Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:49][C:50]1[CH:58]=[CH:57][C:53]([CH:54]([OH:56])[CH3:55])=[CH:52][CH:51]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:56][CH:54]([C:53]2[CH:57]=[CH:58][C:50]([CH3:49])=[CH:51][CH:52]=2)[CH3:55])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(C(C)O)cc1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC(C)c4ccc(C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 72.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (76 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (115 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-methyl-α-methylbenzyl alcohol (52 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (85 mg, yield 67%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C[O-].[Na+].CO.[CH3:13][O:14][C:15]1[CH:73]=[CH:72][C:18]([CH2:19][O:20][C:21]([C:23]2[N:28]3[C:29](=[O:69])[C@@H:30]([NH:31][C:32](=[O:68])[C:33]([C:55]4[N:56]=[C:57]([NH:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[S:58][CH:59]=4)=[N:34][O:35][C:36]([C:39]([O:41][CH:42]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:40])([CH3:38])[CH3:37])[C@H:27]3[S:26][CH2:25][C:24]=2[CH2:70]Cl)=[O:22])=[CH:17][CH:16]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:73]=[CH:72][C:18]([CH2:19][O:20][C:21]([C:23]2[N:28]3[C:29](=[O:69])[C@@H:30]([NH:31][C:32](=[O:68])[C:33]([C:55]4[N:56]=[C:57]([NH:60][C:61]([O:63][C:64]([CH3:65])([CH3:67])[CH3:66])=[O:62])[S:58][CH:59]=4)=[N:34][O:35][C:36]([C:39]([O:41][CH:42]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:40])([CH3:37])[CH3:38])[C@H:27]3[S:26][CH2:25][C:24]=2[CH2:70][S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[O:22])=[CH:17][CH:16]=1
Reactant: Sc1ccncc1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)C(=NOC(C)(C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)C2=C(CSc3ccncc3)CS[C@@H]3[C@H](NC(=O)C(=NOC(C)(C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1
Yield: 64.4 %

Procedure:
To a solution of 4-mercaptopyridine (178 mg; 2 Eq.) in N,N-di-methylformamide (10 ml) at 0° C. are added a solution of sodium methoxide in methanol (1.5 Eq.) and then 7β-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-(1-diphenylmethoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (2) (712 mg; 0.8 mMol.), and the mixture is stirred for 15 minutes. The reaction mixture is diluted with ethyl acetate, washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel chromatography (toluene: ethyl acetate) to give 7β-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-(1-diphenylmethoxycarbonyl-1-methylethoxyimino)acetamido]-3-(4-pyridyl)thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (3) (497 mg).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1.[CH3:21][C@H:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1.C(N(CC)CC)C>C(O)(C)C>[Br:1][C:2]1[C:10]2[C:9]([N:26]3[CH2:25][CH2:24][NH:23][C@@H:22]([CH3:21])[CH2:27]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)ncnc21
Reactant: C[C@H]1CNCCN1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C[C@H]1CN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CCN1
Temperature: 80 °C
Yield: 75 %

Procedure:
To a mixture of pyrrolopyrimidine from step B (76 mg, 0.2 mmol) and (S)-2-methylpiperazine (21 mg, 0.2 mmol) in isopropanol (2 ml) was added triethylamine (0.11 ml, 0.8 mmol). The mixture was heated at 80° C. for 5 mins via microwave and concentrated under vacuum to give crude (S)-5-bromo-4-(3-methylpiperazin-1-yl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (65 mg, 0.15 mmol, 75%) which was used directly for the next step. MS (ES+) [M+H]+=437.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Li].[CH2:6](Br)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1.N>[CH2:1]([OH:4])[C:2]#[C:3][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH3:6]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: C#CCO
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCC#CCO
Reaction time: 1 h

Procedure:
A mixture of 56 1 g of propargyl alcohol in 100 ml of tetrahydrofuran and 15.6 g of lithium in 1 liter of ammonia containing a trace of ferric chloride is stirred for 1 hour. A 76.4 ml portion of hexadecyl bromide is added and the mixture refluxed for 8 hours then evaporated. The residue is dissolved in ether and washed with 10% hydrochloric acid, dried and purified by flash chromatography, to give 47.4 g of the desired compound as white platelets, mp. 60° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[F:19][C:20]1[CH:21]=[C:22]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: COc1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc1F

