Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](Cl)=[O:13])[CH:6]=[CH:5]2.[S:15]1[C:19]2=[CH:20][CH:21]=[CH:22][C:23]([NH2:24])=[C:18]2[N:17]=[C:16]1[NH2:25]>>[NH2:25][C:16]1[S:15][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([NH:24][C:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=4)[CH:8]=3)=[O:13])[C:18]=2[N:17]=1
Reactant: O=C(Cl)c1ccc2cc(Br)ccc2c1
Reactant: Nc1nc2c(N)cccc2s1
Product: Nc1nc2c(NC(=O)c3ccc4cc(Br)ccc4c3)cccc2s1

Procedure:
This material was prepared analogous to the procedure described for Example 1(b). 6-Bromo-naphthalene-2-carbonyl chloride, Example 1(a), (127 mg, 0.47 mmol) reacted with benzothiazole-2,4-diamine (77 mg, 0.47 mmol, prepared according to the procedure described in WO03099284) to give the title compound as an amorphous solid. MS (ESI, pos. ion.) m/z: 400 (M+1).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]#[N:6].N=[O:8].[S:9]([NH2:13])(N)(=[O:11])=[O:10]>>[S:9]([NH:6][C:5](=[O:8])[CH2:4][CH2:3][S:2][CH3:1])(=[O:11])(=[O:10])[NH2:13]
Reactant: N=O
Reactant: NS(N)(=O)=O
Reactant: CSCCC#N
Product: CSCCC(=O)NS(N)(=O)=O
Yield: 67.2 %

Procedure:
According to the U.S. Pat. No. 4,496,737 (Merck) 3-(methylthio)-propionitrile was used as a starting material, which was converted into the corresponding imino-ether base with a yield of 67.2%. The oily product obtained was boiled with 1.5 molar equivalents of sulfamide, for 20 hours. After recovering the excess of sulfamide the product was isolated by column chromatography, with a moderate (26.0%) yield. The N-sulfamyl-3-(methylthio)-propionamide obtained was oxidized into the corresponding sulfoxide with m-chloroperbenzoic acid in a mixture of chloroform and methanol (yield: 83.4%). The sulfoxide compound was then subjected to an elimination reaction by boiling with triethyl amine in an ethanolic medium for 20 to 30 hours. As a result, N-sulfamyl-acrylic amidine of the formula (IV) ##STR6## was isolated by column chromatography with a yield of 37.2%.
Reaction SMILES: [ClH:1].[C:2]([O:5][C@:6]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[O:19][CH2:20]2)[C@H:15]2[O:29][C@@H:14]32)[CH2:11][CH2:10]1)[C:7](=[O:9])[CH3:8])(=[O:4])[CH3:3].O>O1CCCC1>[C:2]([O:5][C@:6]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[O:19][CH2:20]2)[C@H:15]([Cl:1])[C@H:14]3[OH:29])[CH2:11][CH2:10]1)[C:7](=[O:9])[CH3:8])(=[O:4])[CH3:3]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@@H]4O[C@@H]4C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@H](O)[C@@H](Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Concentrated hydrochloric acid (0.1 ml) was adde*d to a solution of 97 mg of 17α-acetoxy-6α,7α-epoxy-2-oxa-4-pregnene-3,20-dione in 4 ml of tetrahydrofuran, and the solution was stirred at room temperature for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 102 mg of 17α-acetoxy-6β-chloro-7α-hydroxy-2-oxa-4-pregnene-3,20-dione.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)c(Cl)c1Cl

Procedure:
A mixture of 2,3-dichloro-4-hydroxybenzaldehyde (19.1 gm., ;b 0.1 mole) and potassium carbonate (34.4 gm., 0.25 mole) in dimethylformamide (50 ml.) is stirred and treated dropwise over 15 minutes with dimethyl sulfate (14.1 gm., 0.11 mole). The reaction is exothermic; after 45 minutes the mixture is poured with stirring into water (300 ml.). The solid product that separates is removed by filtration, washed with water and then washed with a little methanol. After drying the yield of 2,3-dichloro-4-methoxybenzaldehyde is 16 gm., m.p., 117°-118° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[C:3]1=[O:10].[C:11]([O-])(C)(C)C.[K+].CI>C(O)(C)(C)C>[CH3:1][C:2]1([CH3:11])[CH2:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[C:3]1=[O:10]
Reactant: CC(C)(C)[O-]
Reactant: CC1Cc2sccc2C1=O
Agent: [K+]
Solvent: CI
Solvent: CC(C)(C)O
Product: CC1(C)Cc2sccc2C1=O
Reaction time: 1.5 h
Yield: 83.2 %

