Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:3][C:4](=O)[CH3:5].[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])(=O)C.[NH4+].CC1CCCCC1>O.C(O)(=O)C>[C:14]([C:13](=[C:4]([CH3:5])[CH2:3][CH:2]([CH3:1])[CH2:7][CH:8]([CH3:10])[CH3:9])[C:11]#[N:12])([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CC(=O)CC(C)CC(C)C
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC1CCCCC1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(C)CC(C)CC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A 250 ml round-bottom flask equipped with a Dean-Stark apparatus is charged in succession with 25.6 g of 4,6-dimethylheptanone (0.18 mol), 14.34 g of ethyl cyanoacetate (0.127 mol), 1.95 g of ammonium acetate, 6 g of acetic acid, and 100 ml of methylcyclohexane. The mixture is heated to reflux, the water formed being separated off as it is formed. After one hour, the mixture is cooled to ambient temperature and then washed to neutrality with saturated sodium bicarbonate solution. The residue is distilled under vacuum (6 torr) for recovery of the excess ketone (6.5 g) and then under a high vacuum for isolation of the cyano ester VI. 25.8 g of a colorless liquid are collected (b.p.=100-104° C./2.10−1 torr), corresponding to a yield of 85%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].B(F)(F)F.CSC.CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([Cl:11])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: COc1cc(Br)cc(C(=O)O)c1Cl
Agent: FB(F)F
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Br)cc(CO)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To a solution of acid 56 (10.1 g, 38.0 mmol) in THF (100 mL) was added borontrifluoride-dimethylsulfide (14.4 mL, 152 mmol) dropwise at 0° C. under an atmosphere of nitrogen. The mixture was stirred at room temperature for 18 hours. MeOH was added to the reaction mixture dropwise at 0° C. The mixture was extracted with EtOAc/H2O (150 mL/150 mL), dried over MgSO4, filtered, and concentrated in vacuo to provide the crude alcohol 57 (9.50 g, 100%) as yellow oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH2:13])=[CH:7][C:6]=2[Br:14].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][N:20]=1.CCN(CC)CC>C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH:13][C:23]([C:22]1[CH:21]=[N:20][C:19]([C:18]([F:29])([F:17])[F:28])=[CH:27][CH:26]=1)=[O:24])=[CH:7][C:6]=2[Br:14]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Reactant: NCc1cc(Br)c2[nH]c(C(F)(F)F)cc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1cc(Br)c2[nH]c(C(F)(F)F)cc2c1)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
[(2-Trifluoromethyl-7-bromo-1H-indol-5-yl)methyl]amine (Intermediate 9, 230 mg, 0.785 mmol) was dissolved in DCM (10 mL) and 6-(trifluoromethyl)nicotinoyl chloride (ABCR; 181 mg, 0.863 mmol) was added. Et3N (0.219 mL, 1.570 mmol) was added and the reaction mixture was then left to stir at room temperature for 30 min. The reaction mixture was quenched with water then the organic layer was collected, dried (MgSO4), filtered and evaporated to dryness. The resulting residues were purified by MDAP to give the title compound, (200 mg);
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]3[C:17]([C:33]#[N:34])=[C:18]([NH:20][C:21](=[O:32])[CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])[S:19][C:13]=3[CH2:12]2)=[O:10])[CH2:4][O:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(C#N)(C)=O.O>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[C:17]([C:33]#[N:34])=[C:18]([NH:20][C:21](=[O:32])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[S:19][C:13]=2[CH2:12]1)=[O:10]
Reactant: COc1ccccc1CCC(=O)Nc1sc2c(c1C#N)CCN(C(=O)OCC1COC(C)(C)O1)C2
Agent: CC(=O)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccccc1CCC(=O)Nc1sc2c(c1C#N)CCN(C(=O)OCC(O)CO)C2
Yield: 80 %

Procedure:
0,26 mmol of 3-Cyano-2-[3-(2-methoxy-phenyl)-propanoylamino]-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester (Example 30) are dissolved in 10 ml AcCN/H2O (2/1) and 0.1 eq PTSA is added. After stirring over night, some triethylamine is added and the solvent removed. Recrystallization from ethanol gives the desired product in 80% yield.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[CH:3]=1.[CH2:21](O)[CH3:22]>S(=O)(=O)(O)O>[OH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[N:5]=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:3]=1
Reactant: CCCOc1ccccc1-c1nc(O)cc(C(=O)O)n1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCCOc1ccccc1-c1nc(O)cc(C(=O)OCC)n1

