Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])(Cl)=[S:2].[CH2:5]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH3:8]>C(OCC)C>[CH2:5]([N:9]([CH2:10][CH2:11][CH2:12][CH3:13])[C:1]([Cl:4])=[S:2])[CH2:6][CH2:7][CH3:8]
Reactant: CCCCNCCCC
Reactant: S=C(Cl)Cl
Solvent: CCOCC
Product: CCCCN(CCCC)C(=S)Cl
Reaction time: 1 h

Procedure:
To a solution of 29.9g (0.26 mole) thiophosgene in 600 ml ethyl ether at 0° was added a solution of 25.8g (0.20 mole) dibutylamine 20.2g (0.20 mole) triethylamine and 250 ml ethyl ether over a period of 35 minutes during which time solids formed. After stirring an additional one hour, the mixture was filtered and the resulting filtrate was removed of volatiles under reduced pressures to yield 35g of crude dibutylthiocarbamoyl chloride.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[C:18]1([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][C:28](B4OC(C)(C)C(C)(C)O4)=[CH:29][CH:30]=3)[N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[C:12]1([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH2:11])[C:10]=3[C:2]([C:28]3[CH:27]=[C:26]4[C:31]([CH:32]=[CH:33][C:24]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:25]4)=[CH:30][CH:29]=3)=[CH:3]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)cn2-c1ccccc1
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: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2-c1ccccc1

Procedure:
Following the general procedure for the Suzuki coupling, 5-iodo-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (27 mg, 0.080 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (26.5 mg, 0.080 mmol), Na2CO3 (22 mg, 0.21 mmol) and Pd(PPh3)4 (6 mg, 0.005 mmol) in DMF (2.5 mL)/water (0.5 mL). The crude material was purified by chromatography on an SCX column (1 g/6 mL barrel) followed by column chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-12)→1% MeOH in CH2Cl2(13-33)→2% MeOH in CH2Cl2 (34-40)], yielding the title compound as an off-white solid. 1H NMR (CDCl3, 400 MHz): δ=5.31 (brs, 2H), 7.38-7.42 (m, 1H), 7.43 (s, 1H), 7.47-7.52 (m, 1H), 7.53-7.59 (m, 4H), 7.75 (dd, J=2.0, 8.4 Hz, 1H), 7.75-7.79 (m, 2H), 7.94 (d, J=8.4 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 8.18-8.22 (m, 2H), 8.26 (d, J=8.4 Hz, 1H), 8.35-8.37 (m, 1H), 8.44 (s, 1H). MS (ES+): m/z 414.0 (25) [MH+]. HPLC: tR=3.4 min (OpenLynx, polar—5 min).
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:8]([C:11]1[C:16]2[NH:17][C:18]3[CH:19]=[C:20]([C:24](O)=[O:25])[CH:21]=[CH:22][C:23]=3[C:15]=2[N:14]=[C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:12]=1)(=[O:10])[NH2:9].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO.C(#N)C>[O:1]1[CH2:7][CH2:6][CH2:5][N:4]([C:24]([C:20]2[CH:21]=[CH:22][C:23]3[C:15]4[N:14]=[C:13]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:12]=[C:11]([C:8]([NH2:9])=[O:10])[C:16]=4[NH:17][C:18]=3[CH:19]=2)=[O:25])[CH2:3][CH2:2]1
Reactant: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(C(=O)O)ccc12
Reactant: C1CNCCOC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CO
Product: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(C(=O)N3CCCOCC3)ccc12
Reaction time: 1 h
Yield: 73.3 %

