Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[CH2:19][N:18]([CH2:20][C:21]([O:23]C)=[O:22])[C:17](=[O:25])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].Cl.O>CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][N:18]([CH2:20][C:21]([OH:23])=[O:22])[C:17](=[O:25])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CN1C[C@H](c2ccc(OC)c(OC3CCCC3)c2)CC1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C2CC(=O)N(CC(=O)O)C2)cc1OC1CCCC1
Reaction time: 10 h
Yield: 100.8 %

Procedure:
Methyl (4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone-1-acetate (250 mg, 0.72 mmol) was treated with 8 mL of a 1M solution of potassium hydroxide in 95% methanol. After 10 hours, the reaction solution was acidified with 2N HCl to pH 3, and 30 mL of water was added. The resulting mixture was then extracted with ethyl acetate (2×60 mL) and the organic layer was concentrated. Chromatographic purification (methanol/dichloromethane 5:100) afforded 242 mg (quantitative yield) of 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone-1-acetic acid: 1H NMR (300 MHz, CDCl3) δ 6.85-73 (m, 3H), 4.84-4.74 (m, 1H), 4.20 (d, J=12.0 Hz, 1H), 4.12 (d, J=12.0, 1H), 3.82 (s, 4H), 3.66-3.46 (m, 2H), 2.89 (dd, J=16.8, 8.7 Hz, 1H), 2.58 (dd, J=16.8, 8.4 Hz, 1H), 2.00-1.72 (b, 6H), 1.70-1.50 (b, 2H).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH:19]([NH2:22])([CH3:21])[CH3:20]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:22][CH:19]([CH3:21])[CH3:20])[N:6]=1)[CH:2]=[CH2:3]
Reactant: CC(C)N
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: O
Product: C=CCNc1nc(NC(C)C)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
A mixture of 250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 694 mg (11.74 mmol) of isopropylamine was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and crystals thus precipitated were filtered to give 270 mg (yield: 99.4%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(=O)([O-])[O-].[Na+].[Na+].O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:29](Cl)=[O:30])[CH2:28][CH2:27][C:22]3([O:26][CH2:25][CH2:24][O:23]3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>CC1C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:29]([N:2]([CH3:3])[CH3:1])=[O:30])[CH2:28][CH2:27][C:22]3([O:26][CH2:25][CH2:24][O:23]3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(C2(C(=O)Cl)CCC3(CC2)OCCO3)cc1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C2(C(=O)N(C)C)CCC3(CC2)OCCO3)cc1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred and cooled (<0° C.) mixture of 49.5 parts of N-methylmethanamine solution 40%, 93 parts of sodium carbonate and 1000 parts of water is added dropwise a solution of 124 parts of 8-(4-methoxyphenyl)-1,4-dioxaspiro[4,5]decane-8-carbonyl chloride in 675 parts of methylbenzene. Upon completion, stirring is continued overnight at room temperature. The layers are separated and the organic phase is washed with water, dried, filtered and evaporated, yielding 128 parts (100%) of 8-(4-methoxyphenyl)-N,N-dimethyl-1,4-dioxaspiro[4,5]decane-8-carboxamide as a residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][C:3]=1[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:12])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(CCCO)ccc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(CCCBr)ccc1F
Reaction time: 4 h
Yield: 41.2 %