Procedure:
The title compound was prepared from the product of Example 65A and 3-fluoro-4-methoxyphenylboronic acid according to General Method B: LC-MS Method B (ESI+) m/z 354.0 (M+H)+, retention time 1.80 minutes.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=CC=C[CH:5]=1.N[C@H]([C:20]([OH:22])=[O:21])CCCCN.N[C@H](C(O)=O)[CH2:25][CH:26]([CH3:28])[CH3:27]>>[NH:1]([C:20]([O:22][C:26]([CH3:28])([CH3:27])[CH3:25])=[O:21])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH:4]([CH3:5])[CH3:9]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
Yield: 120 mg Rf value: 0.43 (ethyl acetate:butanol:acetic acid: water=1:1:1:1) Amino acid analysis: Asp 1.00; Ser 1.95; Pro 2.06 Val 0.98; Leu 2.01
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19](O)[CH2:20][C:21]2[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=2)[O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:16]=[CH:17][CH:18]=1.O=S(Cl)Cl.[SH:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].C(N(CC)CC)C>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]([S:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:20][C:21]2[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=2)[O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CCS
Reactant: CCOC(=O)COc1cccc(CC(O)c2cccc(OCc3ccc4ccccc4n3)c2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCSC(Cc1cccc(OCC(=O)OCC)c1)c1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product obtained from Step C in 50 mL of CH2Cl2 is treated with 2 mL of SOCl2. The reaction mixture is stirred at room temperature for 2 hr. and then evaporated to dryness. The crude product thus obtained in 20 mL of CH2Cl2 is treated with ethyl 3-mercaptopropionate and triethylamine (1:1) for 16 hr. at room temperature. After evaporation of solvent, the crude product is purified by flash column chromatography to obtain ethyl 2-(3-(2-(3-(2-quinolinylmethyloxy)phenyl)-2-(carbethoxyethylthio)ethyl)phenoxy)acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH:31]=[CH2:32]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:32][CH2:31][CH:30]=[CH2:29])=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-BOC-tyrosine methyl ester (10.0 g, 33.9 mmol) was dissolved in DMF (40 mL) and potassium carbonate (5.62 g, 40.7 mmol) and 4-bromo-1-butene (4.13 mL, 40.7 mmol) were added. The mixture was stirred at rt for 18 h before being diluted with EtOAc (120 mL) and partitioned with 1M hydrochloric acid. The organic phase was washed with hydrochloric acid and then with brine before being dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica using a gradient of EtOAc and (50/70) petroleum ether to yield a white solid, 3.20 g, 27%. Rf=0.82 (1/2 EtOAc/(50/70) petroleum ether).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][N:17]=[C:16]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=3[N+:31]([O-:33])=[O:32])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[N:15][C:16]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](=[O:28])[NH:41][CH:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)=[CH:24][C:23]=2[N+:31]([O-:33])=[O:32])=[N:17][CH:18]=1
Reactant: Cc1cnc(Nc2ccc(C(=O)O)cc2[N+](=O)[O-])nc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(Nc2ccc(C(=O)NC3CCN(C)CC3)cc2[N+](=O)[O-])nc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
A mixture of 4-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-methylpyrimidin-2-yl)amino)-3-nitrobenzoic acid (0.075 g, 0.164 mmol), 1-methylpiperidin-4-amine (37 mg, 0.33 mmol), HATU (140 mg, 0.37 mmol), and DIEA (0.1 mL, 0.6 mmol) in DMF (3.0 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with aqueous saturated sodium bicarbonate solution and saturated brine solution. The crude mixture was loaded onto silica gel and purified using 0-10% MeOH/DCM gradient containing 10% NH4OH to give the title compound (73 mg, 80%). MS (ES+) C27H38N8O5 requires: 554. found: 555 [M+H]+
Reaction SMILES: [O-:1][N+:2]1[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[N:5]=[C:4]([CH2:15][CH2:16][CH2:17][OH:18])[N:3]=1)[CH2:12][CH2:11][CH2:10]3.Cl.[CH3:20][N:21]([CH3:28])[CH2:22][CH2:23][CH2:24][C:25](O)=[O:26].C1CCC(N=C=NC2CCCCC2)CC1.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:20][N:21]([CH3:28])[CH2:22][CH2:23][CH2:24][C:25]([O:18][CH2:17][CH2:16][CH2:15][C:4]1[N:3]=[N+:2]([O-:1])[C:7]2[CH:8]=[C:9]3[C:13]([CH2:12][CH2:11][CH2:10]3)=[CH:14][C:6]=2[N:5]=1)=[O:26]
Reactant: [O-][n+]1nc(CCCO)nc2cc3c(cc21)CCC3
Reactant: CN(C)CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCCC(=O)OCCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Temperature: 20 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
A mixture of alcohol 70 (100 mg, 0.41 mmol), 4-(dimethylamino)butanoic acid hydrochloride (68 mg, 0.41 mmol), DCC (93 mg, 0.45 mmol), DMAP (5 mg, 0.04 mmol) and Et3N (0.06 mL, 0.41 mmol) in DCM (20 mL) was stirred at 20° C. for 16 h. The solvent was evaporated and the residue purified by chromatography, eluting with a gradient (0-10%) of MeOH/20% EtOAc/DCM, to give the ester 309 (137 mg, 94%) as a pale-brown oil: 1H NMR δ 8.25 (s, 1H, H-9), 7.74 (s, 1H, H-5), 4.21 (t, J=6.3 Hz, 2H, CH2O), 3.06-3.15 (m, 6H, H-6, H-8, CH2), 2.73 (br s, 2H, H-7), 2.56 [s, 6H, N(CH3)2], 2.37 (t, J=7.0 Hz, 2H, CH2), 2.18-2.29 (m, 4H, CH2), 1.92-1.99 (m, 2H, CH2); 13C NMR δ 172.6, 164.9, 154.9, 149.1, 147.4, 132.3, 122.7, 114.2, 63.7, 57.7, 43.9 (2), 33.6, 33.2, 32.8, 31.3, 26.8, 25.7, 21.0; HRMS calcd for C19H26N4O3 (M+) m/z 358.2005, found 358.2006.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C([O:13]C(N(C)C)N(C)C)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[O:13])[N:3]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1cccc(F)n1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cccc(F)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Fluoro-6-methylpyridine (14.4 g, 0.13 mol) and tert-butoxybis(dimethylamino)methane (Bredereck's reagent; 34.9 g, 0.20 mol) are heated at 140° C. for 24 h. The reaction is cooled and diluted with THF (100 mL). Sodium periodate (75 g) in water (400 mL) is added at 0-5° C., and the reaction mixture is then stirred for 24 h at room temperature. The precipitate is filtered through celite, and the filtrate extracted 5× with diethyl ether. The combined ether layers are washed with water, brine, and dried (MgSO4). Most of the solvent is removed by concentration at 0° C. (by keeping ice in the bath) to provide 2-Fluoropyridine-6-carboxaldehyde.
Reaction SMILES: [N:1]#[C:2][NH2:3].C(OC(=O)[N:10]([CH:23]([CH3:25])[CH3:24])[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1)(C)(C)C.[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([C:36](=[O:39])[CH2:37]Br)=[CH:35][C:30]=2[O:29][CH2:28]1>>[NH2:1][C:2]1[N:3]=[C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][NH:10][CH:23]([CH3:24])[CH3:25])=[CH:19][CH:18]=2)[S:22][C:37]=1[C:36]([C:34]1[CH:33]=[CH:32][C:31]2[O:27][CH2:28][O:29][C:30]=2[CH:35]=1)=[O:39]
Reactant: O=C(CBr)c1ccc2c(c1)OCO2
Reactant: N#CN
Reactant: CC(C)N(CCOc1ccc(N=C=S)cc1)C(=O)OC(C)(C)C
Product: CC(C)NCCOc1ccc(Nc2nc(N)c(C(=O)c3ccc4c(c3)OCO4)s2)cc1

