Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([N:10]1[C@H:13]([S:14][CH2:15][C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[O:17])[C@H:12]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]1=[O:34])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].N1C(C)=CC=CC=1C.S(Cl)([Cl:45])=O.C(OCC)(=O)C>C1COCC1>[Cl:45][CH:2]([N:10]1[C@H:13]([S:14][CH2:15][C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[O:17])[C@H:12]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]1=[O:34])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)C(O)N1C(=O)[C@@H](NC(=O)Cc2ccccc2)[C@H]1SCC(=O)C1CCCCO1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)C(Cl)N1C(=O)[C@@H](NC(=O)Cc2ccccc2)[C@H]1SCC(=O)C1CCCCO1

Procedure:
t-Butyl 2-hydroxy-2-[(3R,4R)-3-phenylacetamido-4-[(RS)-tetrahydropyran-2-ylcarbonylmethylthio]azetidin-2-on-1-yl]acetate (1.9g) in dry THF (10ml) was treated with 2,6-lutidine (0.62g, 0.67ml) followed by thionyl chloride (0.69g, 0.42ml) in THF (5ml) dropwise at <-20° C. under argon. The reaction mixture was allowed to warm slowly to ca 0° C. at which point no starting material was observed by t.l.c. (ethyl acetate). The reaction mixture was filtered and solvent removed in vacuo, the residue dissolved in toluene and evaporated to afford crude t-butyl (RS)-2-chloro-2-((3R,4R)-3-phenylacetamido-4-[(RS)-tetrahydropyran-2-ylcarbonylmethylthio]azetidin-2-on-1-yl]acetate as a brown gum. This was dissolved in dry dioxan (10ml) and treated with tri-n-butylphosphine (1.79g, 2.2ml). The reaction mixture was stirred until loss of starting material was observed by t.l.c. (ethyl acetate) ca 0.5h. After removal of solvent in vacuo the title compound was obtained by flash chromatography (eluting with 50,60,80% ethyl acetate in hexane, ethyl acetate) as a pale brown foam (1.95g, 75%); vmax (CH2Cl2) 3417(w), 1762, 1681, 1625cm-1. [Mass spectrum +ve ion (thioglycerol) MH+ (677)].
Reaction SMILES: [F:1][C:2]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]([O:8]C(=O)C)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13].[CH3:19][C:20]1[O:27][C:23](/[CH:24]=[N:25]/O)=[CH:22][CH:21]=1.C(N(CC)CC)C.O>N1C=CC=CC=1>[F:1][C:2]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]([O:8]/[N:25]=[CH:24]/[C:23]2[O:27][C:20]([CH3:19])=[CH:21][CH:22]=2)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13]
Reactant: Cc1ccc(/C=N/O)o1
Reactant: CCOC(=O)C1(F)C(=O)NC(=O)NC1OC(C)=O
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(F)C(=O)NC(=O)NC1O/N=C/c1ccc(C)o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.5 %

Procedure:
In 70 ml of pyridine were dissolved 18.3 g (70 mmol) of ethyl 5-fluoro-6-acetoxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate and 13.1 g (105 mmol) of (E)-5-methylfurfuraldoxime (containing 13% of the Z form), and 7.07 g (70 mmol) of triethylamine was added to the solution, followed by stirring at room temperature for 15 hours. The reaction solution was poured into 500 ml of ice-cooled water, and crystals precipitated were collected by filtration and washed with water. The crystals were dried under reduced pressure (P2O5) and recrystallized from 170 ml of ethanol to give 11.8 g of ethyl 5-fluoro-6-[(E)-5-methylfurfurylideneaminooxy]-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate. m.p. 181°-182° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:29][CH:30]([CH3:32])[CH3:31])=[C:13]([C:15]2[NH:28][C:18]3=[N:19][C:20]([CH2:23][C:24]([O:26]C)=[O:25])=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:29][CH:30]([CH3:32])[CH3:31])=[C:13]([C:15]2[NH:28][C:18]3=[N:19][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc2nc(-c3cc(OCc4ccccc4)ccc3OC(C)C)[nH]c2n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc(CC(=O)O)nc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.9 %

