Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[C:3]=1[OH:12].[C:13](=S)(OCC)[S-:14].[K+]>C(O)C>[CH:9]([C:4]1[C:3]2[O:12][C:13]([SH:14])=[N:1][C:2]=2[C:7]([CH3:8])=[CH:6][CH:5]=1)([CH3:10])[CH3:11]
Reactant: CCOC(=S)[S-]
Reactant: Cc1ccc(C(C)C)c(O)c1N
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(C(C)C)c2oc(S)nc12
Yield: 60.3 %

Procedure:
To a solution of 4-chloro-6-isopropyl-3-methyl-2-nitrophenol (1.82 g, 7.92 mmol) obtained in Example 97 in ethanol (40 ml) was added 10% palladium carbon catalyst (1.8 g) and the mixture was stirred under hydrogen atmosphere at 60° C. for 3 hours. After the reaction was over, the reaction solution was filtered with celite and the filtrate was concentrated to provide 1.60 g of 2-amino-6-isopropyl-3-methylphenol (yield 99%) as pale brown solid. To a solution of this aminophenol (1.65 g, 7.92 mmol) in ethanol (25 ml) was added potassium O-ethyl dithiocarbonate (1.52 g, 9.50 mmol) and the mixture was heated to reflux for 8 hours and the solvent was evaporated. The resulting residue was dissolved in water, acidified to pH, 3-4 with 2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, a saturated sodium chloride solution successively, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was crystallized from ethyl acetate-hexane to provide 0.99 g (yield 60%) of 7-isopropyl-2-mercapto-4-methylbenzoxazole as pale yellow needles.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[C:11](Cl)[C:10]([CH:14]=[CH2:15])=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[C:23](P(C(C)(C)C)C(C)(C)C)(C)(C)[CH3:24].B1(C=C)OB(C=C)OB(C=C)O1.C1C=CN=CC=1>O1CCOCC1>[C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[C:11]([CH:23]=[CH2:24])[C:10]([CH:14]=[CH2:15])=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Reactant: C=Cc1ncc(C(=O)OC(C)(C)C)cc1Cl
Agent: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: C=Cc1cc(C(=O)OC(C)(C)C)cnc1C=C
Temperature: 100 °C

Procedure:
A mixture of 5-chloro-6-vinyl-nicotinic acid tert.-butyl ester (2.0 g), Cs2CO3 (3.4 g), tri(tert.-butyl)phosphine (0.04 eq.), tris(dibenzylidenacetone)dipalladium (0.02 eq.), and 2,4,6-trivinylcyclotriboroxane pyridine complex (2.0 g) in dioxane (30 mL) is degassed and heated at 100° C. for 15 h. The mixture is cooled to rt, and diluted with ether (200 mL). The mixture is extracted with 1M aq. NaOH (2×50 mL) and brine (50 mL). The org. phase is dried (Na2SO4), filtered and evaporated. The residue is purified by FC (SiO2, EA-heptane) to give 5,6-divinyl-nicotinic acid tert.-butyl ester (0.89 g) as an oil. LC-MS: tR=1.01 min, [M+1]+=232.04.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[S:11]1[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12]1.[OH-:18].[Na+].Cl>C(O)C.O>[OH:18][C:13]1([C:16]2[O:17][C:6]3[C:5]([C:3](=[O:4])[CH:2]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:14]=[CH:15][S:11][CH2:12]1
Reactant: O=C(CO)c1ccccc1
Reactant: O=Cc1ccsc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1cc(C2(O)C=CSC2)oc2ccccc12
Yield: 36 %

