Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.C([O:5][C:6]([C:8]1[S:12][CH:11]=[N:10][C:9]=1[N:13]1[C:17](=[O:18])[NH:16][C:15]([CH:19]([C:36]2[CH:45]=[C:44]([O:46][CH3:47])[C:39]3[O:40][CH2:41][CH2:42][O:43][C:38]=3[C:37]=2[F:48])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:31]=C(C(F)(F)F)O[N:28]=3)=[CH:23][CH:22]=2)=[N:14]1)=[O:7])C.[OH-].[Na+]>[Fe].C(O)(=O)C>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([NH:20][CH:19]([C:36]2[CH:45]=[C:44]([O:46][CH3:47])[C:39]3[O:40][CH2:41][CH2:42][O:43][C:38]=3[C:37]=2[F:48])[C:15]2[NH:16][C:17](=[O:18])[N:13]([C:9]3[N:10]=[CH:11][S:12][C:8]=3[C:6]([OH:7])=[O:5])[N:14]=2)=[CH:22][CH:23]=1)(=[NH:28])[NH2:31]
Reactant: CCOC(=O)c1scnc1-n1nc(C(Nc2ccc(-c3noc(C(F)(F)F)n3)cc2)c2cc(OC)c3c(c2F)OCCO3)[nH]c1=O
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncsc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2 ml of a methanol solution containing 57 mg of 4-(3-{(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiazole-5-carboxylic acid ethyl ester, 0.2 ml of a 5 N sodium hydroxide aqueous solution was added. The resulting mixture was stirred at room temperature for 18 hours, and then 2 ml of methanol, 2 ml of acetic acid, and 38 mg of iron powder were added thereto. The mixture was stirred at 60° C. for 18 hours and then at 65° C. for 6 hours, under a nitrogen atmosphere. After cooling, the reaction mixture was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 4-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)methyl]-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}thiazole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)[C:5]([OH:7])=[O:6].[Si:18](OS(C(F)(F)F)(=O)=O)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].[CH3:33]COC(C)=O>C(Cl)Cl.N1C(C)=CC=CC=1C>[CH3:33][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([N:11]2[CH2:12][CH2:13][CH:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:15][CH2:16]2)=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)c(Cl)c1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)c1ccc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)c(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 0.70 g of 3-chloro-4-(4-hydroxypiperidino)benzoic acid in 15 ml of methylene chloride, 1.5 ml of 2,6-lutidine and 2.7 g of tert-butyldimethylsilyltriflate were added, and the mixture was stirred at room temperature for 2 weeks. To the reaction solution, EtOAc was added, and the organic layer was washed with water and brine and then dried over sodium sulfate. After the evaporation of the solvent, the obtained residue was purified by silica gel column chromatography (eluent: hexane-EtOAc=5:1˜4:1) to obtain 0.90 g of 4-(4-tert-butyldimethylsilyloxypiperidino)-3-chlorobenzoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][NH:12][CH3:13].[CH2:14]=O>C(O)(=O)C>[CH3:11][N:12]([CH2:14][C:5]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:10]=[CH:9][C:8]=2[NH:7][CH:6]=1)[CH3:13]
Reactant: C=O
Reactant: CNC
Reactant: Clc1ccc2[nH]ccc2c1
Solvent: CC(=O)O
Product: CN(C)Cc1c[nH]c2ccc(Cl)cc12

Procedure:
The starting material is prepared as follows: 5-Chloroindole (4.00 g) is added to a mixture of 40% aqueous dimethylamine (4.5 ml), and 37% aqueous formaldehyde (2.6 ml) in glacial acetic acid (6.4 ml) while stirring at 10°. The cooling bath is removed and the mixture stirred at room temperature for 3 hours. The mixture is made basic with ammonium hydroxide whereupon a precipitate is formed. The solid is collected, washed with water and dried to give 5-chloro gramine, m.p. 149°-151°.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:14]([OH:16])=O.[CH2:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[ClH:3].[CH2:17]([N:24]1[CH2:29][CH2:28][N:27]([C:14]([C:6]2[NH:5][C:13]3[C:8]([CH:7]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)=[O:16])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cl
Product: O=C(c1cc2ccccc2[nH]1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
Thionyl chloride (1.62 ml, 22.3 mmol) was added to a solution of indole-2-carboxylic acid (3.0 g, 18.6 mmol) in toluene (40 ml), the mixture heated at reflux for 3 h and then cooled to room temperature. 1-Benzylpiperazine (3.7 ml, 20.4 mmol) was added and the resultant precipitate collected by filtration, washed with toluene, and dried in vacuo to give 2-(4-benzylpiperazin-1-yl) carbonyl indole hydrochloride (6.5 g, 98%). M.p. >210° C. (dec).
