Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:31][C:30]([CH3:33])([CH3:32])[O:29][C:27](=[O:28])[NH:22][CH2:23][C:24](=[O:25])[NH:1][C@H:2]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a solution of L-Lys(Z)OMe 40 (1.05 g, 2.6 mmol) in dry DMF (40 mL) was added Boc-GlyOH (494 mg, 2.8 mmol), HATU (977 mg, 2.57 mmol), and DIEA (2.03 mL, 11.7 mmol). The mixture was stirred at rt overnight. The solvent was then removed in vacuo and the residue was dissolved in EtOAc (100 mL) and washed with saturated NaHCO3 solution water and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude compound was purified on column of silica gel (2% MeOH/DCM) to give the subject compound (960 mg, yield 90%). Intermediate 41 was characterized by the following spectroscopic data: 1H NMR (DMSO-d6, 300 MHz) δ (ppm) 8.12 (t, 1H), 7.98 (t, 1H), 7.47-7.38 (m, 5H), 6.98 (t, 1H), 5.13 (s, 2H), 4.56 (m, 1H), 4.05 (d, 2H), 3.65 (s, 3H), 3.02 (m, 2H), 1.90 (m, 2H), 1.55 (m, 2H), 1.38 (s, 9H), 1.25 (m, 2H).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[Sn](Cl)[Cl:13].C([O-])(O)=O.[Na+]>C(O)C>[Cl:13][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cccc(F)c1Br
Reactant: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc(F)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 119.5 %

Procedure:
To the solution of 2-bromo-3-fluoronitrobenzene (100 mg, 0.46 mmol) in ethanol (5 ml), Tin (II) chloride (520 mg, 2.3 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The NaHCO3 (aq) was added to pH=7. Then was extracted with ethyl acetate (3x). The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give desired product (80 mg, 93%). EI-MS m/z 191 (M+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[N:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[S:29][C:28]3[C:23](=[N:24][CH:25]=[CH:26][C:27]=3Cl)[CH:22]=2)=[O:20])=[CH:14][CH:13]=1>>[N:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[S:29][C:28]3[C:23](=[N:24][CH:25]=[CH:26][C:27]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:22]=2)=[O:20])=[CH:14][CH:13]=1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: O=C(Nc1ccncc1)c1cc2nccc(Cl)c2s1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)Nc5ccncc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid pyridin-4-ylamide by a procedure analogous to Example 1C. MS: 400 (MH+); HPLC Rf: 4.24 min.; HPLC purity: 99%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)[CH:15]=2)[CH2:9][CH2:8]1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:47]2[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=2[CH2:49][Cl:50])[CH:40]=[C:41]([O:45][CH3:46])[C:42]=1[O:43][CH3:44]>>[ClH:50].[ClH:50].[CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]4[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=4)[CH:15]=3)[CH2:11][CH2:12]2)[CH2:49][C:48]2[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=2[C:39]2[CH:40]=[C:41]([O:45][CH3:46])[C:42]([O:43][CH3:44])=[C:37]([O:36][CH3:35])[CH:38]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc(-c2ccccc2CCl)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCC(Nc4cccc(SC)c4)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(N(Cc4ccccc4-c4cc(OC)c(OC)c(OC)c4)c4cccc(SC)c4)CC3)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
4-(3-Methylthioanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (143 mg) and 2-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a dihydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]=[C:8]([NH:14][NH2:15])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CN(C)/[CH:20]=[N:21]/[C:22](=O)[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]>C(O)(=O)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]=[C:8]([N:14]4[C:22]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[F:30])=[N:21][CH:20]=[N:15]4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: NNc1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CN(C)/C=N/C(=O)c1ccc(F)cc1F
Solvent: CC(=O)O
Product: Fc1ccc(-c2ncnn2-c2nc3c(s2)CCOc2cc(Br)ccc2-3)c(F)c1
Temperature: 90 °C
Yield: 65 %