Procedure:
A solution of 3 g (22.2 mmol) of 2-hydroxyacetophenone, 2.5 g (22.2 mmol) of thiophene 3-carboxaldehyde and 3 g NaOH (in 15 ml of water) in 50 ml of ethanol was stirred for 12 hours before the solution was poured into 300 ml of water. The resulting mixture was neutralized with dilute HCl to yield a chalcone. The yellow precipitate obtained was filtered and dried. The product was purified by recrystallized from methylene chloride. Further oxidation of above chalcone was carried out with excess of H2O2 (30%) in ethanol under basic conditions for 12 hours. The resulting solution was poured into 300 ml water and acidified with dilute HCl. Yellow precipitate obtained was filtered and dried. Product was recrystallized from THF/hexane mixture. Yield: 36%. Quantum Yield: (1.8 relative to 3HF in methyl cyclohexane), Extinction coefficient: εmax (M-1 cm-1)=2000. λmax (abs)=343 nm and λmax (em)=526 nm. MP=195°-196° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]([OH:18])[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4])=[CH:15][CH:14]=1
Reactant: C#CC(=O)OC
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc(Cl)cc1
Reaction time: 0.17 h

Procedure:
A solution of 8.36 ml (0.1 mol) of methyl propiolate in 100 ml of tetrahydrofuran was treated at -78° under argon with 68.8 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 14.06 g (0.1 mol) of 4-chlorobenzaldehyde in 100 ml of tetrahydrofuran was added within 40 minutes. The reaction mixture is stirred at -78° for a further 20 minutes, then brought to room temperature and treated with 100 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-(4-chlorophenyl)-4-hydroxy-2-butynoate as a red oil.
Reaction SMILES: C(OCC)(=O)C.[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:25]([N:27]=[N+]=[N-])=[O:26])[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OC(N[C@H](C(NN)=O)CC1N=CNC=1)=O)C1C=CC=CC=1.[OH:52][CH2:53][CH2:54][NH:55][C:56]([C@@H:58]1[CH2:62][CH2:61][CH2:60]N1)=[O:57]>CN(C=O)C>[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:25]([N:27]1[CH2:60][CH2:61][CH2:62][C@H:58]1[C:56]([NH:55][CH2:54][CH2:53][OH:52])=[O:57])=[O:26])[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NCCO)[C@@H]1CCCN1
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NCCO)OCc1ccccc1

Procedure:
To an ethyl acetate solution of Nα -benzyloxycarbonyl-L-histidinazide (4) prepared from Nα -benzyloxycarbonyl-L-histidine hydrazide (3) (6.07 g) by a known method was added 10 ml of a DMF solution of 2.31 g of (S)-N-(2-hydroxyethyl)-2-pyrrolidinecarboxamide (53) under ice-cooling and they were reacted overnight in a refrigerator. The reaction mixture was concentrated and the residue thus formed was subjected to silica gel column chromatography. By eluting the product with chloroform-methanol-aqueous ammonia (90:10:1), 3.43 g of Nα -benzyloxycarbonyl-L-histidyl-N-(2-hydroxyethyl)-L-prolinamide (54) was obtained.
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])[CH:3]=O.[NH2:14][C:15]([NH2:17])=[O:16].COC1C=CC=CC=1N>C(O)C>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][C:2]1[O:16][C:15]([NH2:17])=[N:14][CH:3]=1
Reactant: COc1ccccc1CC(Cl)C=O
Reactant: NC(N)=O
Solvent: CCO
Solvent: COc1ccccc1N
Product: COc1ccccc1Cc1cnc(N)o1

Procedure:
A mixture of 2-chloro-3-(2-methoxylphenyl)-propionaldehyde (10 g, crude from above) and urea (9.6 g, 0.16 mol) was dissolved in ethanol (250 mL) and then heated to reflux overnight. The solvent was evaporated to dryness. The residue was diluted with dichloromethane (250 mL) and then washed with sodium hydroxide (10% aqueous solution, 100 mL) and water (50 mL). The organic layer was extracted three times with hydrochloric acid (5% aqueous solution, 250 mL). The combined aqueous layers were adjusted to pH 9 to 10 with a 10% aqueous solution of sodium hydroxide and then extracted three times with dichloromethane (300 mL). The organic layer was separated, dried over sodium sulfate, and evaporated to dryness. The crude product was purified by silica gel column chromatography to yield the yellow-red solid product. (0.72 g, 0.35% from 2-methoxyaniline). ESI-MS m/z calc. 204.1. found 205.1 (M+1)+ 1H NMR (CDCl3) δ 7.26-7.20 (m, 1H), 7.14 (d, J=7.2 Hz, 1H), 6.91-6.86 (m, 2H), 6.35 (s, 1H), 4.49 (bs, 2H), 3.85 (s, 2H), 3.82 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[C:19]([CH3:28])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].[C:33]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:32][C:2]([CH3:1])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:33])[S:24]([CH3:27])(=[O:26])=[O:25])=[C:19]([CH3:28])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29]
Reactant: CCC(CC)(c1ccc(NS(C)(=O)=O)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(N(C)S(C)(=O)=O)c(C)c1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a mixture of N-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-methanesulfonamide (230 mg, 0.5 mmol), triphenyl phosphine (197 mg, 0.75 mmol), MeOH (0.03 mL, 0.75 mmol), and THF (10 mL) is added diethylazodicarboxylate (0.12 mL, 0.75 mmol) and stirred overnight. The reaction is concentrated and chromatographed (0% to 25% EtOAc/Hex) to give the title compound (180 mg, 76%).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=1.O.[OH-].[Li+]>CO.C1COCC1.O>[C:15]1([NH:14][C:12]2[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH:13]=2)[C:3]([OH:21])=[O:2])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(Nc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)c(Nc2ccccc2)c1
Yield: 96 %

