Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=2[C:5]([CH:21]=O)=[C:4]([CH3:23])[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:43](Br)(Br)([Br:45])[Br:44]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]([CH:21]=[C:43]([Br:45])[Br:44])=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(C)cc(Cl)c32)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=C(Br)Br)c(C)cc(Cl)c32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7-chloro-5-methyl-1-tosyl-1H-indole-4-carbaldehyde (48 mg, 0.138 mmol) and PPh3 (109 mg, 0.414 mmol) in DCM (1.4 mL) at 0° C., was added CBr4 (68.6 mg, 0.207 mmol) and the reaction was warmed to room temperature. After 10 minutes the reaction mixture was loaded onto silica gel and was purified by flash chromatography (0-50% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (d, J=3.79 Hz, 1H) 7.88 (s, 1H) 7.73 (m, J=8.59 Hz, 2H) 7.42 (m, J=7.83 Hz, 2H) 7.23 (s, 1H) 6.71 (d, J=3.79 Hz, 1H) 2.37 (s, 3H) 2.23 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:14]1[CH2:24][CH2:23][CH2:22][C@@H:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15]1.C(N(CC)C(C1CCCN(C2CCN(C(C3C4C(=CC=C(C)C=4)N=C(C4C=CN=CC=4)C=3)=O)CC2)C1)=O)C>>[CH2:20]([O:19][C:17]([C@@H:16]1[CH2:22][CH2:23][CH2:24][N:14]([CH:10]2[CH2:11][CH2:12][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9]2)[CH2:15]1)=[O:18])[CH3:21]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: CCN(CC)C(=O)C1CCCN(C2CCN(C(=O)c3cc(-c4ccncc4)nc4ccc(C)cc34)CC2)C1
Product: CCOC(=O)[C@@H]1CCCN(C2CCN(Cc3ccccc3)C2)C1

Procedure:
Reductive amination of 1-benzyl-pyrrolidin-3-one with (3R)-ethyl nipecotate was carried out according to the procedure described above for Intermediate 1 to give (3R)-1-(1-benzyl-pyrrolidin-3-yl)-piperidine-3-carboxylic acid ethyl ester (containing a small amount of the isopropyl ester) as a yellow oil (1.23 g, 39%).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.I[C:28]1[C:29](=[O:43])[NH:30][C:31](=[O:42])[N:32]([CH:41]=1)[C@@H:33]1[O:40][C@H:37]([CH2:38][OH:39])[C@@H:35]([OH:36])[CH2:34]1.[CH3:44][O:45][C:46](=[O:49])[CH:47]=[CH2:48]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:46](/[CH:47]=[CH:48]/[C:28]1[C:29](=[O:43])[NH:30][C:31](=[O:42])[N:32]([CH:41]=1)[C@@H:33]1[O:40][C@H:37]([CH2:38][OH:39])[C@@H:35]([OH:36])[CH2:34]1)([O:45][CH3:44])=[O:49]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 70 °C
Yield: 70.3 %

Procedure:
A mixture of Pd(OAc)2 (0.316 g, 1.41 mmol), PPh3 (0.741 g, 2.82 mmol), and triethylamine (4.9 mL) in 1,4-dioxane (50 mL) was stirred at 70° C. until an intense red colour had developed. To this 5-iodo-2′-deoxyuridine (10 g, 28.24 mmol) and methylacrilate (4.862 g, 56.48 mmol, 5.1 mL) in 1,4-dioxane (20 mL) were added and the mixture stiffed at refluxed for 30 mins. The reaction was filtered while still hot and the 20 filtrate cooled over night at 4° C. The resulting pale yellow precipitate was filtered, washed with DCM and dried in vacuo to give the product as white solid (6.2 g, yield 70.7%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N:10]=[C:11]=[S:12].[N:13]1[C:22]2[CH2:21][CH2:20][CH2:19][CH:18]([NH2:23])[C:17]=2[CH:16]=[CH:15][CH:14]=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]([NH:23][CH:18]1[CH2:19][CH2:20][CH2:21][C:22]2[N:13]=[CH:14][CH:15]=[CH:16][C:17]1=2)=[S:12]
Reactant: NC1CCCc2ncccc21
Reactant: Fc1ccc(N=C=S)c(Cl)c1Cl
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CC#N
Product: Fc1ccc(NC(=S)NC2CCCc3ncccc32)c(Cl)c1Cl

