Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:17]=[C:18]([C:22]([NH2:25])([CH3:24])[CH3:23])[CH:19]=[CH:20][CH:21]=3)[N:12]([CH3:26])[N:11]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[F:34][C:35]([F:43])([F:42])[CH2:36][NH:37][S:38](Cl)(=[O:40])=[O:39]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:17]=[C:18]([C:22]([NH:25][S:38]([NH:37][CH2:36][C:35]([F:43])([F:42])[F:34])(=[O:40])=[O:39])([CH3:24])[CH3:23])[CH:19]=[CH:20][CH:21]=3)[N:12]([CH3:26])[N:11]=2)=[CH:6][CH:7]=1
Reactant: Cc1c(CCc2ccc(F)cc2)nn(C)c1-c1cccc(C(C)(C)N)c1
Reactant: O=S(=O)(Cl)NCC(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1c(CCc2ccc(F)cc2)nn(C)c1-c1cccc(C(C)(C)NS(=O)(=O)NCC(F)(F)F)c1

Procedure:
Prepared by the procedure of Example 1 Step 3 using the amine from Step 3 (72 mg, 0.20 mmol), Et3N (114 μL, 0.82 mmol) and 2,2,2-trifluoroethylsulfamoyl chloride (121 mg, 0.61 mmol) to yield, after purification by column chromatography on silica using 80-100% Et2O/iso-hexanes the title sulfamide (23 mg, 22%). 1H NMR (CDCl3, 500 MHz) δ 7.54 (1H, d, J=7.8 Hz), 7.48 (1H, t, J=7.8 Hz), 7.42 (1H, s), 7.23 (1H, d, J=7.5 Hz), 7.19 (2H, dd, J=8.5, 5.6 Hz), 6.97 (2H, t, J=8.5 Hz), 4.71 (1H, s), 4.43 (1H, t, J=7.4 Hz), 3.74 (3H, s), 3.57 (2H, quintet, J=7.4 Hz), 2.98-2.92 (2H, m), 2.87-2.82 (2H, m), 1.87 (3H, s), 1.79 (6H, s). MS (ES+) C24H28F4N4O2S requires: 512, found: 513 (M+H+, 100%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O)([O-:11])=[O:10]>C(OC(=O)CC)(=O)CC>[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[CH:1][C:2]1[N:3]=[N:4][C:5]([CH:8]=[CH:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=1)([O-:11])=[O:10]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: Cc1ccc(C)nn1
Agent: CCC(=O)OC(=O)CC
Product: O=[N+]([O-])c1ccccc1C=Cc1ccc(C=Cc2ccccc2[N+](=O)[O-])nn1
Yield: 39.8 %

Procedure:
First, 24 g of 3,6-dimethylpyridazine and 67 g of o-nitrobenzaldehyde were dissolved in 600 ml of propionic anhydride, then heated under reflux so as to obtain 33 g of 3,6-di(o-nitrostyryl)pyridazine.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1CCCC1)([O:18][C:19](C)(C)[CH3:20])=O>>[C:4]([O:3][C:1]([N:8]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:20][CH2:19][OH:18])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCCCCC1
Reactant: CC(C)(C)OC(=O)N1CCCC1
Product: CC(C)(C)OC(=O)N1CCCCCC[C@@H]1CCO

Procedure:
This compound is prepared in a manner analogous to that described in Example 3, but 1-Boc-azocane is used insead of 1-Boc-pyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([CH3:33])[CH:22]([C:24]1OC2C=CC=CC=2N=1)[OH:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[K+].[Br-]>CCOC(C)=O>[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([CH3:33])[CH:22]([C:24]1[O:8][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH3:9])[C:2]=2[N:1]=1)[OH:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(O)c1nc2ccccc2o1
Reactant: Cc1cccc(O)c1N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1cccc2oc(C(O)[C@H](C)NC(=O)OCc3ccccc3)nc12
Yield: 35 %