Procedure:
A mixture of compound 1A (4.56 g, 16.0 mmol) and lithium hydroxide monohydrate (2.0 g, 48.0 mmol) in MeOH (32 mL), THF (32 mL) and water (16 mL) was heated to reflux for 0.5 h. HPLC indicated that the reaction was complete. The organic solvents were removed under reduced pressure, and the aqueous residue was diluted with water. The pH was adjusted to 3.0 with 6N aqueous hydrochloric acid. The resulting precipitate was collected by vacuum filtration, rinsed with water and dried under reduced pressure to provide 3.95 g (96%) of 1B as a bright yellow solid. HPLC retention time=2.75 min. (Condition A) and LC/MS M++1=258+.
Reaction SMILES: [CH2:1]([N:8]([CH3:16])[C:9]1[CH:14]=[N:13][CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[OH:34]>>[CH2:1]([N:8]([CH3:16])[C:9]1[N:10]=[C:11]([C:23]2[CH:22]=[CH:21][C:20]([OH:34])=[C:19]([O:18][CH3:17])[CH:24]=2)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: CN(Cc1ccccc1)c1cncc(Cl)n1
Product: COc1cc(-c2cncc(N(C)Cc3ccccc3)n2)ccc1O
Yield: 51 %

Procedure:
In a procedure analogous to Example 22, reaction of N-benzyl-6-chloro-N-methylpyrazin-2-amine and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol furnished the product (51%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([N+:22]([O-])=[O:23])[CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:25]NO.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:25][N:22]([OH:23])[C:15]1[CH:14]=[C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:5][N:4]=2)[CH:18]=[CH:17][C:16]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reactant: CNO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(O)c1cc(Oc2ncc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-1,2-dinitrobenzene (2.50 g, 6.88 mmol), N-methylhydroxyamine (1.15 g), K2CO3 (1.14 g, 8.26 mmol) and THF (20 ml) is stirred at RT for 48 hours. The reaction mixture is filtered and the filtrate is concentrated. The resulting residue is taken up in CH2Cl2, washed, dried and evaporated to give N-methyl-N-[2-nitro-5-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenyl]-hydroxyamine (IXB; R is H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1.[Br:19]Br>C(O)(=O)C.Br>[Br:19][CH:9]([C:10]1[CH:11]=[CH:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=1)[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:18]
Reactant: BrBr
Reactant: CSc1ccc(CC(=O)c2ccccc2C)cc1
Agent: Br
Solvent: CC(=O)O
Product: CSc1ccc(C(Br)C(=O)c2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the ketone from Step 2 (5.92 g, 23.1 mmol) in acetic acid (50 mL) and 33% HBr in acetic acid (2 mL) was treated with a 1.1M solution of bromine in acetic acid (21.7 mL, 23.8 mmol) and stirred at room temperature for 2 hours. The solution was concentrated in vacuo and the residue taken up in dichloromethane, washed with 1N NaHSO3 and sat. aq. NaHCO3, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a yellow solid which was used directly in the next step without further purification (5.97 g, 77%): mp 85°-89° C. 1H NMR (CDCl3) 300 MHz 7.56 (d, J=7.9 Hz, 1H), 7.41 (d, J=8.5 Hz, 2H), 7.37 (d, J=7.7 Hz, 1H), 7.22 (m, 4H), 6.18 (s, 1H), 2.47 (s, 3H), 2.44 (s, 3H). Mass spectrum M+H=341.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[N:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH:29]4[CH2:31][CH2:30]4)=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1>>[CH:29]1([C:25]2[CH:26]=[C:27]([CH3:28])[C:22]([N:19]3[CH2:20][CH2:21][N:16]([C:14]([C:11]4[CH:10]=[CH:9][C:8]([N:1]5[CH2:5][CH2:4][CH2:3][C:2]5=[O:6])=[N:13][CH:12]=4)=[O:15])[CH2:17][CH2:18]3)=[N:23][CH:24]=2)[CH2:30][CH2:31]1
Reactant: O=C1CCCN1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)nc2)CC1
Yield: 4.5 %

