Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[C:5]([C:8]1[C:16]2[S:15][C:14]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:13][C:12]=2[CH:11]=[C:10]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:9]=1)(=O)[CH3:6]>CN(C=O)C>[CH2:24]([O:23][C:10]1[CH:9]=[C:8](/[C:5](/[CH3:6])=[N:4]/[O:3][CH3:2])[C:16]2[S:15][C:14]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:13][C:12]=2[CH:11]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CON
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(C(C)=O)c2s1
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(/C(C)=N/OC)c2s1
Temperature: 60 °C
Yield: 78 %

Procedure:
O-Methyl hydroxylamine hydrochloride (289 mg, 3.46 mmol) was added to 1-(7-acetyl-5-benzyloxy-1,3-benzothiazol-2-yl)-3-ethyl-urea (650 mg, 1.73 mmol) in DMF (7 mL). The reaction mixture was heated to 60° C. for 2 h after which time LCMS indicated clean conversion to the desired product. The reaction was diluted with EtOAc, washed with water then brine and the organic layer dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound an off white solid, 550 mg, 78% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH:15]([CH3:17])[CH3:16])([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1>CCCCCC.CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]([CH3:16])[CH3:17])([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)C1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Solvent: CCCCCC
Solvent: CC(C)O
Product: CC(C)[C@]1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Yield: 48.9 %

Procedure:
1-(2-Chloropyrimidin-4-yl)-3-isopropyl-2-oxopyrrolidine-3-carbonitrile (14.1 g) obtained in Step C of Example 5 was resolved by HPLC (column: CHIRALPAK IC, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=200/800) to give the title compound (6.9 g) having a shorter retention time.
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4](OCC)=[O:5].[CH3:13][C:14]1([CH3:31])[CH2:18][C:17]2[C:19]([CH3:30])=[C:20]([CH3:29])[C:21]([CH3:28])=[C:22]([CH:23]=[CH:24][C:25](=[O:27])[CH3:26])[C:16]=2[O:15]1.[OH-].[Na+]>CO>[CH3:13][C:14]1([CH3:31])[CH2:18][C:17]2[C:19]([CH3:30])=[C:20]([CH3:29])[C:21]([CH3:28])=[C:22]([CH:23]3[CH2:3][C:4](=[O:5])[CH2:26][C:25](=[O:27])[CH2:24]3)[C:16]=2[O:15]1
Reactant: CC(=O)C=Cc1c(C)c(C)c(C)c2c1OC(C)(C)C2
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C)c2c(c(C3CC(=O)CC(=O)C3)c1C)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1.57 g of sodium in 68 ml of absolute methanol was added 10.35 ml of diethyl malonate. After stirring for 20 minutes, the mixture was added 8 g of the 4-(2,3-dihydro-2,2,4,5,6-pentamethylbenzofuran-7-yl)-3-buten-2-one in 17.5 g of absolute methanol, refluxed for 4 hours and added 150 g of 5% aqueous solution of sodium hydroxide. The reaction mixture was cooled to room temperature and washed three times with 50 ml of diethyl ether. 2N aqueous solution of hydrochloric acid was added dropwise into the aqueous layer until the bubble of carbon dioxide ceased. And then, solid was dissolved in ethyl acetate and washed with water. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford 16.7 g of 5-(2,3-dihydro-2,2,4,5,6-pentamethyl-benzofuran-7-yl)cyclohexane-1,3-dione as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[F:32][C:33]([F:47])([F:46])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:43]4[CH2:44][CH2:45][N:40]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[C:33]([F:46])([F:32])[F:47])[CH2:41][CH2:42]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: FC(F)(F)c1ccccc1N1CCNCC1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2ccccc2C(F)(F)F)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-[2-(trifluoromethyl)phenyl]piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=659.99 (M+H+); retention time=1.1 minutes.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:14][OH:15])[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:14][O:15][S:23]([CH3:26])(=[O:25])=[O:24])[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2csc(CO)n2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2csc(COS(C)(=O)=O)n2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-yl]-methanol (925 mg, 4.60 mmol) in dry CH2Cl2 (20 mL) was treated at 0° C. with Et3N (0.83 mL, 5.94 mmol) followed by DMAP (57 mg, 0.46 mmol) and Ms-Cl (0.46 mL, 5.80 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:2 hept-EA) gave the title compound as a yellow oil. LC-MS-conditions 01: tR=0.73 min, [M+H]+=280.19.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[O:16]1CCOCC1>>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:14][CH3:15])[N:3]=[C:2]([CH:1]=[O:16])[CH:11]=[N:10]2
Reactant: COc1cc2ncc(C)nc2cc1OC
Reactant: C1COCCO1
Product: COc1cc2ncc(C=O)nc2cc1OC
Temperature: 100 °C
Yield: 73 %

