Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[NH:6][N:5]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH:1]([C:4]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[N:6]([CH2:19][C:20]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:26][CH2:27]2)=[O:21])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C(C)C)[nH]n1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)c1cc(C(C)C)n(CC(=O)N2CCN(c3ccc(F)cc3)CC2)n1

Procedure:
Protocol T was followed using 3,5-Diisopropyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 6.92-7.0 (m, 2H), 6.80-6.88 (dd, 2H), 5.88 (s, 1H), 4.92 (s, 2H), 3.70-3.80 (t, 4H), 2.90-3.10 (m, 4H), 1.40-1.60 (m, 12H). 13C NMR (400 MHz, CDCl3): 160.6, 158.2, 150.2, 119.2, 118.0, 100.0, 50.8, 50.5, 50.2, 45.2, 42, 28.2, 26.0, 22.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]3[CH:19]=[CH:20][N:21]=[C:9]23)=[C:4]([F:22])[CH:3]=1.[N+:23]([O-])([OH:25])=[O:24].S(=O)(=O)(O)O>>[Cl:1][C:2]1[C:7]([N+:23]([O-:25])=[O:24])=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[N:10]3[CH:19]=[CH:20][N:21]=[C:9]23)=[C:4]([F:22])[CH:3]=1
Reactant: O=c1cc(C(F)(F)F)n2ccnc2n1-c1ccc(Cl)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1cc(C(F)(F)F)n2ccnc2n1-c1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 0 °C

Procedure:
8-(4-Chloro-2-fluorophenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (0.8 g) was added to a mixture of concentrated nitric acid (60%, d=1.38; 1 ml) and concentrated sulfuric acid (10 ml) under ice-cooled condition. The mixture was reacted for 30 minuets at 0° C., poured into ice water (150 ml) and then extracted with ether. The extract layer was washed with water, an aqueous saturated sodium hydrogencarbonate solution and water in this order, and dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the compound of interest (0.65 g) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([NH:41][C@H:42]([C:45]([NH2:47])=[O:46])[CH2:43][OH:44])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[OH-].[Na+].[Cl-].[Na+]>CO.ClCCl>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH2:41][C@H:42]([C:45]([NH2:47])=[O:46])[CH2:43][OH:44]
Reactant: NC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: NC(=O)[C@@H](N)CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(Z)-1-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-ethene-Fmoc-L-serineamide (1.04 g, 1.56 mmols) was dissolved in 10 ml of methanol and 10 ml of dichloromethane, and 1.7 ml (3.4 mmols) of an aqueous solution of 2-N sodium hydroxide were added thereto. The mixture was stirred at room temperature for 24 hours. A saturated aqueous solution of sodium chloride was added thereto, and the resulting mixture was extracted three times with dichloromethane. The extract was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The product was purified using a silica-gel plate (mixture of 5-% by volume methanol and dichloromethane) to produce 315 mg of the final compound in a yield of 50.2%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][O:46][C:47]1[CH:48]=[C:49]([CH:52]=[C:53]([O:55][CH3:56])[CH:54]=1)[CH2:50][NH2:51]>CN(C=O)C>[CH3:56][O:55][C:53]1[CH:52]=[C:49]([CH:48]=[C:47]([O:46][CH3:45])[CH:54]=1)[CH2:50][NH:51][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:22]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: COc1cc(CN)cc(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc(OC)c1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 3,5-dimethoxybenzylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-(3,5-dimethoxybenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide. LCMS; retention time 3.32 min, MH+ 444.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[C:18]([CH2:19][Cl:20])=[N:17][C:16]([C:21]([OH:23])=[O:22])=[N:15]1)=[O:6].[CH3:28]O>>[CH3:28][O:22][C:21]([C:16]1[N:17]=[C:18]([CH2:19][Cl:20])[N:14]([C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[C:5](=[O:6])[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=2[Cl:2])[N:15]=1)=[O:23]
Reactant: O=C(O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Reactant: CO
Agent: Cl
Product: COC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1

