Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].CN(C)C=O.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([OH:27])[CH:26]=1.C(N(C(C)C)C(C)C)C>C(Cl)(=O)C(Cl)=O.O>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([OH:27])[CH:26]=1)=[O:11])([CH3:4])[CH3:5])#[N:2]
Reactant: COc1ccc(N)cc1O
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (4.92 g, 26.0 mmol) produced in Example C6(ii) in oxalyl chloride (20 mL) was added N,N-dimethylformamide (0.1 mL), and the mixture was stirred at room temperature for 30 min. Excessive reagent was evaporated under reduced pressure, the obtained residue was dissolved in tetrahydrofuran (20 mL), and 5-amino-2-methoxyphenol (4.17 g, 30.0 mmol) and N-ethyl-N-(1-methylethyl)propan-2-amine (6.46 g, 50.0 mmol) were sequentially added dropwise under ice-cooling. The reaction solution was stirred at room temperature for 18 hr, and poured into water. The mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (5 mL)/tetrahydrofuran (5 mL), 8N aqueous sodium hydroxide solution (1 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=5:1) and triturated with diethyl ether to give the title compound (4.70 g, 58%) as a pale-yellow solid.
Reaction SMILES: C(OC(=O)NCC(O)[CH:10]([OH:36])[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:24]([CH3:35])[CH:23]=1)(C)(C)C>C(Cl)Cl>[CH3:35][C:24]1[CH:23]=[C:22]([NH:21][C:14]2[C:13]3[C:18](=[CH:19][CH:20]=[C:11]([CH:10]=[O:36])[CH:12]=3)[N:17]=[CH:16][N:15]=2)[CH:27]=[CH:26][C:25]=1[O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1cc(Nc2ncnc3ccc(C(O)C(O)CNC(=O)OC(C)(C)C)cc23)ccc1Oc1ccccc1
Solvent: ClCCl
Product: Cc1cc(Nc2ncnc3ccc(C=O)cc23)ccc1Oc1ccccc1
Reaction time: 1 h

Procedure:
4-(3-Methyl-4-phenoxy-phenylamino)-quinazoline-6-carbaldehyde is prepared by adding NaIO4 (1.5 mL, 0.65 M in H2O) to a slurry of silica gel (1 g) in DCM (6 mL) followed by the addition of {2,3-dihydroxy-3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-propyl}-carbamic acid tert-butyl ester (from Step A, ˜0.64 mmol) in DCM (2 mL). The reaction mixture stirs for 1 hour, is filtered and washed with DCM (20 mL), and concentrated to give 280 mg of crude product. The product is used without further purification in Step E.
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:5]=[CH:6][C:7]2[C:11]([C:12](=[O:28])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)=[C:10]([C:29]3[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=3)[S:9][C:8]=2[CH:37]=1.B(Cl)(Cl)[Cl:39].C(O)C.CO>ClCCCl>[Cl:1][CH2:8][CH2:37][Cl:39].[ClH:39].[OH:3][C:4]1[CH:5]=[CH:6][C:7]2[C:11]([C:12](=[O:28])[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:17][CH:18]=3)=[C:10]([C:29]3[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=3)[S:9][C:8]=2[CH:37]=1
Reactant: ClB(Cl)Cl
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCO
Solvent: CO
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 35 °C
Reaction time: 18 h

Procedure:
A solution of 6-methoxy -2-(4-methoxyphenyl)-3-[4-(2-piperidinylethoxy)benzoyl]benzo[b]thiophene hydrochloride (2.0 g) in 1,2-dichloroethane (20 mL) was treated with boron trichloride (2.0 mL). The resulting mixture was stirred at 35° C. for about 18 hours. A:mixture of ethanol and methanol (10 mL, 95:5, 3A) was treated with the reaction mixture from above, causing the alcoholic mixture to reflux. Upon complete addition, the resulting crystalline slurry was stirred at 25° C. After one 1 hour, the crystalline product was filtered, washed with cold ethanol (10 mL), and dried at 40° C. in vacuo to give 1.78 g of the title compound. The X-ray powder diffraction pattern is identical to that reported in Table 1.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([C:12](O)=[O:13])=[CH:8][C:7]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:6]1=2)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]([C:12]([Cl:23])=[O:13])=[CH:8][C:7]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:6]1=2)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCn1c2c(cc(C(=O)O)c1=O)CCCCCC2
Solvent: Cc1ccccc1
Product: CCCCn1c2c(cc(C(=O)Cl)c1=O)CCCCCC2

