Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:58]1([CH2:63][CH2:64][NH2:65])[CH2:62][CH2:61][CH2:60][CH2:59]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:65][CH2:64][CH2:63][N:58]5[CH2:62][CH2:61][CH2:60][CH2:59]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCN1CCCC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NCCN2CCCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 2-(pyrrolidin-1-yl)ethanamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (m, 1H) 1.38 (m, 2H) 1.65 (t, J=13.1 Hz, 3H) 1.79-1.92 (m, 6H) 2.03 (m, 2H) 3.08 (m, 2H) 3.33 (s, 3H) 3.35 (d, J=5.8 Hz, 2H) 3.61 (m, 4H) 3.96 (s, 3H) 4.12 (t, J=13.0 Hz, 2H) 4.40-4.58 (m, 1H) 7.53 (d, J=8.6 Hz, 1H) 7.56 (s, 1H) 8.22 (s, 1H) 8.24 (d, J=1.3 Hz, 1H) 8.29 (d, J=7.8 Hz, 1H) 8.7 (dd, J=10.1, 1.3 Hz, 1H). [M+H] calc'd for C28H37F2N7O3 558. found 558.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14](Cl)(=[O:16])=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C>C1COCC1>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)(=[O:16])=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCc2ccc(S(=O)(=O)N3CCCCC3)cc2C1

Procedure:
21.1 g (77 mmol) of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride (prepared as described in G. Grunewald et al. J. Med. Chem 1999, 42, 118-134) in 50 ml of THF were added dropwise to a solution of 6.0 g (70 mmol) of piperidine and 10.9 g (84 mmol) of diisopropylethylamine in 230 ml of THF, and the mixture was heated under reflux for two hours. After the reaction was complete, the solvent was removed in vacuo, the residue was taken up in dichloromethane/water and, after making alkaline with 10% strength sodium hydroxide solution and separating the phases, the organic phase was dried over sodium sulfate. The crude product remaining after filtration and removal of the solvent was purified by column chromatography on silica gel (mobile phase: methylene chloride with 3% methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19](=[O:28])[C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:27])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH:46]1([C:49](Cl)=[O:50])[CH2:48][CH2:47]1>C(Cl)Cl>[C:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:49]([CH:46]2[CH2:48][CH2:47]2)=[O:50])=[CH:3][CH:4]=1)[CH:9]1[CH2:10][CH2:11][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19](=[O:28])[C:20]2[C:21]([CH3:27])=[CH:22][CH:23]=[CH:24][C:25]=2[CH3:26])[CH2:13][CH2:14]1)#[N:38]
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(N)cc2)CC1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(NC(=O)C3CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
To a solution of COMPOUND 142 (61 mg, 0.12 mmol) in CH2Cl2 (1 mL) and Et3N (33 μL, 0.24 mmol) was added cyclopropanecarbonyl chloride (17 μL, 0.18 mmol) and the solution was stirred at room temperature for 4 hours to afford COMPOUND 153 as a white solid (69 mg, 100%) following work-up and purification. 1H NMR (CDCl3) δ 0.75-0.83 (m, 2H), 1.01 (m, 6H), 1.01-1.16 (m, 1H), 1.42-1.61 (m, 2H), 1.61-1.77 (m, 3H), 2.15 (t, 1H, J=11.1 Hz), 2.30 (s, 6H), 2.55 (t, 1H, J=10.8 Hz), 2.74-2.86 (m, 3H), 3.28 (t, 1H, J=11.1 Hz), 3.54 (m, 1H), 3.76 (s, 2H), 3.85 (m, 1H), 6.50 (d, 2H, J=6.49 (d, 2H, J=8.4 Hz), 6.91-6.99 (m, 3H), 7.24 (d, 2H, J=9.3 Hz), 7.36-7.44 (m, 4H), 7.50 (br s, 1H), 8.40 (br s, 1H). 13C NMR (CDCl3) δ 7.98, 8.39, 13.77, 15.72, 19.54, 29.29, 30.57, 31.31, 40.14, 44.03, 48.66, 52.46, 57.39, 60.82, 112.78, 114.85, 119.40, 122.01, 127.67, 128.79, 129.56, 129.66, 130.50, 130.82, 131.47, 134.45, 138.91, 142.66, 145.31, 170.35, 172.09. ES-MS m/z 578 (M+H). Anal. Calcd. for C36H43N5O2.0.3CH2Cl2: C, 72.28; H, 7.28; N, 11.61. Found. C, 72.57; H, 7.38; N, 11.30.
Reaction SMILES: Cl.[NH2:2]O.[OH-].[K+].COCCOCCOC.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24](=[N:27][OH:28])[C:25]#[N:26]>O>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]1[C:25]([NH2:2])=[N:26][O:28][N:27]=1
Reactant: NO
Reactant: N#CC(=NO)c1nc2ccccc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOCCOC
Product: Nc1nonc1-c1nc2ccccc2[nH]1
Temperature: 170 °C
Yield: 48.6 %

