Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:29]=[C:28]([C:37](=[O:41])[N:38]([CH3:40])[CH3:39])[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].C(O[C:45]([CH2:47][CH2:48]C1C(OCCCC(OCC)=O)=CC=CC=1CCCCCCOC1C=C(C=C(C2C=CSC=2)C=1)C(O)=O)=O)C.N1CCCCC1>>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:29]=[C:28]([C:37]([N:38]3[CH2:40][CH2:48][CH2:47][CH2:45][CH2:39]3)=[O:41])[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccsc2)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Solvent: C1CCNCC1
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCCCC3)cc(-c3ccsc3)c2)c1CCC(=O)O

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(3-dimethylcarbamoyl-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy}-butyric acid starting from 3-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-thiophen-3-yl-benzoic acid and piperidine.
Reaction SMILES: [C:1]1([C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14]C(O)(CC3C=CC=CC=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)CCN2CC[C:49]([OH:59])([CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)CC2)C=CC=CC=1>>[C:1]1([C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:52]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=3[Cl:36])([CH2:49][OH:59])[CH2:12][CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1(Cc2ccccc2)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: Cl
Product: OCC1(c2ccccc2Cl)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1

Procedure:
1-(3,3,3-triphenylpropyl)-4-hydroxy-4-benzylpiperidine and 1-(3,3,3-triphenylpropyl)-4-hydroxy-4-benzylpiperidine hydrochloride;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:16])[CH:3]=1.[CH3:17][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:13]=2[CH:14]([OH:15])[CH3:17])=[C:4]([F:16])[CH:3]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cnccc1-c1ccc(Cl)cc1F
Solvent: C1CCOC1
Product: CC(O)c1cnccc1-c1ccc(Cl)cc1F
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 31.2 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)nicotinaldehyde (0.12 g, 0.509 mmol) (prepared as in Example 5, Part B) in anhydrous THF (15 mL) was added methyl magnesium bromide (3.0 M in diethyl ether) (0.364 g, 3.06 mmol) at −60° C. dropwise. After complete addition the solution was stirred at −60° C. for 10 min. The reaction mixture was then allowed to warm to room temperature and stirred for 1 h. The reaction was quenched by addition of saturated aqueous ammonium chloride solution (15 mL). The organics were extracted with ethyl acetate (3×20 mL) and washed with water (1×15 mL) and brine (1×15 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via preparative TLC (20% ethyl acetate in hexane) to afford 1-(4-(4-chloro-2-fluorophenyl)pyridin-3-yl)ethanol (40 mg, 0.159 mmol, 31% yield) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.50 (s, 1H), 7.15-7.26 (m, 3H), 7.07 (d, J=3.8 Hz, 1H), 4.82 (q, J=6.3 Hz, 1H), 3.06 (bs, 1H), 1.40 (d, J=6.3 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.Cl[CH2:11][CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[K+].O>C1(C)C=CC=CC=1>[C:14]1([CH:13]=[CH:12][CH2:11][N:1]2[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCC=Cc1ccccc1
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)C1CCN(CC=Cc2ccccc2)CC1
Yield: 86.9 %

Procedure:
A mixture of 60.0 g of isonipecotamide (4-piperidinecarboxamide), 75.0 g of (3-chloropropenyl)benzene and 72 g of potassium acid carbonate suspended in 700 ml of toluene are heated with stirring at their reflux temperature for a period of 4 hours. The reaction mixture is cooled, water added thereto and filtered. The crude product is washed with water, ether and recrystallized from a 5:1 ethanol/water mixture to yield 99.4 g of 1-(3-phenyl-2-propenyl)-4-piperidinecarboxamide as light beige needles having a m.pt. of 189.5°-191.5° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][CH2:7][C:8]([CH3:18])([N:10]1[CH:14]=[C:13]([N+:15]([O-])=O)[N:12]=[CH:11]1)[CH3:9])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]2[C:27](=[C:28]([F:30])[CH:29]=1)[CH2:26][CH:25]([NH:31][CH:32]([CH2:36][CH2:37][CH3:38])[C:33](O)=[O:34])[CH2:24][CH2:23]2>>[CH2:1]([O:3][CH2:4][CH2:5][NH:6][CH2:7][C:8]([N:10]1[CH:14]=[C:13]([NH:15][C:33](=[O:34])[C@@H:32]([NH:31][CH:25]2[CH2:24][CH2:23][C:22]3[C:27](=[C:28]([F:30])[CH:29]=[C:20]([F:19])[CH:21]=3)[CH2:26]2)[CH2:36][CH2:37][CH3:38])[N:12]=[CH:11]1)([CH3:18])[CH3:9])[CH3:2]
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: CCOCCNCC(C)(C)n1cnc([N+](=O)[O-])c1
Product: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CNCCOCC)cn1

