Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=O.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNCC1
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cc(Cl)c(CN2CCCCC2)c(Cl)c1
Yield: 79.6 %

Procedure:
To a pre-stirred solution of 2,6-dichloro-4-hydroxybenzaldehyde (1.88, 9.8 mmol) and piperidine (1.07 mL, 10.8 mmol) in DCM (40 mL) was added sodium triacetoxyborohydride (3.13 g, 14.8 mmol) in portions. After 14 h the reaction mixture was quenched by the addition of water (50 mL), the pH of the solution adjusted to 2 by the addition of hydrochloric acid and the solution washed with DCM (50 mL). The pH of the aqueous phase was then adjusted to 9 by the addition of saturated aqueous sodium carbonate and then the organic component was extracted with DCM (50 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound as a beige solid (2.03 g, 80%) that was used without further purification. 1H NMR (CD3OD, 300 MHz): 6.81-6.77 (m, 2H), 3.72 (s, 2H), 2.67-2.57 (m, 4H), 1.64-1.54 (m, 4H), 1.51-1.44 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][C:11](C)([O-])[CH3:12].[K+].BrC(C)C>CS(C)=O.[Cl-].[Na+].O>[CH:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([CH3:12])[CH3:10]
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1cccc(O)c1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)Br
Solvent: CS(C)=O
Product: CC(C)Oc1cccc(C=O)c1
Reaction time: 0.33 h
Yield: 57.2 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (6.00 g, 49.1 mmol) in DMSO (100 mL) was added potassium t-butoxide (6.34 g, 56.5 mmol) and the resulting mixture was stirred for 20 mins. A sample of 2-bromopropane (7.25 g, 59 mmol) was added and the reaction was stirred for 18 hrs. It was then diluted with brine (100 mL) and extracted with ethylacetate (3×125 mL). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes, 10:90) to afford 4.61 g (57%) of 3-isopropoxybenzaldehyde as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@:6]1([O:41][C@H:40]([CH2:42][OH:43])[C@@H:11]([O:12][C@@H:13]2[O:30][C@H:29]([CH2:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]2[O:15][C:16](=[O:18])[CH3:17])[C@H:9]([OH:10])[C@H:8]1[NH:44][C:45](=[O:47])[CH3:46])[OH:7].S1C=CC=C1[C@@:53]1([O:83][C@@H:82]([CH3:84])[C@@H:73]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[C@@H:64]([O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C@@H:55]1[O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)O.[Sn](Cl)Cl>C(OCC)C.Cl([O-])(=O)(=O)=O.[Ag+]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@:6]1([O:41][C@H:40]([CH2:42][OH:43])[C@@H:11]([O:12][C@@H:13]2[O:30][C@H:29]([CH2:31][O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]2[O:15][C:16](=[O:18])[CH3:17])[C@H:9]([OH:10])[C@@:8]1([C@@H:53]1[O:83][C@@H:82]([CH3:84])[C@@H:73]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[C@@H:64]([O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C@@H:55]1[O:56][CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[NH:44][C:45](=[O:47])[CH3:46])[OH:7]
Reactant: CC(=O)N[C@@H]1[C@@H](O)[C@H](O[C@@H]2O[C@H](COCc3ccccc3)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@@H](CO)O[C@]1(O)c1cccs1
Reactant: C[C@@H]1O[C@@](O)(c2cccs2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Ag+]
Agent: Cl[Sn]Cl
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Product: CC(=O)N[C@]1([C@@H]2O[C@@H](C)[C@@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[C@@H](O)[C@H](O[C@@H]2O[C@H](COCc3ccccc3)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@@H](CO)O[C@]1(O)c1cccs1