Procedure:
The title compound was prepared from 2,3-dichloro-4-fluorophenylisothiocyanate and 5,6,7,8-tetrahydroquinolin-5-ylamine using General Procedure 1. 1H NMR (DMSO-d6, 400 MHz) 1.77-1.93 (m, 2H), 1.93-2.12 (m, 2H), 2.81-2.97 (m, 2H), 5.70-5.83 (m, 1H), 7.28 (dd, 1H, J=4.7 Hz, J=7.8 Hz), 7.51 (t, 1H, J=8.9 Hz), 7.62-7.78 (m, 2H), 8.37 (d, 1H, J=8.5 Hz), 8.43 (dd, 1H, J=1.4 Hz, J=4.5 Hz), 9.39 (s, 1H); RP-HPLC (Hypersil®-100 C18, 5 μm, 100 Å, 10 cm; 5%-100% acetonitrile-0.1M ammonium acetate over 5 min, 2 mL/min), then 100% acetonitrile isocratic 1 minutes, Rt min. (98.9%); MS: M+H+ 370.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:8][CH2:7][CH:5]2[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(2,2-Dimethyl-1,3-dioxolan-4-yl)methanol (33; 7.56 mmol, 1.0 g) was taken up in 20 mL of dichloromethane. Triethylamine (26.46 mmol, 3.687 mL) was then added, followed by p-toluensulfonyl chloride (15.12 mmol, 2.88 g) and catalytic amount of 4-dimethylamino pyridine. The reaction was allowed to stir at room temperature for 18 h. The crude reaction mixture was diluted with dichloromethane, washed successively with saturated aqueous sodium bicarbonate solution, water, dried (Na2SO4) and concentrated under reduced pressure. The resulting residue 34 was used for the next step without further purification (89% crude yield).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Br:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=1[CH2:37]Br.O>C1COCC1>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]([CH2:37][C:30]2[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:29]=2[Br:28])[NH2:17])=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Br)c(CN(N)c2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
To a solution of [4-(benzyloxy)phenyl]hydrazine hydrochloride (2.0 g) in THF (25 mL) was added dropwise a THF solution (1.9 M, 8.4 ml) of sodium hexamethyldisilazide under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1-bromo-2-(bromomethyl)-4-methoxybenzene (2.23 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.56 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:12](Cl)=[O:13]>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:6]=[C:12]=[O:13])=[O:5]
Reactant: NC(=O)c1ccccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccccc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
0.23 g (1.5 mmol) of 2-chlorobenzamide and 0.19 g (1.6 mmol, 1.1 eq) of oxalyl chloride were added to 10 ml of 1,2-dichloroethane and then the mixture was stirred for 8 hours at 100° C. The reaction solution was cooled down to room temperature. The reaction solvent and excessive oxalyl chloride were removed by distillation under reduced pressure to obtain 2-chlorobenzoyl isocyanate in an oily state. 10 ml of fresh 1,2-dichloroethane and 0.28 g (1.5 mmol) of 2,3-dichloro-4-cyano aniline were successively added thereto, reacted for 2 hours and filtered to obtain 0.25 g (Yield 45%) of the title compound as a solid.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:2]1
Reactant: C1CCNC1
Reactant: O=C1CCc2ccccc21
Product: C1=C(N2CCCC2)c2ccccc2C1