Procedure:
270 ml of a 6 N solution of hydrogen chloride in methanol is added to a solution of 133.0 g (0.30 mole) of 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid (crystals containing an equimolar amount of methanol; see German `Offenlegungschrift` No. 2,159,527, page 32) in 1400 ml of methanol, and the whole is refluxed for 18 hours. The reaction mixture is then concentrated in vacuo; water is added to the residue and extraction is performed twice with methylene chloride. The organic phase is washed once with saturated potassium bicarbonate solution, twice with water and once with saturated sodium chloride solution; it is subsequently dried over sodium sulphate and concentrated in vacuo. The residue is recrystallised from 1 liter of methanol. After drying there is obtained 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 130°-132°.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[C:6]([Br:13])[C:3]=1[CH2:4][NH2:5].C([O-])([O-])=O.[Na+].[Na+].[C:20](ON1C(=O)CCC1=O)([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21]>O1CCOCC1>[C:20]([NH:5][CH2:4][C:3]1[C:2]([Br:1])=[CH:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=1[Br:13])([O:22][CH2:23][CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[C:36]1=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:21]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: NCc1c(Br)cc(C(=O)O)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NCc1c(Br)cc(C(=O)O)cc1Br)OCC1c2ccccc2-c2ccccc21
Yield: 88.2 %

Procedure:
To a solution of 2,6-dibromo-4-carboxybenzylamine (20 g, 0.064 mol) in dioxane (500 mL), was added an aqueous solution of Na2CO3 (10%, 410 mL) with stirring. After stirring at 26° C. for 15 min was added Fmoc-OSu (30.5 g, 0.09 mol) in portions for 2 h and allowed to stir at ambient temperature for 24 h. The solid precipitate was filtered off and washed with diethyl ether (3×200 mL), followed by methanol (3×200 mL). The solid salt was acidified with an aqueous solution of HCl (3 N, 100 mL) to pH=2. The precipitate was filtered under suction and dried. The crude solid was recrystalised from methanol/diethyl ether to give N-(Fmoc)-2,6-dibromo-4-carboxybenzylamine (30 g, 87%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12]([OH:14])=O.[F:15][C:16]1([F:33])[CH2:21][CH2:20][N:19]([CH:22]([C:25]2[CH:26]=[N:27][C:28]([S:31][CH3:32])=[N:29][CH:30]=2)[CH2:23][NH2:24])[CH2:18][CH2:17]1>>[F:33][C:16]1([F:15])[CH2:21][CH2:20][N:19]([CH:22]([C:25]2[CH:26]=[N:27][C:28]([S:31][CH3:32])=[N:29][CH:30]=2)[CH2:23][NH:24][C:12]([C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[N:8][C:9]=3[CH:10]=[CH:11][C:2]=2[Cl:1])=[O:14])[CH2:18][CH2:17]1
Reactant: CSc1ncc(C(CN)N2CCC(F)(F)CC2)cn1
Reactant: O=C(O)c1c(Cl)ccc2ncccc12
Product: CSc1ncc(C(CNC(=O)c2c(Cl)ccc3ncccc23)N2CCC(F)(F)CC2)cn1

Procedure:
Compound 582, 6-chloro-quinoline-5-carboxylic acid [2-(4,4-difluoro-piperidin-1-yl)-2-(2-methylsulfanyl-pyrimidin-5-yl)-ethyl]-amide was prepared analogous to Example B.30 by coupling 6-chloro-quinoline-5-carboxylic acid and 2-(4,4-difluoro-piperidin-1-yl)-2-(2-methylsulfanyl-pyrimidin-5-yl)-ethylamine.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:21]([C:24]1[CH:30]=[CH:29][C:27](N)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>COC(C)CCO.[Cu]>[N+:21]([C:24]1[CH:30]=[CH:29][C:27]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][CH2:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH2:2][CH2:3]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCc2cc(CCCN3CCNCC3)ccc2N1
Agent: [Cu]
Agent: COC(C)CCO
Agent: O=C([O-])[O-]
Product: O=C1CCc2cc(CCCN3CCN(c4ccc([N+](=O)[O-])cc4)CC3)ccc2N1

