Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:15]=1[NH2:16]>>[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:15]=1[NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: COc1ccc(Cl)cc1N
Product: COc1ccc(Cl)cc1Nc1ccccc1CC(=O)O

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-methoxy-5-chloroaniline to yield 2-[(2-methoxy-5-chlorophenyl)amino]phenylacetic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:16][CH2:17][C:18]([NH2:20])=[O:19])[CH2:12][CH2:13][CH2:14]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>ClCCl>[CH2:1]([O:8][C:9]([N:11]([CH2:16][CH2:17][C:18]([NH2:20])=[O:19])[CH2:12][CH2:13][CH2:14][Br:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: NC(=O)CCN(CCCO)C(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: NC(=O)CCN(CCCBr)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of acrylamide (2 g) in ethanol (30 mL) was added 3-amino-1-propanol (3.23 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. To the residue were added tetrahydrofuran (30 mL) and N-(benzyloxycarbonyloxy)-succinimide (14 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=40/1-20/1-5/1) to give 3-[N-benzyloxycarbonyl-N-(3-hydroxypropyl)-amino]propionamide (3.51 g). To a solution of the obtained 3-[N-benzyloxycarbonyl-N-(3-hydroxypropyl)amino]propionamide (0.5 g) and carbon tetrabromide (0.65 g) in dichloromethane (5 mL) was added triphenylphosphine (1.03 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/4-dichloromethane/methanol=10/1) to give the title compound (0.41 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.Cl.[NH2:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][SH:15].[OH-].[Na+]>C(OCC)C.C(O)C>[NH2:12][C@@H:13]([CH2:14][S:15][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:16]([OH:18])=[O:17]
Reactant: COc1ccc(CO)cc1
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(CSC[C@H](N)C(=O)O)cc1
Reaction time: 1 h
Yield: 63.8 %

Procedure:
4-Methoxybenzyl alcohol (280 g, 1780 mmol) dissolved in diethylether (400 mL) was added in drops to a mixture of diethylether (400 mL) and conc. hydrochloric acid (400 mL) over 2 h, and the mixture was stirred for 1 h. The organic layer was separated, and added to a solution prepared by dissolving L-cysteine (197 g, 1625 mmol) and 2N aqueous sodium hydroxide solution (980 mL) to ethanol (1890 mL). The mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction mixture was cooled to 0°, and neutralized to pH 7 using 3N aqueous hydrochloric acid solution. The resulting solid was filtered and dried to give the title compound (250 g, Yield 64%).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:10]1[O:14][N:13]=[C:12]([CH3:15])[N:11]=1)[CH3:9])(C)(C)C.Cl>O1CCOCC1>[CH3:15][C:12]1[N:11]=[C:10]([C@H:8]([NH2:7])[CH3:9])[O:14][N:13]=1
Reactant: Cc1noc([C@@H](C)NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1noc([C@@H](C)N)n1
Temperature: 20 °C
Reaction time: 16 h
Yield: 151.9 %

Procedure:
To a solution of tert-butyl[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]carbamate (6.0 g, 26.4 mmol) in dioxane (40 mL) were added 4N hydrochloric acid in dioxane (30 mL). The reaction mixture was stirred at 20° C. for 16 h. The solution was concentrated and dried by vacuum to give hydrochloride salt of (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine (5.1 g). 1H NMR (500 MHz, CD3OD): δ 4.90-4.83 (m, 1H); 2.41 (s, 3H); 1.72 (d, J=7.0 Hz, 3H). MS128.2 (M+1).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:16]([NH:20][OH:21])([CH3:19])([CH3:18])[CH3:17]>C1C=CC=CC=1>[CH2:1]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[N+:20]([C:16]([CH3:19])([CH3:18])[CH3:17])[O-:21])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(C=O)cc1
Reactant: CC(C)(C)NO
Solvent: c1ccccc1
Product: CCCCCCOc1ccc(C=[N+]([O-])C(C)(C)C)cc1
Yield: 55.8 %

