 (d, J=1.7 Hz, 1H), 4.2 (m, 3H), 3.75 (m, 1H), 2.85 (m, 2H), 2.35 (m, 2H); MS (AP/Cl): 347.2 (M+H)+.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][N:31](C(OC(C)(C)C)=O)[CH:32]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[CH3:12][C:6]1([CH3:13])[N:5]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]2[CH:3]=[C:2]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)[S:10][C:9]=2[C:8](=[O:11])[NH:7]1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)CN1c2cc(Br)sc2C(=O)NC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1c2cc(-c3cn[nH]c3)sc2C(=O)NC1(C)C
Temperature: 80 °C
Reaction time: 18 h
Yield: 4.8 %

Procedure:
A flask was charged with ethyl (6-bromo-2,2-dimethyl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-1(2H)-yl)acetate (120 mg, 0.346 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (288 mg, 0.978 mmol), K3PO4 (277 mg, 1.3 mmol) and DMF (1 mL). The flask was purged with argon. Then, 1,1′-bis(diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (8.0 mg, 0.0098 mmol) was added to the mixture. The flask was purged with argon again. After stirring at 50° C. for 18 h and at 80° C. for 18 h, water and EtOAc were added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, EtOAc to 90:10 EtOAc/MeOH), then crystallized from MeOH/EtOAc/heptane to give the title compound (5.6 mg, 5%) as a brown solid:
Reaction SMILES: [F:1][CH:2]([F:15])[S:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[CH:6][CH:5]=1.S(=O)(=O)(O)[OH:17].[N+]([O-])(O)=O>>[F:15][CH:2]([F:1])[S:3]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[CH:6][CH:5]=1)=[O:17]
Reactant: FC(F)Sc1ccc(-n2cnnn2)cc1
Reactant: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: O=S(c1ccc(-n2cnnn2)cc1)C(F)F

Procedure:
1-[p-(Difluoromethylthio)phenyl]-1H-tetrazole (1.0 gram) was added to a cold mixture of 5 ml. of concentrated sulfuric acid and 5 ml. of concentrated nitric acid and stirred for 40 minutes in the cold, then for 40 minutes at room temperature. The reaction mixture was poured onto ice and extracted with ethyl acetate. The ethyl acetate solution was extracted with water, dried over magnesium sulfate, and evaporated to afford an oil which was crystallized from ethyl acetate-hexane. Two recrystallizations from the same solvents gave 143 mg. of product, m.p. 109°-112° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=1[N+:28]([O-])=O)[O:12][CH:13]1[C:19](=[O:20])[NH:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CO.[Pt]=O>[NH2:28][C:27]1[CH:26]=[CH:25][C:11]([O:12][CH:13]2[C:19](=[O:20])[NH:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[CH2:15][CH2:14]2)=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccccc2CCC1Oc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(OC2CCc3ccccc3NC2=O)cc1OCc1ccccc1

Procedure:
A solution of 3-(3-benzyloxy-4-nitrophenoxy)-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (3.0 g, 7.4 mmol) in 50 mL EtOAc/MeOH (1:1) is hydrogenated at 1 atm over platinum oxide for 2.5 h. The catalyst is filtered and the filtrate evaporated to give the title compound which is used directly in the next step.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[C:8]([NH2:15])[CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH:6]=[CH:5]1)([CH3:3])[CH3:2].[C:16](N1C=CN=C1)(N1C=CN=C1)=[S:17]>ClCCl>[CH:1]([N:4]1[C:12]2[C:7](=[C:8]([N:15]=[C:16]=[S:17])[CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(N)c2ccn(C(C)C)c12
Solvent: ClCCl
Product: COc1ccc(N=C=S)c2ccn(C(C)C)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-isopropyl-7-methoxy-1H-indol-4-ylamine (U) (1 eq) in dichloromethane was added 1,1′-thiocarbonyldiimidazole (1.2 eq). The reaction was stirred for 2 hrs at room temperature then evaporated to dryness. Further purification by column chromatography produced the pure desired product.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:51]([OH:53])=[O:52])[CH3:50])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[N:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[CH2:60][CH2:61][NH-:62].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:51]([OH:53])=[O:52])[CH3:50])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[CH2:60][CH2:61][NH-:62]
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)O)C(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH-]CCc1ccccn1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)O)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 140 mg of Z-Phe-His-OH, 100 mg of H-Leu-Val-Ala-2-(2-pyridyl)-ethyl amide, 50 mg of HOBt and 66 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B7). Rf (B7)=0.26, Rf (B11)=0.45.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=2)[O:4]1)[CH3:2].C1C(=O)N([Br:25])C(=O)C1>C(#N)C>[Br:25][C:6]1[CH:7]=[C:8]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[C:10]2[C:5]=1[O:4][CH:3]([CH2:1][CH3:2])[CH2:12][CH2:11]2
Reactant: CCC1CCc2cc(NS(C)(=O)=O)ccc2O1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCC1CCc2cc(NS(C)(=O)=O)cc(Br)c2O1
Temperature: 25 °C
Reaction time: 7 h
Yield: 47.1 %

Procedure:
To a solution of the title compound from Step 5 (170 mg, 0.667 mmol) in ACN (6 mL) was added NBS (156 mg, 0.867 mmol). The mixture was stirred for 7 h at rt. It was then extracted with DCM, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified with prep-TLC (PE/EA 3:1) to give the title compound (105 mg, 47%) as a gray solid. 1H NMR (400 MHz, CDCl3): δ 7.23 (d, J=2.4 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 6.24 (s, 1H), 4.01-3.99 (m, 1H), 2.97 (s, 3H), 2.84-2.77 (m, 2H), 2.04-1.99 (m, 1H), 1.85-1.66 (m, 3H), 1.09 (t, J=7.2 Hz, 3H).