Procedure:
A mixture of 1,4-oxazepane (15 mg, 0.15 mmol), 4-carbamoyl-2-phenyl-5H-pyrido[3,2-b]indole-7-carboxylic acid (50 mg, 0.15 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.071 mL, 0.41 mmol) in dry DMF (1.3 mL) was stirring for a few minutes and then benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (80 mg, 0.18 mmol) was added. After 1 hr, the reaction was diluted with MeOH and preparative HPLC (PHENOMENEX® Luna 30×100 mm C18, Solvent A=10% acetonitrile -90% H2O—0.1% TFA; Solvent B=90% acetonitrile—10% H2O —0.1% TFA, 10-70% B gradient over 18 min) afforded 7-(1,4-oxazepane-4-carbonyl)-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxamide (45 mg, 0.11 mmol, 70% yield) as a yellow solid. MS (ESI) m/z 415.09 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.75 (1H, br. s.), 8.65 (1H, br. s.), 8.50 (1H, s), 8.31 (3H, d, J=7.63 Hz), 7.92 (1H, br. s.), 7.78 (1H, br. s.), 7.56 (2H, t, J=7.63 Hz), 7.45 (1H, t, J=7.32 Hz), 7.28 (1H, d, J=7.63 Hz), 3.77 (5H, br. s.), 3.65 (1H, br. s.), 3.50 (2H, br. s.), 1.94 (1H, br. s.), 1.79 (1H, br. s.).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH2:34][O:35][CH3:36])[NH:28][C:27](=[O:38])[CH2:26]2>>[CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](/[CH:17]=[C:26]3\[C:27](=[O:38])[NH:28][C:29]4[C:25]\3=[CH:24][C:23]([F:22])=[C:31]([NH:32][C:33](=[O:37])[CH2:34][O:35][CH3:36])[CH:30]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4cc(NC(=O)COC)c(F)cc43)c(C)c2C1=O
Yield: 53.6 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide 7a as starting materials to obtain (Z)—N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide 7 (37 mg, yield 53.6%) as a brown solid.
Reaction SMILES: [F-].[Cs+].[CH3:3][C:4]1[S:8][C:7](B(O)O)=[CH:6][CH:5]=1.[Cl:12][C:13]1[CH:29]=[CH:28][C:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:20][CH2:21][C:15]=2[C:14]=1OS(C(F)(F)F)(=O)=O>COCCOC.CCOC(C)=O>[Cl:12][C:13]1[CH:29]=[CH:28][C:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:27])[C:23]([F:25])([F:26])[F:24])[CH2:20][CH2:21][C:15]=2[C:14]=1[C:7]1[S:8][C:4]([CH3:3])=[CH:5][CH:6]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: Cc1ccc(B(O)O)s1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)s1
Temperature: 90 °C
Yield: 70.4 %

Procedure:
Add tetrakistriphenylphosphine palladium(0) (27 mg, 0.024 mmol), cesium fluoride (143 mg, 0.942 mmol) and 5-methyl-thiophen-2-yl-boronic acid (134 mg, 0.942 mmol) to a stirred solution of 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.471 mmol) in anhydrous DME (8 mL) at room temperature. Heat at 90° C. overnight. Cool the reaction mixture to room temperature, dilute with EtOAc and wash with water. Extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 19:1) to obtain 7-chloro-6-(5-methyl-thiophen-2-yl)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (124 mg, 70%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH2:7](O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CCCCCCCCCCO
Reactant: CC(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCOC(=O)C(C)O
Temperature: 145 °C
Yield: 13.9 %

Procedure:
A 500 ml one neck round bottom flask equipped with a Dean Stark trap, condenser and nitrogen inlet-outlet was charged with 22.52 g (0.75 moles) lactic acid, 47.46 g (0.98 moles) decyl alcohol, 3 ml sulfuric acid and 220 mL toluene. The mixture was heated to 145° C. for 20 hours and water was collected as the reaction proceeded. The acid was neutralized by washing three times with 50 ml saturated sodium bicarbonate solution. Approximately 50 ml ether was needed to break the emulsion. The organic layer was collected and dried over magnesium sulfate. Decyl lactate was distilled under high vacuum to yield 24.03 g (12.4% yield) of clear colorless liquid. According to GC the product is 97.78% pure.
Reaction SMILES: [N:1]([CH2:4][S:5][CH3:6])=[C:2]=[O:3].[N+:7](=[C:9]1[C:13](/[CH:14]=[CH:15]/[C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[N:12][CH:11]=[N:10]1)=[N-:8]>CS(C)=O>[CH3:6][S:5][CH2:4][N:1]1[C:2](=[O:3])[N:10]2[CH:11]=[N:12][C:13](/[CH:14]=[CH:15]/[C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[C:9]2[N:7]=[N:8]1
Reactant: CSCN=C=O
Reactant: N#Cc1ccc(/C=C/C2=NC=NC2=[N+]=[N-])cc1
Solvent: CS(C)=O
Product: CSCn1nnc2c(/C=C/c3ccc(C#N)cc3)ncn2c1=O
Reaction time: 8 h
Yield: 8.1 %

