Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.N([O-])=[O:16].[Na+]>O>[N+:11]([C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2](=[O:16])[S:3][C:4]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: O=N[O-]
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c2ccc([N+](=O)[O-])cc2s1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
28.75 g of 2-amino-6-nitrobenzothiazole, 210 g of 30% hydrochloric acid and 29.5 g of water are introduced into a 750 ml pressure vessel at room temperature and subsequently heated to 50° C. After the reaction mixture has been stirred for 30 minutes, it is cooled to 20° C. 50.75 g of aqueous sodium nitrite solution are then metered in at a uniform rate in the course of 3 hours at 20°-30° C., with very vigorous stirring. After metering in has ended, stirring is continued for 2.5 hours at 20°-30° C. Then, excess nitrite is removed by adding approximately 15 g of 18% aqueous urea solution. The reaction vessel is subsequently sealed, and the reaction mixture is heated for 5 hours at 140°-150° C. (pressure approximately 4 bar). After the mixture has cooled to 20° C., the crystalline product is filtered off with suction, washed until neutral and dried at 60° C. to constant weight. 27.3 g of 6-nitrobenzothiazol-2-one with a pure substance content of 97.8% are obtained (corresponding to 92.4% yield). The product which is redissolved under alkaline conditions has a DSC melting point of 252.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:18][CH2:17][C@H:16]([NH2:19])[C:15]2=[O:20])[C@H:10]([CH2:21][CH2:22][CH3:23])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:25]([NH:28][C:29](=[O:44])[NH:30][C:31]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:32]=1[C:33](O)=[O:34])([CH3:27])[CH3:26].C(N(C(C)C)CC)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>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:33](=[O:34])[C:32]3[CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=[CH:39][C:31]=3[NH:30][C:29]([NH:28][CH:25]([CH3:26])[CH3:27])=[O:44])[C:15]2=[O:20])[C@H:10]([CH2:21][CH2:22][CH3:23])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Agent: CCN(CC)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2NC(=O)NC(C)C)C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (1R,3R,4S)-{4-[(3S)-3-amino-2-oxo-pyrrolidin-1-yl]-3-propyl-cyclohexyl}-carbamic acid tert-butyl ester (0.27 mmol assumed) in DMF (4 mL) was charged with 2-(3-isopropyl-ureido)-5-trifluoromethyl-benzoic acid (82 mg, 0.3 mmol), N,N-diethylisopropylamine (0.19 mL, 1.1 mmol), and BOP (142 mg, 0.32 mmol). The reaction was stirred for 48 h at RT and then partitioned between EtOAc and sat. NaHCO3; the aqueous phase was back extracted with EtOAc (1×). The organic phases were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford (1R,3R,4S)-(4-{(3S)-3-[2-(3-isopropyl-ureido)-5-trifluoromethyl-benzoylamino]-2-oxo-pyrrolidin-1-yl}-3-propyl-cyclohexyl)-carbamic acid tert-butyl ester. MS found: (M+H)+=612.3.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C:9]1([C:32]([NH2:34])=[O:33])[CH2:14][CH2:13][N:12]([C:15]([C:17]2[C:18]3[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=3[S:20][C:21]=2[NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[O:16])[CH2:11][CH2:10]1.C(O)(=O)C.[CH2:39]([O:41][C:42](OCC)([O:50]CC)[CH2:43][CH2:44][C:45](OCC)=O)[CH3:40]>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:26]([NH:25][C:23](=[O:24])[NH:22][C:21]1[S:20][C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=2[C:17]=1[C:15]([N:12]1[CH2:11][CH2:10][C:9]2([N:8]=[C:45]([CH2:44][CH2:43][C:42]([O:41][CH2:39][CH3:40])=[O:50])[NH:34][C:32]2=[O:33])[CH2:14][CH2:13]1)=[O:16])[CH3:27]
Reactant: CCOC(=O)CCC(OCC)(OCC)OCC
Reactant: CCNC(=O)Nc1sc2ccccc2c1C(=O)N1CCC(N)(C(N)=O)CC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1sc2ccccc2c1C(=O)N1CCC2(CC1)N=C(CCC(=O)OCC)NC2=O
Temperature: 85 °C
Yield: 65 %

