Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:26]2[CH2:27][CH2:28][CH:23]([C:20]3[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:29])[F:30])=[CH:18][CH:19]=3)[CH2:24][CH2:25]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: FC(F)(F)c1ccc(C2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CCC(c2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 70 °C
Reaction time: 3 h
Yield: 53.5 %

Procedure:
(R)-2-Chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.329 g, 1.51 mmol) and 4-(4-trifluoromethylphenyl)piperidine (0.40 g, 1.66 mmol) were dissolved in DMF (5 ml) followed by stirring at 70° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate twice. The organic phases were combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethylphenyl)piperidin-1-yl]propan-2-ol (0.361 g, yield 54%) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[F:16][C:17]1([F:32])[O:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]3([C:29](Cl)=[O:30])[CH2:28][CH2:27]3)=[CH:25][C:19]=2[O:18]1>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:29]([C:26]2([C:24]3[CH:23]=[CH:22][C:20]4[O:21][C:17]([F:32])([F:16])[O:18][C:19]=4[CH:25]=3)[CH2:28][CH2:27]2)=[O:30])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)n1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.7 %

Procedure:
To a solution of 6-bromopyridin-2-amine (660 mg, 3.8 mmol) and Et3N (1.1 mL, 7.7 mmol) in dichloromethane (5 mL) was added a solution of 1-(2,2-difluorobenzo-[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (1.0 g, 3.8 mmol) in dichloromethane (5 mL). The resulting reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (5 mL) and was washed with 1 N aqueous HCl (1×10 mL) and saturated aqueous NaHCO3 (1×10 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-70% ethyl acetate in hexane to yield N-(6-bromopyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (780 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.01-7.99 (m, 1H), 7.75-7.71 (m, 1H), 7.54 (m, 1H), 7.41-7.39 (m, 1H), 7.36-7.30 (m, 2H), 1.52-1.49 (m, 2H), 1.20-1.17 (m, 2H). ESI-MS m/z calc. 396.0. found 397.3 (M+1)+. Retention time 2.12 minutes.
Reaction SMILES: C([O-])(O)=O.[Na+].[CH3:6][NH2:7].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:7][CH3:6])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a mixture of sat aq. NaHCO3 (42 g, 0.50 mol), CH2Cl2 (400 mL) and methylamine (51.7 g, 0.50 mol, 30% in methanol) was added a solution of 4-bromo-benzenesulfonyl chloride (130 g, 0.50 mol) in CH2Cl2 (100 mL). The reaction was stirred at 20° C. overnight. The organic phase was separated and dried over Na2SO4. Evaporation of the solvent under reduced pressure provided 4-bromo-N-methyl-benzenesulfonamide (121 g, crude), which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ 7.65-7.74 (m, 4H), 4.40 (br, 1H), 2.67 (d, J=5.4 Hz, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:8]3[CH:9]=[C:10]([C:20]4[C:25]([Cl:26])=[CH:24][N:23]=[C:22](Cl)[N:21]=4)[N:11]([CH2:16][O:17][CH2:18][CH3:19])[C:12]=3[CH:13]=[CH:14][CH:15]=2)=[O:6])[CH2:3][CH2:2]1.Cl.[NH2:29][C@@H:30]1[CH2:34][CH2:33][CH2:32][C@@H:31]1[OH:35].CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:26][C:25]1[C:20]([C:10]2[N:11]([CH2:16][O:17][CH2:18][CH3:19])[C:12]3[CH:13]=[CH:14][CH:15]=[C:7]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])[C:8]=3[CH:9]=2)=[N:21][C:22]([NH:29][C@@H:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[OH:35])=[N:23][CH:24]=1
Reactant: CCOCn1c(-c2nc(Cl)ncc2Cl)cc2c(C(=O)NC3CC3)cccc21
Reactant: N[C@@H]1CCC[C@@H]1O
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOCn1c(-c2nc(N[C@@H]3CCC[C@@H]3O)ncc2Cl)cc2c(C(=O)NC3CC3)cccc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 59.6 %

