Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N([O-])=O.[Na+].[OH-].[Na+].[BrH:18]>O>[Br:18][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1cccc2ncccc12
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Brc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. mixture of 1.0022 g (6.94 mmol) 5-aminoquinoline (9) and 6 mL 24% aqueous hydrobromic acid was added a solution of 0.5 g (7 mmol) sodium nitrite in 3 mL H2O. After 5 min at 0° C., the mixture was added over 5 min to 1.2026 g (8.38 mmol) cuprous bromide in 10 mL 47% aqueous hydrobromic acid. After stirring at room temperature for 7.5 h, the reaction mixture was basified with ice and 50% aqueous NaOH and filtered. The filtrate was extracted three times with 50 mL ethyl ether, and the combined ether layers were concentrated in vacuo. The resulting residue was combined with precipitate from the above filtration, dissolved in 50% MeOH:CH2Cl2 and filtered. The filtrate was concentrated in vacuo, dissolved in 10% (10% NH4OH:MeOH):CH2Cl2 and filtered over silica. The filtrate was concentrated in vacuo to yield 10. 1H NMR (DMSO, 400 MHz) δ 8.997 (d, 1H, J=2.83 Hz, ArH); 8.525 (d, 1H, J=8.59 Hz, ArH); 8.089 (d, 1H, J=8.50 Hz, ArH); 8.000 (d, 1H, J=7.49 Hz, ArH); 7.741-7.701 Hz (m, 2H, ArH); MS (Electrospray): m/z 207.9, 209.9 (M+H, 79Br, 81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][C:3]=1[CH3:21].[O:22]=[C:23]1[CH:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][NH:24]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:29](=[O:30])[C:27]3[CH:26]=[CH:25][N:24]=[C:23]([OH:22])[CH:28]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:4][C:3]=1[CH3:21]
Reactant: O=C(O)c1cc[nH]c(=O)c1
Reactant: Cc1cc(-c2cc(N)cnc2OCC(F)(F)F)ccc1Cl
Product: Cc1cc(-c2cc(NC(=O)c3ccnc(O)c3)cnc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-Chloro-3-methyl-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example 57 a) and 1,2-dihydro-2-oxo-4-pyridinecarboxylic acid (CAN 22282-72-0) as starting materials; LC-MS (UV peak area/ESI) 100%, 436.0689 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[NH:9][C:10]([S:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[O:22]([CH3:24])[Na]>CO.O>[CH2:21]([S:20][C:10]1[NH:9][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:22][CH3:24])[CH:7]=2)=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:11]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CSc1nc(-c2ccc(F)cc2)c(-c2ccnc(Cl)c2)[nH]1
Reactant: CO[Na]
Solvent: O
Solvent: CO
Product: COc1cc(-c2[nH]c(SCc3ccccc3)nc2-c2ccc(F)cc2)ccn1

Procedure:
A suspension of 25a (0.1 g; 0.25 mmol) in methanolic NaOCH3 solution (30%, 2 ml) was diluted with methanol (5 ml) and stirred under reflux for 13 h. The reaction mixture was diluted with H2O and the aqueous solution was extracted with CH2Cl2 (3×). The combined organic extract was washed with saturated NaCl solution, dried over Na2SO4 and concentrated. The oily residue was purified by column chromatography (SiO2 60, CH2Cl2/ethyl acetate 1+1).
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][N:15]4[C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:33][O:32][C:30](=[O:31])[CH2:29][O:20][C:18]1[CH:17]=[CH:16][N:15]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([C:2]4([NH2:1])[CH2:3][CH2:4][CH2:5]4)=[CH:11][CH:10]=3)[N:13]=[C:14]2[CH:19]=1
Reactant: COC(=O)CBr
Reactant: NC1(c2ccc(-c3nc4cc(O)ccn4c3-c3ccccc3)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c1
Reaction time: 0.13 h
Yield: 34.5 %