Procedure:
A solution of 4-hexyloxybenzaldehyde (3.83 g, 18.6 mmol) in 120 mL of benzene was refluxed with N-tert-butylhydroxylamine (3.32 g, 37.2 mmol) for 18 hours. The reaction mixture was then concentrated by rotary evaporation and the resulting residue was purified by silica gel column chromatography using 50:50 ethyl acetate/hexane to afford the title compound (2.88 g, 55.8 % yield) as a solid, m.p. 69.0° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[S:12])SCC.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[S:12]
Reactant: CCSC(=S)Nc1ccccn1
Reactant: CC(C)(C)OC(=O)NCCCCN
Product: CC(C)(C)OC(=O)NCCCCNC(=S)Nc1ccccn1
Yield: 340.3 %

Procedure:
Ethyl 2-pyridyldithiocarbamate (500 mg) and t-butyl 4-amino-butylcarbamate (474 mg) were reacted in a similar manner to in Reference Example 58, and crystallized from n-hexane-diethyl ether to give the title compound (2.78 g).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:11][OH:12].N1C=CC=CC=1>CCO>[C:1]1([CH2:7][CH:8]=[N:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=CCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=CCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31 %

Procedure:
Phenylacetaldehyde (12.0 g, 7.8 ml, 0.1 mol) was dissolved in EtOH (360 ml) and mixed while stirring successively with hydroxylamine hydrochloride (10.4 g, 0.15 mol) and abs. pyridine (9.7 ml, 0.12 mol). After stirring for 1.5 h at RT, the reaction mixture was concentrated, the residue taken up in toluene (1×100 ml) and the solvent removed again under vacuum. The oily residue was stirred with EtOAc (350 ml) and water (90 ml) for 15 min. Subsequently, the phases were separated. The organic phase was washed with water (2×80 ml), dried and concentrated. The oil obtained crystallised after a short time. The oil was recrystallised from n-hexane (20 ml). Compound V was obtained as a white solid in a yield of 31% (4.13 g) having a melting point of 90-94° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]=[CH:10][N:9]([C:12]3[CH:13]=[C:14]([NH:26][C:27](=[O:29])[CH3:28])[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[F:25])[CH:17]=3)[C:6]2=[N:7][CH:8]=1)#[CH:2].[N-:30]=[N+:31]=[N-:32].[Na+].Br[CH2:35][CH:36]1[CH2:38][CH2:37]1>CN(C=O)C.[Cu](I)I>[CH:36]1([CH2:35][N:30]2[CH:2]=[C:1]([C:3]3[CH:4]=[C:5]4[N:11]=[CH:10][N:9]([C:12]5[CH:13]=[C:14]([NH:26][C:27](=[O:29])[CH3:28])[CH:15]=[C:16]([C:18]6[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=6[F:25])[CH:17]=5)[C:6]4=[N:7][CH:8]=3)[N:32]=[N:31]2)[CH2:38][CH2:37]1
Reactant: C#Cc1cnc2c(c1)ncn2-c1cc(NC(C)=O)cc(-c2ccc(F)cc2F)c1
Reactant: BrCC1CC1
Reactant: [N-]=[N+]=[N-]
Agent: I[Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(CC5CC5)nn4)cnc32)c1
Yield: 82.6 %