Procedure:
A stirred solution of 6-hydroxy-2-(2-propoxyphenyl) pyrimidine-4-carboxylic acid (1.06g) in ethanol and concentrated sulphuric acid (0.5 ml) was heated under reflux for 3 hours. Most of the ethanol was removed under reduced pressure, then ice-water was added to the residue. The mixture was made alkaline (pH 10-11) with sodium carbonate solution and then extracted with chloroform (3×25 ml). The combined chloroform extracts were washed with water, dried (magnesium sulphate) and evaporated under reduced pressure to yield after washing with petroleum ether (b.p. 40°-60°) the title compound, 0.85g, m.p. 135.5°-137° C. A sample (0.4g) was recrystallised from ethanol to yield the pure title compound, 0.22g, m.p. 137°-8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[N:10][N:11]3[C:16]([OH:17])=[CH:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:31][C:32]([F:43])([F:42])[CH2:33]OS(C(F)(F)F)(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[N:10][N:11]3[C:16]([O:17][CH2:33][C:32]([F:43])([F:42])[F:31])=[CH:15][CH:14]=[N:13][C:12]=23)=[CH:6][CH:7]=1
Reactant: Oc1ccnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-pyrazolo[1,5-a]pyrimidin-7-ol (I-12A-1a; 65 mg, 0.18 mmol) and Cs2CO3 (59 mg, 0.18 mmol) in DMF (1.5 ml) was added a DMF solution (0.1 ml) of trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (42 mg, 0.18 mmol). After stirring at 60° C. overnight, the mixture was extracted from pH 7 water with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and then concentrated, in vacuo, to afford the crude product. Purification on a Chromatotron using 1:0:0, 20:1:0, and then 20:0:1 methylene chloride/ethyl acetate/methanol as eluants afforded, in addition to two N-alkylated isomers, product 12A-1 (16.5 mg, 21%) as a solid: +ESI MS (M+1) 438.4; 1H NMR (400 MHz, CD3OD) δ 8.56 (d, J=5.0 Hz, 1H), 7.55–7.41 (m, 6H), 7.24 (d, J=8.7 Hz, 2H), 6.80 (d, J=5.0 Hz, 1H), 5.16 (q, J=7.9 Hz, 2H).
Reaction SMILES: C([CH:3](CCCC)[CH2:4][NH2:5])C.[C:10]([OH:18])(=O)[CH:11]([CH2:13][C:14]([OH:16])=O)[OH:12].[C:19]1([CH3:25])[CH:24]=[CH:23][CH:22]=[CH:21]C=1>>[CH3:3][CH2:4][N:5]1[C:14](=[O:16])[CH2:13][C:11]([CH2:25][CH2:19][CH2:24][CH2:23][CH2:22][CH3:21])([OH:12])[C:10]1=[O:18]
Reactant: Cc1ccccc1
Reactant: CCCCC(CC)CN
Reactant: O=C(O)CC(O)C(=O)O
Product: CCCCCCC1(O)CC(=O)N(CC)C1=O
Temperature: 100 °C