Procedure:
1-Butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocycloocta[b]pyridine-3-carboxylic acid (B-01) (416 mg, 1.50 mmol) was dissolved in toluene (15 ml), and to the reaction mixture was added thionyl chloride (328 μL, 4.50 mmol), and the reaction mixture was reacted at 65° C. for 20 min. The reaction mixture was evaporated under reduced pressure to give 1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocycloocta[b]pyridine-3-carbonyl chloride (B-02).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[CH3:33])(=[O:25])=[O:24].[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][NH2:41])[CH:35]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:41][CH2:40][C:36]3[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=3)=[O:19])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[CH3:33])(=[O:25])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)c(C)c1
Reactant: NCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)c(C)c1
Yield: 23.7 %

Procedure:
Reaction of oxalyl chloride (31 λL, 0.35 mmol) and benzoic acid 44 (92 mg, 0.24 mmol) with subsequent coupling to 3-pyridinylmethylamine (27 λL, 0.26 mmol) gave benzamide 45 (27 mg, 24%) as a clear gum: 1H NMR δ 9.22 (t, J=5.8 Hz, 1H, CONH), 8.57 (d, J=1.5 Hz, 1H, H-2′), 8.47 (dd, J=4.7, 1.5 Hz, 1H, H-6′), 8.00 (d, J=8.4 Hz, 2H, H-2, H-6), 7.88 (d, J=8.4 Hz, 2H, H-3, H-5), 7.74 (br d, J=7.8 Hz, 1H, H-4′), 7.57 (d, J=8.1 Hz, 1H, H-5″) 7.37 (dd, J=7.8, 4.7 Hz, 1H, H-5′), 7.27 (br s, 1H, H-3″), 7.18 (d, J=8.1 Hz, 1H, H-6″), 4.61 (s, 2H, CH2SO2), 4.51 (d, J=5.8 Hz, 2H, CH2N), 2.55 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.15 (s, 3H, CH3); MS m/z 476.6 (MH+, 100%). Anal. calcd for C26H25N3O4S.½CH3CO2CH2CH3: C, 64.72; H, 5.63; N, 8.09. Found: C, 64.72; H, 5.60; N, 7.75%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[O:5][CH:6]([CH2:10][CH3:11])[C:7](O)=[O:8].C1(C)C=CC=CC=1.C(Cl)([Cl:25])=O.C(=O)=O>O.CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[O:5][CH:6]([CH2:10][CH3:11])[C:7]([Cl:25])=[O:8]
Reactant: O=C(Cl)Cl
Reactant: CCC(Oc1cc(C)cc(C)c1)C(=O)O
Agent: O=C=O
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCC(Oc1cc(C)cc(C)c1)C(=O)Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
A mixture of 2-(3,5-dimethylphenoxy)-butyric acid [849 g (4.1 moles)], 1075 ml toluene, and 8 ml dimethylformamide was heated to 60° C. in a 5-liter flask fitted with a gas inlet tube, a stirrer, a thermometer and a dry ice condenser. Phosgene, 472 g (4.8 moles), was passed into the solution at 60°-70° C. The mixture was then heated at 60°-70° C. for thirty minutes. The dry ice condenser was then replaced with a water-cooled condenser and the solution was purged with nitrogen to remove excess phosgene and HCl. After 2 hours, purging was discontinued and the solution was vacuum stripped to leave 2-(3,5-dimethylphenoxy)butyryl chloride, 931 g (101% yield), nD30 1.5050.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14](O)=[O:15])=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:19][CH:18]=3)[C:9]=2[CH3:27])=[CH:4][CH:3]=1.Cl.[CH3:29][NH:30][CH3:31].C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([N:30]([CH3:31])[CH3:29])=[O:15])=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:19][CH:18]=3)[C:9]=2[CH3:27])=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccc(S(N)(=O)=O)cc2)c(C(=O)O)n(C)c1-c1ccc(Cl)cc1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1c(-c2ccc(S(N)(=O)=O)cc2)c(C(=O)N(C)C)n(C)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a stirred solution of 5-(4-chlorophenyl)-1,4-dimethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxylic acid (49ε, 1.00 g, 2.47 mmol) in DMF (15 ml) was added θHOBT (0.41 g, 2.72 mmol) at room temperature, which was then followed by the addition of dimethylamine hydrochloride (0.40 g, 4.94 mmol). the reaction mixture was cooled to 0° C. and to the cooled reaction mixture was then added EDC (0.71 g, 3.70 mmol) and triethylamine (1.00 g, 1.37 ml, 9.88 mmol). The reaction mixture was then stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. Ethyl acetate (100 ml) was added to the residue so obtained. The mixture so obtained was then washed with saturated sodium bicarbonate solution (20 ml) followed by washing with brine (20 ml). The organic layer obtained was dried over anhydrous sodium sulphate. The dried organic layer was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography over silica gel (100-200 mesh) using 90% ethyl acetate in hexanes as an eluent to obtain the title compound (0.94 g, 88.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)([Cl:14])=O.[C:17]1([CH:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCOCC>[OH2:5].[Cl:11][C:9]1[CH:10]=[C:2]2[C:3](=[CH:7][CH:8]=1)[C:4]([Cl:14])=[C:25]1[C:26]([CH2:27][CH2:28][CH:23]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:24]1)=[N:1]2.[Cl:11][C:9]1[CH:10]=[C:2]2[C:3](=[CH:7][CH:8]=1)[C:4]([Cl:14])=[C:25]1[C:26]([CH2:27][CH2:28][CH:23]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:24]1)=[N:1]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Solvent: CCOCC
Product: Clc1ccc2c(Cl)c3c(nc2c1)CCC(c1ccccc1)C3
Product: O
Yield: 70 %