Procedure:
(2-Ethoxy-ethyl)-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-amine was reduced and then coupled with 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 492.6 m/z (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C:7]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2OCC[O:23]2)=[C:18]([F:27])[CH:17]=1)([CH3:15])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].NC(N)=S>CCO.O>[F:27][C:18]1[CH:17]=[C:16]([C:7]([CH3:15])([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[CH:21]=[CH:20][C:19]=1[CH:22]=[O:23]
Reactant: CC(C)(C)OC(=O)C(C)(C(=O)OC(C)(C)C)c1ccc(C2OCCO2)c(F)c1
Agent: NC(N)=S
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C(=O)OC(C)(C)C)c1ccc(C=O)c(F)c1

Procedure:
Di-tert-butyl[4-(1,3-dioxolan-2-yl)-3-fluorophenyl](methyl)malonate (0.91 g, 2.30 mmol) and thiourea (0.87 g, 11.4 mmol) were stirred in refluxing EtOH/H2O (6.7 mL/6.7 mL) for 7 hours. Room temperature was attained and the solvent removed in vacuo. H2O (100 mL) was added to the residue and the products extracted into EtOAc (2×100 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give the clean product (pale yellow gum). 1H NMR (CDCl3) δ 10.33 (s, 1H), 7.82 (t, J=8.1 Hz, 1H), 7.31 (dd, J=8.1, 1.8 Hz. 1H). 7.27 (dd, J=12.0, 1.8 Hz, 1H), 1.77 (s, 3H), 1.46 (s, 18H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:69]([NH:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[CH3:70]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[N:71]([CH2:69][CH3:70])[C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: CCNc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 66 h

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)ethoxy]-5-chloro-benzoic acid (0.060 g), TBTU (0.096 g) and HOBt (0.030 g) in DMF (1 ml) was added DIPEA (0.052 ml) followed by N-ethylaniline (0.038 ml) after 15 min. The reaction mixture was stirred at room temperature for 66 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.080 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:20])=[C:11]([CH:13]3[C:17](=[O:18])[CH2:16][CH2:15][C:14]3=[O:19])[N:12]=2)=[CH:4][CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:20])=[C:11]([C:13]3[C:17](=[O:18])[CH2:16][CH2:15][C:14]=3[O:19][CH3:21])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)CCC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC1=C(c2nc(-c3ccc(Cl)cc3)sc2C)C(=O)CC1
Temperature: 40 °C
Yield: 66.6 %

Procedure:
To a solution of 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-cyclopentane-1,3-dione (1.12 g, 3.66 mmol) in acetone (20 ml) was added potassium carbonate (1.04 g, 7.32 mmol), followed by iodomethane (455 μl, 7.32 mmol), and the reaction heated to 40° C. for 6 hours. The solvent was then removed from the crude reaction mixture under reduced pressure and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, dry loaded onto silica and purified by flash chromatography to give 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-3-methoxy-cyclopent-2-enone (780 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:22])[CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:12].CS(C)=O>CCOCC>[CH2:11]([O:13][C:14](=[O:22])[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)[CH3:12]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CC1CCNCC1
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(=O)CC1CCN(c2ccc(C(C)=O)cc2)CC1
Temperature: 150 °C

