Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:40])[C@@H:16]2[CH2:20][C@@H:19]([NH:21][C:22](=[O:32])[CH2:23][NH:24]C(OC(C)(C)C)=O)[CH2:18][N:17]2C(OC(C)(C)C)=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:41]>O1CCOCC1>[ClH:41].[ClH:41].[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:40])[C@@H:16]2[CH2:20][C@@H:19]([NH:21][C:22](=[O:32])[CH2:23][NH2:24])[CH2:18][NH:17]2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)Nc2ccc(Cc3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)N[C@H]1CN[C@H](C(=O)Nc2ccc(Cc3ccccc3)cc2)C1
Reaction time: 2 h

Procedure:
trans-4-(N-tert-Butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-proline 4-benzylphenylamide (A, 158 mg) was dissolved in 4 N hydrogen chloride in 1,4-dioxane (6 mL). After stirring for 2 hr, the reaction mixture was evaporated in vacuo to give white solids. The solids were washed with ether to afford the title compound (A, 103 mg): 1H NMR (400 MHz, D2O) δ 2.59 (dd, J=7.8, 6.4 Hz, 2H), 3.48 (dd, J=12.7, 4.8 Hz, 1H), 3.83 (dd, J=12.7, 6.4 Hz, 1H), 3.85 (s, 2H), 4.00 (s, 2H), 4.62 (m, 1H), 4.73 (m, 1H), and 7.28-7.42 (m, 9H).
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](N1C=CN=C1)([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19]>C(#N)C>[N:20]1([C:18]([N:15]2[CH2:14][CH2:13][N:12]([C:10](=[O:11])[CH2:9][CH2:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:17][CH2:16]2)=[O:19])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: O=C(CCc1ccccc1)N1CCNCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CC#N
Product: O=C(CCc1ccccc1)N1CCN(C(=O)n2ccnc2)CC1
Reaction time: 3 h
Yield: 92.2 %

Procedure:
1-(3-Phenylpropanoyl)piperazine hydrochloride (1.0 g) was dissolved in acetonitrile, and 1,1′-carbonyldiimidazole (950 mg) was added thereto at room temperature, followed by stirring at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5) to obtain 1-(1H-imidazol-1-ylcarbonyl)-4-(3-phenylpropanoyl)piperazine (1.13 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([CH2:23][OH:24])=[CH:10][CH:9]=1)[CH3:2]>[O-2].[Mn+2].C1(C)C=CC=CC=1>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([CH:23]=[O:24])=[CH:10][CH:9]=1)[CH3:26]
Reactant: CCN(CC)CCCNc1ccc(CO)c2sc3ccccc3c(=O)c12
Agent: [Mn+2]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCN(CC)CCCNc1ccc(C=O)c2sc3ccccc3c(=O)c12
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A mixture of 1-[[3-(diethyiamino)propyl]amino]-4-(hydroxymethyl) thioxanthen-9-one (3.82 g) , toluene (60 mL) and manganese oxide (7.5 g) was refluxed for 6.5 hours. The mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated in vacuo to afford 3.3 g (87%) of 1-[[3-(diethylamino) propyl]amino]-9-oxothioxanthen-4-carboxaldehyde as a brown oil.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[NH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1>C(#N)C>[Cl:18][C:15]1[N:16]=[CH:17][C:12]([CH2:11][NH:10][C:3]([S:2][CH3:1])=[CH:4][N+:5]([O-:7])=[O:6])=[CH:13][CH:14]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCc1ccc(Cl)nc1
Solvent: CC#N
Product: CSC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1
Yield: 62 %