Procedure:
To a slurry of 15 g (0.0874 mol) of 2-amino-4-chlorobenzoic acid and 150 ml of phosphorous oxychloride is added dropwise 15 g (0.0871 mol) of 4-phenylcyclohexanone. The mixture is stirred at reflux for 3 hours and then concentrated in vacuo. The residue is dissolved in methylene chloride and added slowly to an ice-NH4OH mixture. The mixture is stirred for 1/2 hour and extracted with methylene chloride. The combined extracts are washed with water, dried over Na2SO4, and concentrated in vacuo to yield a dark solid. Trituration with ether provides 20 g (70%) of title compound: m.p. 134°-136° C.; IR 1605, 1585 and 1480 cm-1 ; NMR (CDCl3) δ 8.12-8.0 (m, 2H), 7.54-7.46 (m, 1H), 7.44-7.26 (m, 5H), 3.50-2.88 (m, 5H), and 2.28-2.02 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([Cl:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2].[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][C:12]([Cl:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cc(Cl)cc2c1Cl
Reactant: CCCCN
Product: CCCCNc1c(C(=O)OCC)cnc2c(OC)cc(Cl)cc12

Procedure:
4,6-Dichloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.84 mmol) was treated with butylamine following general procedure B to afford 4-butylamino-6-chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (230 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (155 mg) following general procedure E. The above ethylamide (155 mg, 0.45 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 1-butyl-9-chloro-3-ethyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (87 mg). LCMS: m/z 362 [M+1]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:17][C@H:18]([OH:30])[C:19]2[C:27]3[S:26][C:25](=[O:28])[NH:24][C:23]=3[C:22]([OH:29])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)(=O)=O.FC(F)(F)C(O)=O.[F:45][C:46]([F:61])([F:60])[C:47]([N:49]1[CH2:54][C:53]2([CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[O:52][CH2:51][CH2:50]1)=[O:48].C(N(CC)CC)C>CC#N>[OH:30][C@H:18]([C:19]1[C:27]2[S:26][C:25](=[O:28])[NH:24][C:23]=2[C:22]([OH:29])=[CH:21][CH:20]=1)[CH2:17][N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:57]2[CH2:58][CH2:59][C:53]3([O:52][CH2:51][CH2:50][N:49]([C:47](=[O:48])[C:46]([F:45])([F:60])[F:61])[CH2:54]3)[CH2:55][CH2:56]2)=[CH:14][CH:13]=1)[C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCOS(C)(=O)=O)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: O=C(N1CCOC2(CCNCC2)C1)C(F)(F)F
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Cc1ccc(OCCN2CCC3(CC2)CN(C(=O)C(F)(F)F)CCO3)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 60 °C
Reaction time: 25 h