Procedure:
This material was prepared as a 1:1 mixture of isomers in 35% yield from the above cyanohydrin (707 mg, 3.02 mmol) and 2-amino-m-cresol (409 mg, 3.32 mmol) using the procedure described above for compound 16. An analytical sample was obtained by recrystallization from EtOAc in hexanes (1.3:1 mixture of isomers). mp: 98° C.; IR (KBr) υ 1701, 1690 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.38-7.20 (m, 7H), 7.15-7.10 (m, 1H), 5.39 and 5.29 (2×d, J=7.9 and 5.4 Hz, 1H), 5.15-4.90 (m, 3H), 4.40 and 4.23 (2×br s, 2H), 2.58 (S, 3H), 1.34 and 1.14 (2×d, J=6.7 and 7.0 Hz, 3H); 13C-NMR (100.6 MHz, CDCl3) δ 164.82, 164.22, 156.28, 156.12, 150.72, 150.65, 139.40, 136.27, 130.61, 130.43, 128.51, 128.40, 128.14, 128.01, 127.91, 125.20, 125.14, 125.04, 124.98, 108.20, 108.13, 71.02, 70.62, 66.96, 66.77, 50.45, 50.27, 17.35, 16.39, 12.24; FAB MS m/z: 341 (MH+); HRMS calcd for C19H21N2O4 (MH+) 341.1501, found: 341.1490; Anal (C19H2ON2O4) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](I)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:17]([Sn:21]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])Cl)[CH2:18][CH2:19][CH3:20].[NH4+].[Cl-]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn:21]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:17][CH2:18][CH2:19][CH3:20])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(I)n[nH]c2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(Cl)ccc12
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 77.3 %

Procedure:
To a solution of 6-chloro-3-iodo-1H-indazole (337 mg, 1.21 mmol) in dry tetrahydrofuran (20 mL) was added drop-wise isopropylmagnesium chloride (1.33 mL, 2M in THF, 2.66 mmol) at −16° C. under N2 atmosphere. After stirring for 20 minutes, tributylchlorostannane (472 mg, 1.45 mmol) was added drop-wise at −16° C., and then it was warmed to 20° C. for 2 h. Then NH4Cl solution (2 mL) was added and product extracted with dichloromethane (15 mL), organic phase was washed with water (2×20 mL) and brine (2×20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford 6-chloro-3-(tributylstannyl)-1H-indazole (413 mg, crude) as yellow oil which was used to next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([Cl:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:21](O)(=O)C.C(N)=N>CCO.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:6]([Cl:12])[C:7]2[N:11]=[CH:21][NH:10][C:8]=2[CH:9]=1)=[O:20]
Reactant: CC(=O)O
Reactant: COC(=O)c1cc(N)c(N)c(Cl)c1Nc1ccccc1
Agent: N=CN
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2[nH]cnc2c(Cl)c1Nc1ccccc1
Temperature: 80 °C
Reaction time: 44 h
Yield: 100.3 %

Procedure:
4,5-Diamino-3-chloro-2-phenylamino-benzoic acid methyl ester 6b (0.32 g, 1.09 mmol) and formamidine acetate (72 mg, 1.64 mmol) in EtOH (36 mL) are heated, with stirring, to 80° C. After 44 hours, the reaction mixture is cooled to room temperature and diluted with EtOAc and washed with water (3×), saturated NaHCO3, and brine. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to give 0.33 g (99%) clean desired product as a solid. MS APCI (+) m/z 302.3 (M+1) detected.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[NH:15][C:14](=[O:23])[C:13]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14](=[O:23])[NH:15]2)=[CH:20][CH:19]=1
Reactant: Nc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=c1[nH]c2cc(Cl)ccc2c(NS(=O)(=O)c2ccccc2)c1-c1ccccc1

Procedure:
Benzene sulphonylchloride (0.94 ml) and 4-amino-7-chloro-3-phenyl-2(1H)-quinolone (1 g) (Example 2) were reacted in a similar manner to that as described in Example 4. An additional step was required to remove the tert butyldimethylsilyl protecting group using methanolic-HCl for 20 mins to afford the title compound (0.050 g); mp 268° C. (ethanol); δ (360 MHz, DMSO-d6) 7.14 (6H, m, aromatics), 7.32 (5H, m, aromatics), 7.49 (1H, m, aromatics), 7.67 (1H, d, J =8.7 Hz, 5H), 10.02 (1H, br s, 4NH), 12.15 (1H, br s, 1NH); m/z 410 (M+).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:2]1[CH:3]=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)Cc1cc(F)ccc1C(F)(F)F
Reactant: OCc1ccccc1
Product: O=C(O)Cc1cc(OCc2ccccc2)ccc1C(F)(F)F

Procedure:
Prepared according to the procedure described in Example 185, Step 1, using the following starting materials: 5-fluoro-2-(trifluoromethyl)phenylacetic acid and benzyl alcohol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)([OH:17])=[O:16]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:4]1[N:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1cccc(Br)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cccc(-c2ccc(C(=O)O)cc2)n1
Yield: 77 %