Procedure:
To an ice-cooled stirred solution of 13.2 g of hydroxylamine hydrochloride (190 mmol, 3 eq) in 20 ml of water, 15.3 g of potassium hydroxide (27.2 mmol, 4.3 eq) are slowly added. Then 60 ml of diglyme (diethylene glycol dimethyl ether) and 11.8 g of (1H-benzoimidazol-2-yl)-hydroxyimino-acetonitrile (63.4 mmol, 1 eq) are added. The ice-bath is removed and the reaction mixture is heated to reflux for 8 h (bath temperature 170° C.). After cooling to room temperature, the reaction mixture is filtered and the residue is washed with water to give the first crop of the desired product (6.2 g). The filtrate is treated with 150 ml of water. The resulting suspension is filtered and washed with water to provide a second product crop (2.17 g). Both crops are combined and used in the next step.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:10]2[C:5](=[N:6][C:7]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=34)=[N:8][CH:9]=2)[N:4]1[C@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C=O)C>[C:29]([N:25]1[CH2:26][CH2:27][CH2:28][C@H:23]([N:4]2[C:3](=[O:2])[NH:11][C:10]3[C:5]2=[N:6][C:7]([C:12]2[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=24)=[N:8][CH:9]=3)[CH2:24]1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n([C@H]5CCCNC5)c4n3)c2c1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)N1CCC[C@H](n2c(=O)[nH]c3cnc(-c4cnn5ccc(C#N)cc45)nc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
To a solution of the compound obtained in example 6 (31 mg, 0.063 mmol) in anhydrous DMF (3 mL), acetic anhydride (0.007 mL, 0.08 mmol) and anhydrous TEA (0.02 mL, 0,127 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, and the solvent was concentrated off. It was quenched with saturated NaHCO3 aqueous solution (15 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were dried over anhydrous Mg2SO4, filtered and concentrated. The crude residue was flash chromatographed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 14.5 mg of the desired compound (57% yield).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11](F)=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.[F:19][C:20]([F:26])([F:25])[C:21]([OH:24])([CH3:23])[CH3:22]>CN1C(=O)N(C)CC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:24][C:21]([CH3:23])([CH3:22])[C:20]([F:26])([F:25])[F:19])=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1
Reactant: CC(C)(O)C(F)(F)F
Reactant: Fc1ccc(Br)cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Product: CC(C)(Oc1ccc(Br)cc1C(F)(F)F)C(F)(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
Potassium tert-butoxide (236 mg, 2.1 mmol) was added to a solution of 5-bromo-2-fluorobenzotrifluoride (485 mg, 2.0 mmol) and 2-trifluoromethyl-2-propanol (0.24 mL, 2.2 mmol) in DMI (0.5 mL) at room temperature, and the mixture was stirred at 100° C. for two hours. The reaction solution was purified by silica gel column chromatography to give 4-bromo-1-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-2-trifluoromethyl-benzene (349 mg, 50%).
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH:29]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@@H:30]([C:41]([OH:43])=O)[C@H:31]([CH3:40])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[CH:51]1[C:59]2[C:58]3[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][C:57]=3[O:56][C:55]=2[CH:54]=[CH:53][C:52]=1[NH2:65]>>[CH2:33]([O:32][C@H:31]([CH3:40])[C@@H:30]([NH:29][C:44](=[O:45])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:41]([NH:65][C:52]1[CH:53]=[CH:54][C:55]2[O:56][C:57]3[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][C:58]=3[C:59]=2[CH:51]=1)=[O:43])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: C[C@H](OCc1ccccc1)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: C[C@@H](OCc1ccccc1)[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 18.6 %