Procedure:
4-Amino-1-(2-(3-ethylureido)benzo[b]thiophene-3-carbonyl)piperidine-4-carboxamide (7, 100 mg, 1.0 equivalent) as prepared in Example 7 was dissolved in toluene (0.09 M) and DMF (0.26 M), and to which acetic acid (2.0 equivalents), and ethyl 4,4,4-triethoxybutanoate (4.0 equivalents) were added and the reaction mixture was heated to 85° C. for 9 hrs. The reaction mixture was then partitioned between ethyl acetate and water and the separated organics was washed with brine and dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography (5%-10% MeOH/CH2Cl2 gradient) to afford ethyl 3-(8-(2-(3-ethylureido)benzo[b]thiophene-3-carbonyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-2-yl)propanoate (10, 65%). Two rotamers observed (ratio 1.3:1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.O.[CH3:28][N:29](C=O)C>[C-]#N.[C-]#N.[Zn+2].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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH:23]1([N:20]2[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][N:11]3[CH2:12][CH2:13][N:8]([C:5]4[N:4]=[N:3][C:2]([C:28]#[N:29])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)[CH2:18][CH2:19]2)[CH2:26][CH2:25][CH2:24]1
Reactant: O=C(CN1CCN(c2ccc(Cl)nn2)CC1)N1CCN(C2CCC2)CC1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1ccc(N2CCN(CC(=O)N3CCN(C4CCC4)CC3)CC2)nn1
Temperature: 120 °C

Procedure:
In a sealed tube, dissolve 3-chloro-6-{4-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]piperazin-1-yl}pyridazine (205 mg, 0.541 mmol), Zn(CN)2 (39 mg, 0.325 mmol), Pd2dba3 (12.3 mg, 0.0135 mmol) and DPPF (15 mg, 0.027 mmol) in DMF (3 mL). Add I drop of H2O and degas the solution with N2. Seal the tube and heat at 120° C. overnight. Cool and dilute with 3 N HCl (30 mL). Extract with CH2Cl2 (2×25 mL). Discard these extracts. Basify the aqueous layer with 10 N NaOH and extract with CH2Cl2 (3×35 mL). Combine, dry (MgSO4) and evaporate the organic extracts to yield the title compound. 1H NMR (CDCl3) δ 7.44 (d, 1H), 6.83 (d, 1H), 3.84-3.1 (m, 4H), 3.66-3.58 (m, 4H), 3.26 (s, 2H), 2.75-2.66 (m, 5H), 2.33-2.29 (m, 4H), 2.07-2.01 (m, 2H), 1.91-1.85 (m, 2H), 1.76-1.70 (m, 2H); LC-MS (M+1) 370.00.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][C:29]1[CH:33]=[C:32]([C:34](O)=[O:35])[O:31][N:30]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([C:32]5[O:31][N:30]=[C:29]([CH3:28])[CH:33]=5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: Cc1cc(C(=O)O)on1
Agent: Cl
Product: Cc1cc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4OCC5)CC3)CC2)on1

Procedure:
The title compound, white solid (99 mg, 90%), MS (ISP) m/z=440.4 [(M+H)+], mp 199° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 3-methyl-isoxazole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][C:10]1([CH3:18])[CH2:17][C:15](=O)[CH2:14][C:12](=[O:13])[CH2:11]1>C(O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:14]1[C:12](=[O:13])[CH2:11][C:10]([CH3:18])([CH3:9])[CH2:17][CH:15]=1
Reactant: Nc1ccccc1Cl
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)CC=C(Nc2ccccc2Cl)C(=O)C1

