Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[C:3]=1[C:4](O)=O.[CH3:15][O:16][C:17]([C:19]1[S:23][C:22]2[C:24]([N+:28]([O-:30])=[O:29])=[CH:25][CH:26]=[CH:27][C:21]=2[CH:20]=1)=[O:18].[NH2:31][C:32]1[C:33]([O:47][CH3:48])=[C:34]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:35]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:37]=1>>[CH3:15][O:16][C:17]([C:19]1[S:23][C:2]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[C:3]=2[CH:4]=1)=[O:18].[C:38]([C:36]1[CH:35]=[C:34]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[C:33]([O:47][CH3:48])=[C:32]([NH:31][C:17]([C:19]2[S:23][C:22]3[C:24]([N+:28]([O-:30])=[O:29])=[CH:25][CH:26]=[C:27]([Cl:1])[C:21]=3[CH:20]=2)=[O:18])[CH:37]=1)([CH3:40])([CH3:41])[CH3:39]
Reactant: COC(=O)c1cc2cccc([N+](=O)[O-])c2s1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COC(=O)c1cc2c(Cl)ccc([N+](=O)[O-])c2s1
Product: COc1c(NC(=O)c2cc3c(Cl)ccc([N+](=O)[O-])c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
4-Chloro-7-nitro-benzo[b]thiophene-2-carboxylic acid methyl ester was prepared from 2,6-dichloro-3-nitro-benzoic acid using a procedure analogous to that described in Example 1 for 7-nitro-benzo[b]thiophene-2-carboxylic acid methyl ester. Then, following the procedure described in Example 1, the ester was hydrolyzed and the resulting acid coupled with N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide to provide 4-chloro-7-nitro-benzo[b]thiophene-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][O:6][CH:5]([C:8]([OH:10])=O)[O:4][CH2:3]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N(Cl)C(=O)C1.[CH3:38][O:39][C:40]([C:42]1[S:43][C:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:45][C:46]=1[NH:47][CH:48]([CH3:50])[CH3:49])=[O:41]>ClCCCl>[CH3:38][O:39][C:40]([C:42]1[S:43][C:44]([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)=[CH:45][C:46]=1[N:47]([CH:48]([CH3:50])[CH3:49])[C:8]([CH:5]1[O:4][CH2:3][CH:2]([CH3:1])[CH2:7][O:6]1)=[O:10])=[O:41]
Reactant: CC1COC(C(=O)O)OC1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)C
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1OCC(C)CO1)C(C)C
Yield: 35.7 %

Procedure:
A solution 5-methyl-[1,3]dioxane-2-carboxylic acid (53 mg, 0.47 mmol)in 1,2-dichloroethane at 0° C. was treated with PPh3 (124 mg, 0.47 mmol), NCS (63 mg, 0.47 mmol) and isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (100 mg, 0.36 mmol). The reaction was heated at reflux for 3 days. The mixture was evaporated to a residue that was purified by silica gel column chromatography using EtOAc:hexanes as eluent to furnished 3-[isopropyl-(5-methyl-[1,3]dioxane-2-carbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (51.8 mg, 35% yield). 1H NMR (CDCl3, 400 MHz): 7.65 (d, 2H), 7.42 (m, 3H), 7.10 (s, 1H), 4.90 (q, 1H), 4.55 (s, 1H), 4.00 (dd, 1H), 3.90 (dd, 1H), 3.85 (s, 3H), 3.10 (t, 1H), 2.95 (t, 1H), 2.10 (m, 1H), 1.25 (d, 3H), 1.05 (d, 3H), 0.58 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]=O)[N:6]2[N:5]=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[N:13]1([CH2:11][C:10]2[N:6]3[C:7]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[CH:8][CH:9]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: Nc1ncnn2c(C=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Nc1ncnn2c(CN3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.5 %

