Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:20]3[O:21][C:22]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:23][C:24](=[O:26])[CH:25]=3)[S:9][C:8]=2[CH:7]=1.[OH-].[Na+:35]>CO>[Na+:35].[N:27]1([C:22]2[O:21][C:20]([C:14]3[CH:13]=[CH:12][CH:11]=[C:10]4[C:15]=3[S:16][C:17]3[CH:18]=[CH:19][C:6]([O:5][CH2:4][C:3]([O-:33])=[O:2])=[CH:7][C:8]=3[S:9]4)=[CH:25][C:24](=[O:26])[CH:23]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: COC(=O)COc1ccc2c(c1)Sc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])COc1ccc2c(c1)Sc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Temperature: 60 °C
Yield: 100 %

Procedure:
To a solution of [6-(6-Morpholin-4-yl-4-oxo-4H-pyran-2-yl)-thianthren-2-yloxy]-acetic acid methyl ester (22 mg, 0.045 mmol in methanol (2 ml) was added solid sodium hydroxide (2 mg, 0.045 mmol). The mixture was stirred vigorously and heated to 60° C. for 1 hour. After this time, the mixture was concentrated in vacuo to dryness to give the title compound (22.4 mg, 100%) and used without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[NH2:16][C@H:17]([CH3:23])[CH:18]([CH:20]1[CH2:22][CH2:21]1)[OH:19].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:16][C@H:17]([CH3:23])[CH:18]([CH:20]3[CH2:22][CH2:21]3)[OH:19])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: C[C@@H](N)C(O)C1CC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C(O)C1CC1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (272 mg, 0.989 mmol), (2R)-2-amino-1-cyclopropylpropan-1-ol hydrochloride (300 mg, 1.978 mmol) and DIPEA (0.691 ml, 3.96 mmol) were heated to 110° C. in NMP (3.297 ml) for 4 hrs. The reaction was then cooled to rt and ice-water added. After the ice had melted, the mixture was extracted with ethyl acetate (3×). The combined organics were then dried (MgSO4) and evaporated in vacuo before purifying by column chromatography using hexane ethyl acetate as eluent to give 6-bromo-4-(((2R)-1-cyclopropyl-1-hydroxypropan-2-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (111 mg, 0.299 mmol, 30.2% yield) as a mixture of diastereoisomers. 1H NMR (500 MHz, CCl3D) δ 7.93-7.78 (m, 1H), 7.68-7.52 (m, 1H), 6.93 (d, J=1.7 Hz, 1H), 5.44 (br. s., 1H), 4.53-4.27 (m, 1H), 4.13 (q, J=7.2 Hz, 1H), 2.99 (dd, J=9.2, 3.1 Hz, 1H), 1.48 (d, J=6.7 Hz, 3H), 1.27 (t, J=7.1 Hz, 2H), 1.14-0.99 (m, 1H), 0.65-0.53 (m, 2H), 0.43-0.27 (m, 2H).
Reaction SMILES: O[C:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.O>O1CCOCC1>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:2](=[CH2:6])[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=1
Reactant: COc1ccc(C(C)(O)C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: C=C(C(=O)O)c1ccc(OC)cc1
Yield: 78.2 %