Procedure:
According to a modification of the procedure of Noland et al (Noland, W. E.; Kaneswaran, V. J. Org. Chem. 1981, 46, 1940-1944.), 1-indanone (25.0 g, 0.189 mol) and 50 mL of pyrrolidine which had been dried over 3A sieves were added to a 500 mL, 3-neck flask equipped with an overhead stirrer, Dean-Stark apparatus and condenser which was maintained under a dry N2 atmosphere. Benzene (200 mL dried over 4A sieves) was added and the solution was brought to reflux for 30 hours. At the end of this period 1H NMR analysis of a reaction aliquot indicated a 93:7 mole percent ratio of desired product to starting material. The bulk of the solvent was removed in vacuo and the crude dark product was distilled (6″ Vigreaux column) to give pure enamine as a light yellow oil (24.3 g, 0.132 mol) in 70 percent yield. This compound was both air and water sensitive and was transferred to the dry box upon distillation. Capillary GC analysis indicated a hexane solution of distillate to be of 99 area percent purity: bp=125-127° C. @ 2.0 mm, bp. lit=118-120° C. @ 1 mm;
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=1.[OH-].[Na+]>O.C1C=CC=CC=1>[Br:2][CH2:3][CH2:4][NH:5][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([O:7][CH3:6])=[CH:9][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCCBr
Reactant: COc1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(C(=O)NCCBr)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred and cooled (ice-bath) solution of 27.5 parts of 2-bromoethanamine hydrobromide in 200 parts of water is added a solution of 28.9 parts of 4-methoxy-2-nitrobenzoyl chloride in 63 parts of benzene at 5°-10° C. While stirring vigorously, there is added dropwise a solution of 10.8 parts of sodium hydroxide in 250 parts of water at 5°-10° C. Upon completion, stirring is continued for 2 hours at this temperature. The supernatant phase is decanted and the oily residue is stirred in 2-propanol. The product is filtered off and dried, yielding 27.5 parts (68%) of N-(2-bromoethyl)-4-methoxy-2-nitrobenzamide; mp. 133.8° C.
Reaction SMILES: CO[C:3]([C@H:5]1[C@@H:10]([OH:11])[CH2:9][CH2:8][CH2:7][NH:6]1)=[O:4].C(N(C(C)C)C(C)C)C.[Cl:21][C:22]1[C:29]([CH3:30])=[C:28]([N:31]=[C:32]=[O:33])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25].NC(N)=O.N1CC(=O)NC1=O>C(Cl)Cl>[Cl:21][C:22]1[C:29]([CH3:30])=[C:28]([N:31]2[C:3](=[O:4])[CH:5]3[CH:10]([OH:11])[CH2:9][CH2:8][CH2:7][N:6]3[C:32]2=[O:33])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: COC(=O)[C@@H]1NCCC[C@@H]1O
Reactant: Cc1c(N=C=O)ccc(C#N)c1Cl
Agent: NC(N)=O
Agent: O=C1CNC(=O)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(N2C(=O)C3C(O)CCCN3C2=O)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58.3 %

Procedure:
To a suspension of compound 53B (0.20 g, 0.77 mmol) in CH2Cl2 (3 mL) cooled to 0° C. was added i-Pr2EtN (0.178 mL, 1.00 mmol). After stirring at 0° C. for 20 min, compound 23E (0.095 g, 0.59 mmol) in CH2Cl2 (1 mL) solution was added, along with 4 Å molecular sieves (0.5 g), and the resulting mixture stirred at rt until urea formation was completed (˜2 h). The mixture was then stirred at rt until hydantoin formation was complete (˜15 h). The reaction mixture was loaded on a silica gel column, eluted with 40% EtOAc/hexane, and 5% MeOH in EtOAc/hexane (1:1) to afford 0.11 g of the title compound as an off-white powder. HPLC: 99% at 1.67-1.79 min; Conditions: Phenom. Luna C18 (4.6×50 mm); Eluted with 0% to 100% B; 4 min gradient (A=90% H2O—10% ACN—0.1% H3PO4 and B=10% H2O—90% ACN—0.1% H3PO4), Flow rate at 4 mL/min., UV detection at 220 nm). The compound was further loaded on a Chiral AD column, eluted with 25% isopropanol in hexane isocratic to afford 50 mg each of enantiomer 53a (isomer A; retention time=14.2 min; 100% e.e.) and enantiomer 53b (isomer B; retention time=20 min; 100% e.e.) of the title compound as white powders. Chiral HPLC Conditions: (CHIRALPAK® AD column 4.6×250 mm; 25% isopropanol in hexane over 30 min at flow rate 1.0 mL/min, UV detection at 220 nm); MS (ES) m/z 320 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([O:9][CH3:10])=[C:6]([F:8])[CH:7]=1.[Br:12][C:13]1[CH:18]=[C:17](/[C:19](/[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=2[C:34]#[N:35])=[N:20]\S(C(C)(C)C)=O)[CH:16]=[CH:15][N:14]=1>>[Br:12][C:13]1[CH:18]=[C:17]([C:19]2([C:2]3[CH:3]=[C:4]([CH3:11])[C:5]([O:9][CH3:10])=[C:6]([F:8])[CH:7]=3)[C:27]3[C:28](=[C:29]([F:33])[CH:30]=[CH:31][CH:32]=3)[C:34]([NH2:35])=[N:20]2)[CH:16]=[CH:15][N:14]=1
Reactant: CC(C)(C)S(=O)/N=C(\c1ccnc(Br)c1)c1cccc(F)c1C#N
Reactant: COc1c(C)cc(Br)cc1F
Product: COc1c(C)cc(C2(c3ccnc(Br)c3)N=C(N)c3c(F)cccc32)cc1F