Procedure:
To 4-aminopyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (235 mg, 1.45 mmol) in 1,2-dichroloethane (5 ml) was added morpholine (0.25 ml, 2.9 mmol) and sodium triacetoxyborohydride (611 mg, 2.9 mmol). The reaction mixture was stirred at rt under N2 for 16 h. The reaction was quenched with saturated aq. sodium bicarbonate and followed by extraction with CH2Cl2. The organic was dried over Na2SO4, concentrated and purified via column chromatography (5:95 v/v CH3OH—CH2Cl2) to afford 66 mg of the title compound (yield 20%). 1H-NMR (DMSO-d6) δ 7.80 (s, 1H), 7.62 (br, 2H), 6.83 (d, J=4 Hz, 1H), 6.52 (d, J=4 Hz, 1H), 3.75 (s, 2H), 3.51 (t, J=4 Hz, 4H), 2.37 (t, J=4 Hz, 4H); MS [M+H]+=234; LCMS RT=1.00 min.
Reaction SMILES: [C:1]1([C:7]2([C:12](O)=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)C(C1C=CC=CC=1)[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19].[CH2:47](N1C[C@H]2C(N)CC[C@H]2C1)[C:48]1C=CC=CC=1>>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][C:18]([NH:20][C@H:21]2[C@H:28]3[C@H:24]([CH2:25][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=4)[CH2:27]3)[CH2:23][CH2:22]2)=[O:19])[CH:10]=[CH:9][CH:8]=[CH:48][CH:47]=1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Reactant: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: O=C(CC(c1ccccc1)c1ccccc1)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21

Procedure:
The title compound was prepared by substituting 3,3-diphenylpropanoic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4R*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 2: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.28 (d, J=7.4, 1H), 7.74 (s, 1H), 7.45 (t, J=7.7, 1H), 7.38 (dd, J=1.8, 7.4, 4H), 7.28 (dt, J=7.6, 9.4, 4H), 7.20-7.17 (m, 4H), 5.00 (t, J=7.8, 1H), 4.34-4.26 (m, 1H), 3.56 (d, J=13.5, 1H), 3.43 (d, J=13.5, 1H), 3.14 (d, J=7.9, 2H), 2.65 (dd, J=2.1, 8.3, 1H), 2.45-2.36 (m, 1H), 2.36-2.28 (m, 2H), 2.26-2.19 (m, 2H), 1.98-1.89 (m, 1H), 1.72 (ddd, J=6.3, 12.5, 14.5, 1H), 1.43 (dt, J=7.4, 14.1, 1H), 1.34-1.25 (m, 1H); MS (ESI+) m/z 493 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Br:8])[N:3]=1.[N:9]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CC(O)C>[Br:8][C:4]1[N:3]=[C:2]([N:12]2[CH2:13][CH2:14][CH2:15][N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]2)[CH:7]=[N:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Brc1cncc(Br)n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCCN(c2cncc(Br)n2)CC1
Temperature: 120 °C
Yield: 94.6 %

Procedure:
A mixture of 2,6-dibromopyrazine (5.0198 mmol; 1194.1 mg), tert-butyl 1,4-diazepane-1-carboxylate (5.271 mmol; 1055.6 mg), and triethylamine (15.06 mmol; 1539 mg; 2.12 mL) in IPA (10 mL) in a sealed pressure vial was heated at 120° C. overnight. The mixture was cooled to room temperature, and then concentrated. The residue was purified on silica elute with 0 to 100% EtOAc in Heptane to afford tert-butyl 4-(6-bromopyrazin-2-yl)-1,4-diazepane-1-carboxylate (1.6965 g, 95%). MS (ESI) m/z: 357 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[N:6]=[C:7]2Cl.[Si:18]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:34])=[C:31]([CH:33]=1)N)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].[CH3:35]C(C)([O-])C.[Na+]>C1COCC1>[Si:18]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:34])=[C:31]([NH:6][C:7]2[C:8]3[CH:9]=[CH:10][N:11]=[C:2]([Cl:1])[C:3]=3[C:4]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=3[CH:35]=2)[CH:33]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: Fc1ccc2nc(Cl)c3ccnc(Cl)c3c2c1
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1N
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1Nc1cc2ccc(F)cc2c2c(Cl)nccc12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,5-dichloro-9-fluorobenzo[c]-2,6-naphthyridine (Example 1, Step 5) (150 mg, 0.56 mmol) and 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methylaniline (155 mg, 0.62 mmol) in THF (9.3 mL) was added sodium tert-butoxide (65 mg, 0.67 mmol). The reaction stirred at 60° C. for 30 minutes was then quenched by the addition of sat. aq. NaHCO3 solution. The mixture was extracted with EtOAc and the extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by silica gel column chromatography (0-50% EtOAc/heptane) afforded the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][NH2:34])[CH:29]=[CH:30][CH:31]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18]([NH:34][CH2:33][CH2:32][C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=4)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2]
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Reactant: NCCc1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NCCc4cccc(F)c4)=NC3=O)cc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 67.2 %

