Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([C@@H:20]([CH3:23])[CH2:21][CH3:22])[C:17]([OH:19])=[O:18].[CH:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:33]=[C:34]([C:35]([O:37][CH3:38])=[O:36])[C:27]=12)=O>C(Cl)Cl>[C:42]([O:41][C:39]([N:32]1[C:28]2=[N:29][CH:30]=[CH:31][C:26]([CH2:24][NH:15][C@H:16]([C@@H:20]([CH3:23])[CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[C:27]2[C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Reactant: CC[C@H](C)[C@@H](N)C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 10 mL round bottom flask was added sodium triacetoxyborohydride (104 mg, 0.493 mmol), (2R,3S)-2-amino-3-methylpentanoic acid (43.1 mg, 0.329 mmol), and DCM (2 mL). The mixture was stirred at room temperature for 30 min, after which was added 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (50 mg, 0.164 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 2 h and then quenched with MeOH (3 drops). The mixture concentrated to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C21H29N3O6, 420; found, 420.6.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:10][CH2:11][C:12]([N:14]([CH3:15])[CH3:16])=[O:13])=[C:2]([NH:1][S:25]([C:19]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=2[F:17])(=[O:27])=[O:26])[CH:7]=1
Reactant: CN(C)C(=O)CCSc1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Solvent: c1ccncc1
Product: CN(C)C(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(F)cc1F
Yield: 71.7 %

Procedure:
Following General Procedure B, the title compound (364 mg, 72%) was prepared from 3-((2-amino-4-chlorophenyl)thio)-N,N-dimethylpropanamide (300 mg, 1.167 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (248 mg, 1.167 mmol) in pyridine (5 ml).
Reaction SMILES: [CH3:1][Li].[C:3]1([CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH:11]=[CH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl-].[NH4+]>C(OCC)C.O.[Cu]Br>[CH3:1][CH:10]1[CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:14][CH2:13][C:12](=[O:15])[CH2:11]1
Reactant: O=C1C=CC(c2ccccc2)CC1
Reactant: [Li]C
Agent: [Cu]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CC1CC(=O)CCC1c1ccccc1
Temperature: -20 °C
Yield: 37.4 %

Procedure:
Under a nitrogen atmosphere, a stirred mixture of 2.9 grams (0.020 mole) of copper(I) bromide in 10 mL of diethyl ether was cooled to -20° C., and 50 mL (0.070 mole) of 1.4M methyllithium in diethyl ether was added slowly. Upon completion of addition, a solution of 4.6 grams (0.027 mole) of 4-phenyl-2-cyclohexenone in 5 mL of diethyl ether was added dropwise at a rate to maintain the reaction mixture temperature below -20° C. Upon completion of addition, a solution of 4.2 grams (0.080 mole) of ammonium chloride in 20 mL of water was added. Upon completion of addition, the reaction mixture was stirred as it warmed to ambient temperature. The reaction mixture was then diluted with 200 mL of diethyl ether and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished commencing with 10% diethyl ether in petroleum ether and finishing with 15% diethyl ether in petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.9 grams of 3-methyl-4-phenylcyclohexanone as a liquid. The NMR spectrum was consistent with the proposed structure, and it indicated that the product was predominantly the trans isomer. The reaction-was repeated on a larger scale. The 3-methyl-4-phenylcyclohexanone isolated from the larger reaction was a solid, mp 71.5°-72.5° C. The NMR spectrum of a sample from the larger reaction was also consistent with the proposed structure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O=[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[N:1]1([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: c1ccc2c(c1)CCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc32)CC1
Reaction time: 3 h
Yield: 98.5 %