Procedure:
The title compound was synthesized as described in Example 24i starting from 5-bromo-1-fluoro-2-methoxy-3-methylbenzene (177 mg, 0.81 mmol) and (E)-N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (300 mg, 0.73 mmol) to give the title compound which was used without further purification (330 mg, 99%). MS (ES+) m/z 444, 446 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C@H:18]2[C:31]([OH:33])=O)[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:37]=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:19][C@H:18]2[C:31]([NH2:37])=[O:33])[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(=O)O)C1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
A 3 L round bottom flask was charged with (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (75.5 g, 0.158 mol), EDC.HCl (33.5 g, 0.175 mol), 1-hydroxybenzotriazole (23.6 g, 0.175 mol), and dichloromethane (1 L). The reaction was stirred at room temperature for 2 h, during which time it changed from a white suspension to a clear solution. Ammonia (gas) was bubbled into the solution until the pH was strongly basic (paper) and the reaction was stirred for 10 min; this ammonia addition was repeated and the reaction was stirred for an additional 10 min. Water was added. The organic phase was washed with sat. NaHCO3, NaH2PO4, and brine before being concentrated in vacuo. The residue was slurried with acetonitrile (0.5 L) and then concentrated in to give (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxamide as a white solid (75.9 g, ˜100%), which was used in the next step without further purification. LC/MS for primary peak: [M-Boc+H]+=375.3; [M+H]+=475.4; [M-tBu+H]+=419.3. 1H-NMR (400 MHz, d-MeOH): δ 7.35 (m, 5H), 5.11 (s, 2H), 4.25 (m, 2H), 3.70 (m, 1H), 3.6 (m,1H), 3.45 (m, 1H), 2.91 (m, 1H), 2.38 (m, 1H), 2.12 (m, 1H), 1.9-2.05 (m, 2H), 1.65-1.9 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[C:5]([O:10]C)=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].ClC1C=CC(OC)=C(OC)C=1.C(Cl)(=O)C1C=CC=CC=1.II.N1C=CC=CC=1OC(=O)C1C=CC=CC=1>FC(F)(F)C(O)=O>[OH:8][C:6]1[C:5]([OH:10])=[CH:4][C:3]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[C:2]([Cl:1])[CH:7]=1
Reactant: COc1cc(Cl)c(C(=O)c2ccccc2)cc1OC
Agent: COc1ccc(Cl)cc1OC
Agent: II
Agent: O=C(Oc1ccccn1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(Cl)c1ccccc1
Product: O=C(c1ccccc1)c1cc(O)c(O)cc1Cl

Procedure:
The afore-mentioned dihydroxyketone can also be obtained in two stages analogously to Example 9(a) and (b). The (2-chloro-4,5-dimethoxyphenyl)-phenylmethanone required for this purpose can be obtained by acylating 4-chloro-1,2-dimethoxybenzene with benzoyl chloride in the presence of iodine. It is easier to obtain, however, if one equivalent of 4-chloro-1,2-dimethoxybenzene is heated in a bomb tube at 150° for 2 hours with 1.1 equivalents of (2-pyridinyl)-benzoate in trifluoroacetic acid. After working up and demethylation in a manner analogous to Example 9(b), the desired (4,5-dihydroxy-2-chlorophenyl)phenylmethanone is obtained.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6](I)[C:5]([O:9][CH3:10])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[N:7]=[C:6]([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[C:5]([O:9][CH3:10])=[CH:4][CH:3]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1ccc(F)nc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(F)nc1-c1cccnc1
Temperature: 25 °C
Yield: 73.9 %

Procedure:
6-Fluoro-2-iodo-3-methoxypyridine (52 mg), tetrakistriphenylphosphine palladium(0) (24 mg), and 3-pyridineboronic acid (76 mg) were suspended in a mixed solvent composed of N,N-dimethylformamide (0.75 ml) and a 2 N aqueous potassium carbonate solution (0.75 ml), and the suspension was stirred at 80° C. for 4 hr. The reaction solution was cooled to room temperature, the reaction solution was then filtered, and the solvent was removed from the filtrate by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give 6-fluoro-3-methoxy-[2,3′]bipyridine (31 mg, yield 72%).
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:15]([N:11]1[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=[C:2]1[Cl:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
8-Chlorotheophylline (50 g, 0.23 mol) was suspended in 600 ml of DMF and benzyl bromide (31 ml, 0.26 mol) and potassium carbonate (64 g, 0.46 mol) were added. The mixture was stirred at room temperature for 20 hours. The solvent was evaporated and the residue was dissolved in 250 ml of water and 400 ml of DCM. The layers were separated and the aqueous layer was extracted with 150 ml of DCM. The combined organic layer was washed with 100 ml of brine, dried over magnesium sulphate, filtered, and the solvent was evaporated to give compound (2A) as white crystals.
Reaction SMILES: [CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH3:7][N-:8][CH3:9].C[N-]C.[Ti+4:13].[CH:14]1[CH2:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH3:7][N-:8][CH3:9].[CH:15]1([Ti+3:13])[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: C1=CCC=C1
Reactant: [Ti+4]
Agent: C[N-]C
Solvent: Cc1ccccc1
Product: [Ti+3]C1C=CC=C1