Procedure:
N-2-Ethylhexyl DL-malimide was prepared by the reaction of 2-ethylhexyl amine with DL-malic acid. DL-Malic acid (10.327 g, 77.015 mmole) and toluene (40 mL) were weighed into a 250 mL 3-necked round-bottomed flask equipped with a teflon-coated magnetic stir bar. A Claisen adapter was placed in the center neck, a Dean-Stark trap was placed on top of the Claisen adapter, and a condenser was placed in the neck of the Dean-Stark trap. A nitrogen inlet adapter was placed on the condenser. In the left neck was placed a pressure-equalizing addition funnel containing 2-ethylhexyl amine (9.955 g, 77.02 mmole) and toluene (10 mL, added to ensure complete transfer of the amine). In the right neck was placed a rubber septum which held a thermocouple. The apparatus was purged with nitrogen for 10-15 minutes and then heated to ˜100° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[CH2:16]([O:18][P:19]([CH2:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br)([O:21][CH2:22][CH3:23])=[O:20])[CH3:17]>C(O)C>[CH2:22]([O:21][P:19]([CH2:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][C:5]([NH:4][C:1](=[O:3])[CH3:2])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O:18][CH2:16][CH3:17])=[O:20])[CH3:23]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCOP(=O)(Cc1ccccc1CBr)OCC
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1CP(=O)(OCC)OCC)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 0.43 g (18.8 mmol) Na in 50 mL of dry ethanol was added 4.09 g (18.8 mmol) of solid diethyl acetamidomalonate portionwise. This mixture was stirred at reflux under nitrogen for 2 h, then cooled to room temperature. Then, 6.05 g (18.8 mmol) of 2-(diethylphosphonomethyl)benzyl bromide in 40 mL of ethanol was added dropwise and the mixture stirred for 24 h. The salt which precipitated was removed by filtration and the solvent concentrated at reduced pressure to yield a viscous oil. This oil was chromatographed on a column of silica gel with ethyl acetate as eluant. The combined fractions were concentrated under reduced pressure to yield 6.67 g (79%) of the product as a clear oil. IR(neat): 1745.9, 1676.5, 1501.6, 1375.6, 1247.1, 1649.1, 969.4 cm-1. 1H NMR (CDCl3) δ 1.0-1.4 (m, 12H); 2.0 (s, 3H); 2.9 (s, 1H); 3.3 (s, 1H); 3.8-4.4 (m, 10H); 5.8-7.4 (m, 5H). Anal. Calcd. for C21H32NPO8 0.5H2O: C, 54.06; H, 6.92; N, 3.00. Found: C, 53.73; H, 7.11; N, 3.27.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17][CH2:16][CH2:15][CH2:14]1.O>C(Cl)Cl>[CH:12]([C:13]1([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC1(CO)CCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1(C=O)CCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
To a solution of oxalyl chloride (456 μL, 5.38 mmol) in DCM (30.0 mL) at −78° C. was added DMSO (637 μL, 8.97 mmol) and the resulting mixture was stirred for 5 minutes. tert-Butyl [1-(hydroxymethyl)cyclopentyl]methylcarbamate (1.03 g, 4.48 mmol) in DCM (10.0 mL) was added and the resulting mixture was stirred for 30 minutes at −78° C. TEA (2.50 mL, 17.9 mmol) was added and the resulting mixture was allowed to warm to ambient temperature over 30 minutes. Water was added. The organic phase was washed sequentially with 0.1 N HCl, water, saturated sodium bicarbonate solution, and brine, and then dried over sodium sulfate and the solvent was removed in vacuo to afford the product (957 mg, 94%). 1H NMR (300 MHz, CDCl3): δ 9.39 (s, 1H), 4.94 (br s, 1H), 3.25 (d, 2H), 1.89-1.46 (m, 8H), 1.41 (s, 9H).
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)[CH:3]([CH3:6])[C:4]#[N:5].[CH:16]1([CH:22]=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([CH2:22][NH:13][C:9]2[CH:8]=[C:7]([CH:2]([OH:1])[CH:3]([CH3:6])[C:4]#[N:5])[CH:12]=[CH:11][CH:10]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(C#N)C(O)c1cccc([N+](=O)[O-])c1
Reactant: O=CC1CCCCC1
Product: CC(C#N)C(O)c1cccc(NCC2CCCCC2)c1

Procedure:
Hydrogenation of the mixture of 3-hydroxy-2-methyl-3-(3-nitrophenyl)propanenitrile and aldehyde 29 following the method used in Example 11 gives 3-(3-(cyclohexylmethylamino)phenyl)-3-hydroxy-2-methylpropanenitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15]C(=O)C)=[C:4]([NH:19][C:20]2[C:29]3[C:24](=[N:25][C:26]([CH2:30][CH2:31][CH3:32])=[CH:27][CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:3]=1.O.[OH-].[Na+]>Cl>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[NH:19][C:20]1[C:29]2[C:24](=[N:25][C:26]([CH2:30][CH2:31][CH3:32])=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1
Reactant: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccccc3NC(C)=O)ccnc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccccc3N)ccnc2n1
Temperature: 25 °C