Procedure:
A mixture of 12.75 parts of 2-chloroaniline and 14 parts of dimedone is dissolved in 40 volume parts of ethanol under warming, followed by the addition of 3 drops of glacial acetic acid. The solution is refluxed in a water bath for 2 hours, after which time the ethanol is distilled off and the resulting residue is allowed to cool, whereupon yellow crystals separate. These crystals are collected by filtration, washed with ispropyl ether and recrystallized from acetone. The procedure yields 3-(2-chloroanilino-5,5-dimethyl-2-cyclohexen-1-one as colorless prisms melting at 150°-152°C. Elementary analysis: C14H16NOCL Calcd. C, 67.32; H, 6.45; N, 5.60 Found C, 67.13; H, 6.31; N, 5.82 (b) A mixture of 40 parts of dimedone and 36.4 parts of 2-chloroaniline is heated at 170°-175°C for 45 minutes followed by cooling. The resulting reaction product is recrystallized to obtain yellow cubes. The crystals are collected by filtration, washed well with isopropyl ether and recrystallized from acetone. The procedure yields colorless prisms of 3-(2-chloroanilino)-5,5-dimethyl-2-cyclohexen-1-one. Melting point: 150°-152°C. By procedures similar to those described in Example 1-(a) and (b), the following compounds are produced.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:5]=2[C:4](=[O:14])[O:3]1.C(O)(=O)C.N#N>CO.[Pd]>[C:2]([OH:7])(=[O:3])[CH3:1].[NH2:13][CH2:12][C:10]1[CH:9]=[CH:8][C:6]2[O:7][C:2]([CH3:15])([CH3:1])[O:3][C:4](=[O:14])[C:5]=2[CH:11]=1
Reactant: CC1(C)OC(=O)c2cc(C#N)ccc2O1
Agent: [Pd]
Agent: N#N
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)OC(=O)c2cc(CN)ccc2O1
Reaction time: 22 h
Yield: 74.8 %

Procedure:
To a solution of 2,2-dimethyl-4-oxo-4H-1,3-benzodioxine-6-carbonitrile (12 g, 0.06 mol) in methanol (500 mL) was added glacial acetic acid (3.5 g, 0.059 mol) and passed N2 for 30 min. To this was added Pd/C (2.4 g, 20%) and hydrogenated under 2 Bars of pressure for 22 h. The reaction mixture was filtered through celite and filtrate concentrated under vacuum. To the solid was added EtOAc (200 mL), stirred for 20 h and filtered. The solid was dried under vacuum to give 6-(aminomethyl)-2,2-dimethyl-4H-1,3-benzodioxin-4-one acetate (6 g, 38%). TLC:CHCl3/MeOH, 9:1, Rf: 0.15
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([NH2:10])=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].O=[C:12]([CH3:16])[C:13](O)=[O:14]>CO>[CH2:1]([N:3]1[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:10]=[C:12]([CH3:16])[C:13]1=[O:14])[CH3:2]
Reactant: CCNc1ccccc1N
Reactant: CC(=O)C(=O)O
Solvent: CO
Product: CCn1c(=O)c(C)nc2ccccc21
Yield: 56.7 %

Procedure:
5.4 g (39.6 mM) of N-ethylbenzene-1,2-diamine and 2.76 ml (39.6 mM) of 2-oxopropanoic acid in 200 ml of methanol were refluxed for 8 h. The solvent was removed under vacuum. The residue was further purified by silica gel column chromatography, using dichloromethane, followed by dichloromethane/dimethylketone (95/5) as eluant to give 4.2 g of 1-ethyl-3-methyl-quinoxalin-2(1H)-one as a yellow solid. Yield: 56.7%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[C@@H:15]([CH:16]=[CH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][C@H:12]1[OH:25])[CH3:2].[CH2:27](O)[CH2:28][OH:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[C:15](=[CH:16][CH2:17][C:18]2([O:29][CH2:28][CH2:27][O:24]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][C@H:12]1[OH:25])[CH3:2]
Reactant: OCCO
Reactant: CCCCCC(=O)C=C[C@H]1CC[C@@H](O)[C@@H]1CCCCCCC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCC1(CC=C2CC[C@@H](O)[C@@H]2CCCCCCC(=O)OCC)OCCO1
Temperature: 25 °C

Procedure:
5 g 9β-hydroxy-15-oxo-13-prostenoic acid ethyl ester are boiled with 5 ml ethylene glycol and 0,5 g p-toluene sulfonic acid in 150 ml dry benzene for 20 hours and water is removed. After cooling to room temperature the reaction mixture is given to a mixture of 150 ml saturated aqueous NaHCO3 -solution and 750 ml diethyl ether. The organic layer is separated, washed with water, dried over Na2SO4 and the solvent is removed by destillation. One obtains 15,15-ethylenedioxy-9β-hydroxy-12-prostenoic acid ethyl ester after chromatographical purification of the residue (silicagel/diisopropyl ether); IR: 3500, 1740 and 1470 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:33][OH:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:55]1[C:59](=[O:60])[C:58]2=[CH:61][CH:62]=[CH:63][CH:64]=[C:57]2[C:56]1=[O:65].C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([S:13][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][C@@H:9]1[CH2:33][O:34][N:55]1[C:56](=[O:65])[C:57]2=[CH:64][CH:63]=[CH:62][CH:61]=[C:58]2[C:59]1=[O:60])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1CO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1CON1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 96.8 %