Reaction SMILES: C(NC(C)C)(C)C.[C:8]12([CH3:18])[C:15]([CH3:17])([CH3:16])[CH:12]([CH2:13][CH2:14]1)[CH2:11][C:9]2=[O:10].[CH:19](=[O:21])[CH3:20].C(=O)([O-])O.[Na+]>C1COCC1.CCCCCC>[OH:21][CH:19]([CH:11]1[CH:12]2[C:15]([CH3:17])([CH3:16])[C:8]([CH3:18])([CH2:14][CH2:13]2)[C:9]1=[O:10])[CH3:20].[OH:21][CH:19]([CH:11]1[CH:12]2[C:15]([CH3:17])([CH3:16])[C:8]([CH3:18])([CH2:14][CH2:13]2)[CH:9]1[OH:10])[CH3:20]
Reactant: CC12CCC(CC1=O)C2(C)C
Reactant: CC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)C1C(=O)C2(C)CCC1C2(C)C
Product: CC(O)C1C2CCC(C)(C1O)C2(C)C
Reaction time: 0.25 h
Yield: 126.5 %

Procedure:
2.50 ml of 2.5M n-butylithium hexane solution was added dropwise to a tetrahydrofuran solution comprising 4 ml THF and 1.00 ml diisopropylamine at −78° C. and the mixture was stirred for 15 minutes. Then, a solution comprising 4 ml THF with 0.91 g camphor dissolved therein was added dropwise to the above solution at −78° C., then, 0.27 g of acetaldehyde was further added and the mixture was stirred for 15 minutes. Thus, 3-(1-hydroxyethyl)-camphor was synthesized. This reaction solution was admixed with 50 ml of saturated sodium hydrogen carbonate aqueous solution and restored to room temperature. The reaction product was extracted with diethylether. 5 ml of the above 3-(1-hydroxyethyl)-camphor diethylether solution was gradually added dropwise to 10 ml of a diethylether solution comprising 10 ml diethylether and 0.11 g lithium aluminum hydride and the mixture was stirred at room temperature for 30 minutes. 0.5 ml of water and 0.5 ml of 2N-NaOH were added to the reaction solution to separate the solids out. The separated-out solids were filtered off and the solvent was removed under vacuum. The residue was purified by means of silica gel column chromatography (eluent: hexane/ethylacetate=7/3) and 0.75 g of 3-(1-hydroxyethyl)-borneol was obtained (yield: 95%).