Procedure:
2.87 Grams of 6-(3-piperazinylpropyl)-3,4-dihydrocarbostyril, 2.0 g of p-nitroaniline, 0.8 g of potassium carbonate and 0.2 g of copper powder were mixed in 80 ml of 3-methoxybutanol and refluxed by heating for 5 hours. Then 3 g of activated carbon was added to the reaction mixture and filtered with Celite, then the mother liquor was concentrated under a reduced pressure to obtain a residue. The residue was purified by a silica-gel chromatography and recrystallized from isopropanol to obtain 0.55 g of 6-{3-[4-(4-nitrophenyl)-1-piperazinyl]propyl}-3,4-dihydrocarbostyril in yellow needle-like crystals, having the melting point of 189°-192° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: Nc1ccc(Br)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.97 g, 9.2 mmol) was dissolved in 150 mL dry diethyl ether under Ar, cooled in an ice water bath, added dry pyridine (3.7 mL, 45.8 mmol) followed by the dropwise addition of oxalyl chloride (2 mL, 22.9 mmol). A precipitate forms immediately. The reaction was stirred vigorously at 0° C. for 2 hours, then at ambient temperature for one hour. Added 100 mL diethyl ether, filtered off solids washing with diethyl ether. Concentrated the filtrates to an off-white oil. Redissolved oil in 100 mL dry DCM under Ar, cooled to 0° C., added 3 mL pyridine followed by 2-amino-5-bromopyridine (1.32 g, 7.6 mmol). The reaction was allowed to warm to ambient temperature, stirred for 3 hours then concentrated. Redissolved in 250 mL EtOAc, washed with 10% HCl (3×100 mL), brine (100 mL), dried with MgSO4, filtered and concentrated to yield title compound as a yellow sticky solid. (2.74 g, 97%) APCI (AP−): 368.0, 370.0 (M−H)−.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15]1([Mg]Br)[CH2:17][CH2:16]1>C1COCC1>[CH:15]1([C:12]2([OH:13])[N:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:9](=[O:14])[CH2:10][CH2:11]2)[CH2:17][CH2:16]1
Reactant: O=C1CCC(=O)N1Cc1ccccc1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: O=C1CCC(O)(C2CC2)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
To 1-(phenylmethyl)-2,5-pyrrolidinedione (1 g, 5.29 mmol) in THF (50 mL) at −78° C. was added cyclopropylmagnesium bromide (42.3 mL, 21.1 mmol) dropwise. The reaction mixture was allowed to warm to 0° C. and stirred for an additional 2 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride and transferred to a separatory funnel. EtOAc was added, and the organic phase was separated. The aqueous layer was further extracted with EtOAc, and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% hexanes to 80% EtOAc/hexanes) afforded the title compound (400 mg, 33%) as a yellow solid. LC-MS (ES) m/z=232 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([O:1][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C)nc(O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1nc(C)cc(C)n1
Yield: 26.8 %

Procedure:
2-Hydroxy-4,6-dimethyl pyrimidine (10g, 0.08 mol) was dissolved in 150ml of dimethylformamide. Ethyl bromoacetate (13.5g, 0.08 mol) was added and also, subsequently, 11.lg of potassium carbonate. The reaction mixture was refluxed overnight. A precipitate had formed which was filtered off and the solvent was then evaporated off from the filtrate to form a crude oily product. Following purification by flash chromatography, 4.5g of the title product were obtained in the form of a red oil.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][C:11]1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:10]([O:8][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9])[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1CCCCC1
Solvent: CCO
Product: CCOC(=O)C1CCCCC1
Temperature: 78.5 °C
Reaction time: 8 h
Yield: 2904.2 %

