Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH:22]=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:24](P(=O)(OCC)OCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH:22]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C=O
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
A solution containing 164 mg of 5-(3,5-dichloro-phenylsulphanyl)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde, 103 mg of diethyl benzylphosphonate and 27 mg of sodium hydride (60% in mineral oil) in 5 ml of anhydrous tetrahydrofuran was stirred under nitrogen at rt for 16 h. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum spirit 40°-60° C. (1:10) for the elution to give 162 mg of 5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-4-styryl-1H-pyrazole as a pale yellow solid. Mass spectrum (EI) m/z 436 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]([F:22])([F:21])[F:20].FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:40](=[O:55])[C:41]1[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[C:43]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:42]=1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]([C:40](=[O:55])[C:41]1[CH:46]=[C:45]([C:47]([F:50])([F:48])[F:49])[CH:44]=[C:43]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:42]=1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]([F:20])([F:21])[F:22]
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: COC(=O)CNc1cnccc1-c1ccccc1OC(F)(F)F
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1OC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 284, from [4-(2-trifluoromethoxy-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester and 3-methanesulfonyl-5-trifluoromethyl-benzoyl chloride (example 223, intermediate d). The crude product was used in the next step without further purification. Brown sticky liquid. MS (ESI): m/z=577.2 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl-].[Cl-].[Ca+2].N1C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]([O:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:4]
Reactant: COc1ccc(CO)cc1
Reactant: O=C(Br)CBr
Agent: [Ca+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(COC(=O)CBr)cc1

Procedure:
20.2 g (0.1 mol) of bromoacetyl bromide are dissolved in 100 ml of toluene, this solution is cooled to -10° C. (CaCl2 tube) and 8.7 g (0.11 mol) of pyridine are added dropwise at -10° C. Thereafter, 13.8 g (0.1 mol) of 4-methoxybenzyl alcohol, dissolved in 20 ml of toluene are added dropwise to this mixture in the course of 20 minutes at -10° C., and the mixture is allowed to react for 1 hour at this temperature.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.C1(C)C(S(O)(=O)=O)=CC=CC=1.[Cl:22][C:23]1[CH:30]=[C:29]([F:31])[C:28]([C:32]2[C:36]([Cl:37])=[C:35]([O:38][CH:39]([F:41])[F:40])[N:34]([CH3:42])[N:33]=2)=[CH:27][C:24]=1C=O.C(N(CC)CC)C>O1CCCC1>[Cl:37][C:36]1[C:32]([C:28]2[CH:27]=[C:24]([CH:1]([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])[C:23]([Cl:22])=[CH:30][C:29]=2[F:31])=[N:33][N:34]([CH3:42])[C:35]=1[O:38][CH:39]([F:41])[F:40]
Reactant: CCOC(OCC)OCC
Reactant: Cn1nc(-c2cc(C=O)c(Cl)cc2F)c(Cl)c1OC(F)F
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(OCC)c1cc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl

Procedure:
20 ml of triethyl orthoformate and 0.1 g of toluenesulfonic acid were added to a solution of 3 g (8.8 mmol) of 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorobenzaldehyde in 50 ml of tetrahydrofuran. After the mixture had been refluxed for 2 hours, it was treated with 3 ml of triethylamine. The mixture was subsequently concentrated. The residue was treated with 50 ml of water. The product was subsequently extracted from the aqueous phase using ethyl acetate. The organic phase was then washed using saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and finally concentrated. The crude product was purified by means of column chromatography on silica gel (eluent: hexane/ethyl acetate=9:1). Yield: 1 g.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>O1CCCC1>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COc1ccc(CN)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2ccccc2[N+](=O)[O-])cc1
Reaction time: 18 h