Procedure:
This compound was prepared from cyanamide, isopropyl-[2-(4-isothiocyanato-phenoxy)-ethyl]-carbamic acid tert-butyl ester of Example 135 and 1-benzo[1,3]dioxol-5-yl-2-bromo-ethanone (of Example 132) following a procedure similar to Example 130. Mass spectrum (ES) MH+=441.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])[CH2:6][S:7]C(=O)C)(=[O:3])[CH3:2].[Cl-].[Na+]>O.N>[C:1]([NH:4][CH:5]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])[CH2:6][SH:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(=O)NC(CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
N,S-Diacetyl-D,L-cysteinyl-L-proline (0.3 g.) is dissolved in a mixture of water (4 ml.) and concentrated ammonia (4 ml.) under a blanket of argon. The solution is stored for thirty minutes at room temperature, saturated with sodium chloride and extracted with ethyl acetate and chloroform. The organic layers are pooled and concentrated to dryness in vacuo to obtain N-acetyl-D,L-cysteinyl-L-proline, yield 0.1 g., Rf =0.25 (silica gel; benzene:acetic acid, 75:25).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>CC(C)=O>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:10]=[CH:9][CH:8]=[CH:7][C:3]2=3)=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: c1ccc2c(c1)NCCO2
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(CN2CCOc3ccccc32)cc1
Reaction time: 8 h