Procedure:
Compound 44-3 (5.47 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (9.39 g) and N-bromosuccinimide (6.37 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 4 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.10 g) as a colorless oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:13]([O:18][C@@H:19]3[O:36][C@H:35]([CH2:37][O:38]C(=O)C)[C@@H:30]([O:31]C(=O)C)[C@H:25]([O:26]C(=O)C)[C@H:20]3[O:21]C(=O)C)=[N:14][NH:15][C:16]=2[CH3:17])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C@@H:19]1([O:18][C:13]2[C:12]([CH2:11][C:8]3[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[CH:6][CH:7]=3)=[C:16]([CH3:17])[NH:15][N:14]=2)[O:36][C@H:35]([CH2:37][OH:38])[C@@H:30]([OH:31])[C@H:25]([OH:26])[C@H:20]1[OH:21]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a solution of 4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (61 mg) in ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (0.53 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent:distilled water, eluent:methanol) to give 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)-methyl]-5-methyl-1H-pyrazole (39 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:48]2[CH2:47][CH2:46][CH:45]([NH:44][C:36]3[NH:35][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=3)[CH2:50][CH2:49]2)([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(F)cc3)C2)cc(OC)c1OC
Agent: I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)cc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 4.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (2.65 g, 5.5 mmol) (prepared from (+)-1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine) and (1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt (3.9 g, 8.25 mmol) to give, after chromatography on silica gel eluting with methanol/ethyl acetate 1/1, the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:15][OH:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[C:10]([CH:15]=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ncccc1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: O=Cc1ncccc1OCc1ccccc1
Temperature: 80 °C

Procedure:
(3-(benzyloxy)pyridin-2-yl)methanol (87 g, 400 mmol) was dissolved in anhydrous dioxane (80 mL). Manganese dioxide (351 g) was added and the mixture was heated for 2 hours at 80° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:35])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:35])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[CH:34]=[CH:33][N:32]=[CH:31]4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {5-chloro-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M49) (0.15 g, 0.29 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (55 mg, 47%).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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].C(Cl)Cl>[CH3:25][C:26]1[CH:31]=[C:30]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[S:17][C:18]5[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=5[N:20]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH:29]=[CH:28][N:27]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: Clc1nccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)ccn1
Temperature: 100 °C

Procedure:
A suspension of N-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (180 mg, 0.507 mmol), 2-methylpyridin-4-ylboronic acid (278 mg, 2.03 mmol), PdCl2(dppf)-CH2Cl2 adduct (41.4 mg, 0.051 mmol), and sodium carbonate (323 mg, 3.04 mmol) in 1,4-dioxane (3 mL) and water (2 mL) was sparged with argon for 5 min, then heated to 100° C. for 2 h. The reaction mixture was partitioned between EtOAc and 1M NaOH. The aqueous layer was extracted with EtOAc (2×) and the combined organics was dried over Na2SO4 and concentrated. The crude material was absorbed on Silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 70% EtOAc in hexane, to provide N-(4-(3-(2-methylpyridin-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine as white solid. MS (ESI, pos. ion) m/z: 412.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[Br-].[O:16]1CCO[CH:17]1[CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOCCN(CCOCCOC)CCOCCOC>ClCCl.C([O-])([O-])=O.[K+].[K+]>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10](/[CH:11]=[CH:21]/[CH:17]=[O:16])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(-c2ncccn2)cc1
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Product: O=C/C=C/c1ccc(-c2ncccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A mixture of 4-(2-pyrimidinyl)-benzaldehyde (1.83 g, 9.94 mmol, prepared as described in WO 9828264), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (6.45 g, 15.02 mmol), and TDA-1 (3.20 mL, 10.00 mmol) in dichloromethane (50 mL) and sat. aq. K2CO3 (50 mL) was heated to reflux for 20 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. THF (25 mL) and 10% HCl (25 mL) were added and the mixture was stirred for 1 h at rt. The mixture was cooled to 0° C., the precipitated solids were removed by filtration, washed with water and air-dried. Recrystallization from 2-propanol provided 1.20 g (57%) of the title compound as a light yellow solid. MS 211 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=O)[C:11]([C:16]#[N:17])=[CH:12][NH:13]2)=[CH:8][CH:7]=1.S(Cl)([Cl:21])=O>CN(C)C=O>[Cl:21][C:10]1[C:9]2[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=2)[N:13]=[CH:12][C:11]=1[C:16]#[N:17]
Reactant: COCCOc1ccc2c(=O)c(C#N)c[nH]c2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(Cl)c(C#N)cnc2c1

