Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][C:23]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH:26]=[C:25]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[N:24]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:22][C:23]2[N:24]=[C:25]([C:37]3[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=3)[CH:26]=[C:27]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[N:28]=2)=[CH:8][C:7]=1[CH3:13]
Reactant: COC(=O)COc1ccc(O)cc1C
Reactant: COc1ccc(-c2cc(-c3ccc(OC)cc3)nc(CBr)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)COc1ccc(OCc2nc(-c3ccc(OC)cc3)cc(-c3ccc(OC)cc3)n2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(4-Hydroxy-2-methyl-phenoxy)-acetic acid methyl ester 4 (0.13 g, 0.66 mmol) is dissolved in dry acetonitrile (3 mL). Cesium carbonate (0.40 g, 1.2 mmol) is added, followed by 32-bromomethyl-4,6-bis-(4-methoxy-phenyl)-pyrimidine 24 from Step C above. The mixture is stirred under nitrogen at room temperature for 18 hours. The resulting suspension is filtered, the solids are washed with more acetonitrile, and the resulting clear solution is concentrated to yield crude {4-[4,6-Bis-(4-methoxy-phenyl)-pyrimidin-2-ylmethoxy]-2-methyl-phenoxy}-acetic acid methyl ester 25 as an oil. MS calculated for C29H29N2O6 (M+H+) 500.19. found 500.1.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C-:22]#[N:23].[K+]>O>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)#[N:23]
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: [C-]#N
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC1NC(=O)NN=C1c1ccc(C#N)cc1
Temperature: 0 °C
Yield: 45.8 %

Procedure:
In the same manner as Example 18-(1), there was produced a solution containing the diazonium salt derived from 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (3.06 g). The solution was neutralized carefully with saturated aqueous sodium carbonate followed by addition of an ice-cooled solution of potassium cyanide (1.88 g) and cuprous cyanide (1.17 g) in water (12 ml). The mixture was stirred for an hour and the crystals which formed were recovered by filtration, washed with water, 1N aqueous sodium hydroxide, 1N hydrochloric acid and water in that order and dissolved in aqueous ethanol. The solution was treated with activated carbon and concentrated to dryness under reduced pressure. The residue was purified by silica gel (190 g) column chromatography [eluent: chloroform-methanol (20:1)] to give 6-(4-cyanophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.469 g).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[N:14][C:5]2[N:6]([C:11](=[O:13])[CH3:12])[C@@H:7]([CH3:10])[CH2:8][NH:9][C:4]=2[CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>C(OCC)(=O)C>[C:11]([N:6]1[C@@H:7]([CH3:10])[CH2:8][N:9]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[C:4]2[CH:3]=[C:2]([Br:1])[CH:15]=[N:14][C:5]1=2)(=[O:13])[CH3:12]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(=O)N1c2ncc(Br)cc2NC[C@@H]1C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ncc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 50 °C
Yield: 98.3 %

