Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.C(COC)OC.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>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:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[CH:7][C:8]([CH3:12])=[N:9]3)=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(I)cc2n1
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1cc(N2CCCC2)c2ccc(-c3cccc(Cl)c3)cc2n1
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
A mixture of 1.5 g 7-iodo-2-methyl-4-pyrrolidin-1-yl-quinoline (Example 3.1), 256 mg tetrakis(triphenylphosphine)palladium and 30 ml Dimethoxyethane is stirred under argon for 15 min. 1.04 g 3-Chlorophenylboronic acid and 7 ml Ethanol are added. The resulting red solution is stirred for another 10 min. at room temperature and treated afterwards with 19 ml of a 2M aqueous solution of sodium carbonate. The mixture is refluxed for 1.5 h under vigorous stirring. After the reaction is complete, the reaction mixture is concentrated on a rotary evaporator. The residue is taken up in 50 ml water and extracted twice with 50 ml ethyl acetate. The combined organic phases are washed with 50 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate and filtered. The filtrate is evaporated and the residue is chromatographed on silica gel (eluent: Dichloromethane/Methanol 19:1 then 4:1). The pure fractions are combined and evaporated. 1.235 g of 7-(3-Chloro-phenyl)-2-methyl-4-pyrrolidin-1-yl-quinoline are obtained as a colorless oil. MS (ISP): 323.3 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:16]#[N:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+]>O.[Cu].[Cu]I>[N:18]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]([C:16]#[N:17])[C:11](=[O:15])[NH:12][C:13]=3[CH3:14])=[CH:4][CH:3]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: [Cu]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(-n2ccnc2)cc1
Temperature: 200 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
A mixture of 1,2-dihydro-5-(4-fluorophenyl)-6-methyl-2-oxo-3-pyridinecarbonitrile (5.0 grams), imidazole (25 grams), potassium carbonate (5 grams), copper (0.5 grams) and copper (I) iodide (0.5 grams) is heated just at 200° C. for 24 hours and then at 260° C. for 8 hours. After cooling, the reaction mixture is diluted with water and filtered. The filtrate is acidified with 6N hydrochloric acid and the precipitate is collected. This solid is boiled in 1 liter of methanol and the hot mixture is filtered. The filtrate is evaporated to a volume of 200 ml and cooled to give 0.7 grams of 1,2-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3-pyridinecarbonitrile: mp 300°-301° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:36])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:20]=[C:19]([NH:21][CH2:22][C@H:23]3[O:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]3)[C:18]3[C:13](=[N:14][CH:15]=[CH:16][N:17]=3)[CH:12]=2)=[CH:7][CH:6]=1.Cl>CC(=O)OCC>[CH3:36][N:4]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:20]=[C:19]([NH:21][CH2:22][C@H:23]3[O:28][CH2:27][CH2:26][NH:25][CH2:24]3)[C:18]3[C:13](=[N:14][CH:15]=[CH:16][N:17]=3)[CH:12]=2)=[CH:9][CH:10]=1)[CH2:3][CH2:2][OH:1]
Reactant: CN(CCO)c1ccc(-c2cc3nccnc3c(NC[C@@H]3CN(C(=O)OC(C)(C)C)CCO3)n2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(CCO)c1ccc(-c2cc3nccnc3c(NC[C@@H]3CNCCO3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-tert-butyl 2-((7-(4-((2-hydroxyethyl)(methyl)amino)phenyl)pyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholine-4-carboxylate was dissolved in EA (20 mL), 5M HCl in EA (10 mL) was added, the mixture was stirred at room temperature overnight. It was concentrated, treated with NH3.H2O, concentrated, purified by preparative TLC to give 10 mg reddish-brown solid. MS (m/z): 395 (M+H)+
Reaction SMILES: [C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Br:14])[C:6]1=[O:15])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].Cl>CO.O1CCCC1>[C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Br:14])[CH:6]1[OH:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1Cc2c(Br)cccc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C1Cc2c(Br)cccc2C1O