Procedure:
To a stirred, degassed mixture of 2-bromo-6-methylpyridine (3 g, 17 mmol), sodium carbonate (10.8 g, 100 mmol) and 4-carboxybenzeneboronic acid (2.3 g, 14 mmol) in DME (150 ml) and water (150 ml) under an argon atmosphere was added tetrakis(triphenylphosphine) palladium (0) (350 mg) and the mixture heated to reflux for 18 h. On cooling, ˜50% of the solvent was removed in vacuo and the residual aqueous solution was washed with EtOAc, then acidified to pH1 with concentrated HCl and washed with further EtOAc. The aqueous was then adjusted to pH 5 by addition of potassium carbonate causing formation of a white precipitate which was collected by filtration, washed with water and dried to give the title compound as a white solid (2.3 g). MS (ES): MH+ 212.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])=[CH:6][CH:5]=1>C(O)(=O)C.[Pd].[Pt](=O)=O>[F:21][C:2]([F:1])([F:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][NH:12][CH2:13][CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH2:19]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1cncc(-c2ccc(CC(F)(F)F)cc2)c1
Agent: O=[Pt]=O
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)C1CNCC(c2ccc(CC(F)(F)F)cc2)C1
Reaction time: 6 h

Procedure:
A solution of 9.20 g (23.4 mmol, purity 75%) of the compound from Example 52A in concentrated acetic acid (192 ml) was admixed with 1.94 g of palladium/carbon (10% palladium) and 2.23 g of platinum (IV) oxide. This was followed by hydrogenation under a hydrogen atmosphere at standard pressure for 6 h, then addition of another 1.00 g of palladium/carbon (10% palladium) and 2.00 g of platinum(IV) oxide, and hydrogenation under a hydrogen atmosphere at standard pressure overnight. Subsequently, a further 1.00 g of palladium/carbon (10% palladium) and 3.00 g of platinum(IV) oxide were added, and hydrogenation was effected under a hydrogen atmosphere at standard pressure for a further 24 h. The reaction solution was filtered through Celite, the filter residue was washed with methanol/water and the combined filtrates were concentrated under reduced pressure. The residue was taken up in dichloromethane and then washed with a 1 N aqueous sodium carbonate solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 6.64 g (85% of theory, purity 90%)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([SH:15])=[N:6][C:5]=2[N:16]=1.Cl.Cl[CH2:19][C:20]1[N:21]=[C:22]([CH3:25])[S:23][CH:24]=1.CCN(C(C)C)C(C)C>CS(C)=O.CN1C(=O)CCC1>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([S:15][CH2:19][C:20]3[N:21]=[C:22]([CH3:25])[S:23][CH:24]=3)=[N:6][C:5]=2[N:16]=1
Reactant: C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: Cc1nc(CSc2nc(N[C@H](C)CO)c3sc(N)nc3n2)cs1
Reaction time: 1 h
Yield: 36.2 %

Procedure:
A stirred solution of the product of step (b) (0.05 g) in DMSO (4 ml) was treated with a solution of 4-chloromethyl-2-methylthiazole hydrochloride (0.029 g) and Hunig's base (0.025 g) in NMP (0.5 ml) and stirred for 1 hour. The solution was purified by reverse phase preparative HPLC on Nova-pak® C18 column, using 10 to 60% acetonitrile in 0.1% aqueous ammonium acetate at 50 ml/min over 10 min to give the titled compound (0.021 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:10]#[N:11].Cl[CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1.CS(C)=O.[OH-].[Na+]>O>[C:10]([C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)#[N:11]
Reactant: COc1ccccc1C(C#N)Cc1ccccn1
Reactant: ClCn1cncn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1C(C#N)(Cc1ccccn1)Cn1cncn1
Reaction time: 2 h