Procedure:
2-Hydroxy-2-(4-methoxyphenyl)propionic acid (35 g, 178 mmol) was dissolved in dioxane (700 ml) and concentrated sulfuric acid (60 ml) was added thereto. The reaction mixture was refluxed for 2 hours under heating. The reaction solution was cooled and, after adding water, extracted with ethyl acetate. The organic layer was washed with saturated sodium thiosulfate solution and water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 24.8 g (yield: 72%) of the title compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cl)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cc(Cl)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
Step N1. A mixture of dimethyl 5-chloroisophthalate (6.84 g, 30 mmol), in methanol (150 mL) was treated with 1M sodium hydroxide (27 mL, 27 mmol) and the reaction stirred at room temperature for 16 hours. The mixture was concentrated under vacuum and the resulting residue was dissolved in water. The mixture was extracted with ethyl acetate three times. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated to afford 3-chloro-5-(methoxycarbonyl)benzoic acid (4.8 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:21]2[C:16](=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([OH:22])[CH:20]=2)[CH:15]=[N:14]1.[H-].[Na+].[CH2:28](Br)[C:29]#[CH:30].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:21]2[C:16](=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([O:22][CH2:30][C:29]#[CH:28])[CH:20]=2)[CH:15]=[N:14]1
Reactant: O=[N+]([O-])c1cc2cnn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2cc1O
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc2c(cnn2-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
To a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-6-hydroxy-5-nitroindazole [Compound No. 31] (3 g) in N,N-dimethylformamide, 60% sodium hydride (0.5 g) was added, and the resultant mixture was stirred while cooling with ice. After 10 minutes, propargyl bromide (1.2 g) was added thereto, and the resultant mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured into water and extracted with diethyl ether. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-nitro-6-propargyloxyindazole (2.8 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:12]Br>C(Cl)(Cl)Cl.CC(O)=O>[Br:12][C:5]1[CH:6]=[C:7]([C:8]([F:9])([F:11])[F:10])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncccc1C(F)(F)F
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Nc1ncc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-amino-3-trifluoromethylpyridine (0.980 g, 5.92 mmol) is dissolved in CHCl3 (7 ml) and AcOH (5 ml). The reaction mixture is cooled to 0-10° C. (ice-bath) and bromine (0.424 ml, 8.3 mmol) dissolved in CHCl3 is slowly added drop wise. The reaction mixture is stirred at this temperature for 1 hour then allowed to warm room temperature. The solvents are removed in vacuo and the residue is dissolved in EtOAc washing with saturated NaHCO3. The organic portion is dried over MgSO4, filtered and concentrated to afford the title compound.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([O:22][CH2:23][CH2:24]NC(OC(C)(C)C)=O)[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(CC2C(C(OC)=O)=C(O)C(C3C=COC=3)=CC=2)(=O)=O)C=CC=CC=1.[C:64]([O:68][C:69]([NH:71][CH2:72]CCBr)=[O:70])([CH3:67])([CH3:66])[CH3:65]>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:22][CH2:23][CH2:24][CH2:72][NH:71][C:69]([O:68][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:70])[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCCNC(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 10, starting from methyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 114) and 3-(t-butoxycarbonylamino)propyl bromide.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)[CH:3]=[O:4].[C:15](O)(=[O:17])[CH3:16]>>[C:15]([O:4][CH:3]=[C:2]([CH3:1])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)O
Reactant: CC(C=O)Cc1ccc2c(c1)OCO2
Product: CC(=O)OC=C(C)Cc1ccc2c(c1)OCO2

Procedure:
Thereafter, the same operations as the procedure (a), the step (2) and the step (3) (procedure (c)) in Example 2 were carried out to provide 27.7 g of 2-methyl-3-(3,4-methylenedioxyphenyl)propanal. The amount of acetic acid contained in the resulting 2-methyl-3-(3,4-methylenedioxy-phenyl)propanal was 18 ppm.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:28]([CH:29]3[CH2:31][CH2:30]3)=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([F:32])[CH:21]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][NH:34][S:35]([NH2:38])(=[O:37])=[O:36]>>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:28]([CH:29]3[CH2:31][CH2:30]3)=[CH:27][C:23]([C:24]([NH:38][S:35](=[O:37])(=[O:36])[NH:34][CH3:33])=[O:25])=[C:22]([F:32])[CH:21]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Reactant: CNS(N)(=O)=O
Product: CNS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F