Procedure:
To a reaction flask under argon is added 1,4-dioxane (20 mL), 2-methyl-6,7-dimethoxyquinoxaline (1.09 g, 5.3 mmol) and SeO2, (1.8 g, 16 mmol). The mixture is heated to 100° C. for 2 hours 45 minutes, cooled, and filtered through Celite. The pad is washed with portions of EtOAc and CH2Cl2. The resulting solution is concentrated, taken up in MeOH/CH2Cl2, loaded onto a silica gel column, and chromatographed (30% EtOAc/CH2Cl2) to provide an off-white solid (73% yield).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:25]C)[C:15]2[C:20]([CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44]([OH:46])=O>[OH-].[OH-].[Pd+2]>[NH:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:25])[C:15]2[C:20]([CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:46]
Reactant: CCN(c1ncccc1C=C(C)C)C1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1ccc[nH]1
Agent: [Pd+2]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [OH-]
Product: CC(C)Cc1cccnc1N(C)C1CCN(C(=O)c2ccc[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 20 and making non-critical variations but starting with 1-benzyl-4-[N-methyl-N-(3-(2-methyl-1-propenyl)-2-pyridinyl)amino]piperidine (XXII, EXAMPLE 16, 0.27 g, 0.80 mmol), Pearlman's catalyst (0.1 g), CDI (0.26 g, 1.6 mmol) and pyrrole-2-carboxylic acid (0.18 g, 1.6 mmol), the title compound is obtained, HRMS Calcd. for C20H28N4O=340.2263, found=340.2277.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2([CH3:22])[CH3:21])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[CH2:17][C:16]2([CH3:22])[CH3:21])=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CCNCC2(C)C)cn1
Reactant: COc1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN2CCN(Cc3ccc(NC(=O)OC(C)(C)C)nc3)C(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.6 %

Procedure:
A mixture of [5-(2,2-dimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (Step 109.3) (3.85 g, 12 mmol), 4-methoxybenzyl bromide (2.6 mL, 18 mmol, 1.5 equiv) and triethylamine (1.83 mL, 13.2 mmol, 1.1 equiv) in DCM (25 mL) was stirred for 16 h at rt and concentrated. The residue was purified by silica gel column chromatography (DCM→DCM/MeOH, 97:3) to afford 1.88 g of the title compound as a white solid. Title compound: ESI-MS: 441.3 [M+H]+; tR=3.12 min (System 1).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](O)=[O:5].C([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[O:22])[CH2:16][CH2:15]1)(=O)C(C)C>>[F:1][C:2]([F:8])([F:7])[CH2:3][C:4]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=2)=[O:22])[CH2:16][CH2:15]1)=[O:5]
Reactant: CC(C)C(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Reactant: O=C(O)CC(F)(F)F
Product: O=C(Nc1ccc(C(F)(F)F)cc1)NC1CCN(C(=O)CC(F)(F)F)CC1
Yield: 87 %

Procedure:
3,3,3-Trifluoropropionic acid (67 mg, 0.522 mmol) was reacted with PTU (100 mg, 0.348 mmol) as the same manner as the synthesis of 1-(1-isobutyrylpiperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (120 mg, 0.302 mmol, 87% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.80 (s, 1H), 7.58 (s, 4H), 6.38 (d, J=7.8 Hz, 1H), 4.19 (d, J=13.3 Hz, 1H), 3.79 (d, J=13.8 Hz, 1H), 3.71 (m, 4H), 3.16 (t, J=11.1 Hz, 1H), 2.85 (t, J=11.7 Hz, 1H), 1.84 (m, 2H), 1.30 (m, 2H).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1.C([Li])CCC.[OH-].[Na+]>O1CCCC1.CCCCCC>[C:3]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17]2)=[CH:6][CH:5]=1)#[CH:2]
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(C=C(Br)Br)cc2)CC1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#Cc1ccc(CC[C@H]2CC[C@H](CCCCC)CC2)cc1
Reaction time: 1.5 h

Procedure:
In an analogous manner to Example 5, a solution of β,β-dibromo-p-[2-(trans-4-pentylcyclohexyl)ethyl]styrene in absolute tetrahydrofuran was placed in a sulphonation flask and treated within 5 minutes with a solution of butyl lithium in hexane. After completion of the addition, the mixture was stirred at the same temperature for a further 90 minutes, then poured into 1N sodium hydroxide and extracted with petroleum ether. The organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography of the residue on silica gel with hexane gave pure 1-ethynyl-4-[2-(trans-4-pentylcyclohexyl)ethyl]benzene as colourless crystals; m.p. (C-N) 25.5° C., cl.p. 42.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].C(N(CC)CC)C.[CH3:28][C:29]1([CH2:34][NH2:35])[CH2:33][CH2:32][NH:31][CH2:30]1>C(#N)C>[NH2:35][CH2:34][C:29]1([CH3:28])[CH2:33][CH2:32][N:31]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:30]1
Reactant: CC1(CN)CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(CN)CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)C1
Yield: 95 %