Procedure:
To a mixture of 3,4-dihydro-2H-benzo[b][1.4]oxazine (0.500 g, 3.70 mmol) and potassium carbonate (2.56 g, 18.5 mmol) in acetone (25 mL) was added 1-(bromomethyl)-4-nitrobenzene (0.959 g, 4.44 mmol). The mixture was heated to reflux and stirred overnight. After 16 hrs the mixture was concentrated in vacuo, diluted with EtOAc, and washed with water and brine. The organic fraction was dried over Na2SO4, concentrated in vacuo, and the crude residue was purified by silica gel chromatography using 100% Hexanes to 30% Hexanes:EtOAc to afford 4-(4-nitrobenzyl)-3,4-dihydro-2H-benzo[b][1.4]oxazine as an orange oil. MS found: M+H+=271.1.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:37]=[CH:36][C:27]([C:28]([NH:30][N:31]2[NH:35][CH:34]=[CH:33][S:32]2)=[O:29])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1>>[CH3:20][S:17]([NH:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:21]=[CH:22][C:2]([C:25]2[CH:26]=[C:27]([C:28](=[O:29])[NH:30][N:31]3[NH:35][CH:34]=[CH:33][S:32]3)[CH:36]=[CH:37][C:24]=2[CH3:23])=[N:3][CH:4]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NN2NC=CS2)cc1-c1ccc(C(=O)NCc2cccc(NS(C)(=O)=O)c2)cn1

Procedure:
N-(3-Methylsulphonylaminobenzyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 2.80 min, MH+523. NMR: δH [2H6]-DMSO 9.35, (1H, t), 9.17, (2H, m), 8.38, (1H, d), 8.26, (1H, s), 8.09, (1H, d), 7.83, (1H, d), 7.52, (1H, d), 7.31, (1H, t), 7.22, (1H, s), 7.11, (2H, m), 4.52, (2H, d), 2.99, (3H, s), 2.46, (3H, s).
Reaction SMILES: S(Cl)([Cl:3])=O.C(OC([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:15][CH2:14]1)=O)(C)(C)C.[CH3:24]O>>[ClH:3].[NH2:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:18]1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCC(=O)O)CC1
Reactant: CO
Product: COC(=O)CC[C@H]1CC[C@H](N)CC1
Product: Cl
Reaction time: 0.17 h