Procedure:
A solution of (isocyanatomethyl)(methyl)sulfane (337 mg, 3.27 mmol) in dry DMSO (1 mL) was added dropwise in the dark under nitrogen to a stirred suspension of (E)-4-(2-(4-diazo-4H-imidazol-5-yl)vinyl)benzonitrile (600 mg, 2.71 mmol) in DMSO (6 mL) and the mixture was stirred overnight. The resulting solution was poured into ice and the precipitate was filtered and washed successively with water and diethyl ether. The crude product was dried under vacuum and was absorbed on silica and purified by flash chromatography using DCM:MeCN (95:5) as eluent to give the pure title compound as a bright yellow solid (71 mg, 8%). δH (DMSO d6): 8.87 (1H, s), 7.94-7.97 (2H, d, J=8.6), 7.85-7.87 (2H, d, J=8.6), 7.73 (2H, s), 5.40 (2H, s), 2.27 (3H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH2:9])[CH2:5][CH2:6][O:7][CH3:8].Cl[C:11]1[CH:16]=[C:15]([CH3:17])[NH:14][C:13](=[O:18])[C:12]=1[N+:19]([O-:21])=[O:20].C(N(C(C)C)CC)(C)C>CC#N.C(Cl)Cl>[CH3:17][C:15]1[NH:14][C:13](=[O:18])[C:12]([N+:19]([O-:21])=[O:20])=[C:11]([NH:9][C@H:4]([CH2:3][O:2][CH3:1])[CH2:5][CH2:6][O:7][CH3:8])[CH:16]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Reactant: COCCC(N)COC
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCC[C@@H](COC)Nc1cc(C)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-methoxymethyl-3-methoxypropylamine (4.19 g, 22.3 mmol), and 4-chloro-6-methyl-3-nitropyridone (3.87 g, 22.3 mmol) were mixed in CH3CN (70 mL) and diisopropyl-ethylamine (9.4 mL, 53.6 mmol) was added. The reaction was stirred at 25° C. for 16 h and at reflux for 2.5 h. The solvent was stripped off and the residue was dissolved in CH2Cl2 (150 mL) and the CH2Cl2 was washed with water (80 mL). The water was extracted with CH2Cl2 (50 mL) and the combined organic extracts were dried (MgSO4) and stripped in vacuo. The residue was crystallized from EtOAc and washed with 40% EtOAc/hexanes to give the product, (4.8 g, 75%). NMR(DMSO)d 9.13 (d, 1H, J=8.8 Hz), 5.9 (s, 1H), 3.92-4.02 (m, 1H), 3.20-3.25 (m, 2H), 3.28-3.4 (m, 2H), 3.25 (s, 3H), 3.18 (s, 3H), 2.09 (s, 3H), 1.65-1.90 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:24][C:25]([N:27]3[CH2:32][CH2:31]O[CH2:29][CH2:28]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=3)[C:3]=12.[F:33]C1C=C(C=CC=1)C(CC#N)=O.N1CCCC1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:24][C:25]([N:27]3[CH2:32][CH2:31][CH2:29][CH2:28]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:33])[CH:18]=3)[C:3]=12
Reactant: N#CCC(=O)c1cccc(F)c1
Reactant: O=C(Cn1nc(-c2ccc(F)cc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCOCC1
Solvent: C1CCNC1
Product: O=C(Cn1nc(-c2cccc(F)c2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCCC1

Procedure:
Example 72 (Compound 79) was synthesised following a similar procedure outlined in Example 68 (Compound 75), using 3-fluorobenzoylacetonitrile instead of 4-fluorobenzoylacetonitrile in step 1 and pyrrolidine instead of morpholine in step 7. Compound 79 was obtained as a yellow solid (13.1 mg).
Reaction SMILES: [N+:1]([CH2:4][C@@]1(CC(OC(C)(C)C)=O)C[C@H]2[C@@H]1C=CC2)([O-:3])=[O:2].[CH3:20][C:21]1[CH2:22][C@H:23]2[C@@H:26]([C:27]=1[CH3:28])[C:25](=[CH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]2>>[CH3:20][C:21]1[CH2:22][C@@H:23]2[C@H:26]([C:27]=1[CH3:28])[C@@:25]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([CH2:4][N+:1]([O-:3])=[O:2])[CH2:24]2
Reactant: CC(C)(C)OC(=O)C[C@]1(C[N+](=O)[O-])C[C@@H]2CC=C[C@@H]21
Reactant: CC1=C(C)[C@H]2C(=CC(=O)OC(C)(C)C)C[C@H]2C1
Product: CC1=C(C)[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]