Procedure:
The product from Example 185d was dissolved in 50% HCl:H2O and heated to 100° C. for 1 hr. Reaction mixture was then cooled to room temperature, made basic with 2N NaOH, and extracted with CH2Cl2. Dried over Na2SO4, filtered and concentrated under vacuum giving the crude title compound. Purified by HPLC with TFA providing the product as a trifluoroacetic acid (87 mg, 64%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.35 Hz, 3 H), 1.79-1.92 (m, J=7.43, 7.43, 7.43, 7.43, 7.43 Hz, 2 H), 2.32 (s, 3 H), 3.00 (t, J=7.54 Hz, 2 H), 6.34 (d, J=6.99 Hz, 1 H), 6.49 (t, J=7.54 Hz, 1 H), 6.68 (d, J=6.99 Hz, 1 H), 6.92 (d, J=8.09 Hz, 1 H), 7.05-7.13 (m, 1 H), 7.15-7.20 (m, 1 H), 7.24 (d, J=8.46 Hz, 1 H), 7.28 (s, 1 H), 7.84 (d, J=8.82 Hz, 1 H), 8.42 (d, J=6.99 Hz, 1 H), 9.06 (d, J=8.82 Hz, 1 H); MS (ESI+) m/z 401 (M+H−TFA)+; (ESI−) m/z 399 (M−H−TFA)−.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=O.C(O)(C(F)(F)F)=O>>[F:13][C:14]1[CH:15]=[C:16]([CH:17]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: COc1ccc(C=O)cc1F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1F
Yield: 58.5 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (4.80 g, 30.0 mmol), 3-fluoro-4-methoxybenzaldehyde (4.86 g, 1.05 equiv.) and TFA (4.6 mL, 2 equiv.) to give the title compound (5.2 g, 59%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[C:11](O)=[O:12].C(Cl)Cl.Cl.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([CH:10]2[C:11](=[O:12])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8][CH2:9]2)[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COc1ccc(C(CSc2ccccc2N)C(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2CSc3ccccc3NC2=O)cc1OC
Yield: 90.6 %

Procedure:
A solution of 9.1 g of the product of Step C, 180 ml of methylene chloride, 6.25 g of 1-ethyl-3-(3-dimethylamino propyl) carbodiimide hydrochloride and 9 ml of triethylamine was stirred for 90 minutes at ambient temperature and the methylene chloride was evaporated off. The residue was taken up in 90 ml of ethyl acetate and after separation, 7.8 g of the expected product were obtained melting at 174° C. An analytical sample was obtained by crystallization of 200 mg of crude product from 10 ml of ethyl acetate to obtain 120 mg of the desired product melting at 184° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:9][S:8][CH:7]2[N:4]([C:5](=[O:11])[CH:6]2[NH2:10])[C:3]=1[C:12]([OH:14])=[O:13].ClC[CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([O-:21])=[O:20].[C:24](OCC1CSC2N(C(=O)C2N)C=1C(O)=O)(=O)C.ClCOC(=O)CC>>[C:19]([O:21][CH2:24][O:13][C:12]([C:3]1[N:4]2[CH:7]([S:8][CH2:9][C:2]=1[CH3:1])[CH:6]([NH2:10])[C:5]2=[O:11])=[O:14])(=[O:20])[C:18]([CH3:23])([CH3:22])[CH3:17]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: CC(C)(CCCl)C(=O)[O-]
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: CCC(=O)OCCl
Product: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(N)C2SC1

Procedure:
When in the procedure of Example 8 appropriate amounts of 3-methyl-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and chloromethylpivalate are substituted respectively for 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and chloromethylpropionate, 3-methyl-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid pivalyloxymethyl ester is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5](Cl)=[O:6].[CH3:15][NH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].CCN(C(C)C)C(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([N:16]([CH3:15])[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[O:6]
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 57 %