Procedure:
A mixture of N-cyclopropyl-2-(2,5-dichloropyrimidin-4-yl)-1-(ethoxymethyl)-1H-indole-4-carboxamide (10 g, 25 mmol), (1S,2R)-2-aminocyclopentanol hydrochloride (4.1 g, 30 mmol) and DIPEA (5 mL, 30 mmol) in DMSO (70 mL) is stirred at 100° C. for 3 h, then poured into water and extracted with EA. The combined extracts are washed with aqueous saturated sodium chloride, dried over Na2SO4 and concentrated in vacuo. The residue is purified by chromatography on silica gel to give 2-{5-chloro-2-[(1R,2S)-2-hydroxycyclopentylamino]pyrimidin-4-yl}-N-cyclopropyl-1-(ethoxymethyl)-1H-indole-4-carboxamide (7 g, 60.3%). MS (m/z): 470 (35Cl) and 472 (37Cl) (M+H)+
Reaction SMILES: C(O)(=O)C.[C:5]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH2:14])=[NH:13].C[O:22][C:23](=O)/[C:24](/[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[C:25](\O)/[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C[O-].[Na+]>CO>[C:29]([O:28][C:26]([C:25]1[C:24]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:23]([OH:22])[N:14]=[C:12]([CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:13]=1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: N=C(N)Cc1ccccc1-c1ccccc1
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a stirred solution of 2-biphenyl-2-yl-acetamidine acetate salt (5-01) (2.5 g, 9.2 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (4.2 g, 13.88 mmol) in methanol (60 mL) was added sodium methoxide (1.5 g, 27.77 mmol) at 0° C., then the reaction mixture was allowed to warm to room temperature and was stirred for 16 h. After completion of the reaction, it was quenched with 1N HCl, evaporated and w ater was added. The mixture was extracted with ethyl acetate and the separated organic part was dried over sodium sulfate and concentrated under reduced pressure to get a crude product, which was purified using a normal silica column using 30% ethyl acetate in hexane to get 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (6-01) (2.5 g, 57.63%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:15][CH2:16][CH2:17][OH:18].C(OC(=O)[NH:25][CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(C)(C)C>>[CH3:13][O:12][C:6]1[CH:5]=[C:4]2[C:9]([N:10]=[CH:11][C:2]([O:18][CH2:17][CH2:16][CH2:15][N:30]3[CH2:31][CH2:32][CH:27]([CH2:26][NH2:25])[CH2:28][CH2:29]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: OCCCBr
Reactant: COc1ccc2ncc(Cl)nc2c1
Product: COc1ccc2ncc(OCCCN3CCC(CN)CC3)nc2c1

Procedure:
The title compound is prepared as a brown viscous oil following Scheme 1 and in analogy to Example 1 using 2-chloro-7-methoxy-quinoxaline, 3-bromo-propan-1-ol and piperidin-4-ylmethyl-carbamic acid tert-butyl ester as starting materials.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:9](=O)[CH2:10][Br:11])(C)(C)C.[C:24](=[S:32])([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OCC)C>CC#N>[BrH:11].[N+:20]([C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@@H:8]([C:9]2[N:31]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:32][CH:10]=2)[NH2:7])=[CH:19][CH:18]=1)([O-:22])=[O:21]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)CBr
Reactant: NC(=S)c1ccccc1
Solvent: CC#N
Solvent: CCOCC
Product: Br
Product: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 63 %

Procedure:
A mixture of [3-bromo-1-(4-nitro-benzyl)-2-oxo-propyl]-carbamic acid tert-butyl ester, 37, (1.62 g, 4.17 mmol) and benzothioamide (0.630 g, 4.59 mmol), in CH3CN (5 mL) is refluxed for 24 hours. The reaction mixture is cooled to room temperature and diethyl ether (50 mL) is added to the solution and the precipitate that forms is collected by filtration. The solid is dried under vacuum to afford 1.059 g (63%) of the desired product. ESI+ MS 326 (M+1).
Reaction SMILES: Br.Br[C:3]1[N:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=[C:7]2[CH:6]=[N:5][CH:4]=1.O.[NH2:17][NH2:18]>C(O)C>[NH:17]([C:6]1[C:7]2[N:8]([N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH:3]=[CH:4][N:5]=1)[NH2:18]
Reactant: NN
Reactant: FC(F)(F)c1nc2cncc(Br)n2n1
Agent: Br
Solvent: CCO
Solvent: O
Product: NNc1nccn2nc(C(F)(F)F)nc12
Reaction time: 8 h