Procedure:
A suspension of (8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-hydrazine (312 mg, 1 mmol) and N-[1-dimethylamino-meth-(E)-ylidene]-2,4-difluoro-benzamide (232 mg, 1.1 mmol) in acetic acid (6 mL) was heated at 90° C. for 3 h, allowed to cool down to RT and filtered. The precipitate was washed with diethyl ether and dried to afford the title compound as a beige solid (300 mg, 65%). LCMS (Method B): RT=4.51 min, [M+H]+=461 and 463. 1H NMR (DMSO-d6): 8.50 (1 H, s), 7.82 (1 H, td, J=8.4, 6.4 Hz), 7.57 (1 H, ddd, J=10.4, 9.4, 2.5 Hz), 7.39-7.30 (2 H, m), 7.23 (1 H, d, J=2.0 Hz), 7.13 (1 H, dd, J=8.6, 2.0 Hz), 4.33 (2 H, t, J=5.0 Hz), 3.34 (2 H, t, J=5.0 Hz).
Reaction SMILES: C[O:2][CH:3]=[CH:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[NH:10][N:9]=[CH:8]2.Cl(O)(=O)(=O)=O>O1CCCC1.O.C(OCC)(=O)C>[CH3:14][C:12]1[CH:13]=[C:5]([CH2:4][CH:3]=[O:2])[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[CH:8]2
Reactant: COC=Cc1cc(C)c2[nH]ncc2c1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CC=O)cc2cn[nH]c12
Reaction time: 2 h

Procedure:
To a solution of 5-(2-methoxy-vinyl)-7-methyl-1H-indazole (365 mg, 1.94 mmol, 1.0 equiv.) in tetrahydrofuran (8 mL) was added 60% perchloric acid (0.63 mL, 3 equiv) in one portion under nitrogen. After 2 h, more perchloric acid (0.63 mL) was added. After 4 h, LCMS indicated that no starting material was present. The reaction mixture was diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with water (3×). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give an off-white solid. The crude material was carried on without further purification. MS (ESI) [M+H]+=175.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:28])[C:10]=1[C:11]([N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[C:17]([NH:22][C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])[C:16]=2[CH:15]=[CH:14]1)=[O:12])[C:5]([OH:7])=O.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:59][C@H:60]([C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH3:61]>CN(C)C=O.O>[Cl:28][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Cl:1])[C:10]=1[C:11]([N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[C:17]([NH:22][C:23]([CH:25]3[CH2:26][CH2:27]3)=[O:24])[C:16]=2[CH:15]=[CH:14]1)=[O:12])[C:5]([NH:59][C@H:60]([C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH3:61])=[O:7]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(O)c1cc(Cl)c(C(=O)n2ccc3c(NC(=O)C4CC4)nccc32)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)NC(=O)c1cc(Cl)c(C(=O)n2ccc3c(NC(=O)C4CC4)nccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.1 %

Procedure:
A stirred solution of 3,5-dichloro-4-({4-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[3,2-c]pyridin-1-yl}carbonyl)benzoic acid (100 mg, 0.23 mmol) in anhydrous dimethylformamide (5 mL) was treated with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (68 mg, 0.358 mmol), 1-hydroxy-7-azabenzotriazole (37 mg, 0.276 mmol), N,N-diisopropylethylamine (89 mg, 0.69 mmol). Ethyl alaninate (38 mg, 0.25 mmol) was added and the reaction mixture was stirred at room temperature for about 16 hours. The reaction mixture was poured into water (100 mL) and extracted with ethylacetate (2×30 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated to give crude product which was purified by flash silica gel column chromatography using linear gradient ethyl acetate and hexane to afford ethyl N-[3,5-dichloro-4-({4-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[3,2-c]pyridin-1-yl}carbonyl)benzoyl]alaninate (43 mg, 34%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:26]([O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C@H:35]([C:39]([NH:41][C:42]1[CH:47]=[C:46]([F:48])[C:45]([C:49]([CH3:55])([CH3:54])[CH2:50][O:51][CH2:52][CH3:53])=[C:44]([F:56])[CH:43]=1)=[O:40])[NH:34][CH2:33][CH2:32]2)[CH3:27].[C:57]([O:61][C:62](=[O:71])[CH2:63][C@@H:64]1[CH2:67][C@H:66]([C:68](O)=[O:69])[CH2:65]1)([CH3:60])([CH3:59])[CH3:58].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:26]([O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C@H:35]([C:39](=[O:40])[NH:41][C:42]1[CH:47]=[C:46]([F:48])[C:45]([C:49]([CH3:54])([CH3:55])[CH2:50][O:51][CH2:52][CH3:53])=[C:44]([F:56])[CH:43]=1)[N:34]([C:68]([C@@H:66]1[CH2:65][C@H:64]([CH2:63][C:62]([O:61][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:71])[CH2:67]1)=[O:69])[CH2:33][CH2:32]2)[CH3:27]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)O)C1
Reactant: CCOCC(C)(C)c1c(F)cc(NC(=O)[C@@H]2NCCc3cc(OCC)ccc32)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCC(C)(C)c1c(F)cc(NC(=O)[C@H]2c3ccc(OCC)cc3CCN2C(=O)[C@H]2C[C@@H](CC(=O)OC(C)(C)C)C2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU (90 mg, 0.24 mmol) was added to a solution of (R)-6-ethoxy-N-(4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (101 mg, 0.22 mmol), cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (50.8 mg, 0.24 mmol) and DIEA (0.085 mL, 0.47 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give tert-butyl 2-(cis-3-((R)-6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (135 mg, 0.215 mmol, quant.).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:13][CH2:14][OH:15])[C:10]([NH2:12])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[N:17]1C(=O)C2C(=CC=CC=2)C1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O.NN>C(Cl)Cl>[NH2:17][O:15][CH2:14][CH2:13][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:10]([NH2:12])=[O:11]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CCO)C(N)=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](CCON)C(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 21.2 %