Procedure:
Following the procedure of Example 30, triethylamine (0.43 mL, 3.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.31 g, 1.6 mmol), N-hydroxybenzotriazole (0.22 g, 1.6 mmol), N-Boc-D-Thr(Bzl)-OH (0.42 g, 1.4 mmol), and 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.25 g, 1.2 mmol) provided tert-butyl {(1R,2R)-2-(benzyloxy)-1-[(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylamino)carbonyl]propyl}carbamate (0.11 g). MS (ESI) m/z 493 ([M+H]+); MS (ESI) m/z 491 ([M−H]−).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:19]=[CH:18][O:17][N:16]=3)[N:4]2[N:3]=1.[CH2:20]([N:23]1[CH:27]=[N:26][C:25]([CH2:28][OH:29])=[N:24]1)[CH2:21][CH3:22]>>[O:17]1[CH:18]=[CH:19][C:15]([C:14]2[N:4]3[N:3]=[C:2]([O:29][CH2:28][C:25]4[N:26]=[CH:27][N:23]([CH2:20][CH2:21][CH3:22])[N:24]=4)[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[N:16]1
Reactant: CCCn1cnc(CO)n1
Reactant: Clc1nn2c(-c3ccon3)nnc2c2ccccc12
Product: CCCn1cnc(COc2nn3c(-c4ccon4)nnc3c3ccccc23)n1

Procedure:
The title-compound was prepared from 6-chloro-3-(isoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine (described in Example 34 part b) and 1-propyl-3-hydroxymethyl-1,2,4-triazole prepared as described in WO-A-9804559 using the procedure given for Example 71, 1H NMR (360 MHz, CDCl3) δ 0.95 (3H, t, J=7.4 Hz, CH3), 1.89-1.99 (2H, m, CH2), 4.15 (2H, t, J=7.0 Hz, CH2), 5.73 (2H, s, CH2), 7.40 (1H, d, J=1.7 Hz, Ar—H), 7.80 (1H, t, J=7.2 Hz, Ar—H), 7.96 (1H, t, J=6.9 Hz, Ar—H), 8.09 (1H, s, Ar—H), 8.28 (1H, d, J=7.9 Hz, Ar—H), 8.70 (1H, s, Ar—H), 8.74 (1H, d, J=7.7 Hz, Ar—H); MS tES+) m/e 377 1MH]+.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[C:10](=S)=[S:11].N#CCl>C(Cl)Cl.O>[CH:1]1([N:7]=[C:10]=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: S=C=S
Agent: N#CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: S=C=NC1CCCCC1
Yield: 98.4 %

Procedure:
In one hour 0.5 mole of cyclohexyl amine, 0.5 mole of sodium hydroxide and 60 grams of water were treated with 0.5 mole of carbon disulfide. The N-cyclohexyl sodium dithiocarbamate solution was stirred for a further hour at 50° C. There were added 1,000 cc of water, 20 grams of sodium hydroxide and 250 cc of methylene chloride. Under stirring there were led in at 6° C, 0.515 mol of cyanogen chloride. After the separation the methylene chloride layer was distilled. There were isolated 69.5 grams of cyclohexyl isothiocyanate (B.P. 98.5° C/13 mm Hg), corresponding to a yield of 98.4% of theory.
Reaction SMILES: [CH2:1]([CH2:3]N)[OH:2].C1(C)C(C)=CC=CC=1.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](=[N:29][O:30][CH3:31])[C:27]#[N:28])=[CH:16][CH:15]=1>O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C.O>[CH3:31][O:30][N:29]=[C:26]([C:27]1[O:2][CH2:1][CH2:3][N:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][CH2:18][C:17]1[CH:16]=[CH:15][C:14]([Cl:13])=[CH:33][CH:32]=1
Reactant: CON=C(C#N)c1ccccc1OCc1ccc(Cl)cc1
Reactant: NCCO
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: Cc1ccccc1C
Solvent: O
Product: CON=C(C1=NCCO1)c1ccccc1OCc1ccc(Cl)cc1
Yield: 9.8 %