Procedure:
A solution of (R)-2-(4-((tert-butoxycarbonyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)amino)methyl)phenoxy)ethyl methanesulfonate (example 108, step c) (2.20 g) in MeCN (8.5 mL) was added dropwise to a solution of 2,2,2-trifluoro-1-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone trifluoroacetate (example 12, step d) (1.18 g) and triethylamine (0.81 mL) in MeCN (8.5 mL) at RT under argon. The resulting mixture was stirred at 60° C. under argon for 25 h. After cooling to RT the solvent was removed in vacuo. The brown residue was taken up in DCM (35 mL), washed with water (2×35 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The yellow solid was purified by silica gel chromatography eluting with 0-10% MeOH/DCM to give the subtitle compound as a yellow solid. Yield 729 mg.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[CH3:35][CH:36]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH:44]([CH3:46])[CH3:45])[C:39]=1[NH:47][C:48](=[O:56])[CH2:49][P:50](=O)([O-:54])[O:51][CH2:52][CH3:53])[CH3:37]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:45][CH:44]([C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([CH:36]([CH3:35])[CH3:37])[C:39]=1[NH:47][C:48](=[O:56])[CH2:49][P:50]([NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:54])[O:51][CH2:52][CH3:53])[CH3:46]
Reactant: CCOP(=O)([O-])CC(=O)Nc1c(C(C)C)cccc1C(C)C
Reactant: NCC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(CC(=O)Nc1c(C(C)C)cccc1C(C)C)NCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 18.9 %

Procedure:
To a solution of 2,2-diphenylethylamine (0.45 g, 2.3 mmol) and triethylamine (0.35 mL, 2.5 mmol) in methylene chloride (10 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (0.48 g, 2.5 mmol), followed by (±)-[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic acid, ethyl ester (Example 5) (0.74 g, 2.3 mmol). 4-Dimethylaminopyridine (DMAP) (0.1 g) is added and the solution is stirred for 48 hours at room temperature. Additional portions of triethylamine (0.1 mL) and EDCI (0.1 g) are added and stirring is continued for another 24 hours. The reaction mixture is diluted with methylene chloride, washed with water, brine, dried over magnesium sulfate, and concentrated. Flash chromatography (ethyl acetate) affords 0.22 g of the product as a white solid. Recrystallization from ethyl acetate/hexane affords 0.18 g of the title compound as a white solid; mp 172°-176° C.
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[N+:11]([O-:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[O-:15])=O.[C:16]([CH2:18][C:19]([NH:21][NH2:22])=[O:20])#[N:17]>C(O)C>[C:16]([CH2:18][C:19]([NH:21][N:22]=[CH:1][C:3]1[C:12]([CH3:13])=[N+:11]([O-:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[O-:15])=[O:20])#[N:17]
Reactant: N#CCC(=O)NN
Reactant: Cc1c(C=O)[n+]([O-])c2ccccc2[n+]1[O-]
Solvent: CCO
Product: Cc1c(C=NNC(=O)CC#N)[n+]([O-])c2ccccc2[n+]1[O-]

Procedure:
A suspension comprising 20.4 grams (0.1 mole) of 2-formyl-3-methylquinoxaline-1,4-dioxide (m.p. of 180°-182° C.) and 9.9 grams (0.1 mole) of cyanoacetylhydrazine in 200 ml of ethanol was stirred for 4 hours at room temperature. The separated product was sucked off and washed with ethanol, so yielding 22.2 grams (78% of theoretical) of crude material. Upon crystallization from dimethylformamide, yellow crystals melting at a temperature within the range of 255°-260° C. were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C@@H:3]1[CH2:7][CH2:6][N:5](C(OCCCC)=O)[CH2:4]1.[ClH:16]>C(Cl)Cl>[ClH:16].[CH3:1][N:2]([CH3:15])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CCCCOC(=O)N1CC[C@@H](N(C)C)C1
Agent: Cl
Solvent: ClCCl
Product: CN(C)[C@@H]1CCNC1
Reaction time: 3 h