Procedure:
To a solution of (S)-2-(tert-butyldimethylsilyloxy)-4-hydroxybutanamide (4.85 g, 20.8 mmol) in CH2Cl2 (150 mL) was added 2-hydroxyisoindoline-1,3-dione (5.1 g, 31.2 mmol) and triphenylphosphine (8.2 g, 31.2 mmol). The resultant mixture was cooled to 0° C. and diisopropyl azodicarboxylate (6.0 ml, 31.2 mmol) was slowly added dropwise with an addition funnel under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was concentrated to provide clear oil, which was purified by flash chromatography (60% EtOAc—Hexane). The resultant pale yellow compound was dissolved in CH2Cl2 (60 ml). Hydrazine hydrate (670 μL, 8.8 mmol) was added. The reaction mixture was stirred at ambient temperature for 8 h. The resultant solid was filtered off and the filtrate concentrated under reduced pressure to provide a clear yellow oil of (S)-4-(aminooxy)-2-(tert-butyldimethylsilyloxy)butanamide (1.1 g, 4.4 mmol). [M+H] calc'd for C10H24N2O3Si, 249; found, 249.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(C(C)C)C(C)C)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CN1CCNCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccnc(Cl)n2)CC1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A mixture of 2,4-dichloropyrimidine (0.967 g, 6.49 mmol), 1-methylpiperazine (0.65 g, 6.40 mmol), and ethyldiisopropylamine (2.8 mL, 16.22 mmol) in ethanol (13 mL) was stirred at −10° C. for 2 h and then at r.t. overnight. The mixture was partitioned between H2O/brine (3:1; 100 mL) and chloroform (3×70 mL). The combined organic phases were washed once with brine (50 mL) an dried over MgSO4. Removal of solvent yielded a pale-beige solid, which was washed with ethyl acetate/ultrasound to give the desired product as a colourless powder, which was further washed with Et2O. Additional product was obtained upon fractional crystallization of the washing solution. A total of 0.741 g (3.48 mmol, 54%) of 2-chloro-4-(4-methylpiperazin1-yl)pyrimidine was obtained. LC/ESI-MS: m/z=213 [M(35Cl)+H]+; Rt=0.5 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.O>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:14]([O:15][CH3:16])[CH3:13])=[O:9])=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(CO)cc1
Yield: 109.2 %

