Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:8][O:9][C:10]([C:12]1([NH2:20])[CH2:17][CH2:16][N:15]([O:18][CH3:19])[CH2:14][CH2:13]1)=[O:11].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[CH2:29][C:30](Cl)=[O:31].O>C(#N)C>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[CH2:29][C:30]([NH:20][C:12]1([C:10]([O:9][CH3:8])=[O:11])[CH2:17][CH2:16][N:15]([O:18][CH3:19])[CH2:14][CH2:13]1)=[O:31]
Reactant: COC(=O)C1(N)CCN(OC)CC1
Reactant: Cc1ccc(C)c(CC(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C1(NC(=O)Cc2cc(C)ccc2C)CCN(OC)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 71.6 %

Procedure:
To 5.4 g of potassium carbonate and 2 g of 4-Amino-1-methoxy-piperidine-4-carboxylic acid methyl ester hydrochloride in 10 ml of acetonitrile, 1.94 g of (2,5-dimethyl-phenyl)-acetyl chloride in 5 ml of acetonitrile are added at a temperature of 0-5° C. After stirring for 22 h at room temperature the reaction mixture is poored on cold water and extracted with ethyl-acetate. The organic phase is dried over sodium sulfate, filtered and evaporated to yield 2.13 g of methyl 4-[2-(2,5-dimethyl-phenyl)acetylamino]-1-methoxy-piperidine-4-carboxylate as beige cristalline solid. 1H-NMR (CDCl3): □ 1.95-2.30 (br signals, total 4H), 2.27 (s, 3H), 2.33 (s, 3H), 2.77-3.23 (br signals, total 4H), 3.48 (s, 3H), 3.54 (s, 2H), 3.71 (s, 3H), 5.40 (br s, 1H), 7.02 (s, 1H), 7.04 (d, 1H), 7.11 (d, 1H).
Reaction SMILES: Cl.[C:2](N)(=[O:9])[C:3]1C=C[CH:6]=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([NH:35][C:36]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[O:37])=[C:23]([CH:34]=1)[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1)=[O:25].O1CCC(=O)CC1>>[ClH:18].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([NH:35][C:36]([CH:38]2[CH2:39][CH2:40][N:41]([CH:4]3[CH2:3][CH2:2][O:9][CH2:6][CH2:5]3)[CH2:42][CH2:43]2)=[O:37])=[C:23]([CH:34]=1)[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1)=[O:25]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NC(=O)C1CCNCC1
Reactant: NC(=O)c1ccccc1
Agent: Cl
Agent: O=C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NC(=O)C1CCN(C2CCOCC2)CC1

Procedure:
Using methods substantially equivalent to those described in example 27, 5-chloro-N-(5-chloropyridin-2-yl)-2-[1-(tetrahydropyran-4-yl)piperidin-4-ylcarbonyl]amino]-benzamide hydrochloride (0.25 g, 56%) was prepared from 5-chloro-N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]benzamide trifluoroacetate and tetrahydro-4H-pyran-4-one. The preparative RPHPLC (C18) purification procedure was elution with a linear gradient of 90/10 to 50/50 (0.01% HCl/acetonitrile) over 180 min.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([O:25][CH2:26][C:27](Cl)=[O:28])(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:18]1([CH2:17][O:25][CH2:26][C:27]([N:14]2[CH2:13][CH2:12][N:11]([C:9](=[O:10])[CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:16][CH2:15]2)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)COC(=O)c1ccccc1
Reactant: O=C(CCc1ccccc1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(CCc1ccccc1)N1CCN(C(=O)COCc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(3-phenylpropionyl)piperazine (115 g) in toluene (557 ml) and triethylamine (76 ml) was added benzoyloxyacetyl chloride (87 ml) at such a rate to keep the temperature below 30° C. After 30 min water (577 ml) was added and the reaction was stirred for a further 30 min. The layers were separated and the organic layer was washed with sodium carbonate and sodium chloride solution. The dried solution was evaporated in vacuo to give 193 g of 1-[(phenylmethoxy)acetyl]-4-(3-phenylpropionyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)(=[O:15])=[O:14].Cl[CH2:27][C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)(=[O:15])=[O:14])[CH2:27][C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29]
Reactant: CCN(CC)C(=O)CCl
Reactant: COc1ccc(S(=O)(=O)Nc2cc(C(C)(C)O)ccc2Cl)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CN(c1cc(C(C)(C)O)ccc1Cl)S(=O)(=O)c1ccc(OC)c(OC)c1
Temperature: 80 °C
Yield: 92.2 %