Procedure:
Compound [13] (0.2-4.81 g, 0.234-5.78 mmol) is dissolved with compound [17] (0.17-4.15 g, 0.37-9.25 mmol) in dry diethyl ether (5-100 ml) and stirred with 4 Å molecular sieves (0.1-6.8 g), silver perchlorate (0.15-3.59 g 0.702-17.34 mmol) and tin(II) chloride (0.13-3.29 g, 0.702-17.34 mmol) until the reaction is complete. The mixture is subsequently filtered, and the crude product compound [18] obtained after concentration is purified by chromatography on silica gel with an ethyl acetate/isohexane gradient (0.25-6.2 g, 0.2-4.91 mmol, about 85% yield). FAB-MS: M+H+ =1262. NMR data consistent with Nicolaou et al., J. Am. Chem. Soc. 114:3127 (1992) and C. W. Hummel, Ph.D. Dissertation, University of California, San Diego (1993).
Reaction SMILES: C([N:8]1[CH2:13][C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH:12]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:13]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C2=CCCN(Cc3ccccc3)C2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C2CCCNC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of 1-benzyl-5-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (1.5 g, 5.4 mmol) in 50 mL of methanol was added 10% Pd/C (1.14 g). Hydrogen gas was introduced via balloon and the reaction mixture was stirred overnight at rt. The reaction mixture was then filtered through Celite, and the filter pad was washed with additional methanol (100 mL). The filtrates were combined, and the methanol was evaporated under reduced pressure to give 3-(4-methoxyphenyl)piperidine (950 mg, 3.73 mmol, 69.4% yield). LCMS (Method 107): (ES-API), m/z 192.2 (M+H) RT=1.497 min; 1H NMR (300 MHz, DMSO-d6) δ 7.13 (dt, J=8.5, 2.0 Hz, 2H), 6.84 (dt, J=8.5, 2.2 Hz, 2H), 3.72 (s, 3H), 3.17 (s, 2H), 2.93 (d, J=10.6 Hz, 2H), 2.49-2.39 (m, 1H), 1.81 (d, J=1.9 Hz, 1H), 1.74-1.57 (m, 1H), 1.57-1.40 (m, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[OH-].[Na+].[F:10][C:11]([F:23])([F:22])[C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1.C(Cl)Cl.O.FC(F)(F)C1C=CC(S(Cl)(=O)=O)=CC=1>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([S:18]([C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:10])([F:22])[F:23])=[CH:17][CH:16]=2)(=[O:20])=[O:19])[CH2:7]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C[C@H]1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
(2S)-2-methylpiperazine (15 g, 150 mmol) was dissolved in tetrahydrofuran (300 mL) and the solution was cooled down to 0° C. Sodium hydroxide (150 mL, 449 mmol) was added, then 4-(trifluoromethyl)benzenesulfonyl chloride (40 g, 164 mmol) (dissolved in 200 ml THF) was added dropwise and the resulting mixture was stirred for 1 h. Further 4-(trifluoromethyl)benzenesulfonyl chloride (0.06 eq, 2.2 g) was added and mixture stirred for 10 min. The mixture was diluted with DCM (500 ml) and water (500 ml) and stirred for 5 min. The phases were separated, the aqueous layer was extracted with DCM (1000 ml) and the organic phases concentrated under reduced pressure. The residue was taken-up with 1 M HCl (500 ml) and washed with DCM in order to extracted impurities. The aqueous phase was basified to pH=9 with NaOH 3M, extracted with DCM (3×500 ml) and the combined organic phases dried over Na2SO4 before the solvent was removed under reduced pressure to give the title compound (30 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7]C(=O)OCC2C=CC=CC=2)[CH2:3][CH2:2]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].Cl.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:34])(=O)=O)=CC=1.[Cl-].[NH4+]>C1COCC1.ClCCl.C(N(CC)CC)C>[F:34][CH2:18][S:19]([N:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC1CCNCC1)OCc1ccccc1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC1CCN(S(=O)(=O)CF)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (10 mL) was added to a dichloromethane (90 mL) solution of Benzyl piperidin-4-ylcarbamate (5.09 g) at 0° C. followed by the dropwise addition of methanesulfonyl chloride (which may be referred to as sbo1; 3 mL; TCI) and the resulting mixture was slowly stirred overnight with raising to room temperature. 1 N Hydrochloric acid (90 mL; WAKO) was added to the reaction mixture solution, the resulting mixture was stirred for approx. 10 minute, the resulting mixture was extracted with chloroform, the organic layer was dried, then the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen; chloroform/methanol). 200 mg of this purified compound was dissolved in THF (4 mL) and the resulting mixture was added dropwise to a THF (5 mL) solution of LDA prepared from diisopropylamine (0.2 mL; WAKO) and normal butyllithium (1.6 M, 1 mL; KANTO) at −78° C. The resulting mixture was stirred for 30 minutes followed by the dropwise addition of THF (3 mL) solution of N-fluorobenzenesulfonimide (320 mg) and the resulting mixture was slowly stirred overnight with raising to room temperature. Saturated aqueous ammonium chloride solution was added to the reaction mixture solution and the resulting mixture was extracted with ethyl acetate. The organic layer was dried, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen; chloroform/methanol). The title compound (10 mg) was obtained from this purified product according to the method described in Step c of Reference Example N-14.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:2].[C:11]([Mg]Br)#[CH:12]>O1CCCC1>[OH:2][CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)[C:11]#[CH:12]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(C#N)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-Formyl-benzonitrile (1.5 grams, 10.0 mmole) in tetrahydrofuran (20 ml) at −78° C. was added 0.5 M ethynyl magnesium bromide (26 ml, 13.0 mmole) dropwise. The mixture was stirred at −78° C. for 30 minutes and allowed to warm to room temperature over one hour. The reaction was cooled to 0° C., quenched with 10 ml methanol, poured into 200 ml water, acidified with oxalic acid and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to give an oil which was purified via flash chromatography on silica using 30% ethyl acetate/hexane as eluent to give a solid. (1.6 g). MW 157.18; MS (m/e) 157 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[OH2:10].[OH2:11].O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH3:9])(=[O:11])=[O:10])=[N:6][CH:7]=1
Reactant: CSc1ccc(Br)cn1
Reactant: O
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)c1ccc(Br)cn1
Yield: 92 %

