Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[C:6](=[O:11])([O:9][CH3:10])OC.CO.[C:14](=O)(OC)[O:15][CH3:16]>C[O-].C[O-].C([Sn+2]CCCC)CCC>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:11])[O:9][CH2:10][CH2:14][O:15][CH3:16]
Reactant: COC(=O)OC
Reactant: COCCO
Agent: CCCC[Sn+2]CCCC
Agent: C[O-]
Solvent: CO
Product: COCCOC(=O)OCCOC
Temperature: 102 °C
Yield: 87.5 %

Procedure:
A total of 76.1 grams (1 mole) of 2-methoxyethanol, 67.6 grams (0.75 moles) of dimethyl carbonate, and 0.5 grams of dibutyltin dimethoxide were combined in a 250 milliliter round bottom three-neck flask equipped with a straight distillation head and a magnetic stirrer. The flask contents were heated to reflux at an initial temperature of 73° C. at the head and 102° C. in the kettle. After seven minutes at reflux, a methanol/dimethyl carbonate azeotrope was slowly removed overhead. A total of 55.9 grams of material was removed overhead (64° C.-88° C.) over a period of about 21 hours after which time the kettle temperature rose to 145° C. After this time, the flask contents were cooled and put under vacuum. The desired product was collected at a temperature of 97° C.-105° C. at 3 mm Hg. A total of 77.98 grams (87.5 percent yield) of bis(2-methoxyethyl)carbonate was obtained at a purity of greater than 99 percent as analyzed by capillary gas chromatography on a DB-1701 column.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8](/[CH:10]=[CH:11]/[C:12]([O:14]C)=[O:13])[CH:7]=[CH:6][C:5]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH3:2].[OH-].[K+]>CO.O>[CH2:1]([O:3][C:4]1[CH:9]=[C:8](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:7]=[CH:6][C:5]=1[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH3:2]
Reactant: CCOc1cc(/C=C/C(=O)OC)ccc1-c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1cc(/C=C/C(=O)O)ccc1-c1ccc(OC)cc1

Procedure:
The preparation is carried out analogously to Example 2 from 1.0 g (3.2 mmol) of methyl 3(E)-(2-ethoxy-4′-methoxybiphenyl-4-yl)acrylate, 50 ml of a 10% solution of potassium hydroxide in methanol and 2 ml of water and gives 3(E)-(2-ethoxy-4′-methoxybiphenyl-4-yl)acrylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:10]1[C:11]([CH3:21])=[CH:12][C:13]([C:16]([NH:18][CH2:19][OH:20])=[O:17])=[N:14][CH:15]=1.[Si:32]([O:49][CH2:50][CH2:51]O)([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Si:32]([O:49][CH2:50][CH2:51][O:20][CH2:19][NH:18][C:16]([C:13]1[CH:12]=[C:11]([CH3:21])[C:10]([CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[S:22]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[CH:15][N:14]=1)=[O:17])([C:45]([CH3:46])([CH3:47])[CH3:48])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1cc(C(=O)NCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: CC(C)(C)[Si](OCCO)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1cc(C(=O)NCOCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 60 °C
Yield: 50.6 %