Procedure:
Using pyrrolidin-2-one (130 mg) and (6-bromopyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (554 mg) described in Preparation Example 144 and by the reaction and treatment in the same manner as in Example 1, the title compound (25 mg) was obtained.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([NH2:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>ClCCl.O>[CH2:12]([NH:20][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCN
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCNS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.07 h
Yield: 95 %

Procedure:
A solution of toluene-4-sulfonyl chloride (5.0 g, 0.026 mol) in dry dichloromethane (150 ml) was cooled to 0° C. during the dropwise addition of n-octylamine (9.6 ml, 0.058 mol) with stirring over 4 minutes. The reaction mixture was then allowed to stir for 30 minutes before being diluted with dichloromethane (200 ml) and water (200 ml). The organic layer was separated and washed consecutively with 1 M HCl, 0.5 M Na2CO3 and brine before being dried over anhydrous Na2SO4. The solution was filtered and concentrated in vacuo to a crude solid which was purified by flash chromatography (silica gel, 11% ethyl acetate in hexane) to give the title compound as a white solid (7.0 g, 94%). This material was then used immediately in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:6][NH:7][C:8](=[O:23])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C@H:19]([CH3:22])[CH2:20][OH:21].C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>CN(C)C1C=CN=CC=1.ClCCl>[C:36]([O:21][CH2:20][C@H:19]([NH:18][C:10]1[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=1[C:8]([NH:7][CH2:6][C:5]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:23])[CH3:22])(=[O:38])[CH3:37]
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H](C)CO)cc1OC
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H](C)COC(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of (R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)-5-nitrobenzamide (5.00 g), 4-dimethylaminopyridine (1.57 g, 12.8 mmol) and triethylamine (1.79 mL) in dichloromethane (150 mL) was added acetyl chloride (1.83 mL), and the mixture was stirred for 5 hours at ambient temperature. The mixture was washed with 1N-hydrochloric acid, water, an aqueous saturated sodium bicarbonate solution and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether. The obtained product was recrystallized from a mixture of ethyl acetate and hexane (1:1) to give (R)-2-(2-acetoxy-1-methylethylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide as yellow crystals (5.10 g).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24]2)[C:8]2[N:13]=[N:12][N:11](CC3C=CC(OC)=CC=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C:25]([F:28])([F:29])[CH2:24]2)[C:8]2[N:13]=[N:12][NH:11][C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1

