Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=[N:23][NH2:24])[NH2:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C2C(=CC(CN3C4=NC(C#N)=CN=C4N=N3)=CC=2)C=CC=1.Cl.[NH:48]([C:50](N)=[O:51])N>>[NH2:22]/[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)=[N:23]/[NH:24][C:50]([NH2:48])=[O:51]
Reactant: NNC(N)=O
Reactant: NN=C(N)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: Cl
Agent: N#Cc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: NC(=O)N/N=C(/N)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1

Procedure:
The title compound was prepared in analogy to the synthesis of compound 64.2 from 1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine-6-carbonitrile and hydrazinecarbox-amide hydrochloride. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.80 (s, 1H), 8.88 (m, 1H), 8.34 (d, 1H), 8.05 (d, 1H), 8.00 (d, 1H), 7.86 (d, 1H), 7.52 (dd, 1H), 6.18 (s, 2H). LCMS (method B): [MH]+=363, tR=1.70 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=O)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.C(Cl)(=O)C(Cl)=O>C1COCC1.CN(C=O)C>[ClH:1].[Cl:1][C:2]1[N:3]2[C:4](=[N:21][C:22]3[C:23]([C:24]2=[O:26])=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)(=[O:12])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccccc4C(=O)O)nc(Cl)nc32)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Cl)n2c(=O)c4ccccc4nc32)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 189.8 %

Procedure:
A mixture of 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzoic acid (28 g, 63.2 mmol) in THF (500 mL) was treated with 2 drops of DMF and oxalyl chloride (8.30 mL, 95 mmol), and was stirred at rt for 3 h. The resulting slurry was filtered to obtain 5-chloro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride as a yellow solid (27.67 g, 95%). 1H NMR (free base) (400 MHz, DMSO-d6) δ ppm 2.37 (s, 3H), 7.07 (d, 4.21 Hz, 1H), 7.34 (d, J=4.21 Hz, 1H), 7.47 (d, 8.06 Hz, 2H), 7.53-7.63 (m, 1H), 7.78-7.90 (m, 1H), 8.00 (d, J=8.42 Hz, 2H), 8.18 (dd, J=7.78 Hz, 1.74 Hz, 1H), 9.28 (d, J=8.42 Hz, 1H); ESIMS (M+H)+=424.97.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([O-:14])=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CN1C(=O)CCC1>[C:24]([O:23][C:21]([N:15]1[CH2:20][CH2:19][N:18]([C:9]2[C:8]([C:12]([OH:14])=[O:13])=[CH:7][N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:10]=2)[CH2:17][CH2:16]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)c1ncc(C(=O)[O-])c(Cl)n1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(C(C)(C)C)ncc2C(=O)O)CC1
Yield: 79.7 %

Procedure:
Using a procedure analogous to Example B40, 2-tert-butyl-4-chloropyrimidine-5-carboxylate from Example B40 (0.30 g, 1.24 mmol) and tert-butyl piperazine-1-carboxylate (1.15 g, 6.18 mmol) in presence of NMP (catalytic amount) were combined to afford 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-tert-butylpyrimidine-5-carboxylic acid (0.36 g, 80% yield). MS (ESI) m/z: 365.0 (M+H+).
Reaction SMILES: [NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:33][C@H:34]([C:39]([OH:41])=[O:40])[CH2:35][CH2:36][S:37][CH3:38]>C1COCC1.O>[C:14]([O:13][C:11]([NH:1][C@H:2]([C:8]([NH:33][C@H:34]([C:39]([OH:41])=[O:40])[CH2:35][CH2:36][S:37][CH3:38])=[O:10])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Reactant: CSCC[C@H](N)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: CSCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)O