Procedure:
To a refluxing mixture of 6.61 g of 1,1-bis(methylthio)-2-nitroethylene and 100 ml of acetonitrile was added a solution of 4.28 g of 5-aminomethyl-2-chloropyridine in 10 ml of acetonitrile dropwise over a period of 3 hours and 30 minutes and the whole mixture was further refluxed for 2 hours. After cooling, the insolubles (by-product; 1,1-bis(6-chloro-3-pyridylmethylamino)-2-nitroethylene) were filtered off and the filtrate was concentrated and washed with ethyl acetate to give 4.83 g of 1-(6-chloro-3-pyridylmethylamino)-1-methylthio-2-nitroethylene. The ethyl acetate washings were concentrated and the residue was purified by column chromatography (eluent: dichloromethane-methanol (30:1)) to give a further crop (1.15 g) of the same compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:25])[N:16]2[CH2:19][CH:20]2[O:24][CH2:23][CH2:22][O:21]2)=[N:11][CH:10]=1.C(Cl)(Cl)Cl>CN(C)C=O.[Cu]=O.O>[O:24]1[CH2:23][CH2:22][O:21][CH:20]1[CH2:19][N:16]1[C:17]2[C:12](=[N:11][CH:10]=[C:9]([N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)[CH:18]=2)[CH:13]=[CH:14][C:15]1=[O:25]
Reactant: O=c1ccc2ncc(Br)cc2n1CC1OCCO1
Reactant: c1c[nH]cn1
Agent: O=[Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1ccc2ncc(-n3ccnc3)cc2n1CC1OCCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
To a suspension of 77 mg of sodium hydride in 2 mL of N,N-dimethylformamide, 0.13 g of imidazole was added, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture, 0.20 g of 7-bromo-1-((1,3-dioxolan-2-yl)methyl)-1,5-naphthyridin-2(1H)-one was added dividedly, and then 18 mg of copper (II) oxide was added thereto. The reaction mixture was stirred at 135 to 140° C. for 30 minutes. The reaction mixture was cooled to room temperature, then chloroform and water were added thereto, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resultant residue, a mixed solvent of diethyl ether: ethyl:acetate (3:1) was added, and the solid was filtered off to obtain 0.12 g of 1-((1,3-dioxolan-2-yl)methyl)-7-(1H-imidazol-1-yl)-1,5-naphthyridin-2(1H)-one as a yellow solid.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Zn+])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21](Cl)[C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3C=[N:17][C:16]=2[CH:27]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[C:7]([C:6]3[CH:9]=[CH:10][C:3]([F:2])=[CH:4][CH:5]=3)=[N:17][C:16]=2[CH:27]=1
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: Clc1ccc2c(c1)N=Cc1ccccc1N2Cl
Agent: [Cl-]
Product: Fc1ccc(C2=Nc3cc(Cl)ccc3Nc3ccccc32)cc1
Yield: 71.3 %

Procedure:
4-Fluorobenylzinc chloride (0.5 ml, 0.5 M in THF, 0.4 mmol) and 8,5-dichloro-5H-dibenzo[b,e][1,4]diazepine (160FE64) (26 mg, 0.1 mmol) were reacted according GP10 to give 23 mg of the title compound (160FE70). MS (ESI) 323 (MH+). Purity for MH+ (UV/MS) 98/100.
Reaction SMILES: C(OCC)C.O[CH:7]([CH2:15][C:16]([CH2:19][Si](C)(C)C)=[C:17]=[CH2:18])[CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.O>CCOC(C)=O>[CH2:19]=[C:16]1[C:17](=[CH2:18])[C:10]23[O:14][CH:7]([CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11]3)[CH2:15]1
Reactant: C=C=C(CC(O)CC1CCCC1=O)C[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C=C1CC2CC3CCCC3(O2)C1=C
Temperature: -78 °C
Yield: 78.6 %

Procedure:
1.1 mL of diethyl ether was added to 2-(2-hydroxy-4-trimethylsilanylmethyl-hexa-4,5-dienyl)-cyclopentanone (70 mg, 0.26 mmol) under nitrogen atmosphere. While stirring at −78° C., TMSOTf (48 μL, 0.26 mmol) was added. While stirring the reaction mixture, the reaction temperature was slowly increased to room temperature for 3 hours. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, H2O was added. After stirring for about 5 minutes, the reaction mixture was diluted with EtOAc and washed with water and saturated brine. The organic layer was separated from the reaction mixture and dried with anhydrous MgSO4. The solvent was removed under reduced pressure and the remaining material was purified with column chromatography (EtOAc/n-hexane=1/15) to obtain 36 mg of the product (77%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12](Cl)[N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:17][O:18][C:19](=[O:22])[CH2:20][NH2:21].C(N(CC)CC)C>CN(C=O)C.O>[CH3:17][O:18][C:19](=[O:22])[CH2:20][NH:21][C:12]1[CH:13]=[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[C:10]([Cl:15])[N:11]=1
Reactant: COC(=O)CN
Reactant: Clc1cc(Cc2ccccc2)nc(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNc1cc(Cc2ccccc2)nc(Cl)n1
Temperature: 70 °C
Yield: 15.6 %