Procedure:
To a solution of 2-tert-butyl-4-bromo-1-indanone in a mixture of methanol (100 ml) and tetrahydrofuran (200 ml) was added sodium borohydride (1.58 g) at room temperature. After stirring at the same temperature, the reaction mixture was poured into dilute hydrochloric acid, and the aqueous layer was saturated with saline and extracted with ether. The organic layer was saturated with a saturated aqueous saline solution, dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residual concentrate (7.49 g) thus obtained was used for the next reaction without further purification.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH:6]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:17]([O:16][C:14]([NH:13][CH:6]([CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[CH2:5][CH2:4][C:3]([OH:21])=[O:2])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)CCC(NC(=O)OC(C)(C)C)C1CCCCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CCC(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-tert-butoxycarbonylamino-4-cyclohexyl-butyric acid methyl ester (9 g) in MeOH (100 mL) was added 1N NaOH (31 mL) and the reaction mixture was stirred at room temperature overnight. Citric acid (7 g) was then added, and the MeOH was removed under vacuum. The product was extracted with EtOAc (300 mL). The organic layer was washed with aqueous NaCl solution, dried with MgSO4, and evaporated to yield 4-tert-butoxycarbonylamino-4-cyclohexyl-butyric acid as an off white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.[CH3:12][NH:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH3:12])=[O:11]
Reactant: CCCCNC
Reactant: O=C(O)CCCCCCCBr
Product: CCCCN(C)C(=O)CCCCCCCBr

Procedure:
Using the procedure of Step A of Example 3, 5 g of 8-bromo octanoic acid and 13 ml of N-methyl butylamine were reacted to obtain after chromatography on silica (eluant: methylene chloride-acetone 95-5), 6.14 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[C:6]([S:8][CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:7]=1.[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1>[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20]([NH:16][C:4]1[CH:5]=[C:6]([S:8][CH:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)[CH:7]=[C:2]([F:1])[CH:3]=1)=[O:21]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: CN1CCC(Sc2cc(N)cc(F)c2)CC1
Solvent: C1COCCO1
Product: CN1CCC(Sc2cc(F)cc(NC(=O)c3ccc(F)cc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.4 %

Procedure:
Combine 3-fluoro-5-(1-methyl-piperidin-4-ylsulfanyl)-phenylamine (preparation 114, 0.11 g, 0.46 mmol), 1,4-dioxane (5 mL) and 2-chloro-4-fluoro-benzoyl chloride (0.09 g, 0.46 mmole), stir and heat at reflux. After 3 hr., cool to ambient temperature. Load on an SCX column (10 g), wash with methanol, elute with 2M ammonia/methanol. Concentrate eluent. Purify residue by silica gel flash chromatography eluting with 10% (2M NH3/methanol)/methylene dichloride to obtain the title compound (0.03 g, 17%). Mass spectrum: Obs. m/z 397.0974; calc. m/z 397.0953; 1H NMR (CDCl3) free base: 7.9 (bs, 1H), 7.8 (m, 1H), 7.4 (m, 1H), 7.3 (s, 1H), 7.2 (m, 1H), 7.1 (m, 1H), 6.9 (m, 1H), 3.2 (m, 1H), 2.8 (m, 2H), 2.3 (s, 3H), 2.0 (m, 4H), 1.7 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.O=[CH:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:22].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:22][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH3:20])[CH2:16][CH2:17]3)[C:11](=[O:18])[NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: O=C1NC[C@H](c2ccc(F)cc2)C12CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H](CN1CCC2(CC1)C(=O)NC[C@@H]2c1ccc(F)cc1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
A reaction mixture containing 0.25 g (1.0 mmol) of (R)-4-(4-fluorophenyl)-2,8-diazaspiro[4.5]decan-1-one, 0.25 g (1.44 mmol) of the (S)-tert-butyl 1-oxopropan-2-ylcarbamate, 2 mL of THF, 1 mL of DCM, and 1 g (2.5 mmol) of MP-sodium triacetoxyborohydride resin was rotated overnight. The reaction mixture was filtered and the solvents were removed under reduced pressure. The residue was subjected to silica gel chromatography to give 250 mg (61%) of tert-butyl (S)-1-((R)-4-(4-fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)propan-2-ylcarbamate as a colorless oil. 1HNMR (400 MHz, CD3OD) δ ppm 7.35-7.31 (m, 2H), 7.10-7.06 (m, 2H), 3.85 (brs, 1H), 3.73-3.68 (m, 1H), 3.55-3.51 (m, 2H), 3.39-3.27 (m, 1H), 3.10-2.87 (m, 2H), 2.78-2.59 (m, 3H), 2.01-1.72 (m, 5H), 1.42 (s, 9H), 1.32-1.20 (m, 1H), and 1.11 (d, 3H, J=2.4 Hz); LCMS m/z: 406.2 (M+H)+.
Reaction SMILES: II.[C:3]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[CH2:4][C:5]([O-:7])=O.C(N(CC)C(C)C)(C)C.[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:10]([O:9][C:3](=[O:8])[CH2:4][C:5]([NH:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([O:28][C:27]([F:26])([F:36])[F:37])[CH:30]=1)=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: II
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)OCc1ccccc1)Nc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.4 %