Procedure:
Following the procedure of Reference Example 32, 7-(2-methoxyethoxy)-4-oxo-1,4-dihydroquinoline-3-carbonitrile (800 mg, 3.28 mmol), thionyl chloride and a catalytic amount of N,N-dimethylformamide provides 748 mg of 4-chloro-7-(2-methoxyethoxy)quinoline-3-carbonitrile as an off-white solid solid, mp 143-145° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]#[N:7].Cl.[NH2:9][OH:10].N1C=CC=CC=1>CCO>[OH:10][NH:9][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[NH:7]
Reactant: N#Cc1nccs1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: N=C(NO)c1nccs1

Procedure:
To a solution of thiazole-2-carbonitrile (0.42 g, 3.80 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (0.53 g, 7.60 mmol) and pyridine (0.27 g, 3.40 mmol). The resulting reaction mixture was refluxed for 15 h. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added EtOH and filtered. The filtrate was evaporated under reduced pressure and used as such for the next step (crude yield 0.50 g, 91% crude yield).
Reaction SMILES: C(O)C.Cl[C:5]1[N:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1.[CH3:14][NH2:15]>C1COCC1>[CH3:14][NH:15][C:5]1[N:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1
Reactant: CN
Reactant: CC(=O)c1ccc(Cl)nc1
Solvent: C1CCOC1
Solvent: CCO
Product: CNc1ccc(C(C)=O)cn1
Temperature: 130 °C

Procedure:
A mixture of 2 mL of ethanol, 280 mg (1.80 mmol) of 1-(6-chloropyrid-3-yl)ethanone and 4.50 mL (9 mmol) of a 2 M solution of methylamine in THF is heated in a Biotage microwave reactor at 130° C. for 30 minutes. The reaction medium is evaporated to dryness. The crude product is taken up in water and extracted with EtOAc. The organic phase is dried over magnesium sulfate and evaporated to dryness. 258 mg of 1-(6-methylaminopyrid-3-yl)ethanone are obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O-].[Na+].Cl[CH2:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[C:19]([NH2:25])=[N:20][C:21](N)=[N:22][CH:23]=2)[C:14]([CH:26]([CH3:28])[CH3:27])=[CH:13][C:12]=1[O:29][CH3:30])=[O:9]>CO>[NH2:25][C:19]1[C:18]([O:17][C:15]2[C:14]([CH:26]([CH3:28])[CH3:27])=[CH:13][C:12]([O:29][CH3:30])=[C:11]([N:10]3[CH2:5][CH2:6][CH2:7][C:8]3=[O:9])[CH:16]=2)=[CH:23][N:22]=[C:21]([CH3:1])[N:20]=1
Reactant: C[O-]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1NC(=O)CCCCl
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(C)C)c(Oc2cnc(C)nc2N)cc1N1CCCC1=O
Yield: 47 %

Procedure:
To a solution of 5 ml 1.9 M NaOMe in MeOH was added 4-Chloro-N-[5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-butyramide (0.495 g, 1.3 mmol). After 6 h the solution was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with H2O, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 1-[5-(4-amino-2-methyl-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-pyrrolidin-2-one (0.230 g, 47%) as white solid; [MH]+=358; mp (HCl salt)>300° C.
Reaction SMILES: [I-:1].[K+].S(F)(O[C:7]([F:14])([F:13])[C:8]([F:12])=[C:9]([F:11])[F:10])(=O)=O>COCCOCCOCCOCCOC>[F:13][C:7]([I:1])([F:14])[C:8]([F:12])=[C:9]([F:11])[F:10]
Reactant: [I-]
Reactant: O=S(=O)(F)OC(F)(F)C(F)=C(F)F
Agent: COCCOCCOCCOCCOC
Agent: [K+]
Product: FC(F)=C(F)C(F)(F)I
Temperature: 20 °C
Reaction time: 12 h

