Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:13])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+]>CC(N(C)C)=O>[C:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]3[NH:6][C:4](=[O:5])[C:3]4[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:1]=3)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:13])[CH3:12]
Reactant: NC(=O)c1ccccc1N
Reactant: CC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)N1CCN(c2ccc(-c3nc4ccccc4c(=O)[nH]3)cc2)CC1
Temperature: 150 °C
Yield: 88.6 %

Procedure:
To a mixture of 2-aminobenzamide (1.0 g, 7.35 mmol) and 4-(4-acetylpiperazin-1-yl)benzaldehyde (1.71 g, 7.35 mmol) in DMA (60 mL) was added p-TsOH (0.140 g, 0.73 mmol) and NaHSO3 (0.841 g, 8.1 mmol). The reaction mixture was heated at 150° C. for 21 hours, concentrated to half-volume, diluted with water (300 mL), extracted with CH2Cl2 (2×200 mL), washed with brine (200 mL), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 100% CH2Cl2 to 100% (92:7:1 CHCl3/MeOH/concentrated NH4OH), to afford 2-(4-(4-acetylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one as a yellow solid (2.27 g, 89%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:17])=O>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCCCCc1ccccc1
Yield: 93.8 %

Procedure:
6-Phenylhexanoic acid (2.5 g, 13 mmol) was treated with thionyl chloride (3.0 ml, 41.1 mmol) and stirred under reflux for 3 h. The mixture was evaporated under reduced pressure to remove thionyl chloride and then distilled at 92-95° C./0.1 mbar to give the product as a colourless oil (2.57 g, 94%).
Reaction SMILES: I[CH2:2][CH3:3].[Br:4][C:5]1[C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:7][C:8]([OH:13])=[C:9]([CH:12]=1)[C:10]#[N:11].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:4][C:5]1[C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:7][C:8]([O:13][CH2:2][CH3:3])=[C:9]([CH:12]=1)[C:10]#[N:11]
Reactant: N#Cc1cc(Br)c(-c2ccc(F)cc2)nc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nc(-c2ccc(F)cc2)c(Br)cc1C#N

Procedure:
Iodoethane (1.43 mL) was added to a mixture of 5-bromo-6-(4-fluorophenyl)-2-hydroxynicotinonitrile (3.49 g), potassium carbonate (3.29 g), and DMF (30 mL), and the resultant mixture was stirred at 80° C. for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (3.00 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][NH:10][C:11]([NH2:13])=[S:12])([CH3:4])([CH3:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][NH:10][C:11]([N:13]=[CH:17][N:18]([CH3:20])[CH3:19])=[S:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)NCCNC(N)=S
Product: CN(C)C=NC(=S)NCCNC(=O)OC(C)(C)C
Yield: 51 %

Procedure:
The title compound was synthesised from (2-Thioureido-ethyl)-carbamic acid tert-butyl ester and Dimethylformamide dimethyl acetal according to the procedure described for Example C in 51% yield. MS (m/e): 275.4 (MH+, 100%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9](OC)=[O:10])=[CH:7][C:6]=1[F:15])[CH3:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([CH2:9][OH:10])=[CH:7][C:6]=1[F:15])[CH3:4]
Reactant: COC(=O)c1ccc([C@H](C)N)c(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@H](N)c1ccc(CO)cc1F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cooled (0° C.) suspension of (S)-methyl 4-(1-aminoethyl)-3-fluorobenzoate hydrochloride (0.109 g, 0.468 mmol) in THF (15 mL) was added a solution of LAH in THF (2.0 M, 1.05 mL, 2.10 mmol, 4.49 equiv) and the resulting mixture was stirred at 0° C. for 2 h 20 min and at room temperature for 2½ h. The reaction mixture was quenched by addition of a mixture of Na2SO4 decahydrate and Celite (1:1 by weight) until gas evolution ceased. The reaction mixture was filtered, washed with EtOAc. The filtrate was concentrated and used for the next reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:32]=[CH:31][C:13]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]([P:23](=[O:30])([O:27]CC)[O:24]CC)([F:22])[F:21])=[CH:12][C:11]=2[O:33][CH3:34])=[C:4]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[N:3]=1.C[Si](Br)(C)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:32]=[CH:31][C:13]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]([P:23](=[O:24])([OH:27])[OH:30])([F:22])[F:21])=[CH:12][C:11]=2[O:33][CH3:34])=[C:4]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(OCCOCCC(F)(F)P(=O)(OCC)OCC)cc1OC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(OCCOCCC(F)(F)P(=O)(O)O)cc1OC
Temperature: 22 °C
Reaction time: 18 h