Procedure:
A solution of indoline 1 (2.0 g, 16.78 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (3.68 g, 18.46 mmol) in dry 1,2-dichloroethane (30 mL) was treated with acetic acid (2.4 mL, 42.00 mmol) followed by NaBH(OAc)3 (5.34 g, 25.2 mmol) at 0° C. The resulting mixture was brought to room temperature and stirred for 3 h. The reaction was basified with 1 N NaOH solution (50 mL) and product was extracted into ethyl acetate (2×50 mL). The combined ethyl acetate layer was washed with brine (25 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography (ethyl acetate:hexanes, 1:4) to obtain compound 2 (5.0 g, 99%) as a syrup. 1H NMR (CDCl3) δ 7.05 (t, 2H, J=7.8 Hz), 6.62 (t, 1H, J=7.2 Hz), 6.43 (d, 11, J=7.5 Hz), 4.25-4.20 (m, 2H), 3.55-3.46 (m, 2H), 3.35 (t, 2H, J=8.4 Hz), 2.95 (t, 2H, J=8.4 Hz), 2.77 (t, 2H, J=12.3 Hz), 1.81-1.77 (m, 2H), 1.63-1.51 (m, 2H), 1.47 (s, 9H); ESI-MS (m/z, %) 303 (MH+, 5), 247 (100).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1([CH3:17])[O:12][CH2:11][C:10]([CH2:15][CH3:16])([CH2:13][OH:14])[CH2:9][O:8]1.O>N1C=CC=CC=1>[CH3:1][S:2]([OH:4])(=[O:8])=[O:3].[CH3:6][C:7]1([CH3:17])[O:8][CH2:9][C:10]([CH2:15][CH3:16])([CH2:13][OH:14])[CH2:11][O:12]1
Reactant: CS(=O)(=O)Cl
Agent: CCC1(CO)COC(C)(C)OC1
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulphonyl chloride (15 ml.) was added dropwise to a stirred solution of 2,2-dimethyl-5-ethyl-5-hydroxymethyl-1,3-dioxane 1 (33.0 g) in dry pyridine (100 ml.) at 0°. The mixture was stirred for two hours at room temperature and then poured into water. The aqueous mixture was extracted with ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. 2,2-Dimethyl-5-ethyl-5-hydroxymethyl-1,3-dioxane methane sulphonate was obtained as a colourless oil (39 g.) which solidified on standing. The compound was used without further purification.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]([N:8]=[N:9][C:10]1(Cl)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:7])[CH3:6].O>CO>[CH:5]([N:8]=[N:9][C:10]1([N:1]=[N+:2]=[N-:3])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:7])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)N=NC1(Cl)CCCCC1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)N=NC1(N=[N+]=[N-])CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 9.75 grams (0.15 moles) of sodium azide in 100 mls of 70% aqueous methanol in a 250 ml erlenmeyer flask cooled in an ice bath, was added 18.85 grams (0.1 moles) of 1-isopropylazo-1-chlorocyclohexane (from Example 3-2) over 15 minutes while holding the reaction temperature below 10° C. After the addition was complete the mixture was stirred an additional 20 minutes at room temperature, poured into 200 ml water and extracted into 100 ml of pentane. The pentane solution was washed successively with 50 ml portions of water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and weighed 18.4 grams (94.4 % crude yield). It was not shock sensitive and its infrared spectrum was in agreement with the structure of 1-isopropylazo-1-azidocylohexane (strong azide band at 2100 cm-1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2)[CH3:6])=[O:4].[C:28]([NH:31][C:32]1[N:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40](O)=[O:41])=[CH:34][CH:33]=1)(=[O:30])[CH3:29].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[C:28]([NH:31][C:32]1[N:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40]([NH:1][CH2:2][C:3]([N:5]([C:7]2[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:10][O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]3)[CH3:6])=[O:4])=[O:41])=[CH:34][CH:33]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Nc1ccc(/C=C/C(=O)O)cn1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a mixture of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (100 mg), (E)-3-(6-acetamidopyridin-3-yl)acrylic acid (56.1 mg) and N,N-dimethylformamide (2 ml) were added 1-hydroxybenzotriazole (43.4 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (56.9 mg) in a nitrogen stream at 0° C., and the resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into water, and extracted with chloroform. The organic layer was washed with an aqueous solution of saturated sodium hydrogencarbonate, water and brine successively, and dried over magnesium sulfate, and thereafter the solvent was removed under reduced pressure. The residue was purified by preparative thin-layer chromatography (methanol:dichloromethane=1:10, v/v), and solidified with diethyl ether and ethyl acetate to give 8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2methylquinoline (FR173657) (78.8 mg) as a grayish white solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([C:12]1[CH:17]=[C:16]([SH:18])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]=1[OH:23])([CH3:11])[CH3:10].[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH:25]1[NH:34][C:35](=[O:38])[CH:36]=[CH2:37])[CH2:31]2>CO>[CH3:11][C:9]([C:12]1[CH:17]=[C:16]([S:18][CH2:37][CH2:36][C:35]([NH:34][CH:25]2[CH:26]3[CH2:32][CH:30]4[CH2:29][CH:28]([CH2:33][CH:24]2[CH2:31]4)[CH2:27]3)=[O:38])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]=1[OH:23])([CH3:8])[CH3:10]
Reactant: C=CC(=O)NC1C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SCCC(=O)NC2C3CC4CC(C3)CC2C4)cc(C(C)(C)C)c1O