Procedure:
To a solution of N-[2-chloro-5-(1-hydroxy-1-methyl-ethyl)-phenyl]-3,4-dimethoxy-benzenesulfonamide (0.98 g, 2.5 mmol) in DMF (7.5 mL) was added 2-Chloro-N,N-diethyl-acetamide (0.418 g, 1.1 eq) and K2CO3 (0.35 g, 1 eq). The mixture was heated at 80° C. over night, cooled and partitioned between EA and water. The organic layer was washed several times with water and brine, dried over MgSO4 and concentrated. The residue was purified by chromatography on SiO2 (hex/EA 1:1, EA) to give the product as a colourless foam (1.15 g, 92%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][CH:6]1Br)(=[O:3])[CH3:2].[SH:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>C(#N)C.[Cl-].[Zn+2].[Cl-].[N-]1C=CN=C1.[Ag+]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[S:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Reactant: N#Cc1ccc(S)cc1
Agent: [Ag+]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(C#N)cc2)SC[C@H]1OC(C)=O
Temperature: 50 °C
Yield: 16.5 %

Procedure:
A suspension of 625 mg (1.76.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide, 200 mg (1.48.10-3 mol) of 4-mercaptobenzonitrile and a 400 pm molecular sieve in 10 ml of acetonitrile is stirred in the presence of 605 mg (4.4.10-3 mol) of zinc chloride and 310 mg (1.8.10-3 mol) of silver imidazolate, in the absence of light, under an inert atmosphere. After heating at 50° C. for 3 h, the reaction mixture is filtered on Celite® in ethyl acetate. The filtrate is washed with a 1N solution of hydrochloric acid, water, a 1N solution of sodium hydroxide, water and finally a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure. After purification by chromatography on silica gel using a hexane/ethyl acetate mixture (3/1 v/v) as the eluent, and precipitation in ether, 100 mg (yield: 17%) of the expected product are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:19]=4[S:20][C:16]=3[CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:4][CH:3]=1.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:31][O:30][C:28](=[O:29])[CH2:27][O:25][C:22]1[CH:23]=[CH:24][C:18]2[C:17]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)=[C:9]4[C:14](=[CH:15][C:16]=3[S:20][C:19]=2[CH:21]=1)[CH:13]=[CH:12][CH:11]=[CH:10]4
Reactant: COC(=O)CBr
Reactant: Oc1ccc(-c2c3ccccc3cc3sc4cc(O)ccc4c23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2c(c1)sc1cc3ccccc3c(-c3ccc(O)cc3)c12
Reaction time: 2.5 h
Yield: 58.1 %

Procedure:
11-(4-Hydroxy-phenyl)-benzo[b]naphtho[2,3-d]thiophen-3-ol (1.36 g, 3.96 mmol), methyl bromoacetate (0.38 mL, 4.01 mmol), potassium carbonate (0.548 g, 3.97 mmol) and N,N-dimethylformamide (21 mL) were combined and stirred at ambient temperatures for 2.5 h. The reaction mixture was added to water and extracted with ethyl acetate and THF. Silica gel was added to the organic phase and the solvent was removed. The adsorbate was flash chromatographed (eluent:gradient dichloromethane to 98:2 dichloromethane:acetonitrile) to provide the title compound as a white solid (0.953 g, 58%): mp: 229-231° C: NMR (DMSO-d6); δ9.78 (s, 1 H), 8.51 (s, 1 H), 8.00 (d, J=8 Hz, 1 H), 7.56-7.39 (m, 4 H), 7.18 (d, J=9 Hz, 2 H), 7.05 (d, J=9 Hz, 2 H), 6.79 (dd, J=9, 2 Hz, 1 H), 6.66 (d, J=9 Hz, 1 H), 4.86 (s, 2 H), 3.68 (s, 3 H); MS (EI): 414 (100%, M+); Anal. Calc. for C25 H18O4S: C, 72.45, H, 4.38, N, 0.00. Found: C, 71.78, H, 4.41, N, 0.13.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:18]([Cl:20])[Cl:19]>>[C:18]([Cl:20])([Cl:19])=[O:1].[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: ClCCl
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: O=C(Cl)Cl