Procedure:
At −5° C., 2.9 ml (40.5 mmol) of thionyl chloride were slowly added dropwise to 100 ml of methanol, and the mixture was stirred at this temperature for 10 min. 5 g (18.4 mmol) of 3-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}propanoic acid were then added in one portion, and the reaction mixture was stirred at room temperature overnight. After the reaction had gone to completion, the solvent was evaporated under reduced pressure. This gave 3.97 g (17.9 mmol, 97% of theory) of a colorless solid.
Reaction SMILES: [CH2:1]([C:4]1C(OC)=CC(C(Cl)=O)=CC=1OC)[CH:2]=C.[CH3:17][O:18][C:19](=[O:29])[C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([OH:28])[CH:21]=1.C(Br)C=C.COC(=O)C1C=C(OC)C=C(OCC=C)C=1.COC(=O)C1C=C(OC)C(CC=C)=C(O)C=1>>[CH3:17][O:18][C:19](=[O:29])[C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([OH:28])[C:21]=1[CH2:4][CH:1]=[CH2:2]
Reactant: C=CCc1c(OC)cc(C(=O)Cl)cc1OC
Reactant: COC(=O)c1cc(O)cc(OC)c1
Agent: C=CCOc1cc(OC)cc(C(=O)OC)c1
Agent: C=CCc1c(O)cc(C(=O)OC)cc1OC
Solvent: C=CCBr
Product: C=CCc1c(O)cc(OC)cc1C(=O)OC

Procedure:
4-Allyl-3,5-dimethoxy-benzoyl chloride. Starting from 3-hydroxy-5-methoxybenzoic acid methyl ester by reaction with allyl bromide, 3-allyloxy-5-methoxybenzoic acid methyl ester is prepared. B.p. 128°-30°C/0.4 mmHg. This compound is subjected to the allylic rearrangement performed as described by Tarbell in Organic Reactions, Vol. II, New York, 1944 and a mixture of 4-allyl-3-hydroxy-5-methoxybenzoic acid methyl ester and 2-allyl-3-hydroxy-5-methoxybenzoic acid methyl ester is obtained. By hydrolysis under alkaline conditions and separation by fractioned crystallization the pure 4-allyl-3-hydroxy-5-methoxybenzoic acid is obtained. M.p. 202°-3°C (from methanol). The reaction with dimethylsulfate according to the procedure described by F. Benington et al. in Journal Org.Chem. 25, 2066, 1960 affords the corresponding 4-allyl-3,5-dimethoxy-benzoic acid. M.p. 188°-90°C (from light petroleum). This compound is allowed to react with thionyl chloride and 4-allyl-3,5-dimethoxy-benzoyl chloride is prepared. M.p. 56°-57°C (from light petroleum).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([N:11]([CH2:30][C:31]3[CH:47]=[CH:46][C:34]([CH2:35][NH:36][S:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=4)(=[O:39])=[O:38])=[CH:33][CH:32]=3)[CH2:12][C:13]3[N:17](COCC[Si](C)(C)C)[C:16]4[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=4[N:14]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl>>[NH:14]1[C:15]2[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=2[N:17]=[C:13]1[CH2:12][N:11]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:35][NH:36][S:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)(=[O:38])=[O:39])=[CH:46][CH:47]=1)[CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: C[Si](C)(C)CCOCn1c(CN(Cc2ccc(CNS(=O)(=O)c3ccccn3)cc2)C2CCCc3cccnc32)nc2ccccc21
Agent: Cl
Product: O=S(=O)(NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1)c1ccccn1
Yield: 84.2 %

Procedure:
Using General Procedure E: Reaction of pyridine-2-sulfonic acid 4-({(5,6,7,8-tetrahydro-quinolin-8-yl)-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-ylmethyl]-amino}-methyl)-benzylamide (100 mg, 0.15 mmol); and 6N HCl (3.9 mL) for 3 h at 50° C. followed by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH: 94:3:3) gave the title compound (68 mg, 85%) as a white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]#[C:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl.N1C=CC=CC=1.C(OCC)(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]#[C:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(C#Cc2cc(Cl)ccc2N)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C#Cc2cc(Cl)ccc2NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
To a solution of methyl 4-[2-(2-amino-5-chlorophenyl)ethynyl]benzoate (136 mg; prepared in Reference Example 16.) in methylene chloride (2 ml), pyridine (77 μl) and 4-chlorobenzenesulfonyl chloride (106 mg) were added at 0° C. under an atmosphere of argon. The mixture was stirred for 24 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane-AcOEt) to give the title compound (207 mg) having the following physical data.