Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:24]Br)=[O:5])[CH3:2].[CH2:26]([O:28][C:29](=[O:43])[CH2:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=1[O:41][CH3:42])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:24][N:31]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=1[O:41][CH3:42])[CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:43])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccc(Oc3ccccc3)cc2)nc1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc(Oc3ccccc3)cc2)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.8 %

Procedure:
A mixture of 4-bromomethyl-2-(4-phenoxy-phenyl)-thiazole-5-carboxylic acid ethyl ester (1.12 g, 2.68 mmole), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (737 mg, 2.90 mmole) and potassium carbonate (555 mg, 4.03 mmole) in anhydrous dimethylformamide (8 ml) was stirred at room temperature for 20 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (1.20 g). MS: (+) m/z 613.07 (M+Na+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[NH2:9][C@@H:10]([C:13]([OH:15])=[O:14])[CH2:11][SH:12]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:9][C@@H:10]([C:13]([OH:15])=[O:14])[CH2:11][S:12]2)[CH:2]=1
Reactant: O=Cc1cccnc1
Reactant: N[C@H](CS)C(=O)O
Solvent: CCO
Product: O=C(O)[C@H]1CSC(c2cccnc2)N1
Temperature: 25 °C
Yield: 53.8 %

Procedure:
A solution of 1.07 g of pyridine-3-aldehyde and 1.21 g of D-cysteine in 60% v/v aqueous ethanol was heated under reflux for 4 hours. The mixture was cooled to room temperature and the resulting solid material was removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, and 5 ml of ethanol were added to the resulting residue. Collecting the precipitated crystals by filtration gave 1.13 g (yield 54%) of the title compound, melting at 138°-139° C.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[C:6](=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:10][CH:11]=2)[N:7]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CN(C=O)C>[O:19]1[CH2:20][CH2:21][N:16]([CH2:2][C:3]2[O:4][C:5]3[C:6](=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:10][CH:11]=3)[N:7]=2)[CH2:17][CH2:18]1
Reactant: COC(=O)c1cccc2oc(CCl)nc12
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2oc(CN3CCOCC3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.2 %

Procedure:
A mixture of the product from Step B (281 mg, 1.24 mmol) and morpholine (2.0 mL, 23 mmol) in DMF (10 mL) was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure and the residue was treated with ethyl acetate (10 mL). The formed precipitate was filtered off and mother liquor was concentrated under reduced pressure to afford methyl 2-(morpholinomethyl)benzoxazole-4-carboxylate (333 mg, 97%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.01 (dd, J=9.0, 1.0 Hz, 1H), 7.74 (dd, J=9.0, 1.0 Hz, 1H), 6.40 (t, J=7.8 Hz, 1H), 4.02 (s, 2H), 3.97 (s, 3H), 3.78-3.74 (m, 4H), 2.69-2.65 (m, 4H); MS (ESI+) m/z 277 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][C:21]([OH:26])([C:24]#[CH:25])[CH2:22][OH:23]>>[OH:26][C:21]([CH3:20])([CH2:22][OH:23])[C:24]#[C:25][C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: C#CC(C)(O)CO
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)CO
Yield: 15 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-methylbut-3-yne-1,2-diol to give the titled compound as an off-white solid (30.8 mg, 15%).
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH2:32][CH:33]1[CH2:38][N:37]2[N:39]=[C:40]([C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:47][CH:46]=3)[C:41]([C:42]([NH2:44])=[O:43])=[C:36]2[NH:35][CH2:34]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:11]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[N:2]1[CH2:32][CH:33]1[CH2:38][N:37]2[N:39]=[C:40]([C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:47][CH:46]=3)[C:41]([C:42]([NH2:44])=[O:43])=[C:36]2[NH:35][CH2:34]1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(CO)C2
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(CN1C(=O)c3ccccc3C1=O)C2
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
To a solution of isoindoline-1,3-dione (74 mg, 0.5 mmol) in THF (20 mL) was added PPh3 (393 mg, 1.5 mmol) and 6-(hydroxymethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (180 mg, 0.5 mmol). DIAD (253 mg, 1.25 mmol) was added dropwise at 0° C. and stirred for 10 min. The mixture was allowed to warm to it and stirred for 16 hr. Concentrated and purified by chromatography column on 5 g of silica gel eluting with DCM/CH3OH to afford 200 mg (62%) of 6-((1,3-dioxoisoindolin-2-yl)methyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid. MS (ESI) m/e [M+1]+ 493.9.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=O.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=C>>[CH:7]([C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:5]=1)=[O:8]
Reactant: C=CC(=O)OCC
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Product: CCOC(=O)C=Cc1ccc(C=O)cc1
Yield: 46 %