Procedure:
To 1.05 g (3.50 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added 15 ml of acetonitrile, 1.0 g (9.9 mmol) of triethylamine and 0.7 g (6 mmol) of the 3-methyl-3-pyrrolidinemethanamine. The mixture was refluxed 18 hours and cooled. Filtration gave 1.31 g of the title compound, mp 189°-191° C.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:24]=[CH:23][O:22][N:21]=1>>[O:22]1[CH:23]=[CH:24][C:20]([NH:19][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[N:21]1
Reactant: Nc1ccon1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: O=C(Nc1ccon1)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 3-aminoisoxazole as the starting materials.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[CH:6][C@@H:7]([CH3:50])[C@H:8]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[CH2:9][C@@H:10]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C>C(Cl)Cl.C1(C)C=CC=CC=1>[Si:13]([O:12][CH2:11][C@H:10]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)[CH2:9][C@@H:8]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[C@H:7]([CH3:50])[CH:6]=[CH:5][CH2:4][OH:3])([C:26]([CH3:29])([CH3:27])[CH3:28])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C=C[C@@H](C)[C@@H](C[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCc1ccc(OC)cc1)OCc1ccc(OC)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(CO[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@@H](OCc2ccc(OC)cc2)[C@H](C)C=CCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To a stirred solution of ester 91 (600 mg, 0.84 mmol) in CH2Cl2 (6 mL) at −40° C. under argon was added slowly over 10 min via syringe DibalH in toluene (9 mL, 1M). After 30 min at −40° C., the reaction mixture was quenched by slow addition of MeOH (0.6 mL) and warmed to rt. The reaction mixture was poured into a vigorously stirred solution of saturated Rochelle salt in H2O (8 mL) and EtOAc (12 mL) and stirred overnight. The aqueous layer was separated and extracted with EtOAc (3×5 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography (20% EtOAc in hexanes) to produce 450 mg (80%) of the alcohol, a clear liquid: 1H NMR (300 MHz, CDCl3) δ 7.70-7.66 (m, 4H), 7.39-7.35 (m, 6H), 7.21-7.18 (m, 4H), 6.85-6.82 (m, 4H), 5.68-5.65 (m, 2H), 4.64 (d, J=11.1 Hz, 1H), 4.51 (d, J=11.0 Hz, 1H), 4.46 (d, J=11.1 Hz, 1H), 4.24 (d, J=11.0 Hz, 1H), 4.10-4.06 (m, 2H), 3.78 (s, 6H), 3.81-3.52 (m, 4H), 2.60-2.56 (m, 1H), 1.57-1.51 (m, 2H), 1.05 (s, 9H), 1.03 (d, J=6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 159.0, 135.6, 135.1, 133.5 (2C), 131.1, 130.3, 130.0, 127.6, 129.4, 129.6, 83.1, 75.2, 72.4, 72.2, 64.4, 63.7, 55.2, 34.7, 26.8, 19.2, 15.4; IR (thin film) 3295, 3045, 2958, 2941, 2910, 2857, 1241, 1097 cm−1; HRMS (EI) cald for C41H52O6Si 668.3599, found 668.3596.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8]C)=[O:7].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+].[OH-].[Na+]>CN(C)C=O.O>[Cl:17][C:4]1[C:3]([CH2:2][O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Oc1ccccc1
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1COc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 g (2.93 mmol) of methyl 3-bromomethyl-2-chloro-4-methylsulfonylbenzoate and 0.28 g (2.93 mmol) of phenol were dissolved in 20 ml of dimethylformamide and treated with 0.14 g (3.51 mmol) of 60% strength sodium hydride. The mixture was stirred overnight at room temperature and then concentrated in a high vacuum on a rotary evaporator. The residue was dissolved in 16 ml of tetrahydrofuran and 8 ml of water and the solution was refluxed for 4 h together with 0.23 g of NaOH (5.85 mmol). It was then allowed to cool and was largely concentrated on a rotary evaporator, and the aqueous residue was then treated with 2 M HCl. It was then extracted with methylene chloride, and the combined organic phase was dried over MgSO4 and completely concentrated on a rotary evaporator.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.O.[NH2:10][NH2:11]>>[CH3:8][C:4]1[N:3]=[C:2]([NH:10][NH2:11])[CH:7]=[CH:6][CH:5]=1
Reactant: NN
Reactant: Cc1cccc(Br)n1
Solvent: O
Product: Cc1cccc(NN)n1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A mixture of 2-bromo-6-methyl-pyridine (602.10 g) and hydrazine hydrate (1570 ml) was refluxed at 120° C. for 6 hours, and then stirred at room temperature for about 48 hours. The solid separated was extracted with diethylether (3×1.5 L) and the combined ether extracts were washed with brine, dried over Na2SO4, filtered and concentrated (−430 g). The residue was stirred in a mixture of ether (200 ml) and hexane (1.5 L), filtered and washed with 5% diethylether in hexane to give a pale yellow solid (sticky). The solid was vacuum distilled at 106-113° C./2 mm, which solidified instantly. The solid was then dissolved in 2 L of diethylether and precipitated by adding 2 L of hexane, filtered and vacuum dried to give 1-(6-methylpyridin-2-yl)hydrazine as white solid (240 g).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([CH:31]([CH3:33])[CH3:32])[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[OH:30][C:27]1[CH:28]=[CH:29][C:24]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=2)=[CH:25][C:26]=1[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)c1cc(Br)ccc1O
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1O
Temperature: 80 °C
Reaction time: 16 h
Yield: 32.5 %