Procedure:
4-(Hydroxymethyl)benzoic acid (3.00 g, 19.7 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.31 g, 23.7 mmol) in chloroform (30 mL) was stirred with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.54 g, 23.7 mmol), 1-hydroxybenzotriazole (3.20 g, 23.7 mmol) and N,N-diisopropylethylamine (8.04 mL, 47.3 mmol) at room temperature for one day. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a mixture containing the title compound as a colorless oil (4.20 g). The resulting mixture was used for the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][CH:33]=1)[CH2:15][N:16]1[C:22](=[O:23])[C@H:21]2[CH2:24][CH2:25][CH2:26][C@H:20]2[NH:19][C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]1=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]1(=[O:48])[N:38]([CH2:39][C:40](Cl)=[O:41])[C:37](=[O:43])[C:36]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:35]12.C([O-])(O)=O.[Na+]>ClCCCl.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][CH:33]=1)[CH2:15][N:16]1[C:22](=[O:23])[C@H:21]2[CH2:24][CH2:25][CH2:26][C@H:20]2[N:19]([C:40](=[O:41])[CH2:39][N:38]2[C:37](=[O:43])[C:36]3=[CH:44][CH:45]=[CH:46][CH:47]=[C:35]3[C:34]2=[O:48])[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]1=2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: O=C(Nc1cccc(CN2C(=O)[C@H]3CCC[C@H]3Nc3ccccc32)c1)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: O=C(Nc1cccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)c1)OCc1ccccc1
Yield: 55.5 %

Procedure:
To a solution of (3aR*,10aS*)-9-[3-(benzyloxycarbonylamino)benzyl]-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (1.9 g, 4.3 mmol) in 1,2-dichloroethane (50 mL) was added phthalimidoacetyl chloride (1.1 g, 4.7 mmol) at room temperature and the mixture was refluxed for 17 hours. After cooling, saturated aqueous NaHCO3 solution (30 mL) was added and the mixture was diluted with water and extracted with 2 portions of chloroform. The pooled organic layer was washed with saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from diethyl ether to provide 1.5 g (yield 55%) of the title compound. m.p. 224°-225° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[CH:7][N:6]=[C:5]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1.[Cl:21][CH2:22][C:23](Cl)=[O:24]>>[ClH:12].[Cl:12][C:11]1[CH:10]=[C:9]2[C:4]([C:5]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)=[N:6][CH:7]=[N:8]2)=[CH:3][C:2]=1[NH:1][C:23](=[O:24])[CH2:22][Cl:21]
Reactant: Cc1cccc(Nc2ncnc3cc(Cl)c(N)cc23)c1
Reactant: O=C(Cl)CCl
Product: Cc1cccc(Nc2ncnc3cc(Cl)c(NC(=O)CCl)cc23)c1
Product: Cl
Yield: 79 %

Procedure:
Using an analogous procedure to that described in Example 4, 6-amino-7-chloro-4-(3'-methylanilino)quinazoline was reacted with 2-chloroacetyl chloride to give 7-chloro-6-(2-chloroacetamido)-4-(3'-methylanilino)quinazoline hydrochloride in 79% yield;
Reaction SMILES: [CH3:1][N:2]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][C:24]([C:27]1[S:28][CH:29]=[CH:30][N:31]=1)=[CH:23]2)[S:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH2:11][S:12][CH2:13][C:14]([O:16]C)=[O:15])(=[O:5])=[O:4].[OH-].[Na+]>CO.O1CCCC1>[CH3:1][N:2]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][C:24]([C:27]1[S:28][CH:29]=[CH:30][N:31]=1)=[CH:23]2)[S:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH2:11][S:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:5])=[O:4]
Reactant: COC(=O)CSCc1sccc1S(=O)(=O)N(C)c1cccc2cc(-c3nccs3)[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1CSCC(=O)O
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To a solution of methyl ({[3-({methyl[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]amino}sulfonyl)-2-thienyl]methyl}thio)acetate (300 mg) in methanol (2 mL) and tetrahydrofuran (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL) at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was concentrated, and 1N hydrochloric acid (5 mL) was added to the residue. The precipitated crystals were collected by filtration, washed with water, and dried to give the title compound (276 mg, yield 96%) as colorless crystals. melting point 193° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B(O)O)[C:6]([O:12][CH3:13])=[CH:5][N:4]=1.Br[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[C:15]([C:7]2[C:6]([O:12][CH3:13])=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:20]=1
Reactant: COc1cc(B(O)O)c(OC)cn1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Br
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Product: COc1cc(-c2cc(Cl)ccc2[N+](=O)[O-])c(OC)cn1