Procedure:
A microwave vial was charged with 4′-fluoroacetophenone (1.2 Ml, 10.4 mmol, 1.0 equiv) and 2-(piperidin-4-yl)-acetic acid ethyl ester (3.5 g, 20.7 mmol, 2.0 equiv) in 20 Ml DMSO. The homogeneous reaction was heated to 150° C. for 20 min. The cooled reaction was then diluted with ether and washed sequentially with saturated ammonium chloride, water, and brine. The organic extracts were then dried over sodium sulphate, filtered, and concentrated in vacuo. Purification by flash chromatography (10-40% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (t, J=7.07 Hz, 3H) 1.47 (d, J=12.13 Hz, 2H) 1.62 (br.s., 1H) 1.90 (d, J=12.63 Hz, 2H) 2.04-2.15 (m, J=11.18, 11.18, 7.45, 7.45, 3.79, 3.66 Hz, 1H) 2.33 (d, J=7.07 Hz, 2H) 2.57 (s, 3H) 2.97 (td, J=12.57, 2.15 Hz, 2H) 3.93 (d, J=12.88 Hz, 2H) 4.20 (q, J=7.07 Hz, 2H) 6.96 (d, J=6.82 Hz, 2H) 7.92 (d, J=9.09 Hz, 2H); (M+H)+290.1.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:8]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[N:8]1([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: C1CNCCNCCCNCCNC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN1CCCNCCNCCCNCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In a first phase, ethyl (1,4,8,11-tetraazacyclotetradec-1-yl)ethanoate is obtained by slowly adding 6.68 g (40.0 mmol) of ethyl bromoacetate onto a solution of 40 g (200.0 mmol) of cyclam and 16 g (116 mmol) of potassium carbonate in 1 L of chloroform. The reaction mixture is maintained under stirring at room temperature for 48 h. After filtration on celite and evaporation of the solvent, the residue is taken up in petroleum ether. The excess cyclam is filtered off, the filtrate is concentrated and ethyl (1,4,8,11-tetraazacyclotetradec-1-yl)ethanoate (so-called compound 5.0) is thereby obtained, as 11.21 g of a slightly yellow oil (yield=98%) which is used without any purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([O:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:4][C:3]=1[CH3:19].C([Li])CCC.[C:25](=[O:27])=[O:26].[OH-].[Na+]>C1COCC1.CCOCC>[C:8]([C:6]1[C:5]([O:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:4][C:3]([CH3:19])=[C:2]([CH:7]=1)[C:25]([OH:27])=[O:26])([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C=O
Reactant: COCCOCOc1cc(C)c(Br)cc1C(C)(C)C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCCOCOc1cc(C)c(C(=O)O)cc1C(C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of 1-bromo-5-tert-butyl-4-(2-methoxy-ethoxymethoxy)-2-methyl-benzene from Example ZZ (44.7 g, 135 mmol) in dry THF was cooled to -78° C. under nitrogen and treated with 1.6M n-butyllithium (93 mL, 149 mmol). The solution was stirred at -78° C. for 45 minutes and then poured over crushed dry ice. The mixture was allowed to warm to room temperature. Et2O (100 mL) and 2N NaOH (200 mL) were added; the organic layer was separated and re-extracted with 2N NaOH. The aqueous layers were combined, acidified to pH 2 with 6N HCl, and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated to give the title compound. 1H NMR (CDCl3) δ 1.35 (s, 9 H), 2.57 (s, 3 H), 3.37 (s, 3 H), 3.57 (m, 2 H), 3.81 (m, 2 H), 5.35 (s, 2 H), 6.98 (s, 1 H), 8.01 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)(=[O:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:33](O)[CH2:34][CH2:35][OH:36].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)(=[O:12])=[O:11])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:33][CH2:34][CH2:35][OH:36]
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(C)c2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a solution of 5-methyl-3-(3-methylphenylsulfonyloxy)phenol (560 mg, 2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol) and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as a colorless oil (605 mg, 90%). 1H-NMR (300 MHz, CDCl3) δ 7.69 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.41 (t, J=7.6 Hz, 1H), 6.62 (s, 1H), 6.41 (s, 1H), 6.36 (s, 1H), 4.13 (t, J=7.2 Hz, 2H), 3.81 (m, 2H), 2.43 (s, 3H), 2.24 (s, 3H), 1.96 (m, 2H), 1.61 (br s, 1H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([C:11]1[O:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2C=1C(O)=O)[CH2:8][CH2:9][CH3:10].CN(C=O)C>C(Cl)Cl>[CH2:7]([C:11]1[O:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:1]=1[C:2]([Cl:4])=[O:3])[CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCc1oc2ccccc2c1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
Oxalyl chloride (6 mL, 68.8 mmol) was added under nitrogen at room temperature to a solution of 2-butyl-benzofuran-3-carboxylic acid (3.00 g, 13.7 mmol), prepared in the previous step, in 40 mL of methylene chloride. After the addition 10 μL of DMF was added and the reaction stirred at room temperature for 3 h. The solvent and the excess oxalyl chloride were removed under reduced pressure. To remove any residual oxalyl chloride the residue was taken up in benzene and then concentrated under reduced pressure to give 2-butyl-benzofuran-3-carbonyl chloride (3.00 g, 92%) as a white solid that was used in the next step without additional purification.
Reaction SMILES: Cl[C:2](=[CH:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].CN(C=O)C.[SH:14][C:15]1[NH:16][C:17]2[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[CH:20][C:18]=2[N:19]=1>O>[OH:8][CH:7]1[N:19]2[C:15](=[N:16][C:17]3[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[CH:20][C:18]=32)[S:14][CH:2]1[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=C(O)c1ccc2nc(S)[nH]c2c1
Reactant: COC(=O)C(Cl)=CO
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1Sc2nc3cc(C(=O)O)ccc3n2C1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Methyl 2-chloro-3-hydroxypropenoate (114 g) was added to DMF (460 ml) solution of 2-mercaptobenzoimidazole-5-carboxylic acid (135 g), and the mixture was stirred overnight at 60° C. After cooling to room temperature, water (3 L) was gradually added to the reaction solution and stirred. The thus precipitated crystals were collected by filtration to obtain crude crystals of 2-methyl hydrogen 2,3-dihydro-3-hydroxythiazolo[3,2-a]benzoimidazole-2,7-dicarboxylate (168 g). Next, the thus obtained crude crystals were suspended in 1,4-dioxane (1.5 L), and the suspension was mixed with 4 M HCl 1,4-dioxane solution (500 ml) and stirred at room temperature for 60 hours. The resulting precipitate was collected by filtration and washed with 1,4-dioxane to obtain crude crystals of 2-methyl hydrogen 2,3-dihydro-3-hydroxythiazolo[3,2-a]benzoimidazole-2,6-dicarboxylate hydrochloride (189 g). The thus obtained crude crystals were slowly added to concentrated sulfuric acid (750 ml) which was heated at 60° C. and stirred at the same temperature for 1 hour. After cooling to room temperature, the reaction solution was poured into ice water, and the thus precipitated crystals were collected by filtration to obtain the title compound (152 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[N:14]([CH2:19][CH:20]([OH:22])[CH3:21])[S:15]([CH3:18])(=[O:17])=[O:16].C(N(CC)CC)C>ClCCCl>[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[N:14]([CH2:19][CH:20]([O:22][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:21])[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(C)c1N(CC(C)O)S(C)(=O)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1N(CC(C)OS(C)(=O)=O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
31.4 ml (46.6 g, 0.4 moles) of methanesulfonyl chloride are added dropwise, within one hour, to a solution of 94.5 g (0.368 moles) of 1-[N-(2,6-dimethylphenyl)-methane-sulfonamido]-2-propanol and 55.3 ml (40.5 g, 0.4 moles) of trietyl amine in 600 ml of 1,2-dichloroethane. During the addition the mixture is cooled with ice to maintain its temperature at 10°-12° C. The mixture is stirred at room temperature for additional 4 hours and then washed thrice with 100 ml of water, each. The dichloroethane solution is dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, and the thick, oily residue is triturated with 120 ml of isopropanol. The resulting crystals are filtered off, washed with ice-cold isopropanol and dried. 93.2 g (75.8%) of 1-[N-(2,6-dimethylphenyl)-methane-sulfonamido]-2-methanesulfonyloxy-propane are obtained as a white, crystalline substance melting at 111°-114° C.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[O:5].C1C(=O)N([Br:22])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][C:2]([CH3:14])([CH3:13])[CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][Br:22])=[CH:10][CH:11]=1)=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)CC(C)(C)C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)CC(=O)c1ccc(CBr)cc1
Yield: 89.7 %