Procedure:
The procedure described in Example 28 is repeated, except that 8.23 g (0.05 mol) of 4-formylbenzoyl chloride and 6.25 g (0.0625 mol) of ethyl acrylate are used. After a reaction time of 13 hours at 120° C., 4.7 g (0.023 mol) of ethyl 4-formylcinnamate are obtained, corresponding to a yield of 46% of theory; boiling point 137°-140° C./13 Pa.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:14][CH:15]1[CH2:32][CH:31]2[N:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]3[C:28]([C:34](O)=[O:35])([NH:29][C:30]2=[O:33])[CH2:27]3)[CH2:16]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:51]1([S:54]([NH2:57])(=[O:56])=[O:55])[CH2:53][CH2:52]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:14][CH:15]1[CH2:32][CH:31]2[N:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]3[C:28]([C:34]([NH:57][S:54]([CH:51]4[CH2:53][CH2:52]4)(=[O:56])=[O:55])=[O:35])([NH:29][C:30]2=[O:33])[CH2:27]3)[CH2:16]1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1Br
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.8 %

Procedure:
A solution of 50 (151 mg, 0.257 mmol) and carbonyldiimidazole (162 mg, 0.437 mmol) in dry THF (10 mL) was stirred at reflux under nitrogen for 2 h. Optionally, the azalactone derivative, if desired, can be isolated. Then, the reaction mixture was cooled to room temperature and cyclopropylsulfonamide (58 mg, 0.482 mmol) and DBU (76 mg, 0.502 mmol) were added. The resulting solution was stirred at 50° C. for 12 h, then cooled to room temperature. The reaction mixture was quenched with water and extracted with AcOEtethyl acetate, dried (MgSO4), filtered and evaporated. The crude material was purified by column chromatography (CH2Cl2/EtOAc, 95:5). The solid obtained was triturated in water, filtered, dried under high vacuum, triturated in diethylether and dried again under high vacuum to give 138 mg (77%) of the title product 51 as a white powder: m/z=691 (M+H)+; 1H-NMR (CDCl3): 10.70 (br s, 1H), 8.12 (d, J=9.1 Hz, 1H), 7.97 (d, J=6.3 Hz, 1H), 7.54 (d, J=6.3 Hz, 1H), 7.21 (d, J=9.1 Hz, 1H), 6.70 (bs, 1H), 5.88 (bs, 1H), 5.74 (dd, J=17.3 Hz, 8.3 Hz, 1H), 5.16 (t, J=10.4 Hz, 1H), 4.74 (dd, J=9.4 Hz, 7.3 Hz, 1H), 4.11-3.98 (m, 4H), 3.69-3.55 (m, 2H), 3.27-3.10 (m, 1H), 3.02-2.89 (m, 1H), 2.83 (s, 3H), 2.58-2.35 (m, 3H), 2.29-2.13 (m, 1H), 2.11-1.92 (m, 2H), 1.75-0.76 (m, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([CH2:22]Br)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:24]#[N:25].[NH:26]1[CH2:45][CH2:44][CH2:43][C@H:27]1[C:28]([NH:30][C@H:31]([C:36]([NH:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[O:37])[C@H:32]([CH2:34][CH3:35])[CH3:33])=[O:29].C(N(CC)CC)C>ClCCl>[N:24]#[N:25].[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([CH2:22][N:26]1[CH2:45][CH2:44][CH2:43][C@H:27]1[C:28]([NH:30][C@H:31]([C:36]([NH:38][CH2:39][CH:40]([CH3:41])[CH3:42])=[O:37])[C@H:32]([CH2:34][CH3:35])[CH3:33])=[O:29])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)NCC(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CBr)OCc1ccccc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1CC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)NCC(C)C