Procedure:
A reaction vial was charged with (S)-1-(7-bromo-3-methyl-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)ethanone (0.054 g, 0.2 mmol) and N,N-diisopropylethylamine (0.245 mL, 1.40 mmol) was added. Isopropyl chloroformate (1.0 M solution in toluene, 1.00 mL, 1.00 mmol) was added, and the reaction was heated at 50° C. overnight. The reaction was diluted with ethyl acetate (3 mL) and washed with saturated aqueous sodium bicarbonate solution (2 mL). The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via column chromatography on silica gel (eluting with 20% ethyl acetate-hexane) to afford (S)-isopropyl 4-acetyl-7-bromo-3-methyl-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-carboxylate (0.070 g, 98%) as a colorless oil. MS (ESI, pos. ion) m/z 356, 358 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].F[C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:26])[NH:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=[N:16]2)=[C:11]([O:27][CH3:28])[CH:10]=1>CS(C)=O.CCOCC>[CH3:28][O:27][C:11]1[CH:10]=[C:9]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:18]=[C:17]2[C:12]=1[C:13](=[O:26])[NH:14][C:15]([C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=1)=[N:16]2
Reactant: COCCO
Reactant: COc1cc(F)cc2nc(-c3ccnc(C)c3)[nH]c(=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COCCOc1cc(OC)c2c(=O)[nH]c(-c3ccnc(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxy-ethanol (0.64 g, 8.40 mmol) in anhydrous DMSO (4 mL) was added sodium hydride (60% suspension in mineral oil, 0.12 g, 5.00 mmol) in small portions and the reaction mixture was stirred at room temperature for 30 minutes. To this mixture was added a solution of 7-fluoro-5-methoxy-2-(2-methyl-pyridin-4-yl)-3H-quinazolin-4-one (0.24 g, 0.84 mmol) in anhydrous DMSO (12 mL). The reaction mixture was stirred at 80° C. for 3 hours, then cooled to room temperature, and diluted with ether (500 mL). The solid was filtered and washed with ether. The crude compound was purified by column chromatography (silica gel 230-400 mesh; 4% methanol in dichloromethane). The compound was further purified by preparative HPLC to give the title compound as a white solid. Yield: 60 mg (21%). MP 260-262° C. 1H NMR (400 MHz, DMSO-d6): δ 8.62 (d, J=5.07 Hz, 1H), 7.98 (s, 1H), 7.88 (d, J=5.07 Hz, 1H), 6.80 (d, J=2.34 Hz, 1H), 6.61 (d, J=2.34 Hz, 1H), 4.25 (t, J=4.68 Hz, 2H), 3.86 (s, 3H), 3.71 (t, J=3.90 Hz, 2H), 3.33 (s, 3H), 2.57 (s, 3H). MS (ES) m/z: 342.07 (M+1) (100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[CH:11]=[CH:10][C:9]=2[CH3:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[CH:11]=[CH:10][C:9]=2[CH3:16])=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2c(C)ccc(C)c2[nH]1
Product: CCOC(=O)c1cc2c(C)ccc(C)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound was prepared in accordance with the general method of example 12b) from 4,7-dimethyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:32])/[C:11](/[CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.Cl.C(N(CC)CCCN=C=NCC)C.[O:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH:55]1[O:60][NH2:61]>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:32])/[C:11](/[CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:61][O:60][CH:55]2[CH2:56][CH2:57][CH2:58][CH2:59][O:54]2)=[O:18])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NOC1CCCCO1
Reactant: O=C(O)CCCC/C=C(\COc1cccc2ccccc12)C(=O)NCCCn1ccnc1
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCCC/C=C(\COc1cccc2ccccc12)C(=O)NCCCn1ccnc1)NOC1CCCCO1
Temperature: 0 °C
Reaction time: 18 h
Yield: 62.7 %

Procedure:
(E)-8-(3-(1H-imidazol-1-yl)propylamino)-7-((naphthalen-1-yloxy)-methyl)-8-oxo-6-octenoic acid (286 mg, 0.65 mM) obtained in Example (2-1-2) was dissolved in dimethylformamide (3 ml), and triethylamine (136 μl, 0.98 mM) was added thereto. Then, the resulting mixture was cooled to 0° C., and to the mixture, N-hydroxy-6-trifluorobenzotriazole (144 mg, 0.72 mM), 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (162 mg, 0.85 mM) and tetrahydropyranyloxyamine (114 mg, 0.98 mM) were added and stirred at room temperature for 18 hrs. After the completion of reaction, ice water was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with an aqueous saturated sodium bicarbonate solution and brine in order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 220 mg of the title compound (yield 63%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][NH:6][C:7]1[S:8][C:9]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)=[N:10][N:11]=1.[CH3:19][S:20][CH2:21][CH2:22][OH:23]>C1(C)C=CC=CC=1.ClC(Cl)C>[CH3:19][S:20][CH2:21][CH2:22][O:23][C:1](=[O:2])[N:6]([C:7]1[S:8][C:9]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)=[N:10][N:11]=1)[CH3:5]
Reactant: CNc1nnc(-c2cncc(F)c2)s1
Reactant: CSCCO
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CC(Cl)Cl
Product: CSCCOC(=O)N(C)c1nnc(-c2cncc(F)c2)s1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 108.8 %