Procedure:
A mixture N-(5-(6-ethynyl-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide (300 mg, 0.77 mmol), sodium azide (76 mg, 1.15 mmol, 1.5 eq.), (bromomethyl)cyclopropane (125 mg, 0.92 mmol, 1.2 eq.), copper iodide (14 mg, 0.07 mmol, 0.1 eq.) in DMF was stirred for 16 h at RT. The mixture was quenched with water and the precipitate formed was filtered and dried to give the crude product which was purified by preparative HPLC to give the product in 82.6% yield (310 mg). 1H NMR (300 MHz, DMSO): δ 10.4 (s, 1H) 8.99 (d, 2H), 8.80 (s, 1H), 8.63 (d, 1H), 8.30 (s, 1H), 7.91 (d, 1H), 7.76-7.68 (m, 2H), 7.49-7.41 (m, 1H), 7.30-7.25 (m, 1H), 4.21 (m, 2H), 2.12 (s, 3H), 1.23 (m, 1H), 0.63-0.60 (2H, d) 0.50-0.48 (2H, d); LC-MS (ESI): Calculated mass: 485.4; Observed mass: 486.1 [M+H]+ (rt: 1.52 min).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]2[O:26][CH3:27])(=O)=O)=CC=1.[NH3:28]>C1COCC1>[NH2:28][CH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]1[O:26][CH3:27]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1COS(=O)(=O)c1ccc(C)cc1
Reactant: N
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CN

Procedure:
A mixture of intermediate (49) (0.065 mol) in THF (250 ml) was treated with liquid NH3 in an autoclave at 125° C. during 16 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was partitioned between a 5% aqueous NaOH solution and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 16 g of 1,1-dimethylethyl (trans)-4-(aminomethyl)-3-methoxy-1-piperidinecarboxylate (intermediate (50).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=1[OH:20].Br[CH2:22][CH2:23][CH2:24][CH2:25]Br>>[CH:4]1[C:3]2[C:11]3[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=3[O:20][CH2:25][CH2:24][CH2:23][CH2:22][O:1][C:2]=2[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=1
Reactant: BrCCCCBr
Reactant: CC(=O)c1ccc(-c2ccc(C(C)=O)cc2O)c(O)c1
Product: CC(=O)c1ccc2c(c1)OCCCCOc1cc(C(C)=O)ccc1-2

Procedure:
was synthesized from 1,1′-(2,2′-dihydroxy-[1,1′-biphenyl]-4,4′-diyl)-diethanone and 1,4-dibromobutane by following an analogous procedure described in Step 1, Example 1. m/z 325.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:17][C:16]=1[NH2:26])([O-:14])=[O:13].C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:26][C:16]2[CH:17]=[C:18]([C:21]3[NH:22][CH:23]=[CH:24][CH:25]=3)[CH:19]=[CH:20][C:15]=2[N+:12]([O-:14])=[O:13])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1cc(-c2ccc[nH]2)ccc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2cc(-c3ccc[nH]3)ccc2[N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 101.1 %

Procedure:
A solution of 4-methoxybenzoyl chloride (145, 0.175 g, 1.0 mmol), aniline 144 (79.2 mg, 0.39 mmol) and 4-(dimethylamino)pyridine (catalytic amount) was stirred at room temperature for 24 h. The reaction mixture was diluted with DCM, treated with saturated NaHCO3, stirred for 3 h and diluted with AcOEt. Organic phase was collected, washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated to provide compound 146 (0.133 g, 100% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15].[H-].[Na+].[CH3:18]I>COCCOC>[CH3:1][C:2]1([CH3:18])[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15]
Reactant: CI
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C)C2
Temperature: 30 °C