Procedure:
5-bromo-2-methylsulfanyl pyridine (3.47 g) was dissolved in a mixed solvent of dichloromethane and methanol with the ratio of 5:1 (v/v) and magnesium monoperoxyphthalate hexahydrate was slowly added dropwise. After completing the reaction for 3 hours at room temperature, magnesium monoperoxyphthalate hexahydrate was filtered out, sodium bicarbonate and salt water was added to dilute, and extracted with dichloromethane to separate an organic layer. The separated organic layer was dried with anhydrous magnesium sulfate and distilled under reduced pressure. As a result, 5-bromo-2-methylsulfonyl pyridine (3.7 g, yield: 92%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl-].[F:11][C:12]([F:40])([F:39])[C:13]1[CH:38]=[CH:37][C:16]([CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:15][CH:14]=1.[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:17][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:11])([F:39])[F:40])=[CH:38][CH:37]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Fc1ccc(C=Cc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
8.9 g of (72 mmol) of 4-fluorobenzaldehyde and 32 g (72 mmol) of (4-trifluromethylbenzyl)triphenylphosphonium chloride were dissolved in 300 ml of methylene chloride. While vigorously stirring the solution, 280 ml (0.84 mol) of 3N sodium hydroxide was dropwise added at room temperature. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was subjected to liquid separation. The organic layer was washed twice with water and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: n-hexane) to obtain 12.4 g of 4-fluoro-4'-trifluoromethylstilbene.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:13])[O-])[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=3)[N:32]=[CH:31][N:30]=2)=[CH:24][C:22]=1[NH2:23]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:23][C:22]2[CH:24]=[C:25]([O:28][C:29]3[C:38]4[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=4)[N:32]=[CH:31][N:30]=3)[CH:26]=[CH:27][C:21]=2[Cl:20])=[O:13])[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2ncnc(Oc3ccc(Cl)c(N)c3)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)[O-])n(-c2ccccc2)n1
Product: COc1cc2ncnc(Oc3ccc(Cl)c(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c3)c2cc1OC
Yield: 20 %

Procedure:
The title compound was prepared from 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate (100 mg, 0.30 mmol) and 2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)aniline (100 mg, 0.30 mmol) using the procedure in Example 115C to give 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (34 mg, 0.06 mmol, 20%). 1H NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.81 (s, 1H), 8.56 (s, 1H), 8.11 (s, 1H), 7.57-7.52 (m, 6H), 7.44-7.40 (m, 2H), 7.01 (d, 1H), 6.36 (s, 1H), 3.98 (s, 6H), 1.24 (s, 9H); LC-MS (ESI) m/z 573 (M)+.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:8][C:3]1[CH:2]=[CH:1][C:6]([OH:7])=[C:5]([CH:4]=1)[C:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:15]
Reactant: O=C1CCC(=O)O1
Reactant: Cc1ccc(O)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(O)c(C(=O)CCC(=O)O)c1

