Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([CH3:16])[CH:15]=1)[C:10](Cl)=[O:11].FC(F)(F)C(O)=O.[CH2:24]([C@@H:31]1[CH2:36][CH:35]([NH:37][C:38](=[O:43])[C:39]([F:42])([F:41])[F:40])[CH2:34][CH2:33][NH:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.O>[CH2:24]([C@@H:31]1[CH2:36][CH:35]([NH:37][C:38](=[O:43])[C:39]([F:42])([F:40])[F:41])[CH2:34][CH2:33][N:32]1[C:10](=[O:11])[C:9]1[CH:8]=[C:7]([CH3:6])[CH:15]=[C:14]([CH3:16])[CH:13]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(NC1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)cc(C(=O)N2CCC(NC(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
710 mg of solid sodium bicarbonate and 712 mg of 3,5-dimethylbenzoyl chloride are added to a stirred mixture of 1.39 g (3.44 mmol) of (2R,4RS)-N-(2-benzyl-4-piperidyl)trifluoroacetamide trifluoroacetate and 10 ml of toluene/water (1:1) cooled in ice-water. The reaction mixture is then allowed to warm to room temperature, subsequently stirred for 2 hours and partitioned between toluene and 1N sodium bicarbonate solution. The organic phases are washed with water, dried over magnesium sulfate and evaporated to dryness. The colourless oil is chromatographed on silica gel with ethyl acetate/hexane 1:2, resulting in the title compound. This is used further without further purification.
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:10])([F:9])[CH2:7][NH2:8].C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])=[N:24][O:25][C:26]=2[CH3:27])=[N:16][CH:15]=1.O>O1CCOCC1>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:23]1[C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([C:13]([NH:8][CH2:7][C:6]([F:10])([F:9])[F:5])=[O:12])=[CH:15][N:16]=2)=[C:26]([CH3:27])[O:25][N:24]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2F)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.5 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 1.17 mL, 2.3 mmol) was added dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine (188 μL, 2.3 mmol) in dioxane (15 mL) and the resulting mixture was stirred at room temperature for 1.5 h. Then 6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.58 mmol) was added. The resulting mixture was then heated at 85° C. for 2 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=2:1 to 1:1) afforded the title compound (210 mg, 88%) which was obtained as a colourless oil. MS: m/e=410.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[C:16]1([N:22]2[C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:25](=[O:32])[NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO>C1C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([NH:8][CH2:10][CH2:9][N:29]2[CH2:28][CH2:27][C:26]3([N:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][NH:24][C:25]3=[O:32])[CH2:31][CH2:30]2)=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C(c1ccc(F)cc1[N+](=O)[O-])N1CC1
Solvent: CO
Solvent: c1ccccc1
Product: O=C(NCCN1CCC2(CC1)C(=O)NCN2c1ccccc1)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 15 parts of 1-(4-fluoro-2-nitrobenzoyl)-aziridine, 12 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 8.8 parts of methanol and 56 parts of benzene is stirred first for 1.50 hours at reflux and further overnight at room temperature. The reaction mixture is evaporated. The residue is dissolved in trichloromethane and the solution is washed with water. Then there are added 8 parts of methanol and silica gel and the whole is stirred for 10 minutes. The silica gel is filtered off and the filtrate is evaporated. The residue is stirred in 2,2'-oxybispropane. The product is filtered off and crystallized from 4-methyl-2-pentanone. It is filtered off and dried, yielding 13 parts of 4-fluoro-2-nitro-N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro-[4,5]dec-8-yl)ethyl]benzamide; mp. 160° C.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][Si:9]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11])[CH2:2][CH2:3][CH3:4].[CH:16]([N:19]=[C:20]=[N:21][CH:22]([CH3:24])[CH3:23])([CH3:18])[CH3:17]>>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][Si:9]([O:14][CH3:15])([O:10][CH3:11])[O:12][CH3:13])[C:20]([NH:21][CH:22]([CH3:24])[CH3:23])=[N:19][CH:16]([CH3:18])[CH3:17])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)N=C=NC(C)C
Reactant: CCCCNCCC[Si](OC)(OC)OC
Product: CCCCN(CCC[Si](OC)(OC)OC)C(=NC(C)C)NC(C)C
Reaction time: 2 h