Procedure:
A mixture of methyl {2-[5-(benzyloxy)-2-isopropoxyphenyl]-3H-imidazo[4,5-b]pyridin-5-yl}acetate (25 mg) and 1N sodium hydroxide (0.5 ml) in methanol (5 ml) was stirred at room temperature for 18 hr. The reaction mixture was adjusted with 1N citric acid to pH 4, and the precipitated crystals were collected by filtration and washed with diethyl ether to give the title compound (14 mg, yield 51%) as colorless crystals. purity 96%. M+H: 418. 1H NMR (CD3OD) δ: 1.45 (6H, d, J=6.0 Hz), 4.06 (2H, s), 4.78-4.83 (1H, m), 5.16 (2H, s), 7.28-7.58 (8H, m), 7.84 (1H, d, J=2.8 Hz), 8.28 (1H, d, J=8.3 Hz).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][OH:21])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1>CO.O=[Pt]=O>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20][OH:21])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: OCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Agent: O=[Pt]=O
Solvent: CO
Product: OCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Yield: 71.1 %

Procedure:
500 mg (1.5 mmol) 3-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol in 25 ml MeOH were hydrogenated in the presence of 120 mg PtO2. H2O, filtration over silica gel and evaporation yielded 360 mg (71%) 3-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propan-1-ol, which was directly subjected to the following reaction.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH2:12][CH2:13][CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6](=[CH:16][C:17](O)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:50][O:51][C:52](=[O:59])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][NH2:58]>[Cl-].[Na+].O.CN(C=O)C>[CH3:50][O:51][C:52](=[O:59])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][NH:58][C:17](=[O:18])[CH:16]=[C:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH2:12][CH2:13][CH:14]=[CH:15][C:9]=2[CH:8]=[CH:7]1
Reactant: O=C(O)C=C1C=CC2=C(CCC=C2)c2ccccc21
Reactant: COC(=O)CCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCCCCNC(=O)C=C1C=CC2=C(CCC=C2)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.9 %

Procedure:
2-(10,11-dihydro-5H-dibenzocyclohepten-5-ylidene)acetic acid (250 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzo-triazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 6-aminocaproic acid methyl ester hydrochloride (219 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (313 mg, 83% yield) as a white solid. LC-MS (m/z) 378 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C@@H:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:7](C(OCC2C=CC=CC=2)=O)[C:6]1=[O:27])[CH2:2][CH2:3][CH3:4]>[Pd].CO>[CH2:1]([N:5]1[CH2:9][C@@H:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH:7][C:6]1=[O:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CCCCN1C[C@@H](C(=O)OC(C)(C)C)NC1=O
Yield: 88.1 %

Procedure:
6.7 g of tert.-butyl (4S)-1-n-butyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate, 0.1 g of palladium-black and 200 ml of methanol are treated in the same manner as described in Example 1-(3). 3.8 g of tert.-butyl (4S)-1-n-butyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless syrup. Yield: 88.1%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:20]([O:22][CH2:23]C)=[O:21])[CH:16]=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([C:20]([O:22][CH3:23])=[O:21])[CH:16]=[N:17]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of ethyl 7-[(3-chlorophenyl)methoxy]quinoline-3-carboxylate (Example 3, 20 mg, 0.06 mmol) in MeOH (1 mL) and THF (1 mL) was added K2CO3. The reaction was stirred overnight at ambient temperature. The crude reaction mixture was concentrated onto silica and purification (FCC, SiO2, 0-40%, EtOAc/hexanes) afforded the title compound as a white solid (12 mg, 63%). 1H NMR (400 MHz, CDCl3) δ 9.37 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.3 Hz, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.50 (d, J=2.3 Hz, 2H), 7.38-7.30 (m, 4H), 5.21 (s, 2H), 4.00 (s, 3H). [M+H]=328.2.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[N:11][CH:10]=1.[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25]>ClCCl>[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:27][CH2:23][CH:24]([CH3:26])[CH3:25])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[N:11][CH:10]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Reactant: CC(C)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CNc1c([N+](=O)[O-])cnc2cc(Br)cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
Triethylamine (17.97 mL, 129.0 mmol) was added to a solution of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine (24.8 g, 86.0 mmol) in dichloromethane (200 mL) at 0° C. Isobutylamine (9.40 mL, 94.6 mmol) was added dropwise to the mixture, and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was condensed under reduced pressure to a solid, which was triturated with water (200 mL). The precipitate was filtered, washed sequentially with water and hexanes, and dried to yield 27.5 g of 7-bromo-3-nitro[1,5]naphthyridin-4-yl-(2-methylpropyl)amine as a yellow powder, mp 114-115° C.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:13]=[C:12]([CH2:14][CH2:15][CH:16]=O)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]1([CH:7]=[CH:8][C:9]2[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][N:26]3[CH2:25][CH2:24][N:23]([CH2:22][C:21]4[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=4[C:19]([F:33])([F:34])[F:18])[CH2:28][CH2:27]3)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1ccccc1CN1CCNCC1
Reactant: O=CCCc1cc(C=Cc2ccccc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1CN1CCN(CCCc2cc(C=Cc3ccccc3)no2)CC1
Yield: 76.8 %

