Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[N:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]1)#[CH:20].F[B-](F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.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.[Cu]I>[CH3:18][N:16]1[CH:17]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:20]#[C:19][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)[CH:14]=[N:15]1
Reactant: Cn1cc(Nc2ncc(C(F)(F)F)c(Cl)n2)cn1
Reactant: C#Cc1ccccc1C1(C(N)=O)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3C3(C(N)=O)CC3)n2)cn1
Temperature: 100 °C

Procedure:
To a degassed mixture of 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine A74 (0.178 g, 0.640 mmol), 1-(2-ethynylphenyl)cyclopropanecarboxamide K6 (0.172 g, 0.928 mmol), PdCl2(PPh3)2 (0.005 g, 0.007 mmol), t-Bu3PH.BF4 (0.005 g, 0.02 mmol) and copper(I) iodide (0.003 g, 0.02 mmol) in DMF (8.0 mL) was added DIPEA (0.33 mL, 1.9 mmol). The mixture was heated in the microwave for 2×20 minutes at 100° C. before being concentrated under reduced pressure. Purification by silica gel column chromatography (Isolera, 0-100% EtOAc petroleum benzine 40-60° C. then 0-20% MeOH in EtOAc) gave the title compound A75 (0.120 g, 44%). LCMS-D: rt 3.30 min; m/z 427.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]([CH:13]=[CH2:14])[OH:12]>C(Cl)Cl.O=[Mn]=O>[CH:13]([C:11]([C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:12])=[CH2:14]
Reactant: C=CC(O)c1cc(OC)ccc1OC
Agent: O=[Mn]=O
Solvent: ClCCl
Product: C=CC(=O)c1cc(OC)ccc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Activated MnO2 (100 g) was added in portions to a mechanically stirred solution of 2,5-dimethoxyphenyl vinyl carbinol (12.5 g, 0.064 mole) in 250 ml of methylene chloride. The mixture was stirred at room temperature for 24 hours and then filtered through a patch of Celite. The filtrate was concentrated to give a brown oil which was purified by column chromatography on silica gel, using diethyl ether/hexane (1/1) as eluant. The compound was obtained as a light brown oil; 7.2 g; IR (neat) 1680 cm-1 ; NMR (CDCl3) δ6.85-7.1 (m, 4H); 6.3 (d, 1H); 5.8 (d, 1H); 3.8 and 3.85 (two singlets, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[Cl:17])=[O:11])=O)=[CH:4][N:3]=1.Cl.ClC1C=CSC=1C(=O)CN.ClC1C=CC(C(Cl)=O)=CN=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[O:11][C:10]([C:12]3[S:13][CH:14]=[CH:15][C:16]=3[Cl:17])=[CH:9][N:8]=2)=[CH:18][CH:19]=1
Reactant: O=C(NCC(=O)c1sccc1Cl)c1ccc(Cl)nc1
Agent: Cl
Agent: NCC(=O)c1sccc1Cl
Agent: O=C(Cl)c1ccc(Cl)nc1
Product: Clc1ccc(-c2ncc(-c3sccc3Cl)o2)cn1

Procedure:
6-Chloro-N-[2-(3-chloro-thiphen-2-yl)-2-oxo-ethyl]-nicotinamide: The title compound was prepared from 2-(3-chloro-thiophen-2-yl)-2-oxo-1-ethylamine hydrochloride and 6-chloronicotinoyl chloride by a procedure similar to Example 98a as a white solid (0.044 g, 30%). 1H NMR (CD3OD): 8.74 (d, J=8.74 Hz, 1H), 8.13 (d, J=6.3 Hz, 1H), 7.79 (d, J=5.4 Hz, 1H), 7.48 (d, J=9.0 Hz, 1H), 7.07 (d, J=5.4 Hz, 1H), 4.75 (s, 2H).
Reaction SMILES: C[Al](C)C.[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.C([O:16][C:17]([C:19]1[C:20]([S:35][CH2:36][CH3:37])=[N:21][C:22]2[C:27]([C:28]=1[CH3:29])=[CH:26][CH:25]=[C:24]([O:30][C:31]([F:34])([F:33])[F:32])[CH:23]=2)=O)C.CCCCCC.C(Cl)Cl>C1(C)C=CC=CC=1.Cl>[CH2:36]([S:35][C:20]1[C:19]([C:17]([NH:11][CH2:10][C:9]2[CH:12]=[CH:13][C:6]([F:5])=[CH:7][CH:8]=2)=[O:16])=[C:28]([CH3:29])[C:27]2[C:22](=[CH:23][C:24]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:25][CH:26]=2)[N:21]=1)[CH3:37]
Reactant: CCOC(=O)c1c(SCC)nc2cc(OC(F)(F)F)ccc2c1C
Reactant: NCc1ccc(F)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCSc1nc2cc(OC(F)(F)F)ccc2c(C)c1C(=O)NCc1ccc(F)cc1
Temperature: 90 °C
Yield: 60.7 %