Procedure:
A mixture of 1-fluoro-2-nitrobenzene (20 g) and 4-methoxybenzylamine (18.52 ml) in dry tetrahydrofuran (100 ml) was stirred at 23° for 18 h under a nitrogen atmosphere. The mixture was filtered, then the organic layer was concentrated in vacuo to an oil. Ethanol (50 ml) was added and a solid separated. After filtration, the title compound was obtained as an orange solid (16.35 g). The filtrate was concentrated in vacuo and the residue was treated with further ethanol (10 ml) to give a further amount of title compound (7.9 g). M.p. 81°-2° T.l.c. CH-EA (8:2), Rf 0.55.
Reaction SMILES: [Cl:1][C:2]1[C:11](/[CH:12]=C/C2C=CC=CC=2)=[N:10][C:9]2[NH:8][C:7](=[O:20])[CH2:6][O:5][C:4]=2[CH:3]=1.CSC.CN(C=[O:28])C>CO>[Cl:1][C:2]1[C:11]([CH:12]=[O:28])=[N:10][C:9]2[NH:8][C:7](=[O:20])[CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C1COc2cc(Cl)c(/C=C/c3ccccc3)nc2N1
Solvent: CO
Solvent: CSC
Product: O=Cc1nc2c(cc1Cl)OCC(=O)N2
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 68 %

Procedure:
7-Chloro-6-((E)-styryl)-4H-pyrido[3,2-b][1,4]oxazin-3-one (8.0 g, 27.9 mmole) was dissolved in a mixture of DMF (400 mL) and methanol (40 mL), and the solution was cooled to −78° C. Ozone was bubbled through the solution with stirring for 45 minutes, then the excess ozone was removed by bubbling oxygen through the solution for 30 min. Dimethylsulfide (21 mL, 279 mmole) was added to the solution, and the reaction was stirred at −78° C. for 3 hr, then at room temperature overnight. The solvent was removed in vacuo, and the residue was triturated with Et2O (150 mL). The collected solid was washed with additional Et2O and dried to afford a white solid (4 g, 68%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16]Cl)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:57][N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:61]3[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]3)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(CCl)cc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc(-n3nc(C(C)(C)C)cc3NC(=O)N[C@H]3CC[C@@H](Oc4ccc5nnc(N6CCCCC6)n5c4)c4ccccc43)cc2)CC1
Temperature: 50 °C
Yield: 7.3 %

Procedure:
To a solution of Intermediate 106b (0.25 mmol) in THF (2.5 mL) was added DIPEA (130 μL, 0.75 mmol) followed by N-methylpiperazine (83 μL, 0.75 mmol). The reaction mixture was heated at 50° C. for 18 h in a sealed tube, then cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM followed by HPLC (C18 X-select column, 10-98% gradient MeCN in H2O, 0.1% HCO2H), to give the title compound (13 mg, 7%). LCMS (Method 5): Rt 3.44 min, m/z 717 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.57-1.66 (2H, m), 1.68-1.77 (4H, m), 1.79-1.95 (2H, m), 1.98-2.19 (5H, m), 2.22-2.46 (8H, m), 3.14 (4H, t, J=5.3 Hz), 3.49 (2H, s), 4.76-4.85 (1H, m), 5.54 (1H, t, J=4.4 Hz), 6.33 (1H, s), 7.09 (1H, d, J=8.6 Hz), 7.17 (1H, dd, J=9.8, 2.2 Hz), 7.25-7.47 (8H, m), 7.59-7.65 (2H, m), 8.11 (1H, s).
Reaction SMILES: [NH:1]([C:22]([O:24]C(C)(C)C)=O)[C@H:2]([C:12]([O:14]N1C(=O)CCC1=O)=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6]C(C)(C)C.[NH2:29][C@H:30](C(O)=O)[CH2:31][CH2:32][C:33](=[O:35])[OH:34].[CH3:39][N:40]1[C@@H:57]2[CH2:58][C:45]3[CH:46]=[CH:47][C:48]([O:59][CH3:60])=[C:49]4[O:50][C@H:51]5[C:52]([CH2:54][CH2:55][C@@H:56]2[C@:43]5([C:44]=34)[CH2:42][CH2:41]1)=[O:53]>>[CH2:31]([C@H:30]([NH2:29])[C:22]([NH:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][CH2:4][C:5]([OH:6])=[O:11])=[O:24])[CH2:32][C:33]([OH:35])=[O:34].[CH3:39][N:40]1[C@@H:57]2[CH2:58][C:45]3[CH:46]=[CH:47][C:48]([O:59][CH3:60])=[C:49]4[O:50][C@H:51]5[C:52]([CH2:54][CH2:55][C@@H:56]2[C@:43]5([C:44]=34)[CH2:42][CH2:41]1)=[O:53]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Product: N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Glu-Glu-Hydrocodone was prepared by a similar method to Example 38 except the amino acid starting material was Boc-Glu(OtBu)-OSu and the conjugate starting material was Glu-Hydrocodone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2OC(=O)[S:10][N:9]=2)=[CH:4][CH:3]=1.[C:14]([C:17]#[N:18])(=[O:16])[CH3:15]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:18]=[C:17]([C:14](=[O:16])[CH3:15])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)C#N
Reactant: O=c1oc(-c2ccc(F)cc2)ns1
Solvent: Cc1ccccc1
Product: CC(=O)c1nc(-c2ccc(F)cc2)ns1
Reaction time: 3 h