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[O:3][C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:25]([CH2:26][CH2:27][C@:5]12[CH3:6])[C@:18]1([CH2:19][O:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:13](=[CH:14][C:15](=[O:28])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3.COC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>O1CCCC1>[CH3:29][Si:2]([CH3:1])([CH3:30])[O:3][C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:25]([CH2:26][CH2:27][C@:5]12[CH3:6])[C@:18]1([CH2:19][O:20][Si:21]([CH3:22])([CH3:23])[CH3:24])[C@H:13]([CH2:14][C:15](=[O:28])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CC[C@@H]2O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: C1CCOC1
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC(=O)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CC[C@@H]2O[Si](C)(C)C

Procedure:
Hydrogenation of 19-hydroxy-5-androstenes by means of 10% palladium on charcoal results in good yields of the corresponding 19-hydroxy-5α-androstanes. Suitable steroid substrates which fulfill the 5-ene requirement for stereoselectivity during the reduction include 3β,19-dihydroxy-5-androstenes, 19-hydroxy-5-androsten-3-ones, 19-hydroxy-5-androsten-3-one 3-cyclic ethyleneketal and 3-alkoxy-3,5-androstadien-19-ols. Typical reduction conditions utilize 2-10parts of the steroid substrate to 1 part catalyst with methanol or ethanol as solvent and hydrogen pressures ranging from 1 to 3 atmospheres. In this manner 1β,17α-dimethyl-5-androstene-3β,17β,19-triol, 7α-methyl-19-tetrahydropyranyloxy-5-androsten-3β,17β-diol and 6α-methyl-3β,19-dihydroxy-5-androsten-17-one are reduced to 1β,17α-dimethyl-5α-androstane-3β,17β,19-triol, 7α-methyl-19-tetrahydropyranyloxy-5α-androstan-3β,17β-diol and 6α-methyl-3β,19-dihydroxy-5α-androstan-17-one, respectively. 19-Hydroxy-1α-methyl-4-androstene-3,17-dione is converted to its cyclic ethyleneketal by heating at reflux temperatures with p-toluenesulfonic acid and ethyleneglycol in benzene. The ketal which forms is then reduced and hydrolyzed to form 19-hydroxy-1α-methyl-5α-androstan-3,17-dione. 17β,19-Di(trimethylsiloxy)-4-androsten-3-one can be converted to the methyl enol ether by the action of trimethylorthoformate, p-toluenesulfonic acid and methanol in tetrahydrofuran. The 3-methoxy-3,5-diene which forms is then catalytically reduced to yield 17β,19-di(trimethylsiloxy)-5α-androstan-3-one. The ethylenol ether of 19-hydroxy-4-androsten-3,17-dione acetate can also be reduced to yield 19-hydroxy-5α -androstane-3,17-dione acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][NH:14][C:15]3[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([N:23]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:16]=3[NH2:42])[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:43](OCC)(OCC)(OCC)[CH2:44][CH3:45].Cl>C1(C)C=CC=CC=1>[CH2:44]([C:45]1[N:14]([CH2:13][C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:12]=2)[C:15]2[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([N:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[CH2:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)[C:16]=2[N:42]=1)[CH3:43]
Reactant: CCOC(CC)(OCC)OCC
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c(NCc3cc(-c4ccc(F)cc4)no3)c2N)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCc1nc2c(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)nc(C)c(C)c2n1Cc1cc(-c2ccc(F)cc2)no1
Yield: 39.2 %

Procedure:
N4-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-N2,N2-bis(4-methoxybenzyl)-5,6-dimethylpyridine-2,3,4-triamine (6.00 g, 10.6 mmol), triethyl orthopropionate (3.2 mL, 16 mmol), concentrated hydrochloride acid (0.2 mL), and toluene (30 mL) were combined and treated according to the method described in Part E of Example 18 with the modification that no additional triethyl orthopropionate was added. 2-Ethyl-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-N,N-bis(4-methoxybenzyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (2.52 g) was obtained as a yellow solid.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]=[C:2]2[C:9]([OH:11])=[O:10]>CCOC(C)=O.[Pd]>[CH:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]=[C:2]2[C:9]([OH:11])=[O:10]
Reactant: O=C(O)C1=CC2C=CC1CC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)C1=CC2CCC1CC2
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