Procedure:
A solution of Boc-L-Gln (Bachem, 4.92 g, 20 mmole) in THF (45 ml) was cooled to -15°, neutralized with N-methylmorpholine (2.2 ml, 20 mmole) and treated with isobutylchlorocarbonate 2.74 g (20 mmole). After 5 min a solution of L-methionine (4.48 g, 30 mmole) and N-methylmorpholine (3.3 ml. 30 mmole) in H2O (45 ml) was added. (Some warming was necessary to obtain a clear solution of the methionine salt). The mixture was stirred and allowed to warm up to room temperature; gradually a clear solution formed. After 1.5 hr the solution was concentrated in vacuo to remove most of the THF and then acidified with a 20% solution of citric acid in H2O. Saturation with NaCl and extraction with EtOAc (3×50 ml), was necessary to isolate the desired material. The organic layer was washed with H2O and evaporated with a stream of N2. The solid residue was suspended in warm EtOAc (100 ml), stirred for 1 hr, filtered, washed with EtOAc and dried. The product (4.75 g, 63%) melted at 149°-150°; [α]D20 -11.8° (c 2, DMF); RfB, 0.60; RfE, 0.73, Glu, 1.0; Met, 1.0. The proton nmr spectrum, in CD3COOD, showed the expected resonances.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:20]([CH3:26])([CH2:23][CH:24]=[CH2:25])[CH:21]=[O:22])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=[CH:6]2.CC(=CC)C.P([O-])(O)(O)=[O:33].[Na+].Cl([O-])=O.[Na+]>C(O)(C)(C)C.O.CCOC(C)=O>[C:16]([O:15][C:13]([N:8]1[C:9]2[C:5](=[C:4]([C:20]([CH3:26])([CH2:23][CH:24]=[CH2:25])[C:21]([OH:33])=[O:22])[C:3]([O:2][CH3:1])=[CH:11][C:10]=2[CH3:12])[CH:6]=[CH:7]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: O=P([O-])(O)O
Reactant: C=CCC(C)(C=O)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCC(C)(C(=O)O)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To (±)-tert-butyl 5-methoxy-7-methyl-4-(2-methyl-1-oxopent-4-en-2-yl)-1H-indole-1-carboxylate (Example 156-C) (2 g, 5.60 mmol) in tert-butanol (37.3 mL) and water (18.65 mL) was added 2-methyl-2-butene (5.93 ml, 56.0 mmol), sodium dihydrogen phosphate (2.69 g, 22.38 mmol) and then sodium chlorite (2.53 g, 22.38 mmol). The reaction was allowed to stir at room temperature overnight for 17 hours. At this point the reaction was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were dried over MgSO4 and concentrated to obtain the title compound that was use in the next step without further purification. MS (ESI+) m/z 374.3 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:36]1[CH2:39][CH2:38][CH2:37]1>CN(C=O)C.C(OCC)(=O)C>[CH:36]1([O:1][C:2]2[CH:28]=[CH:27][C:5]3[N:6]=[C:7]([N:9]4[CH2:10][CH2:11][CH:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH3:18])[CH2:13][CH2:14]4)[O:8][C:4]=3[CH:3]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: C[C@@H](COC1CCN(c2nc3ccc(O)cc3o2)CC1)NC(=O)OC(C)(C)C
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](COC1CCN(c2nc3ccc(OC4CCC4)cc3o2)CC1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 66.4 %

Procedure:
To a solution of tert-butyl [(1S)-2-{[1-(6-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]oxy}-1-methylethyl]carbamate (500 mg) in DMF (5 mL) were added cesium carbonate (1.7 g) and bromocyclobutane (265 mg), and the mixture was stirred at room temperature for 15 hr and at 60° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (378 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([I:33])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>ClCCl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([I:33])[C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: COc1c(I)cc(C(=O)Cl)cc1C#N
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(I)cc(C(=O)N2CSc3ccccc32)cc1C#N
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (317 mg) and 37% formalin (0.21 mL) in the same manner as in Example 1 was dissolved in dichloromethane (6 mL), and triethylamine (0.70 mL) and 3-cyano-5-iodo-4-methoxybenzoyl chloride (527 mg) were added to the solution, and then the mixture was stirred at room temperature for 14 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the title compound (435 mg) as a yellow oily substance.
Reaction SMILES: Br.Br[CH:3]1[C:14](=[O:15])[C:7]2[N:8]3N=C[N:11]=[C:9]3S[C:6]=2[CH2:5][CH2:4]1.NC1[CH:22]=[CH:21][CH:20]=[CH:19]N=1>C(O)C>[CH:19]1[N:8]2[C:9](=[N:11][C:6]3[CH2:5][CH2:4][CH2:3][C:14](=[O:15])[C:7]=32)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C1c2c(sc3ncnn23)CCC1Br
Reactant: Nc1ccccn1
Agent: Br
Solvent: CCO
Product: O=C1CCCc2nc3ccccn3c21
Yield: 32 %