Procedure:
To a flask was added 5.0 g. (0.021 mole) of 2-(2-methoxyphenyl)-3-(2-pyridyl)propionitrile, 5.0 g. (0.031 mole) of 1-(chloromethyl)-1,2,4-triazole, and 150 ml. of DMSO, followed by 10 g. (0.125 mole) of 50% aqueous sodium hydroxide over 30 minutes. The reaction exothermed to 40° C. and was stirred for an additional two hours. After cooling, water was added and the organic material extracted with ether. The combined ether extracts were then washed with water, dried using magnesium sulfate, filtered, and the ether removed by rotary evaporation to obtain 3.0 g. of organic residue which was recrystallized from ether yielding 1.3 g. of the product as a grey solid, melting point 155°-158° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[N:9]=[C:8]([CH3:16])[C:7]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:2][CH2:3][CH3:4].[NH3:22]>CO>[NH2:22][C:10]1[N:9]=[C:8]([CH3:16])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: CCCCNc1c(C(=O)OCC)c(C)nc(Cl)c1[N+](=O)[O-]
Reactant: N
Solvent: CO
Product: CCCCNc1c(C(=O)OCC)c(C)nc(N)c1[N+](=O)[O-]

Procedure:
177.9 g. of 4-butylamino-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester (0.5 Mol.) dissolved in 500 ml. of methanol are heated with 300 ml. of aqueous ammonia (30%) in an autoclave at about 60° for 10 hours. After this time, the solvent is distilled off and the residual 6-amino-4-butylamino-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester is recrystallized from methanol, yield 135 g.; m.p. 98°-99°.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[C:11]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.CCOC(C)=O>[CH3:11][O:9][C:8]([C@H:5]1[CH2:6][CH2:7][C@@H:2]([OH:1])[CH2:3][CH2:4]1)=[O:10]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CC[C@@H](O)CC1
Reaction time: 2 h

Procedure:
To a solution of trans-4-hydroxycyclohexanecarboxylic acid (5.0 mmol, 721 mg), K2CO3 (15.0 mmol, 2.07 g) in DMF (17 mL) is added iodomethane (6.0 mmol, 0.374 mL). After stirring for 2 h, the mixture is diluted with EtOAc. The mixture is washed with H2O and brine, dried over Na2SO4 and concentrated. The residue is used to next reaction without further purification (643 mg, 81%); ESI-MS m/z: 159 [M+1]+, Retention time 1.34 min. (condition A).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=1)[N:7]=3.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[OH-:54].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:19]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([OH:54])=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][CH:17]=[N:16]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: [OH-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O)cc1OCC2
Temperature: 90 °C
Yield: 45.5 %

Procedure:
Alternatively, 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (9.5 g, 25.4 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (855 mg, 2.0 mmol), tris(dibenzylideneacetone)dipalladium (0) (475 mg, 0.5 mmol) and potassium hydroxide (4.2 g, 76.2 mmol) were suspended in dioxane (29 mL) and water (15 mL). The suspension was degassed with nitrogen and the reaction mixture heated at 90° C. for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL). The aqueous fraction was acidified to pH˜5 by addition of hydrochloric acid (1M) causing a precipitate to form. The suspension was extracted with ethyl acetate (3×15 mL). The combined organic extracts were dried (MgSO4), concentrated in vacuo. The resultant residue was triturated with diethyl ether to yield 490 as an orange solid (3.6 g, 46%). 1H NMR (400 MHz, DMSO-d6) δ 9.90 (1H, br s), 8.22 (1H, d, J=8.9 Hz), 7.88 (1H, s), 7.82 (1H, s), 6.61 (1H, dd, J=8.9, 2.6 Hz), 6.41 (1H, d, J=2.6 Hz), 5.90 (1H, sept, J=6.5 Hz), 4.49-4.39 (4H, m), 1.47 (6H, d, J=6.5 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:8])[CH3:2].[NH2:24][CH2:25][C@@H:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[OH:27]>>[OH:27][C@H:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[CH2:25][NH:24][CH:19]1[CH2:20][CH2:21][N:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:23])=[O:8])=[CH:11][CH:12]=2)[CH2:17][CH2:18]1
Reactant: CCOC(=O)CNC(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCOC(=O)CNC(=O)Nc1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from {3-[4-(4-oxo-piperidin-1-yl)-phenyl]-ureido}-acetic acid ethyl ester (which was obtained in Example 366) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20 (t, J=7.1 Hz, 3 H), 1.20–1.40 (m, 2 H), 1.80–1.95 (m, 2 H), 2.50–2.70 (m, 5 H), 2.92 (s, 3 H), 3.40–3.50 (m, 2 H), 3.83 (d, J=5.9 Hz, 2 H), 4.10 (q, J=7.1 Hz, 2 H), 4.47 (dd, J=8.0, 4.3 Hz, 1 H), 6.28 (t, J=5.9 Hz, 1 H), 6.75–6.85 (m, 3 H), 7.00 (dd, J=8.3, 2.0 Hz, 1 H), 7.15–7.25 (m, 3 H), 8.45 (s, 1 H); MS (ES) m/z: 550.5 (MH+); HRMS Calcd. for C25H36N5O7S (MH+): 550.2330. Found: 550.2319.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[C:9](OCC)(=[O:16])[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:16])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccncc1
Reactant: Cc1cccc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1cccc(Cl)n1)c1ccncc1
Temperature: 45 °C