Procedure:
The suspension of 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14 g) (71 mg, 0.2 mmol), m-fluorophenylethylamine (28 ul, 0.22 mmol) and DIEA (diisopropylethylamine) (0.11 mL, 0.44 mmol) in acetonitrile (2 mL) was stirred under at 80° C. for 4 h. After cooling to room temperature, the solid was collected by filtration, washed with a little bit of acetonitrile and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-5% methanol in methylene chloride in 30 min) afforded 4-ethoxy-6-[2-[2-(3-fluoro-phenyl)-ethylamino]-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (60 mg, 67%) as a light yellow solid: LC-MS m/e 447 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][CH2:10][C:11]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:10][C:11]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CNCc1cccc(Br)n1)NC1CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N(CC(=O)NC1CCCC1)Cc1cccc(Br)n1
Temperature: 0 °C

Procedure:
N2-[(6-Bromopyridin-2-yl)methyl]-N-cyclopentylglycinamide (0.25 g, 0.80 mmol) was dissolved in dichloromethane (3.2 mL) and triethylamine (0.34 mL, 2.4 mmol) was added. The reaction was cooled to 0° C. and methanesulfonyl chloride (0.069 mL, 0.88 mmol) was added and the reaction was allowed to warm to room temperature. The solution was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude mixture was purified by silica gel chromatography to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([N:11]2[C:15](=[O:16])[NH:14][N:13]=[N:12]2)[C:5]=1[Cl:17].CI.[C:21](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:17][C:5]1[C:6]([N:11]2[C:15](=[O:16])[N:14]([CH3:21])[N:13]=[N:12]2)=[C:7]([Cl:10])[CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:18]
Reactant: COC(=O)c1ccc(Cl)c(-n2nn[nH]c2=O)c1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c(-n2nnn(C)c2=O)c1Cl
Temperature: 60 °C
Yield: 98.5 %

Procedure:
Methyl-2,4-dichloro-3-(4,5-dihydro-5-oxo-1H-tetrazol-1-yl)benzoate (4.00 g), methyl iodide (2.36 g) and potassium carbonate (2.29 g) were suspended in N,N-dimethylformamide (30 ml) and stirred at 60° C. After reaction, cold water was added to the reaction mixture and the mixture was extracted with ethyl acetate (150 ml) and dried with anhydrous magnesium sulfate. By distilling off the ethyl acetate, the objective methyl 2,4-dichloro-3-(4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-1-yl)benzoate (4.13 g, yield 98%) was obtained. mp: 135-137° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[N:11][CH:12]=1.[B:20](OC)([O:23]C)[O:21]C.Cl>O.C(OCC)C>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([B:20]([OH:23])[OH:21])=[CH:12][N:11]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCOc1ccc(Br)cn1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CCCCCCOc1ccc(B(O)O)cn1
Reaction time: 1 h

Procedure:
250 mmol of n-butyllithium (1.6M solution in n-hexane) are added dropwise at 0° C. with exclusion of moisture and under a protective-gas atmosphere to a solution of 250 mmol of 5bromo-2-hexyloxypyridine in 500 ml of abs. diethyl ether. The mixture is stirred at this temperature for a further 1 hour, and 275 mmol of trimethyl borate are subsequently added slowly. After the mixture has been stirred at 0° C. for a further hour, a solution of 175 ml of water and 25 ml of 37 percent hydrochloric acid is added dropwise. The mixture is stirred at room temperature for 1 hour, the phases are then separated, the aqueous phase is extracted a number of times with dichloromethane, and the combined organic extracts are dried using magnesium sulfate. The solvents are removed in vacuo. After drying in a high vacuum, the red-brown, high-viscosity crude product is reacted further without additional purification.
Reaction SMILES: [C:1]1([C:7](=[CH2:11])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:14])=O>>[C:1]1([C:7](=[CH2:11])[C:8]([Cl:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: C=C(C(=O)O)c1ccccc1
Product: C=C(C(=O)Cl)c1ccccc1