Procedure:
Heat a mixture of 3,3,4′-trimethylbutyrophenone (2 g, 10.52 mmol), NBS (2.061 g, 11.57 mmol), and AIBN (43 mg, 0.263 mmol) in carbon tetrachloride (60 mL) for 14 h at reflux. Cool the reaction, mixture to ambient temperature and wash sequentially with water, 1M aqueous HCl, 5% aqueous NaHCO3 and brine. Concentrate the organic layer in vacuo to provide the desired intermediate as oil (2.54 g, 90%) that was used without any further purification.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[N:6]=1.[Cl-].[NH4+]>C1COCC1>[Cl:14][C:7]1[N:6]=[C:5]([O:2][CH3:1])[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
Sodium methoxide (1.40 g) was gradually added to a THF (50 mL) solution of 2,6-dichloro-3-nitropyridine (5.00 g) over 30 minutes under ice-cooling. Then, the reaction solution was agitated at 0° C. for 1 hour, and agitated at room temperature for further 12 hours. The reaction solution was poured into a saturated ammonium chloride solution (50 mL), and extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 2:1), and 2.90 g (58%) of 6-chloro-2-methoxy-3-nitropyridine was obtained. The physical properties of the compound are as follows.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[NH:10][CH2:9]1)(C)(C)C.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9]1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccc(C#N)cc2C1
Product: N#Cc1ccc2c(c1)CC(N)CN2Cc1ccccc1