Procedure:
To a solution of diethyl (3-(2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)-3-methoxyphenoxy)ethoxy)-1,1-difluoropropyl)phosphonate (1 equiv.) in CH2Cl2 (0.10 M) at 0° C. was slowly added trimethylsilyl bromide (10 equiv.). After 1 h the ice-bath was removed and the reaction mixture was allowed to stir at 22° C. for 18 h. At this point the volatiles were removed in vacuo and the resulting residue was purified by Reverse Phase-HPLC using a 20-90% 0.5 mM NH4OAc (in MeCN) to 10 mM NH4OAc (in water) gradient to deliver the title compound (70%) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:44]=[C:43](OS(C(F)(F)F)(=O)=O)[CH:42]=[CH:41][C:40]=1[Cl:53])[CH3:35]>>[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:44]=[C:43]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:19])[F:21])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH3:32])[CH:42]=[CH:41][C:40]=1[Cl:53])[CH3:35]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)ccc1Cl
Product: CCOC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)ccc1Cl

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (2-chloro-5-trifluoromethanesulfonyloxy-phenyl)-acetic acid ethyl ester.
Reaction SMILES: N(C(C)(CC(OC)(C)C)C#N)=NC(C)(CC(C)(OC)C)C#N.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:34]([C:35]([F:38])([F:37])[F:36])=[N:33][N:32]=[N:31]2)=[CH:26][C:25]=1[CH3:39].[Br:40]N1C(=O)C2=CC=CC=C2C1=O>ClCCl>[Br:40][CH2:39][C:25]1[CH:26]=[C:27]([N:30]2[C:34]([C:35]([F:38])([F:36])[F:37])=[N:33][N:32]=[N:31]2)[CH:28]=[CH:29][C:24]=1[F:23]
Reactant: O=C1c2ccccc2C(=O)N1Br
Reactant: Cc1cc(-n2nnnc2C(F)(F)F)ccc1F
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: ClCCl
Product: Fc1ccc(-n2nnnc2C(F)(F)F)cc1CBr
Temperature: 25 °C

Procedure:
2,2′-Azobis(4-methoxy-2,4-dimethylvaleronitrile) (50 mg) was added by three portions to the mixture of 1-(4-fluoro-3-methylphenyl)-5-(trifluoromethyl)-1H-tetrazole and N-bromophtalimide (1.44 g) in dichloromethane (16 ml) at 30° C. and the whole was stirred at reflux for 3 hours. After being cooled to room temperature, the mixture was washed with aqueous sodium hydrogen carbonate and aqueous sodium thiosulfate successively. The organic layer was separated, dried over magnesium sulfate, and evaporated under reduced pressure to give a crude 1-[3-(bromomethyl)-4-fluorophenyl]-5-(trifluoromethyl)-1H-tetrazole (3:7).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([Cl:13])[N:5]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[N:3]=1.[CH3:24][O:25][CH:26]([O:29][CH3:30])[CH2:27][NH2:28].C(N(C(C)C)CC)(C)C>O1CCOCC1>[Cl:13][C:6]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([NH:28][CH2:27][CH:26]([O:29][CH3:30])[O:25][CH3:24])[N:3]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[N:5]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc([N+](=O)[O-])cc2)nc1Cl
Reactant: COC(CN)OC
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc([N+](=O)[O-])cc2)nc1NCC(OC)OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A mixture of methyl [4,6-dichloro-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (2.0 g, 5.6 mmol), aminoacetaldehyde dimethylacetal (0.68 g, 6.5 mmol) and diisopropylethylamine (1.5 mL, 8.4 mmol) in 1,4-dioxane (50 mL) was stirred at 80° C. for 2 hours. The mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extracts were washed with aq NaHCO3 and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative MPLC (silica gel, hexane:ethyl acetate, 2/1) to give methyl [4-chloro-6-[(2,2-dimethoxyethyl)amino]-2-(4-nitrobenzyl)pyrimidin-5-yl]-acetate (1.89 g, 79%) as a gray solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH:12]1(Br)[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(C)=O.O>[CH:12]1([O:1][C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][C:8]3=[O:11])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrC1CCCC1
Reactant: O=C1CCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: O=C1CCc2ccc(OC3CCCC3)cc21
Yield: 81 %

