Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[CH2:9][O:8][C:5]([C:10]3[O:11][CH:12]=[CH:13][CH:14]=3)([O:6][CH2:7]1)[O:4][CH2:3]2.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH3:1][C:2]12[CH2:3][O:4][C:5]([C:10]3[O:11][C:12]([Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:13][CH:14]=3)([O:6][CH2:7]1)[O:8][CH2:9]2
Reactant: CC12COC(c3ccco3)(OC1)OC2
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C23OCC(C)(CO2)CO3)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
2-(4-Methyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)furan (2.0 g, 10.2 mmol) was dissolved in THF (20 ml) and the solution was cooled to −78° C. n-Buli (1.6M solution in hexanes, 7.7 ml, 12.32 mmol) was added and the mixture stirred at −78° C. for 30 min, allowed to warm to 0° C. for 20 min. and then recooled to −78° C. The tributyltin chloride (3.5 ml, 4.68 g, 14.4 mmol) was added and stirring was continued at −78° C. for 15 min. The mixture was allowed to warm gradually to room temperature and stirring continued for three days. The reaction was quenched by the addition of water, and extracted with ethyl acetate. This solution was washed with water, dried (MgSO4), and concentrated in vacuo to give the title compound as a yellow oil (4.7 g, 9.7 mmol, 95%); δH [2H6]DMSO 6.52 (1H,d), 6.38 (1H,d), 3.96 (6H,s), 0.77-1.63 (30H,m).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[Na+].[Na+].[I:20]I.Cl>O.C1COCC1>[OH:13][C:9]1[C:10]([I:20])=[C:11]2[C:6]([CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:12]2)=[CH:7][CH:8]=1
Reactant: II
Reactant: N#Cc1ccc2ccc(O)cc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc2ccc(O)c(I)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
A mixture of 7-cyano-2-naphthol (22.3 g, 131.8 mmol), sodium carbonate (29.3 g, 277 mmol) and I2 (31.8 g, 125.2 mmol) in water (500 mL) and THF (80 mL) at 0 ° C was stirred at room temperature for 3 h, acidified with 1M HCl and extracted with ethyl acetate. The extracts were washed with saturated Na2S2O3 and brine, dried (Na2SO4) and concentrated. The product was recrystallized from ethyl acetate to yield 33 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([CH3:19])(=O)=[O:17])[CH:11]=2)[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=1.ClC1N=C(Cl)C(C(F)(F)F)=CN=1.Cl.CS(C1C=C(CN)C=CC=1)=O.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([CH3:19])=[O:17])[CH:11]=2)[C:5]([C:20]([F:22])([F:21])[F:23])=[CH:4][N:3]=1
Reactant: CS(=O)(=O)c1cccc(CNc2nc(Cl)ncc2C(F)(F)F)c1
Agent: CS(=O)c1cccc(CN)c1
Agent: Cl
Agent: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)c1cccc(CNc2nc(Cl)ncc2C(F)(F)F)c1

Procedure:
Prepared according to the procedure described above for 2-chloro-N-[3-(methylsulfonyl)benzyl]-5-(trifluoromethyl)pyrimidin-4-amine (XLIVa) using 2,4-dichloro-5-trifluoromethylpyrimidine (XL, 324 mg, 1.5 mmol), 1-[3-(methylsulfinyl)phenyl]methanamine hydrochloride (249 mg, 1.2 mmol) and diisopropylethylamine (0.65 mL, 3.75 mmol) in THF (10 mL). Pure desired 2-chloro-N-[3-(methylsulfinyl)benzyl]-5-(trifluoromethyl)pyrimidin-4-amine (XLVa, 162 mg) was isolated as the non-polar component by chromatography eluting with hexane:ethyl acetate 25:75. 1H NMR (DMSO-d6) δ: 8.61 (t, J=5.7 Hz, 1H), 8.44 (s, 1H), 7.67 (s, 1H), 7.49-7.58 (m, 2H), 7.45 (dt, J=6.6, 2.0 Hz, 1H), 4.70 (d, J=5.9 Hz, 2H), 2.72 (s, 3H). 13C NMR (DMSO-d6) δ: 162.59, 158.35, 155.74 (q, J=5 Hz), 146.49, 139.73, 129.47, 129.24, 123.43 (q, J=272 Hz), 122.40, 122.36, 105.16 (q, J=32 Hz), 43.84, 43.23. A HMBC 3-bond correlation is observed between the C4—N-proton at 8.61 ppm and the C5-carbon at ˜105 ppm.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=O)[N:4]=1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:5]1[N:4]=[C:3]([CH3:2])[CH:8]=[C:7]([CH3:9])[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)[nH]c(=O)n1
Agent: Cl
Product: Cc1cc(C)nc(Cl)n1
Yield: 56.1 %

Procedure:
A suspension of 4,6-dimethyl-1H-pyrimidin-2-one hydrochloride (3.0 g, 18.75 mmol) in dry POCl3 (25 mL, 272 mmol) was refluxed for 18 hours. The reaction mixture was evaporated to dryness and the residue dissolved in dichloromethane. The solution was washed with sodium bicarbonate solution until the pH of the aqueous washings were neutral, then with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 2-chloro-4,6-dimethyl-pyrimidine (1.5 g, 56%) as a solid.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[C:15]#[C:16][Si](C)(C)C)([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O>CN(C=O)C.[Cu]I>[C:1]([N:5]1[C:6]2[C:7](=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=2)[CH:15]=[CH:16]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Nc1ccc([N+](=O)[O-])cc1C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)n1ccc2cc([N+](=O)[O-])ccc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of tert-butyl-(4-nitro-2-trimethylsilanylethynyl-phenyl)-amine (10 mg, 0.035 mmol) in DMF (2 mL), was added CuI (13 mg, 0.07 mmol) under N2 protection. The reaction mixture was stirred at 100° C. overnight. At this time, EtOAc (4 mL) was added to the mixture. The mixture was filtered and the filtrate was washed with water, brine, dried over Na2SO4 and concentrated under vacuum, to obtain 1-tert-butyl-5-nitro-1H-indole (7 mg, 93%). 1H-NMR (CDCl3, 300 MHz) δ 8.57 (d, J=2.1 Hz, 1H), 8.06 (dd, J=2.4, 9.3 Hz, 1H), 7.65 (d, J=9.3 Hz, 1H), 7.43 (d, J=3.3 Hz, 1H), 6.63 (d, J=3.3 Hz, 1H), 1.76 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH3:2].[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:21][C:5]([S:17]([CH3:20])(=[O:19])=[O:18])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][CH:9]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C(C)(CCc1ccc(B(O)O)cc1)S(C)(=O)=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(CCc1ccc(Oc2ccccc2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of {4-[4-ethoxy-3-methyl-3-(methylsulfonyl)-4-oxobutyl]phenyl}boronic acid (599 mg, 1.83 mmol) in methylene chloride (3 mL) was added phenol (86 mg, 0.91 mmol), pyridine (148 uL, 1.83 mmol) and copper (II) acetate (157 mg, 0.866 mmol). The mixture was stirred at ambient temperature under open atmosphere for 2 days. Silica gel was added and the mixture was concentrated to dryness and purified via silica gel chromatography eluting with ethyl acetate/heptanes to afford ethyl 2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanoate as an oil. 312 mg. LCMS: (M+1) 377.2
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[CH3:17])[CH3:13]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCOC(=O)C1(CC)CCCC1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1(CC)CCCC1OC(=O)c1ccccc1C
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-ethyl-cyclopentane carboxylate (4.90 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.22 ml) was slowly added, then 2-methyl-benzoyl chloride (5.28 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 8.99 g of yellow liquid. MS: m/e 304(M+″), 261, 244, 139, 119(base), 91.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH3:18])[CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20]([CH3:27])([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[NH2:21]>>[CH3:19][C:20]([NH:21][C:14]([C:12]1[CH:11]=[CH:10][C:9]([O:17][CH3:18])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[CH3:27]
Reactant: CC(C)(N)c1ncco1
Reactant: COc1ccc(C(=O)O)nc1-c1cccc(Cl)c1
Product: COc1ccc(C(=O)NC(C)(C)c2ncco2)nc1-c1cccc(Cl)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid (Example 81 c) and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): m/e=372.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[O:26])[C:12]3[CH:17]=[CH:16][N:15]([CH2:18][O:19]CC[Si](C)(C)C)[C:13]=3[N:14]=2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:19][CH2:18][N:15]1[C:13]2[N:14]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:27])([F:28])[F:1])=[CH:8][CH:7]=3)[NH:10][C:11](=[O:26])[C:12]=2[CH:17]=[CH:16]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)nc2c1ccn2CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
