Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[N:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([C:24]#[C:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:19][CH:20]=3)[C:15]2=[O:33])=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>>[O:33]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[C:18]([C:24]#[C:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:17]=2)[CH:22]=[N:23][N:14]1[CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]([OH:34])=[O:5])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2ncc3ccc(C#CCc4ccccc4)cc3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Cn2ncc3ccc(C#CCc4ccccc4)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[1-oxo-7-(3-phenyl-prop-1-ynyl)-1H-3-azaisoquinolin-2-ylmethyl]benzoic acid tert-butyl ester [0.20 g, 0.44 mmol, Example 1A, Step (2)] is treated with trifluoroacetic acid (5 mL) and the reaction mixture stirred at room temperature for 30 minutes. The solution is evaporated to dryness, the residue is dissolved in ethyl acetate, washed with water, brine, dried over MgSO4 and evaporated to dryness. The brown solid is triturated with acetonitrile, the solid collected by filtration, and washed with acetonitrile. The solid is then dissolved in hot ethyl acetate, evaporated onto silica gel, and purified on a 2.5×10 cm silica gel column eluted with hexanes/ethyl acetate 1:1, followed by ethyl acetate. Drying will afford the purified product.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:13]([OH:17])[C:14]([OH:16])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[CH3:22][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[C:5]([CH:13]([OH:17])[C:14]([O:16][CH3:22])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(O)C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
To solution of [3,5-bis(trifluoromethyl)phenyl](hydroxy)acetic acid (510 mg, 1.77 mmol) in benzene (10 mL) was added MeOH (1.5 mL) followed by (trimethylsilyl)diazomethane (1.06 mL of a 2M solution in hexanes, 2.12 mmol). After 10 minutes, the reaction was quenched with several drops of HOAc (add until yellow color disappears). The reaction was concentrated and purified by flash chromatography with 10 to 80% EtOAc/hexanes to afford methyl [3,5-bis(trifluoromethyl)phenyl](hydroxy)acetate. 1H NMR (CDCl3, 500 MHz) δ 7.94 (s, 2H), 7.85 (s, 1H), 5.32 (s, 1H), 3.83 (s, 3H), 3.68 (bs, 1H).
Reaction SMILES: [H][H].[CH2:3]([O:10][CH2:11][C@@H:12]1[C@@H:16]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C@@H:13]1[OH:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[Pt]=O.C(OCC)C>[CH2:3]([O:10][CH2:11][C@@H:12]1[C@H:16]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:14][C@H:13]1[OH:22])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C[C@H]1C=C[C@H](O)[C@@H]1COCc1ccccc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOCC
Product: COC(=O)C[C@@H]1CC[C@@H](O)[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
In an atmosphere of hydrogen, a mixture of 10.0 g of (1S,2S,3S)-2-benzyloxymethyl-3-methoxycarbonylmethyl-4-cyclopenten-1-ol (prepared in Reference Example 1), 60.0 mg of platinum oxide and 50 ml of diethyl ether was stirred for 2.5 hrs at room temperature. The mixture was filtered for removing platinum oxide. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 8.55 of the title compound having the following physical characteristics, in a 85% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19](COS(C)(=O)=O)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN[CH2:36][CH2:37][CH2:38][OH:39].O.[CH3:41][N:42](C)[CH:43]=O>>[C:1]([O:5][C:6]([N:8]([C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]2[CH:17]=[CH:18][C:19]([CH2:36][CH2:37][CH2:38][OH:39])=[CH:20][C:21]=2[CH2:41][NH:42][CH3:43])[CH2:14][CH2:15]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](c2ccc(COS(C)(=O)=O)cc2)CC1
Reactant: CN(C)C=O
Reactant: CNCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1

