Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[OH:23].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37](Cl)=[O:38]>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:37](=[O:38])[CH2:36][O:23][C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]1=2
Reactant: COc1cc(C(F)(F)F)ccc1Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(F)(F)F)ccc1N1C(=O)COc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Yield: 106.9 %

Procedure:
To a flask charged with 2-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-5-nitrophenol (1.75 g, 5.33 mmol) and cesium carbonate (8.69 g, 26.7 mmol) was added DMF (21.33 ml) followed by chloroacetyl chloride (0.854 ml, 10.66 mmol), dropwise over 5 min. The resulting solution was maintained at rt for 1 h. Quenched reaction with saturated ammonium chloride (25 mL) and diluted with EtOAc (25 mL). Separated layers, and extracted aqueous layer with EtOAc (3×25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated via rotary evaporation to provide 4-(2-methoxy-4-(trifluoromethyl)phenyl)-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (2.10 g, 5.70 mmol, 107% yield) as a yellow solid. The crude product was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=2[N:3]=1>Br[Zn]CCCCC#N>[Cl:22][C:7]1[CH:6]=[CH:5][C:4]2[N:3]=[C:2]([CH2:4][CH2:9][CH2:10][CH2:11][C:2]#[N:3])[CH:11]=[CH:10][C:9]=2[C:8]=1[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:13]
Reactant: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: N#CCCCC[Zn]Br
Product: N#CCCCCc1ccc2c(C(=O)NCC3CCCCC3)c(Cl)ccc2n1
Yield: 210.8 %

Procedure:
Prepared according to the method of example 67 (a) using 2,6-dichloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide (prepared as in Example 43 (a)) (500 mg) and bromo(4-cyanobutyl)-zinc (30 mL, 0.5 M solution in tetrahydrofuran). Purification (SiO2, methanol:dichloromethane 1:200 as eluant) gave the sub-title compound as a solid (600 mg).
Reaction SMILES: C1(C(O)(C2C=CC=CC=2)C(OCC2CCN(CCCCCC=O)CC2)=O)CCCCC1.[CH:32]1([C:38]([OH:65])([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:39]([O:41][CH2:42][CH:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH:54]3OCCO3)[CH2:45][CH2:44]2)=[O:40])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.O1[C:70]2([CH2:75][CH2:74][NH:73][CH2:72][CH2:71]2)[O:69]CC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH:32]1([C:38]([OH:65])([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:39]([O:41][CH2:42][CH:43]2[CH2:44][CH2:45][N:46]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][N:73]3[CH2:74][CH2:75][C:70](=[O:69])[CH2:71][CH2:72]3)[CH2:47][CH2:48]2)=[O:40])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C(OCC1CCN(CCCCCC2OCCO2)CC1)C(O)(c1ccccc1)C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=CCCCCCN1CCC(COC(=O)C(O)(c2ccccc2)C2CCCCC2)CC1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCN(CCCCCCN2CCC(COC(=O)C(O)(c3ccccc3)C3CCCCC3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (1-(6-oxohexyl)piperidin-4-yl)methyl 2-cyclohexyl-2-hydroxy-2-phenylacetate (prepared as Preparation intermediate 15 but using (1-(5-(1,3-dioxolan-2-yl)pentyl)piperidin-4-yl)methyl 2-cyclohexyl-2-hydroxy-2-phenylacetate (0.20 g, 0.47 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (0.133 g, 0.93 mmol) in THF (5 mL), sodium triacetoxyborohydride (0.294 g, 1.39 mmol) was added. The reaction mixture was stirred at RT for 18 hours. The reaction mixture was partitioned between DCM and saturated aqueous sodium hydrogen carbonate. The organic phase was removed, and the aqueous phase was extracted with further DCM. The combined organics were dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The crude product was dissolved in THF (2 mL) and 2M aqueous HCl and heated at 60° C. for 18 hours. The reaction mixture was allowed to cool to RT and then quenched with saturated aqueous sodium hydrogen carbonate. The mixture was extracted twice with ethyl acetate. The organic phases were dried (magnesium sulfate), filtered and concentrated under reduced pressure. The product was isolated (0.193 g, 80%).
Reaction SMILES: C([O:8][C:9]1[C:38]([CH3:39])=[CH:37][C:12]([C:13]([C:15]2[N:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:23][CH2:22]3)[CH:16]=2)=[O:14])=[CH:11][C:10]=1[CH3:40])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[C:10]([CH3:40])=[CH:11][C:12]([C:13]([C:15]2[N:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:23][CH2:22]3)[CH:16]=2)=[O:14])=[CH:37][C:38]=1[CH3:39]
Reactant: [H][H]
Reactant: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc(C)c1O
Reaction time: 1 h