Procedure:
A solution of phosgene (20%, 0.39 mL, 0.8 mmol) in toluene was pipetted at a dropwise rate into a suspension of methyl-[5-(5-fluoropyridin-3-yl)-[1,3,4]thiadiazol-2-yl]-amine (0.15 g, 0.7 mmol) in dichloroethane (10 mL) at 1° C., stirred for 5 minutes and treated with a solution of 4-N,N-dimethylaminopyridine (0.192 g, 1.6 mmol) in dichloroethane (3 mL). The ice bath was removed after 30 minutes. The reaction mixture was stirred at 23° C. for 90 minutes, refluxed under nitrogen for 14 hours, cooled to 0° C. and reacted with 2-methylthio ethanol (0.033 g, 0.35 mmol). The ice bath was removed after 10 minutes. The reaction mixture was stirred at 23° C. for 1 hour, refluxed for 1 hour, cooled, and diluted with dichloroethane (30 mL). The reaction mixture was washed with dilute hydrochloric acid (0.1 N, 2×20 mL), saturated aqueous NaHCO3 (40 mL), and brine (30 mL), and then dried over MgSO4 and chromatographed on silica to afford the title compound as a white solid (0.125 g, 53%): mp 104-106° C.; 1H NMR (400 MHz, CDCl3) δ 8.90 (br t, 1H), 8.56 (d, J=2.8 Hz, 1H), 8.04 (ddd, J=9.1, 2.5, 1.0 Hz, 1H), 4.52 (t, J=6.8 Hz, 2H), 3.75 (s, 3H), 2.87 (t, J=6.8 Hz, 2H), 2.21 (s, 3H); ESIMS m/z 329 ([M+H]+).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[C:15]1([C:21]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:22][CH2:23][CH2:24][CH2:25]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH2:4][N:3]([CH3:2])[CH2:25][CH2:24][CH2:23][NH:22][C:21]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CNCCOc1ccccc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1OCCN(C)CCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 90 °C
Reaction time: 15.5 h

Procedure:
8.05 g (0.0370 mol) of N-methyl-2-(2-methoxyphenoxy) ethylamine hydrochloride, 15.5 g (0. 0407 mol) of N-triphenylmethyl-3-bromopropylamine, (0.0925 mol) of potassium carbonate and 75 ml of N,N-dimethylformamide are introduced, under argon, into a 500 ml, three-necked, round-bottomed flask. The mixture is stirred for 15.5 h at 90° C. The reaction mixture is treated with a mixture of water and ice and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and concentrated under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=2)=[O:4].Cl.Cl[C:17]1[S:18][C:19]2[C:20]([N:25]=1)=[N:21][CH:22]=[CH:23][CH:24]=2.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][C:17]1[S:18][C:19]3[C:20]([N:25]=1)=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:8]=2)=[O:4]
Reactant: Clc1nc2ncccc2s1
Reactant: COC(=O)c1cc2ccc(O)cc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(Oc3nc4ncccc4s3)cc2[nH]1
Temperature: 60 °C
Yield: 52.7 %

Procedure:
To a solution 6-hydroxy-1H-indole-2-carboxylic acid methyl ester (4.0 g, 21 mmol) and 2-chloro-thiazolo[4,5-b]pyridine hydrochloride (4.3 g, 21 mmol) in MeCN:DMF (4:1, 250 mL) was added Cs2CO3 (13.8 g, 42 mmol) and the reaction mixture was heated (60° C., 4 h). The reaction mixture was cooled (rt) and partitioned between EtOAc (300 mL) and saturated NH4Cl (200 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×200 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using MeOH (0.2 M NH3):DCM (0-15%) to provide the title compound as a brown solid (3.6 g, 53%). MS (ESI): mass calcd. for C16H11N3O3S, 325.1; m/z found, 326.0[M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.18 (s, 1H), 8.52 (dd, J=4.8, 1.7, 1H), 8.39 (dd, J=8.0, 1.7, 1H), 7.82 (d, J=8.7, 1H), 7.53 (d, J=2.2, 1H), 7.34 (dd, J=8.0, 4.8, 1H), 7.26 (dd, J=2.2, 0.9, 1H), 7.19 (dd, J=8.7, 2.2, 1H), 3.88 (s, 3H).
Reaction SMILES: NC1C(=O)N2C([C:16](O)=[O:17])=C(CSC3NN=NC=3)CS[C@H]12.[CH:21]1[C:26]([C@@H:27]([NH2:50])[C:28]([NH:30][C@@H:31]2[C:34](=[O:35])[N:33]3[C:36]([C:47]([OH:49])=[O:48])=[C:37]([CH2:40][S:41][C:42]4[N:46]=[N:45][NH:44][CH:43]=4)[CH2:38][S:39][C@H:32]23)=[O:29])=[CH:25][CH:24]=[C:23]([OH:51])[CH:22]=1>C(Cl)Cl>[CH:25]1[C:26]([C@@H:27]([NH2:50])[C:28]([NH:30][C@@H:31]2[C:34](=[O:35])[N:33]3[C:36]([C:47]([OH:49])=[O:48])=[C:37]([CH2:40][S:41][C:42]4[N:46]=[N:45][NH:44][CH:43]=4)[CH2:38][S:39][C@H:32]23)=[O:29])=[CH:21][CH:22]=[C:23]([OH:51])[CH:24]=1.[CH3:16][OH:17]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12
Agent: N[C@@H](C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3c[nH]nn3)CS[C@H]12)c1ccc(O)cc1
Solvent: ClCCl
Product: CO