Procedure:
is prepared by treating 2-phenyl-acrylic acid with thionyl chloride to afford 2-phenyl-acryloyl chloride. The latter is subsequently treated with N-methylalanine in dichloromethane according to the following literature: H. P. Ward, E. F. Jenkins J. Org. Chem. 1945, 10, 371-373.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16]Cl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:7]=2[CH:25]=1.[CH2:28]([NH2:31])[C:29]#[CH:30].[I-].[K+]>CN(C)C=O>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][NH:31][CH2:28][C:29]#[CH:30])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:7]=2[CH:25]=1
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Reactant: C#CCN
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCNCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 19, 8 -(trifluoromethyl)-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide is reacted at room temperature with propargylamine in the presence of potassium iodide to give 8-(trifluoromethyl)-1-[[(2-propynyl)amino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 23 8 -Chloro-1-[[(2-propynyl)amino]methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[C:15]2[CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:10][CH:9]=1.[I:24]I.I>O.C(O)(=O)C>[I:24][C:13]1[CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])[C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([O:7][CH3:6])[CH:17]=2
Reactant: COc1ccc2cccc(CCNC(C)=O)c2c1
Reactant: II
Agent: I
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2cc(I)cc(CCNC(C)=O)c2c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A solution is formed by adding 46.25 ml of glacial acetic acid and 1.25 ml of concentrated sulphuric acid to 2.5 ml of water. 2.5 g of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide (10.31 mmol) are dissolved in 30 ml of that solution. 2.09 g of iodine (8.25 mmol) and 0.91 g of HIO3 (5.16 mmol) are then added to the reaction mixture, causing a grey precipitate to appear in a solution that has turned red. The reaction mixture is heated for 15 hours at 65° C., 5.14 ml of concentrated hydriodic acid (13.41 mmol) are added and heating is continued for 2 hours. The suspension is then poured into 200 ml of water and the precipitate that forms is filtered off. The precipitate is dissolved in ethyl acetate and washed with 1M NaHCO3, the organic phase is then concentrated, and purified by chromatography on silica gel, using a dichloromethane/methanol mixture, 99.5/0.5, as eluant, to yield the title product.
Reaction SMILES: [C:1]([N:11](C)[C@H:12]([C:19]([NH:21][C@H:22]([C:35]([NH2:37])=[O:36])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=1)=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(OCC1C=CC=CC=1)=O.[H][H]>CO.[C].[Pd]>[NH:11]([CH3:1])[C@H:12]([C:19]([NH:21][C@H:22]([C:35]([NH2:37])=[O:36])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([C:31]([CH3:34])([CH3:32])[CH3:33])[CH:25]=1)=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:11]([CH3:1])[C@@H:12]([C:19]([NH:21][C@H:22]([C:35]([NH2:37])=[O:36])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([C:31]([CH3:34])([CH3:32])[CH3:33])[CH:25]=1)=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: CN(C(=O)OCc1ccccc1)[C@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN[C@@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)c1ccccc1
Product: CN[C@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)c1ccccc1

Procedure:
A mixture of Z-N-Me-Phg-Tyr(3-tBu)-NH2 (4.03 g) and 10% palladium carbon (2.0 g) in methanol (200 ml) was stirred in a hydrogen atmosphere for 4 hours. The reaction mixture was filtered and the filtrate was distilled off under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of methylene chloride, methanol and aqueous ammonia at a ratio of 100:5:1) to give N-Me-Phg-Tyr(3-tBu)-NH2 in 1.48 g (50%) and N-Me-D-Phg-Tyr(3-tBu)-NH2 in the amount of 920 mg (31%).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8](/[CH:11]=[C:12](\[C:18]3[CH:31]=[CH:30][C:29]4[S:28](=[O:33])(=[O:32])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21](C(OC(C)(C)C)=O)[C:20]=4[CH:19]=3)/[C:13]([O:15]CC)=[O:14])[CH2:7][CH2:6]2)[O:4]CC1.[OH-].[Na+].Cl>CO.CC(C)=O>[O:33]=[S:28]1(=[O:32])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][C:20]2[CH:19]=[C:18](/[C:12](=[CH:11]\[CH:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]3)/[C:13]([OH:15])=[O:14])[CH:31]=[CH:30][C:29]1=2
Reactant: CCOC(=O)/C(=C/C1CCC2(CC1)OCCO2)c1ccc2c(c1)N(C(=O)OC(C)(C)C)c1ccccc1S2(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: O=C1CCC(/C=C(/C(=O)O)c2ccc3c(c2)Nc2ccccc2S3(=O)=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.14 g of tert-butyl 2-[(E)-2-(1,4-dioxa-spiro[4.5]dec-8-yl)-1-ethoxycarbonylvinyl]-5,5-dioxo-5H-phenothiazine-10-carboxylate are dissolved in 130 ml of methanol, and 7.0 ml of a 2 M NaOH solution are added. The reaction mixture is heated at the boil under reflux for two hours. Methanol is removed under reduced pressure and the reaction mixture is adjusted to pH 4 by addition of concentrated hydrochloric acid. The precipitated solid is dissolved in 200 ml of ethyl acetate and dried over MgSO4, and the solvent is then removed under reduced pressure. The residue obtained in this manner is dissolved in 20 ml of acetone, and 4 ml of 50% strength hydrochloric acid solution are added. The reaction mixture is stirred at room temperature for 30 minutes. The acetone is removed under reduced pressure and the residue is taken up in 100 ml of water and 100 ml of ethyl acetate. The organic phase is dried over MgSO4, and the solvent is then removed under reduced pressure. This gives 840 mg of (E)-2-(5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(4-oxocyclohexyl)acrylic acid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21](OCC)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.O1CCCC1.CO.[BH4-].[Li+]>O>[CH3:1][O:2][CH2:3][CH:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][CH2:21][OH:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC(C)COC)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CCO)S3)[nH]c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.4 %