Procedure:
A solution of 8.86 g of [N-(benzyloxycarbonyl)-L-phenylalanyl]methyl bromide 6.71 g of N2 -L-prolyl-N1 -isobutyl-L-isoleucinamide and 2.60 g of triethylamine in 400 ml of dichloromethane was stirred at room temperature overnight. The solvent was removed by evaporation and the crude product was chromatographed on silica gel using ethyl acetate for the elution. The resulting product was triturated with a mixture of petroleum ether (b.p. 40°-60° C.) and ethyl acetate to give 8.70 g of N2 -[N-[[N-(benzyloxycarbonyl)-L-phenylalanyl]methyl]-L-prolyl]-N1 -isobutyl-L-isoleucinamide as an off-white solid of m.p. 80°-81° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH2:11][O:12][CH3:13])[CH:10]=1)[C:6]#[N:7].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([NH2:33])[CH:22]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)N)=[CH:17][CH:16]=1>CC#N>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]2[NH:33][C:6]([C:5]3[CH:4]=[C:3]([CH2:2][OH:1])[CH:10]=[C:9]([CH2:11][O:12][CH3:13])[CH:8]=3)=[N:7][CH:22]2[C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[CH:19][CH:20]=1
Reactant: NC(c1ccc(Cl)cc1)C(N)c1ccc([N+](=O)[O-])cc1
Reactant: COCc1cc(C#N)cc(CO)c1
Solvent: CC#N
Product: COCc1cc(CO)cc(C2=NC(c3ccc([N+](=O)[O-])cc3)C(c3ccc(Cl)cc3)N2)c1

Procedure:
{3-[5-(4-Chloro-phenyl)-4-(4-nitro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-5-methoxymethyl-phenyl}-methanol was prepared from 3-hydroxymethyl-5-methoxymethyl-benzonitrile and 1-(4-chloro-phenyl)-2-(4-nitro-phenyl)-ethane-1,2-diamine in an analogous manner as described in example 35. LR-MS (ES): 452 [(M+H)+], 493 [(M+H+CH3CN)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8]([N:17]3[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]3)=[N:7][C:6]=2[CH:11]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(Cl)cc2nc(S)oc12
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)cc2nc(N3CCN(C)CC3)oc12

Procedure:
5-Chloro-7-methyl-2-mercaptobenzoxazole (200 mg) was dissolved in chloroform (20 ml), N-methylpiperazine (0.55 ml) was added dropwise to the solution and then the mixture was stirred with heating for 3 days. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=20:1) to obtain the title compound 5-chloro-7-methyl-2-(4-methyl-1-piperazinyl)benzoxazole (270 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:34]=[C:35]([O:37][CH:38]([CH3:40])[CH3:39])[CH:36]=1)[C:8]([NH:10][CH:11]([CH2:32][CH3:33])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:14]=1)=O)([CH3:3])[CH3:2].O=P(Cl)(Cl)Cl>C(#N)C>[CH2:25]([O:24][CH2:23][CH2:22][O:21][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][C:16]=1[O:19][CH3:20])[C:8]([C:7]1[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:36]=[C:35]([O:37][CH:38]([CH3:40])[CH3:39])[CH:34]=1)=[N:10][CH:11]([CH2:32][CH3:33])[CH2:12]2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCC(Cc1ccc(OC)c(OCCOCc2ccccc2)c1)NC(=O)c1cc(OC(C)C)cc(OC(C)C)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCC1Cc2cc(OCCOCc3ccccc3)c(OC)cc2C(c2cc(OC(C)C)cc(OC(C)C)c2)=N1