Procedure:
A 250 mL Schlenk flask is charged with titanium tetrakis(dimethylamide), 2.48 g (11.06 mmole), and toluene, 100 mL. Freshly cracked cyclopentadiene monomer, 2.7 mL (33.18 mmole), is added to the magnetically stirred solution. The mixture is refluxed 1 hour giving a deep red solution. All volatiles are removed under vacuum at room temperature leaving a viscous deep red oil. The oil is transferred to a microdistillation apparatus and a low melting solid is distilled at 70° C. under vacuum (0.05 mm Hg). The product is determined to be cyclopentadienyltitanium tris(dimethylamide).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23](O)=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:26].ON1C2C=CC=CC=2N=N1.Cl.[CH3:39][O:40][C:41](=[O:47])[C@H:42]([CH:44]([CH3:46])[CH3:45])[NH2:43].C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:43][CH:42]([CH:44]([CH3:46])[CH3:45])[C:41]([O:40][CH3:39])=[O:47])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:26]
Reactant: Cc1cc(-c2cc(C(=O)O)on2)ccc1NC(=O)Nc1c(F)cccc1F
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3c(F)cccc3F)c(C)c2)no1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(4-(3-(2,6-difluorophenyl)ureido)-3-methylphenyl)isoxazole-5-carboxylic acid (1.0 equiv.) was dissolved in 25 ml of DMF, N,N′-dicyclocarbodiimide (1.2 equiv.) and 1-hydroxybenzotriazole (1.0 equiv.) was added and stirred at room temperature for 10 min. L-valine methyl ester hydrochloride (1.5 equiv.) was neutralized with triethylamine (1.5 equiv.) in 10 ml of DMF and was added to the above mixture and the resulting reaction mixture was stirred at room temperature for 48 hours. DMF was evaporated and then diluted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in a chloroform and methanol mixture, adsorbed on silica (100-200 mesh) and purified by flash chromatography on silica gel, and then eluted with 0-2% methanol in chloroform to obtain a crude product.
Reaction SMILES: C(OCC)C.Br[C:7]1[C:11](OC)([CH3:12])[CH2:10][CH2:9][C:8]=1[CH3:15].C([Li])CCC.[CH:21](=[C:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1)[CH2:22][CH2:23][CH3:24]>O>[C:25]1([CH:21]([C:7]2[C:11]([CH3:12])=[CH:10][CH2:9][C:8]=2[CH3:15])[CH2:22][CH2:23][CH3:24])[CH:26]=[CH:27][CH2:28][CH:29]=1
Reactant: COC1(C)CCC(C)=C1Br
Reactant: CCCC=C1C=CC=C1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CCCC(C1=CCC=C1)C1=C(C)CC=C1C
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
15 ml of diethylether was added to 2-bromo-3-methoxy-1,3-dimethyl-cyclopentene (2 g, 9.75 mmol), and the result was cooled to −30° C. Then, n-butyllithium (2.7 g, 9.75 mmol) was added and the reactant solution was incubated at an elevated temperature for 15 minutes and again cooled to −30° C. Then, 1 eq. (1.3 g) of the 5-butylidene-cyclopenta-1,3-diene prepared in (1-1) was added, and the result was incubated for 3 hours. Then, 15 ml of diethylether and 15 ml of water were added, and the resultant solution was washed with 30 ml of 1 N HCl for 3 minutes and neutralized with 30 ml of an aqueous saturated sodium bicarbonate solution. An organic layer was separated, dried over magnesium sulfate to remove water and then subjected to solvent removal in a rotary evaporator. The resultant residue was purified through silica-based column chromatography (hexane) to give 2-(1-cyclopenta-1,4-dienylbutyl)-1,3-dimethylcyclopenta-1,3-diene (yield: 65%).