Procedure:
A solution of 400 mg (1.15 mmol) of 5-bromo-2-(trifluoromethyl) [1,2,4]triazolo[1,5-a]pyrazine hydrobromide in 2.5 mL of dry ethanol was treated dropwise with 0.799 mL (11.5 mmol) of hydrazine hydrate, and stirring was continued at ambient temperature overnight. The reaction mixture was concentrated to dryness, and the residue was extracted with dichloromethane and then with tetrahydrofuran. The organic extracts were washed with saturated sodium bicarbonate aqueous solution, filtered, and concentrated. Purification of the residue by preparative HPLC (C18 reverse phase column, 10-60% acetonitrile in water containing 0.05% trifluoroacetic acid) afforded the title compound as a yellow solid. LC-MS 219 (M+1).
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.Cl.[NH:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH3:15].CCN(CC)CC.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([N:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH3:15])=[O:5]
Reactant: CNCC(=O)OC
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN(C)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.1 %

Procedure:
A solution of Boc-Gly-OH (2.70 g, 15.4 mmol) and the HCl salt of H2N-Sar-OMe (2.15 g, 15.4 mmol) in CH2Cl2 (50 mL) was treated sequentially with Et3N (2.2 mL, 15.8 mmol), DCC (3.20 g, 15.5 mmol), and DMAP (306 mg, 2.5 mmol) and the reaction mixture was stirred at 25° C. for 20 h. A white precipitate formed in the first 10 min and was removed by filtration at the end of the reaction. The filtrate was concentrated in vacuo. Flash chromatography (SiO2, 5×16 cm, 40% EtOAc-hexane eluent) afforded 200 (3.21 g, 4.01 g, theoretical, 80%) as a colorless oil which solidified on standing: mp 72-73° C. (EtOAc-hexane, colorless cubes); Rf=0.32 (50% EtOAc-hexane); 1H NMR (CDCl3, 400 MHz) 4:1 mixture of two conformers, for the major conformer: 5.44 (s, 1H), 4.14 (s, 2H), 4.02 (d, 2H, J=4.3 Hz), 3.73 (s, 3H), 3.02 (s, 3H), 1.43 (s, 9H); 13C NMR (CDCl3, 100 MHz) for major conformer: 169.3, 168.7, 155.7, 79.6, 52.2, 49.4, 42.2, 35.2, 28.3; IR (KBr)max 3419, 2978, 2934, 1754, 1715, 1667, 1488, 1424, 1367, 1249, 1208, 1175, 1120, 1051, 952, 871, 764, 712 cm−1; FABHRMS (NBA-NaI) m/z 283.1259 (M+Na+, C11H20N2O5 requires 283.1270).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([OH:25])=O)[CH:13]=2)[CH2:3][CH2:2]1.[CH3:26][NH:27][CH2:28][CH2:29][OH:30].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([N:27]([CH2:28][CH2:29][OH:30])[CH3:26])=[O:25])[CH:13]=2)[CH2:3][CH2:2]1
Reactant: CNCCO
Reactant: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)O)cc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)N(C)CCO)cc2n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.9 %