Procedure:
Zinc acetate dihydrate (400 mg, 1.8 mmol), ethanolamine (975 mg, 15.9 mmol) and xylene (8 ml) were added to 2-(4-chlorobenzyloxy)-α-methoxyiminophenylacetonitrile (4.00 g, 13.3 mmol), and the mixture was stirred under reflux for 63 hours. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give isomer A (1.31 g, 28.6%, as crystals) and isomer B (0.45 g, 9.8%, as crystals) of 2-(4-chlorobenzyloxy)phenyl 2-oxazolin-2-yl ketone O-methyloxime.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[CH:4]=[C:5]([CH3:7])[CH3:6].[CH3:10][C:11]([CH3:15])=[CH:12]CO.[N+](C1C=C([N+]([O-])=O)C=CC=1O)([O-])=O>>[CH3:1][O:2][CH:3]([O:8][CH2:9][CH:10]=[C:11]([CH3:15])[CH3:12])[CH:4]=[C:5]([CH3:7])[CH3:6]
Reactant: CC(C)=CCO
Reactant: COC(C=C(C)C)OC
Agent: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Product: COC(C=C(C)C)OCC=C(C)C
Temperature: 25 °C
Reaction time: 76 h

Procedure:
In a 50 ml. one-neck flask was placed 5.5 g. (0.0422 mol.) of 1,1-dimethoxy-3-methyl-2-butene and 10.0 g. (0.116 mol.) of prenol and 0.40 g. (0.002 mol.) of 2,4-dinitrophenol. The resulting solution was degassed with nitrogen and sealed with a serum cap and stirred at room temperature for 76 hours. The reaction solution was then diluted with 100 ml. of hexane and washed with 3 × 100 ml. of 1.0 N aqueous NaOH solution and 2 × 100 ml. of saturated aqueous NaCl solution. The combined water washings were back with extracted 1 × 50 ml. of hexane. The combined hexane solutions were dried (Na2SO4) and concentrated to give 9.0 g. of crude product. Distillation of 8.3 g. at 20 mmHg and a bath temperature of 55°-60° gave 1.48 g. of prenol. Continued distillation initially at 0.20 mmHg gave 2.43 g. of 1-methoxy-1-(3-methylbut-2-enoxy)-3-methyl-2-butene (b.p. 40°-45° at 0.02 mmHg) and finally at 0.050 mmHg gave 3.29 g. of 1,1-bis-(3-methylbut-2-enoxy)-3-metylbut-2-ene (b.p. 70°-75° at 0.050 mmHg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](=[O:26])[O:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH:14]=2.[C:27](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](=[O:26])[O:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([N:20]1[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][CH2:21]1)[CH:14]=2
Reactant: O=c1oc2cc(N3CCNCC3)ccc2cc1-c1nc2ccccc2s1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc3cc(-c4nc5ccccc5s4)c(=O)oc3c2)CC1
Reaction time: 4 h
Yield: 47.3 %

Procedure:
100 mg (0.28 mmol) 3-Benzothiazol-2-yl-7-piperazin-1-yl-chromen-2-one were dissolved in 15 mL DMF and treated under argon with 183 mg (2 eq.) cesium carbonate, cooled below 5° C. and treated with 1 eq (0.018 mL) Mel. After stirring for 4 h, the reaction mixture is diluted with 100 mL dichloromethane and washed twice with ice-water. The organic phase is evaporated and the residue column chromatographed (silica gel, dichloromethane/EtOH 9:1). Recrystallization from methanol/dichloromethane yields 50 mg (47%) desired product as an orange powder.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[H-].[Na+].F[C:10]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=1[CH:12]=O>CS(C)=O>[CH3:6][O:5][C:1]([C:2]1[S:3][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[CH:12]=1)=[O:4]
Reactant: COc1ccc(F)c(C=O)c1
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cc2cc(OC)ccc2s1
Yield: 13.8 %

Procedure:
To a solution of methyl thioglycolate (0.647 mL, 7.14 mmol, 1.1 eq.) in 14 mL of DMSO was added NaH 50% (0.405 g, 10.1 mmol, 1.56 eq.) and the mixture was stirred for 5 Min., before 2-fluoro-5-methoxybenzaldehyde (1.00 g, 6.49 mmol) was added (strongly exothermic). When the internal temperature had reached again 25° C., the reaction mixture was poured onto crashed ice and the precipitate filtered off and dried to obtain 0.199 g of the title compound as off-white solid.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([O:3]CC)=[O:2].Cl.C(O)(=O)C>O>[C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([OH:3])=[O:2]
Reactant: CCOC(=O)CCCCC1CCCC1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCCCC1CCCC1=O