Procedure:
2-Bromo-1,3-cyclohexadione (9.55 g) prepared in Example 1, Route 1 (A) and 2-aminopyridine (4.7 g) were dissolved into absolute ethanol (200 ml), and the reaction mixture was heated to reflux for 20 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved into water. The solution was neutralized with sodium carbonate, extracted with chloroform three times, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant:methylene chloride: acetonitrile=2:1) to give the titled compound (3.0 g, 32%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH:36]=O.N1CCCCC1>CO>[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2/[CH:36]=[C:7]1\[O:8][C:4]2[C:3]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=2[C:6]\1=[O:9]
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccc(Cl)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) obtained in Example A16, Step 1 in methanol (1.2 mL) was added with 5-chloro-1H-indole-3-carboxaldehyde (0.0515 g, 0.287 mmol) and piperidine (0.00244 g, 0.0287 mmol), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, and added with methanol (4 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-({2-[(5-chloro-1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0730 g, 49%).
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(Cl)(=O)=O)(C)C.[Si:20]([C@@:27]1([OH:67])[C@@H:31]([CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[O:30][C@@H:29]([N:41]2[CH:48]=[C:47]([CH2:49][O:50][C@H:51]([C:56]3[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:57]=3[N+:64]([O-:66])=[O:65])[C:52]([CH3:55])([CH3:54])[CH3:53])[C:45](=O)[NH:44][C:42]2=[O:43])[CH2:28]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].C([N:70](CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:20]([C@@:27]1([OH:67])[C@@H:31]([CH2:32][O:33][Si:34]([C:37]([CH3:39])([CH3:40])[CH3:38])([CH3:36])[CH3:35])[O:30][C@@H:29]([N:41]2[CH:48]=[C:47]([CH2:49][O:50][C@H:51]([C:56]3[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:57]=3[N+:64]([O-:66])=[O:65])[C:52]([CH3:53])([CH3:55])[CH3:54])[C:45]([NH2:70])=[N:44][C:42]2=[O:43])[CH2:28]1)([C:23]([CH3:25])([CH3:24])[CH3:26])([CH3:22])[CH3:21]
Reactant: CCN(CC)CC
Reactant: COc1ccc([N+](=O)[O-])c([C@@H](OCc2cn([C@H]3C[C@@](O)([Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O3)c(=O)[nH]c2=O)C(C)(C)C)c1
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])c([C@@H](OCc2cn([C@H]3C[C@@](O)([Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O3)c(=O)nc2N)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
2,4,6-Triisopropyl benzenesulfonyl chloride (363 mg, 1.2 mmol) was added to a solution of compound 48 (170 mg, 0.24 mmol), DMAP (32 mg, 0.26 mmol), and triethylamine (0.34 mL, 2.4 mmol) in anhydrous CH2Cl2 (8.0 mL). The mixture was stirred at room temperature overnight under a nitrogen atmosphere, concentrated in vacuo, and the residue was dissolved in a solution of NH3 in 1,4-dioxane (0.5 M, 20 mL). The mixture was transferred into a sealed tube and was heated at 90° C. overnight. The mixture was cooled to room temperature, concentrated in vacuo, dissolved in CH2Cl2 (20 mL), and washed with brine (50 mL). The organic and aqueous phases were separated, and the aqueous phase was extracted with CH2Cl2 (30 mL) three times. The combined organic phase was dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield 3′,5′-O-bis-(tert-butyldimethylsilyl)-5-[(S)-1-(5-methoxy-2-nitrophenyl)-2,2-dimethyl-propyloxy]methyl-2′-deoxycytidine 49 (110 mg, 65% for two steps). 1H NMR (400 MHz, DMSO-d6): δ 7.96 (d, J=8.8 Hz, 1H, Ph-H), 7.50 (br s, 1H, NH2), 7.38 (s, 1H, H-6), 7.08 (dd, 1H, J=2.8 and 8.8 Hz, Ph-H), 7.04 (d, 1H, J=2.8 Hz, Ph-H), 6.80 (br s, 1H, NH2), 6.13 (t, 1H, J=6.4 Hz, H-1′), 5.09 (s, 1H, Ph-CH), 4.31 (m, 1H, H-3′), 4.25 (d, 1H, J=12.8 Hz, 5-CH2a), 4.08 (d, 1H, J=12.8 Hz, 5-CH2b), 3.87 (s, 3H, OCH3), 3.76 (m, 1H, H-4′), 3.64 (m, 2H, H-5′), 3.76 (dd, 1H, J=2.8 Hz, H-5′b), 2.10 (m, 1H, H-2′a), 2.00 (m, 1H, H-2′b), 0.87 (s, 9H, C(CH3)3), 0.78 and 0.76 (2 s, 18H, SiC(CH3)3), 0.07, 0.06, −0.01, and −0.04 (4 s, 12H, SiCH3).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]4)=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.Cl.O1CCOCC1>>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:8]3[C:7]4[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][C:6]=4[O:10][CH:9]=3)=[CH:19][CH:18]=2)[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-c3coc4ccnc(N)c34)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nccc2occ(-c3ccc4c(c3)CCN4)c12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 96.3 %