Procedure:
50 mg palladium/charcoal (10%) were added to 390 mg (0.7 mmol) 1-{1-[6-(4-benzyloxy-3,5-dimethyl-benzoyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one in 50 mL MeOH and the mixture was hydrogenated for 40 min in a 5 psi hydrogen atmosphere at RT. The catalyst was removed by suction filtering and the filtrate was evaporated down. The residue was triturated with some MeOH, suction filtered and washed with diethyl ether. The suction filtered catalyst was decocted with 120 mL MeOH for 1 h, filtered hot and the filtrate was evaporated down. The residue was triturated with a little MeOH, suction filtered and dried. The two batches of solid were combined and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [Cl:1][C:2](=[CH2:12])[CH2:3][C:4]1([C:9]([OH:11])=O)[CH2:8][CH2:7][CH2:6][CH2:5]1.OC(C(F)(F)F)=O.[NH2:20][C@@H:21]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:30][CH:29]=1)[C:22]([N:24]([CH3:26])[CH3:25])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[C:31]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:32]=[CH:33][C:28]([CH2:27][C@H:21]([NH:20][C:9]([C:4]2([CH2:3][C:2]([Cl:1])=[CH2:12])[CH2:5][CH2:6][CH2:7][CH2:8]2)=[O:11])[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:29][CH:30]=1
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: C=C(Cl)CC1(C(=O)O)CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(Cl)CC1(C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)C(=O)N(C)C)CCCC1
Temperature: 25 °C
Reaction time: 47 h
Yield: 70 %

Procedure:
To a solution of 1-(2-chloroallyl)cyclopentanecarboxylic acid (51 mg, 0.27 mmol) in DMF (1 mL) and CH2Cl2 (2 mL) was added (S)-2-amino-3-(biphenyl-4-yl)-N,N-dimethylpropanamide TFA salt (109 mg, 0.41 mmol) and TEA (0.19 mL, 1.35 mmol). To the mixture at room temperature was added HATU (154 mg, 0.41 mmol) and stirred at room temperature for 47 hours. The mixture was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by TLC preparation plates using 70% EtOAc/heptane to give (S)—N-(3-(biphenyl-4-yl)-1-(dimethylamino)-1-oxopropan-2-yl)-1-(2-chloroallyl)cyclopentanecarboxamide (83 mg). HPLC retention time=1.76 minutes (condition B); MS (m+1)=439.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.66 (m, 5H), 1.89-2.05 (m, 3H), 2.64 (d, J=15.3 Hz, 1H), 2.70 (d, J=15.3 Hz, 1H), 2.85 (s, 3H), 2.95 (s, 3H), 2.95 (dd, J=13.6, 6.1 Hz, 1H), 3.05 (dd, J=13.6, 6.1 Hz, 1H), 5.05 (s, 1H), 5.10 (s, 1H), 5.08-5.13 (m, 1H), 6.70 (d, J=8.1 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.32-7.38 (m, 1H), 7.44 (t, J=7.7 Hz, 2H), 7.54 (d, J=8.1 Hz, 2H), 7.58-7.65 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CC(C)([O-])C.[K+].[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19].O>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:24])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 1.5 h