Procedure:
215 mg (purity 85%, 1.0 mmol) of 2,5-dimethoxypyridin-4-ylboronic acid and 236 mg (1.0 mmol) of 2-bromo-4-chloro-1-nitrobenzene in the presence of XPhos precatalyst were reacted according to General Method 2B. Yield: 124 mg (purity 93%, 39% of theory)
Reaction SMILES: [CH2:1]([N:3]1[C:12](=O)[C:11]2[NH:10][C:9]([CH:14]([CH3:16])[CH3:15])=[N:8][C:7]=2[N:6]([CH2:17][CH3:18])[C:4]1=[O:5])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].[OH-].[Na+]>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12](=[S:20])[C:11]2[NH:10][C:9]([CH:14]([CH3:16])[CH3:15])=[N:8][C:7]=2[N:6]([CH2:17][CH3:18])[C:4]1=[O:5])[CH3:2]
Reactant: CCn1c(=O)c2[nH]c(C(C)C)nc2n(CC)c1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCn1c(=S)c2[nH]c(C(C)C)nc2n(CC)c1=O

Procedure:
1,3-diethyl-8-isopropyl-xanthine (6.25 g, 25 mM) (J Amer Chem Soc 1953,75, 114-5) and 6.8 g (30 mM) of phosphorus pentasulfide were refluxed in 86 ml of pyridine for 3 days. At 10-20° C., 33.5 ml of 2N NaOH are added with cooling. The solid was filtered off and washed with pyridine. The filtrate was evaporated in vacuo to dryness, the residue suspended in 50 ml of water, adjusted to pH 7.5, the solid collected, washed with water and dried. The product was redissolved in 30 ml NaOH, treated twice with 0.5 g of charcoal, filtered, and acidified with 5N HCl to pH 3. At 5° C., the solid was collected, washed and dried. The compound had a mp of 168-70° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CS(C)=O.O>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][CH2:5][C:4]2[CH:9]=[CH:10][CH:11]=[CH:2][CH:3]=2)[C:11]=1[O:12][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:5]([O:7][CH3:8])=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
Methyl 3,4,5-trihydroxybenzoate (16) (55.24 g, 0.3 mol), benzyl chloride (113.93 g, 0.9 mol), potassium carbonate (124.39 g, 0.9 mol) and potassium iodide (catalytic amount) were mechanically stirred in dry DMSO (200 mL) at room temperature overnight. Water (200 mL) was added and the crude product isolated by filtration. Evaporation of residual solvents in a vacuum desiccator left a pale yellow solid which was essentially pure product. Yield: 128.2 g (94%).
Reaction SMILES: CC(C)([O-:4])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][CH:9]=1.[CH2:17]1[CH2:21][O:20][CH2:19][CH2:18]1>>[CH2:19]([O:20][C:21](=[O:4])/[CH:17]=[C:14](/[C:11]1[CH:12]=[CH:13][C:8]([Br:7])=[CH:9][CH:10]=1)\[CH3:15])[CH3:18]
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [K+]
Product: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of potassium tert-butoxide (10.45 g, 90.43 mmol) in THF (250 ml) was stirred under nitrogen atmosphere. A solution of triethyl phosphonoacetate (18.1 ml, 90.43 mmol) in THF (100 ml) was then added and the reaction mixture was stirred for 30 minutes at room temperature. A solution of 1-(4-Bromo-phenyl)-ethanone (6 g, 30.14 mmol) in THF (100 ml) was then added dropwise over 5 minutes. The reaction mixture was heated to reflux. After 3 hours the reaction mixture was cooled to ambient temperature and THF was removed under reduced pressure. The reaction mixture was dissolved in H2O, extracted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica (Hept:EtOAc 8:2) to afford the title compound (8.1 g, 99%).
Reaction SMILES: [CH2:1]1[O:8][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([NH2:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16]>>[CH2:9]([NH:17][CH2:1][CH:2]([OH:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:1][CH:2]([OH:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC1CO1
Reactant: NCCCCCCCN
Product: CCCCCC(O)CNCCCCCCCNCC(O)CCCCC

Procedure:
Condensation of 1-heptene oxide and 1,7-heptanediamine affords N,N'-(1,7-heptylene)-bis [2-hydroxyheptylamine] (I: R = CH3 (CH2)4, R' = H, X = (CH2)7, Z = H).