Procedure:
To a solution of (2R,4S)-1-t-butoxycarbonyl-4-tritylthiopyrrolidine-2-methanol (2:1.37 g:2.88 mMol.) in tetrahydrofuran (8.6 ml) under ice cooling are added triphenylphosphin (892 mg: 3.40 mMol.). N-hydroxyphthalimide (705 mg: 4.32 mMol.) and azodicarboxylic acid diethyl ester (0.59 ml: 3.74 mMol.), and the mixture is stirred under ice cooling for 90 minutes. The reaction mixture is diluted with ethyl acetate (30 ml) and ice water (30 ml). The organic layer is taken, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel chromatography to give (2R,4S)-1-t-butoxycarbonyl-2-phtalimidooxymethyl-4-tritylthiopyrrolidine (3:1.73 g). Yield: 97%. IR ν (KBr) cm-1 : 3420, 1790, 1735, 1694. 1NMR δ (CDCl3) ppm: 1.35(s, 9H), 1.8 to 2.4(m, 2H), 2.7 to 3.2(m, 2H), 3.8 to 4.3(m, 2H), 7.1 to 7.6(m, 15H), 7.6 to 7.9(m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=O)=[CH:6][C:5]=1C1C=CC=CC=1[N+]([O-])=O.[C:23](O)(=O)[CH3:24]>[Fe]>[N:10]1[C:8]2[CH:7]=[CH:6][CH:5]=[CH:23][C:24]=2[NH:10][C:8]=1[C:7]1[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:22])=[CH:12][CH:11]=1
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc(C(N)=O)cc1-c1ccccc1[N+](=O)[O-]
Agent: [Fe]
Product: COC(=O)c1ccc(-c2nc3ccccc3[nH]2)cc1
Yield: 86 %

Procedure:
To a solution of (2-nitrophenyl)-terephthalamic acid methyl ester (0.23 g, 0.76 mmol) in glacial acetic acid (2.5 mL) was added iron powder (<5 μm mesh, 0.12 g, 2.1 mmol) and the mixture stirred at reflux for 1 h. The mixture was cooled, stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was partitioned between saturated sodium bicarbonate (10 mL) and ethyl acetate (10 mL), the phases separated and the organic layer washed with saturated NaHCO3 (10 mL). The organic extract was dried (MgSO4), filtered and concentrated to give cyclized methyl 4-(benzimidazol-2-yl)-benzoate (0.163 g, 86%). 1H NMR (CDCl3) δ 3.96 (s, 3H), 7.32 (m, 2H), 7.53 (br, 1H), 7.84 (br, 1H), 8.17 (m, 4H), 9.65 (br, 1H (NH)).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([N:14]1[CH2:18][CH2:17]OC1=O)([O:11][CH2:12][CH3:13])=[O:10].COCCOCCO>>[CH2:12]([O:11][C:9](=[O:10])[NH:14][CH2:18][CH2:17][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:13]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)N1CCOC1=O
Agent: Cl
Solvent: COCCOCCO
Product: CCOC(=O)NCCNc1ccccc1
Temperature: 160 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
A mixture of aniline hydrochloride (8.7 g, 66.9 mmole), N-carboethoxy-2-oxazolidinone (10.1 g, 63.5 mmole) and 25 ml of 2-(2-methoxyethoxy)ethanol was heated to 160° C. Gas evolution began occurring at 140° C. and continued for 3 hours. The dark homogenous reaction solution was allowed to cool to ambient temperature and worked up according to the procedure described in Example 1. Distillation at 170° C. (0.5 mm) gave a 26 percent yield of a clear oil which slowly solidified on standing.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([CH2:21][OH:22])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([CH:21]=[O:22])[CH2:19][CH2:20]2)=[CH:16][CH:17]=1
Reactant: OCC1(c2ccc(Br)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=CC1(c2ccc(Br)cc2)CC1
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a solution of DMSO (2.18 mL, 30.7 mmol) in dry DCM (15.0 mL) under nitrogen atmosphere, was added oxalyl chloride (1.21 mL, 14.2 mmol) at −78° C. The reaction mixture was stirred at this temperature for 30 min followed by addition of solution of (1-(4-bromophenyl)cyclopropyl)methanol (2.7 g, 11.8 mmol), in DCM (15.0 mL). The reaction mixture was stirred at −78° C. for 45 min followed by addition of triethylamine (8.2 mL, 59.2 mmol) and further stirring at same temperature for 15 min and then at r.t. for 15 min. The reaction mixture was diluted with DCM (100 mL) and water (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to afford title compound (2.6 g, 93%) as viscous oil which was used as such in the next step.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl[C:24]1[N:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:24]3[N:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=3)=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Reactant: Clc1ncc(Br)cn1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cnc(N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)nc1
Temperature: 125 °C