Procedure:
A mixture of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (264 mg, 656 μmol) and TFA (5.00 mL) was refluxed for 8 h under N2 atmosphere. The reaction mixture was concentrated in vacuo to afford crude to 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine. The residue was used for the next reaction without further purification.
Reaction SMILES: [C:1]1([CH:7](O)[C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.Cl.[C:38]([CH2:40][NH:41][C:42]([C@@H:44]1[CH2:48][C@@H:47]([S:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)(=[O:51])=[O:50])[CH2:46][NH:45]1)=[O:43])#[N:39]>ClCCl>[C:38]([CH2:40][NH:41][C:42]([C@@H:44]1[CH2:48][C@@H:47]([S:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)(=[O:50])=[O:51])[CH2:46][N:45]1[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([F:11])([F:10])[F:9])=[O:43])#[N:39]
Reactant: OC(c1ccccc1)C(F)(F)F
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1C(c1ccccc1)C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 1-phenyl-2,2,2-trifluoroethanol (0.4 mmole) in dichloromethane (1.4 ml) was added at −50° C. diisopropylethyl amine (2.0 mmole) and triflic anhydride (0.42 mmole) and stirring was continued at −50° for 1 h. To the mixture was added at −50° C. a solution of (2S,4R)-4-benzenesulfonyl-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride (0.4 mmole) prepared in analogy to experiment K1 in dichloromethane (0.4 ml) and stirring was continued at 22° C. for 2 d. The mixture was partitioned between ethyl acetate and water, the organic layer was dried, evaporated and the residue was chromatographed on silica to give (2S,4R)-4-benzenesulfonyl-1-(2,2,2-trifluoro-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless solid. MS: 452.1 [M+H]+.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[C:10]3[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O>CO>[CH:1]1([NH:7][C:8]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[C:10]3[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][C:9]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(C=O)cnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(CO)cnc21

Procedure:
4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (104 mg, 0.279 mmol) in methanol (3 mL) was stirred with sodium borohydride (15.8 mg, 0.418 mmol) at room temperature for 2 hours, after addition of water, the reaction mixture was extracted with chloroform twice, and the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting pale yellow oil containing the title compound was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[O:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([NH:26][NH2:27])=[O:25])(=[O:20])=[O:19])[CH2:14][CH2:13]1>CO.C(O)(=O)C>[Cl:1][C:2]1[C:3]([F:11])=[C:4](/[C:8](=[N:27]/[NH:26][C:24](=[O:25])[C:23]2[CH:28]=[CH:29][CH:30]=[C:21]([S:18]([N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)(=[O:19])=[O:20])[CH:22]=2)/[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: CC(=O)c1cccc(Cl)c1F
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cccc(Cl)c1F
Temperature: 120 °C
Yield: 43.1 %

Procedure:
1-(3-Chloro-2-fluorophenyl)ethanone (20 mg, 0.116 mmol) and 3-(morpholinosulfonyl)benzohydrazide (33.1 mg, 0.116 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound (22 mg) as a solid. 1H NMR (400 MHz, CDCl3): δ 9.43 (s, 1H), 8.37 (m, 1H), 8.16 (m, 1H), 7.87 (d, 1H, J=7.2 Hz), 7.65 (m, 1H), 7.41 (m, 1H), 7.10 (t, 1H, J=8.0 Hz), 3.71 (m, 4H), 2.95 (m, 4H), 2.38 (s, 3H). ESI-MS: 440.1 [M+H]+.
Reaction SMILES: C1(OC)C=CC=CC=1.[N+:9]([C:12]1[CH:28]=[CH:27][C:15]2[O:16][C:17]3[C:23]([N+:24]([O-])=O)=[CH:22][CH:21]=[CH:20][C:18]=3[O:19][C:14]=2[CH:13]=1)([O-])=O.[H][H]>[Pd].C1COCC1>[NH2:9][C:12]1[CH:28]=[CH:27][C:15]2[O:16][C:17]3[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][C:18]=3[O:19][C:14]=2[CH:13]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)Oc1cccc([N+](=O)[O-])c1O2
Reactant: [H][H]
Agent: [Pd]
Solvent: COc1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)Oc1cccc(N)c1O2
Reaction time: 8 h
Yield: 98 %

Procedure:
To a mixture of 1000 ml of anisole and 1000 ml of THF were added 81 g (0.295 mole) of 2,6-dinitrodibenzodioxin and 25 g of 10% palladium/carbon and hydrogen gas was passed through the mixture for 8 hours at room temperature with stirring. The 10% palladium/carbon was filtered and rinsed with THF. The filtrate and the rinsings were mixed, concentrated, and dried under reduced pressure to give 61.9 g (0.289 mole) of 2,6-diaminodibenzodioxin in a 98.0% yield. The product showed a purity of 94.2 area % (HPLC, 254 nm).