Procedure:
Preparation I2, Step 1: A solution of mono-benzyl malonate (1.1 g, 5.6 mmol) in 3:1 CH2Cl2/DMF (28 mL) was treated sequentially with N,N-diisopropylethylamine (2.5 mL, 14.0 mmol), meta-trifluoromethoxy-phenylamine (0.75 mL, 5.6 mmol), and HATU (2.6 g, 6.7 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide N-(3-trifluoromethoxy-phenyl)-malonamic acid benzyl ester as an oil (1.65 g).
Reaction SMILES: Cl[CH:2]1[CH:10]([CH:11]=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[N:19]1([C:2]2[N:3]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: O=CC1c2ccccc2N(c2cccnc2)C1Cl
Reactant: C1CNCCN1
Product: O=Cc1c(N2CCNCC2)n(-c2cccnc2)c2ccccc12
Yield: 23 %

Procedure:
2-chloro-1-(pyridin-3-yl)-1,3-dihydroindole-3-carboxaldehyde is reacted with piperazine as described in Example 2 to give, after flash chromatography, the title compound (23% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH3:11]>O1CCCC1>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:11])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)Cl)cc1
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
To an ice-cold solution of 4-amino-benzoyl chloride (0.38 g, 2.45 mmol) in tetrahydrofuran (2 ml) was added aqueous ammonia solution (15 ml). The reaction mixture was stirred at room temperature for 12 hr. The solvent was removed under vacuum, water added and the compound was extracted into ethyl acetate. The organic layer was dried and concentrated under vacuum. The crude compound was purified using silica gel column chromatography, using chloroform/methanol as eluent, to yield 4-amino-benzamide (0.1 g, 30%).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([F:27])[C:25]=1[F:26])[N:22]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:21]=[C:20]2[NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40]>O.O1CCOCC1.C(OCC)(=O)C.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:26][C:25]1[C:24]([F:27])=[C:23]2[C:19]([C:20]([NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[N:21][N:22]2[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:18][C:17]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2c(F)c(F)c(Br)cc12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2c(F)c(F)c(-c3ccccc3)cc12
Yield: 96.3 %