Procedure:
1.12 ml (2.24 mmol, 2M in toluene)trimethyl aluminium and 260 μl (2.24 mmol) 4-fluorobenzylamine were added in succession to a solution of 200 mg (0.56 mmol) 2-ethylsulfanyl-4-methyl-7-(trifluoromethyloxy)-quinoline-3-carboxylic acid ethyl ester (VVV25) in toluene (7 ml) and the mixture was then heated for 3 h at 90° C. Then it was diluted with 0.5M hydrochloric acid and extracted with EE. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/DCM 3:2) of the residue yielded 150 mg (0.34 mmol, 61%) 2-ethylsulfanyl-N-[(4-fluorophenyl)-methyl]-4-methyl-7-(trifluoromethyloxy)-quinoline-3-carboxamide. MS: m/z 439.1 [M+H]+.
Reaction SMILES: N1C=CC=N1.[CH3:6][O:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([CH2:14][C:15]#[N:16])=O)=[CH:10][CH:9]=1.Cl.[C:20]([NH:24][NH2:25])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([N:24]1[C:15]([NH2:16])=[CH:14][C:12]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:18][CH:17]=2)=[N:25]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1ccc(C(=O)CC#N)cc1
Reactant: CC(C)(C)NN
Agent: Cl
Agent: c1cn[nH]c1
Product: COc1ccc(-c2cc(N)n(C(C)(C)C)n2)cc1

Procedure:
General procedure for pyrazole formation: An ethanolic solution (3 mL) of 4-methoxybenzoylacetonitrile (500 mg, 2.85 mmol), t-butylhydrazine hydrochloride (391 mg, 3.14 mmol), and catalyticp-toluenesulfonic acid was stirred under argon at 90° C. for 4 h in a sealed tube. The reaction was concentrated and the residue partitioned between EtOAc and sat. NaHCO3. The organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel with a gradient of 10-30% EtOAc in Hexanes which yielded 2-tert-Butyl-5-(4-methoxyphenyl)-2H-pyrazol-3-ylamine: 1H NMR (400 MHz, CDCl3) δ 1.70 (s, 9H), 3.58 (br.s, 2H), 3.84 (s, 3H), 5.85 (s, 1H), 6.91 (d, J=8.8 Hz, 2H), 7.69 (d, J=8.8 Hz, 2H); MS (ES+): m/z 246 [MH+], m/z 190 [M-tbutyl].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[N:13]=[C:14]2[C:19](=[O:20])[NH:18][NH:17][CH:16]=[C:15]2[N:21]=1.[OH:22]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:11])(=[O:22])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[N:13]=[C:14]2[C:19](=[O:20])[NH:18][NH:17][CH:16]=[C:15]2[N:21]=1
Reactant: COc1cc(S(C)=O)ccc1-c1nc2c[nH][nH]c(=O)c-2n1
Reactant: OO
Solvent: CC(=O)O
Product: COc1cc(S(C)(=O)=O)ccc1-c1nc2c[nH][nH]c(=O)c-2n1
Temperature: 25 °C
Reaction time: 0.92 h

Procedure:
A quantity of 0.07 gm of 2-(2-methoxy-4-methylsulfinyl-phenyl)-5H-imidazo[4,5-d]pyridazin-4-one is dissolved in 5 ml of glacial acetic acid, mixed with 0.05 ml of 30% hydrogen peroxide, and stirred first for 55 minutes at ambient temperature then for two hours at 40°-50° C., Then, a further 0.05 ml of hydrogen peroxide are added, and the mixture is heated for another hour. The product precipitated is subjected to suction filtration and washed with ether.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16](O)=[O:17])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:44]1[CH2:49][CH2:48][CH:47]([CH2:50][OH:51])[CH2:46][CH2:45]1>CN(C=O)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:44]2[CH2:49][CH2:48][CH:47]([CH2:50][OH:51])[CH2:46][CH2:45]2)=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2ccccc2n1Cc1ccc(F)cc1
Reactant: OCC1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc2ccccc2n1Cc1ccc(F)cc1)N1CCC(CO)CC1
Reaction time: 22 h