Procedure:
3-Fluoro-5-trifluoromethylbenzoyl chloride (92 mg, 0.41 mmol, CAS RN 171243-30-4) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (40 mg, 0.20 mmol, example 1, intermediate a) and DIPEA (70 μL, 0.40 mmol) in THF (1 mL). After 2 h, an additional 25 μL of acyl chloride was added. The reaction mixture was stirred overnight, filtered and all volatiles removed. The resulting oil was purified by flash chromatography on silica gel eluting with 33-50% EtOAc in n-hexane to yield the product as a waxy solid (45 mg, 57%). MS (ESI): m/z=470.0 [M+H]+.
Reaction SMILES: CO.[CH3:3][C@H:4]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>C(Cl)Cl>[OH:15][C@@H:6]([CH2:5][C@H:4]([CH3:3])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CCCC[C@@H](C)CC(=O)CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CO
Product: CCCC[C@@H](C)C[C@H](O)CC(=O)OC(C)(C)C
Yield: 73 %

Procedure:
In a 200 ml autoclave were charged 50 ml of methanol, 14.0 g of t-butyl (R)-5-methyl-3-oxononanoate obtained in Step 5, and a solution of 0.49 g of (S)-di[2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]tetrachlorodiruthenium triethylamine in 40 ml of methylene chloride, and the mixture was allowed to react under a hydrogen pressure of 60 kg/cm2 for 18 hours. The solvent was removed by distillation under reduced pressure to obtain 13.6 g of a crude product, which was then purified by silica gel column chromatography to obtain 10.3 g (72.5%) of the titled compound.
Reaction SMILES: [CH:1]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1I)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:30]([N:34]1[C:42](=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]1=[O:44])[CH2:31][C:32]#[CH:33].O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH:1]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[C:33]#[C:32][CH2:31][CH2:30][N:34]1[C:42](=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]1=[O:44])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Reactant: Clc1ccc(NC(c2ccccc2)c2ccccc2)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1cc(Cl)ccc1NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
5 g(11.93 mmol, 1 eq) benzhydryl-(4-chloro-2-iodo-phenyl)-amine made in Example 1 was combined with 5 mL DMF. 0.42 g(0.598 mmol, 0.05 eq) dichlorobis-(triphenylphosphine)-palladium, 0.24 g(1.26 mmol, 0.11 eq) copper iodide and 1.8 g (17.58 mmol, 1.5 eq) triethylamine were added. The mixture was stirred at 25 C and 2.72 g (13.65 mmol, 1.14 eq) 2-but-3-ynyl-isoindole-1,3-dione was added in one portion. The mixture warmed to 40 C and was cooled back to room temperature. It became semi-solid after 2 h; an LC showed that at this time the reaction was complete. The mixture was diluted with 10 mL DMF and then 5 mL water was added slowly. Stirring was continued until solids precipitated. The vessel was cooled to 0-5 C and stirred at this temperature for 30 min. The resulting solid was collected by filtration and washed with 10 mL DMF/water 2:1 and 2×10 mL MeOH. The 8.78 g wet solid was dried at 40 C in vacuo for 14 h to obtain 5.55 g product (95%) with 95% purity.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][C@@H:37]1[CH3:42])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([CH2:20][C:17]2[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:28])[CH3:1])[N:22]([CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=2)[CH2:38][C@@H:37]1[CH3:42])=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Product: C[C@H]1CN(Cc2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CCN1C(=O)OC(C)(C)C
Yield: 43.3 %

Procedure:
Following General Procedure C, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (3.8 g, 10.05 mmol) and (S)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (5.03 g, 25.13 mmol) gave (S)-4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-ylmethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester as a white solid (2.45 g, 45%) [following SiO2 chromatography, eluting with 50% EtOAc/petroleum ether). MS(ESI) m/z 563.3 (M+H)+
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.[CH3:16][Zn]C.C(OCC)(=O)C.O>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:16])[N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Zn]C
Reactant: Clc1cc(Cc2ccccc2)nc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Cc2ccccc2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
4-Benzyl-2,6-dichloro-pyrimidine (2.5 g, 10.5 mmol) was dissolved in tetrahydrofuran (40 mL) under an atmosphere of nitrogen and subsequently treated with dimethylzinc (2M in toluene, 5.76 mL) and tetrakis(triphenylphosphine)palladium(0) (245 mg). After stirring for 18 h at ambient temperature, ethyl acetate and water were added, the phases separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. Column chromatography on silica gel using heptane/ethyl acetate 9:1 v/v) as eluent afforded the title compound (1.89 g, 83%) as colorless oil.