Procedure:
About 2 min after dissolving 3-[3-(2-phenylvinyl)isoxazol-5-yl]propanal (10 mg, 0.05 mmol) and 1-[2-(trifluoromethyl)benyl]piperazine (9.2, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (28 mg, 0.13 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 16.4 hr and followed the same processes as in Example 1 to obtain 14 mg (69.8%) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1>>[CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:5]([C:7]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]3[N:33]4[C:29]([S:30][CH:31]=[CH:32]4)=[N:28][C:27]=3[CH3:34])=[O:25])[CH2:18]2)=[O:9])[N:6]=1
Reactant: Cc1ccc(-c2sc(C)nc2C(=O)O)cc1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Product: Cc1ccc(-c2sc(C)nc2C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)cc1

Procedure:
prepared by reaction of 2-methyl-5-p-tolyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH:11][C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14](O)=O)=[CH:9][CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+].[OH-].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:14]1[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=[C:10]2[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=[CH:8][C:9]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1ccccc1Nc1ccnn1C1CCCC1
Agent: [NH4+]
Agent: [OH-]
Product: Clc1c2ccccc2nc2c1cnn2C1CCCC1
Temperature: 0 °C

Procedure:
A mixture of N-(1-cyclopentylpyrazol-5-yl) anthranilic acid (21 g, 0.0775 mol) and POCl3 (100 ml) was refluxed for 8 hours. The reaction mixture was poured into ice-water and neutralized with NH4OH. A gum formed which was extracted with CH2Cl2. The CH2Cl2 layer was then washed with water, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with 40% to 70% CH2Cl2 /hexane to afford 7.5 g of 4-chloro-1-cyclopentyl-1H-pyrazolo[3,4-b]quinoline, m.p. 97°-98 ° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:25]=[CH:24][C:23]2[O:22][C:21]3[C:16](=[CH:17][C:18]([C:26]([NH:28][CH2:29][CH2:30][CH2:31][N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])=[O:27])=[CH:19][CH:20]=3)[C:15](=O)[C:14]=2[CH:13]=1)=[O:11])[CH2:2][CH2:3][CH3:4]>[Pd]>[CH2:37]([N:32]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:31][CH2:30][CH2:29][NH:28][C:26]([C:18]1[CH:19]=[CH:20][C:21]2[O:22][C:23]3[C:14](=[CH:13][C:12]([C:10]([NH:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:42][CH2:43][CH2:44][CH3:45])=[O:11])=[CH:25][CH:24]=3)[CH2:15][C:16]=2[CH:17]=1)=[O:27])[CH2:38][CH2:39][CH3:40]
Reactant: CCCCN(CCCC)CCCNC(=O)c1ccc2oc3ccc(C(=O)NCCCN(CCCC)CCCC)cc3c(=O)c2c1
Agent: [Pd]
Product: CCCCN(CCCC)CCCNC(=O)c1ccc2c(c1)Cc1cc(C(=O)NCCCN(CCCC)CCCC)ccc1O2