Procedure:
mixing bisphenol A, an aqueous caustic solution, methylene chloride and phosgene by means of at least one motionless mixer to form a fine dispersion of the partially phosgenated derivatives of bisphenol A in said aqueous solution,
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[NH2:15])[CH2:3][CH2:2]1.[CH3:16][O:17][CH:18]([O:22][CH3:23])N(C)C>>[CH3:23][O:22][CH:18]([O:17][CH3:16])[N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[N:15]=[CH:9][N:10]([CH3:14])[CH3:11])[CH2:3][CH2:2]1
Reactant: Nc1nccn1CCCC1CCNCC1
Reactant: COC(OC)N(C)C
Product: COC(OC)N1CCC(CCCn2ccnc2N=CN(C)C)CC1
Temperature: 100 °C

Procedure:
A mixture of 1-[3(4-piperidinyl)propyl]-1H-imidazole-2-amine (0.5 g, 0.0024M) and dimethylformamide dimethylacetal (7 ml) was heated at 100° C. for 10 hrs. The reaction was then stripped to dryness to give 4-[3-(2[[[dimethylamino)methylene]amino]-1H-imidazol-1-yl]propyl]-1-piperidinecarboxaldehyde dimethylacetal. The solution of the piperidinecarboxaldehyde dimethylacetal in chloroform (4 ml) was added to the mixture of 6-aminopenicillanic acid (0.46 g, 0.0216M) and diisopropylethylamine (0.37 ml) in chloroform (10 ml) at 0° C. and then stirred at room temperature for 31/2 hrs. After this period, the solvent was removed and water (20 ml) was added. The aqueous solution, after being washed with ethylacetate, was acidified from about pH 3 to about 3.5 and purified on Sephadex L-20 columns to give [2S-(2alpha,5alpha,6beta)]-6-[[[4-[3 -[2-[[(dimethylamino)methylene]amino]-1H-imidazol-1-yl]propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 1.7 molar hydrochloride 2.6 molar hydrate (0.64 g, 64% yield).
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[CH3:22][C:23]1[N:24]=[C:25]([N:33]2[CH2:38][CH2:37][CH2:36][NH:35][C:34]2=[O:39])[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:35]2[CH2:36][CH2:37][CH2:38][N:33]([C:25]3[S:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([CH3:22])[N:24]=3)[C:34]2=[O:39])=[CH:16][CH:17]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1sc(N2CCCNC2=O)nc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCCN(Cc3ccc(F)cc3)C2=O)nc1C

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 1-(bromomethyl)-4-fluorobenzene to react with ethyl 4-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in quantitative yield: MS (ES+) m/z 378.2 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=1.I[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])=[CH:23][CH:22]=1.[C@@H]1(N)CCCC[C@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>ClCCl.CO.[Cu]I>[N+:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:23]=[CH:22][C:21]([N:10]2[C:9]3[CH:8]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:26][CH:25]=1)([O-:35])=[O:34]
Reactant: c1ccc(-c2ccc3c(c2)[nH]c2ccccc23)nc1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(I)cc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])c1ccccc1-c1ccc(-n2c3ccccc3c3ccc(-c4ccccn4)cc32)cc1
Temperature: 112.5 °C
Reaction time: 96 h
Yield: 94.2 %