Procedure:
To a stirred mixture of 4-(3,4-dihydro-2H-chromen-4-yloxy)-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid (70 mg, 0.21 mmol, STEP 2) and 2-(methylamino)ethanol (31 mg, 0.41 mmol) in dimethylformamide (2 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (67 mg, 0.35 mmol) and 1-hydroxybenzotriazole hydrate (HOBt) (60 mg, 0.41 mmol) at room temperature. After stirring at room temperature for 18 hours, the reaction mixture was quenched with sodium hydrogencarbonate aqueous solution (5 mL), and extracted with ethyl acetate (50 mL×2). The combined extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuum. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=10:1 as an eluent). The residue was suspended with diethyl ether, and collected by filtration to afford the title compound as a white solid (24 mg, 24%):
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([N:33]1[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:23]2[C:18]3[N:19]=[C:20]([CH3:22])[N:21]=[C:16]([C:8]4[CH:9]=[C:10]([O:14][CH3:15])[C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:25][C:24]=2[CH3:26])=[O:28])[CH2:35][CH2:34]1)(=[O:38])[CH3:37]
Reactant: COc1cc(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(-c2nc(C)nc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f59) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: S(Cl)(Cl)=O.O(C(CC)C(O)=O)C1C=CC=CC=1.O(C(CC)C(Cl)=O)C1C=CC=CC=1.[O:31]([CH:38]([CH2:44][CH3:45])[C:39]([N:41]=[C:42]=[S:43])=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl:46][C:47]1[CH:48]=[C:49]([CH:51]=[CH:52][C:53]=1[O:54][C:55]1[C:64]2[C:59](=[CH:60][C:61]([O:67][CH3:68])=[C:62]([O:65][CH3:66])[CH:63]=2)[N:58]=[CH:57][CH:56]=1)[NH2:50]>C(O)C.C1(C)C=CC=CC=1>[Cl:46][C:47]1[CH:48]=[C:49]([NH:50][C:42]([NH:41][C:39](=[O:40])[CH:38]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:44][CH3:45])=[S:43])[CH:51]=[CH:52][C:53]=1[O:54][C:55]1[C:64]2[C:59](=[CH:60][C:61]([O:67][CH3:68])=[C:62]([O:65][CH3:66])[CH:63]=2)[N:58]=[CH:57][CH:56]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: CCC(Oc1ccccc1)C(=O)N=C=S
Agent: CCC(Oc1ccccc1)C(=O)Cl
Agent: CCC(Oc1ccccc1)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC(Oc1ccccc1)C(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(Cl)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2-phenoxybutanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2-phenoxybutanoyl isothiocyanate was prepared using the resultant 2-phenoxybutanoyl chloride as a starting compound according to the description of the literature. 2-Phenoxybutanoyl isothiocyanate thus obatined was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 16 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (25 mg, yield 27%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)([O-])=O.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>CO.C(Cl)Cl.[Pd]>[C:21]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)(=[O:24])[CH:22]=[CH2:23]
Reactant: C=CC(=O)Cl
Reactant: CC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc(OC(C)=O)cc1
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
H2 is bubbled through a solution of 1 (280 mg, 1.54 mmol) and 10 mg of 10% Pd on carbon in 20 ml of MeOH for 1 hr. The catalyst is removed by filtration. Triethylamine (410 μl, 3.08 mmol) is added to the filtrate which was chilled on ice, then acryloyl chloride (250 μl, 3.08 mmol, Aldrich) in 10 ml of dry CH2Cl2 is added dropwise with stirring over 0.5 hr under Ar. The reaction is then allowed to return to ambient temperature, followed by 2 hr of stirring. Anion exchange resin (Bio-Rad, AG-MP1, OH−) (4 equivalents based on acryloyl chloride) is added, the mixture is filtered, and the filtrate is treated with sufficient cation exchange resin (Dowex, 50W×8, H+) to bring the mixture to neutrality (moist pH paper). The resin is removed by filtration, and the solvent is removed by rotary evaporation to yield an off-white solid (268 mg, 85%). ESI-MS (M+H)+: 206.1. 1H-NMR (acetone-d6) δ 9.15 (1H, br, NH), 7.78 (2H, d, J=9.0 Hz, NHCCH), 7.08 (2H, d, J=9.0 Hz, NHCCHCH), 6.55˜6.37 (2H, m, COCHCHH (anti to each other)), 5.75 (1H, dd, J=9.8 and 2.2 Hz, COCHCHH (syn to COCH)), 2.25 (3H, s, CH3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:24]=[CH:23]2.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:30]([C:25]2[CH:24]=[CH:23][C:22]3[C:27](=[CH:28][CH:29]=[C:20]([Cl:19])[CH:21]=3)[CH:26]=2)(=[O:31])=[O:32])[CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 63 h

Procedure:
In dichloromethane (18 ml), 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperazine (517 mg) and 6-chloro-2-naphthylsulfonyl chloride (588 mg) were dissolved under ice cooling. To the resulting solution, diisopropylethylamine (0.59 ml) was added, followed by stirring at room temperature for 63 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1), whereby the title compound (688 mg, 71%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[O:3][C@@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]([CH2:7]O)[N:6]=1.S(Cl)([Cl:17])=O>C(Cl)Cl>[Cl:17][CH2:7][CH:5]1[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:3][C:2]([CH3:1])=[N:6]1
Reactant: CC1=NC(CO)[C@H](c2ccccc2)O1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1=NC(CCl)[C@H](c2ccccc2)O1
Reaction time: 8 h