Procedure:
An alcoholic solution of N,N'-bis(3-di-n-butylaminopropyl)-9-oxoxanthene-2,7-dicarboxamide, prepared in Example 3, can be used with a palladium catalyst to effect a hydrogenation to give N,N'-bis(3-di-n-butylaminopropyl)xanthen-2,7-dicarboxamide.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[Br:19].C([O-])(=O)C.[Na+].[N:34]#[C:35]Br.O>C(O)C>[Br:19][C:10]1[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]=1[CH2:8][N:7]([CH2:6][C:5]1[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:4]=1)[C:35]#[N:34]
Reactant: N#CBr
Reactant: FC(F)(F)c1cc(CNCc2cc(C(F)(F)F)ccc2Br)cc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1Br
Reaction time: 0.33 h

Procedure:
To the product of step B (873 g, 1.82 mol) in ethanol (4.6 L) was added sodium acetate (452 g, 5.46 mol). The resulting mixture was stirred for 20 minutes and then cyanogen bromide (386 g, 3.64 mol) was added. This mixture was stirred for 2 hours at which point the reaction was complete as evidenced by LC analysis. Water (4 L) was added and volatiles were removed in vacuo. Toluene (4 L) was added and the mixture was stirred until 2 clear layers formed. The layers were separated and the aqueous layer was washed with toluene (2 L). The combined organics were washed with brine (1 L), dried over sodium sulfate, filtered, and concentrated (910 g yield). 1H-NMR (CDCl3) δ 7.83 (s, 1H), 7.71 (m, 3H), 7.54 (d, 1.7 Hz, 1H), 7.46 (dd, 2.1 Hz, 8.3 Hz, 1H), 4.38 (s, 2H), 4.34 (s, 2H). Mass Spec (ESI): M+1=505.0
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:38]([O:40][CH3:41])=[O:39])=[N:34][C:35]=1[O:36][CH3:37].O>C(O)C.ClCCl>[C:18]([O:17][C:16]([NH:15][C:11]1([C:8]2[CH:9]=[CH:10][C:5]([C:3]3[N:29]=[C:30]4[C:35]([O:36][CH3:37])=[N:34][C:33]([C:38]([O:40][CH3:41])=[O:39])=[CH:32][N:31]4[C:2]=3[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:6][CH:7]=2)[CH2:14][CH2:13][CH2:12]1)=[O:22])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1cnc(N)c(OC)n1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)c1cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c(OC)n1

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [Int-1-A] (715 mg, 1.45 mmol, 1.0 eq), methyl 5-amino-6-methoxypyrazine-2-carboxylate (265 mg, 1.45 mmol, 1 eq.; see step 1) were dissolved in ethanol. The reaction vessel was equipped with a Dean-Stark trap containing 4 Å molsieves and then the reaction mixture refluxed for 17 h. The reaction mixture was diluted with 20 mL dichloromethane and treated with water. The organic phase was washed with 1 N hydrochloric acid and brine, filtered through a Whatman-filter and the solvent was removed by the use of a rotary evaporator. Finally purification was achieved via MPLC (Isolera, 50 g Snap-cartridge, eluent:hexane→hexane/ethyl acetate 9/1) to deliver 97 mg (12%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:20][C:21](=O)[C:22]([F:25])([F:24])[F:23]>CO.ClCCl>[C:13]1([C:10]2([CH2:9][O:8][C:7]3[C:2]4[N:3]([CH:20]=[C:21]([C:22]([F:25])([F:24])[F:23])[N:1]=4)[CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ncccc1OCC1(c2ccccc2)CC1
Reactant: O=C(CBr)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: FC(F)(F)c1cn2cccc(OCC3(c4ccccc4)CC3)c2n1
Yield: 99 %