Procedure:
A stirred mixture of 274 g. of 2-carbalkoxy(mixed methyl and ethyl esters)-2-(4-carbethoxybutyl)cyclopentan-1-one (Example 1), 600 ml. of 20% hydrochloric acid and 325 ml. of acetic acid is heated at reflux for 20 hours. Solution occurs in approximately one-half hour. The solution is cooled and diluted with water and extracted with ether. The combined extracts are washed with saline and dried over magnesium sulfate and evaporated. The residue is evaporated twice with toluene to give 144 g. of an oil.
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:18]1=[O:36]>C1(C)C=CC=CC=1.[Pd]>[CH2:14]([O:13][C:11]([CH:10]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C:18]1=[O:36])[CH2:9][CH:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)C=CC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC(O)c1ccccc1)NC1CCc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 18 h

Procedure:
Ethyl 3-benzoylacrylate (13a) (55.6 g, 250 mmoles) is dropped into a solution of (3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one (11) (66.2 g, 227 mmoles) in 200 ml of toluene, at room temperature in 1 h. The resulting mixture is left under stirring for 18 h, then added with 10% Pd—C (26 g, 22 mmoles) and hydrogenated at 3 atm for 18 h at room temperature. The solvent is evaporated off and the residue is purified by chromatography (eluent: hexane-ethyl acetate 7:3). A mixture of isomeric products is isolated.
Reaction SMILES: [C:1]1(=[O:18])[N:5]([CH:6]2[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2)[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>ClCCl>[C:4]1(=[O:13])[N:5]([CH:6]2[CH2:7][CH2:8][C:9](=[O:12])[CH2:10][CH2:11]2)[C:1](=[O:18])[C:2]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A solution of 4-phthalimido cyclohexanol (7.1 g, 0.029 mole) in dichloromethane (250 ml) was treated with pyridinium chlorochromate (8.6 g, 0.04 mole) and the resulting dark mixture was stirred at room temperature overnight. Diethyl ether (50 ml) was added and the mixture filtered through keiselguhr. The filtrate was concentrated in vacuo and the residue purified by column chromatography (SiO2 ; CHCl3 /EtOAc) to give 4-phthalimido cyclohexanone as a white solid (6.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].[CH3:30][N:31]1[CH2:36][CH2:35][CH:34]([NH:37][CH3:38])[CH2:33][CH2:32]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:37]([CH3:38])[CH:34]2[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]2)=[O:26])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11]
Reactant: CNC1CCN(C)CC1
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CN1CCC(N(C)C(=O)c2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccccc3Cl)cc2F)CC1

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid (example 216, step 4) was coupled with 1-methyl-4-(methylamino)piperidine using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=524.3 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13]C)[CH:11]=2)[C:6]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:5]1)(=[O:3])[CH3:2].B(Br)(Br)Br>ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[C:6]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)Cc1cn(C(C)=O)c2cc(OC)ccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)Cc1cn(C(C)=O)c2cc(O)ccc12
Reaction time: 18 h
Yield: 31.6 %

Procedure:
To a solution of methyl (1-acetyl-6-methoxy-1H-indol-3-yl)acetate (0.67 g, 2.56 mmol) (Example 13) in dichloromethane (10 mL) was added 1 M BBr3 in dichloromethane (10.3 mL, 10.3 mmol) at −78° C. under argon. Stirring was continued at −78° C. for 1 h, at 0° C. for 3 h and at rt for 18 h consecutively. The reaction mixture was quenched with water and dichloromethane was added. Solid NaHCO3 was added to adjust the pH of the mixture to 8. The mixture was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to yield a yellow solid (200.0 mg, 32%). LC/MS m/z 248 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 7.77 (d, 1H), 7.52 (s, 1H), 7.28 (d, 1H), 6.71 (dd, 1H), 3.71 (s, 2H), 3.61 (s, 3H), 2.55 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][C:9](SC)=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[NH2:18]>>[Br:1][C:2]1[C:7]2[O:8][C:9]([NH:18][C:17]3[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:15]([O:14][CH3:13])[CH:16]=3)=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CSc1nc2ccnc(Br)c2o1
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1cc(Nc2nc3ccnc(Br)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.6 g (2.61 mmol) 4-bromo-2-methylsulfanyl-oxazolo[5,4-c]pyridine are heated to 100° C. until it liquefies, then 0.977 g (5.23 mmol) 3,4,5-trimethoxyanilin is added in small portions with stirring. Stirring is continued for 2 h. The reaction mixture is cooled to room temperature and purified by chromatography (silicagel, hexane=>EtOAc) to afford the title compound.