Procedure:
A stirred suspension of 2-methyl-5-methoxy-6,7-dichloro-1-indanone (12.2 g., 0.05 mole) and sodium hydride (1.43 g., 0.06 mole) in anhydrous 1,2-dimethoxyethane (500 ml.) is heated in an inert atmosphere at 80°-85° C. for 1 hour, cooled to 30° C. and treated with methyl iodide (8 ml.) The reaction mixture is refluxed for 15 minutes, then the solvent is distilled at reduced pressure. The crude product is poured into water (500 ml.), extracted into ether, washed with water and dried over magnesium sulfate. After evaporation of the ether the product is crystallized from methylcyclohexane affording 8.2 g. of 2,2-dimethyl-5-methoxy-6,7-dichloro-1-indanone which melts at 142° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([N:16]2[CH2:20][C@H:19]([CH2:21][N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[N:23]3)[O:18][C:17]2=[O:28])[CH:6]=[C:7]([F:15])[C:8]=1[C:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=1.N1C=CC=CC=1.[CH3:35][C:36]1([CH3:44])[O:40][C@H:39]([C:41](Cl)=[O:42])[CH2:38][O:37]1.O>ClCCl>[CH3:35][C:36]1([CH3:44])[O:40][C@H:39]([C:41]([N:12]2[CH2:11][CH:10]=[C:9]([C:8]3[C:7]([F:15])=[CH:6][C:5]([N:16]4[CH2:20][C@H:19]([CH2:21][N:22]5[CH:26]=[C:25]([CH3:27])[N:24]=[N:23]5)[O:18][C:17]4=[O:28])=[CH:4][C:3]=3[F:2])[CH2:14][CH2:13]2)=[O:42])[CH2:38][O:37]1
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Reactant: Cc1cn(C[C@H]2CN(c3cc(F)c(C4=CCNCC4)c(F)c3)C(=O)O2)nn1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Cc1cn(C[C@H]2CN(c3cc(F)c(C4=CCN(C(=O)[C@@H]5COC(C)(C)O5)CC4)c(F)c3)C(=O)O2)nn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
(5R)-3-[3,5-Difluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-5-[(4-methyl-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one hydrochloride (Intermediate 53) (1.13 g, 2.75 mmol) was suspended in dichloromethane (20 ml). Pyridine (2.22 ml, 27.50 mmol) was added and the solution was cooled to 0° C. A solution of (4S)-2,2-dimethyl-1,3-dioxolane-4-carbonyl chloride (WO 01/81350, 0.89 g, 5.43 mmol) in dichloromethane (10 ml) was added. After 2 hours, the solution was poured into water, the organic phase was washed with brine, dried over magnesium sulfate and concentrated under vacuum. Chromatography on silica gel with ethyl acetate gave 542 mg of the title product.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:11])[C:5]([C:9]#[N:10])=[C:6](Cl)[N:7]=1.[SH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[NH:3][C:4](=[O:11])[C:5]([C:9]#[N:10])=[C:6]([S:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:7]=1
Reactant: SCCc1ccccn1
Reactant: N#Cc1c(Cl)nc(N)[nH]c1=O
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(SCCc2ccccn2)nc(N)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a stirred suspension of 500 mg (2.93 mmol) 2-amino-4-chloro-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile in 10 ml DME were added 0.61 g (4.40 mmol) 2-mercapto-ethylpyridine and 1.10 ml (7.33 mmol) DBU and the mixture stirred at room temperature for 1 hour. The reaction mixture was then partitioned between water and ethyl acetate and the organic phase was dried over sodium sulfate and concentrated in vacuo. Chromatography (dichloromethane then methanol/dichloromethane 5/95) followed by trituration in ether/methanol afforded 310 mg (39%) 2-amino-6-oxo-4-(2-pyridin-2-yl-ethylsulfanyl)-1,6-dihydro-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 274 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[S:5][C:6]=1[CH3:7].C([N:14]([CH:17]([CH3:19])[CH3:18])CC)(C)C.C1(N)CC1>S(Cl)(Cl)=O.O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:14][CH:17]2[CH2:19][CH2:18]2)=[O:10])[S:5][C:6]=1[CH3:7]
Reactant: Cc1sc(C(=O)O)cc1Br
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: Cc1sc(C(=O)NC2CC2)cc1Br
Temperature: 70 °C
Reaction time: 2 h