Procedure:
To a cold (O ° C.) solution of 6-chloro-2-picoline (14.5 mL, 132.3 mmol) and ethyl isonicotinate (20.0 g, 132.3 mmol) in tetrahydrofuran (300 mL) was added lithium bis(trimethylsilyl)amide (280 mL 1.0 M in tetrahydrofuran, 278 mmol) dropwise via a pressure equalizing funnel over 1 hour. Upon complete addition, the cold bath was removed and the resulting solution was heated at 45° C. for 15 hours. The mixture was cooled to room temperature, methanol was added, and the solution was concentrated to give 2-(6-chloro-2-pyridinyl)-1-(4-pyridinyl)ethanone as a syrup, that was used without further purification. This syrup (11.7 g, 50 mmol) was dissolved in methanol (200 mL). To this solution was added hydroxylamine hydrochloride (17.5 g, 250 mmol) followed by the addition of a sodium hydroxide solution (10 g, 250 mmol in 30 mL of water). The resulting suspension was heated at reflux for 2 hours and then allowed to cool to room temperature. The mixture was concentrated and water was added to the resulting slurry. A white precipitate formed, which was collected by filtration, washed with water and dried to give 2-(6-chloro-2-pyridinyl)-1-(4-pyridinyl)ethanone oxime (10.5 g, 850%) as a white solid. 1H NMR (CDCl3): δ 9.6 (broad s, 1H), 8.65 (d, 2H), 7.70 (d, 2H), 7.58 (t, 1H), 7.22 (m, 2H), 4.40 (s, 2H); MS m/248 (M+1).
Reaction SMILES: [C:1]([N:20]=[N+:21]=[N-:22])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][CH3:28])(=[O:26])[C:24]#[CH:25]>CC(C)=O.CCOCC>[CH3:28][O:27][C:23]([C:24]1[N:22]=[N:21][N:20]([C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:25]=1)=[O:26]
Reactant: C#CC(=O)OC
Reactant: [N-]=[N+]=NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nn1
Temperature: 25 °C
Yield: 62 %

Procedure:
To a suspension of sodium azide (19.0 g : 0.283 Mol.) in dimethyl- formamide (130 ml) is added trityl chloride (76.0 g : 0.273 Mol.), and the mixture is stirred at room temperature for 5 hours. The reaction mixture is diluted with water and extracted with ether. The extract is washed with brine, dried over sodium sulfate, and concentrated to give trityl azide. To a solution of this azide in acetone (300 ml) is added methyl propiolate (24 ml : 0.27 Mol.), and the mixture is heated under reflux for 6 days. The reaction mixture is cooled to the room temperature and diluted with ether. The separating crystals are collected by filtration to give 1-trityl-1,2,3-triazol-4-ylcarboxylic acid methyl ester (62.0 g) as colorless crystals. Yield: 62%. mp. 189° to 190° C. NMR δ (CDCl3) ppm: 3.93(s, 3H), 7.05-7.15(m, 6H), 7.3-7.4(m, 9H), 8.02(s, 1H).
Reaction SMILES: Cl.C([O:4][C:5](=[O:8])[CH2:6][NH2:7])C.[C:9]1([N:15]=[C:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C1C=CC=CC=1>[C:9]1([NH:15][C:16]([NH:7][CH2:6][C:5]([OH:4])=[O:8])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(O)CNC(=O)Nc1ccccc1
Reaction time: 5 h

Procedure:
7.0 g of glycine ethyl ester hydrochloride was suspended in 100 ml of benzene, and 10 ml of phenylisocyanate and 8 ml of triethylamine were added thereto. The mixture was stirred for 5 hours and benzene was distilled away. Ethyl acetate was added to the residue, washed with water and brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled away and 100 ml of 1N aqueous solution of sodium hydroxide was added to the resulting residue. The solution was stirred at 50° C. for 2 hours. Insoluble substance was filtered off and the filtrate was acidified with concentrated hydrochloric acid. The precipitated crystals were collected by filtration and recrystallized from methanol/water to give 6.8 g of phenylcarbamoylglycine.