Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][C:10]=3[O:9][CH2:8]2)[NH:16][CH2:15][CH2:14]4)[CH2:4][CH2:3]1>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:11]3[CH2:12][C:13]4[C:17](=[CH:18][C:10]=3[O:9][CH2:8]2)[N:16]=[CH:15][CH:14]=4)[CH2:4][CH2:3]1.[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:11]3[CH2:12][C:13]4[C:17](=[CH:18][C:10]=3[O:9][CH2:8]2)[N:16]=[CH:15][CH:14]=4)[CH2:4][CH2:3]1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)CCN3
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CN1CCC2(CC1)COC1=C2CC2=CC=NC2=C1
Reaction time: 18 h

Procedure:
A stirred solution of 1'-methyl-2,3,5,6-tetrahydrospiro[furo[3,2-f]indole-3,4'-piperidine] (D67, 1.0 g, 4.1 mmole) in dichloromethane (70 ml) at room temp. under argon was treated with manganese dioxide (0.68 g, 8.2 mmole). The mixture was stirred for 18 hours, then additional manganese dioxide was added (0.30 g, 2.4 mnmole). The mixture was stirred for an additional 24 hours, then filtered through a pad of kieselguhr and the filtrate concentrated under vacuum. The two components present were separated by chromatography on neutral alumina. Elution with ether gave the title compound as a white solid (0.41 g, 41%), further elution with ethyl acetate gave the second component.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.[ClH:27]>CO.C(OCC)(=O)C>[ClH:27].[ClH:27].[ClH:27].[CH3:26][N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:16]=[CH:15][C:14]([CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:19][CH:18]=2)[CH2:21][CH2:22]1
Reactant: CN1CCN(c2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCN(c2ccc(C3CCCNC3)cc2)CC1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 3-(4-(4-methylpiperazin-1-yl)-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 5.56 mmol) in methanol (20 mL) was added 4N hydrochloric acid in ethyl acetate (20 mL) at room temperature. After stirring for 1 h, the resulting suspension was concentrated in vacuo. The residue was washed with ethyl acetate to furnish 3-(4-(4-methylpiperazin-1-yl)-phenyl)-piperidine trihydrochloride (1.84 g, 4.99 mmol, 90%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8]C(=O)O[C:11](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.CN(C=O)C>O>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=1[C:11]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([Br:14])=[CH:16][CH:17]=1)=[O:12]
Reactant: Nc1ccc(Br)cc1
Reactant: O=c1[nH]c2c(Cl)cccc2c(=O)o1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(Cl)cccc1C(=O)Nc1ccc(Br)cc1
Temperature: 130 °C

Procedure:
A mixture of 8-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (0.80 g, 4.05 mmol) and 4-bromoaniline (0.70 g, 4.05 mmol) with anhydrous DMF (1 mL) was heated at 130° C. for 2 hours. Water (50 mL) was added, and the product was extracted with ethyl acetate (200 mL). The organic phase was separated, washed with water (100 mL), brine (100 mL) and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo, and the crude material was washed with ether, to give 2-amino-N-(4-bromophenyl)-3-chlorobenzamide as an off-white solid. Yield 1.17 g (89%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:33])[C:28]([F:32])([F:31])[CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:33])[C:28]([F:32])([F:31])/[CH:29]=[CH:30]/[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: C=CC(F)(F)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Reactant: Ic1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C(F)(F)/C=C/c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 59, Step 1, using 1-{4′-[4-(2,2-difluoro-1-hydroxy-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and iodobenzene.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]1[O:16][CH2:15][O:14][CH:13]1[CH2:17][OH:18].Cl>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:18][CH2:17][CH:13]2[CH2:12][O:16][CH2:15][O:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1COCO1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COCO2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