Procedure:
A mixture of 1,1-dimethylethyl 5-(4-aminofuro[3,2-c]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (1.04 g, 2.96 mmol) and HCl, 4.0 M in dioxane (15 mL, 60.0 mmol) was stirred at room temperature under Nitrogen for 4.5 hr. The reaction mixture was then concentrated in vacuo to give 3-(2,3-dihydro-1H-indol-5-yl)furo[3,2-c]pyridin-4-amine (973 mg, 2.85 mmol, 96% yield) dihydrochloride (2HCl) as an off-white solid. LC/MS (ES) m/z=252 [M+H]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]2.[Br:16]Br.O>Br>[Br:16][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][C:2]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]1)[CH2:3]2
Reactant: BrBr
Reactant: O=C1NC(=O)C2(Cc3ccccc3C2)N1
Agent: Br
Solvent: O
Product: O=C1NC(=O)C2(Cc3ccc(Br)cc3C2)N1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of (±)-spiro[imidazolidine-4,2′-indane]-2,5-dione (1.0 g, 4.97 mmol) in 48% HBr (30 mL) was added Br2 (3.1 g, 19.9 mmol) and the reaction mixture was allowed to stir at ambient temperature for 4 days. The reaction was poured onto ice (30 g) and H2O (10 mL) and the solid precipitate filtered off, washed with H2O (4×20 mL), and dried in vacuo to give the title compound as a light brown solid. MS: m/z=282 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]=[CH:17][CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)=[N:6][CH:7]=1.[B-][N+](C)(C)C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: [B-][N+](C)(C)C
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Reaction time: 24 h