Procedure:
The acylation of 7-amino-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (7-TACA) to BL-S640 has been carried out in methylene chloride with D-(-)-p-hydroxyphenylglycyl chloride hydrochloride. The yield to BL-S640 methanol solvate was about 45% on a biopotency basis. There was about 15% activity in the mother liquor and about 25% insoluble solids which is unreacted 7-TACA and 7-TACA decomposition product with degraded β-lactam.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][NH:12][O:13][CH3:14].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([O:13][CH3:14])[CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A suspension of 2.3 g (12.81 mmol) of 6-chloronicotinoyl chloride and 1.53 g (15.37 mmol) of N,O-dimethylhydroxylamine in 46 mL of dichloromethane was cooled to 0° C. After dropwise addition of 5.36 mL (38.4 mmol) of triethylamine the resulting reaction mixture was warmed to RT and stirred for further 16 h. The mixture was subsequently washed with water (40 mL), 5% citric acid (40 mL), water (40 mL), and brine (40 mL). The organic layer was dried with Na2SO4, filtered, and the solvent was evaporated at reduced pressure yielding the titled compound as an oil. Amount 2.30 g. Yield 89%.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:12]([B-](F)(F)F)=[CH2:13].[K+].ClCCl.C(N(CC)CC)C>C(O)CC>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([CH:12]=[CH2:13])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: C=C[B-](F)(F)F
Reactant: Clc1nc2c(Br)cccn2n1
Agent: [K+]
Solvent: ClCCl
Solvent: CCCO
Solvent: CCN(CC)CC
Product: C=Cc1cccn2nc(Cl)nc12
Temperature: 90 °C

Procedure:
To a suspension of 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.50 g, 2.2 mmol), potassium vinyltrifluoroborate (0.34 g, 2.6 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (35 mg, 0.043 mmol) in 1-propanol (10 mL) was added triethylamine (0.30 mL, 2.2 mmol). The mixture was heated at 90° C. for 6 hours under an atmosphere of nitrogen. The mixture was cooled to room temperature and the volatiles were evaporated under reduced pressure. The residue was diluted with dichloromethane (50 mL) and filtered through a plug of diatomaceous earth. The filtrate was washed with 2N Hydrochloric acid (2×10 mL) and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue was purified via chromatography (silica gel column 24 g and 0%→2% methanol: dichloromethane). 2-Chloro-8-vinyl-[1,2,4]triazolo[1,5-a]pyridine was isolated as a white solid (0.336 g, 87%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.40 (d, J=6.8 Hz, 1H), 7.53 (d, J=7.3 Hz, 1H), 7.08-6.94 (m, 2H), 6.59 (d, J=17.6 Hz, 1H), 5.70 (d, J=11.2 Hz, 1H). MS=180, 182 (MH)+.
Reaction SMILES: [CH3:1][C:2]([CH3:19])=[CH:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:6]1.[CH:20]([NH:23][NH:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH:20]([N:23]([C:16](=[O:18])/[CH:15]=[CH:14]/[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:4][CH:3]=[C:2]([CH3:1])[CH3:19])[CH:6]=1)[NH:24][C:25](=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:22])[CH3:21]
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: CC(C)=CCn1cc(/C=C/C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)=CCn1cc(/C=C/C(=O)N(NC(=O)c2ccccc2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To solution containing (E)-3-(1-(3-methylbut-2-enyl)-1H-indol-3-yl)acrylic acid (160 mg, 0.62 mmol, 1.0 equivalent), N′-isopropylbenzohydrazide (167.5 mg, 0.94 mmol, 1.5 equivalent) and HATU (357.4 mg, 0.94 mmol, 1.5 equivalent) dissolved in DMF (5.0 ml), N,N-diisopropylethylamine (DIPEA)(0.16 ml, 0.94 mmol, 1.5 equivalent) was slowly drop-wise added and stirred at room temperature for 24 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=1:1) and dried so that yellow solid form of (E)-N′-isopropyl-N′-(3-(1-(3-methylbut-2-enyl)-1H-indol-3-yl)acryloyl)benzohydrazide was obtained. (99.8 mg, 39%).
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:46][C:47]1[CH:52]=[C:51](B(O)O)[CH:50]=[CH:49][N:48]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:7][CH2:8][C@@H:9]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])[C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:51]4[CH:50]=[CH:49][N:48]=[C:47]([Cl:46])[CH:52]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)(=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4]
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Cc1cc2nc(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc2nc(-c3cccc(-c4ccnc(Cl)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 120 °C