Procedure:
Perfluoroallyl iodide (CF2CFCF2I) was prepared by transferring 8.5 g of dry potassium iodide, 20 ml of tetraglyme and 42.5 millimoles of perfluoroallyl fluorosulfate by vacuum line to a 100-ml flask. The mixture was warmed to 20° C. and stirred for 12 hours in a dark room. The mixture was then fractionated through -100° C. and -196° C. traps, with the product being collected in the -100° C. trap.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[NH:12][CH:13]=1)(C)(C)C.Cl>>[CH3:17][O:16][C:14]([C:11]1[NH:12][CH:13]=[C:9]([CH2:8][CH2:7][C:6]([OH:18])=[O:5])[CH:10]=1)=[O:15]
Reactant: COC(=O)c1cc(CCC(=O)OC(C)(C)C)c[nH]1
Agent: Cl
Product: COC(=O)c1cc(CCC(=O)O)c[nH]1
Yield: 94.9 %

Procedure:
Methyl 4-(3-tert-butoxy-3-oxopropyl)-1H-pyrrole-2-carboxylate (473 g, 1.87 mmol) was treated for about 12 h at rt with 4 N HCl (5 mL). The solvent was removed and the white solid product was dried to give 350 mg (95%) of 3-(5-(methoxycarbonyl)-1H-pyrrol-3-yl)propanoic acid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.64 (t, J=7.35 Hz, 2H), 2.84 (t, J=7.35 Hz, 2H), 3.85 (s, 3H), 6.79 (dd, J=6.66, 2.22 Hz, 2H), 9.08 (br s, 1H); LCMS-MS (ESI+) 198.2 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]O)=[CH:5][CH:4]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(CCCO)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(CCCBr)cc1
Yield: 91.5 %

Procedure:
Compound 72-2 (4.22 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (7.58 g) and N-bromosuccinimide (5.14 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (5.37 g) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]3[C:14]([C:25]([OH:27])=O)=[CH:15][N:16](COCC[Si](C)(C)C)[C:11]3=[N:10][CH:9]=2)[CH:5]=[N:4]1)[CH3:2].C1(C2N=C3C(C(O)=O)=CN(COCC[Si](C)(C)C)C3=NC=2)CC1.[CH3:51][C:52]1([CH3:59])[CH2:57][CH2:56][CH2:55][CH2:54][CH:53]1[NH2:58].Cl.NC1(C(O)(C)C)CCCC1>>[CH3:51][C:52]1([CH3:59])[CH2:57][CH2:56][CH2:55][CH2:54][CH:53]1[NH:58][C:25]([C:14]1[C:12]2[C:11](=[N:10][CH:9]=[C:8]([C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=3)[N:13]=2)[NH:16][CH:15]=1)=[O:27]
Reactant: CCn1cc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)cn1
Reactant: CC1(C)CCCCC1N
Agent: CC(C)(O)C1(N)CCCC1
Agent: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Agent: Cl
Product: CCn1cc(-c2cnc3[nH]cc(C(=O)NC4CCCCC4(C)C)c3n2)cn1

Procedure:
2-(1-Ethyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2,2-dimethyl-cyclohexyl)-amide was prepared according to the procedure outlined in Example 1, steps 4-5 substituting 2-(1-ethyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid for 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid and 2,2-dimethylcyclohexylamine [Example 21, steps 1-2] for 2-(1-amino-cyclopentyl)-propan-2-ol hydrochloride in step 4. MS: (M+H)+=367.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([O:21][CH2:22][CH3:23])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)C.COC(=O)C(OC)CC1C=CC=C(OCC2C=CC=CC=2)C=1>>[CH3:1][O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1
Reactant: CCOC(=O)C(=Cc1cccc(OCc2ccccc2)c1)OCC
Agent: COC(=O)C(Cc1cccc(OCc2ccccc2)c1)OC
Product: CCOC(Cc1cccc(OCc2ccccc2)c1)C(=O)OC