Procedure:
To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.36 g), 4-bromo-2-isopropylphenol (0.3 g) in DMF (8.0 mL) was added potassium carbonate (0.5 g) and PdCl2dppf (60 mg) under nitrogen. The mixture was stirred at 80° C. for 16 h. The reaction was cooled down, diluted with ethyl acetate, washed with water, brine, dried and concentrated. The product tert-butyl 4-(4-hydroxy-3-isopropylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (0.12 g) was obtained by Combiflash.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10]I)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CO>[CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10][N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1nc(CI)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Solvent: CO
Product: COC(=O)c1nc(CN2CCN(C)CC2)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Reaction time: 16 h

Procedure:
A mixture of 8.0 g (0.015 mole) of 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(iodomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester [see Example 13 b)] and 3.3 ml of 1-methyl-piperazine in 160 ml of methanol is stirred for 16 hours at 40°. The reaction solution is then concentrated in vacuo; water is added to the residue and extraction is performed twice with methylene chloride. The organic phase is washed twice with icewater, and extraction is then performed twice with 2N hydrochloric acid solution. To the aqueous acidified extracts there are added ice and sufficient 5N sodium hydroxide solution to bring the pH-value to 10. The base that has precipitated is taken up in ether. The organic phase is washed twice with saturated sodium chloride solution; it is afterwards dried over sodium sulphate and concentrated in vacuo to dryness. There is obtained 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-[(4-methyl-1-piperazinyl)-methyl]-1H-1,2,4-triazole-3-carboxylic acid methyl ester as solidified foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:38]=[CH:37][C:15]3[C:16]4C([CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)=CN(C2N(C3C=CC(F)=CC=3F)N=CN=2)[N:17]=4)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC2C3[N:48](CCOC=2C=1)[CH:47]=[C:46]([C:52]1[N:53]([CH:57]([CH3:59])[CH3:58])[N:54]=[CH:55][N:56]=1)N=3>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:38]=[CH:37][C:15]3[C:16]4[N:48]([CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH:47]=[C:46]([C:52]2[N:53]([CH:57]([CH3:59])[CH3:58])[N:54]=[CH:55][N:56]=2)[N:17]=4)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc3c(c2)OCCc2cn(-c4ncnn4-c4ccc(F)cc4F)nc2-3)C1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(C(=O)OC(C)(C)C)C3)cc1OCC2

Procedure:
3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester was prepared similarly to 3-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl}-azetidine-1-carboxylic acid tert-butyl ester from 8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene and 3-azetidine-1-carboxylic acid tert-butyl ester zinc iodide. LCMS: RT=4.61 min, M+H+=451.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[NH:31][C:32](=[O:47])[C@H:33]([CH2:36][CH2:37][CH2:38][NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[NH:34][CH3:35]>>[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[NH:31][C:32](=[O:47])[C@H:33]([CH2:36][CH2:37][CH2:38][NH:39][C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[N:34]([C:18](=[O:20])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Nc1ccc2ccccc2c1
Product: CN(C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Nc1ccc2ccccc2c1
Yield: 57.6 %

Procedure:
Boc-tyrosine (400 mg) and Nδ-Boc-Nα-methylornithine β-naphthylamide (454 mg) were coupled (Procedure B) to afford titled compound (447 mg) as a glassy solid: 1H NMR (400 MHz, CDCl3) δ1.50 (m, 21H), 1.77 (m, 1H), 2.73 (s, 3H), 2.76 (m, 2H), 2.99 (dd, J=10.8; 6.8 Hz, 1H), 3.09 (dd, J=12.8; 13.2 Hz, 1H), 4.70 (m, 1H), 4.87 (m, 1H), 6.89 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.0 Hz, 2H), 7.41 (m, 2H), 7.75 (m, 4H), and 8.26 (s, 1H).