Procedure:
The compound of interest (4.5 g, 85%) was obtained as an oil substance in the same way as in paragraph (1-c) using tert-butyl(±)-(1S,5R)-[3,4-dimethylbicyclo[3.2.0]hept-3-en-6-ylidene]acetate (4.2 g, 18 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[OH:15][C@H:16]([CH3:30])[CH2:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([S:18]([CH2:17][C@H:16]([OH:15])[CH3:30])(=[O:20])=[O:19])=[CH:29][CH:28]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: C[C@@H](O)CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: C[C@@H](O)CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
100 mg of (R)-propylene oxide′ was reacted with methyl 4-mercaptobenzoate via Procedure S to afford (R)-methyl 4-(2-hydroxypropylthio)benzoate. 169 mg of (R)-methyl 4-(2-hydroxypropylthio)benzoate was reacted via Procedure R to give (R)-methyl 4-(2-hydroxypropylsulfonyl)benzoate. 179 mg of (R)-methyl 4-(2-hydroxypropylsulfonyl)benzoate was hydrolyzed via Procedure M to give (R)-4-(2-hydroxypropylsulfonyl)benzoic acid. 45 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (R)-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 431.2 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[S:26])[NH:5][NH:6][C:7](=O)[CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[CH3:9])[CH3:2]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]1[S:26][C:7]([CH:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH3:9])=[N:6][N:5]=1)[CH3:2]
Reactant: CCOC(=S)NNC(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: O=S(=O)(O)O
Product: CCOc1nnc(C(C)Oc2ccc(Oc3ccc(Cl)cc3)cc2)s1
Temperature: 0 °C
Yield: 52.4 %

Procedure:
To 10 ml of concentrated sulfuric acid cooled to -5° C. was added, with stirring, 2.0 g of 3-[2-[4-(4-chlorophenoxy)phenoxy]-propionyl]-thiocarbazic acid-O-ethyl ester gradually. After stirring at the same temperature for 10 minutes, the reaction mixture was poured over 100 g of ice followed by extracting with ethyl acetate. The resulting ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel to obtain 1.0 g of the compound No. 7 described in Table 1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)#[CH:11].C(N)CCC>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.CCOCC.[Cu]I>[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:10]#[C:11][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1)[CH:21]=[CH:20]2
Reactant: Cc1cc(I)ccc1N
Reactant: C#Cc1ccc2cc(OC)ccc2c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCCCN
Product: COc1ccc2cc(C#Cc3ccc(N)c(C)c3)ccc2c1

Procedure:
4-iodo-2-methylbenzenamine 24 (233 mg, 1 mmol) on reaction with 2-ethynyl-6-methoxynaphthalene (25c, 182 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 4-((6-methoxynaphthalen-2-yl) ethynyl)-2-methyl benzenamine (26c) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl-4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 4-((6-methoxynaphthalen-2-yl)ethynyl)-2-methylbenzenamine (26c) with 2-methyl-4H-benzo[d][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h After completion of the reaction as indicated by TLC. then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 3-(4-((6-methoxynaphthalen-2-yl)ethynyl)-2-methylphenyl)-2-methylquinazolin-4(3H)-one (29c). Reaction of 3-(4-((6-methoxynaphthalen-2-yl)ethynyl)-2-methylphenyl)-2-methylquinazolin-4(3H)-one (29c, 430 mg, 1 mmol) with 3,4,5-trimethoxybenzaldehyde (30l, 196 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (61) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH:44]([CH3:46])[CH3:45])[C:15]([C:17]2[C:18]([C:40]([F:43])([F:42])[F:41])=[CH:19][C:20]3[O:25][C:24]([CH3:31])(C(OCC)=O)[C:23](=[O:32])[N:22]([CH2:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[C:21]=3[CH:39]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Mg]Br.[Cl-].[NH4+]>O1CCCC1>[OH:5][C:1]([C:24]1([CH3:31])[C:23](=[O:32])[N:22]([CH2:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[C:21]2[CH:39]=[C:17]([C:15]([N:14]([CH:44]([CH3:45])[CH3:46])[C@@H:10]3[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]3)=[O:16])[C:18]([C:40]([F:43])([F:41])[F:42])=[CH:19][C:20]=2[O:25]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc2N(CCCCOC)C1=O
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCCCN1C(=O)C(C)(C(C)(C)O)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 151.2 %