Procedure:
6.0 g of trans-N-tert.butoxycarbonyl-N-methyl-4-(4-methanesulphonyloxymethylphenyl)cyclohexylamine, 4.2 g of potassium carbonate and 1.6 g of N-methyl-3-hydroxypropylamine are heated together to 50° C. in 50 ml of dimethylformamide overnight. The mixture is poured into water and extracted with ethyl acetate. After drying of the organic phase, removal of the solvent and recrystallisation from petroleum ether, 7.1 g of the title compound are obtained, melting point 63°-65° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16](F)[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].[SH:29][CH2:30][C:31](OCC)=O.CN1CC[CH2:39][C:38]1=[O:42]>O>[Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:22])=[CH:14][C:15]([N+:19]([O-:21])=[O:20])=[C:16]([CH2:31][C:30]([O:42][CH2:38][CH3:39])=[S:29])[CH:17]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:9])([F:8])[F:10]
Reactant: CN1CCCC1=O
Reactant: CCOC(=O)CS
Reactant: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)c(Cl)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=S)Cc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1[N+](=O)[O-]
Temperature: 28 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
At 25° C., 1.5 g (4.5 mmole) 4-chloro-3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole, 0.69 g (5.0 mmole) K2CO3, 0.55 mL (5.0 mmole) ethyl mercaptoacetate, and 0.05 g (0.5 mmole) CuF2 were slurried in 15 mL 1-methyl-2-pyrrolidinone. The reaction mixture was stirred 28° C. for 24 hours. The mixture was cooled, diluted with 100 mL cold water, and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4, and stripped in vacuo. The residue was purified chromato-graphically using 10% diethyl ether and 15% methylene chloride in hexane as the eluent to give 0.86 g (43%) of (5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluoro-2-nitrophenyl)thio-acetic acid, ethyl ester as a yellow solid, mp 79° C.
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[C:30]1([CH3:39])[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([OH:38])=O)[CH:31]=1>>[CH3:39][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=1)[C:36]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:38]
Reactant: Cc1cccc(C(=O)O)c1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: Cc1cccc(C(=O)N(C)[C@H](Cc2ccccc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c1

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with m-toluic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(3-methylbenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 484 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[OH:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[CH:20]([CH3:22])[CH3:21].[C:23]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:9])[CH3:10])=[CH:4][C:3]=1[O:11][CH3:13].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:23])=[CH:15][C:14]=1[CH:20]([CH3:22])[CH3:21]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1cc(O)ccc1Cl
Reactant: CC(C)c1ccc(Cl)c(O)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)C)ccc1Cl
Product: COc1ccc(Cl)c(C(C)C)c1
Temperature: 50 °C

Procedure:
To a solution of 2-chloro-5-isopropyl-phenol and 4-chloro-3-isopropyl-phenol from step 1 (8.694 g, 47.1 mmol) in 50 mL DMF was added K2CO3. Iodomethane (3.5 mL, 56.5 mmol) was added and the mixture was warmed to 50° C. After 4 hours H2O was added. The mixture was extracted with ethyl acetate, washed with H2O, washed and washed with brine. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give 1-chloro-4-isopropyl-2-methoxy-benzene and 1-chloro-2-isopropyl-4-methoxy-benzene (9.289 g) as a 7:3 inseparable mixture in the form of a pale yellow oil, which was used directly in the following step.
Reaction SMILES: C1(CCCCCCCCC2C=CC=CC=2[C:21]2[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[N:25]=2)C=CC=CC=1.[CH3:28][I:29]>>[I-:29].[CH3:28][N+:25]1[C:24]([CH3:27])([CH3:26])[CH2:23][O:22][CH:21]=1
Reactant: CI
Reactant: CC1(C)COC(c2ccccc2CCCCCCCCc2ccccc2)=N1
Product: C[N+]1=COCC1(C)C
Product: [I-]

Procedure:
Following the procedures of Example 1(a), (b) and (c), to 8-phenyloctylmagnesium bromide (from 24.25 mmoles of 8-phenyloctyl bromide and 21.27 mmoles of magnesium) in distilled tetrahydrofuran (40 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (17.10 mmoles) in tetrahydrofuran (20 ml). [The 8-phenyloctyl bromide was prepared from 8-phenyloctanol, carbon tetrabromide and triphenylphosphine in methylene chloride as described in Example 6(a).] After stirring for 24 hours, the reaction mixture was similarly worked up to yield 2-[2-(8-phenyloctyl)phenyl]-4,4-dimethyloxazoline as an oil. A solution of the oxazoline (11.58 mmoles) in methyl iodide (20 ml) was refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-trimethyloxazolinium iodide as a white solid (mp 76.5°-78° C.). To an ice cold solution of the iodide (9.46 mmoles) in methanol (35 ml) was added in portions sodium borohydride (9.20 mmoles). Treatment of the reaction mixture as in Example 1(c) results in the isolation of the desired product as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([C:33]([F:36])([F:35])[F:34])=[C:11]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][NH:29][CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[F:15].[C:37](Cl)(=[O:40])[O:38][CH3:39].FC1C(C(F)(F)F)=C(C2CCN(C(C3C4CCN(C([O-])=O)CC=4NN=3)=O)CC2)C=CC=1F>>[F:8][C:9]1[C:10]([C:33]([F:34])([F:35])[F:36])=[C:11]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][N:29]([C:37]([O:38][CH3:39])=[O:40])[CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:20][CH2:21]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: COC(=O)Cl
Reactant: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Agent: O=C([O-])N1CCc2c(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)n[nH]c2C1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCc2c(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)n[nH]c2C1