p-Toluenesulfonyl chloride (76.2 g, 0.4 mole) was added to a solution of 104.1 g (1 mole) glycerol formal (a mixture comprised of 67% 1,3-dioxacyclohex-5-ol and 33% (1,3-dioxacyclopent-4-yl)methanol) in 1000 ml. pyridine cooled to 0° C. under nitrogen. After standing at 0° C. for 20 hr. the reaction mixture was allowed to warm to room temperature and added to 1500 ml. of 6N aqueous hydrochloric acid. The resulting mixture was extracted with four 500 ml. portions of ethyl acetate. The combined ethyl acetate extracts were washed with two 500 ml. portions of 6N aqueous hydrochloric acid solution, two 500 ml. portions of water and 500 ml. saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily product (78.4 g) consisted of ca a 2:1 mixture of 1,3-dioxacyclopent-4-ylmethyl tosylate and 1,3-dioxacyclohex-5-yl tosylate which was used without purification in a subsequent step (Preparation K).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4](Cl)[N:3]=1.Cl.[NH2:13][CH:14]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:15]([NH2:17])=[O:16].CCN(C(C)C)C(C)C.O>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:13][CH:14]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:15]([NH2:17])=[O:16])[C:5]([F:10])=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: NC(=O)C(N)CC(F)(F)F
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: N#Cc1cc(F)c(NC(CC(F)(F)F)C(N)=O)nc1Cl
Yield: 100.1 %

Procedure:
A solution of 2,6-dichloro-3-cyano-5-fluoropyridine (134 mg, 0.701 mmol), 2-amino-4,4,4-trifluorobutanamide hydrochloride (135 mg, 0.701 mmol) and DIEA (0.365 mL, 2.10 mmol) in DMSO (3 mL) was stirred at 95 C for 3 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo to give crude 2-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)-4,4,4-trifluorobutanamide (218 mg).
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[F:9][C:10]1[CH:11]=[CH:12][C:13]([N+:30]([O-:32])=[O:31])=[C:14]([N:16]2[C:21](=[O:22])[NH:20][C:19](=[O:23])[N:18]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:17]2=[O:29])[CH:15]=1>CN(C)C=O.C(OCC)(=O)C.CCOCC>[F:9][C:10]1[CH:11]=[CH:12][C:13]([N+:30]([O-:32])=[O:31])=[C:14]([N:16]2[C:21](=[O:22])[N:20]([CH3:3])[C:19](=[O:23])[N:18]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:17]2=[O:29])[CH:15]=1
Reactant: COC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(F)ccc2[N+](=O)[O-])c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CI
Product: COC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(F)ccc2[N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (5.0 mL, 80.31 mmol) and potassium carbonate (11.12 g, 80.45 mmol) are added to a solution of methyl 3-(5-fluoro-2-nitrophenyl)tetrahydro-2,4,6-trioxo-s-triazine-1(2H)-acetate (25.65 g, 75.40 mmol) in N,N-dimethylformamide. The reaction mixture is stirred at room temperature overnight, concentrated in vacuo and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water, 0.08M sodium metabisulfite solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow oil. The oil is dissolved in a refluxing ethyl acetate/ether (1:1) solution and the resultant solution is chilled end treated dropwise with hexanes to obtain a solid. The solid is collected, washed with an ether/ethyl acetate/hexanes (1:1:8) solution and dried overnight in vacuo at 50° C. to give the title product as a solid, mp 121.8°-122.3° C.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:12]([CH:22]([CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:23]=[O:24])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>C1COCC1>[CH2:12]([CH:22]([CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:23]([OH:24])[CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC/C=C\CCBr
Reactant: CCCCC/C=C\CCCC(C=O)CCC/C=C\CCCCC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(O)CC/C=C\CCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A 100 mL round bottom flask was charged with magnesium turnings (0.6 g, 25.7 mmol) and a stir bar. The flask was dried with a heat gun for 5 minutes. The flask was charged with THF (5 mL) and a single grain on iodine. A solution of (Z)-1-bromonon-3-ene (4.5 g, 22.0 mmol) in THF (5 mL) was added slowly to the mixture and reaction was refluxed for 30 minutes under nitrogen. The solution was cooled to room temperature and a solution of (Z)-2-((Z)-dec-4-enyl)dodec-6-enal 7 (4.7 g, 14.7 mmol) in THF (5 mL) was added. The solution was stirred overnight at room temperature and upon completion the mixture was poured into 5% HCl (50 mL) and ice (100 mL). The solution was extracted with ether (2×150 mL) and the combined ether extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography (column: 2″ W×8″ L; eluted with 100% Hexanes to 5% ethyl acetate in hexanes) to afford (6Z,15Z)-11-((Z)-dec-4-enyl)henicosa-6,15-dien-10-ol 17 as a colorless oil (5.4 g, 82%). Rf 0.5 (10% EtOAc-Hexanes).