Procedure:
The following was added sequentially to DMF (10 mL): 1-(4-fluorobenzyl)-1H-indole-2-carboxylic acid (1.175 g, 4.36 mmol), DIPEA (2.29 mL, 13.09 mmol), EDC (1.00 g, 5.24 mmol), and HOBT (802 mg, 5.24 mmol). This solution was allowed to stir at rt for 1.5 h, at which time 4-piperidinemethanol (754 mg, 6.55 mmol) was added. Stirring continued for 22 h at rt, at which time the solution was partitioned between water and 1:1 solution of ethyl acetate:diethyl ether. The organic extract was then washed with saturated aq. sodium carbonate, dried with magnesium sulfate, and concentrated in vacuo. Purification was accomplished via silica gel flash chromatography (100 g silica, 80% EtOAc/Hexanes.) Resulting residue was crystallized via diethyl ether/hexane trituration to give the title compound as a white solid. (Yield: 1.507 g, 4.11 mmol, 94%) 1H NMR (400 MHz, CDCl3) 7.63, 7.37, 7.28-7.22, 7.14, 7.08, 6.91, 6.60, 5.46, 4.65, 4.13, 3.42, 2.76, 1.76-1.54, 1.05, 0.71
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.O.NN.O>C(O)CO>[F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2-c2ccc(F)cc21
Agent: NN
Solvent: OCCO
Solvent: O
Product: Fc1ccc2c(c1)Cc1ccccc1-2
Temperature: 180 °C

Procedure:
2-Fluoro-9-fluorenone, 20 (1.78 gms, 8.9 mmol) was dissolved in ethylene glycol(60 mL) under a nitrogen atmosphere. Hydrazine hydrate(1.8 mL) was added and the mixture was heated at 180° C. for two hours. The mixture was then cooled and poured into water. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to yield the title compound.
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].[NH2:30][C:31]1[CH:39]=[CH:38][C:34]([CH2:35][CH2:36][OH:37])=[CH:33][CH:32]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[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]([CH2:20][NH:30][C:31]2[CH:39]=[CH:38][C:34]([CH2:35][CH2:36][OH:37])=[CH:33][CH:32]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: Nc1ccc(CCO)cc1
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: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNc3ccc(CCO)cc3)ccc21
Yield: 99.9 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (30.0 mg, 0.0730 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 4-aminophenethyl alcohol (40 mg, 0.29 mmol), acetic acid (0.084 mL, 1.5 mmol) and sodium triacetoxyborohydride (46 mg, 0.22 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain Compound 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)phenylaminomethyl]indol-2-yl}isoindolinone (38.8 mg, yield 100%).
Reaction SMILES: [H-].[Na+].[CH3:3]N(C=O)C.[CH:8]([N:11]1[C:15]([C:16]2[N:17]=[C:18]3[C:24]4[CH:25]=[CH:26][C:27]([C:29]5[NH:33][C:32]([CH3:34])=[N:31][CH:30]=5)=[CH:28][C:23]=4[O:22][CH2:21][CH2:20][N:19]3[CH:35]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].IC>C1COCC1.O>[CH3:3][N:31]1[CH:30]=[C:29]([C:27]2[CH:26]=[CH:25][C:24]3[C:18]4[N:19]([CH:35]=[C:16]([C:15]5[N:11]([CH:8]([CH3:10])[CH3:9])[N:12]=[CH:13][N:14]=5)[N:17]=4)[CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)[N:33]=[C:32]1[CH3:34]
Reactant: CN(C)C=O
Reactant: Cc1ncc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: Cc1nc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a 100 mL round bottom flask charged with NaH (12 mg, 0.5 mmol) was added DMF (6 mL) dropwise, followed by 271 (100 mg, 0.25 mmol). After stirring for about 1 hour, iodomethane (48 mg, 0.33 mmol) was added dropwise at 0° C. in THF. Then the mixture was allowed to warm up to room temperature slowly and stirred for 2 hours. The reaction mixture was poured into water, extracted with EtOAc, the organic phase was dried over anhydrous Na2SO4, concentrated, then purified by pre-TLC (EtOAc) to give 50 mg (52% Yield) of 282. 1H NMR (CDCl3, 400 MHz): δ8.48 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.64 (s, 1H), 7.48-7.44 (m, 2H), 7.14 (s, 1H), 6.04-5.98 (m, 1H), 4.51-4.43 (m, 4H), 3.62 (s, 3H), 2.45 (s, 3H),1.60 (d, J=6.8 Hz, 6H), and 15 mg (16% yield) of the regioisomer 9-(1,2-dimethyl-1H-imidazol-5-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 291 1H NMR (CDCl3, 400 MHz): δ8.57 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.87 (s, 1H), 7.69 (s, 1H), 7.16 (d, J=6.8 Hz, 1H), 7.06-7.04 (m, 2H), 6.02-5.96 (m, 1H), 4.54-4.52 (m, 2H), 4.48-4.47 (m, 2H), 3.59 (s, 3H), 2.46 (s, 3H), 1.60 (d, J=6.8 Hz, 6H). LC-MS: m/z=389 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][S:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(F)ccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1cc(F)ccc1F)c1ccccc1
Temperature: 40 °C