Procedure:
p-Cresol was reacted with succinic anhydride and aluminium chloride in a similar manner to the procedure described in Example 8 (i) to give 3-(5-methyl-2-hydroxybenzoyl)-propionic acid.
Reaction SMILES: I.[CH3:2][S:3][N:4]=[CH:5][NH:6][CH2:7][CH2:8][CH2:9][C@H:10]([C:27]([NH:29][C@@H:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[CH3:31])=[O:28])[NH:11][C:12](=[O:26])[CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(Cl)Cl.[CH:43]1[CH:48]=[CH:47][C:46]([CH2:49][O:50][C:51](Cl)=[O:52])=[CH:45][CH:44]=1.[C:54]([O-:57])([O-])=[O:55].[K+].[K+]>O>[C:51]([N:6]([C:5]([C:54]([O:57][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:55])=[N:4][S:3][CH3:2])[CH2:7][CH2:8][CH2:9][C@H:10]([C:27]([NH:29][C@@H:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[CH3:31])=[O:28])[NH:11][C:12](=[O:26])[CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([O:50][CH2:49][C:46]1[CH:47]=[CH:48][CH:43]=[CH:44][CH:45]=1)=[O:52]
Reactant: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCNC=NSC)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: I
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCN(C(=O)OCc2ccccc2)C(=NSC)C(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
(R)-N5 -[Methylthio(iminomethyl)]-N2 -(diphenylacetyl)-(R)-N-[1-(4-methoxyphenyl)ethyl]ornithine amide hydroiodide (1.38 g; 2.09 mmol; from step (c) above), CH2Cl2 (100 mL), Cbz-Cl (0.75 mL; 5.22 mmol), water (100 mL) and K2CO3 (1.16 g; 8.36 mmol) were combined and stirred for 18 h at room temperature. The organic layer was separated and washed with KHSO4 solution (twice), NaHCO3 solution (twice) and brine (twice), dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica column eluting with hexanes:EtOAc (3:1). Fractions containing the desired product were combined and concentrated in vacuo to afford 0.65 g (39%) of the sub-title compound. The material was used without farther characterization.
Reaction SMILES: [C:1]([C:4]1[N:12]=[C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[N:10]=[C:9]2[C:5]=1[NH:6][C:7](=[O:30])[N:8]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])(=[O:3])[NH2:2].N/[C:32](/C#N)=C(\NC(NC1C=CC=CC=1OC)=O)/C#N.C(C1C=CC(C(O)=O)=CC=1)=O>C(N(CC)CC)C>[CH3:32][O:18][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([C:11]2[N:10]=[C:9]3[C:5]([NH:6][C:7](=[O:30])[N:8]3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:4]([C:1](=[O:3])[NH2:2])[N:12]=2)=[CH:21][CH:20]=1
Reactant: COc1ccccc1NC(=O)N/C(C#N)=C(\N)C#N
Reactant: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(-c3ccc(C(=O)O)cc3)nc21
Agent: O=Cc1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2nc(C(N)=O)c3[nH]c(=O)n(-c4ccccc4OC)c3n2)cc1
Yield: 51 %

Procedure:
4-[6-Carbamoyl-9-(2-methoxy-phenyl)-8-oxo-8,9-dihydro-7H-purin-2-yl]-benzoic acid. (Z)-1-(2-Amino-1,2-dicyanovinyl)-3-(2-methoxyphenyl)urea (See Example 2.A) (0.30 g, 1.2 mmol), 4-formylbenzoic acid (0.44 g, 2.65 mmol) and triethylamine (3.0 mL) were reacted according to General Procedure B. The crude residue was purified using Biotage silica gel chromatography (0-100% ethyl acetate in hexanes) to afford the title compound in 99.4% purity (0.129 g, 0.069 mmol, 51% yield). 1H NMR (300 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.56 (s, 1H), 8.48 (d, J=8.2, 1H), 8.03 (s, 1H), 7.99 (d, J=8.5, 1H), 7.49-7.61 (m, 1H), 7.31 (d, J=8.5, 1H), 7.17 (td, J=7.7, 1.1, 1H), 3.76 (s, 1H); MS (ESI) m/z 420.1 [M+1]+; mp 328-332° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])C=[CH:5][C:3]=1[OH:4].[CH3:10][C:11](=[CH2:19])[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[OH:9][C:7]1[CH:8]=[C:2]([CH3:1])[C:3]([OH:4])=[CH:5][C:19]=1[C:11]([CH3:20])([CH3:10])[CH2:12][CH:13]=[CH:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: C=C(C)CCCC(=O)OC
Reactant: Cc1cc(O)ccc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: COC(=O)C=CCC(C)(C)c1cc(O)c(C)cc1O