Procedure:
5-[(2,5-Difluorophenyl)[(4-fluorophenyl)sulfonyl]meth yl]-N-(1-hydroxymethyl)-4-methylpyridine-2-carboxamide (113 mg, 0.251 mmol) obtained in Example 85, and a solution of 2-(tert-butyldiphenylsilyloxy)ethanol (136 mg, 0.453 mmol) and p-toluenesulfonic acid (10 mg) in benzene (5 ml) were stirred for 3 hours with heating to 60° C. The reaction solution was returned to room temperature, and then was concentrated under reduced pressure. Ethyl acetate was added to the resulting concentration residue, and the mixture was washed sequentially with saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to flash silica gel column chromatography, and the fraction obtained from an elution with 25% ethyl acetate/hexane was concentrated under reduced pressure, to obtain the title compound (93 mg, 0.127 mmol, 51%) as an amorphous substance.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.Cl.[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:21]1>>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([N:20]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[CH2:21]2)=[O:16])=[CH:7][CH:8]=1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: c1cc(C2CCNC2)ccn1
Agent: Cl
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(c2ccncc2)C1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 4-pyrrolidin-3-ylpyridine hydrochloride (11.1 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (11.6 mg). Calcd for C20H16F3N3O2: 387.1195, found 387.1193.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(Cl)CCl.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[N:20][C:21]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=O)=[CH:27][CH:26]=3)=[N:22][CH:23]=2)=[CH:14][CH:13]=1.[NH4+].[Cl-]>CN(C1C=CN=CC=1)C.ClCCl.CN1C(=O)CCC1>[CH2:1]([N:3]([CH2:4][CH3:5])[C:33](=[O:35])[CH2:32][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:21]2[N:22]=[CH:23][C:18]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=3)=[CH:19][N:20]=2)=[CH:30][CH:29]=1)[CH3:2]
Reactant: COc1ccc(-c2cnc(Nc3ccc(CCC(=O)O)cc3)nc2)cc1
Reactant: CCNCC
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN(CC)C(=O)CCc1ccc(Nc2ncc(-c3ccc(OC)cc3)cn2)cc1
Reaction time: 3 h

Procedure:
4-(3-Diethylamino-propyl)-phenyl]-[S-(4-methoxy-phenyl)-pyrimidin-2-yl]-amine can be prepared by the following procedure. Diethylamine (10 mmol), EDC (25 mmol) and DMAP (0.1 mmol) are dissolved in dichloromethane (3 mL) and added to the crude 3-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-propionic acid dissolved in NMP (from example 5ao) at rt. After 3 h, sat. aq NH4Cl is added and the mixture is extracted with EtOAc. The combined extracts are dryed over anhydrous Na2SO4 and solvent is removed. Purification by preparative HPLC yields N,N-diethyl-3-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-propionamide.
Reaction SMILES: [Na].O[CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][O:6][C:5]1=[O:10].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][O:6][C:5]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1OCCCC1=CO
Reactant: NCc1ccccc1
Agent: [Na]
Product: O=C1OCCCC1=CNCc1ccccc1
Yield: 36 %