Procedure:
15.3 g of the product of step (v) and 12.4 g POCl3 in 250 ml acetonitrile are stirred for 5 hrs. under reflux. The reaction mixture is concentrated, the residue taken up in ethyl acetate and extracted with Na2CO3 solution and brine. The organic phase is dried over Na2SO4, filtered and evaporated and the residue purified chromatographically on silica gel (e 0.04-0.63 mm) to yield the title compound as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=1.[CH2:21]([P:24]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([O:36][CH3:37])[CH:30]=1)([CH2:26][CH2:27]C)=[O:25])[CH2:22]C.Cl>COCCO.C(O)C>[CH2:21]([P:24]([C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:2]2[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=2)=[C:31]([O:36][CH3:37])[CH:30]=1)([CH2:26][CH3:27])=[O:25])[CH3:22]
Reactant: CCCP(=O)(CCC)c1ccc(N)c(OC)c1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cnnc(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: COCCO
Product: CCP(=O)(CC)c1ccc(Nc2cc(Nc3ccccc3S(=O)(=O)C(C)C)cnn2)c(OC)c1

Procedure:
To a solution of 6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine (prepared in Example 73: 0.02 mmol) and 4-(Dipropylphosphoryl)-2-methoxyaniline (0.7 mmol) in 1 mL of 2-Methoxy ethanol, is added 1 mL of 2.5M HCl in Ethanol. The reaction mixture is heated in a sealed tube at 140 degree until formation of the desired compound. The reaction mixture is filtered through a syringe filter and can be purified by Prep-HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[O:12]=[C:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:3]=2)[NH:8]1
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
To a stirred solution of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (2.5 g, 15.3 mmol) in dry DMF (10 ml) was added potassium carbonate (4.2 g, 30.3 mmol) and ethyl bromoacetate (2.4 g, 14.3 mmol). The reaction was stirred at room temperature for 2 h. Completion of the reaction was monitored by TLC. Solvent was removed under vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with water (20 mL), brine (20 mL), and dried over sodium sulfate. The organic layer was concentrated under vacuum to afford 2.7 g of crude material which was purified by silica gel flash chromatography (24 g, 2% methanol in chloroform) to afford 2.8 g (73%) of ethyl 2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)acetate as a white solid. 1H NMR: 400 MHz, DMSO-d6: δ 1.21 (t, J=7.20 Hz, 3H), 2.40 (t, J=7.20 Hz, 2H), 2.83 (t, J=8.00 Hz, 2H), 4.17 (q, J=7.20 Hz, 2H), 4.69 (s, 2H), 6.71-6.80 (m, 3H), 9.92 (s, 1H). LCMS: RT 1.31 min. LCMS (ES-API), m/z 250.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([CH3:25])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.Br[CH2:27][CH2:28][CH2:29][Cl:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:30][CH2:29][CH2:28][CH2:27][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:14][C:15]3[C:16]([CH3:25])=[N:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (200 mg) was dissolved in N,N-dimethylformamide (10 ml) to prepare a solution. 1-Bromo-3-chloropropane (474 mg) and potassium carbonate (416 mg) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (203 mg, yield 83%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2O.P(Cl)(Cl)([Cl:19])=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[Cl:19]
Reactant: CS(=O)(=O)c1cnc2ccc(Br)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cnc2ccc(Br)cc2c1Cl
Temperature: 100 °C
Yield: 59 %