Procedure:
A solution of 28.6 g of 5,6-dihydro-5-methyl-4H-cyclopenta[b]thiophen-4-one in 210 ml of tert.-butanol is added dropwise at from +25° to +30° C. to a solution of 23.1 g of potassium tert.-butanolate in 250 ml of tert.-butanol. The dark reddish-brown solution is stirred for 1.5 hours, and then 12.9 ml of methyl iodide are added. After stirring for 1 hour, the reddish-brown suspension is filtered and the filtrate is concentrated by evaporation. After distillation of the residue there are obtained 26.0 g of 5,6-dihydro-5,5-dimethyl-4H-cyclopenta[b]thiophen-4-one in the form of a colourless oil having a boiling point of 43° C. at 0.03 mbar.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH3:16])[N+:12]([O-])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C(OC(=O)C)(=[O:23])C.CO>C(O)(=O)C>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:16][OH:23])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: Cc1cc(OCc2ccc(C(F)(F)F)cc2)cc[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: OCc1cc(OCc2ccc(C(F)(F)F)cc2)ccn1
Temperature: 80 °C

Procedure:
3.4 g (12 mmol) of the title compound from Example 2 are warmed to 80° C. in 5 ml of glacial acetic acid and 10 ml of acetic anhydride are added dropwise at this temperature with stirring. The mixture is then warmed to 110°-120° C. for 2 hours, allowed to cool to 80° C., 10 ml of methanol are added, the mixture is heated to reflux for a further 15 minutes and subsequently concentrated. The residue is taken up in 10 ml of methanol and rapidly added dropwise at 10° C. to 50 ml of 2N methanolic NaOH. The solution is then clarified over charcoal, concentrated, the residue treated with 50 ml, extracted three times using 50 ml of dichloromethane, and the organic phase dried and concentrated. The crystallized residue is triturated with a petroleum ether/diisopropyl ether mixture (1:1), and the product is filtered off with suction, washed with a little diisopropyl ether and dried in vacuo, m.p. 96°-98° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C@H:12]1([CH2:20][OH:21])[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]1.CCN(CC)CC>C(Cl)Cl>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:19][CH2:18][C@H:15]2[CH2:16][CH2:17][C@H:12]([CH2:20][OH:21])[CH2:13][CH2:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OC[C@H]1CC[C@H](CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](CO)CC2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
4-Toluenesulfonyl chloride (742.5 g, 3.75 mol) was added to a solution of trans-cyclohexane-1,4-diyldimethanol (500 g, 4.17 mol) and Et3N (695 g, 5 mol) in DCM (6000 mL) at −20° C. The mixture was stirred at room temperature for 10 h and then quenched with water (10 L). The organic layer was separated, the aqueous layer was extracted with DCM (2×3 L), and the combined organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give trans-4-(hydroxymethyl)cyclohexylmethyl 4-methylbenzenesulfonate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:14])[C:10]([NH:12][CH3:13])=[S:11])=[CH:4][CH:3]=1.[CH3:15]N(C)NCC1C=NC=CC=1.ClC1C(CN)=CC=C(Cl)N=1>>[CH3:15][S:11][C:10](=[N:12][CH3:13])[N:9]([CH2:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:14]
Reactant: CNC(=S)N(C)Cc1ccc(Cl)nc1
Reactant: CN(C)NCc1cccnc1
Agent: NCc1ccc(Cl)nc1Cl
Product: CN=C(SC)N(C)Cc1ccc(Cl)nc1