Procedure:
Following the procedure of Example 4, triethylamine (0.5 ml) was added to a solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.19 g, 0.005 mole) and the N-tricyclo[3.3.1.13,7 ]dec-2-yl-2-propenamide (1.02 g, 0.005 mole) in methanol (100 ml) and the solution stirred at room temperature for 12 hours. The solvent and triethylamine were removed on a rotary evaporator and the product purified by chromatography on silica, recrystallized from ethyl acetate/ethyl ether/hexane and dried, m.p. ca. 155.5°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1cc(I)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1cc(-c2ccccc2)ccn1
Yield: 15.5 %

Procedure:
A mixture of 2-chloro-4-iodopyridine (20.0 g, 82 mmol), phenylboronic acid (10.2 g, 82 mmol), Pd(Ph3P)4 (2.84 g 2.46 mmol), sodium carbonate (26.0 g, 246 mmol), DME (600 mL) and water (150 mL) was degassed with nitrogen and then refluxed overnight. The reaction was concentrated and the extracted with ethyl acetate. The ethyl acetate layer was dried on Na2SO4 and then vacuum distilled to give 2-chloro-4-phenylpyridine (2.79 g. 12.7 mmol. 82% yield).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C:13]#[N:14].C(=O)(O)[O-].[Na+].[Br:20]Br>C(Cl)(Cl)Cl>[Br:20][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:13]#[N:14])[C:4]=1[CH3:12]
Reactant: BrBr
Reactant: Cc1cc2ccccc2c(O)c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1c(C#N)c(O)c2ccccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
1-hydroxy-3-methyl-2-naphthonitrile (1.065 g, 5.8 mmol) was dissolved CHCl3 (24 mL) and combined with sodium bicarbonate (952 mg, 11.3 mmol) and bromine (330 μL, 6.43 mmol) and allowed to stir at room temperature overnight. The reaction was quenched by adding 10 mL of 10% sodium thiosulfate and the mixture stirred until decolorization was maximal. The solids were removed by filtration as crude product (1.47 g, 97% yield.) 1H-NMR: (300 MHz, DMSO-d6): δ 8.334 (d, J=8.0 Hz, 1H); 8.166 (d, J=8.4 Hz, 1H); 7.81-7.77 (m, 1H); 7.65-7.61 (m, 1H); 2.65 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:24][O:25][C:26]1[CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:30][C:31]=1[C:32]([O:34][CH3:35])=[O:33].O>CC#N.CN(C)C1C=CN=CC=1>[CH3:35][O:34][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:23])[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=3)([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:4]=2)=[CH:27][C:26]=1[O:25][CH3:24]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c2)cc1OC
Temperature: 80 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
4-Chloro-3-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (50 mg) was dissolved in CH3CN (2 mL). To this solution was added 3-methoxy-4-methoxycarbonyl-phenylboronic acid pinacol ester (120 mg, [CAS Reg. No. 603122-40-3]), cupric(II)-acetate (74.5 mg) and 4-dimethylaminopyridine (66.7 mg). The rection mixture was stirred at 80° C. for 18 hours. The mixture was cooled, poured into water, extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by amino phase chromatography (ethyl acetate:heptane=2:3) to give the desired compound as a colorless solid (24 mg, 33%). MS (neg. ion, m/e)=527.9 [(M−H)−].
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([Cl:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][C@H:3]1[OH:23].[S:24]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25]1.Cl.Cl.C(OCC)C>C(Cl)(Cl)Cl>[ClH:22].[Cl:22][C:14]1[CH:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20](=[O:21])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:6][CH2:7][C@H:2]([NH:1][CH2:33][C:30]5[N:29]=[CH:28][C:27]6[O:26][CH2:25][S:24][C:32]=6[CH:31]=5)[C@H:3]([OH:23])[CH2:4]4)[C:13]=1[C:12]=23
Reactant: N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(Cl)c2c43)C[C@H]1O
Reactant: O=Cc1cc2c(cn1)OCS2
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ncc(Cl)c3c2n1CC3CN1CC[C@H](NCc2cc3c(cn2)OCS3)[C@H](O)C1