Procedure:
To a solution of cyclohexanecarboxylic acid (23.1 g, 180 mmol) in ethanol (100 mL) was added p-TsOH (1.027 g, 5.4 mmol). The mixture was heated to 78-79° C., and for several hours solvent was slowly distilled off whereas the volume was kept relatively constant by addition of fresh ethanol. Stirring at reflux temperature was continued overnight. An additional portion of p-TsOH (685 mg, 3.6 mmol) was added and the reaction mixture was stirred at 79° C. for an additional 5 h. The cooled reaction mixture was concentrated to nearly ¼ volume, diluted with TBME and extracted with cold aq. NaHCO3. The aqueous phase was extracted with TBME. The organic phases were washed with water until neutral, combined, dried over sodium sulfate and concentrated to give 26.5 g crude product which was distilled at 40° C. (0.25 mbar) to afford 24.5 g (87%) cyclohexanecarboxylic acid ethyl ester, GC purity >99% (area). 1H-NMR (CDCl3, 300 MHz): ppm 1.22 (t, 3H), 1.08-1.80 (m, 8H), 1.85-1.92 (m, 2H), 2.23-2.32 (m, 1H), 4.11 (q, 2H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:24])=[C:11]([N:16]4[CH2:21][CH:20]([CH3:22])[NH:19][CH:18]([CH3:23])[CH2:17]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:25])[C:6]([C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])=[O:27])=[CH:5]2)[CH2:3][CH2:2]1.[N:38]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:39]=[O:40]>ClCCl>[CH2:45]([O:44][C:42](=[O:43])[CH2:41][NH:38][C:39]([N:19]1[CH:18]([CH3:23])[CH2:17][N:16]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:25])[C:6]([C:26]([NH:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])=[O:27])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:24])[CH2:21][CH:20]1[CH3:22])=[O:40])[CH3:46]
Reactant: CCOC(=O)CN=C=O
Reactant: COc1c(N2CC(C)NC(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(C3CC3)c12
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)N1C(C)CN(c2c(F)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4Cl)cn(C4CC4)c3c2OC)CC1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.18 mmol) of the compound from Example 39A are added to a solution of 25 mg (0.22 mmol) of ethyl isocyanatoacetate in 5 ml of dichloromethane. The reaction mixture is stirred at RT overnight. After the removal of the solvent on a rotary evaporator, the residue is purified by RP-HPLC (method 6). 73 mg (59% of theory) of the title compound are obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)=[CH:5][CH:4]=1.[O:23]([CH2:30][CH2:31][CH2:32]Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH:11]2[CH2:15][CH2:14][N:13]([CH2:32][CH2:31][CH2:30][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:12]2)=[CH:7][CH:8]=1
Reactant: BrCCCOc1ccccc1
Reactant: Fc1ccc(NC(c2ccc(F)cc2)C2CCNC2)cc1
Agent: Cl
Product: Fc1ccc(NC(c2ccc(F)cc2)C2CCN(CCCOc3ccccc3)C2)cc1

Procedure:
The title compound is prepared from N,α-bis(4-fluorophenyl)-3-pyrrolidinemethanamine hydrochloride and 3-phenoxypropylbromide according to the procedure of Example 8.
Reaction SMILES: [OH-].[Na+].[C:3]([OH:10])(=[O:9])/[CH:4]=[CH:5]/[CH:6]=[CH:7]/[CH3:8].[Cl-].[Zn+2:12].[Cl-]>O>[C:3]([O-:10])(=[O:9])/[CH:4]=[CH:5]/[CH:6]=[CH:7]/[CH3:8].[Zn+2:12].[C:3]([O-:10])(=[O:9])/[CH:4]=[CH:5]/[CH:6]=[CH:7]/[CH3:8]
Reactant: C/C=C/C=C/C(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C/C=C/C=C/C(=O)[O-]
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 76.5 %

Procedure:
A solution of 47% (w/w) sodium hydroxide (5.5 g) is added to slurry of sorbic acid (5.6 g, 0.05 mol) in water (100 mL) at 70° C. to give a clear slightly alkaline solution. A solution of zinc chloride (3.4 g, 0.025 mol) in water (50 mL) is added and a precipitate is formed immediately. The mixture is stirred at 70° C. for further 2.5 hours. The precipitate is then filtered and dried to yield 5.5 g (76%) zinc sorbate as a fine white powder. IR absorption bands: 1521 and 1418 cm−1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:13][CH2:14][CH3:15])[N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:16]1([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[NH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:16]1([C:22](=[N:23][C:2]2[CH:3]=[C:4]([CH:10]=[C:11]([O:13][CH2:14][CH3:15])[N:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cc(Cl)nc(OCC)c1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(N=C(c2ccccc2)c2ccccc2)nc(OCC)c1
Temperature: 110 °C
Yield: 94.4 %