Reaction SMILES: Cl[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[CH:7]=[O:8].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[O:15]([C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[CH:7]=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=CC1=C(Cl)CCC1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=CC1=C(Oc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of residue (100 g, 0.77 mol) obtained in example 1 in acetone (400 mL), phenol (79.3 g, 0.84 mol) and K2CO3 (126.8 g, 0.92 mol) were added. The mixture was stirred under nitrogen for 12 hours at room temperature and monitored by TLC (petroleum ether/ethyl acetate=10:1). After the reaction completed, the solvent was removed on a rotary evaporator, and water (300 mL) was added. The mixture was extracted with EtOAc (2×100 mL). The organic layer was washed with aqueous sodium carbonate (2×50 mL) and water (50 mL). After dried over sodium sulfate, the solvent was removed and 2-phenoxy-1-formyl-1-cyclopentene was obtained (155 g, contains some phenol), which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:15][N:16](C)[CH:17]=[O:18]>>[C:15]1([NH:16][C:17](=[O:18])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=3)=[CH:6][CH:7]=2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Product: O=C(Nc1ccccc1)Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-(4-Aminophenyl)pyrazin-2(1H)-one (1 g) was dissolved in dimethylformamide (25 ml) and triethylamine (0.05 ml), and the solution filtered through diatomaceous earth. Phenyl isocyanate (1 ml) was added and the dark solution was stirred for 24 hours at room temperature. The solvent was evaporated under reduced pressure to afford a residue which was washed with water. The resultant solid precipitate was collected by filtration to yield 5-[4-(3-phenylureido)phenyl]-2(1H)-pyrazinone.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:14].CCN(CC)CC.CC(O[Na])=O>CO.[Pd]>[CH3:13][O:12][C:11]1[C:3]([CH3:2])=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:14])[CH2:6][CH2:5]2
Reactant: COc1ccc2c(c1CCl)CCC2=O
Agent: [Pd]
Agent: CC(=O)O[Na]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1C)CCC2=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A flask was charged with 3.35 g 4-chloromethyl-5-methoxy-indan-1-one, 0.5 g Pd/C, 2.4 g Et3N and 2 g CH3COONa in 50 mL MeOH, and then evacuated and filled with H2 (1.2 bar) three cycles. The mixture was shaken at r.t. for 6 h. The mixture was concentrated to give the crude product without further purification.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([CH2:11]O)[CH:8]=[CH:7][C:6]=1[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[F:21])([CH3:4])[CH3:3].C(Cl)[Cl:23].S(Cl)(Cl)=O>>[Cl:23][CH2:11][C:9]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[F:21])=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH:10]=1
Reactant: ClCCl
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C(C)(C)C)c1
Solvent: O=S(Cl)Cl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.3 %

Procedure:
To a cooled solution of 8.9 (0.56 g, 1.93 mmol) in dry DCM (3.60 mL, 1.93 mmol) at 0° C., was added thionyl chloride (0.40 mL, 5.48 mmol) dropwise. Upon complete addition of thionyl chloride, the mixture was allowed to warm to room temperature. After 18 hours, the reaction was concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-15% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to provide 8.10 as a colorless solid (0.44 g, 74%). 1H NMR (500 MHz, CDCl3) δ ppm 7.56 (1H, s), 7.25 (5H, dd, J=7.7, 1.6 Hz), 7.01 (2H, m), 6.86 (1H, dd, J=9.0, 3.2 Hz), 6.77 (1H, dd, J=5.9, 3.2 Hz), 4.65 (3H, s), 3.79 (3H, s), 1.24 (9H, s).