Procedure:
Using the N-(6-chloro-3-pyridylmethyl)-N-methyl-N′-methylthiourea otained in (1), the procedure of Example 8 (2) was repeated to give S-methyl-N-(6-chloro-3-pyridylmethyl)-N-methyl-N′-methylisothiourea as oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:34][C:35]1[CH:50]=[CH:49][C:38]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])=[CH:37][CH:36]=1.[CH3:51][C:52]1([CH3:59])[O:56][C@H:55]([CH2:57]O)[CH2:54][O:53]1>C1COCC1.CCOCC.CCCCCCC>[CH3:51][C:52]1([CH3:59])[O:56][C@H:55]([CH2:57][O:34][C:35]2[CH:50]=[CH:49][C:38]([C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])=[CH:37][CH:36]=2)[CH2:54][O:53]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCCC
Product: CC1(C)OC[C@@H](COc2ccc(C(=O)OCc3ccccc3)cc2)O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
In a 250 mL round-bottomed flask was added triphenylphosphine (6.54 g, 24.92 mmol) in THF (79 ml) to give a colorless clear solution. The solution was cooled to 0° C. by ice-bath. After stirring for 15 min, diisopropyl azodicarboxylate (5.11 ml, 24.96 mmol) (orange liquid) was added dropwise over 5 min. The reaction mixture turned into off-white suspension in the process. The reaction mixture was stirred at 0° C. for 30 min. Then a colorless solution of benzyl 4-hydroxybenzoate (5.69 g, 24.92 mmol) and (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (3.00 ml, 23.73 mmol) in THF (39.5 ml) was added to the mixture, keeping the temperature at or below 0° C. The solution turned clear light yellow. The solution was stirred for 2 hr at 0° C. then slowly warmed to ambient temperature and stirred over the weekend. The mixture was concentrated in vacuo to give crude yellow oil (˜27 g). The crude oil was dissolved in ether. Then heptane was added. The resultant precipitate was sonicated and filtered. The filtrate was concentrated and purified via Analogix system using RediSep RS 120 g column, with a gradient of 0-20% EtOAc/Heptane over 10 min at 50 mL/min then hold at 20% ethyl acetate for 20 min. Fractions containing product were combined and concentrated to afford (R)-benzyl 4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoate as white solid (6.17 g, 23.73 mmol). LCMS (Table 1, Method c) Rt=2.89 min, m/z 343.20 (M+H)+
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[CH:4]=[N:5][CH:6]=[C:7]([N:16]2C(C)=CC=C2C)[C:8]=1[N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1.NO.C(N(CC)CC)C.C(O)C>O>[F:23][CH:2]([F:1])[C:3]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:7]([NH2:16])[CH:6]=[N:5][CH:4]=1
Reactant: Cc1ccc(C)n1-c1cncc(C(F)F)c1N1CCN(C)CC1
Agent: NO
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCN(c2c(N)cncc2C(F)F)CC1
Temperature: 25 °C

Procedure:
A solution of 1-[3-(difluoromethyl)-5-(2,5-dimethylpyrrol-1-yl)-4-pyridyl]-4-methyl-piperazine (80 mg, 0.2497 mmol) and NH2OH (165.0 mg, 4.994 mmol) in a mixture of triethylamine (101.1 mg, 139.3 μL, 0.9988 mmol), ethanol (1 mL) and H2O (0.25 mL) was heated at reflux for 20 h. After cooling to RT the reaction was quenched by loading directly onto an SCX-2 cartridge and eluted with MeOH followed by NH3/MeOH. The basic fraction was concentrated in vacuo yielding 5-(difluoromethyl)-4-(4-methylpiperazin-1-yl)pyridin-3-amine that was used in next step without further purification. MS (ES+) 243.1.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:23][CH2:24][C@@H:25]2[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]2)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:22])([F:21])[F:20])=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[N+:1]([C:4]1[C:5]([NH:23][CH2:24][C@@H:25]2[CH2:30][CH2:29][C@H:28]([O:31][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:27][CH2:26]2)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:22])([F:21])[F:20])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@@H](O)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)O[C@H]1CC[C@@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
cis-4-{[5-Nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexanol (3.6 g, 8.16 mmol) was dissolved in dry DCM (150 mL) and cooled to 5° C. Methanesulfonyl chloride (0.94 ml, 12.2 mmol) and diisopropylethylamine (4.26 ml, 24.4 mmol) were added sequentially. After 2 h, the reaction was quenched with cold water (10 mL) and warmed to room temperature. The solution was partitioned between DCM (100 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield a yellow solid. The residue was then chromatographed (silica, 100:1 DCM/MeOH) and washed with cold methanol to yield a pale yellow solid as methanesulfonic acid cis-4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl ester (3.90 g, 7.50 mmol, 92%).
Reaction SMILES: S(Cl)(Cl)=O.[CH:5](N(C(C)C)CC)(C)C.[CH3:14][O:15][C:16](=[O:31])[C@H:17]([CH2:29][OH:30])[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(O)C>[CH2:14]([O:15][C:16](=[O:31])[C@H:17]([CH2:29][OH:30])[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH3:5]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reaction time: 16 h