Procedure:
The title compound was prepared from 3-(3-benzyloxy-phenyl)-2-ethoxy-acrylic acid ethyl ester Example 378, Step 2) via the same procedure used for the preparation of 3-(3-benzyloxy-phenyl)-2-methoxy-propionic acid methyl ester (Example 291, Step 3) to afford the title compound as a colorless oil.
Reaction SMILES: CN(C)P(=O)(N(C)C)N(C)C.[CH3:12][O-:13].[Na+].C1(C)C=CC=CC=1.[CH3:22][O:23][C:24]1[C:39]([O:40][CH3:41])=[C:38]([O:42][CH3:43])[CH:37]=[C:36]([CH3:44])[C:25]=1[C:26]([C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[CH:30][C:29]=1Cl)=[O:27]>O>[CH3:22][O:23][C:24]1[C:39]([O:40][CH3:41])=[C:38]([O:42][CH3:43])[CH:37]=[C:36]([CH3:44])[C:25]=1[C:26]([C:28]1[C:29]([O:13][CH3:12])=[CH:30][N:31]=[CH:32][C:33]=1[Cl:34])=[O:27]
Reactant: C[O-]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cncc2Cl)c(OC)c1OC
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(Cl)cncc2OC)c(OC)c1OC
Yield: 690.4 %

Procedure:
5.0 g (2.8 mmol) of hexamethylphosphoric triamide and 1.1 g (2.1 mmol) of sodium methoxide were added to a toluene (60 ml) solution of 5.0 g (1.4 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3,5-dichloropyridine (compound No. 191), followed by stirring under reflux by heating for 5 hours. After the mixture was cooled, 50 ml of water was added to the mixture to terminate the reaction, and ethyl acetate was added thereto for extraction. The organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 3.4 g (yield 69%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-chloro-5-methoxypyridine (compound No. 244; pale yellow oily substance).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:12]=1[C:13]([NH2:15])=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+]>CC(N(C)C)=O>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[NH:15][C:13](=[O:14])[C:12]3[C:11](=[CH:19][C:18]([F:20])=[CH:17][C:16]=3[F:21])[N:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: NC(=O)c1c(N)cc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c(-c2cccc(Br)n2)nc2cc(F)cc(F)c12
Temperature: 110 °C
Yield: 14.8 %

Procedure:
A mixture of 6-bromopicolinaldehyde (2.8 g, 15 mmol), 2-amino-4,6-difluorobenzamide (2.5 g, 10 mmol), p-toluenesulfonic acid (4.2 g, 22 mmol), NaHSO3 (2.6 g, 25 mmol) and DMA (40 mL) was heated at 110° C. for 48 h in a sealed tube. The reaction mixture was cooled to room temperature and partitioned between water and EtOAc (25 mL). The aqueous phase was extracted with EtOAc (2×25 mL). The organic layers were combined, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The product was purified by crystallization (EtOAc) to provide the title compound (500 mg, 15%): 1H NMR (500 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.32 (d, J=7.7, 0.7 Hz, 1H), 8.05-7.96 (m, 1H), 7.91 (dd, J=7.7, 0.7 Hz, 1H), 7.46-7.29 (m, 2H).
Reaction SMILES: [CH2:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1(=[C:17](CCCC)[CH:18]=[O:19])CCCC[CH2:12][CH2:11][CH2:10]1>>[C:1]1(=[CH:12][CH2:11][CH2:10][CH2:9][CH2:17][CH:18]=[O:19])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCC(C=O)=C1CCCCCCC1
Reactant: C1CCCCCCC1
Product: O=CCCCCC=C1CCCCCCC1

Procedure:
6-cyclooctylidenehexanal is prepared according to the protocol described in Example 7 using cyclooctane in place of 2,4,4-trimethylcyclopentanone. The crude product containing cyclooctylidenehexanal is distilled under reduced pressure: its boiling point is 94° C. at 0.2 torr.