Procedure:
In still a further embodiment, 1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone may be prepared according to the methodology and reagents of Scheme 16A. In this embodiment, a 1,3,4-oxathiazol-2-one ring fragment is generated and subsequently converted to a 1,2,4-thiadiazole ring fragment during the preparation of 1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone. Specifically, 4-fluoro-benzamide is reacted with chlorocarbonylsulfenyl chloride to provide 5-(4-fluoro-phenyl)-1,3,4-oxathiazol-2-one. In one embodiment, the reaction is performed in toluene. In another embodiment, the reaction is performed at elevated temperatures of about 80° C. for about 3 hours. 5-(4-Fluorophenyl)-1,3,4-oxathiazol-2-one is then reacted with acetyl cyanide to provide 1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)-ethanone. In one embodiment, this reaction is performed in 1,2-dichlorobenzene. In another embodiment, this reaction is performed at elevated temperatures of about 160° C. for about 20 hours. 1-(3-(4-Fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone is then converted to a compound of Formula (I-A) by the methods described herein, such as Scheme 1.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:4])=[O:3].Cl[C:19]1[NH:27][C:26]2[C:21](=[N:22][C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:24][CH:25]=2)[N:20]=1>>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][N:15]([C:19]2[NH:27][C:26]3[C:21](=[N:22][C:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:24][CH:25]=3)[N:20]=2)[CH2:14][CH2:13]1)(=[O:3])=[O:4]
Reactant: Clc1nc2nc(-c3ccccc3)ncc2[nH]1
Reactant: CS(=O)(=O)Nc1ccccc1N1CCNCC1
Product: CS(=O)(=O)Nc1ccccc1N1CCN(c2nc3nc(-c4ccccc4)ncc3[nH]2)CC1