Procedure:
Thionyl chloride (5.25 mL, 72 mmol, 3.6 equiv.) is added dropwise to a 0° C. solution of absolute ethyl alcohol (20 ml). Diisopropyl ethylamine (3.45 ml, 19. mmol, 1 equiv.) was added and then 4.8 g of N-CBZ-L-serine methyl ester was added as a solid. Stirring is continued for 16 hours at room temperature. The ethanol and thionyl chloride are then removed by rotary evaporation and the residue is dissolved in ethyl acetate (200 mil). The organic phase is washed with 1N hydrochloric acid (50 ml) and saturated sodium bicarbonate (50 ml) and brine (20 ml). The organic layer is dried with magnesium sulfate. Rotary evaporation of the product gives an oil which is chromatographed on silica gel with hexane/ethyl acetate (3:1) to give N-CBZ-L-serine ethyl ester.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8](O)([CH3:10])[CH3:9])[CH2:4][CH2:3]1.[BrH:12]>[Br-].[Zn+2].[Br-]>[Br:12][C:8]([CH:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)([CH3:10])[CH3:9]
Reactant: CC1CCC(C(C)(C)O)CC1
Reactant: Br
Agent: [Br-]
Agent: [Zn+2]
Product: CC1CCC(C(C)(C)Br)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
2-(4-Methylcyclohexyl)propan-2-ol (0.99 g, 6.39 mmol) was added to a mixture of anhydrous zinc bromide (0.72 g, 3.2 mmol) and 48% HBr (aq). The mixture was stirred at room temperature for 2 h. The mixture was then extracted with diethyl ether (2×20 ml) and the combined extracts were washed with water, dried (MgSO4 /K2CO3) and evaporated under reduced pressure to give the crude title compound as an oil (1.12 g, 80%), νmax (film) 2940, 2915, 2860, 1450, and 1370 cm-1 ; δH (60 MHz, CDCl3) 0.8-2.2 (m), 7.2 (s). Distillation from K2CO3 under reduced pressure removed the impurity resonating at δ7.2.
Reaction SMILES: [CH3:1][C:2]1C=CC(S(OCCC#C)(=O)=O)=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(C(C)C)CC)(C)C>ClCCCl>[CH2:4]([N:25]1[CH2:24][CH2:23][N:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)[CH2:27][CH2:26]1)[CH2:3][C:2]#[CH:1]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCCN1CCN(c2ccccn2)CC1
Yield: 48.4 %

Procedure:
A solution of but-3-ynyl 4-methylbenzenesulfonate (1.27 g), 1-(pyridin-2-yl)piperazine (1.17 g) and diisoproylethylamine (1.37 mL) in 1,2-dichloroethane (7 mL) was heated to reflux overnight. The mixture was concentrated, diluted with sat. aq. NaHCO3 (5 mL) and extracted with DCM (2×50 mL). Drying (Na2SO4) and silica gel flash chromatography (EtOAc/hexane 1:1→1:0) afforded 1-(but-3-ynyl)-4-(pyridin-2-yl)piperazine (0.59 g)
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26]([O:33][C:34](=[O:39])[NH:35][CH2:36][CH2:37]Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(C)C=CC=CC=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:37][CH2:36][NH:35][C:34]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:39])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(NCCBr)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCc1ccc(OCCNC(=O)OCc2ccccc2)cc1
Temperature: 63 °C
Reaction time: 5.5 h
Yield: 97.7 %