A solution of 2-(4-(trifluoromethyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (47.7 mg, 116 μmol) in anhydrous methylene chloride (6.0 mL) was cooled, under nitrogen, to 0° C. The solution was then treated portion-wise with trifluoroacetic acid (1.5 mL). The reaction was stirred under nitrogen at 0° C. for 30 min. At this time, the reaction was warmed to room temperature where it continued to stir for an additional 3 h. At this time, the reaction was diluted with methylene chloride and was concentrated in vacuo onto Celite® while maintaining a water bath temperature less than or equal to 30° C. Flash chromatography (12 g silica gel column, 40-70% ethyl acetate/hexanes) afforded 7-hydroxymethyl-2-(4-trifluoromethyl-phenyl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as an off-white solid (20.9 mg, 58.0%). 1H NMR (300 MHz, DMSO-d6) δ ppm 5.55 (d, J=7.91 Hz, 2H) 6.56 (d, J=3.39 Hz, 1H) 6.63 (t, J=7.35 Hz, 1H) 7.27 (d, J=3.39 Hz, 1H) 7.91 (d, J=8.48 Hz, 2H) 8.37 (d, J=8.10 Hz, 2H) 12.38 (s, 1H). LC-MS calcd. for C14H11F3N3O2 [(M+H)+] 310, obsd. 310.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[N:8]=[N:7][C:6]([CH2:9][O:10][CH2:11][C:12]2[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:5]1.Cl[C:37]1[CH:42]=[CH:41][C:40]([S:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)(=[O:45])=[O:44])=[CH:39][N:38]=1.C(N(CC)CC)C>ClCCl>[Cl:30][C:24]1[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH:16]1[C:15]([C:31]([O:33][CH3:34])=[O:32])=[C:14]([CH3:35])[NH:13][C:12]([CH2:11][O:10][CH2:9][C:6]2[N:7]=[N:8][N:4]([CH2:3][CH2:2][NH:1][C:37]3[CH:42]=[CH:41][C:40]([S:43]([N:46]4[CH2:47][CH2:48][O:49][CH2:50][CH2:51]4)(=[O:45])=[O:44])=[CH:39][N:38]=3)[N:5]=2)=[C:17]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C1=C(COCc2nnn(CCN)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: O=S(=O)(c1ccc(Cl)nc1)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(COCc2nnn(CCNc3ccc(S(=O)(=O)N4CCOCC4)cn3)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.2 %

Procedure:
A solution of 2-(2-aminoethyl)-5-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}tetrazole (0.33 g), 2-chloro-5-(4-morpholinylsulphonyl)pyridine (145 mg) and triethylamine (65 mg) in dichloromethane (15 ml) was heated under reflux for 2 hours, then stirred at room temperature for 16 hours and evaporated. The residue was purified by chromatography on silica (6 g) using dichloromethane plus from 0 to 5% by volume of methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (84 mg), m.p. 112°-114° C. Found: C,56.32; H,5.90; N,10.45. C31H36Cl2N8O8S requires: C,56.13; H,5.80; N,10.48%.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C@@H:9]([CH:16]([CH3:18])[CH3:17])[N:10]=[C:11]([O:14][CH3:15])[CH2:12][N:13]=1.Cl[CH2:20][C:21]1[O:22][CH:23]=[CH:24][CH:25]=1>CCCCCC.C1COCC1>[CH3:6][O:7][C:8]1[C@@H:9]([CH:16]([CH3:18])[CH3:17])[N:10]=[C:11]([O:14][CH3:15])[C@H:12]([CH2:20][C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[N:13]=1
Reactant: ClCc1ccco1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1ccco1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 1.55M solution of butyllithium (6.45 ml, 10 mmol) in hexane was added by syringe to a stirred solution of (2R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (1.84 g, 10 mmol) in THF (50 ml) at -78° C. and the solution stirred for 1 hour at -78° C. A solution of 2-chloromethylfuran (1.3 g, 11 mmol) in THF (10 ml) was added gradually and the stirring continued overnight. The solvent was removed under reduced pressure, the residue dissolved in ethyl acetate (50 ml) and extracted with phosphate buffer (pH 7). The water phase was extracted twice with ethyl acetate (2×20 ml ). The organic layer was dried (MgSO4), solvent evaporated under reduced pressure and the residue purified by flash chromatography (diethyl ether/hexane 15/1, silica gel).