Procedure:
Using 3-hydroxymethylenedihydropiran-2-one sodium salt (50 mmol) and benzylamine (55 mmol) and proceeding according to the abovementioned method A1, 3-benzylaminomethylenetetrahydropiran-2-one (3.91 g, efficiency: 69%) is produced in the form of a white powder.
Reaction SMILES: [S:1]1([CH2:7][CH2:6][CH2:5][CH2:4]1)(=[O:3])=[O:2].[CH2:8]([Li])[CH2:9][CH2:10]C.C(Br)C#C>C1COCC1>[CH2:10]([CH:4]1[CH2:5][CH2:6][CH2:7][S:1]1(=[O:3])=[O:2])[C:9]#[CH:8]
Reactant: [Li]CCCC
Reactant: O=S1(=O)CCCC1
Agent: C#CCBr
Solvent: C1CCOC1
Product: C#CCC1CCCS1(=O)=O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of sulfolane (1.0 g, 8.32 mmol) in THF (5 mL) at −78° C. is added n-butyllithium (5.7 mL of 1.6 M in hexane, 9.1 mmol) dropwise and the solution is stirred at −78° C. for 20 min. To this is added a solution of propargyl bromide (992 mg, 8.34 mmol) in THF (5 mL) dropwise and the mixture is allowed to warm to RT overnight. The mixture is quenched with 1N HCl and extracted with EtOAc. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure. The residue is purified by flash chromatography using hexane/EtOAc (6:4) as eluent to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[F:19][C:20]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:19][C:20]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:25]=[CH:24][C:21]=1/[CH:22]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: O=Cc1cccc(C(F)(F)F)c1F
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cccc(C(F)(F)F)c1F)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (100 mg, 0.404 mmol) in toluene 10 mL was added 2-fluoro-3-(trifluoromethyl)benzaldehyde 78 (77.7 mg, 0.404 mmol). PTSA (153.8 mg, 0.809 mmol) was added to the reaction mixture and stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 79 which was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-2-(2-fluoro-3-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 79 was eluted at 34% ethyl acetate in hexane to afford yellow coloured.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CN(C1C=CC=CN=1)C.[OH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C@H:34]2[CH2:51][C@@:49]3([CH3:50])[C@@H:45]([CH2:46][CH2:47][C:48]3=[O:52])[C@H:44]3[C:35]2=[C:36]2[C:41]([CH2:42][CH2:43]3)=[CH:40][C:39](=[O:53])[CH2:38][CH2:37]2)=[CH:30][CH:29]=1>N1C=CC=CC=1>[CH3:8][C:7]1[CH:9]=[CH:10][C:4]([S:1]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([C@H:34]3[CH2:51][C@@:49]4([CH3:50])[C@@H:45]([CH2:46][CH2:47][C:48]4=[O:52])[C@H:44]4[C:35]3=[C:36]3[C:41]([CH2:42][CH2:43]4)=[CH:40][C:39](=[O:53])[CH2:38][CH2:37]3)=[CH:30][CH:29]=2)(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@]12C[C@H](c3ccc(OCCOCCO)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CCC2=O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCCOc2ccc([C@H]3C[C@]4(C)C(=O)CC[C@H]4[C@@H]4CCC5=CC(=O)CCC5=C43)cc2)cc1
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
320 mg of tosyl chloride and 70 mg of dimethylamino-pyridine are added to 690 mg of the product obtained in Stage D in 5 cm3 of pyridine, then two lots of 115 mg of tosyl chloride is added again. Agitation is carried out for 2 hours and 30 minutes, followed by acidifying with 6N hydrochloric acid, extraction with ethyl acetate, washing with an aqueous solution of sodium bicarbonate, with salt water, drying and evaporating the solvent under reduced pressure, the residue is chromatographed on silica (eluant: ethyl acetate-essence G 7-3 then ethyl acetate). 710 mg of expected product is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19]Br)=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:44]([NH2:48])[CH2:45][CH:46]=[CH2:47].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19][NH:48][CH2:44][CH2:45][CH:46]=[CH2:47])=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOc1ccc(C(CC(=O)N=C(Cc2cc(Cl)c(NC(=O)CBr)c(Cl)c2)NC(=O)OC(C)(C)C)=NOCC)cc1
Reactant: C=CCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCNCC(=O)Nc1c(Cl)cc(CC(=NC(=O)CC(=NOCC)c2ccc(OCC=C)cc2)NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl-1-(3-(4-(allyloxy)phenyl)-3-(ethoxyimino)-propanoylimino)-2-(4-(2-bromoacetamido)-3,5-dichlorophenyl)ethylcarbamate (100 mg) in dichloromethane (0.30 mL) at room temperature was added but-3-en-1-amine hydrochloride (45 mg) and diisopropylethylamine (97 μL), and the resulting solution was stirred at room temperature for 2 h. The solvents were removed in vacuo to give the title compound as a white solid, which was used for Step B without purification. retention time: 2.11 min (method A). MS (ESI) (M+H)+ 689.20.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].C(O)CCC>C(#N)C>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCCCO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 96.2 %

Procedure:
Fluvastatin methyl ester (2.0 g) was added to a mixture of NaOH (1 eq.) and butan-1-ol (15 ml). The mixture was stirred at about 80° C. for 2.5 h, after which the starting material was not detected by HPLC. Then, 40 ml of acetonitrile was dripped into the solution. The mixture was then cooled slowly to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile (45 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 1.96 g (96.2%) of fluvastatin sodium Form VII.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[CH2:6][C:7]1[C:8]([NH:20]C2C=CC=CC=2)=[N:9][C:10]([NH:13]C2C=CC=CC=2)=[N:11][CH:12]=1)C.S(=O)(=O)(O)O.[C:43](O)(=O)[CH3:44]>C(OCC)(=O)C>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:5]2[C:4](=[O:3])[N:20]([C:44]3[CH:43]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:8]3[N:9]=[C:10]([NH:13][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:11]=[CH:12][C:7]=3[CH2:6]2)[CH:32]=[CH:31][C:30]=1[O:33][CH3:34]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1ccc(OC)c(OC)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COc1ccc(C2Cc3cnc(Nc4ccccc4)nc3N(c3ccccc3)C2=O)cc1OC
Temperature: 80 °C