Procedure:
To the solution of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (4.38 g, 15.0 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) and 2-chloro-5-bromopyrimidine (2.90 g, 15.0 mmol) (prepared as in Example 51) in dry degassed DMF (30 ml) was added N,N-diisopropylethylamine (4.2 ml, 30 mmol). The mixture was heated at 120-130° C. overnight. The mixture was then cooled and diluted with ethyl acetate. The solution was washed with 0.5 N citric acid, water and brine, then dried over Na2SO4 and concentrated in vacuo. Purification by flash column (silical gel, hexane:ethyl acetate=6:1, v/v, followed by hexane:ethyl acetate=4:1, v/v) yielded the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]#[CH:11].[N:12]([CH2:15][CH2:16][C@@:17]([CH3:32])([S:28]([CH3:31])(=[O:30])=[O:29])[C:18]([NH:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)=[O:19])=[N+:13]=[N-:14].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>C(O)C.O.[O-]S([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:14]=[N:13][N:12]([CH2:15][CH2:16][C@@:17]([CH3:32])([S:28]([CH3:31])(=[O:30])=[O:29])[C:18]([NH:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[O:19])[CH:11]=1
Reactant: C[C@@](CCN=[N+]=[N-])(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reactant: C#Cc1ccc(OC)cc1Cl
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cn(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)nn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
To a solution of 2-chloro-1-ethynyl-4-methoxybenzene (15 mg, 0.093 mmol, 1 eq) and (2R)-4-azido-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (30 mg 0.093 mmol, 1 eq) in EtOH—H2O (7 mL:1 mL) was added sodium ascorbate (19 mg, 0.093 mmol, 1 eq) and CuSO4 (9 mg, 0.037 mmol, 0.4 eq). The reaction mixture was stirred vigorously at RT overnight. The reaction mixture was concentrated to remove the EtOH/H2O. The residue was dissolved in EtOAc and the CuSO4 solid was filtered off. The filtrated was adsorbed onto silica and purified by flash chromatography on a 12 g silica gel column eluting with 0-100% EtOAc/Hpt to give (2R)-4-[4-(2-chloro-4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (18 mg). To a solution of (2R)-4-[4-(2-chloro-4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (18 mg, 0.037 mmol, 1 eq) in EtOH (93 mL) was added 4 M HCl. The reaction mixture was allowed to stir at RT for 3 h and then concentrated to give (2R)-4-[4-(2-chloro-4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (10 mg, 67% yield). 1H NMR (400 MHz, METHANOL-d4) δ 8.69 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.15 (d, J=2.5 Hz, 1H), 7.09-7.02 (m, 1H), 4.85-4.73 (m, 1H), 4.71-4.57 (m, 1H), 3.87 (s, 3H), 3.07 (s, 4H), 2.63-2.50 (m, 1H), 1.69 (s, 3H). LC-MS M+H+403.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:14](OC(=O)C1C=C(N2CCCCC2)C=CC=1N)[CH3:15].S(Cl)(Cl)=O>C(O)C>[CH2:14]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:15]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)c1cc(N2CCCCC2)ccc1N
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
5-Chloro-2-nitro-benzoic acid (compound A′) (10.0 g) was dissolved in ethanol (100 ml). Thionyl chloride (20 ml) was added dropwise to the solution at 0° C., and the mixture was then heated under reflux with stirring for 48 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure. Distilled water was added to the residue, and the mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution under ice cooling, and was then subjected to separatory extraction with ethyl acetate. The organic layer was dried over sodium sulfate and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 5-chloro-2-nitro-benzoic acid ethyl ester as a useful intermediate (11.0 g, yield 97%).