Procedure:
Following general procedure GP-E1, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone TFA salt (34) and methyl carbonochloridate were converted to 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6Hpyrazolo[3,4-c]pyridine-6-carboxylate as a light orange solid (30 mg, 60%): mp 238-240° C.; 1H NMR (500 MHz, DMSO-d6) δ 13.13 (br s, 0.25H), 12.86 (br s, 0.75H), 7.78-7.70 (m, 1H), 7.51-7.48 (m, 1H), 4.82-4.80 (m, 1H), 4.67-4.65 (m, 1H), 4.54 (s, 1.5H), 4.50 (s, 0.5H), 3.64 (s, 3H), 3.60-3.57 (m, 2H), 3.15-3.13 (m, 2H), 2.79-2.78 (m, 1H), 2.64-2.59 (m, 2H), 1.76-1.68 (m, 4H); ESI MS m/z 473 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:38]=[CH:37][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[C:12]([C:30](=[O:36])[C:31]([O:33]CC)=[O:32])=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].CCCCCC>C1COCC1.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[C:12]([C:30](=[O:36])[C:31]([OH:33])=[O:32])=[CH:11]2)=[CH:37][CH:38]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccc(C(C)(C)C)cc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(Cn2cc(C(=O)C(=O)O)c3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1
Yield: 68.7 %

Procedure:
{1-[4-(tert-Butyl)benzyl]-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-[4-(tert-butyl)benzyl]-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetate (1.72 g, 3.29 mmol), and potassium hydroxide (0.614 g, 10.9 mmol) in THF (20 mL) and water (20 mL) following the procedure described in Step 4 of Example 5. Following work-up, and trituration of the residue with hexane, a solid was obtained. Crystallization from methylene chloride/hexane and drying for 10 hours at 82° C. yielded the title compound as a yellow solid (1.12 g, 69%), mp: 158-160° C. Mass spectrum (−ESI, [M−H]−) m/z 494; 1HNMR (500 MHz, DMSO-d6): δ 13.8-14.1 (br s, 1H), 8.7 (s, 1H), 8.4 (d, 1H, J=1.4 Hz), 7.75 (d, 2H, J=8.7 Hz), 7.7 (d, 1H, J=8.7 Hz), 7.6 (dd, 1H, J=8.6 Hz and 1.7 Hz), 7.45 (d, 2H, J=8.2 Hz), 7.35 (d, 2H, J=8.4 Hz), 7.25 (d, 2H, J=8.4 Hz), 5.6 (s, 2H), and 1.2 ppm (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2(O)[CH:13]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:12][CH2:11][S:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)=[CH:4][CH:3]=1.CS(O)(=O)=O.N[C@H](C(O)=O)CCSC>>[ClH:1].[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[S:10][CH2:11][CH2:12][C:13]=2[CH2:14][N:15]([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CN(C)CC1CCSc2ccccc2C1(O)Cc1ccc(Cl)cc1
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Product: CN(C)CC1=C(Cc2ccc(Cl)cc2)c2ccccc2SCC1
Product: Cl

Procedure:
3.00 g (4RS,5RS)-5-(4-chlorobenzyl)-4-dimethylaminomethyl-2,3,4,5-tetrahydro-benzo[b]thiepin-5-ol (prepared as described in example 1 , stage 1 from (4RS)-4-dimethylaminomethyl-3,4-dihydro-2H-benzo[b]thiepin-5-one and 4-chlorobenzylmagnesium chloride), 17 ml methanesulfonic acid and 1.90 g methionine were stirred at 50° C. for 7 days. After working up, purification and conversion into the hydrochloride, as described in example 6, 1.87 g (59.4% of th.) of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25]([NH:28][CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:28]([CH:29]([CH3:31])[CH3:30])[CH:25]([CH3:27])[CH3:26])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Cl)c2C1=O
Reactant: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)N(Cc1nc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)no1)C(C)C
Yield: 65.7 %

Procedure:
1.82 g (5 mmol) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at 80° overnight with 3 ml (21.3 mmol) of diisopropylamine and 20 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with cyclohexane/ether/isopropanol/ammonia 15/15/5/0.5 there were obtained 1.41 g (66%) of 7-chloro-3-(5-diisopropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 58°-63°, which was converted into the hydrochloride of m.p. 230°-231°.
Reaction SMILES: [Br:1]C1CC2C(=CC=CC=2F)C1=O.[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][C:18]2=[O:24]>[Cu](Br)Br.O1CCOCC1>[Br:1][CH:17]1[CH2:16][C:15]2[C:19](=[CH:20][C:21]([Cl:23])=[CH:22][C:14]=2[Cl:13])[C:18]1=[O:24]
Reactant: O=C1CCc2c(Cl)cc(Cl)cc21
Reactant: O=C1c2cccc(F)c2CC1Br
Agent: Br[Cu]Br
Solvent: C1COCCO1
Product: O=C1c2cc(Cl)cc(Cl)c2CC1Br