Procedure:
25 g of 4-amino-3-nitro-phenol are dissolved in 250 ml of dimethylformamide and 18.5 g of potassium tert.butoxide are added in batches whilst cooling with ice. The mixture is stirred for a further 1.5 hours, then 18.5 ml of ethylbromoacetate are added dropwise, whilst cooling with water, and the mixture is stirred for a further 16 hours at ambient temperature. The solvent is evaporated off in vacuo and the residue is taken up with a mixture of 500 ml of ethyl acetate, 250 ml of tetrahydrofuran and 750 ml of water and the organic phase is washed with saturated saline solution. The aqueous phases are extracted with ethyl acetate, the organic phases are combined and evaporated down and the residue is purified by column chromatography (neutral aluminium oxide; eluant:methylene chloride). Yield: 29 g (75% of theory),
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:26][CH2:27][CH:28]1[CH2:30][CH2:29]1>>[CH:28]1([CH2:27][NH:26][C:3](=[O:25])[C:4]2[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)=[N:14][O:15][C:16]=3[CH3:17])=[N:6][CH:5]=2)[CH2:30][CH2:29]1
Reactant: NCC1CC1
Reactant: COC(=O)c1ccc(NCc2c(-c3ccc(F)cc3)noc2C)nc1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1ccc(C(=O)NCC2CC2)cn1
Yield: 83 %

Procedure:
As described for example 173, 6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinic acid methyl ester (70 mg, 0.2 mmol) was converted, using aminomethylcyclopropane instead of 2,2,2-trifluoroethylamine, to the title compound (80 mg, 83%) which was obtained as an off white foam. MS: m/e=381.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1I.C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[C:45]([N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)=[N:44][N:43]=[CH:42]2.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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(O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[C:45]([N:49]1[CH2:50][CH2:51][O:52][CH2:53][CH2:54]1)=[N:44][N:43]=[CH:42]2
Reactant: O=C(NC1CC1)c1ccc(Cl)c(I)c1
Reactant: Brc1ccc2c(N3CCOCC3)nncc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(NC1CC1)c1ccc(Cl)c(-c2ccc3c(N4CCOCC4)nncc3c2)c1
Temperature: 180 °C
Reaction time: 0.17 h

Procedure:
4-Chloro-N-cyclopropyl-3-iodobenzamide (190 mg, 591 μmol), potassium acetate (174mg, 1773 μmol), bis(pinacolato)diboron (165 mg, 650 μmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (43 mg, 59 μmol) were suspended in dioxane (3.9 mL) and placed in the microwave for 10 min at 180° C. before being added to a mixture of 6-bromo-1-morpholinophthalazine (120 mg, 408 μmol), sodium carbonate-2 M in water (1.2 mL, 2.4 mmol), tetrakis(triphenylphosphine)palladium (68 mg, 59 μmol), and ethyl alcohol (3.9 mL). The combined mixture was heated in the microwave for 10 min at 180° C. The reaction mixture was diluted with 20 mL of EtOAc, added to an addition funnel, and partitioned with sodium bicarbonate (saturated, aqueous). The organic layers were combined, washed 3 times with 20 mL of sodium bicarbonate (saturated, aqueous), separated, combined, dried over sodium sulfate, and concentrated via rotovap to give a crude product. After purification by chromatography, the title compound was obtained. Found MS (ES+): 409 (M+H)+.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CC(N(C)C)=O.Br[C:23]1[CH:24]=[CH:25][C:26]([C:29]([O:31][CH3:32])=[O:30])=[N:27][CH:28]=1>C1COCC1.[Zn]>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][C:23]2[CH:24]=[CH:25][C:26]([C:29]([O:31][CH3:32])=[O:30])=[N:27][CH:28]=2)[CH2:4][CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(CC2CCN(C(=O)OC(C)(C)C)CC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.6 %

Procedure:
Rieke Zinc (slightly excess by estimation) was stirred in 10 mL of THF under argon. tert-Butyl 4-(bromomethyl)piperidine-1-carboxylate (1.0 g, 3.6 mmol) in 5 mL of THF was added. The resulting mixture was stirred at rt for 3 h. The solution was then allowed to settle and the supernatant was transferred via a syringe to a stirred 5 mL of DMA solution. Methyl 5-bromopicolinate (0.78 g, 3.6 mmol) and Cl2Ni(Ph2PCH2CH2PPh2) were added sequentially, and the resulting mixture was stirred at rt for 60 h. LC-MS indicated a partial conversion. The reaction mixture was quenched with 15 mL of sat. NH4Cl, and extracted with 50 mL of EtOAc. The organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give an oil which was purified by silica gel flash chromatography, eluting with 10-80% EtOAc in hexanes, to give methyl 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)picolinate as a white solid (200 mg, 17%).
Reaction SMILES: [C:1]1([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][CH2:13][C:14](Cl)=[O:15].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:12][CH2:13][C:14]([C:4]1[CH:3]=[CH:2][C:1]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=1)=[O:15]
Reactant: CS(=O)(=O)Nc1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C(=O)CCl)cc1
Temperature: -10 °C
Reaction time: 16 h