Procedure:
The compound was prepared in a similar manner to Example 408 from 4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid and N-methylsulfamide. LCMS (Method D): RT=4.48 min, m/z: 524.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 7.46-7.38 (m, 4H), 7.27 (t, J=7.7 Hz, 4H), 7.22-7.08 (m, 3H), 6.95 (d, J=12.7 Hz, 1H), 4.46 (s, 1H), 4.21 (d, J=6.2 Hz, 2H), 3.24 (d, J=7.4 Hz, 2H), 3.00 (t, J=6.6 Hz, 2H), 2.92-2.79 (m, 1H), 2.53 (d, J=4.9 Hz, 2H), 2.11-1.99 (m, 1H), 1.25 (d, J=7.1 Hz, 1H), 0.93-0.83 (m, 2H), 0.67 (m, 2H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:18]#[N:19])=[C:8]([C:10]([OH:17])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1.[H-].[Na+]>CN(C)C(=O)C>[C:37]([O:36][C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:6]2[C:7]([C:18]#[N:19])=[C:8]([C:10]([OH:17])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:12])[CH3:13])[N:9]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:23][CH:24]=1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CCCCc1nc(C(O)(C(C)C)C(C)C)c(C#N)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C(O)(C(C)C)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 90.4 %

Procedure:
Following a procedure similar to that described in Example 45(a), but using 282 mg of 2-butyl-4-[1-hydroxy-2-methyl-1-(1-methylethyl)propyl]imidazole-5-carbonitrile (prepared as described in Preparation 30), 409 mg of t-butyl 4'-(bromomethyl)biphenyl-2-carboxylate and 47 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in 5 ml of N,N-dimethylacetamide, 513 mg of the title compound were obtained as a viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH2:12][OH:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15](OC=C)(=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(OC(C)C)(C)C>[C:1]([O:5][C:6]([NH:8][C@@:9]([CH3:14])([CH2:10][O:11][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=COC(=O)CCCCC
Reactant: CC(CO)(CO)NC(=O)OC(C)(C)C
Solvent: CC(C)OC(C)C
Product: CCCCCC(=O)OC[C@@](C)(CO)NC(=O)OC(C)(C)C
Yield: 84.6 %

Procedure:
To a suspension of 2-t-butoxycarbonylamino-2-methylpropane-1,3-diol (20.0 g, 97.4 mmol) in isopropyl ether (200 ml) were added successively vinyl hexanoate (16.3 ml, 0.10 mol) and lipase [Immunobilized lipase from Pseudomonas sp., TOYOBO, 0.67 U/mg] (0.8 g) with stirring, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, the reaction mixture was filtered and evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (10:1-2:1) as the eluent to afford the title compound (25.0 g, yield: 85%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]2[N:9]([CH2:12][CH3:13])[N:10]=[CH:11][C:3]=12.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1>>[Cl:8][C:6]1[N:5]=[C:4]2[N:9]([CH2:12][CH3:13])[N:10]=[CH:11][C:3]2=[C:2]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=2)[N:7]=1
Reactant: COc1cccc(N)c1
Reactant: CCn1ncc2c(Cl)nc(Cl)nc21
Product: CCn1ncc2c(Nc3cccc(OC)c3)nc(Cl)nc21

Procedure:
4,6-Dichloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidine 5b was reacted with m-anisidine using General Procedure B to give (6-chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(3-methoxy-phenyl)-amine, which was reacted with indazole boronic acid pinacol ester using General Procedure A to give 147. NMR (CDCl3): 1.62 (3H, t), 3.88 (3H, s), 4.62 (2H, q), 6.89 (1H, dd), 7.17 (1H, d), 7.32 (1H, s), 7.40 (1H, t), 7.51 (1H, s), 7.55 (1H, t), 7.64 (1H, d), 8.45 (1H, d), 9.16 (1H, s), 10.20 (1H, br). MS: MH+ 386.19 (100%)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[NH:5][C:4](=[O:13])[C:3]=1[C:14]#[N:15].[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[N:7][CH:8]=1)[NH:5][C:4](=[O:13])[C:3]([C:14]#[N:15])=[C:2]2[N:26]1[CH2:27][CH2:28][N:23]([C:21]([C:17]2[O:16][CH:20]=[CH:19][CH:18]=2)=[O:22])[CH2:24][CH2:25]1
Reactant: N#Cc1c(Cl)c2cc(F)cnc2[nH]c1=O
Reactant: O=C(c1ccco1)N1CCNCC1
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2[nH]c1=O
Yield: 71 %