Procedure:
By following the same reaction as described in Example 19 except that 1-(2-methylsulfonylaminophenyl)piperazine was used in place of 3-tert-butoxycarbonyl-cis-3,7-diazabicyclo[3.3.0]octane, and 8-chloro-2-phenylpurine was used in place of 2-chloro-5-phenylbenzimidazole, the title compound was prepared.
Reaction SMILES: [OH:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:17][C:16]([CH3:18])=[C:15]3[C:11]=2[CH2:12][C@H:13]2[C:19]([CH3:21])([CH3:20])[C@H:14]23)=[O:9])=[CH:4][C:3]=1[CH3:25].[OH-].[Na+].[Na+].[I-].Br[CH2:31][CH2:32][OH:33]>C(O)(C)C.C(O)=O>[OH:33][CH2:32][CH2:31][O:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:17][C:16]([CH3:18])=[C:15]3[C:11]=2[CH2:12][C@H:13]2[C:19]([CH3:21])([CH3:20])[C@H:14]23)=[O:9])=[CH:4][C:3]=1[CH3:25]
Reactant: OCCBr
Reactant: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=CO
Product: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCO
Temperature: 90 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3,5-dimethyl-benzylamide (100 mg) (8.9 mg, 0.025 mmol) in isopropanol (1 mL) is added 2 N aq. NaOH (100 μL), NaI (1 mg, 0.007 mmol) and 2-bromo-ethanol (12.5 mg, 0.1 mmol). The reaction mixture is heated to 90° C. and shaken for 8 h before it is cooled to rt. Formic acid (0.2 mL) is added and the reaction mixture is separated by prep. HPLC to give (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzylamide (5.4 mg) as a colourless lyophilisate. LC-MS: tR=1.00 min, [M+1]+=400.26.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([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])[N:7]=1.[CH2:22]([P:24]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([O:35][CH3:36])[CH:29]=1)([CH2:26][CH3:27])=[O:25])[CH3:23].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:32][C:31]2[CH:33]=[CH:34][C:28]([P:24]([CH2:26][CH3:27])([CH2:22][CH3:23])=[O:25])=[CH:29][C:30]=2[O:35][CH3:36])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CCP(=O)(CC)c1ccc(N)c(OC)c1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: ClCCl
Product: CCP(=O)(CC)c1ccc(Nc2nnc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC)c1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 4-(Diethylphosphoryl)-2-methoxyaniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: Cl[Si](C)(C)C.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[S:13]([C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:15])=[O:14].Cl>ClCCl>[CH3:21][O:20][C:18]([C:17]1[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=1[S:13]([NH:6][C:11]1[CH:24]=[CH:25][C:16]2[C:9](=[CH:8][CH:7]=[CH:22][CH:17]=2)[C:10]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:15])=[O:14])=[O:19]
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: c1ccncc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1ccc2ccccc2c1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 133A (0.50 g, 2.48 mmol) in dichloromethane (8.0 mL) was treated with chlorotrimethylsilane (3.0 mL of 1M solution in CH2Cl2, 2.98 mmol) and pyridine (8.0 mL), stirred at room temperature for 1 hour, treated with methyl 2-(chlorosulfonyl)benzoate (0.873 g, 3.72 mmol), stirred overnight at room temperature treated with 1N HCl (20 mL), and extracted with dichloromethane (2×). The combined organic phases were dried (MgSO4), filtered, and concentrated. The resulting residue was purified by preparative HPLC to provide the desired product. MS (ESI(+)) m/e 400 (M+H)+; (ESI(−)) m/e 398 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.04 (d, 1H), 7.95 (d, 1H), 7.85 (d, 7.90, 1H), 7.80 (d, 1H), 7.72 (m, 2H), 7.65 (ddd, 1H), 7.56 (m, 2H), 7.50 (d, 1H), 3.80 (s, 3H), 3.78 (s, 3H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[C:11]([Cl:23])[C:10]=1[O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:32]N1C(=O)CCC1=O.CN(C=O)C>O>[Br:32][C:12]1[C:13]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[C:10]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27])[C:11]=1[Cl:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)c(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c(Cl)c1Br
Temperature: 25 °C
Reaction time: 120 h
Yield: 66.9 %

Procedure:
A mixture of 0.650 g (1.30 mmol) of 14 and 0.276 g (1.60 mmol) of N-bromosuccinimide (NBS) in 10 Ml of DMF under argon was stirred at 25° C. for 5 days. The reaction mixture was diluted with 30 Ml of water, extracted three times with diethyl ether (50 Ml each), and the combined extracts were washed with 30 Ml of water, and 30 Ml of brine, dried (MgSO4), concentrated, and column chromatographed on silica gel using a gradient mixture of hexane and diethyl ether as eluent gave 0.506 g (67% yield) of bromide 4. 1H NMR (CDCl3) δ 6.41 (s, 1H, Ar, C3-H), 1.03 (s, 9H, t-Bu), 1.02 (s, 9H, t-Bu), 0.97 (s, 9H, t-Bu), 0.23 (s, 6H, Me), 0.22 (s, 6H, Me), 0.18 (s, 6H, Me); 13C NMR (CDCl3) δ 147.3 (s), 147.2 (s), 139.4 (s), 128.3 (s), 111.1 (d), 108.4 (s), 29.9 (q, t-Bu), 26.3 (q, t-Bu), 26.2 (q), 26, 18.9 (s), 18.6 (s), −3.3 (q, Me), −3.4 (q, Me), −3.5 (q, Me), −4.0 (q). Anal. Calcd for C24H46BrClO3Si3: C, 49.51; H, 7.96. Found: C, 49.78; H, 8.11.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])[CH:27]=[N:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][S:32]([CH2:35][CH3:36])(=[O:33])=[O:34])[CH:27]=[N:28][CH:29]=1
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(Cl)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)NCc1cncc(-c2cc3c(cc2Cl)N(C)C(=O)CC3)c1
Temperature: 120 °C
Yield: 30 %