Procedure:
1.87 g (7.8 mmole) of 4-benzyl-2,6-dichloro-pyrimidine was dissolved in 15 mls of DMF. To this solution was added 1.08 g of glycine methyl ester HCl. Next 3.0 mls of triethyl amine was added dropwise and the reaction stirred was then heated to 70° C. for 3 hours. The reaction was diluted with 10 mls of H2O and extracted with two portions of EtOAc. The combined organic layers were washed with two portions of saturated NaCl solution, dried over MgSO4, filter and evaporated under reduced pressure to yield a crude oil. This material was chromatographed on silica gel with 10% Ethyl Acetate-90% Heptane as the eluent. (6-Benzyl-2-chloro-pyrimidin-4-ylamino)-acetic acid methyl ester (0.354 g, 20%) was isolated a clear oil.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@H:12]([NH:16][CH:17]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:24][CH2:23]1)[C:13](O)=[O:14].P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C)C=O.O>[CH2:31]([O:30][C:28]([N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH:17]([NH:16][C@@H:12]2[C:13](=[O:14])[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:10][CH2:11]2)[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:27][CH2:26]1)=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](CSc1ccccc1N)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2NC1=O
Yield: 65.5 %

Procedure:
In N,N-dimethylformamide (5 ml) is dissolved 3-(o-aminophenyl)thio-2(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]aminopropionic acid dihydrochloride (0.16 g), and diethyl phosphorocyanidate (0.3 ml) is added dropwise to the solution. To the mixture is added triethylamine (0.2 ml) and the reaction mixture is stirred under ice-cooling for 1 hour. The reaction mixture is diluted with water (100 ml) and extracted with ethyl acetate (50 ml). The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silicagel column chromatography (hexane: acetone=2:1) to give 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (0.09 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C(N(CC)CC)C>C(OCC)(=O)C.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])c(Cl)c3)CC2)c1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C)nc(N2CCN(c3ccc(N)c(Cl)c3)CC2)c1
Yield: 64.2 %

Procedure:
Stannous chloride dihydrate (2.6 g, 11.5 mmol) was added to a solution of 1-(3-chloro-4-nitro-phenyl)-4-(4,6-dimethyl-pyridin-2-yl)-piperazine (800 mg, 2.31 mmol) in a mixture of ethyl acetate (20 mL) and ethanol (5 mL). The reaction mixture was heated at reflux for 2 h, allowed to cool to ambient temperature and basified with triethylamine. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography over neutral alumina with 10% ethyl acetate in petroleum ether as eluent to afford 2-chloro-4-[4-(4,6-dimethyl-2-pyridyl)piperazin-1-yl]aniline (470 mg, 64%) as a viscous light brown oil.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[NH4+].[N-:12]=[N+:13]=[N-:14].[Na+].N#N.Cl>CN(C=O)C>[N:5]1[NH:12][N:13]=[N:14][C:4]=1[C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[SH:1]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1S
Agent: Cl
Agent: N#N
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Sc1ccccc1-c1nn[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
In a 250 mL round bottom flask was added 2-mercaptobenzonitrile (2.0 g, 14.8 mmol) from Step 1(B) followed by anhydrous DMF (30 mL). Ammonium chloride (1.42 g, 26.64 mmol) and sodium azide (1.73 g, 26.64 mmol) were added to the reaction flask followed by an additional 10 mL of DMF. The reaction mixture was heated to 105° C. under a flow of N2 and stirred overnight. The reaction was worked up by first cooling to room temperature. Next the solution was acidified by the addition of 50 mL of 1N HCl. The solution was extracted with ethyl acetate (2×100 mL) and then washed with brine (100 mL). The combined organics were dried over Na2SO4 and then concentrated under reduced pressure to afford a white solid. The solid was collected by filtration of a heptane/ethyl acetate treatment (7:3, 10 mL) which afforded the title compound as a white solid (1.21 g, 46%); Rf of 0.05″ with 95:5 v/v dichloromethane: methanol; 1H-NMR (400 MHz; DMSO-d6) δ 7.91 (d, 1H), 7.78 (d, 1H), 7.64-7.50 (m, 2H), 2.90 (s, 1H), 2.78 (s, 1H); MS (ESI−) m/z 177.1 (Mz−1).
Reaction SMILES: N1CCCC1.[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:15])[CH3:14].[C:16]([OH:23])(=[O:22])[CH2:17][CH2:18][C:19]([CH3:21])=O>C1(C)C=CC=CC=1>[CH3:21][C:19]1([CH2:18][CH2:17][C:16]([OH:23])=[O:22])[CH2:14][C:13](=[O:15])[C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6]1
Reactant: CC(=O)c1ccccc1O
Reactant: CC(=O)CCC(=O)O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CC1(CCC(=O)O)CC(=O)c2ccccc2O1
Reaction time: 72 h