Procedure:
[4-(4-Hydroxyphenyl)butyl]carbamic acid tert-butyl ester (38 g, 0.143 mole), cesium carbonate (84 g, 0.257 mole), and (2-bromoethyl)carbamic acid benzyl ester 14 (59 g, 0.23 mole) were combined in DMF (200 ml). The mixture was mechanically stirred under nitrogen at 63° C. for 5.5 h, and allowed to stand at room temperature overnight. An additional amount of (2-bromoethyl)carbamic acid benzyl ester 14 (5 g, 0.019 mole) and cesium carbonate (7.1 g, 0.21 mole) were added, and the reaction was further stirred at 65° C. for 1 h. Toluene was then added, and the stirring mixture was allowed to cool to room temperature. The mixture was suction filtered through a medium sintered glass buchner funnel and washed with toluene. The solvents were removed under vacuum at 75° C. The remaining oil was washed with hexanes (2×400 mL), then dissolved in ether (500 ml) and washed with a mixture of water and brine (10:1, 4×100 mL). The remaining solution was suction filtered through a 30 g pad of silica gel and the solvent evaporated. The residue was washed with hexanes (3×400 ml), and then placed under vacuum for 2 h to afford 61.8 g of the product 15 which was used without further purification. 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.54 (m, 4H), 2.56 (t, 2H), 3.20 (m, 2H), 3.50 (m, 2H), 3.98 (t, 2H), 4.75 (br s, 1H), 5.00 (br s, 1H), 5.09 (s, 2H), 6.80 (d, 2H), 7.06 (d, 2H), 7.34 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH3:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:34]2[CH2:35][CH2:36][CH:31]([CH3:30])[CH2:32][CH2:33]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: CC1CCN(Cc2ccc3c(c2)cc(-c2ccc(Cl)c4c2C(=O)NC4)n3C(=O)OC(C)(C)C)CC1
Yield: 50.7 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (41.0 mg, 0.0998 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 4-methylpiperidine (0.048 mL, 0.41 mmol), acetic acid (0.345 mL, 6.03 mmol) and sodium triacetoxyborohydride (169 mg, 0.797 mmol). The reaction mixture was added with water and sodium hydrogen carbonate to adjust the pH of to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(4-methylpiperidinomethyl)indol-2-yl]isoindolinone (25.0 mg, yield 51%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4](P(=O)(OC)OC)[O:3]1.[N:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=O)[C:21]=12.CCN(CC)CC>C1COCC1>[N:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=[C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2](=[O:1])[O:3]3)[C:21]=12
Reactant: O=Cc1cccn2ccnc12
Reactant: COP(=O)(OC)C1OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OC(=Cc2cccn3ccnc23)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.5 %

Procedure:
To a solution of dimethyl 3-oxo-1,3-dihydroisobenzofuran-1-ylphosphonate (610 mg, 2.4 mmol), imidazo[1,2-a]pyridine-8-carbaldehyde (350 mg, 2.4 mmol, 1 equiv.) in THF (5 mL) was added Et3N (0.33 mL 2.4 mmol). The mixture was stirred at rt for 48 h. The precipitation was filtered off and washed with EtOAc. The filtrate was concentrated to give 3-(imidazo[1,2-a]pyridin-8-ylmethylene)isobenzofuran-1(3H)-one (400 mg, 64%) as a yellow solid. Small crude sample (˜20 mg) was purified on RP-HPLC with CH3CN and water as eluent to separated the E/Z isomers (10 mg, 7 mg). 1H NMR (400 MHz, CD3OD) Z-form: δ=8.52 (d, 1H), 7.95-7.91 (m, 2H), 7.62-7.54 (m, 4H), 7.52-7.48 (m, 1H), 7.09 (s, 1H), 7.04 (t, 1H) E-form: δ=8.38 (d, 1H), 8.15 (d, H), 8.05 (d, 1H), 7.95 (d, 1H), 7.90-7.84 (m, 2H), 7.67 (t, 1H), 7.64 (s, 1H), 7.33 (s, 1H), δ 7.05 (t, 1H). LRMS (M+H+) m/z 263.1
Reaction SMILES: CN(C)[CH:3]=[O:4].[Na].[C:7]([O:10][CH2:11][C:12]1[CH2:19][S:18][CH:17]2[N:14]([C:15](=[O:21])[CH:16]2[NH2:20])[C:13]=1[C:22]([OH:24])=[O:23])(=[O:9])[CH3:8].ClC[CH2:27][C:28]([CH3:33])([CH3:32])[C:29]([O-])=[O:30]>C(OCC)(=O)C>[C:29]([O:4][CH2:3][O:23][C:22]([C:13]1[N:14]2[CH:17]([S:18][CH2:19][C:12]=1[CH2:11][O:10][C:7](=[O:9])[CH3:8])[CH:16]([NH2:20])[C:15]2=[O:21])=[O:24])(=[O:30])[C:28]([CH3:33])([CH3:32])[CH3:27]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: CC(C)(CCCl)C(=O)[O-]
Reactant: CN(C)C=O
Agent: [Na]
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(N)C2SC1
Reaction time: 3 h

Procedure:
To 35 ml of dimethyl formamide is added 7.5 g of the sodium salt of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, and the solution is stirred at room temperature for about 30 minutes after which 8 ml of chloromethylpivalate is added. Stirring is continued at room temperature for about 3 hours. The mixture is diluted with ethyl acetate and washed with water. The organic layer is separated and evaporated to dryness. The residue is recrystallized from ethyl acetate to give 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid pivalyloxymethyl ester.