Procedure:
To a solution of 2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-ol (75 mg, 0.21 mmol), methyl bromoacetate (0.02 mL, 0.21 mmol, 1.0 equiv) and Cs2CO3 (138 mg, 0.422 mmol, 2 equiv) in DMF (2.5 mL) was stirred at room temperature for 12 h. The resulting mixture added to water (10 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried (Na2SO4 anh), and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 100% CH2Cl2 for 8 min., gradient to 95% CH2Cl2: 5% MeOH over 5 min.; 95% CH2Cl2: 5% MeOH for 4 min., gradient to 80% CH2Cl2: 20% MeOH over 5 min., 80% CH2Cl2: 20% MeOH for 6.2 min., gradient to 75% CH2Cl2: 25% MeOH over 2.0 min., 75% CH2Cl2: 25% MeOH for 18.2 min.) to give {2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-yloxy}-acetic acid methyl ester (31 mg, 34%):
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]#[N:24]>>[C:23]([CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:24]
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: N#CCc1ccccc1I
Product: COC(=O)CCc1ccc(C#Cc2ccccc2CC#N)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (74 mg, 0.39 mmol) and 2-(2-iodophenyl)acetonitrile (60 μL, 0.43 mmol) according to the general procedure IC to give 74 mg (62%) of an orange solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:4). Rf=0.08 (EtOAc:PE, 1:4); 1H NMR (CDCl3) δ 7.55-7.46 (m, 4H), 7.37-7.34 (m, 2H), 7.21 (d, J=8.4 Hz, 2H), 3.96 (s, 2H), 3.67 (s, 3H), 2.97 (t, J=7.7 Hz, 2H), 2.64 (t, J=7.5 Hz, 2H); 13C NMR (CDCl3) δ 173.0, 141.6, 132.3, 131.7, 131.6, 128.9, 128.5, 128.1, 122.9, 120.4, 117.4, 95.6, 85.7, 51.7, 35.3, 30.8, 22.7; ESI-MS m/z 326.1 (M+Na+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([C:10]2[CH:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:11]=2[CH3:19])[CH:9]=1)=[O:4].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.[NH2:34][C:35]1[C:36]([O:50][CH3:51])=[C:37]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([C:10]2[CH:15]=[C:14]([C:16](=[O:18])[NH:34][C:35]3[CH:40]=[C:39]([C:41]([F:43])([F:42])[F:44])[CH:38]=[C:37]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[C:36]=3[O:50][CH3:51])[CH:13]=[CH:12][C:11]=2[CH3:19])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cn(-c2cc(C(=O)O)ccc2C)nn1
Reactant: COc1c(N)cc(C(F)(F)F)cc1NS(C)(=O)=O
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1cn(-c2cc(C(=O)Nc3cc(C(F)(F)F)cc(NS(C)(=O)=O)c3OC)ccc2C)nn1
Temperature: 10 °C
Reaction time: 1 h
Yield: 5.6 %

Procedure:
1-(5-Carboxy-2-methyl-phenyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (26 mg, 0.101 mmol) was stirred with 21 mg (0.153 mmol) of 1-hydroxy-7-azabenzotriazole (HOAt) in 1 mL of DMF and 24 mg (0. 126 mmol) of EDC was added. After 1 h of stirring at about 10° C., 30 mg (0.106 mmol) of N-(3-amino-2-methoxy-5-trifluoromethyl-phenyl) -methanesulfonamide was added. The mixture was stirred overnight then heated to 60° C. for 6 h. The reaction was then cooled and water was added. The precipitate was collected and chromatographed twice by preparative TLC (5% MeOH in CH2Cl2) and once by flash chromatography (0-4.5% MeOH in dichloromethane). The pure fractions yielded 3 mg (5.6%) of the title compound. ESI MS (m/z 526, 100, M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N+:3]=1[O-:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc(Cl)n1
Solvent: ClCCl
Product: Cc1cccc(Cl)[n+]1[O-]
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
2-Chloro-6-methylpyridine (12.76 g, 0.1 mol) was dissolved together with m-chloroperbenzoic acid (17.56 g, 0.15 mol) in DCM (100 ml) and stirred at 40° C. for 90 minutes. The heating bath was removed and stirring was continued overnight at room temperature. The reaction mixture was quenched with saturated sodium thiosulfate solution and the pH was adjusted to 8 with 1M NaOH. The phases were separated, the aqueous phase extracted with DCM and the combined organic phases were dried over magnesium sulfate. The solvent was removed under reduced pressure and unreacted 2-chloro-6-methylpyridine was removed by distillation (2 mbar, 65° C.). 2-Chloro-6-methyl-pyridine 1-oxide was obtained as residue (6.0 g of a yellow oil, 0.042 mol, 42%). MS (ESI) m/z=144.0 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:21]([OH:24])[CH2:22][CH3:23])[C:5]2[CH2:10][O:9][CH2:8][N:7]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[C:6]=2[N:20]=1.[CH3:25][N:26]=[C:27]=[O:28].CN(C1C=CC=CN=1)C>ClCCl>[CH3:1][C:2]1[N:3]=[C:4]([CH:21]([O:24][C:27](=[O:28])[NH:26][CH3:25])[CH2:22][CH3:23])[C:5]2[CH2:10][O:9][CH2:8][N:7]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[C:6]=2[N:20]=1
Reactant: CCC(O)c1nc(C)nc2c1COCN2c1c(C)cc(C)cc1C
Reactant: CN=C=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCC(OC(=O)NC)c1nc(C)nc2c1COCN2c1c(C)cc(C)cc1C