Procedure:
12.4 Parts of 2-methylhydroquinone, 14.2 parts of methyl 5-methylhex-5-enoate, and 0.5 parts of p-toluene sulphonic acid are heated on a steam bath for 24 hours. The cooled reaction mixture is treated with ether, washed firstly with a 10% aqueous solution of sodium hydroxide, and then with water until the aqueous phase is neutral. The ethereal layer is separated and evaporated to give a viscous oil which after short-path distillion at 0.13 mb gives methyl 5-(2',5'-dihydroxy-4'-methyl-phenyl)-5-methyl-hexenoate with the following percentage composition by weight.
Reaction SMILES: CN([CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=O)C(=O)OC1C=CC=CC=1.NC1C=[C:36]2[C:41](=CC=1)[N:40]([CH2:44]CN(C)C(=O)OC1C=CC=CC=1)[C:39](=O)[CH2:38]C2>C(O)C.C([O-])(O)=O.[Na+]>[CH3:44][N:40]1[CH2:41][CH2:36][CH:15]([N:14]2[CH2:13][CH2:12][CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([NH:24][C:25]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[NH:26])[CH:21]=[CH:22][C:23]2=3)[CH2:38][CH2:39]1
Reactant: CN(CCN1C(=O)CCc2cc(N)ccc21)C(=O)Oc1ccccc1
Reactant: CN(CCN1C(=O)CCc2cc(NC(=N)c3cccs3)ccc21)C(=O)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN1CCC(N2CCCCc3cc(NC(=N)c4cccs4)ccc32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
A solution of compound 8 (321.6 mg, 1.24 mmol) in dry ethanol (10 mL) was treated with compound 6 (707 mg, 2.48 mmol) at room temperature. The reaction mixture was stirred for 16 hours at room temperature then diluted with saturated NaHCO3 solution (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic fractions were washed with brine (50 mL), dried (Na2SO4) and concentrated to give a brown residue. The crude product was purified by column chromatography on silica gel (MeOH:CH2Cl2, 2:98 followed by 2 N NH3 in MeOH:CH2Cl2, 4:96 to 5:95) to give compound 39 (374.6 mg, 81.9%) as a yellow residue. 1H-NMR (DMSO-d6) δ 1.56-1.79 (m, 9H), 1.97 (t, 2H, J=10.5 Hz), 2.16 (s, 3H), 2.65 (brs, 2H), 2.80 (d, 2H, J=10.2 Hz), 2.91 (brs, 2H), 3.12 (m, 1H), 6.30 (brs, 2H), 6.59 (m, 2H), 6.89 (d, 1H, J=8.9 Hz), 7.07 (t, 1H, J=4.5 Hz), 7.57 (d, 1H, J=5.1), 7.70 (d, 1H, J=3.5 Hz); ESI-MS (m/z, %) 369 (MH+, 35), 272 (100). ESI-HRMS calculated for C21H29N4S (MH+), calculated: 369.2101; observed: 369.2107; HPLC-purity: 97.31% by area.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]12[N:37]([CH2:38][CH2:39][OH:40])[CH:34]([CH2:35][CH2:36]1)[CH2:33][NH:32][CH2:31]2>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([N:32]5[CH2:31][CH:30]6[N:37]([CH2:38][CH2:39][OH:40])[CH:34]([CH2:35][CH2:36]6)[CH2:33]5)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25]([N:26]([CH3:28])[CH3:27])=[O:29])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: OCCN1C2CCC1CNC2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5CCO)cn3)nc2n1C1CCCC1
Yield: 59 %

Procedure:
The 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid was combined with 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)ethanol following amide formation method 3 which gave 7-cyclopentyl-2-(5-(8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (18 mg, 59% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.00-8.87 (m, 1H) 8.87-8.78 (m, 1H) 8.57 (d, J=8.08 Hz, 1H) 8.44 (s, 1H) 7.79 (dd, J=8.59, 2.53 Hz, 1H) 6.54-6.43 (m, 1H) 4.81 (dq, J=9.09, 8.93 Hz, 1H) 4.51 (br. s., 1H) 3.82-3.49 (m, 4H) 3.40-2.99 (m, 10H) 2.69-2.44 (m, 4H) 2.16-1.99 (m, 4H) 1.91 (d, J=5.56 Hz, 2H) 1.83-1.45 (m, 4H); HR-MS (m/z MH+) 533.30 RT 2.56 min
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]#[N:13].Cl[C:15]([O:17][CH3:18])=[O:16]>CN(C)C=O>[CH3:18][O:17][C:15](=[O:16])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]#[N:13]
Reactant: COC(=O)Cl
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Solvent: CN(C)C=O
Product: COC(=O)Nc1ccc2[nH]cc(CC#N)c2c1

Procedure:
Following the method of Example 4(i), 5-amino-1H-indole-3-acetonitrile (0.8 g) in dimethylformamide (10 ml) was reacted with methyl chloroformate (0.5 ml) to give the title compound (0.44 g) as a white solid m.p. 146°-8° after column chromatography (Kieselgel 60, 100 g) eluted with ether.