Procedure:
0.194 mole (25 g) of 2,5-difluoroaniline is added to 125 ml of pyridine. 0.2 mole (25.5 ml) of benzenesulphonyl chloride is added, while the temperature is between 35° C. and 45° C. The temperature is maintained at 40° C. for 1 hour after the addition is completed, and then the reaction mixture is poured onto 1 kg of ice and water to which 100 ml of concentrated hydrochloric acid have been added. The expected product precipitates. After filtration and washing, it is treated with a normal sodium hydroxide solution in order to remove insoluble material. The soda-containing filtrate is neutralized with concentrated hydrochloric acid. The expected product, which has precipitated, is filtered off, washed to neutrality and recrystallized from acetic acid. It melts at 115° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[O:26]1CC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br-].C([N+](CCC)(CCC)CCC)CC.C1(C)C=CC=CC=1>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][OH:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C1CO1
Reactant: c1ccc(OCC2CO2)cc1
Agent: CCC[N+](CCC)(CCC)CCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: OCC(O)COc1ccccc1
Reaction time: 6 h

Procedure:
A solution of 150.2 g. phenyl glycidyl ether (1.0 eq.), 200.0 g. AOnPA (1.15 eq., of Example 1), 200.0 g. toluene, 4.0 g. tetrapropylammonium bromide (0.015 eq.), and 1.0 g. phenothiazine was heated at reflux for 6.0 hours. Conversion, measured by residual oxirane titer, was ca. 93%. Upon cooling, the reactor was charged with 186.0 g. of AOnPA (1.07 eq.), 150.0 g. toluene, and 10.0 g. p-toluenesulfonic acid monohydrate (0.05 eq.). The mixture was again heated at reflux. After 6.0 hrs., conversion was 90%. The product was extracted with ether and purified by washing. It had an acrylate titer of 3.8 meq./g. (theory: 4.17 meq./g.) and Brookfield viscosity of 230 centipoise at 25° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(N)(C)C>C1COCC1.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.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(Cl)cc3)c2c1O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)N
Product: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2snc(-c3ccc(Cl)cc3)c2c1O
Temperature: 25 °C
Yield: 37.7 %

Procedure:
To a solution of 7-Bromo-3-(4-chloro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (152.5 mg, 0.369 mmol) in THF (5.2 mL) were added Trimethylsilylacetylene (0.105 mL, 0.738 mmol), PdCl2(PPh3)2 (51.8 mg, 0.0738 mmol), CuI (28.1 mg, 0.147 mmol) and isopropylamine (0.32 mL, 2.28 mmol). The reaction mixture was refluxed for 16 h. After cooling to rt, the mixture was diluted with EtOAc (20 mL), and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography on silica gel. Elution with 0-20% EtOAc/CH2Cl2, gave the desired product (60 mg) as white solid: MS (m/z) 431.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1.FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1ccc(O)cc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Cn1nccc1-c1ccc(OCC(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
A mixture of 4-(1-methyl-1H-pyrazol-5-yl)phenol (500 mg), 2,2,2-trifluoroethyl trifluoromethanesulfonate (999 mg), potassium carbonate (793 g) and acetonitrile (5.0 mL) was stirred at 90° C. for 2 hours. Thereafter, the reaction solution was diluted with chloroform, and insoluble matters were then removed by filtration. The filtrate was concentrated under a reduced pressure, and the residue was then purified by column chromatography (silica gel 60N, chloroform:methanol=100:0 to 98:2), so as to obtain the title compound (485 mg) in the form of a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[N+:3]=1[O-].[NH4+].[Cl-]>CCO.O.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)[n+]1[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cc(N)cc(Cl)n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A solution of 2-chloro-6-methyl-4-nitropyridine 1-oxide (52 g, 0.27 mol) in EtOH and H2O was treated with powdered iron (46 g, 0.83 mol) and NH4Cl (44 g, 0.83 mol). The mixture was stirred at 90° C. for 3 h. After cooling to room temperature the reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (500 mL), dried over magnesium sulfate, filtered and concentrated to afford 2-chloro-6-methylpyridin-4-amine. 1H NMR (400 MHz, CDCl3) δ 6.36 (d, J=1.5 Hz, 1H), 6.28 (d, J=1.2 Hz, 1H), 4.30 (m, 2H), 2.34 (s, 3H). LRMS calc'd for (C6H7ClN2) [M+H]+, 143; found 143.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[C:4]([C:13]#[C:14][CH:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]2)[C:3]=1[OH:24].CN(CCN(C)C)C.C([Zn]CC)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[C:4]2[CH:13]=[C:14]([CH:15]3[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]3)[O:24][C:3]=12
Reactant: CCCC1CCC(C#Cc2c(O)c(F)c(F)c3c2CCCO3)CC1
Agent: CC[Zn]CC
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCCC1CCC(c2cc3c4c(c(F)c(F)c3o2)OCCC4)CC1