Procedure:
157A was prepared from 1C and benzaldehyde by procedures analogous to those described in Example 22A, followed by removal of N-Boc protecting group according to the procedures described in Example 22B.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[O:18][CH:17]=[N:16][CH:15]=3)[CH:12]=2)[NH:7][C:6]1=[O:19])C.Cl.[CH3:21][NH:22][S:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)(=[O:25])=[O:24]>>[CH3:21][NH:22][S:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:4]=[C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:14]4[O:18][CH:17]=[N:16][CH:15]=4)[CH:12]=3)[NH:7][C:6]2=[O:19])=[CH:29][CH:28]=1)(=[O:24])=[O:25]
Reactant: CCOC=C1C(=O)Nc2ccc(-c3cnco3)cc21
Reactant: CNS(=O)(=O)Cc1ccc(N)cc1
Agent: Cl
Product: CNS(=O)(=O)Cc1ccc(NC=C2C(=O)Nc3ccc(-c4cnco4)cc32)cc1
Yield: 56 %

Procedure:
The title compound was prepared in 56% yield from ethoxymethylene-5-oxazol-5-yl-1,3-dihydro-indol-2-one and N-methyl-4-aminophenylmethanesulfonamide hydrochloride according to Procedure J: 1H NMR (DMSO-d6): δ 10.72 (d, 1H), 10.67 (s, 1H), 8.71 (d, 1H), 8.37 (s, 1H), 7.43–7.34 (m, 7H), 6.89 (m, 2H), 4.28 (s, 2H), 2.54 (d, 3H); APCI-MS m/z 409 (MH)−.