Procedure:
469 mg of phenylboronic acid, 760 mg of sodium carbonate in 30 cm3 of water and 379 mg of tetrakis(triphenylphosphine)palladium are added to 1.15 g of N-[5-bromo-6,7-difluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide prepared above, in 150 cm3 of dioxane, and the mixture is refluxed for 4 hours. The reaction medium is diluted with 100 cm3 of ethyl acetate and 75 cm3 of water and is filtered through a sinter funnel packed with Celite. The organic phase is separated out after settling of the phases, washed with 75 cm3 of water and with 75 cm3 of saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 2 g of crude product in the form of a black oil. The crude product is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40–60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (85/15 by volume). The fractions containing the expected product are combined, evaporated under reduced pressure (2 kPa; 50° C.) and dried (90 Pa, 45° C.) to give 1.1 g of N-[6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide in the form of a yellow oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][O:7][C:8](=[O:12])[C:9]([CH3:11])=[CH2:10])=[O:3].CN(C)C.[CH2:17]([OH:20])[C:18]#[CH:19]>C(Cl)Cl>[C:8]([O:7][CH2:6][CH2:5][O:4][C:2]([O:20][CH2:17][C:18]#[CH:19])=[O:3])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)C(=O)OCCOC(=O)Cl
Reactant: C#CCO
Agent: CN(C)C
Solvent: ClCCl
Product: C#CCOC(=O)OCCOC(=O)C(=C)C

Procedure:
A flask use in Example 1 was charged with 19.3 g of 2-methacryloyloxyethyl chloroformate and 11.5 g of trimethylamine in 50.0 g of methylene chloride. To the flask was added 7.0 g of propargyl alcohol dropwise over one hour. The mixture was allowed to react for 6 hours at 30° C. After the reaction, the mixture was processed as in Example 1 to give 2-propargyloxycarbonyloxyethyl methacrylate as colorless liquid. Yield, 53.6% of theory. The product was identified to be the same as the product of Example 1 by the IR spectrum and 1H--NMR.
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH2:12][CH3:13])=[C:9]([O:14][CH3:15])[C:8]([O:16][CH2:17][CH3:18])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:19].[Na+]>O.[Cu]>[CH2:12]([O:11][C:10]1[C:2]([OH:19])=[C:3]([CH:7]=[C:8]([O:16][CH2:17][CH3:18])[C:9]=1[O:14][CH3:15])[C:4]([OH:6])=[O:5])[CH3:13]
Reactant: CCOc1cc(C(=O)O)c(Br)c(OCC)c1OC
Reactant: [OH-]
Agent: [Cu]
Agent: [Na+]
Solvent: O
Product: CCOc1cc(C(=O)O)c(O)c(OCC)c1OC
Temperature: 120 °C

Procedure:
68 g of 2-bromo-3,5-diethoxy-4-methoxybenzoic acid prepared in Referential Example 4 was suspended in 260 ml of water and 32 g of caustic soda and 0.88 g of copper powder were added thereto. The mixture was heated at 120° C. for 3 hr while stirring, and then cooled. Carbon was added thereto, and the mixture was filtered through Celite. The filtrate was neutralized with 140 ml of 6 N hydrochloric acid and 1 l of chloroform was added thereto. The mixture was subjected to liquid-liquid separation. The organic phase was washed with water, dried and then concentrated to prepare 53 g of the crude product (ocherous solid).
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:26])=[NH:25]>>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][O:22][CH2:23][C:24]1[NH:26][C:8](=[O:10])[C:7]2[CH:6]=[CH:5][C:4]([F:11])=[N:3][C:2]=2[N:25]=1
Reactant: O=C(O)c1ccc(F)nc1F
Reactant: N=C(N)COCCc1ccccc1Cl
Agent: Cl
Product: O=c1[nH]c(COCCc2ccccc2Cl)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 2-[2-(2-chloro-phenyl)-ethoxy]-acetamidine hydrochloride. Light brown solid. MS: m/e=334.2 [M+H+].
Reaction SMILES: [F:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][C:5]=1[C:12]([F:15])([F:14])[F:13].S(Cl)([Cl:18])=O>>[Cl:18][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:2][F:1])=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:6]=1
Reactant: OCc1ccc(OCF)c(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Product: FCOc1ccc(CCl)cc1C(F)(F)F
Reaction time: 3 h
Yield: 80.3 %