Procedure:
This compound was prepared from 4-chloro-6-fluoro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (96) and 2-furoyl piperazine according to general procedure E to yield 2.87 g (71%) of 6-fluoro-2-oxo-4-[4-(furan-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (99) as white solids. MP 312° C.; 1H-NMR (DMSO-d6): δ 3.69 (m, 4H), 3.93 (m, 4H), 6.66 (dd, J=1.6, 3.6 Hz, 1H), 7.08 (d, J=3.6 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 8.07 (dd, J=2.8, 9.2 Hz, 1H), 8.69 (d, J=2.8 Hz, 1H), 12.30 (s, 1H); EIMS: 368 (M+1).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([N:12]1[C:24]2[CH:23]=[C:22]3[CH2:25][CH2:26][CH2:27][CH2:28][C:21]3=[C:20]([O:29]C)[C:19]=2[C:18]2[C:17]([C:31]([O:33][CH3:34])=[O:32])=[CH:16][CH:15]=[CH:14][C:13]1=2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[CH2:5]([N:12]1[C:24]2[CH:23]=[C:22]3[CH2:25][CH2:26][CH2:27][CH2:28][C:21]3=[C:20]([OH:29])[C:19]=2[C:18]2[C:17]([C:31]([O:33][CH3:34])=[O:32])=[CH:16][CH:15]=[CH:14][C:13]1=2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(OC)c3c(cc1n2Cc1ccccc1)CCCC3
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cccc2c1c1c(O)c3c(cc1n2Cc1ccccc1)CCCC3
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 93.3 %

Procedure:
Boron tribromide (0.3 mL, 3.0 mM) was slowly added to a stirred solution of 5-benzyl-11-methoxy-7,8,9,10-tetrahydro-5H-benzo[b]carbazole-1-carboxylic acid, methyl ester, (0.12 g, 0.3 mM) in 5 mL methylene chloride at −10° C. After 5.5 h, the mixture was quenched with methanol (3.0 mL, 75.0 mM) and allowed to warm to room temperature with stirring over 2 h. The mixture was diluted with methylene chloride, washed with H2O, 1N HCl, saturated aqueous NaHCO3 solution, and saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 0.108 g (93%) of the title compound 5-benzyl-11-hydroxy-7,8,9,10-tetrahydro-5H-benzo[b]carbazole-1-carboxylic acid, methyl ester as a yellow solid (MP 174–176° C., MW 385.47).
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:16]2[C:7](=[CH:8][C:9]3[C:14]([C:15]=2[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=1.[Na].[Na].[CH3:27][P:28](=[O:31])([O-:30])[O-:29]>O.[Cl-].[Cl-].[Zn+2].[N+]([O-])([O-])=O.[Zn+2].[N+]([O-])([O-])=O.[Zn+2]>[CH:13]1[C:14]2[C:9](=[CH:8][C:7]3[C:16]([C:15]=2[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:10]=[CH:11][CH:12]=1.[CH3:27][P:28](=[O:29])([OH:31])[OH:30]
Reactant: CP(=O)([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CP(=O)(O)O

Procedure:
An ethanolic solution (1 mM) of the di-sodium salt of the product from Example 21 was prepared by the addition of 2 equivalents of 1 M NaOH in water. A fluorescence spectrum was run on the resultant solution; excitation λex 328 nm and gave emission peaks (λem) at 422 nm. Titration experiments were conducted by adding known quantities (μl of a 0.1 M ZnCl2 solution) of metal salts and the emission spectrum were recorded after each addition. A two and a half fold increase in fluorescent intensity of the solution was observed on addition of one equivalent of zinc nitrate. This di sodium (9-anthracyl)-N-benzylamine-methylphosphonate solution could sense, significant and reproducible increase in fluorescent intensity, Zn+2 concentrations down to 10−8M.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([S:17]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([I:1])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Ic1ccc2[nH]ccc2c1
Product: O=S(=O)(c1ccccc1)n1ccc2cc(I)ccc21