Procedure:
To a solution of 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(3,4-dimethoxy-phenyl)-propionic acid ethyl ester (470 mg, 0.94 mmol) (from Example 11b supra) in glacial acetic acid (3 mL) was added concentrated sulfuric acid (0.1 mL) in one portion. The reaction mixture was heated at 80° C. overnight. After cooling, the reaction mixture was diluted with ethyl acetate (50 mL) and quenched with 2 N aqueous sodium hydroxide solution. The organic layer was separated and successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product which was crystallized from ethyl acetate-hexanes to give 6-(3,4-dimethoxy-phenyl)-8-phenyl-2-phenylamino-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one as a light brown solid. (Yield 335 mg, 78.8%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:23]1[N:24]=[C:25]([C:32]([C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[N:40]([CH2:44][CH2:45][CH3:46])[C:39](=[O:47])[N:38]([CH2:48][CH2:49][O:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)[C:37]3=[O:58])=[O:33])[N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=12>O.CN1C(=O)CCC1.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>[F:57][C:54]1[CH:53]=[CH:52][C:51]([O:50][CH2:49][CH2:48][N:38]2[C:37](=[O:58])[C:36]3[C:41](=[CH:42][CH:43]=[C:34]([C:32]([C:25]4[N:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]5=[C:23]([C:7]5[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=5)[C:3]([O:2][CH3:1])=[O:4])[N:24]=4)=[O:33])[CH:35]=3)[N:40]([CH2:44][CH2:45][CH3:46])[C:39]2=[O:47])=[CH:56][CH:55]=1
Reactant: CCCn1c(=O)n(CCOc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(Br)c4ccccn34)ccc21
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCn1c(=O)n(CCOc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(-c4cccc(C(=O)OC)c4)c4ccccn34)ccc21
Temperature: 120 °C
Yield: 69.1 %

Procedure:
2.178 g (12.1 mmol) of 3-methoxycarbonylphenylboronic acid, 4.279 g (20.16 mmol) of potassium phosphate dissolved in 30 ml of water, and 582.4 g (0.504 mmol) of tetrakis(triphenylphosphine)palladium are added to 5.7 g (10.08 mmol) of 6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-[2-(4-fluorophenoxy)ethyl]-1-propylquinazoline-2,4(1H,3H)-dione in 180 ml of NMP. The reaction medium is microwave-heated for 15 minutes at 120° C. and then concentrated under reduced pressure. The solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (100/1) mixture. 4.32 g of a yellow solid are obtained.
Reaction SMILES: C([NH:8][C:9]([C:28]1([C:31]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[O:32])[CH2:30][CH2:29]1)([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:16][CH:15]=1)[C:10]([F:13])([F:12])[F:11])C1C=CC=CC=1.C(O)=O>CO.[Pd]>[NH2:8][C:9]([C:28]1([C:31]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)=[O:32])[CH2:30][CH2:29]1)([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:18][CH:19]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: COc1ccc(C(=O)C2(C(NCc3ccccc3)(c3ccc(OCCCC(F)(F)F)cc3)C(F)(F)F)CC2)cc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: COc1ccc(C(=O)C2(C(N)(c3ccc(OCCCC(F)(F)F)cc3)C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a solution of Intermediate 14G (6 mg, 10.6 μmol) in MeOH (1 mL) containing 4.4% formic acid was added 10% palladium on carbon (2 mg, 2 μmol). The reaction was stirred at rt overnight. The reaction was filtered through Celite®. The filtrate was made basic with sat'd aq NaHCO3, and then evaporated to remove MeOH. The aqueous residue was diluted with sat'd aq NaCl and extracted with EtOAc. The combined organic extracts were washed with sat'd aq NaCl, dried over Na2SO4, filtered and concentrated to provide Intermediate 14H (4 mg, 71%) as a tan glass. LCMS Anal. Calc'd for C23H23F6NO3 475.42, found [M+H] 476.2.
Reaction SMILES: B(Br)(Br)Br.C[O:6][CH2:7][C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:11]=[CH:10][N:9]=1.[OH-].[Na+]>ClCCl>[OH:6][CH2:7][C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:11]=[CH:10][N:9]=1
Reactant: COCc1nccc(N2CCCCC2)n1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: OCc1nccc(N2CCCCC2)n1
Yield: 89 %