Procedure:
A mixture of 7-chloro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (20 mg, 0.06 mmol), ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide (intermediate A-11, 26 mg, 0.09 mmol), bis(triphenylphosphine)-palladium(II) chloride (4.2 mg, 0.006 mmol) and sodium carbonate (2 N aq., 0.06 mL) in DMF (1 mL) was heated in a microwave at 120° C. for 30 minutes. The mixture was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC to afford the title product (7.1 mg, 30%) as a white solid. MS, 394.2 (M+H+)+.
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12](#[N:14])[CH3:13].C[O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2)=[CH:21][CH:20]=1)=O>O1CCCC1>[C:12]([CH2:13][C:17]([C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]2[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2)=[CH:23][CH:24]=1)=[O:16])#[N:14]
Reactant: CC#N
Reactant: COC(=O)c1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C(=O)CC#N)cc2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium 1.6 M in hexane (1.63 ml, 2.61 mmol) was diluted with tetrahydrofuran (2 ml) and cooled to −78° C. Acetonitrile (107 mg, 0.137 ml, 2.61 mmol) was added dropwise and stirring was continuing for 1 hour. (S)-tert-butyl 2-(4-(methoxycarbonyl)phenyl)morpholine-4-carboxylate (420 mg, 1.31 mmol) dissolved in tetrahydrofuran was slowly added to the white slurry over a 10 min period. After 3 hours, the reaction was quenched by addition of saturated ammonium chloride solution (5 ml) and extracted with diethyl ether (10 ml). The organic layer was dried over MgSO4 and evaporated.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.[C:21](OCC)(=[O:23])C.O1CCCC1>C(O)(=O)C>[Cl:1][C:2]1[N:7]2[C:8]([CH:21]=[O:23])=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2nccn12
Reactant: CCOC(C)=O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=Cc1cnc2cccc(Cl)n12
Yield: 37 %

Procedure:
A solution of 5-chloroimidazo[1,2-a]pyridine (997 mg) and hexamethylenetetramine (1.8 g) in acetic acid (10 ml) was stirred at 90° C. for 5 hours. After the reaction mixture was allowed to cool, ethyl acetate-tetrahydrofuran (4/1; 200 ml) was added and the mixture was washed with saturated aqueous solution of sodium chloride. The organic layer was neutralized with 2N-aqueous solution of sodium hydroxide, dried over MgSO4, and concentrated. The resulting crystals were rinsed with diethyl ether to provide the title compound (440 mg, 37%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:14][C:13]2[CH:15]=[C:16]([C:19]([NH:21][C:22]3[C:31]4[O:30][C:29]([C:32]([O:34]CC)=O)=[CH:28][C:27](=[O:37])[C:26]=4[CH:25]=[CH:24][CH:23]=3)=[O:20])[CH:17]=[CH:18][C:12]=2[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:38]>CO.O1CCCC1>[O:37]=[C:27]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:21][C:19]([C:16]3[CH:17]=[CH:18][C:12]4[O:11][CH:10]([CH2:9][O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH2:14][C:13]=4[CH:15]=3)=[O:20])[C:31]=2[O:30][C:29]([C:32](=[O:34])[NH2:38])=[CH:28]1
Reactant: N
Reactant: CCOC(=O)c1cc(=O)c2cccc(NC(=O)c3ccc4c(c3)CC(COCc3ccccc3)O4)c2o1
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1cc(=O)c2cccc(NC(=O)c3ccc4c(c3)CC(COCc3ccccc3)O4)c2o1
Reaction time: 1.5 h

Procedure:
In a solution of ethyl 8-(2-benzyloxymethyl-2,3-dihydrobenzofuran-5-carboxamido)-4-oxo-4H-1-benzopyran-2-carboxylate (528 mg, 1.06 mmol) in methanol (25 ml) and anhydrous tetrahydrofuran (25 ml), ammonia gas was bubbled for 30 minutes. After evaporation to dryness, the resulting solid residue was dissolved in a tetrahydrofuran:methanol 1:1 mixture (15 ml) and added with concentrated HCl (0.5 ml). The mixture was refluxed under stirring for 1.5 h, then the solvents were evaporated off under reduced pressure. The resulting crude was suspended in water and the insoluble solid was recovered by filtration, washed repeatedly with water and dried under vacuum on phosphorous pentoxyde, thereby obtaining 527 mg of the title compound (quantitative yield).