Procedure:
The compound prepared in Example 229 (0.26 g), diphenylmethanimine (0.24 g), cesium carbonate (1.8 g), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.070 g) and Pd(OAc)2 (0.013 g) were dissolved in degassed toluene (4.5 mL) and then heated under argon at 110° C. for 1 hr. The reaction was cooled, diluted with ethyl acetate and filtered through celite (trade mark) with an ethyl acetate wash. The combined organic solutions were purified by column chromatography using an eluant of 0-2% ethyl acetate/dichloromethane to provide the title compound (0.40 g) with the following physical data.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](O)[C:5]2[S:9][C:10]([CH2:12][CH3:13])=[CH:11][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[CH3:1][C:2]1[N:7]=[C:6]([Cl:16])[C:5]2[S:9][C:10]([CH2:12][CH3:13])=[CH:11][C:4]=2[N:3]=1
Reactant: CCc1cc2nc(C)nc(O)c2s1
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1cc2nc(C)nc(Cl)c2s1
Yield: 74 %

Procedure:
2-Methyl-4-hydroxy-6-ethylthienopyrimidine (0.71 g) was dissolved in phosphorus oxychloride (10 mL) and heated to reflux for 19 hours. After concentrating to dryness, the residue was diluted with water (20 mL) and the product was extracted with methylene chloride (3×5 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified on silica gel (50% ethyl acetate/hexane) giving 2-methyl-4-chloro-6-ethylthienopyrimidine (0.58 g). Yield=74%, Rf=0.73 (25% ethyl acetate/hexane).
Reaction SMILES: [CH:1]12[N:8]([C:9]3[CH:14]=[C:13]([CH2:15][N:16]([CH3:18])[CH3:17])[N:12]=[C:11]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH:29]5[CH2:31][CH2:30]5)=[O:27])=[CH:21][CH:20]=4)[N:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=CC(NC(NC3C=CC(B4OC(C)(C)C(C)(C)O4)=CC=3)=O)=C[CH:40]=2)[CH2:35][CH2:34]1>>[CH:1]12[N:8]([C:9]3[CH:14]=[C:13]([CH2:15][N:16]([CH3:17])[CH3:18])[N:12]=[C:11]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]5[CH:31]=[CH:44][C:39]([N:36]6[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]6)=[CH:40][CH:30]=5)=[O:27])=[CH:21][CH:20]=4)[N:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2
Reactant: CN(C)Cc1cc(N2C3CCC2COC3)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Reactant: CN1CCN(c2ccc(NC(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Product: CN(C)Cc1cc(N2C3CCC2COC3)nc(-c2ccc(NC(=O)Nc3ccc(N4CCN(C)CC4)cc3)cc2)n1

Procedure:
A procedure analogous to that used for the preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-cyclopropylurea was used, using 1-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as the boronic ester component. Yield=0.128 g, 65%. MS; 557.5, M+H.
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45](O)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1.[CH3:50][N:51]1[CH:55]=[C:54]([CH2:56][NH2:57])[CH:53]=[N:52]1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45]([NH:57][CH2:56][C:54]4[CH:53]=[N:52][N:51]([CH3:50])[CH:55]=4)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:48][CH:49]=1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cn1cc(CN)cn1
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cnn(C)c1
Yield: 63 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with (1-methyl-1H-pyrazol-4-yl)methanamine, the title compound was obtained as a white solid in 63% yield: mp 205-206° C. (ethyl acetate/hexane); NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), 7.45 (s, 1H), 7.41-7.32 (m, 3H), 7.07-6.98 (m, 2H), 5.88 (t, J=5.3 Hz, 1H), 4.97 (s, 2 H), 4.42 (d, J=5.3 Hz, 2H), 3.88 (s, 3H), 2.62 (s, 3H); MS (ES+) m/z 428.2 (M+1).