Procedure:
A mixture of 45 g of N-butyl-(3-(trimethoxysilyl)propyl)amine (0.191 mol) and of 28.95 g of diisopropylcarbodiimide (0.229 mol, 20% excess) was heated for 20 h at 120° C. (amine conversion of 93%). The final colorless mixture was devolatilized at 120° C. under 1 mbar for 2 h to give 67 g of a colorless, low-viscosity liquid corresponding to the expected guanidine, containing 4 wt % of the initial amine.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[C:21]4[C:27](I)=[N:26][N:25]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]4=[N:23][CH:24]=3)[CH:14]=2)=[O:12])[CH2:7][CH2:6]1.[CH3:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[C:41]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[CH3:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[C:41]=1[C:27]1[C:21]2[C:22](=[N:23][CH:24]=[C:19]([C:15]3[CH:14]=[C:13]([C:11]([N:8]4[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:37])[CH3:1])[CH2:6][CH2:7]4)=[O:12])[CH:18]=[CH:17][CH:16]=3)[CH:20]=2)[N:25]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:26]=1
Reactant: CN(C)CCN1CCN(C(=O)c2cccc(-c3cnc4c(c3)c(I)nn4COCC[Si](C)(C)C)c2)CC1
Reactant: COc1cccc(OC)c1B(O)O
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: O
Solvent: CC#N
Product: COc1cccc(OC)c1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(=O)N4CCN(CCN(C)C)CC4)c3)cc12
Temperature: 120 °C

Procedure:
A mixture of (4-(2-(dimethylamino)ethyl)piperazin-1-yl)(3-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)methanone (50 mg, 0.079 mmol), 2,6-dimethoxyphenylboronic acid (22 mg, 0.118 mmol), tetrakis(triphenylphosphine)palladium(0) (9.1 mg, 0.10 mmol) and sodium carbonate (2M aqueous solution, 0.119 mL, 0.237 mmol) in acetonitrile (1 mL) was heated in a Personal microwave at 120° C. for 30 min. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography purification of the crude product afford (3-(3-(2,6-dimethoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)(4-(2-(dimethylamino)ethyl)piperazin-1-yl)methanone as a clear oil.
Reaction SMILES: [CH2:1]([N:5]([CH2:18][CH2:19][CH2:20][CH3:21])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=O)=[C:8]([O:16][CH3:17])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:22]([C:24]1[C:25](=[C:32]([C:35]#[N:36])[C:33]#[N:34])[O:26][C:27]([CH3:31])([CH3:30])[C:28]=1[CH3:29])#[N:23].C([O-])(=O)C.[NH4+]>C(O)C>[CH2:1]([N:5]([CH2:18][CH2:19][CH2:20][CH3:21])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:29][C:28]2[C:27]([CH3:30])([CH3:31])[O:26][C:25](=[C:32]([C:33]#[N:34])[C:35]#[N:36])[C:24]=2[C:22]#[N:23])=[C:8]([O:16][CH3:17])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCCCN(CCCC)c1ccc(C=CC=O)c(OC)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC=CC2=C(C#N)C(=C(C#N)C#N)OC2(C)C)c(OC)c1
Temperature: 50 °C
Yield: 74.2 %