Procedure:
2-(Pyridin-2-yl)-9H-carbazole (611 mg, 2.5 mmol, 1.0 eq), 4′-iodo-2-nitrobiphenyl (975 mg, 3.0 mmol, 1.2 eq), CuI (48 mg, 0.25 mmol, 0.1 eq), trans-cyclohexane-1,2-diamine (250 uL, 2.5 mmol, 1.0 eq) and K3PO4 (1114 mg, 5.25 mmol, 2.1 eq) were added to a dry pressure vessel equipped with a magnetic stir bar. The vessel was evacuated and back-filled with nitrogen. The evacuation and back-fill procedure was repeated twice. Then solvent dioxane (10 mL) was added under nitrogen. After bubbling with nitrogen for 30 minutes, the mixture was stirred at 110-115° C. in an oil bath for 4 days. Then the mixture was cooled to ambient temperature. The solvent was removed under reduced pressure and the residue was purified through column chromatography on silica gel using hexane/ethyl acetate (10:1-3:1) then dichloromethane/methanol (20:1) as an eluent to obtain the desired product as a solid (1.04 g in 94% yield). 1H NMR (DMSO-d6, 400 MHz): δ 7.36 (t, J=6.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.70-7.92 (m, 8H), 8.05 (t, J=8.4 Hz, 2H), 8.10 (d, J=8.4 Hz, 1H), 8.22 (s, 1H), 8.33 (d, J=7.2 Hz, 1H), 8.39 (d, J=8.0 Hz, 1H), 8.67 (d, J=4.8 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH:9]1[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:13]([S:16][CH2:17][CH:18]([CH3:22])[C:19](O)=[O:20])(=[O:15])[CH3:14].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:12])[CH2:7][N:8]([C:19](=[O:20])[CH:18]([CH3:22])[CH2:17][S:16][C:13](=[O:15])[CH3:14])[CH:9]1[CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNC1CC1
Reactant: CC(=O)SCC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CC1
Temperature: 25 °C

Procedure:
To a solution of N-(cyclopropyl)glycine t-butyl ester (12 g, 0.0702 mol) and 3-acetylthio-2-methylpropionic acid (8.1 g, 0.050 mol) in methylene chloride (200 ml) chilled in an ice bath was added dicyclohexylcarbodiimide (14.4 g, 0.070 mol). The resulting mixture was stirred for sixteen hours at room temperature. The dicyclohexylurea was removed by filtration and washed with diethyl ether. Evaporation of the filtrate yielded the crude product as a pale yellow oil which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][O:8][C:9]2=[O:12])=[CH:5][CH:4]=1>[O-2].[O-2].[Mn+4]>[O:12]=[C:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([CH:2]=[O:1])[CH:11]=2)[CH2:7][O:8]1
Reactant: O=C1OCc2ccc(CO)cc21
Agent: [Mn+4]
Agent: [O-2]
Product: O=Cc1ccc2c(c1)C(=O)OC2

Procedure:
According to a similar procedure to that described in Example 4-(3), 6-(hydroxymethyl)-1 (3H)-isobenzofuranone (3.25 g, 20.8 mmol) obtained from Example 1-(4) or Example 1-(6) and activated manganese dioxide (33 g) were reacted, and the reaction mixture was worked up to afford the title compound as a crude solid. The crude solid was subjected to chromatography on a silica gel (40 g) column (eluent; ethyl acetate) to afford the title compound (2.45 g, 76% yield) as a solid (mp. 134° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH:11]2[CH2:13][C:12]2([CH3:17])[C:14]([OH:16])=[O:15])=[O:10])=[N:6][CH:7]=1.[CH3:18]O>S(Cl)(Cl)=O>[CH3:18][O:15][C:14]([C:12]1([CH3:17])[CH2:13][CH:11]1[C:9](=[O:10])[NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:16]
Reactant: CO
Reactant: CC1(C(=O)O)CC1C(=O)Nc1ccc(Cl)cn1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(C)CC1C(=O)Nc1ccc(Cl)cn1
Temperature: 0 °C