Procedure:
A mixture of 1-[7-methyl-1-(2,4,6-trimethyl-phenyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-5-yl]-propan-1-ol (50 mg), methyl isocyanate (0.25 ml), dimethylaminopyridine (37 mg) in dichloromethane (2 ml) was heated at reflux for 1 hr. The mixture was quenched with water and extracted with chloroform. The organic layer was separated, dried and concentrated to give a clear oil (70 mg). The oil was purified by silica gel thin layer chromatography plate using 40% ethyl acetate in hexane as solvent to give 36 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH:17]([S:11][C:9]2[CH:8]=[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CO
Product: CC(C)(C)c1cc(SC(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2ccccc2)cc(C(C)(C)C)c1O
Yield: 66.3 %

Procedure:
The procedure of Example 1 is repeated using 23.84 grams of 2,6-di-tert-butyl-4-mercaptophenol, 5.31 grams of benzaldehyde, and 150 ml of methyl alcohol. The product is triturated with methyl alcohol to give 18.74 grams (66% yield) of white crystals, mp 122°-124° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][Br:11])[CH3:2].[CH:13]1[CH:18]=[CH:17][C:16]([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1>C(#N)C>[Br-:11].[CH2:1]([O:3][C:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:16]1[CH:15]=[CH:14][CH:13]=[CH:18][CH:17]=1)=[O:12])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)CCCCCCBr
Solvent: CC#N
Product: CCOC(=O)CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
Ethyl-7-bromoheptanoate (2.5 g, 10.54 mmol) and PPh3 (2.764 g, 10.54 mmol) were added to acetonitrile (50 mL) and the mixture was stirred under Ar(g) at reflux for 18 h. The solvent was subsequently removed by evaporation under reduced pressure, and the resulting phosphonium bromide derivative I was dried under high vacuum.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([F:34])=[C:21]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:35][C:36]1[CH:45]=[C:44]2[CH:39]([CH2:40][CH2:41][N:42]([C:46](=[O:51])[C:47]([F:50])([F:49])[F:48])[CH2:43]2)[CH2:38][CH:37]=1.Cl>O1CCOCC1.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:21]1[CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:35][C:36]4[CH:45]=[C:44]5[C:39]([CH2:40][CH2:41][N:42]([C:46](=[O:51])[C:47]([F:50])([F:48])[F:49])[CH2:43]5)=[CH:38][CH:37]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=[CH:19][C:20]=1[F:34])=[O:33]
Reactant: NC1=CCC2CCN(C(=O)C(F)(F)F)CC2=C1
Reactant: O=C(Nc1cc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)ccc1F)c1c(F)cccc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: O=C(Nc1cc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CN(C(=O)C(F)(F)F)CC4)n2)ccc1F)c1c(F)cccc1F
Temperature: 80 °C
Yield: 46.6 %