Procedure:
(4-(Fluoromethoxy)-3-(trifluoromethyl)phenyl)methanol (1.84 g, 8.21 mmol) was dissolved in thionyl chloride (8.09 mL, 111 mmol) and stirred for 3 h. The reaction was taken up in hexanes and washed with water (twice), saturated NaHCO3, and water. The organics were dried over MgSO4, filtered and concentrated under vacuum to give the title compound as a solid (1.60 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.83 (s, 2H), 5.83-6.14 (d, J=53.1 Hz, 2H), 7.46 (d, J=8.46 Hz, 1H), 7.69-7.87 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.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.O>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[CH3:15])[CH:5]=[N:6][CH:7]=2)=[CH:26][CH:25]=1
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(-c2cncc(OC[C@@H]3CCCN3C)c2)cc1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
To s solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (272 mg, 1.00 mmol) in benzene (2.0 mL) were added sodium carbonate (2.0 M, 1.0 mL), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol) and 4-methoxyphenylboronic acid (228 mg, 1.30 mmol). The reaction mixture was refluxed overnight, then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH4OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (174 mg, 58%). MS (CI/NH3) m/z 299 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.71-1.92 (m, 3H), 1.99-2.10 (m, 1H), 2.51 (s, 3H), 2.65-2.74 (m, 1H), 3.09-3.17 (m, 1H), 3.87 (s, 3H), 3.96-4.11 (m, 2H), 7.00 (d, J=8.8 Hz, 1H), 7.36 (t, J=3.0 Hz, J=2.1 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 8.27 (d, J=3.0 Hz, 1H), 8.42 (d, J=2.1 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([F:15])([F:14])[O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO.C1COCC1.O>[F:15][C:5]([F:14])([O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:4]([OH:16])=[O:3]
Reactant: CCOC(=O)C(F)(F)Oc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(F)(F)Oc1ccc(F)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2-difluoro-2-(4-fluorophenoxy)acetic acid ethyl ester (2.9 g, 12 mmol) in a mixture of MeOH (20 ml) and THF (10 ml) was added a solution of NaOH (1.48 g, 37 mmol) in water (10 ml). The reaction mixture was stirred 20 h at rt and 1 h at 40° C. The reaction mixture was concentrated and the remaining aqueous solution was diluted with water (10 ml) and washed with hexanes. The solution was acidified to pH 3 by adding 1N HCl and the heterogeneous mixture was extracted with ethyl acetate. The combined extracts were washed with brine and after drying over sodium sulfate, the solvent was removed to obtain 2,2-difluoro-2-(4-fluorophenoxy)acetic acid as
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH:5]([NH2:8])[C:6]#[N:7])[CH3:2].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:34][O:35][CH2:36][CH2:37][C:38](O)=[O:39]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:9])[CH:5]([C:6]#[N:7])[NH:8][C:38](=[O:39])[CH2:37][CH2:36][O:35][CH3:34])[CH3:2]
Reactant: COCCC(=O)O
Reactant: CCOC(=O)C(N)C#N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)NC(=O)CCOC
Temperature: 0 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
A solution of aminocyanacetic acid ethyl ester (1.00 g, 7.80 mmol) in ethyl acetate (16.00 ml) was cooled to 0° C. and treated with dimethylaminopyridine (0.09 g, 0.78 mmol) and dicyclohexylcarbodiimide (1.93 g, 9.36 mmol). 3-Methoxy-propionic acid (0.81 g, 7.80 mmol) was added portionwise. After completed addition, the mixture was stirred at 0° C. for 1 h) then at room temperature for 3 h. The precipitated dicyclohexylurea was filtered off and the mother liquors washed with water, dried over sodium sulphate and evaporated. The residue was purified by trituration in diisopropylether to yield cyano-(3-methoxy-propionylamino)-acetic acid ethyl ester (1.27 g, 76%), MS (ISP): m/e=215.3 (M+H+).