Compound 11A (600 mg, 3.99 mmol) was dissolved in EtOAc (5 mL), 5% Pd/C (12 mg) was added and the mixture was stirred under a hydrogen balloon for 1.5 h. The reaction mixture was filtered through a pad of celite and concentrated under reduced pressure to give 600 mg of compound 11B as a yellow oil. No further purification was necessary. HPLC conditions: 95% at 2.65 min (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous methanol over 4 minute gradient with 0.2% H3PO4, detecting at 220 nm). C. Bicyclo[2.2.2]oct-2-ene-2-carbonyl chloride (11C)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:26][C:27]#[N:28])[CH2:18][CH2:17][N:16]([C:19]([C:21]4[O:25][N:24]=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[N:29]1([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH:33]=[CH:32][CH:31]=[N:30]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.C(#N)C.O>[O:25]1[C:21]([C:19]([N:16]2[CH2:17][CH2:18][C:13]([CH2:26][C:27]#[N:28])([N:11]3[CH:12]=[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]5[CH:36]=[CH:35][C:34]([N:29]6[CH:33]=[CH:32][CH:31]=[N:30]6)=[CH:40][CH:39]=5)[N:7]=4)[CH:9]=[N:10]3)[CH2:14][CH2:15]2)=[O:20])=[CH:22][CH:23]=[N:24]1
Reactant: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CCN(C(=O)c2ccno2)CC1
Reactant: Nc1ccc(-n2cccn2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: N#CCC1(n2cc(-c3ccnc(Nc4ccc(-n5cccn5)cc4)n3)cn2)CCN(C(=O)c2ccno2)CC1

Procedure:
A mixture of (4-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(isoxazol-5-ylcarbonyl)piperidin-4-yl)acetonitrile (30 mg, 0.08 mmol), 4-(1H-pyrazol-1-yl)aniline (18.9 mg, 0.119 mmol), and p-toluenesulfonic acid (12 mg, 0.067 mmol) in dry 1,4-dioxane (0.6 mL) was refluxed overnight. The mixture was diluted with acetonitrile and water, purified on RP-HPLC to give the desired product as a racemic mixture (22 mg, 52%). LCMS (M+H) 521.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][C:3]=1[NH:14][NH2:15].[CH:16](=O)[CH3:17].[O-:19][C:20]#[N:21].[Na+]>C(O)(C)(C)C.O.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([NH:9][S:10]([CH3:13])(=[O:11])=[O:12])=[CH:4][C:3]=1[N:14]1[C:20](=[O:19])[NH:21][C:16]([CH3:17])=[N:15]1
Reactant: CC=O
Reactant: N#C[O-]
Reactant: CS(=O)(=O)Nc1cc(NN)c(Cl)cc1Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1nn(-c2cc(NS(C)(=O)=O)c(Cl)cc2Cl)c(=O)[nH]1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
A stirring solution of 117.3 grams (0.500 mole) of (2,4-dichloro-5-(methylsulfonylamino)phenylhydrazine in 200 ml of tert-butanol/water (88/12) is cooled to 0° to 5° C., and a solution of 23.4 qrams (0.525 mole--12% excess) of acetaldehyde in 54 grams of tert-butanol/water (88/12) is added dropwise during a 20 minute period. Upon completion of addition, the reaction mixture is stirred for five minutes, and a slurry of 39.8 grams (91.5% pure--0.560 mole--12% molar excess) of sodium cyanate in 90 grams of water is added in one portion. Additional water is used to wash any of the remaining slurry of sodium cyanate from its container into the reaction mixture. The reaction mixture is cooled to 0° to 5° C., and 39.3 grams (0.655 mole--5% equivalent excess, based on equivalents of sodium cyanate and its sodium carbonate impurity) of acetic acid is added dropwise during a 15 minute period. Upon completion of addition, the reaction mixture is stirred for about two hours during which time it is allowed to warm to about 20° C. Upon completion of the two hour stirring time, the reaction mixture is cooled to 10° C., and 321 grams (0.537 mole) of a 12.4% aqueous solution of sodium hypochlorite is added dropwise during a 40 minute period. Upon completion of addition, the reaction mixture is stirred for an additional 40 minutes. The tert-butanol/water medium is then distilled from the reaction mixture by slowly heating the reaction mixture to about 100° C. Upon completion of the distillation, the pot residue is washed with water and dried, yielding 1-(2,4-dichloro-5-methylsulfonylaminophenyl)-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.C([OH:20])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:20])[NH:13]2
Reactant: CCO
Reactant: Fc1cccc(-c2cccc3[nH]ccc23)c1F