Procedure:
To a stirred mixture of ((5S)-2-methyl-5-phenyl-1,3-oxazolin-4-yl)methan-1-ol (1.0 mg, 5.23 mmol) in methylene chloride (15 mL) was added thionyl chloride (570 μL, 7.81 mmol) dropwise at 0° C. The resulting mixture was stirred under an atmosphere of nitrogen for 8 hours, then concentrated under a reduced pressure to afford (5S)-4-chloromethyl-2-methyl-5-phenyl-4,5-dihydro-1,3-oxazole as a white solid (960 mg, M+1=210.1). B. To a stirred mixture of (2R)-3-((2S)-2-methylpiperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol (51 mg, 0.13 mmol) in tert-amylalcohol (5 mL) was added triethylamine (90 μL, 0.65 mmol), followed by (5S)-4-chloromethyl-2-methyl-5-phenyl-1,3-oxazole (29 mg, 0.14 mmol). The resulting mixture was stirred at 95° C. for 12 hours, concentrated, and purified by preparative chromatograph (1:19 MeOH:CH2Cl2) to afford (2R)-3-{(2S)-4-[((4S,5S)-2-methyl-5-phenyl(1,3-oxazolin-4-yl))methyl]-2-methylpiperazinyl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol; (5 mg, M+1=495.2). B. Preparation of a Compound of Formula I
Reaction SMILES: BrBr.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH3:14].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>O1CCOCC1.CCOCC>[N:15]1([C:9]2[NH:10][C:11]3[C:7]([C:8]=2[CH3:14])=[CH:6][C:5]([O:4][CH3:3])=[CH:13][CH:12]=3)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: COc1ccc2[nH]cc(C)c2c1
Reactant: c1c[nH]cn1
Agent: BrBr
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc2[nH]c(-n3ccnc3)c(C)c2c1

Procedure:
A solution of bromine (0.62 ml) in dioxane (25 ml) is added dropwise over a period of 2 hours to a mixture of 5-methoxy-3-methylindole (2.00 g) and imidazole (4.08 g) in dioxane (50 ml) while stirring at 10°. Upon complete addition cooling bath is removed and the suspension is stirred two days at room temperature. The mixture is concentrated in vacuo and the oil obtained is suspended in ether (100 ml) and extracted into 1N hydrochloric acid (2×50 ml). The acid extract is first washed with ether (1×50 ml), the pH is adjusted to pH 6 with 3N sodium hydroxide (38 ml), and the aqueous mixture is then extracted with ether (8×50 ml). This extract is dried over magnesium sulfate, filtered, and concentrated in vacuo to give an oil. This oil is purified by flash chromatography on silica gel (eluent: 95% methylene chloride, 5% methanol) to give 2-(1-imidazolyl)-5-methoxy-3-methylindole as a crystalline solid; NMR (CDCl3): δ10.4 (s, 1H), 7.67 (s, 1H), 3.88 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[O:12])[O:6][CH2:5][CH2:4][O:3]1.[CH2:19]1[CH2:23]OC[CH2:20]1.[Li]N([Si](C)(C)C)[Si](C)(C)C.C(Br)C=C>CCOC(C)=O>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH:10]([CH2:23][CH:19]=[CH2:20])[C:11]([N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[O:12])[O:6][CH2:5][CH2:4][O:3]1
Reactant: CC1(CCCCC(=O)N2CCOC2=O)OCCO1
Reactant: C1CCOC1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C=CCBr
Solvent: CCOC(C)=O
Product: C=CCC(CCCC1(C)OCCO1)C(=O)N1CCOC1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-3 (6.0 g, 23.3 mmol) and THF (125 mL) at −78° C. was added LiN(TMS)2 (18.9 mL, 37.8 mmol, 1.0 M in THF) dropwise over 10 minutes. After 20 minutes, allyl bromide was added. After 10 minutes, the reaction was warmed to 0° C. After 4.0 h, the reaction was diluted with EtOAc, washed with sat. NaHCO3, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 50% EtOAc/hexanes) gave 2-4 as an yellow oil.