Procedure:
A suspension of (1SR,2RS)-2-(5-chloro-pyridin-2-ylcarbamoyl)-1-methyl-cyclopropane-carboxylic acid (176 mg) in MeOH (5 ml) was cooled to 0° C. and treated with thionyl chloride (15 drops). After stirring for 2 hrs at 0° C. additional thionyl chloride (10 drops) was added. The clear solution was concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2−>CH2Cl2/MeOH 9:1) to give (1SR,2RS)-2-(5-chloro-pyridin-2-ylcarbamoyl)-1-methyl-cyclopropanecarboxylic acid methyl ester (163 mg) as colorless amorphous solid. MS 269.5 ([M+H]+).
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].I[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=1.Cl>COCCOC.C1COCC1>[CH:15]([C:12]1[CH:13]=[CH:14][C:9]([CH:4]([C:3]#[N:7])[C:5]#[N:6])=[CH:10][CH:11]=1)=[CH2:16]
Reactant: C=Cc1ccc(I)cc1
Reactant: N#CCC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: C=Cc1ccc(C(C#N)C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To an ice-cooled suspension of NaH (0.792 g, 33.0 mmol) in anhydrous 1,2-dimethoxyethane (20 mL) was added dropwise via syringe a solution of malononitrile (0.99 g, 15 mmol) in anhydrous 1,2-dimethoxyethane (5 mL) under N2. The mixture was stirred for 1 h at room temperature under N2. Next, 1-iodo-4-vinyl-benzene (1.15 g, 5.00 mmol), dry THF (15 mL), and tetrakis(triphenyphosphine)palladium(0) (0.58 g, 0.50 mmol) were added to the resulting pink suspension under an N2 flow, and the reaction mixture stirred at 85° C. for 2 h. After cooling to room temperature, the reaction mixture was poured into ice, neutralized with 10% HCl, and extracted with CH2Cl2 (100 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was then purified by flash chromatography on silica gel eluting with 1:1 hexane: CH2Cl2, to give 0.603 g (71.8%) of the title compound as pale yellow solid: mp 40-42° C. ° C.; 1H NMR (400 MHz, CDCl3): δ 7.526 (d, 2H, J=7.6 Hz), 7.462 (d, 2H, J=7.6 Hz), 6.738 (d×d, 1H, J1=17.6 Hz, J2=10.8 Hz), 5.846 (d, 1H, J=17.6 Hz), 5.398 (d, 1H, J=10.8 Hz), 5.075 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 139.840, 135.372, 127.766, 127.556, 125.245, 116.619, 111.897, 28.050; Anal. Calcd. for C11H8N2: C, 78.55; H, 4.79; N, 16.66. Found; C, 78.76; H, 4.75; N, 16.02.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22]([O:24]C)=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Br:33][CH2:34][Br:35]>O1CCCC1>[CH2:26]([C@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])[C:22](=[O:24])[CH:34]([Br:35])[Br:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCBr
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C(Br)Br
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
Under nitrogen gas, a solution of diisopropylamine (2.4 g, 21.6 mmol) in tetrahydrofuran (10 mL) was added to n-butyllithium (in 1.6 M hexane, 13.5 mL, 21.6 mmol) at 5° C. and the mixture was stirred for 30 minutes (liquor A). Separately, under nitrogen gas in another vessel, a solution was prepared from methyl (S)-2-tert-butyloxycarbonylamino-3-phenylpropanoate (2.0 g, 7.2 mmol), dibromomethane (2.5 g, 14.4 mmol) and tetrahydrofuran (10 mL) and cooled to −70° C. (liquor B). To this liquor B was added said liquor A over 30 minutes at −70° C., and the mixture was stirred for 30 minutes at the same temperature and then warmed to 20° C. This reaction mixture was poured in 25 mL of2N-HCl for hydrolysis and, then, extracted with 10 mL of ethyl acetate. The organic layer was washed with 20 mL of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to recover 2.670 g of black solid. This solid was recrystallized from ethyl acetate/hexane to provide brown crystals of tert-butyl (S)-(1-benzyl-3,3-dibromo-2-oxo-propyl)carbamate (630 mg, 92.2 area %, yield 19%).
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:33])[C@@H:8]([N:15]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])N>CCOC(C)=O.[Pd]>[CH:1]1([O:6][C:7](=[O:33])[C@@H:8]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH2:23])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1[N+](=O)[O-])[C@H](C(=O)OC1CCCC1)c1ccccc1
Agent: [Pd]
Agent: NC(=O)[O-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1N)[C@H](C(=O)OC1CCCC1)c1ccccc1