Procedure:
The 2-bromo-4,6-dichloro-1-indanone is prepared as in Example 14 for the preparation of 2-bromo-4-fluoro-1-indanone but starting with 21.6 g of 4,6-dichloro-1-indanone, 63.56 g of copper bromide and 690 ml of dioxane. 14.5 g of 2-bromo-4,6-dichloro-1-indanone are obtained which melt at 80° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[CH3:14][NH:15][CH3:16].[CH2:17]=O>C(O)(=O)C>[CH3:14][N:15]([CH2:17][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4])[CH3:16]
Reactant: COC(=O)c1cc2ccccc2[nH]1
Reactant: CNC
Reactant: C=O
Solvent: CC(=O)O
Product: COC(=O)c1[nH]c2ccccc2c1CN(C)C
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To 51 g ester from (a) was added a mixture of 38 ml dimethylamine, 40 ml acetic acid and 23.5 ml formaldehyde (35% in water). After 20 hours stirring at 80° C. the mixture was cooled and the product isolated by acid-base separation.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH3:24][C:25]1([CH3:41])[O:30][CH:29]([C:31]([NH:33][CH2:34][CH2:35][C:36](O)=[O:37])=[O:32])[C:28]([CH3:40])([CH3:39])[CH2:27][O:26]1>>[CH3:24][C:25]1([CH3:41])[O:30][CH:29]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:37])=[O:32])[C:28]([CH3:40])([CH3:39])[CH2:27][O:26]1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCCO
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCOC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 88.8 %

Procedure:
N-(2-Hydroxyethyl)oleamide (0.97 g) and 0.78 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain 1.50 g of the title compound (yield: 90%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47])=[C:37]([Cl:48])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:48][C:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 3-chloro-4-(2-propoxyethoxy)phenyl borate (164 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were collected by filtration and recrystallized from ethanol to give colorless crystals of 7-[3-chloro-4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 74) (255 mg).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH:4]=[CH:3]1.[N:14](OCCC(C)C)=[O:15].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[OH:15][N:14]=[C:7]1[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH:4]=[CH:3][N:2]([CH3:1])[C:8]1=[O:9]
Reactant: CN1C=Cc2ccccc2CC1=O
Reactant: CC(C)CCON=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1ccc2ccccc2c(=NO)c1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 65 %

Procedure:
A THF (0.5 L) solution of 3-methyl-2,3-dihydro-1H-3-benzazepin-2-one (113.8 g, 0.657 mol) was cooled to 0° C. and isoamyl nitrite (100.75 g, 0.86 mol) was added dropwise. To the resulting mixture was added LiHMDS (1 N THF solution, 854 mL, 0.854 mol) at a rate such that the temperature remained below 10° C. After addition, the reaction was allowed to stir at room temperature for 2-3 h while monitoring for the reaction progress by HPLC. Upon completion of the reaction, the mixture was cooled to 0° C., and the pH adjusted from 12 to 2-3 using aqueous HCl (2N). The resulting precipitate was stirred for 12-16 h before isolation by filtration and drying to provide 86.3 g (64.9%) of 1-hydroxyimino-3-methyl-2,3-dihydro-1H-3-benzazepin-2-one; mp=225-226° C.; (M+H)+=203.0.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([CH2:14][CH:15]=[O:16])[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1CCC[C@@H]1C(O)=O.Cl[N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32].C(Cl)(Cl)[Cl:34]>>[Cl:34][CH:14]([C:11]1([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)[CH2:12][CH2:13]1)[CH:15]([N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32])[OH:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ClC(Cl)Cl
Reactant: O=CCC1(c2ccc3ncccc3c2)CC1
Agent: O=C(O)[C@H]1CCCN1
Product: O=C1CCC(=O)N1C(O)C(Cl)C1(c2ccc3ncccc3c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) mixture of (1-quinolin-6-ylcyclopropyl)acetaldehyde (9.9 g, 47 mmol), D-proline (1.1 g, 9.4 mmol) in chloroform (200 mL) was added N-chlorosuccinimide (6.26 g, 46.9 mmol). The mixture was stirred at 0° C. for 30 min and then gradually warmed to RT for 2 h. The reaction mixture was quenched with saturated sodium bicarbonate (25 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The precipitate formed was filtered to give the desired product. The filtrate was chromatographed on silica gel with EtOAc in methylene chloride (10%) to afford chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde which was contaminated with pyrrolidine-2,5-dione (13.0 g), and automatically converted to the desired product after a few days. The total desired product obtained is 16 g. LCMS: (M+H)=345.0/347.0.