Procedure:
In a flask containing 128.4 g (0.75 mole) of N-phenylmethanesulfonamide, 169.5 g (1.50 mole) of chloroacetyl chloride in 1 L of methylene chloride under an atmosphere of nitrogen and cooled to about -10° C. add 300 g (2.25 mole) of aluminum chloride. Stir the resulting mixture for about 16 hours. Pour the reaction mixture onto 2 Kg of ice containing 600 mL of concentrated hydrochloric acid. Collect the precipitate and wash with methanol (3×300 mL) and dry in vacuo to give the title compound.
Reaction SMILES: [CH:1]1([C:10]2[O:11][CH2:12][C:13](=[O:20])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:12]2[O:11][C:10]([CH:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][NH:2]3)=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:22]1
Reactant: CCOC(=O)C1=C(C2NCc3ccccc32)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(C2NCc3ccccc32)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 28.5 %

Procedure:
To a solution of ethyl 2-isoindolinyl-4-oxo-4,5-dihydrofuran-3-carboxylate (0.20 g, 0.70 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.11 g, 0.70 mmol) in ethanol (10 mL), L-proline (0.0080 g, 0.070 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.080 g, y. 27%).
Reaction SMILES: C[O:2][C:3](=[S:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:11](=[O:13])[CH3:12])[CH:5]=1.[OH-].[Na+]>O.CO>[C:11]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:10])[C:3]([OH:2])=[S:14])(=[O:13])[CH3:12]
Reactant: COC(=S)c1ccc(C)c(C(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)c1cc(C(O)=S)ccc1C
Reaction time: 6 h
Yield: 79.8 %

Procedure:
3-acetyl4-methylthiobenzoic acid methyl ester (0.43 g) in water:methanol (1:3, 290 ml) containing sodium hydroxide (0.2 g) was stirred for 6 h. Methanol was removed at reduced pressure and the solution acidified with conc. hydrochloric acid to give 3-acetyl-4-methylthiobenzoic acid (0.32 g) after filtration. m/z (API+): 211 (MH+).
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[O-][P:7]([O-:10])([O-:9])=[O:8].[O-][P:12]([O-:15])([O-])=[O:13].[O-:16][P:17]([O-])([O-])=O.[F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].S(=O)(=O)(O)O>>[O:5]=[P:1]12[O:4][P:7]3([O:10][P:12]([O:15][P:17]([O:9]3)([O:3]1)=[O:16])(=[O:13])[O:2]2)=[O:8]
Reactant: O=P([O-])([O-])[O-]
Reactant: O=P(O)(O)O
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [F-]
Product: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Yield: 45 %

Procedure:
In the conventional methods for the production of wet process phosphoric acid, finely ground phosphate rock is reacted with dilute phosphoric acid (10% P2O5 to 25% P2O5) and sulphuric acid which may or may not be diluted. The reaction product is leached (i.e., digested or reacted with the acid) to yield a crude aqueous phosphoric acid solution in which is suspended a substantial quantity of solid impurities. This slurry is filtered to separate most of the undissolved calcium sulfate and other solid impurities to yield a crude (22% P2O5 to 45% P2O5) aqueous product sometimes known as the number one filtrate. This filtrate contains suspended, finely divided, impurities that were not removed during the solid-liquid separation step plus solids that have crystallized after filtration. The solution also contains dissolved impurities. Reference is made to Chapter 16 of Volume II, Phosphorus and its Compounds, Van Wazer, Interscience Publishers (1961).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH:23]1[CH2:25][CH2:24]1)[C:15](O)=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]2[O:10][C:4]3[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=3[N:2]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH:23]1[CH2:24][CH2:25]1
Reactant: Nc1ccc(O)cc1O
Reactant: O=C(O)c1ccc(OCC2CC2)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Oc1ccc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 11.3 %