Procedure:
The free base of the title compound was synthesised from racemic 4-{[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]methyl}-3-chloro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one and [1,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144, Example 61) according to the general method of Example 24(b). The free base of the title compound was converted to the hydrochloride by dissolving in chloroform and adding 1 equivalent of 1M HCl/diethyl ether, then evaporating to dryness. MS as that of free base.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([C:8]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1.[SH:20][C:21]1[NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][NH:27][C:25]=2[N:26]=1>CN(C=O)C>[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([C:8]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][S:20][C:21]3[NH:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][NH:27][C:25]=4[N:26]=3)=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: O=c1[nH]c(S)nc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)c1ccc(CSc2nc3[nH]ccc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In DMF (20 ml) was dissolved 2-mercapto-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (836 ml) followed by addition of 1N-sodium hydroxide (5 ml). Then, under ice-cooling, a solution of 4-(4-chlorobenzoyl)benzyl bromide (1.63 g) in DMF (5 ml) was added dropwise. The mixture was stirred at room temperature for 4 hours, at the end of which time it was poured in ice-water (200 ml). The resulting precipitate was collected by filtration, rinsed with water, and dried. This precipitate was purified by flash column chromatography (3-5% ethanol-containing chloroform) to provide the title compound (1.33 g). 1H-NMR (DMSO-d6) δ: 4.52(2H,s), 6.34-6.37(1H,m), 6.91-6.95(1H,m), 7.61(2H,d,J=8.4Hz), 7.65(2H,d,J=8.4Hz), 7.70(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 11.42(1H,s), 11.95(1H,s).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:9][CH2:8][CH:7](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:6]1)[CH2:2][CH2:3][CH3:4].[C-:21]#[N:22].[Na+].CS(C)=O>O>[CH2:1]([C@H:5]1[CH2:9][CH2:8][CH:7]([C:21]#[N:22])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: [C-]#N
Reactant: CCCC[C@H]1CCC(OS(=O)(=O)c2ccc(C)cc2)C1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCC[C@H]1CCC(C#N)C1
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
A mixture of 190 mg of (1S,3RS)-1-butyl-3-(p-toluene-sulphonyloxy)cyclopentane (prepared in Reference Example 12), 150 mg of sodium cyanide and 1.5 ml of anhydrous dimethyl sulphoxide was stirred for 30 mins. at 50° C. After diluting with 3 ml of water, the mixture was extracted with 10 ml of a mixture of pentane and diethyl ether (1:1). The extract was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulphate, and concentrated under ambient pressure at 50° C. The residue was purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate (1:3) as eluent to give 73 mg of the title compound having the following physical characteristics.
Reaction SMILES: C(O)=[O:2].[CH:4](=[N:11][N:12]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:30][CH:29]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:18][CH:17]=1)=[O:14])C1C=CC=CC=1>O1CCCC1.C(O)C.[OH-].[Pd+2].[OH-]>[CH:4]([NH:11][N:12]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:30][CH:29]=1)[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:21]=1)=[O:14])=[O:2]
Reactant: CN(C)CCOc1ccc(NC(=O)N(N=Cc2ccccc2)c2ccc(Oc3ccccc3)cc2)cc1
Reactant: O=CO
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(NC(=O)N(NC=O)c2ccc(Oc3ccccc3)cc2)cc1