Procedure:
24 g of pyrrolidine are added carefully, at under 30°, to a solution of 41 g of o-hydroxyacetophenone, 25 g of levulinic acid and 100 ml of toluene. The mixture is left to stand for 3 days at 25° and the solution is extracted by shaking with 150 ml of concentrated sodium carbonate solution. The aqueous phase is acidified with 2 N HCl and then extracted by shaking with ether. The ethereal solution is concentrated and distilled, 14 g (20% of the theoretical yield) of 2-methyl-2-β-carboxyethyl-chroman-4-one being obtained: boiling point: 230°/0.1 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[F:11][CH2:12][CH2:13][NH2:14]>>[NH2:1][C:2]1[CH:9]=[C:8]([NH:14][CH2:13][CH2:12][F:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: NCCF
Reactant: N#Cc1cnc(N)cc1F
Product: N#Cc1cnc(N)cc1NCCF

Procedure:
From intermediate 21 and 2-fluoroethanamine, reacted in an analogous manner to the preparation of intermediate 88. (UPLC-MS 6) tR 0.49; ESI-MS 181.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[NH2:32][CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:32][CH2:33][C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)=[O:22])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NCc1cccnc1
Product: O=C(NCc1cccnc1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 3-(aminomethyl)pyridine as in General Procedure 10 to give the title compound. LCMS: m/z=538 (M+H+); retention time=0.59 minutes.
Reaction SMILES: C(C([C:7]([C:10]([CH2:13][OH:14])([F:12])[F:11])([F:9])[F:8])(F)F)(F)F.N#N.C(C(CF)(F)F)(F)(F)[F:18]>>[C:7]([C:10]([CH2:13][OH:14])([F:12])[F:11])([F:18])([F:9])[F:8]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: FCC(F)(F)C(F)(F)F
Agent: N#N
Product: OCC(F)(F)C(F)(F)F
Temperature: 277 °C

Procedure:
The same catalyst was used from Example 4 above. The reactor was cooled to 277° C. The alcohol (CF3CF2CH2OH) flow of 0.49 mL/hr (2.0 sccm, 3.3×10-8 m3 /s), the COCl2 flow of 3.0 sccm (5.0×10-8 m3 /s), the HF flow of 7.0 sccm (1.2×10-7 m3 /s), and an N2 flow of 2 sccm (3.3×10-8 m3 /s) were begun. The gaseous effluent was analyzed by GCMS and found to be 89.3-90.5% CF3CF2CH2F over a 2 hour period with no evidence for catalyst deactivation.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[O:19][CH:16]1[CH2:15][CH2:14][C:11]2([CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(OC2CCC3(CCNCC3)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
9-(3,4-Dichloro-phenoxy)-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (340 mg, 0.82 mmol) was dissolved in dichloromethane (8 mL) and cooled on an ice bath. Trifluoroacetic acid (2 mL) was added and stirred for 2 h at room temperature. Evaporation followed by co-evaporation with toluene and ethyl acetate gave a solid compound. The compound was washed with diethyl ether to give 222 mg (63%) of 9-(3,4-dichloro-phenoxy)-3-aza-spiro[5.5]undecane trifluoroacetic acid salt as a white crystalline compound. Mp. 139, 6-141.2° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@:4]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[N:5]=C(C1C=CC=CC=1)C1C=CC=CC=1.Cl>CO>[CH3:1][O:2][C:3](=[O:30])[C@:4]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:5]
Reactant: CCCC[C@@](Cc1ccccc1)(N=C(c1ccccc1)c1ccccc1)C(=O)OC
Agent: Cl
Solvent: CO
Product: CCCC[C@](N)(Cc1ccccc1)C(=O)OC
Reaction time: 1.5 h