Procedure:
To a solution of N-{5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorophenyl}-2,6-difluorobenzamide (162 mg, 0.34 mmol) in 1,4-dioxane (6 mL) and 2-propanol (2 mL) was added 7-amino-N-trifluoroacetyl tetrahydroisoquinoline (165 mg, 0.68 mmol) followed by catalytic 12M HCl. After heating overnight at 80° C., reaction was quenched with saturated NaHCO3 (25 mL), solvent removed by rotary evaporation, aqueous layer extracted with DCM (25 mL), organic layer concentrated, and purified by column chromatography (5-50% EtOAc in hexanes) to provide the product (109 mg, 47%) as an off-white solid. ESIMS (M+H)+=688.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]2=[C:15]3[N:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]3=[CH:5][C:4]=1[CH:16]=[CH:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1.[C:25]([C:27]1[C:28](=[C:35]([C:38]#[N:39])[C:36]#[N:37])[O:29][C:30]([CH3:34])([CH3:33])[C:31]=1[CH3:32])#[N:26].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[C:25]([C:27]1[C:28](=[C:35]([C:36]#[N:37])[C:38]#[N:39])[O:29][C:30]([CH3:33])([CH3:34])[C:31]=1[CH:32]=[CH:23][C:21]1[S:22][C:18]([CH:17]=[CH:16][C:4]2[CH:5]=[C:6]3[C:15]4[N:10]([CH2:9][CH2:8][CH2:7]3)[CH2:11][CH2:12][CH2:13][C:14]=4[C:3]=2[O:2][CH3:1])=[CH:19][CH:20]=1)#[N:26]
Reactant: COc1c(C=Cc2ccc(C=O)s2)cc2c3c1CCCN3CCC2
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1c(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)s2)cc2c3c1CCCN3CCC2
Temperature: 25 °C
Reaction time: 42 h
Yield: 61.3 %

Procedure:
In 5 ml of ethanol and 1.5 ml of tetrahydrofuran were dissolved 158 mg (0.47 mmol) of 5-[2-(8-methoxy-2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine-9-yl)vinyl]thiophene-2-carboaldehyde and 102 mg (0.51 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. To this mixture was added 36 mg of ammonium acetate, and the mixture was stirred at room temperature for 42 hours. The crystal was filtrated and washed with ethanol. The residue was purified by silica gel column chromatography and washed with ethanol to give 150 mg of a black powdered crystal (yield: 62.0%; mp: 201-204° C.).
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][C:5]=1[N+:14]([O-:16])=[O:15]>O>[CH3:1][NH:2][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][C:5]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CN
Solvent: O
Product: CNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
To a stirred solution of 40% aqueous methylamine was added, in small portions, 30.0 g (0.144 mole) of 4-chloro-3-nitroquinoline. The reaction mixture was then heated at its reflux temperature for about 0.75 hour. After cooling, the mixture was poured in 300 ml of water. The solid was separated by filtration, and was then suspended in 300 ml of water. Acidification with 6N hydrochloric acid to pH 3 to 4 effected dissolution of most of the solid. Filtration was followed by basification of the filtrate with concentrated ammonium hydroxide to pH 8 to 10 to provide a yellow precipitate. The solid was separated by filtration, washed with water, and recrystallized from ethanol to provide yellow 4-methylamino-3-nitroquinoline, m.p. 168°-170° C. Analysis: Calculated for C10H9N3O2 %C, 59.1; %H, 4.5; %N, 20.7; Found: %C, 59.0; %H, 4.2; %N, 20.8.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:17])=[C:5]([CH3:16])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8].C(N(CC)CC)C.[Br:25][C:26]([CH3:31])([CH3:30])[C:27](Br)=[O:28]>ClCCl>[Br:25][C:26]([CH3:31])([CH3:30])[C:27]([NH:1][C:2]1[S:3][C:4]([CH3:17])=[C:5]([CH3:16])[C:6]=1[C:7](=[O:8])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:28]
Reactant: Cc1sc(N)c(C(=O)c2ccc(Cl)cc2)c1C
Reactant: CC(C)(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1sc(NC(=O)C(C)(C)Br)c(C(=O)c2ccc(Cl)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottomed flask was charged with (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone (2 g, 7.53 mmol) and a stirbar. Dichloromethane (75 mL, 0.1 M) was added, followed by triethylamine (1.573 ml, 11.29 mmol, 1.5 equiv). The solution was cooled to 0° C. for the addition of 2-bromo-2-methylpropanoyl bromide (1.163 ml, 9.41 mmol). The solution was stirred at room temperature 1 h, at which point LC/MS analysis showed complete conversion of the starting material. The solution was washed successively with water and brine before being dried with sodium sulfate and concentrated to give a quantitative yield of 2-bromo-N-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-2-methylpropanamide as a yellow amorphous solid (m/z=414/416), which was used crude in the subsequent reaction.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:33]([OH:35])=[O:34])[C:10]([S:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:38](=O)([O-])O.[K+]>CN(C)C=O>[CH3:38][O:34][C:33](=[O:35])[C@@H:9]([C:10]([S:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([CH3:12])[CH3:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 97.2 %