Procedure:
5.80 g (17.3 mmol) of 7,8-difluoro-5-(4-propylcyclohexylethynyl)chroman-6-ol are initially introduced together with 0.26 ml (1.73 mmol) of TMEDA, and 9.6 ml (9.6 mmol) of diethylzinc (1 M soln. in heptane) are added to the mixture at 3° C. When the evolution of gas has subsided, 25 ml of toluene are added, and the batch is refluxed for 40 h. The solution is added to sat. ammonium chloride soln., and the mixture is extracted with toluene. The combined organic phases are washed with water and sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, 1-chlorobutane:pentane=2:1). Further purification is carried out by repeated recrystallisation from ethanol at reduced temperature, giving 4,5-difluoro-2-(4-propylcyclohexyl)-8,9-dihydro-7H-furo[3,2-f]chromene as a colourless solid having a melting point of 89° C. (Δ∈=−5.0).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[Cl:11].[CH:13]1(B(O)O)[CH2:15][CH2:14]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:13]2[CH2:15][CH2:14]2)=[CH:6][C:5]=1[Cl:11]
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1ccc(Br)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(C2CC2)cc1Cl
Temperature: 100 °C
Reaction time: 17 h

Procedure:
2.1 g of crude 4-bromo-2-chloro-benzoic acid methyl ester (8.42 mmol) were dissolved in 38 ml toluene and treated with 0.94 g of cyclopropylboronic acid (10.94 mmol), 6.25 g of potassium phosphate (29.46 mmol), 236 mg of triphenylphosphine (0.84 mmol), 94 mg of palladium acetate (0.42 mmol) and 1.9 ml water. The reaction mixture was stirred 17 h at 100° C. under Argon. After cooling down to RT, the reaction mixture was treated with 80 ml water, extracted with 2×80 ml EtOAc, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The remaining residue was purified by silicagel chromatography (100 g silicagel, heptane/AcOEt 95:5) leading to 1.17 g of 2-chloro-4-cyclopropyl-benzoic acid methyl ester (66%) as a yellow oil. MS (+cEI): 210.1 (M).
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][O:7][N:8]=[C:9]([C:25]1(OCC[O:27]1)[CH3:26])[C:10]([NH:12][CH:13]1[C:23](=[O:24])[N:15]2[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]12)=[O:11].O>CC(C)=O>[CH3:6][O:7][N:8]=[C:9]([C:25](=[O:27])[CH3:26])[C:10]([NH:12][CH:13]1[C:23](=[O:24])[N:15]2[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]12)=[O:11]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)C1(C)OCCO1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(C)=O
Solvent: O
Product: CON=C(C(C)=O)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
70% Perchloric acid (1.09 ml.) was added to a solution of 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-cephem-4-carboxylic acid (syn isomer, 10.9 g.) in acetone (270 ml.) and stirred at room temperature for 3 hours. Water (150 ml.) was added to the resultant solution and acetone was removed in vacuo. Ethyl acetate (300 ml.) was added to the residue and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (400 ml.) and then the ethyl acetate extract was combined with ethyl acetate layer. The organic solution was washed with a sodium chloride saturated aqueous solution, allowed to stand in refrigerator overnight and dried over magnesium sulfate. The solution was concentrated in vacuo and the residue was pulverized with diisopropyl ether to give 7-(2-methoxyimino-3-oxobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 5.75 g.).