Procedure:
In 5 ml of ethanol were dissolved 170 mg (0.59 mmol) of 3-(4-dibutylamino-2-methoxyphenyl)propenal and 129 mg (0.65 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene) propanedinitrile. To this mixture was added 46 mg of ammonium acetate, and the mixture was stirred with heating at 50° C. for 2 hours. The solvent was evaporated off and the residue was purified by silica gel column chromatography to give 206 mg of a dark greenish brown crystal (yield: 74.5%; mp: 181-184° C.)
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][S:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:5])[C:2]([CH3:4])=[CH2:3].I([O-])(=O)(=O)=[O:15].[Na+].C(Cl)(Cl)Cl.CO.C(O)(C(F)(F)F)=O>C(#N)C.O>[C:1]([O:6][CH2:7][CH2:8][S:9]([CH2:10][C:11]([OH:13])=[O:12])=[O:15])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCSCC(=O)O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C=C(C)C(=O)OCCS(=O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
4 (1 g, 4.9 mmol, 1 eqv.) in acetonitrile (ACN) (10 mL) was mixed with a sodium periodate solution (1.1 g, 4.9 mmol, 1 eqv.) dissolved in H2O (10 mL). The reaction mixture was stirred at RT overnight. The completion of the reaction was confirmed by TLC(CHCl3/MeOH/TFA, 75:25:0.1 (v/v), Rf: 0.23). The reaction mixture was filtered via suction filtration to remove sodium iodate salts by EtOAc and dried with MgSO4 and filtered through Ø 185 mm whatman filter papers. The filtrate was concentrated in vacuo and co-evaporated with CH2Cl2. 0.87 g (81% yield) 5 was obtained as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:24]1(=[O:29])(=[O:28])[CH2:27][CH2:26][NH:25]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[N:7][C:2]([N:25]4[CH2:26][CH2:27][S:24]4(=[O:29])=[O:28])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: O=S1(=O)CCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCS4(=O)=O)nc3)CC2)c(C)c1
Yield: 3.5 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (188 mg) described in Preparation Example 127 and [1,2]thiazetidine 1,1-dioxide (54 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (7 mg) was obtained.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[N+:5]([CH:8]([CH3:10])[CH3:9])([O-:7])=[O:6].[OH-].[Na+]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC>[CH3:9][C:8]([N+:5]([O-:7])=[O:6])([CH3:10])[CH2:3][CH2:2][C:1]#[N:4]
Reactant: CC(C)[N+](=O)[O-]
Reactant: C=CC#N
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)(CCC#N)[N+](=O)[O-]

Procedure:
(vii-1) Acrylonitrile and 2-nitropropane are reacted in the presence of hexadecyltrimethyl ammonium chloride in an aqueous alkali solvent such as aqueous sodium hydroxide solution and the like. Then, the reaction mixture is extracted to give 4-methyl-4-nitrovaleronitrile (European Journal of Organic Chemistry (1998), (2), 355–357). The obtained 4-methyl-4-nitrovaleronitrile can be isolated and/or purified by a conventional method, such as crystallization, chromatography and the like, but generally, can be used in the next step without isolation and/or purification.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([Cl:15])[CH:3]=1.Br[C:17]1C=CC(C(O)=O)=C(Cl)[CH:18]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Cl:15][C:4]1[CH:3]=[C:2]([CH:17]=[CH2:18])[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Cl
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1ccc(C(=O)OC(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
tert-Butyl 4-bromo-2-chlorobenzoate (AI18) To a stirred solution of 4-bromo-2-chlorobenzoic acid (5 g, 21.37 mmol) in THF (30 mL) was added di-tert-butyl dicarbonate (25.5 g, 25.58 mmol), TEA (3.2 g, 31.98 mmol) and DMAP (0.78 g, 6.398 mmol), and the reaction mixture was stirred at 25° C. for 18 h. The reaction mixture was diluted with EtOAc and washed with water. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 2-3% EtOAc in n-hexane) to afford the title compound as a liquid (3.2 g, 51%): 1H NMR (400 MHz, CDCl3) δ 7.62 (m, 2H), 7.44 (d, J=8.4 Hz, 1H), 1.59 (s, 9H); ESIMS m/z 290.10 ([M+H]+); IR(thin film) 1728 cm−1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:21][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(CCCOc2cccc3ccccc23)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrC(CCOc1cccc2ccccc12)c1ccccc1
Temperature: 80 °C
Yield: 100.4 %