Procedure:
A solution of 8.0 g of 6-hydroxy-1-indanone, 6.3 ml of cyclopentyl bromide, 16.4 g of potassium carbonate and 10 ml of N,N-dimethylformamide in 100 ml of acetone was heated to 75° for 35 hours. After cooling, the solution was poured into 150 ml of water and extracted twice with 200 ml of ethyl acetate each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The crude product was purified by column chromatography on silica gel (hexane/ethyl acetate 3:1). 9.45 g (81%) of 6-cyclopentoxy-1-indanone were obtained as an orange oil which was used directly in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([O:12][CH3:13])[N:6]=1)=[O:4].Br[C:15]1[CH:16]=[N:17][CH:18]=[N:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C(#N)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)=[N:9][CH:8]=[C:7]([O:12][CH3:13])[N:6]=1)=[O:4]
Reactant: Brc1cncnc1
Reactant: COC(=O)c1nc(OC)cnc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1nc(OC)cnc1Nc1cncnc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
A mixture of 3-amino-6-methoxypyrazine-2-carboxylic acid methyl ester (65 mg, 355 mmol), 5-bromopyrimidine (84.6 mg, 532 μmol) and cesium carbonate (162 mg, 497 μmol) in dioxane (1.5 ml) was treated with tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (36.7 mg, 35.5 μmol) and xantphos (67.8 mg, 117 μmol) under argon atmosphere and the reaction mixture was stirred at 110° C. for 16 h. After cooling down to ambient temperature, the reaction mixture was diluted with acetonitrile/water. The precipitated solid was sucked off, washed with acetonitrile/water, THF and MeOH and dried to yield the product as yellow solid (57 mg, 55.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9].[NH2:14][C:15]1[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[C:22]2[C:17](=[N:18][CH:19]=[CH:20][N:21]=2)[N:16]=1>C(#N)C>[CH3:26][N:25]([CH3:27])[C:23]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][N:21]=2)[N:16]=[C:15]([NH:14][C:12]([NH:11][S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:9])=[O:13])[N:24]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Reactant: CN(C)c1nc(N)nc2nccnc12
Solvent: CC#N
Product: CN(C)c1nc(NC(=O)NS(=O)(=O)c2ccccc2Cl)nc2nccnc12
Yield: 73.9 %

Procedure:
1.5 g (0.0070 mol) of 2-chlorophenylsulfonyl isocyanate were added to a suspension of 1.3 g (0.0068 mol) of 2-amino-4-dimethylaminopteridine in 40 ml of acetonitrile and the mixture was stirred at reflux for 4 hours. The mixture was vacuum filtered and the filtrate was concentrated by evaporation. The residue was treated with acetone to obtain 2.05 g (74% of theory) of N-(4-dimethylaminopteridine-2-yl)-N'-(2-chlorophenylsulfonyl)-urea in the form of light yellow crystals melting at 232° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])[C:10]2[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=2)=[CH:4][CH:3]=1.Cl.[CH3:30][NH:31][CH3:32].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])[C:10]2[C:11]([CH3:19])=[CH:12][C:13]([C:16]([N:31]([CH3:32])[CH3:30])=[O:17])=[N:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)ncc1C(Sc1ccc(F)cc1)c1c(F)ccc(F)c1F
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)C)ncc1C(Sc1ccc(F)cc1)c1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.5 %