Reaction SMILES: [CH3:1][O-:2].[K+].F[C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:6]=1[C:7]([OH:9])=[O:8].O>CO>[CH3:1][O:2][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: C[O-]
Reactant: O=C(O)c1c(F)cccc1C(F)(F)F
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cccc(C(F)(F)F)c1C(=O)O
Reaction time: 40 h

Procedure:
A mixture of potassium methylate in methanol (15 ml, 15%) and 2-fluoro-6-trifluoromethylbenzoic acid (2.08 g, 0.01 mol) is heated to reflux with stirring for 40 hours. Upon cooling to room temperature water is added. The reaction mixture is filtered and the filtrate is acidified with concentrated hydrochloric acid. The solid material is collected by filtration, washed with water and dried yielding white crystals, 1.4 g (64%), mp 130-131° C.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C@:7]23[CH2:14][C@H:13]([NH2:15])[CH2:12][N:11]2[C:10](=[O:16])[N:9]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)[C:8]3=[O:25])=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@:7]23[CH2:14][C@H:13]([NH:15][C:28](=[O:30])[CH3:29])[CH2:12][N:11]2[C:10](=[O:16])[N:9]([C:17]2[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=2)[C:8]3=[O:25])=[CH:26][CH:27]=1
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@@]2(Cc2ccc(Br)cc2)C1
Solvent: C1CCOC1
Product: CC(=O)N[C@@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@@]2(Cc2ccc(Br)cc2)C1
Reaction time: 5 h

Procedure:
To a solution of (5R,7S)-5-(4-Bromobenzyl)-3-(3,5-dichlorophenyl)-7-amino-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.103 g) in THF (4 mL) was added acetic anhydride (0.031 mL). After 5 hours, the reaction mixture was concentrated and purified by chromatography (silica gel: CH2Cl2, Chromatotron) to afford the titled compound (0.125 g). MS (m/z) 510 (MH+). mp 140.7° C.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:3]=1[NH:4][CH:5]1[CH2:10][O:9][C:7](=[O:8])[CH2:6]1.[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20]>>[CH3:16][O:17][CH2:18][C:19]([N:4]([CH:5]1[CH2:10][O:9][C:7](=[O:8])[CH2:6]1)[C:3]1[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:2]=1[CH3:1])=[O:20]
Reactant: Cc1cccc(C)c1NC1COC(=O)C1
Reactant: COCC(=O)Cl
Product: COCC(=O)N(c1c(C)cccc1C)C1COC(=O)C1

Procedure:
3-(2,6-dimethylanilino)-gamma-butyrolactone was acylated with methoxyacetyl chloride according to the procedure described in Example 2C above to yield N-methoxyacetyl-3-(2,6-dimethylanilino)-gamma-butyrolactone.