Procedure:
A solution of ethyl 6-{[[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl](isopropyl)amino]-carbonyl}-4-(4-methoxybutyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (150 mg) in tetrahydrofuran (2 ml) was cooled with ice, and thereto was added dropwise methylmagnesium bromide (1M tetrahydrofuran solution, 1.2 ml), and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (111 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6](S(C)(=O)=O)=[C:5]([N+:11]([O-:13])=[O:12])[N:4]=[C:3]1[CH2:14][OH:15].[C-:16]#[N:17].[K+].CS(C)=O>O>[CH3:1][N:2]1[C:6]([C:16]#[N:17])=[C:5]([N+:11]([O-:13])=[O:12])[N:4]=[C:3]1[CH2:14][OH:15]
Reactant: [C-]#N
Reactant: Cn1c(CO)nc([N+](=O)[O-])c1S(C)(=O)=O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(CO)nc([N+](=O)[O-])c1C#N

Procedure:
2.21 G. (0.01 moles) of 1-methyl-2-hydroxymethyl-4-nitro-5-methylsulfonylimidazole and 0.715 g. of potassium cyanide in 20 ml. of dry dimethylsulfoxide are heated at 100°C. for 30 minutes. The reaction mixture is diluted with an equal volume of water and extracted with ethyl acetate. The combined extracts are dried and evaporated to dryness affording an oily residue which is recrystallized from isopropanol affording 1-methyl-2-hydroxymethyl-4-nitro-5-cyanoimidazole, m.p. 122° to 124°C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20](=O)[CH3:21]>>[CH3:12][O:11][C:4]1[N:3]=[C:2]2[N:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)[C:20]([CH3:21])=[N:8][C:7]2=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1ccccn1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Product: COc1ccc2nc(C)n(-c3ccccn3)c2n1
Yield: 26.6 %

Procedure:
Method B applied to 2-chloro-6-methoxy-3-nitropyridine (94 mg, 0.5 mmol) and N-pyridin-2-ylacetamide (82 mg, 0.6 mmol) afforded the title compound as viscous oil (32 mg, 27%). 1H NMR (DMSO) δ 2.66 (s, 3H), 3.82 (s, 3H), 6.81 (d, J=8.5Hz, 1H), 7.58 (dd, J=7.6, 4.7Hz, 1H), 7.95 (d, J=7.9Hz, 1H), 8.04 (d, J=8.5Hz, 1H), 8.14 (dd, J=7.9, 7.6Hz, 1H), 8.69 (d, J=4.7Hz, 1H).
Reaction SMILES: CC1(OC(N[C@@H]2C(=O)OC(=O)C2)=O)CCC1.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N.CN(C)C=O.[CH3:36][O:37][C:38](=[O:64])[C@H:39]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[NH:40][C:41](=[O:56])[C@H:42]([CH2:52][C:53](=[O:55])[OH:54])[NH:43]C(OC1(C)CCC1)=O>C(N(CC)CC)C>[CH3:36][O:37][C:38](=[O:64])[C@H:39]([CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[NH:40][C:41](=[O:56])[C@H:42]([CH2:52][C:53](=[O:54])[OH:55])[NH2:43]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OC1(C)CCC1
Agent: CC1(OC(=O)N[C@H]2CC(=O)OC2=O)CCC1
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Temperature: 20 °C

Procedure:
Coupling of N-(1-methylcyclobutyloxycarbonyl) aspartic anhydride with phenylalanine methyl ester hydrochloride is carried out in an organic solvent, for example dimethylformamide in the presence of an amine such as triethylamine. The reaction is stirred for several hours at a temperature of about 20°C. Upon completion of the coupling reaction the solvent is removed and the residue dissolved in ethyl acetate. Extraction with acid and removal of the solvent affords a mixture of α and β N-(1-methylcyclobutyloxycarbonyl) aspartyl-phenylalanine methyl ester. The blocking group is removed by stirring the protected dipeptide ester in anhydrous hydrofluoric acid at 0°C. The α-isomer of aspartyl-phenylalanine methyl ester is isolated by treating an aqueous mixture of the α- and β- isomers with β-phenylpropionic acid at a pH of from 3-5. The α-aspartyl phenylalanine methyl ester β-phenylpropionic adduct precipitates out of the solution. The resulting adduct is readily decomposed by treatment with acid to produce α-aspartyl phenylalanine methyl ester.