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To the suspension of 4-(2,3-difluoro-phenyl)-1H-indole (2.85 g, 12.4 mmol) in t-BuOH:ethanol:acetic acid (78.5 mL:46.5 mL:24.13 mL) was added pyridinium tribromide (11.93 g, 37.3 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added with acetic acid (60 mL). Zinc dust (4.1 g, 62.2 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (5×), sat NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 2.32 g (76%) of 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one as an earth colored solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](O)=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[N:14]2)=[N:9][CH:8]=1>CN(C)C=O>[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([Cl:3])=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[N:14]2)=[N:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Temperature: 25 °C
Yield: 84.9 %

Procedure:
Phosphorous oxychloride (24 mL, 257.7 mmol) was added slowly dropwise to a 0° C. suspension of 7-bromo-3-nitro[1,5]naphthyridin-4-ol (60.00 g, 222.2 mmol) in N,N-dimethylformamide (DMF; 410 mL), maintaining the temperature below 10° C. After addition was completed, the reaction was allowed to warm to ambient temperature over a 3 hour period. The reaction mixture was then added to ice water (1700 mL) with stirring. A solid precipitate formed, which was isolated by vacuum filtration and rinsed with water. The material was partitioned between chloroform (3 Liters) and saturated aqueous sodium bicarbonate (300 mL). The organic phase was isolated, dried over anhydrous sodium sulfate, then concentrated under reduced pressure to yield 54.42 g of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine as short, off-white needles.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH:10]#[C:11][CH:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CC(OC)(C)C>[C:11]([CH:12]([O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])#[CH:10]
Reactant: C#CC(O)CCCCC
Reactant: Oc1cccc(F)c1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C#CC(CCCCC)Oc1cccc(F)c1F
Reaction time: 19 h

Procedure:
42.4 g (0.33 mol) of 2,3-difluorophenol are initially introduced in 1.2 l of THF together with 50.0 ml (0.34 mol) of 1-octyn-3-ol and 94.1 g (0.36 mol) of triphenylphosphine, and a solution of 76.1 ml (0.39 mol) of DIAD in 100 ml of THF is added dropwise. After 19 h at 20° C., the mixture is diluted with MTBE, and the batch is washed with water. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, 1-chlorobutane), giving 1-(1-ethynylhexyloxy)-2,3-difluorobenzene as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])/[C:8]([O:10]CC)=[O:9])[N:6]=1.N1C=CC=CC=1.[Cl:32][CH2:33][C:34](Cl)=[O:35]>CC(N(C)C)=O.ClCCl>[Cl:32][CH2:33][C:34]([NH:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])/[C:8]([OH:10])=[O:9])[N:6]=1)=[O:35]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)/C(=N\OCCCNC(=O)OC(C)(C)C)c1csc(N)n1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCO/N=C(\C(=O)O)c1csc(NC(=O)CCl)n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
In a mixture of 15 ml of dimethylacetamide and 15 ml of dichloromethane are dissolved 5.17 g of ethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetate and 1.1 ml of pyridine and, under ice-cooling and stirring, 2.21 ml of chloroacetyl chloride is added dropwise. With ice-cooling, the mixture is stirred for 30 minutes and the reaction mixture is poured into 150 ml of ice-water and extracted with dichloromethane. The extract is washed with water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution in that order and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is subjected to silica gel (200 g) column chromatography, elution being carried out with chloroform-ethyl acetate (9:1 and 5:1). Fractions containing the desired compound are collected and concentrated under reduced pressure. The residue is dissolved in a mixture of 8.8 ml of dioxane and 62 ml of ethanol, followed by addition of 8.8 ml of 2 N aqueous sodium hydroxide solution. The mixture is stirred at room temperature for 48 hours and, then, 1.2 ml of 2 N aqueous sodium hydroxide solution is added and stirring is continued for 6 hours. The reaction mixture is concentrated under reduced pressure and the residue is dilluted with water and washed with ethyl acetate. The solution is adjusted to pH 2.0 with diluted hydrochloric acid and extracted with ethyl acetate. The extract is washed with aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and a mixture of hexane and ethyl acetate (4:1) is added to the residue. The resulting light yellow powder is collected by filtration to give 2.47 g of 2-(2-chloroacetamidothiazol-4-yl)-(Z)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetic acid.