Procedure:
6-Bromo-3-(methylsulfonyl)quinolin-4-ol (573 mg, 1.90 mmol) was added to phosphoryl chloride (19 mL) and the reaction was stirred at 100° C. 16 h. Additional THF (5 mL) was added and the reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was cooled and slowly poured into a 2:1 solution of satd. aq sodium bicarbonate/ethyl acetate that was pre-cooled to 0° C. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with satd. aq.sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the desired product (360 mg, 59%) as a white solid: ESI MS m/z 321 [C10H7BrClNO2S+H]+.
Reaction SMILES: CS([C:4]1[NH:5][CH:6]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[C:8]=1[N+:9]([O-:11])=[O:10])=O.[CH3:16][C:17]1[NH:21][CH:20]=[N:19][C:18]=1[CH2:22][S:23][CH2:24][CH2:25][NH2:26].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31]>C(O)C.C(O)(C)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31].[CH3:16][C:17]1[NH:21][CH:20]=[N:19][C:18]=1[CH2:22][S:23][CH2:24][CH2:25][NH:26][C:4]1[NH:5][CH:6]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CCCCc1c[nH]c(S(C)=O)c1[N+](=O)[O-]
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Solvent: CC(C)O
Product: CCCCc1c[nH]c(NCCSCc2nc[nH]c2C)c1[N+](=O)[O-]
Yield: 9.7 %

Procedure:
2-Methylsulphinyl-3-nitro-4-n-butylpyrrole (2.78 g) was dissolved in ethanol and added to a solution of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (2.08 g) in ethanol (total 100 ml). The mixture was heated under reflux for nine days. The solution was evaporated to dryness, and the residue was chromatographed on a silica gel column using chloroform and ethyl acetate to give 0.65 g of crude product as a brown oil. The crude product was dissolved in isopropanol (30 ml) and reacted with a solution of maleic acid (0.5 g) in 2-propanol. The mixture was warmed on a steam bath for a few minutes and then allowed to cool, yielding bright yellow crystals of 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino-3-nitro-4-n-butylpyrrole maleate (0.19 g), m.p. 94°-95°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:36]I>ClCCl>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][I:36]
Reactant: COC(=O)CCCC#CCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCCC#CCI
Reaction time: 0.67 h
Yield: 82.6 %

Procedure:
A solution of (30) (1.347 g, 8.6 mmol) in 5 mL dichloromethane was added to a mixture of triphenylphosphine (2.725 g, 10.4 mmol), imidazole (726 mg, 10.7 mmol), and iodine (2.602 g, 10.3 mmol) in 34 mL dichloromethane, rinsing with 5 mL dichloromethane. After 40 minutes, the dichloromethane was evaporated in vacuo to about 2 mL and the resulting mixture filtered through basic alumina, washing with 10% ethyl acetate/hexanes. Purification by flash chromatography on silica gel (10% ethyl acetate/hexanes) gave 1.878 g (7.1 mmol, 83%) of the propargyl iodide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23](O)=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:26].ON1C2C=CC=CC=2N=N1.Cl.[CH3:39][O:40][C:41](=[O:47])[C@H:42]([CH:44]([CH3:46])[CH3:45])[NH2:43].C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:43][CH:42]([CH:44]([CH3:46])[CH3:45])[C:41]([O:40][CH3:39])=[O:47])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:26]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: Cc1cc(-c2cc(C(=O)O)on2)ccc1NC(=O)Nc1c(F)cccc1F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3c(F)cccc3F)c(C)c2)no1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(4-(3-(2,6-difluorophenyl)ureido)-3-methylphenyl)isoxazole-5-carboxylic acid (1.0 equiv.) was dissolved in 25 ml of DMF, N,N′-dicyclocarbodiimide (1.2 equiv.) and 1-hydroxybenzotriazole (1.0 equiv.) was added and stirred at room temperature for 10 min. L-valine methyl ester hydrochloride (1.5 equiv.) was neutralized with triethylamine (1.5 equiv.) in 10 ml of DMF and was added to the above mixture and the resulting reaction mixture was stirred at room temperature for 48 hours. DMF was evaporated and then diluted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in a chloroform and methanol mixture, adsorbed on silica (100-200 mesh) and purified by flash chromatography on silica gel, and then eluted with 0-2% methanol in chloroform to obtain a crude product.