Procedure:
A mixture of 26.2 g (0.1 mol) of 1-phenyl-3-(1-naphthalenyloxy)propane, 17.8 g (0.1 mol) of N-bromosuccinimide, 120 ml of carbon tetrachloride and 250 mg of benzoyl peroxide was heated at 80° C. for four hours. The mixture was cooled and the precipitated solid was collected by vacuum filtration. The mother liquor was concentrated under vacuum to provide 34.26 g of a red oil.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[C:4]#[N:5].O.[NH2:12][NH2:13]>CO>[NH:12]([C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[C:4]#[N:5])[NH2:13]
Reactant: NN
Reactant: N#Cc1c(I)ccnc1F
Solvent: CO
Solvent: O
Product: N#Cc1c(I)ccnc1NN
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1.2 g of 2-fluoro-4-iodonicotinonitrile in 20 mL of MeOH at 20° C. are added 2.4 mL of hydrazine hydrate. The yellow suspension is stirred for 20 minutes at 20° C. and is then filtered. The precipitate is washed with methanol to give, after drying under vacuum, 947 mg of a white powder of 2-hydrazino-4-iodonicotinonitrile.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH2:9]([NH2:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:17][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7]
Reactant: O=C(Cl)CCCCBr
Reactant: CCCCCCCCN
Product: CCCCCCCCNC(=O)CCCCBr
Yield: 92.1 %

Procedure:
5-Bromo-N-octylpentanamide (17.49 g) (mp μ30°) was prepared from 5-bromopentanoyl chloride (12.96 g) and octylamine (9.05 g) by an analogous method to that described in Example 2a.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7](C2C=CC(C)=CN=2)[CH:6]=1)=[O:4].[OH-].[Na+]>>[C:14]1([N:11]2[C:12]3[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:13]=3)[CH:9]=[N:10]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)c2cnn(-c3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc2cnn(-c3ccccc3)c2c1

Procedure:
4-(5-Methyl-pyridin-2-yl)-1-phenyl-1H-indazole-6-carboxylic acid methyl ester was treated with NaOH using the procedure of step 3 of Example 1 to afford 445-methyl-pyridin-2-yl)-1-phenyl-1H-indazole-6-carboxylic acid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=O)[C:10]([O:12]CC)=[O:11])[N:8]=1)=[O:2].[OH-].[K+].C(NC1SC(Cl)=C(C(=O)C([O-])=O)N=1)=O.[K+].Cl.[NH2:35][O:36][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>O1CCCC1.N1C=CC=CC=1>[C:41]([O:40][C:38]([CH2:37][O:36][N:35]=[C:9]([C:7]1[N:8]=[C:4]([NH:3][CH:1]=[O:2])[S:5][C:6]=1[Cl:16])[C:10]([OH:12])=[O:11])=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)CON
Reactant: CCOC(=O)C(=O)c1nc(NC=O)sc1Cl
Agent: Cl
Agent: O=CNc1nc(C(=O)C(=O)[O-])c(Cl)s1
Agent: [K+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1nc(NC=O)sc1Cl
Reaction time: 0.17 h
Yield: 42.3 %

Procedure:
Ethyl (2-formamido-5-chlorothiazol-4-yl)glyoxylate (14.5 g) was added to a solution of 1N aqueous potassium hydroxide (110 ml) at ambient temperature, and the mixture was stirred for 10 minutes to prepare the solution of potassium (2-formamido-5-chlorothiazol-4-yl)glyoxylate. After this solution was adjusted to pH 2 with 10% hydrochloric acid under ice-cooling, thereto were added pyridine (20 ml) and a solution of tert-butyl 2-aminooxyacetate (10.3 g) in tetrahydrofuran (50 ml), followed by stirring at ambient temperature for 5 hours. After the reaction mixture was washed with ethyl acetate, the remaining aqueous solution was adjusted to pH 1.5 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave 2-tert-butoxycarbonylmethoxyimino-2-(2-formamido-5-chlorothiazol-4-yl)acetic acid (syn isomer) (8.5 g).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:15]([O:17][CH2:18][CH2:19]O)[CH3:16].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:16][CH2:15][O:17][CH2:18][CH3:19])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1ccc(CC(=O)O)cc1
Reactant: CCOCCO
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CCNc1ccc(CC(=O)OCCOCC)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-(allylamino)phenylacetic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml. toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2-ethoxyethyl 4-(allylamino)phenylacetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[C@H:21]([CH2:22][NH2:23])[CH2:20][C@H:19]2[C@@H:17]1[CH2:18]2)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].CCN(C(C)C)C(C)C>CC1C=CC=CC=1C>[C:9]([O:13][C:14]([N:16]1[C@H:21]([CH2:22][NH:23][C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:20][C@H:19]2[C@@H:17]1[CH2:18]2)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1[C@H](CNc2ncc(Br)cn2)C[C@@H]2C[C@@H]21
Temperature: 138 °C