Procedure:
4-Bromo-5-methylthiophene-2-carboxylic acid (1.05 g, 4.75 mmol) was suspended in thionyl chloride (4.75 mL) and heated to 70° C. for 1.5 h. The mixture was concentrated and dried azeotropically with toluene. The reaction mixture was dissolved in dioxane (11.9 mL) to which diisopropylethylamine (4.14 mL, 23.7 mmol) and cyclopropylamine (1.36 mL, 23.7 mmol) were added and stirred at RT for 2 h. The reaction mixture was diluted with 50 mL ethyl acetate, partitioned with sodium bicarbonate (saturated, aqueous), and the organic layers were washed 2×50 mL with sodium bicarbonate (saturated, aqueous), washed with 3 N HCl, separated, dried over sodium sulfate, and concentrated in vacuo to give the title compound. MS (ES+): 262 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]2[CH:13]=[CH:14][CH:15]=[N:16][C:5]=2[N:4]([CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:3]1=[O:27].C(N(CC)CC)C.ON1C2=NC=CC=C2N=N1.[C:45]([O:49][C:50]([NH:52][C@@H:53]([CH3:57])[C:54](O)=[O:55])=[O:51])([CH3:48])([CH3:47])[CH3:46].Cl.CN(C)CCCN=C=NCC>ClCCl>[Si:20]([O:19][CH2:18][CH2:17][N:4]1[C:5]2[N:16]=[CH:15][CH:14]=[CH:13][C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:2]([NH:1][C:54](=[O:55])[C@@H:53]([NH:52][C:50](=[O:51])[O:49][C:45]([CH3:47])([CH3:46])[CH3:48])[CH3:57])[C:3]1=[O:27])([C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:21])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCN1C(=O)C(N)c2ccccc2-c2cccnc21
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1C(=O)N(CCO[Si](C)(C)C(C)(C)C)c2ncccc2-c2ccccc21
Temperature: 25 °C
Yield: 86.5 %

Procedure:
Cool a mixture of 7-amino-5-[2-(tert-butyl(dimethyl)silyl)oxyethyl]-7H-pyrido[2,3-d][3]benzazepin-6-one (36.3 g, 89.9 mmol), dichloromethane (360 mL), triethylamine (16.3 mL, 116.9 mmol), 3-hydroxytriazolo[4,5-b]pyridine (15.9 g, 116.9 mmol), and (2S)-2-(tert-butoxycarbonylamino)propanoic acid (22.5 g, 116.9 mmol) to 0° C. Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.4 g, 116.9 mmol) and after 5 minutes allow to warm to ambient temperature overnight. Wash with water (500 mL×2), saturated aqueous sodium bicarbonate solution (2×300 mL), brine (300 mL), and then dry over sodium sulfate and concentrate. Purify the residue by flash chromatography, eluting with isopropyl alcohol:hexane (5:95 to 10:90) to give the title compound as a white foam (43.14 g, 77.77 mmol, 86.50%). MS (m/z): 555 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:19]([CH3:22])=[N:20][N:21]=3)[C:13]=2[CH:12]=[C:11]1[C:23]1[NH:27][N:26]=[CH:25][CH:24]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:29][CH3:30]>CN(C=O)C>[CH2:3]([N:10]1[C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:19]([CH3:22])=[N:20][N:21]=3)[C:13]=2[CH:12]=[C:11]1[C:23]1[CH:24]=[CH:25][N:26]([CH2:29][CH3:30])[N:27]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3ccccc3)n12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc(-c2cc3c(ccc4nnc(C)n43)n2Cc2ccccc2)n1
Reaction time: 0.17 h