Procedure:
To a solution of 5-[[(4-fluorophenyl)thio](2,3,6-trifluorophenyl)methyl]-4-m ethylpyridine-2-carboxylic acid (383 mg, 0.94 mmol) in methylene chloride (10 ml), dimethylamine hydrochloride (85 mg, 1.03 mmol), 1-hydroxybenzotriazole (140 mg, 1.03 mmol), 4-methylmorpholine (0.227 ml, 2.07 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg, 1.03 mmol) were added at room temperature. After stirring for 17 hours at room temperature, the reaction mixture was washed with 0.5 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure to obtain the title compound (373 mg, 0.86 mmol, 91%) as a white solid.
Reaction SMILES: C(OC=CC[S:8]C)(=O)C.CO.Cl.[C]=O.[C:15]([O:18][CH:19]([CH2:24][CH2:25][S:26][CH3:27])[C:20]([O:22][CH3:23])=O)(=[O:17])[CH3:16]>O1CCCC1.C1(C)C=CC=CC=1>[C:15]([O:18][CH:19]([CH2:24][CH2:25][S:26][CH3:27])[C:20]([O:22][CH3:23])=[S:8])(=[O:17])[CH3:16]
Reactant: CSCC=COC(C)=O
Reactant: COC(=O)C(CCSC)OC(C)=O
Agent: Cl
Agent: [C]=O
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=S)C(CCSC)OC(C)=O
Temperature: 100 °C
Yield: 17.8 %

Procedure:
0.5 mmoles 1-acetoxy-3-methylthiopropene, (Z: E ratio 43:57), and 2.5 mmoles methanol were charged into a 71 cc stainless steel bomb equipped with a glass liner and a Teflon coated stir bar. Ten mole percent, based on 1-acetoxy-3-methylthiopropene, of a catalyst comprising Pd(Pφ3)4 plus 10 mole percent HCl co-catalyst was added. Toluene was included as an internal standard Five milliliters of tetrahydrofuran as a solvent were also included in the reaction system. The reaction mixture was charged under argon. The bomb was sealed and carbon monoxide at a pressure of 1000 psi (at room temperature) was charged to the bomb, and the bomb was heated to 100° C. and allowed to react for 45.25 hours with stirring. At the termination of the reaction, the reaction products were analyzed by gas chromatography and it was found that 2-acetoxy-4-(methylthio)butanoic acid, methyl ester was produced in a yield of 21.7 percent, and that 2-acetoxy-4-(methylthio)thiobutanoic acid, methyl ester was produced in a yield of 17.8 percent, based on the 1-acetoxy-3-methylthiopropene reactant charged. Note that each of the products is hydrolyzable to methionine hydroxy analog. When this run was repeated without the HCl co-catalyst (run length 44 hours), the yields of the above ester and thioester were3 93 percent.and 4.48 percent, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:22][C:23]1[C:24]([C:35](O)=[O:36])=[N:25][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[N:27][CH:28]=1>C1COCC1>[Cl:22][C:23]1[C:24]([C:35]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]4[CH2:20][CH2:19]4)=[O:15])=[CH:10][CH:9]=3)[C:5]([CH3:21])=[CH:4][CH:3]=2)=[O:36])=[N:25][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[N:27][CH:28]=1
Reactant: O=C(O)c1nc(N2CCCCC2)ncc1Cl
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2nc(N3CCCCC3)ncc2Cl)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (53 mg, 0.189 mmol) and 5-chloro-2-(piperidin-1-yl)pyrimidine-4-carboxylic acid (91.3 mg, 0.38 mmol) were mixed in THF (5 ml) and the mixture shaken in a varian tube for 15 min at room temperature. Carbodiimde resin (500 mg) was added and shaking continued for 48 h. The solution was filtered off and concentrated under vacuum. The residue was chromatographed on a silica gel flash column eluting with ethyl acetate/hexane (1:1) and the solvent evaporated under vacuum to give 5-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(piperidin-1-yl)pyrimidine-4- carboxamide (35 mg). NMR; δH CDCl3 9.50,(1 H, s), 8.40,(1 H, s), 7.83,(2H, d), 7.64,(1H, dd), 7.56,(1H, d), 7.41,(2H, d), 7.27,(1H, d), 6.24,(1H, t), 3.79,(4H, m), 3.35,(2H, m), 2.22,(3H, s), 1.65,(4H, m), 1.08,(1H, m), 0.82,(2H, m), 0.58,(2H, m), 0.30,(2H, m). LCMS: retention time 3.96 min, MH+504.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)(Cl)=O.[NH4+:18].[OH-]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:18])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
5-Fluoro-2-nitro-benzoic acid (17.9 g, 96.8 mmol) was heated in thionyl chloride (35 mL, 5 mol eq.) for two hours at 85° C. (oil bath temperature). The reaction mixture was evaporated, taken up and evaporated twice with dry toluene. The resulting acid chloride was dissolved in dry dioxane (180 mL) and added to an ice-water bath cooled solution of 33% NH4OH (23.5 mL, 2 mol eq.) in dioxane (180 mL). The reaction was allowed to warm up gradually to room temperature and then evaporated to dryness. The crystalline residue was triturated in water (50 mL), collected by filtration, washed with a small amount of water and dried in vacuo at 80° C. to constant weight (17.56 g, 98.5%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11]3C=CS[C:12]=3[C:16]([OH:18])=[O:17])=[C:4]2[CH:3]=[CH:2]1.N[C:20]1[S:21]C=C[C:24]=1C(OC)=O>>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11]3[S:21][CH:20]=[CH:24][C:12]=3[C:16]([OH:18])=[O:17])=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(O)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: COC(=O)c1ccsc1N
Product: O=C(O)c1ccsc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid using methyl 2-aminothiophene-3-carboxylate instead of methyl 3-aminothiophene-2-carboxylate.). LCMS (ESI) 260 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.88 (1H, br. s.) 10.77 (1H, s) 8.16 (1H, d, J=5.66 Hz) 7.41 (1H, dd, J=3.22, 1.85 Hz) 7.23 (1H, d, J=5.86 Hz) 7.01 (1H, d, J=5.86 Hz) 6.94 (1H, d, J=5.66 Hz) 6.47 (1H, d, J=2.73 Hz)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:27][C@H:15]4[C:16]=3[N:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[N:18]=2)=[O:10])[CH2:2]1.[C:28](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:28][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:27][C@H:15]4[C:16]=3[N:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[N:18]=2)=[O:10])[CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCC1CNCCO1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCOC(CNC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@H]2C[C@@H]32)C1
Temperature: 23 °C
Reaction time: 18 h
Yield: 106.2 %