Procedure:
Boron tribromide (6.1 ml) was added dropwise to a stirred solution of 2-methoxymethyl-4-piperidinopyrimidine (3.35 g) in dichloromethane (60 ml) at 0°-5° under nitrogen. After a further 30 minutes the mixture was poured onto ice, the pH raised to 13 (NaOH) and extracted with chloroform. The combined extracts were dried (K2CO3) and the volume reduced. Ether was added to give 2-hydroxymethyl-4-piperidino-pyrimidine (2.78 g) as a crystalline solid, m.p. 92°-3°.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:20]C)[C:14]=2[CH:18]=[O:19])[CH2:9]1)=O)(C)(C)C.[ClH:22]>C(OCC)(=O)C>[ClH:22].[OH:20][C:13]1[CH:12]=[CH:11][C:10]2[CH2:9][NH:8][CH2:17][CH2:16][C:15]=2[C:14]=1[CH:18]=[O:19]
Reactant: COc1ccc2c(c1C=O)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: O=Cc1c(O)ccc2c1CCNC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To 5-formyl-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.41 g, 4.84 mmol) in ethyl acetate (1.0 mL), a 3.3 M solution of anhydrous HCl in ethyl acetate was added and the mixture was stirred at room temperature for 2 h. The precipitated product was collected, washed with ethyl acetate and dried in air. In this manner the title compound (1.03 g, 4.52 mmol, 93.4%) was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:16])([C:13]([NH2:15])=[O:14])[C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:17]1([CH3:29])[CH:22]=[CH:21][C:20]([S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([O:16][C:27]([NH:26][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:29])=[CH:18][CH:19]=2)(=[O:25])=[O:24])=[O:28])([C:10]([NH2:12])=[O:11])[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: NC(=O)C(O)(C(N)=O)c1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)NC(=O)OC(C(N)=O)(C(N)=O)c2ccc(Cl)c(Cl)c2)cc1
Reaction time: 1 h
Yield: 30.4 %

Procedure:
26.3 g of 3,4-dichlorophenylhydroxymalonic acid diamide were dissolved in 350 ml of ethyl acetate at 65° C., and a solution of 19.7 g of p-toluenesulphonyl isocyanate was slowly added. After the mixture had been kept at 70° C. for 1 hour, it was cooled and filtered off with suction. 14 g of 3,4-dichlorophenyl-p-toluenesulphonylaminocarbonyloxy-malonic acid diamide (melting point 178° C., decomposition) were obtained. Further product was to be isolated from the mother liquor.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC([O-])(C)C.[Na+].Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O.O.C1(C)C=CC=CC=1>[C:26]([O:25][C:24](=[O:30])[NH:23][CH:20]1[CH2:21][CH2:22][N:17]([C:2]2[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[NH:11][C:12]3[S:13][CH:14]=[CH:15][N:16]=3)=[CH:4][CH:3]=2)[CH2:18][CH2:19]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
Prepared using general procedure 27. A mixture of 4-bromo-N-(thiazol-2-yl)benzenesulfonamide (500 mg, 1.57 mmol), tert-butyl piperidin-4-ylcarbamate (314 mg, 1.57 mmol), Pd2(dba)3 (43 mg, 0.05 mmol), 2-(di-t-butylphosphino)biphenyl (56 mg, 0.19 mmol), NaOtBu (423 mg, 4.4 mmol) and toluene (4 mL) was stirred at 70° C. for 3 h. After allowing the mixture to cool to RT, H2O (50 mL) and EtOAc (50 mL) were added. After acidifying with a 1 M HCl solution to pH 4, the layers were separated, and the aqueous phase was extracted 3 times with CH2Cl2 (50 mL). The combined organic extracts were dried over MgSO4 and absorbed onto Celite. Purification via silica gel chromatography using 10% MeOH in CH2Cl2 gave tert-butyl-1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)piperidin-4-ylcarbamate as an off-white foam (520 mg, 76%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=439.5; tR=2.56 min.