Procedure:
Palladium(II) hydroxide (60 mg) and formic acid (4.6 g) were added to a solution of 1-benzylidene-2-(4-phenoxyphenyl)-4-[4-(2-dimethylamino-ethoxy)phenyl]semicarbazide (600 mg) in tetrahydrofuran/ethanol (1:1, 30 mL). The mixture was heated under reflux for five hours and then filtered. The filtrate was concentrated and the residue was purified by HPLC. The product with the molecular weight of 434.50 (C24H26N4O4); MS (ESI): 435 ([M+H]+), was obtained in this way.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:25])([CH:22]([CH3:24])[CH3:23])[CH2:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:31]O>>[CH3:31][O:20][C:19](=[O:21])[CH2:18][C:17]([CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)([OH:25])[CH:22]([CH3:23])[CH3:24]
Reactant: CC(C)C(O)(CCc1ccc(OCc2ccccc2)cc1)CC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CC(O)(CCc1ccc(OCc2ccccc2)cc1)C(C)C

Procedure:
A solution of 3-[2-(4-benzyloxy-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid from Example RRRR (10.1 g, 29.5 mmol), MeOH (300 mL), and H2SO4 (0.2 mL) was refluxed for 3 days. The reaction was stripped to dryness and the product was partitioned between ethyl acetate and 5% NaHCO3. The solution was dried (MgSO4), and concentrated to give the title compound.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[CH3:7][C:8]1[NH:9][C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[OH-].[Na+]>CN(C)C=O>[CH:2]([C:11]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([CH3:7])[NH:9][C:10]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:3]
Reactant: CCOC(=O)c1cc(-c2ccccc2Oc2ccccc2)[nH]c1C
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)[nH]c(-c2ccccc2Oc2ccccc2)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
Oxalyl dichloride (0.053 mL, 0.625 mmol) was added dropwise to N,N-dimethylformamide (0.387 mL, 5 mmol) at 0° C. The reaction mixture was removed from the cooling bath and stirred for thirty minutes at ambient temperature. N,N-Dimethylformamide (1 mL) was added to the reaction mixture and stirring was continued for another 30 minutes. The mixture was again cooled to 0° C. and a solution of Example 72b (0.161 g, 0.5 mmol) in N,N-dimethylformamide (2 mL) was added. Stirring was continued at 0° C. for two hours and then at ambient temperature for 3.5 hours. A solution of sodium hydroxide (10 mL, 4 N aqueous) was added and the mixture was stirred for 20 minutes. The reaction mixture was then partitioned between ethyl acetate and water, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 5-50% ethyl acetate in hexanes) to give 0.16 g (92%) of the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].CC[Mg+].[Br-].[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=[O:37]>O1CCCC1>[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]([OH:37])[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(Cc3ccccc3C(F)(F)F)sc21
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(O)c3ccccc3F)c(Cc3ccccc3C(F)(F)F)sc21

Procedure:
5-Bromo-1-isobutyl-3-methyl-6-[2-(trifluoromethyl)benzyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (Example 1 part c)) (100 mg) was dissolved in tetrahydrofuran (2 mls) and EtMgBr (250 ul of 1M solution in tetrahydrofuran) was added. After 10 mins 2-fluorobenzaldehyde (250 ul of a 1M solution in tetrahydrofuran) was added. After 1 hr the reaction was quenched via addition of water. The reaction was concentrated in vacuo and extracted into dichloromethane, concentrated in vacuo and the residue purified via chromatography eluting with 0-100% diethyl ether in isohexane to yield the title compound (9 mg).