Procedure:
A mixture of stage 2 carbamate (4.44 g, 9.78 mmol) and 10% Pd/C (0.7 g) in EtOAc (130 ml) was hydrogenated at room temperature for 18 h under balloon pressure. The Pd/C catalyst was filtered off through a pad of celite. The filtrate was concentrated under reduced pressure to yield a white solid (4.25 g). LCMS purity 100%, m/z 425 [M++H]+,
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[N:22]=[CH:21][C:20]3[C:19]4[CH2:18][C:17]([CH3:24])([CH3:23])[CH2:16][C:15]=4[S:14][C:13]=3[C:12]2=[O:25])[C:3]=1[CH:4]=[O:5].[CH3:26][N:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][N:52]([CH:55]4[CH2:58][O:57][CH2:56]4)[CH2:51][C@@H:50]3[CH3:59])=[CH:45][N:44]=2)[C:28]1=[O:60].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCCC1>[CH3:24][C:17]1([CH3:23])[CH2:16][C:15]2[S:14][C:13]3[C:12](=[O:25])[N:11]([C:6]4[CH:7]=[C:8]([F:10])[CH:9]=[C:2]([C:31]5[CH:30]=[C:29]([NH:42][C:43]6[CH:48]=[CH:47][C:46]([N:49]7[CH2:54][CH2:53][N:52]([CH:55]8[CH2:56][O:57][CH2:58]8)[CH2:51][C@@H:50]7[CH3:59])=[CH:45][N:44]=6)[C:28](=[O:60])[N:27]([CH3:26])[CH:32]=5)[C:3]=4[CH:4]=[O:5])[N:22]=[CH:21][C:20]=3[C:19]=2[CH2:18]1
Reactant: CC1(C)Cc2sc3c(=O)n(-c4cc(F)cc(Br)c4C=O)ncc3c2C1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CC(C)(C)C6)c3C=O)cn(C)c2=O)nc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A 50-mL round bottom flask equipped with a magnetic stirrer and a reflux condenser was charged with 131i (421 mg, 1.0 mmol), (S)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 113f (580 mg, 1.2 mmol), Pd(dppf)Cl2 (59 mg, 0.080 mmol), K3PO4.trihydrate (360 mg, 1.6 mmol), water (6 drops), and tetrahydrofuran (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 6 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was washed with 1:1 petroleum ether/ethyl acetate (20 mL) to afford 131j as a white solid (556 mg, 80%). MS-ESI: [M+H]+ 696.3
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([NH:17][C@@:18]2([C:23]([O:25]CCCC)=[O:24])[CH2:22][CH2:21][O:20][CH2:19]2)=[O:16])[CH:12]=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([NH:17][C@@:18]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][O:20][CH2:19]2)=[O:16])[CH:12]=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOC(=O)[C@]1(NC(=O)c2cncc(NC(=O)OC(C)(C)C)c2)CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cncc(C(=O)N[C@@]2(C(=O)O)CCOC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of n-butyl(S)-3-[(5-tert-butoxycarbonylamino-pyridin-3-carbonyl)-amino]-tetra-hydrofuran-3-carboxylate (29.7 mmol) in 150 mL methanol was combined with 60 mL of 1N sodium hydroxide solution and stirred for three hours at ambient temperature. Then the methanol was distilled off, the solution was then washed with 50 mL tert-butylmethylether and then adjusted to pH 3 with 4N hydrochloric acid. The product that then precipitated was filtered off and further reacted without purification.