Procedure:
To a mixture of ethyl {2-[7-(2-methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (660 mg), tetrahydrofuran (30 mL) and methanol (5 mL) was added lithium borohydride (130 mg) at 0° C. The whole was stirred at room temperature for 5 h. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:1 to 1:0, volume ratio) to give pale yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (380 mg, 62%) as pale yellow prisms. MS 506 (MH+). mp 138-139° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=2)[CH:3]=[CH:2]1.C1CCN2C(=NCCC2)CC1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].O>C(Cl)Cl>[Si:23]([O:11][CH2:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: OCc1ccc2cc[nH]c2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccc2cc[nH]c2c1
Yield: 90.1 %

Procedure:
1 g (1H-indole-6-yl)-methanol (1.0 g, 6.79 mmol) in DCM (25 mL) was added DBU (1.24 g, 8.15 mmol) and tert-butyldimethylsilylchloride (1.14 g, 7.54 mmol). The reaction mixture was stirred 16 hours before water (25 mL) was added. The phases were separated and the organic phase was washed with HCl (0.1 N, 25 mL) and sodium bicarbonate (sat., 25 mL) and dried MgSO4. The solvent was removed in vacuo to give 1.6 g (90%) 6-(tert-butyldimethylsilanyloxymethyl)-indole. This was converted to 1-cyclopropylmethyl-6-hydroxymethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide using general procedure A where R5X=cyclopropyl-methylbromide; NH2A=2-aminothiazole.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[CH3:6][O:7][C:8]1[N:13]=[C:12](/[CH:14]=[CH:15]/[C:16]2[N:34]=[C:19]3[C@H:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH2:21][CH2:22][CH2:23][N:18]3[N:17]=2)[CH:11]=[CH:10][C:9]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1.C(OCC)(=O)C>C(O)C>[S:1]([O:3][S:1]([OH:4])(=[O:3])=[O:2])([OH:2])(=[O:5])=[O:4].[CH3:6][O:7][C:8]1[N:13]=[C:12](/[CH:14]=[CH:15]/[C:16]2[N:34]=[C:19]3[C@H:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH2:21][CH2:22][CH2:23][N:18]3[N:17]=2)[CH:11]=[CH:10][C:9]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1
Reactant: O=S(=O)(O)O
Agent: COc1nc(/C=C/c2nc3n(n2)CCC[C@H]3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=S(=O)(O)OS(=O)(=O)O
Temperature: 25 °C

Procedure:
Concentrated sulfuric acid (11.5 μL) was added to a solution of (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine (98.09 mg) in ethanol (1 mL), and 1 mL of ethyl acetate was added with stirring at room temperature. Since the oily portion was confirmed on the bottom of the recovery flask, the oily substance was dissolved by ultrasonic treatment. Stirring at room temperature under shading for about 30 minutes resulted in precipitation of a solid. The solid was collected by filtration through a glass filter and dried under reduced pressure at room temperature to obtain 127.94 mg of the title compound as white solid crystals.