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.[C:13]([O-:16])(=[O:15])[CH3:14].[K+]>C(#N)C>[C:13]([O:16][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1csc(CBr)n1
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1csc(COC(C)=O)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2.7 g (10.80 mmol) of ethyl 2-(bromomethyl)thiazole-4-carboxylate are dissolved in 108 mL of acetonitrile. 2.225 g (22.67 mmol) of potassium acetate are added and the medium is stirred at room temperature for 14 hours.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[CH2:4][C@@H:3]1[OH:13].[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17].C(N(CC)CC)C>CO>[F:14][C:15]([F:22])([F:21])[C:16]([NH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[CH2:4][C@@H:3]1[OH:13])=[O:17]
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc2c(c1)[C@@H](N)[C@@H](O)C2
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)[C@@H](O)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Step AE (1): To a solution of (1R,2S)-1-amino-6-methoxy-2,3-dihydro-1H-inden-2-ol (500 mg) [E. N. Jacobsen, et. al Organic Synthesis 1999, 76, 46-56] in methanol (10 mL) was added ethyl trifluoroacetate (0.83 mL) followed by triethylamine (0.65 mL), and the reaction mixture was stirred at rt for 12 h. The solvents were removed in vacuo to give 2,2,2-trifluoro-N-((1R,2S)-2-hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-yl)acetamide as an oil. HPLC retention time: 1.77 min (method B). MS (ESI) (M+Na)+ 298.13.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[C:4]([C:3]1[C:2]([N:1]=[CH:13][N:14]([CH3:16])[CH3:15])=[N:9][C:8]([CH3:10])=[CH:7][CH:6]=1)#[N:5]
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(C#N)c(N)n1
Solvent: Cc1ccccc1
Product: Cc1ccc(C#N)c(N=CN(C)C)n1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
A solution of the product of Example 10A (10 g, 75.19 mmol) and N,N-Dimethylformamide dimethyl acetal (11 mL, 82.71 mmol) in toluene (100 mL) was heated at reflux for 6 hours. After cooling to room temperature, the solution was concentrated under vacuum to provide the title compound as a yellow solid (13.78 g, 98%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.41 (s, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 6.87 (d, J=7.7 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H), 8.59 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.ClC1N=C(N2CCOCC2)C2SC=CC=2N=1.C(OC(C1SC=C(C)C=1N)=O)C.[Li]CCCC.[I:51]I>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[C:5]2[S:10][C:9]([I:51])=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(N3CCOCC3)nc(Cl)nc12
Reactant: II
Agent: CCOC(=O)c1scc(C)c1N
Agent: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(I)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: -40 °C
Reaction time: 0.83 h
Yield: 84 %

Procedure:
To a solution of 2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine 39 (3.0 g, 11.1 mmol; prepared according to the procedure for the synthesis of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine but commencing with 3-amino-4-methyl-thiophene-2-carboxylic acid ethyl ester) in THF (60 mL) at −78° C. was added n-BuLi (8.9 mL, 2.5 M in Et2O). The resulting slurry was warmed to −40° C. and stirred 50 min. The reaction mixture was then cooled to −78° C. and a solution of I2 (5.6 g, 22.2 mmol) in THF (30 mL) was added. The solution was warmed to room temperature and stirred 5 h. The reaction was quenched by the addition of water. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with saturated aqueous Na2S2O3, dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-c]pyrimidine 41 (3.8 g, 84% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][CH:6]=1.[CH2:7]([O:9][C:10](=[O:34])[N:11]([C:23]1[CH:28]=[C:27](Br)[N:26]=[C:25]([NH2:30])[C:24]=1[N+:31]([O-:33])=[O:32])[CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)[CH3:8]>[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[CH2:7]([O:9][C:10](=[O:34])[N:11]([C:23]1[CH:28]=[C:27]([C:4]2[O:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[N:26]=[C:25]([NH2:30])[C:24]=1[N+:31]([O-:33])=[O:32])[CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=1)[CH3:8]