Reaction SMILES: Br[CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[CH:20]1([NH:26][CH3:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[CH:20]1([N:26]([CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: CNC1CCCCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)N(C)C1CCCCC1
Yield: 28.5 %

Procedure:
Diethyl bromomalonate (17.0 g), triethylamine (9.1 g), and dry toluene (10 ml) were mixed, and with stirring, the mixture was heated under reflux. Then, N-cyclohexyl-N-methylamine (8.1 g) diluted with dry toluene (5 ml) was added dropwise, and the mixture was heated under reflux for 2.5 hours with stirring. The reaction mixture was washed with water three times, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure to give 5.5 g (29%) of diethyl (N-cyclohexyl-N-methylamino)malonate having the following properties.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:59][N:60]([CH3:78])[C:61]([CH:63]1[CH2:67][CH2:66][N:65]([CH2:68][C:69]2[CH:74]=[CH:73][C:72]([CH2:75][NH:76][CH3:77])=[CH:71][CH:70]=2)[CH2:64]1)=[O:62]>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:76]([CH2:75][C:72]3[CH:71]=[CH:70][C:69]([CH2:68][N:65]4[CH2:66][CH2:67][CH:63]([C:61]([N:60]([CH3:59])[CH3:78])=[O:62])[CH2:64]4)=[CH:74][CH:73]=3)[CH3:77])=[O:26])[CH:20]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: CNCc1ccc(CN2CCC(C(=O)N(C)C)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(C(=O)N(C)C)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (40 mg, 0.105 mmol), EDCI (28 mg, 0.158 mmol), HOBt (21 mg, 0.16 mmol), DIPEA (0.04 mL, 0.21 mmol), N,N-dimethyl-1-{4-[(methylamino)methyl]benzyl}pyrrolidine-3-carboxamide dihydrochloride (40 mg, 0.12 mmol) and DCM (5 mL).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13](C3C=CC(CC(NCC4C=CC=CC=4)=O)=NC=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.ClCCN1CCOCC1.[Br:42]C1C=CC(O)=CC=1>>[Br:42][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:11][CH:12]=1
Reactant: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: ClCCN1CCOCC1
Product: Brc1ccc(OCCN2CCOCC2)cc1

Procedure:
In one aspect, the invention relates to a process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide comprising the steps of: reacting 4-(2-chloroethyl)morpholine with 4-bromophenol to yield 4-(2-(4-bromophenoxy)ethyl)morpholine; (2) coupling 4-(2-(4-bromophenoxy)ethyl)morpholine with 6-fluoropyridin-3-yl-3-boronic acid to yield 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine; reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile; (4) converting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile to methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate; and (5) reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][S:20]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:26]3[CH2:27][CH2:28][CH:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH2:24][CH2:25]3)[S:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CS(=O)(=O)C1CCNCC1
Product: CS(=O)(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde (General Procedure D-2) and 4-methanesulfonyl-piperidine (Example 34) using General Procedure B-3 yielded 2-chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:25][O:26][CH:27]1[CH2:30][CH:29]([C:31](O)=[O:32])[CH2:28]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:31]([CH:29]3[CH2:30][CH:27]([O:26][CH3:25])[CH2:28]3)=[O:32])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: COC1CC(C(=O)O)C1
Product: COC1CC(C(=O)N2C[C@@H](N(C)C(=O)Oc3ccc(F)cc3)[C@H](c3ccc(Cl)cc3)C2)C1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(3-methoxy-cyclobutanecarbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 3-methoxycyclobutanecarboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a light brown oil. MS m/e: 461.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:15].[H-].[Na+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=1[C:31]([F:34])([F:33])[F:32].[I-].[Na+]>CN(C=O)C>[Cl:14][C:10]1[N:9]=[C:8]2[N:7]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[C:31]([F:33])([F:32])[F:34])[C:6]([CH3:15])=[C:5]([CH2:4][C:3]([OH:2])=[O:16])[C:13]2=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: COC(=O)Cc1c(C)[nH]c2nc(Cl)ccc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2ccc(Cl)nc2n1Cc1ccc(S(C)(=O)=O)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred, ice-cooled solution of (6-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (Example 99e) (0.03 g, 0.13 mmol) in DMF (1.0 ml) under an inert atmosphere of Argon is added sodium hydride (0.006 g of a 60% dispersion in mineral oil, 0.14 mmol). The reaction mixture is stirred at 0° C. for 45 minutes and then treated with 1-bromomethyl-4-methanesulfonyl-2-trifluoromethyl-benzene (Example 95a) (0.067 g, 0.21 mmol) followed by sodium iodide (0.031 g, 0.21 mmol). Stirring is continued at 0° C. for 2 hours and then the reaction mixture is poured onto water (15 ml) and extracted with DCM (5 ml). The organic portion is separated and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with ethyl acetate/iso-hexane (1:8 increasing to 1:4) to yield the product which was further purified by trituration with ethyl acetate/iso-hexane to afford the titled product. (MH+ 475).