Procedure:
A solution containing N-(5-chloropyridin-2-yl)-2-(1-Boc-piperidin-4-yl-methylidene)aminobenzamide (1.35 g, 3.05 mmol) and borane trimethylamine complex (667 mg, 9.14 mmol) in glacial acetic acid (50 mL) was heated at reflux for 2 h. The mixture was concentrated and the residue was dissolved in methanol and 12 N HCl. After 24 h, the mixture was concentrated, the residue was dissolved in 2 N ammonia in methanol and concentrated. The residue was triturated from methanol:EtOAc yielding 1.03 g (98%) of the title compound.
Reaction SMILES: CCN(CC)CC.[Br:8][CH2:9][CH2:10]CCC(Cl)=O.[NH:16]1[CH:25]2[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19][CH2:18][CH2:17]1.CCO[C:29]([CH3:31])=[O:30]>>[Br:8][CH2:9][CH2:10][CH2:31][C:29]([N:16]1[CH:25]2[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19][CH2:18][CH2:17]1)=[O:30]
Reactant: CCOC(C)=O
Reactant: O=C(Cl)CCCCBr
Reactant: C1CCC2NCCCC2C1
Solvent: CCN(CC)CC
Product: O=C(CCCBr)N1CCCC2CCCCC21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.37 mL (9.9 mmol) of Et3N and 0.5 mL (4.5 mmol) of 5-bromovaleric acid chloride are added to a solution of 1 mL (4.0 mmol) of the decahydroquinoline in AcOEt. The resulting solution is kept under stirring for 18 h at rt. The solution is then washed with water, and the water re-extracted twice with AcOEt. The pooled organic phases are sequentially washed with 5% solution of NaHCO3, 1N HCl and saturated ammonium chloride solution. Finally the organic phase is dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure. 1.2 g of a yellow oil, which was used without subsequent purification, are obtained.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][C:12]([NH:14][NH2:15])=[O:13])[S:10][C:6]=2[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1.[S:22]([CH2:26][C:27](O)=O)(=[O:25])(=[O:24])[NH2:23]>>[F:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][C:12]3[O:13][C:27]([CH2:26][S:22]([NH2:23])(=[O:25])=[O:24])=[N:15][N:14]=3)[S:10][C:6]=2[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1
Reactant: NS(=O)(=O)CC(=O)O
Reactant: NNC(=O)Cc1nc2c(F)cc(-c3ccccc3)cc2s1
Product: NS(=O)(=O)Cc1nnc(Cc2nc3c(F)cc(-c4ccccc4)cc3s2)o1

Procedure:
Compound 90e was prepared from Compound 90d and 2-sulfamoylacetic acid using the procedure given for Compound 1b. LCMS=1.78 min using analytical method (Q), 405.1 (M+H). 1H NMR (500 MHz, CD3OD) δ 8.07 (d, J=1.7 Hz, 1H), 7.74-7.67 (m, 2H), 7.56 (dd, J=12.0, 1.5 Hz, 1H), 7.52-7.43 (m, 2H), 7.43-7.36 (m, 1H), 4.94-4.88 (m, 2H), 4.78-4.74 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:30]([C:29]2[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:34][CH:33]=2)=[O:31])=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccc([N+](=O)[O-])cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 76.2 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (110 mg) and commercially available 4-nitrobenzoic acid (100 mg) were dissolved in N,N-dimethylformamide (4 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (176 mg) was added, and the admixture was stirred at room temperature for 22 hours. The reaction mixture was then purified in the same manner as described in Example 50 to obtain 126 mg of the title compound (yield: 77%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:15]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:15][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]([CH3:11])=[C:2]([I:1])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(I)cc(C(=O)O)cc1[N+](=O)[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(I)c(C)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a solution of 3-iodo-4-methyl-5-nitro-benzoic acid (16.06 g, 52.3 mmol) in acetone (300 mL) was added K2CO3 (14.46 g, 104.6 mmol) followed by methyl iodide ((3.91 mL, 62.76 mmol). The reaction mixture was stirred at 40° C. overnight, then cooled to room temperature and partitioned between ethyl acetate and brine. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to provide 16.5 g (98%) of 3-iodo-4-methyl-5-nitro-benzoic acid methyl ester.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][N+:18]#[C-:19].C(=O)([O-])[O-:21].[Ca+2].Cl>CC(C)=O.O>[CH3:19][NH:18][C:17](=[O:21])[C:10]([C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11]
Reactant: O=C(Cl)c1ccccc1Oc1ccccc1
Reactant: [C-]#[N+]C
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Ca+2]
Solvent: O
Solvent: CC(C)=O
Product: CNC(=O)C(=O)c1ccccc1Oc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
A mixture of 2-phenoxybenzoyl chloride (1.09 g) and methyl isocyanide (383 mg) was stirred at 50° C. for 3 hours. Then, the mixture was diluted with acetone (10 ml), and water (2 ml) and calcium carbonate (500 mg) were added. The resulting mixture was stirred for 1 hour. The mixture was neutralized with dilute hydrochloric acid and extracted with methylene chloride. After drying the organic layer, the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with hexane-ethyl acetate (6:1) to obtain the title compound as crystals (1.04 g, Yield: 87.1%), mp: 94°-95° C.