Procedure:
To a mixture of (1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (morpholin-2-ylmethyl)-amide (40 mg, 0.097 mmol) and potassium carbonate (26.9 mg, 0.195 mmol) in DMF (0.5 mL) was added iodomethane (6.06 μL, 0.097 mmol). The reaction was stirred at 23° C. for 18 h. The mixture was filtered then purified by HPLC to provide the title compound (TFA salt, 40 mg) as a hygroscopic white solid. LCMS m/z=389.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.37-0.41 (m, 1H), 1.14-1.20 (m, 1H), 2.11-2.21 (m, 1H), 2.25-2.32 (m, 1H), 2.74-3.47 (m, 11H), 3.61-3.69 (m, 1H), 3.77-3.83 (m, 1H), 3.94-4.05 (m, 1H), 7.30-7.35 (m, 1H), 7.59-7.64 (m, 1H), 7.74-7.80 (m, 1H), 8.15-8.21 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>C1COCC1.[Cl-].[NH4+]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)([OH:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCCN(Cc3ccccc3)C2)cc1
Reaction time: 2 h
Yield: 39.6 %

Procedure:
To a solution of 1-benzylpiperidin-3-one (5 g, 26 mmol) in THF (30 mL) was added (4-methoxyphenyl)magnesium bromide (0.5 M in ether) (66 mL, 33 mmol) at rt under a nitrogen atmosphere. The reaction was stirred for 2 h and then diluted with sat. ammonium chloride solution and extracted with ethyl acetate (200 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give crude 1-benzyl-3-(4-methoxyphenyl)piperidin-3-ol (5.1 g, 10.29 mmol, 38.9% yield) with was used in the next step without further purification. LCMS (Method 107): (ES-API), m/z 298.2 (M+H) RT=1.703 min.