Procedure:
A stirred mixture of 2-amino-3-[(1-phenylcyclopropyl)methoxy]pyridine (0.731 g, 3.04 mmol, step 3), 3-bromo-1,1,1-trifluoroacetone (1.3 mL, 13 mmol) and molecular sieves (4.0 g, type 4 Å, beads, 8–12 mesh) in anhydrous methanol (15 mL) was refluxed for 22.5 h under argon. The molecular sieves were filtered off and the filtrate was concentrated in vacuo to yield a brown oil which was dissolved in dichloromethane (100 mL) and washed with a 1:1 (v/v) mixture of saturated aq sodium bicarbonate and water (2×10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the crude desired product. Purification by dry column (600 mL funnel filled with 300 mL of silica gel 10–40μ, Sigma cat. S-6628) eluted with a mixture of ethyl acetate-hexanes (1:3 v/v, containing 0.5% v/v isopropylamine) yielded 1.00 g (99% yield) of 8-[(1-phenylcyclopropyl)methoxy]-2-(trifluoromethyl)imidazo[1,2-α]pyridine (Rf=0.33 in ethyl acetate-hexanes, 1:3 v/v, containing 0.5% v/v isopropylamine). A stirred solution of the free amine (0.950 g, 2.86 mmol) in dichloromethane (4 mL) and anhydrous diethyl ether (16 mL) was treated with ethereal hydrogen chloride to form the hydrochloride salt. After 20 min, the solvent was removed in vacuo, and the residue was triturated in anhydrous diethyl ether to give the title compound as a pale yellow solid (0.414 g, 39% yield). 1H-NMR (300 MHz, CDCl3) δ 8.58 (d, 1H, Ar), 8.55 (s, 1H, Ar), 7.50 (m, 1H, Ar), 7.06 (m, 2H, Ar), 6.91 (m, 2H, Ar), 6.78 (m, 1H, Ar), 6.72 (d, 1H, Ar), 4.11 (s, 2H, CH2O), 0.69 (m, 4H, CH2CH2); 13C-NMR (75 MHz, CDCl3, APT) δ 146.50 (+), 141.44 (+), 137.01 (+), 129.76/129.21 (+), 127.90 (−), 125.98 (−), 121.69/118.12 (+), 120.97 (−), 116.31 (−), 114.85 (−), 107.82 (−), 76.35 (+), 23.03 (+), 13.75 (+); LRMS-FAB m/z: MH+ 333 (100%); Anal. calcd for C18H15N2OF3.HCl: C, 58.63; H, 4.37; N, 7.60%. found: C, 56.80; H, 4.07; N, 7.03%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]#[N:15])=[C:12]([C:16]([O:18]CC)=[O:17])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-:21].[K+].O>C(O)C.C(O)(=O)C>[C:16]([C:12]1[CH:11]=[N:10][N:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=2)[C:13]=1[C:14]([NH2:15])=[O:21])([OH:18])=[O:17]
Reactant: [OH-]
Reactant: CCOC(=O)c1cnn(-c2ccc(C)c(Cl)c2)c1C#N
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(-n2ncc(C(=O)O)c2C(N)=O)cc1Cl

Procedure:
A 9.5 g. portion of ethyl 1-(3-chloro-4-methylphenyl)-5-cyano-4-pyrazolecarboxylate was dissolved in250 ml. of ethanol, and 2 g. of potassium hydroxide was added. The mixture was then stirred under reflux for 30 minutes. One hundred ml. of water wasadded, and the mixture was stirred under reflux for an additional 4 hours. Isolation of the product was attempted, but it was found to be a difficultly separable mixture, and the entire reaction mixture was returned to the flask, redissolved in aqueous ethanol and refluxed for 1 hour on the steam bath with 6 g. of additional potassium hydroxide. The mixture was then diluted with aqueous acetic acid and filtered, and the solids were dried and identified as 5.2 g. of the desired product, m.p. 228°-232° dec. It was identified by elemental analysis.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].C(N(CC)CC)C.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][N:21]=1>CO>[CH3:18][O:19][C:20]1[N:21]=[CH:22][C:23]([CH:24]=[N:2][C:3]2[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=2[OH:10])=[CH:26][CH:27]=1
Reactant: COc1ccc(C=O)cn1
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C=Nc2ccc(O)cc2O)cn1
Reaction time: 8 h

Procedure:
4-Aminoresorcinol hydrochloride (3.09 mmol) and triethylamine (3.25 mmol) were dissolved in dry methanol (20 mL). 6-Methoxynicotinaldehyde (3.09) was added and the mixture was stirred overnight. The solvents were removed under reduced pressure, the mixture diluted with EtOAc, washed with brine (2×), dried (Na2SO4), filtered and evaporated to give 1.31 g as a dark solid. The crude product was taken to the next step without further purification. MS m/z (M+H) 245.