Reactant: CCOC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Reactant: Cc1cocn1
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1cc(-c2nc(C)co2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using 4-methyl-oxazole (36 mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (100 mg) and palladium bis(triphenylphosphine)dichloride (30 mg), giving the product (44 mg) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]([C@@H:9]2[CH2:18][C:17]3[C:12](=[C:13]([F:20])[CH:14]=[C:15]([F:19])[CH:16]=3)[O:11][CH2:10]2)[C:7](=[S:21])[NH:6][CH:5]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.ClCCl>CO>[CH2:22]([NH:1][CH2:2][CH2:3][C:4]1[N:8]([C@@H:9]2[CH2:18][C:17]3[C:12](=[C:13]([F:20])[CH:14]=[C:15]([F:19])[CH:16]=3)[O:11][CH2:10]2)[C:7](=[S:21])[NH:6][CH:5]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1c[nH]c(=S)n1[C@H]1COc2c(F)cc(F)cc2C1
Solvent: CO
Solvent: ClCCl
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CCNCc3ccccc3)c[nH]c1=S)CO2
Reaction time: 64 h

Procedure:
To (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione (2.36 g, 7.58 mmol) and benzaldehyde (0.85 ml, 8.34 mmol) in a mixture of methanol (15 ml), and dichloromethane (15 ml) sodium cyanoborohydride (0.67 g, 10.66 mmol) was added at 20-25° C. in portions. The mixture was stirred for 64 h, quenched with 1N HCl (12 ml) with stirring followed by 3N NaOH (12 ml). The mixture was extracted with DCM (100 ml), the organic phase was washed with brine (50 ml), dried (MgSO4) and evaporated to dryness. The residue was purified on a silica gel column with ethyl acetate and a mixture of ethyl acetate with methanol (9:1) as eluents. Fractions containing the product were collected, evaporated under reduced pressure to approx 20 ml then cooled on ice. The precipitate was collected, washed with ethyl acetate—petroleum ether (1:1) mixture, dried on air. Yield was 1.25 g (41%), the product having a mp 188-90° C. (2-propanol-DCM).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([N:14]([CH3:15])[C:12]1[C:11]([CH3:20])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[CH:33]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)CC(C)C)c(C)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (5-(isobutyl-methyl-amino)-4-methyl-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M109) (0.33 g, 0.62 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a pale brown solid (136 mg, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:16]3=[CH:17][N:18]=[CH:19][CH:20]=[C:15]3[C:14]([CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)=[CH:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:16]3=[CH:17][N:18]=[CH:19][CH:20]=[C:15]3[C:14]([CH2:21][CH2:22][NH2:23])=[CH:13]2)(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S(=O)(=O)n2cc(CCNC(=O)OC(C)(C)C)c3ccncc32)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(S(=O)(=O)n2cc(CCN)c3ccncc32)c1
Reaction time: 2 h

Procedure:
A solution of t-Butyl [2-{1-(3-methoxybenzenesulfonyl)-1H-pyrrolo[2,3-c]pyridin-3-yl}-ethyl]carbamate in CH2Cl2 is treated with trifluoroacetic acid, stirred for 2 h and concentrated in vacuo. The resultant residue is purified by preparative reverse phase HPLC to afford the title-final product.
Reaction SMILES: [O-2:1].[Dy+3:2].[O-2].[O-2].[Dy+3].[Al:6].[Dy]>C(O)(C)C>[O-2:1].[Dy+3:2].[O-2:1].[O-2:1].[Dy+3:2].[O-2:1].[Al+3:6].[O-2:1].[O-2:1].[Al+3:6]
Reactant: [Al]
Agent: [Dy+3]
Agent: [Dy]
Agent: [O-2]
Solvent: CC(C)O
Product: [Al+3]

Procedure:
A dysprosium oxide powder (Purity of 99.99%. Manufactured by Nippon Yttrium Co., Ltd.) and gamma aluminum (AKP-G15 manufactured by Sumitomo Chemical Co., Ltd.) were weighed so that a molar ratio of dysprosium to aluminum was 3:5, and mixed in isopropanol (WAKO JUNYAKU. Special Grade Chemical) with dispersing the powders by the application of ultrasonic wave, followed by removal of isopropanol by an evaporator and a vacuum dryer to obtain a mixed powder of dysprosium oxide and aluminum oxide. This powder was filled in a platinum vessel.