Procedure:
The reaction mixture of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(trifluoromethylsulfonyloxy)phenyl)benzo[d]thiazol-6-yl)ethyl pivalate (30 mg, 0.0438 mmol), 2-chloropyridine-4-boronic acid (10 mg, 0.0657 mmol), 2N K2CO3 (100 μL), Pd(PPh3)4 (5.0 mg, 0.0044 mmol) in dioxane (2 mL) was heated at 120° C. in sealed tube for 2 hs. The reaction was washed by sat. NaHCO3, extracted by EtOAc, dried by MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product (LCMS-ESI+: calc'd for C36H36Cl2N2O3S: 647.2 (M+H+); Found: 647.3 (M+H+).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[S:15][C:14](/[CH:16]=[CH:17]/[CH:18]([OH:20])[CH3:19])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:21][C:22]1([CH3:31])[CH2:27][CH:26]([NH2:28])[CH2:25][C:24]([CH3:30])([CH3:29])[NH:23]1.CCN(C(C)C)C(C)C>CO>[CH3:21][C:22]1([CH3:31])[CH2:27][CH:26]([NH:28][C:5]2[N:10]=[C:9]([C:11]3[S:15][C:14](/[CH:16]=[CH:17]/[CH:18]([OH:20])[CH3:19])=[CH:13][CH:12]=3)[CH:8]=[CH:7][N:6]=2)[CH2:25][C:24]([CH3:30])([CH3:29])[NH:23]1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CC(O)/C=C/c1ccc(-c2ccnc(S(C)(=O)=O)n2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(O)/C=C/c1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1
Temperature: 120 °C

Procedure:
(E)-4-[5-(2-Methanesulfonyl-pyrimidin-4-yl)-thiophen-2-yl]-but-3-en-2-ol (100 mg, 0.32 mmol) was mixed with 2,2,6,6-tetramethyl-piperidin-4-ylamine (0.2 ml, 1.15 mmol) and DIEA (0.2 ml, 1.17 mmol) and heated to 120° C. in a closed flask for 2 hours. The residue was then diluted with MeOH and purified by preparative HPLC to give the title compound. Yield: 25 mg (20%).
Reaction SMILES: Cl[C:2]1[C:3]([O:5][C:6](=[O:8])[CH:7]=1)=[O:4].[Cl:9][C:10]1=[C:11](Cl)[C:12](O[C:15]1=O)=O.C=CC(Cl)=C.Cl>C1C2NC3C(=CC=CC=3)SC=2C=CC=1.ClC1C=CC=CC=1.O>[Cl:9][C:10]1[CH2:15][C:7]2[C:6](=[O:8])[O:5][C:3](=[O:4])[C:2]=2[CH2:12][CH:11]=1
Reactant: O=C1C=C(Cl)C(=O)O1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Agent: C=CC(=C)Cl
Agent: Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Clc1ccccc1
Solvent: O
Product: O=C1OC(=O)C2=C1CC=C(Cl)C2
Temperature: 92 °C
Reaction time: 16 h
Yield: 498.4 %

Procedure:
A 3-necked 50 mL flask was equipped with a pressure equalizing additional funnel, a thermocouple well with a thermocouple, a water cooled condensor and a magnetic stir bar. The flask was charged with 6.62 g (0.05 mol) of monochloromaleic anhydride contaminated with approximately 0.005 mol of dichloromaleic anhydride, 6.1 g of monochlorobenzene and 100 mg of phenothiazine. The contents of the flask were heated to 92° C. and 4.42 g (0.05 mol) of chloroprene was added over 15 to 30 minutes. HCl gas was observed evolving from the reactor. After 16 hours at 92° C., the solvent was removed in-vacuo and triturated with 10 mL of diethyl ether to yield 4.6 g (50% of theoretical) of 4-chloro-3,6-dihydrophthalic anhydride. High resolution mass spectrometry (MS) of the solid resulted in the following analysis: Calculated mass=183.99271; observed mass=183.9924. 13C and 1H nuclear magnetic resonance (NMR) spectra were consistent with the assigned structure.