Procedure:
Sodium hydride (3.3 mg, 0.082 mmol, 60% in mineral oil) was added to a solution of 6-benzyl-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (5.4 mg, 0.016 mmol, from Example 62) in DMF (0.20 mL). After 10 minutes, iodoethane (3.9 μL, 0.049 mmol, Aldrich) was introduced. After 15 minutes reaction time, the reaction was quenched with water. The product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (3.1 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:12]([CH2:22][OH:23])[CH2:11]2)=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[C@H:12]([CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:11]2)=[O:8])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
278.0 mg (0.8 mmol) tert. Butyl (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-hydroxymethyl-pyrrolidine-1-carboxylate are dissolved in 6 ml DCM and combined with 216 μl (1.5 mmol) triethylamine. 89 μl (1.2 mmol) methanesulphonic acid chloride are added while cooling with the ice bath. The reaction mixture is heated to RT and stirred for two hours. Then it is mixed with water and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[S:12][C:11]([N:13](CC2C=CC(OC)=CC=2OC)[S:14]([C:17]2[CH:22]=[C:21]([F:23])[C:20](F)=[CH:19][C:18]=2[F:25])(=[O:16])=[O:15])=[N:10][CH:9]=1.[OH:37][C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][C:39]=1[I:46]>CS(C)=O.C(OCC)(=O)C>[Cl:7][C:8]1[S:12][C:11]([NH:13][S:14]([C:17]2[CH:22]=[C:21]([F:23])[C:20]([O:37][C:38]3[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][C:39]=3[I:46])=[CH:19][C:18]=2[F:25])(=[O:15])=[O:16])=[N:10][CH:9]=1
Reactant: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: N#Cc1ccc(O)c(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2cc(F)c(S(=O)(=O)Nc3ncc(Cl)s3)cc2F)c(I)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a suspension of potassium carbonate (0.068 g, 0.000492 mol) and N-(5-chloro-1,3-thiazol-2-yl)-N-(2,4-dimethoxybenzyl)-2,4,5-trifluorobenzenesulfonamide (Preparation 334, 0.200 g, 0.000418 mol) in dimethyl sulfoxide (3.0 mL) was added 4-hydroxy-3-iodobenzonitrile (Preparation 342, 0.108 g, 0.000441 mol) and was stirred at 65° C. under nitrogen for 16 hours. The reaction was diluted with ethyl acetate (10.0 mL). The organic phase was washed with saturated aqueous sodium chloride solution (2×10.0 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was dissolved in dichloromethane (1.5 mL), treated with trifluoroacetic acid (1.5 mL) and stirred at room temperature under nitrogen for 16 hours. Reaction was concentrated in vacuo and residue dissolved in ethyl acetate (10.0 mL). The organic extract was washed with saturated aqueous sodium bicarbonate solution (2×10.0 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The resulting residue was purified using ISCO™ (12 g SiO2) eluting with methanol:dichloromethane (gradient 0:1 to 1:39, by volume) to afford the title compound as an orange solid, 165 mg, 35% yield.
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([N+:14]([O-:16])=[O:15])=[C:7]([F:13])[CH:8]=2)[N:3]=1.[CH3:17][C:18]([CH3:21])([O-:20])[CH3:19].[K+].C1(C)C=CC=CC=1.P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C>[C:18]([O:20][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9](=[CH:8][C:7]([F:13])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=2)[N:10]=1)([CH3:21])([CH3:19])[CH3:17]
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1cc2nc(Cl)c(Cl)nc2cc1F
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CC(C)(C)Oc1nc2cc(F)c([N+](=O)[O-])cc2nc1Cl
Yield: 69.9 %

Procedure:
To a solution of 2,3-dichloro-6-fluoro-7-nitroquinoxaline 5.24 g in tetrahydrofran (50 mL), was added dropwise a solution of potassium tert-butoxide 2.51 g in tert-butanol 60 mL at −10 to −8° C. for about 1 hr. After the addition, the mixture was stirred at 0° C. for 1 hr, to which toluene 100 mL and a solution of 0.1M sodium dihydrogen phosphate 20 mL were added, then which was poured into a separatory funnel. The organic layer was washed with water and saturated saline, dried over MgSO4, and evaporated under reduced pressure. The residue was purified with silica gel column (120 g, toluene:hexane=1:1), to give the title compound (pale yellow crystal) 4.19 g.