Procedure:
To a solution of 4-aminoresorcinol hydrochloride (5.00 g), 3-chloro-4-(cyclopropylmethoxy)benzoic acid (6.38 g) and diisopropylethylamine (7.37 mL) in DMF (50 mL) was added HATU (11.8 g), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a suspension of the obtained residue, hexachloroethane (16.7 g) and triphenylphosphine (18.5 g) in acetonitrile (50 mL) was added triethylamine (11.8 mL), and the mixture was stirred at room temperature for 15 min, and then with heating at 80° C. for 2 hr. The reaction mixture was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.00 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH:7]([O:11][C:12](=[O:14])[CH3:13])[C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18](Br)[CH2:19][CH2:20][CH3:21]>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[C:7]([O:11][C:12](=[O:14])[CH3:13])([C:8](=[O:9])[CH3:10])[CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCBr
Reactant: CC(=O)OC(C(C)=O)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(OC(C)=O)(C(C)=O)C(=O)OC(C)(C)C
Yield: 75.4 %

Procedure:
According to the general alkylation method, tert-butyl-2-acetoxy-aceto-acetate (219a) (1.08 g, 5.00 mmol), NaH (156 mg, 6.5 mmol) and butylbromide (538 μL, 685 mg, 5.00 mmol) were reacted in DMF (10 mL) to give 2-acetoxy-2-acetyl-hexanoic-acid-tert-butylester (250i) (1026 mg, 3.77 mmol, 75%) as a slightly yellow oil. Then, 250i (731 mg, 2.68 mmol) and 51 mg (0.27 mmol) p-TsOH.H2O were stirred in 9.0 mL benzene according to decarboxylation method A. Kugelrohr distillation at 1.0 mbar and 60° C. gave 251i (415 mg, 2.41 mmol, 90%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:16][C:17]1[C:26]([O:27][CH3:28])=[CH:25][C:20]2[NH:21][C:22](=[O:24])[S:23][C:19]=2[CH:18]=1>>[CH3:28][O:27][C:26]1[C:17]([NH:16][C:2]2[C:3]3[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:18][C:19]2[S:23][C:22](=[O:24])[NH:21][C:20]=2[CH:25]=1
Reactant: CCOC(=O)c1cc2c(Cl)ncnc2[nH]1
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Product: CCOC(=O)c1cc2c(Nc3cc4sc(=O)[nH]c4cc3OC)ncnc2[nH]1

Procedure:
75 mg (332 μmol) ethyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (CAS-No: 187725-00-4) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 20.0 mg (15%) of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:5]=2[C:6](OC)=[O:7])[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH:1]1([C:4]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:5]=2[CH2:6][OH:7])[CH2:3][CH2:2]1
Reactant: COC(=O)c1c(F)cccc1C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1c(F)cccc1C1CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of methyl 2-cyclopropyl-6-fluorobenzoate (3, 4.54 g, 23.4 mmol) in anhydrous tetrahydrofuran (30 mL) at room temperature was added lithium aluminium hydride (1.42 g, 37.4 mmol) in small portions and the mixture was stirred overnight. The reaction mixture was cooled to 0° C. and water (3 mL) was added dropwise, the mixture was warmed to room temperature and an additional portion of water (30 mL) was added. The solids were removed by filtration, and the aqueous filtrate was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over magnesium sulfate and evaporated. Purification by column chromatography over silica using n-hexane:ethyl acetate (8:1) as eluent afforded the title compound (3.28 g, 19.8 mmol, 84%) as a pale yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][OH:9])(=[O:4])=[O:3].[Cr]([O-])(OCl)(=O)=O.[NH+]1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(CO)c1
Agent: O=[Cr](=O)([O-])OCl
Agent: c1cc[nH+]cc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-methylsulfonyl benzyl alcohol (3.5 g, 28.6 mmol) in dichloromethane (50 mL) was added pyridinium chloro chromate (PCC) (9.1 g, 42.2 mmol). The mixture was stirred at room temperature for 3 hours. After workup and column chromatography on silica gel eluting with hexane:ethyl acetate, 1:1, 3-methylsulfonylbenzaldehyde was obtained as white solid.