Procedure:
5-Bromo-2-chloro-pyrimidine (18.4 mmol) is added to a solution of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (14.1 mmol) in o-xylene (28 mL). K2CO3 (42.4 mmol) and DIPEA (42.4 mmol) are added and the mixture is heated to 138° C. for 16 h. The mixture is cooled to RT and filtered. The residue is washed with DCM and the combined filtrates are concentrated in vacuo to give a crude product which is purified by flash chromatography (gradient: heptane/EtOAc 90/10 to 85/15). LC-MS: tR=1.05 min; [M+H]+=369.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[C:4]([Cl:21])[N:3]=1.[CH3:22][NH:23][CH2:24][CH2:25][OH:26]>O>[Cl:21][C:4]1[CH:5]=[C:6]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:7]=[C:2]([N:23]([CH2:24][CH2:25][OH:26])[CH3:22])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(Cl)nc(Cl)c2)CC1
Reactant: CNCCO
Solvent: O
Product: CN(CCO)c1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc(Cl)n1

Procedure:
A solution of tert-butyl 4-(2,6-dichloro-4-pyridyl)-5,6-dihydro-2H-pyridine-1-carboxylate (395 mg, 1.20 mmol) and 2-(methylamino)ethanol (3.5 mL, 44 mmol) in a glass vial was heated in oil bath at 100° C. for 4 h. After cooled, it was diluted with water (50 mL), extracted with EtOAc (2×50 mL). The combined EtOAc were dried over Na2SO4, filtered, concentrated in vacuo, and dried under high vacuum to give orange syrup. It was carried on without further purification. LC-MS: m/z=367 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH2:14]([O:21][C:22]([NH:11][CH2:10][CH2:9][C:8]1[C:12]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:13]=2)[NH:6][CH:7]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCc1c[nH]c2ccc(F)cc12
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(F)cc12)OCc1ccccc1
Temperature: 0 °C
Yield: 68 %

Procedure:
To a strirred solution of 0.83 g (4-6 mmol) of 5-fluorotryptamine and 0.48 g (0.55 mL, 5 mmol) of nmethylmorpholine in 10 mL of DMF at 0° C. was added dropwise 0.72 mL (5 mmol) of benzylchloroformate. The reaction mixture was allowed to stir at 0° C. under argon. After 1.5 hours of stirring, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride, dried over anhydrous Na2SO4, and concentrated under vacuum. The resulting residue was purified by flash chromatography using hexane:ethyl acetate (2:1) as an eluent to yield 1 g (68%) of N-(Benzyloxycarbonyl)-5-fluorotryptamine as a white solid. mp 104°-105° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[C:3]=1[O:11][CH3:12].[CH:13]([B-](F)(F)F)=[CH2:14].[K+]>CCO.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]>[F:10][C:4]1[C:3]([O:11][CH3:12])=[C:2]([CH:13]=[CH2:14])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: C=C[B-](F)(F)F
Reactant: COc1c(Br)ccc(C#N)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCO
Product: C=Cc1ccc(C#N)c(F)c1OC

Procedure:
A mixture of 4-bromo-2-fluoro-3-methoxybenzonitrile (6.0 g, 26 mmol), potassium vinyltrifluoroborate (4.20 g, 31.3 mmol) and Pd(dppf)Cl2 (0.8 g) in 60 mL of EtOH and 60 mL of TEA was refluxed under Ar for 4 hours. The resulting mixture was concentrated and the residue was purified by column chromatography (PE:EtOAc=20:1) to afford 2-fluoro-3-methoxy-4-vinylbenzonitrile.