Procedure:
To a solution of methyl-α-butyl-N-(diphenylmethylene)phenylalaninate (0.31 g, 0.78 mmol) from step A in 10 mL MeOH was added 3.33M hydrochloric acid (0.69 mL, 2.3 mmol). After 1.5 h at rt, the reaction was concentrated in vacuo to remove volatiles, then redissolved in saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (2×), the combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (20 g silica, 0->30% EtOAc/hexanes) afforded methyl-α-butylphenylalaninate as a viscous oil. 1H NMR (400 MHz, d4-MeOH) δ 7.30-7.23 (m, 3H), 7.14-7.12 (m, 2H), 3.68 (d, J=13.1, 1H), 3.18 (d, J=13.1, 1H), 1.92 (m, 1H), 1.61 (m, 1H), 1.51-1.32 (m, 3H), 1.12 (m, 1H) M+H=236.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.[OH-].[NH4+].[Cu]I>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([C:12]#[C:11][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)[CH:7]=1
Reactant: N#Cc1ncc(Cl)cc1Cl
Reactant: C#Cc1ccc(OCCC)cc1
Agent: [Cu]I
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1ccc(C#Cc2cnc(C#N)c(Cl)c2)cc1
Temperature: 25 °C

Procedure:
A solution of 3,5-dichloropicolinonitrile (1.0 eq.), 1-ethynyl-4-propoxybenzene (commercially available) (1.0 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol %), copper (I) iodide (20 mol %), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 50° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% ethyl acetate in hexane to give 3-chloro-5-((4-propoxyphenyl)ethynyl)picolinonitrile as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].F[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 130 °C
Reaction time: 17 h
Yield: 95.8 %

Procedure:
4-Chloro-3-(trifluoromethyl)phenol (1.19 g, 6.06 mmol), methyl 4-fluorobenzoate (0.934 g, 6.06 mmol) and potassium carbonate (2.51 g, 18.2 mmol) were stirred in dimethylsulfoxide (10 mL) at 120° C. overnight under an atmosphere of nitrogen. The temperature was then increased to 130° C. and the reaction mixture stirred for a further 17 hours. The reaction mixture was cooled to room temperature. Water (100 mL) was added and the mixture extracted with ethyl acetate (3×50 mL). The combined organic phase was washed sequentially with water (50 mL) and brine (50 mL), dried over magnesium sulphate, filtered and concentrated in vacuo to afford the title compound as a yellow oil (1.92 g, 96%, contains residual dimethylsulfoxide). This material was taken on crude in subsequent steps.
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:12][CH3:13].[OH-].[Na+].S(OCC)(O[CH2:20][CH3:21])(=O)=O>C(Cl)C1C=CC=CC=1.C([NH+](CC)CC)C>[CH2:20]([O:7][CH2:6][C:5]1[CH:8]=[C:9]([O:10][CH3:11])[C:2]([Br:1])=[C:3]([O:12][CH3:13])[CH:4]=1)[CH3:21]
Reactant: COc1cc(CO)cc(OC)c1Br
Reactant: CCOS(=O)(=O)OCC
Agent: CC[NH+](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCc1ccccc1
Product: CCOCc1cc(OC)c(Br)c(OC)c1
Temperature: 27.5 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a mixture of 4-bromo-3,5-dimethoxybenzylalcohol (44.5 g), triethylammonium benzyl chloride (2.05 g) and 20% aqueous sodium hydroxide solution (288 g) was added diethyl sulfate (41.7 g) under ice-cooling, and the mixture was stirred overnight at 25-30° C. After stirring for 1 hour at 70° C., the mixture was cooled and extracted with toluene. The toluene layer was washed with water and saturated aqueous NaCl solution and dried over magnesium sulfate. The solvent was removed in vacuo to yield 4-bromo-3,5-dimethoxybenzyl ethyl ether (49.5 g) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[C:21]([CH2:22][N:23]3C(=O)C4=CC=CC=C4C3=O)=[N:20][N:19]=[C:18]2[Br:34])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=O.NN>>[Br:34][C:18]1[N:17]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][C:6]=3[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])=[N:23][CH2:22][C:21]2=[N:20][N:19]=1
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1-n1c(Br)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Product: Fc1ccccc1C1=NCc2nnc(Br)n2-c2ccc(Cl)cc21

Procedure:
The 5-chloro-2-(3-bromo-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl)-2'-fluorobenzophenone is reacted with hydrazine to form the titled compound.