Procedure:
This compound was prepared from 5-iodo-1H-indole and benzenesulfonylchloride by the method outlined under 1.a).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[CH:24]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Reactant: CN(C)CCCCl
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(CCCN(C)C)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 179.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.52 g) and 3-chloro-N,N-dimethylpropylamine hydrochloride (0.49 g) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-({1-[3-(dimethylamino)propyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.1 g) was obtained. By the reaction and treatment in the same manner as in Example 105 using this compound, N-({1-[3-(dimethylamino)propyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.73 g) was obtained.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[CH:21][C:20]=3[CH2:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[CH:21][C:20]=3[CH2:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)cc2CCC(C)(C)C)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)O)C4CC4)c3)c(CCC(C)(C)C)c2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((3-(3,3-dimethylbutyl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)oxy)methyl)phenyl)propanoate in ethanol (3.0 mL) was added 1N aqueous sodium hydroxide solution (3.0 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (90 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.S(O)(O)(=O)=O.[NH2:52][C:53]1[NH:54][CH:55]=[CH:56][N:57]=1.[OH-].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:52][C:53]1[NH:54][CH:55]=[CH:56][N:57]=1)=[O:6]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: Nc1ncc[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(C(=O)Nc2ncc[nH]2)cccc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
5.0 g (27.4 mmol) of 2-amino-3-nitro-benzoic acid, 12.48 g (32.9 mmol) of HBTU were suspended in 20 mL of DMF. To this suspension, 10 mL of DIEA was added, and the resulting mixture was stirred for 10 minutes to form a paste. To this paste, 10 mL of DMF was added followed by 9 g (68.2 mmol) of 2-amino imidazole sulfate. The resulting mixture was heated at 75° C. for 3.0 h. The reaction mixture was cooled to room temperature and 5 mL of 2N NaOH was added followed by 200 mL of brine solution. A solid precipitated from the solution and was collected by filtration, washed with water (300 ml), ethyl acetate (100 ml), and dried under vacuum to provide 5.3 g (75%) of 2-amino-N-(1H-imidazol-2-yl)-3-nitro-benzamide as a yellow solid. The product was hydrogenated according to the general procedure C to give 2,3-diamino-N-(1H-imidazol-2-yl)-benzamide (4.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:45]=[CH:44][C:5]([CH2:6][N:7]([CH2:26][CH2:27][CH2:28][S:29](=[O:43])(=[O:42])[NH:30]CC2C=CC(OC)=CC=2OC)[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)=[O:9])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:45]=[CH:44][C:5]([CH2:6][N:7]([CH2:26][CH2:27][CH2:28][S:29](=[O:43])(=[O:42])[NH2:30])[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(CNS(=O)(=O)CCCN(Cc2ccc(Cl)cc2)C(=O)C2(C)CCN2C(=O)Cc2cc(C)cc(C)c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(CCCS(N)(=O)=O)Cc2ccc(Cl)cc2)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
1-[2-(3,5-Dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (4-chloro-benzyl)-[3-(2,4-dimethoxy-benzylsulfamoyl)-propyl]-amide, compound 168 was dissolved in TFA and stirred at 20° C. for 15 h. The crude was concentrated under reduced pressure then partitioned between water and EtOAc. The organic layer was washed twice with water, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc/DCM/MeOH: 1/0/0/0 then 0/1/0/0 then 50/50/95/5 then 50/50/90/10) to afford 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (4-chloro-benzyl)-(3-sulfamoyl-propyl)-amide.