Procedure:
To the solution of N-t-butoxycarbonyl-S-trityl-D-penicillamine (A-2) (6.0 g) in dimethylformamide (40 ml), were added methyl iodide (1.5 ml) and potassium hydrogencarbonate (2.4 g), and the mixture was stirred for 14 hours. To the reaction mixture was added ice-water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated saline, and dried over magnesium sulfate. The solvent was evaporated off under reduced pressure, to give N-t-butoxycarbonyl-S-trityl-D-penicillamine methyl ester (6.0 g).
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.[CH:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C(Cl)Cl>[Cl:52][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][C:48]=1[Cl:51])[CH2:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([C@H:35]2[CH2:34][O:33][C:29]3=[CH:30][C:31]4[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]5[CH:11]=[CH:10][C:9]([C:12]6[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=6[CH3:19])=[CH:8][CH:7]=5)[C:3]([OH:2])=[O:53])=[O:22])[N:24]([C:21](=[O:22])[NH:20][C@H:4]([C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=5)[CH3:3])[CH2:25][C:26]=4[CH:27]=[C:28]3[O:36]2)=[CH:42][CH:41]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: c1ccccc1
Solvent: ClCCl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)N[C@@H](C)c3ccccc3)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester in DCM was added (S)-1-isocyanato-ethyl)-benzene (5 equiv) and the reaction was stirred at rt for 1 hour. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 886.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[CH2:4][CH2:5][O:6][C:7]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:8]=1[C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([O:21][CH2:22][CH2:23][CH3:24])=[CH:13][C:14]=1[C:15]2=[O:20])[CH3:2].F[B-](F)(F)F.[O:34]=[N+:35]=[O:36]>C(Cl)Cl>[CH2:27]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:8]=1[C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([O:21][CH2:22][CH2:23][CH3:24])=[C:13]([N+:35]([O-:36])=[O:34])[C:14]=1[C:15]2=[O:20])[CH3:28]
Reactant: O=[N+]=O
Reactant: CCCOc1cc(OC)c2c(c1)C(=O)c1cccc(OCCN(CC)CC)c1-2
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCCOc1cc(OC)c2c(c1[N+](=O)[O-])C(=O)c1cccc(OCCN(CC)CC)c1-2
Temperature: 25 °C
Yield: 41.8 %

Procedure:
Prepare a solution of 5-(2-diethylamino-ethoxy)-4-methoxy-2-propoxy-fluoren-9-one (1.1 g, 2.9 mmole) in 100 mL anhydrous methylene chloride at -72° C. under argon while stirring. Add nitronium tetrafluoroborate (0.42 g, 3.2 mmole) in one continuous portion. Allow the mixture to warm to room temperature for 3 hours while the solution darkens. Stir an additional 2 hours, then check reaction progress with an aliquot by thin layer chromatography. Quench the reaction with water and transfer to a seperatory funnel. Retain the organic layer and filter off an insoluble red solid from the interface. Wash with water and methylene chloride. Take up the solid into 5% sodium hydroxide and stir vigorously. Extract with methylene chloride and chromatotron the organics, combine the CH2Cl2 fractions and dry over MgSO4, filter and concentrate on the rotary evaporator. Chromatograph the resulting residue, eluting with methanol/CH2Cl2 (5:95) to obtain 0.52 g (52%) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10](=O)([O-])[O-].[K+].[K+].CN(C)C=O.C(=O)(OC)OC>O>[CH3:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: c1ccc2c(c1)CCN2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(=O)OC
Solvent: O
Product: CN1CCc2ccccc21
Temperature: 130 °C
Reaction time: 14 h
Yield: 95 %

Procedure:
Indoline (3 g, 0.025 mol), potassium carbonate (1.59), N,N-dimethylformamide (20 mL) and dimethyl carbonate (6.4 mL ,0.076 mol) were mixed together and heated to reflux (around 130 ° C.) for 14 h. The reaction, monitored by HPLC, went to completion within 14 h. The reaction mixture was cooled down to room temperature, then was slowly diluted with water (50 mL) and extracted with tert-butyl methyl ether (60 mL ). The organic extract was washed with water (3×50 mL) and the solution was evaporated to constant weight under reduced pressure to furnish 3.13 g of the product, N-methylindoline as a light yellow oil (95% yield).