Procedure:
In a dried reaction flask, the crude (R)-butyl 3-(dimethylamino)pyrrolidine-1-carboxylate (2.0 g) obtained in the above step was added to CH2Cl2 (30 mL). HCl gas was passed thereto for 3 h. The solution was concentrated under reduced pressure to obtain a crude yellow viscous material (1.5 g).
Reaction SMILES: C1(NN)C=CC=CC=1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[C:17]=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25].C(O)=[O:27].[OH-].C1([NH+]2C[N:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[CH3:47])[C:38](NC3C=CC=CC=3C)=[N:37]2)C=CC=CC=1>>[OH-:27].[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH+:16]1[CH2:17][N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[C:38]([NH:39][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[CH3:47])=[N:37]1
Reactant: Cc1ccccc1NC1=N[NH+](c2ccccc2)CN1c1ccccc1C
Reactant: Cc1ccccc1N=C=Nc1ccccc1C
Reactant: O=CO
Agent: [OH-]
Solvent: NNc1ccccc1
Product: Cc1ccccc1NC1=N[NH+](c2ccccc2C)CN1c1ccccc1C

Procedure:
A similar reaction of phenylhydrazine with di-(2methylphenyl)carbodiimide and subsequent cyclization of the resulting condensate with formic acid resulted in 1-phenyl-4-(2-methylphenyl)-3-(2-methylphenylamino)-1H-1,2,4-triazolium hydroxide, inner salt V.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([N:25]([CH2:27][CH2:28][OH:29])[CH3:26])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:15][C:14]([Cl:24])=[CH:13][CH:12]=2)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:24][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([N:25]([CH2:27][CH2:28][OH:29])[CH3:26])[C:8]([C:6]([OH:7])=[O:5])=[C:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(CCO)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(CCO)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 42 step B from 6-chloro-2-[(2-hydroxy-ethyl)-methyl-amino]-4-phenyl-quinoline-3-carboxylic acid tert-butyl ester and TFA. Light yellow solid. MS (ESI): 355 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:11][CH:12]1[C:17](=[O:18])[N:16]2[CH:19]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:20](=[O:26])[N:21]([CH:23]([CH3:25])[CH3:24])[CH2:22][CH:15]2[N:14]([S:35]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=2[Cl:45])(=[O:37])=[O:36])[CH2:13]1>>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][CH:19]2[N:16]3[C:17](=[O:18])[CH:12]([NH:11][C:8]([C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=4)=[O:10])[CH2:13][N:14]([S:35]([C:38]4[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=4[Cl:45])(=[O:37])=[O:36])[CH:15]3[CH2:22][N:21]([CH:23]([CH3:25])[CH3:24])[C:20]2=[O:26])=[CH:29][CH:30]=1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reactant: Cc1cnc(C(=O)O)cn1
Product: Cc1cnc(C(=O)NC2CN(S(=O)(=O)c3ccc(Cl)cc3Cl)C3CN(C(C)C)C(=O)C(Cc4ccc(Cl)cc4)N3C2=O)cn1

Procedure:
Synthesis took place in analogy to Example 29e using 5-methylpyrazine-2-carboxylic acid and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW=678.10 (calculated, monoisotopic); measured value (M+H)+: 679.06
Reaction SMILES: O=[C:2]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][C:5]([O:7]CC(C)C)=[O:6].[BH4-].[Na+].O.C(OCC)(=O)C>C(O)C>[CH3:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:2]1[O:7][C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: CCCCCCC(=O)CCC(=O)OCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCC1CCC(=O)O1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In 200 ml of 99.5% ethanol, was dissolved 24.2 g (0.10 mol) of isobutyl 4-oxodecanoate. Thereto was added 4.2 g (0.11 mol) of sodium borohydride in small quantities, and then the mixture was stirred for 10 minutes at 25° C. The solution was poured into 1 L of water, and 1 L of ethyl acetate was further added thereto followed by stirring to thereby extract the product into the ethyl acetate phase. Ethyl acetate was distilled off followed by vacuum distillation, yielding γ-decalactone (a compound in which R61 represents an n-pentyl group in the above formula (39)). Gas chromatographic analysis showed that the yield of γ-decalactone relative to isobutyl 4-oxodecanoate was 93%. In the resulting γ-decalactone, a plastic-like flavor or acid taste was not observed at all, but it had a good peach-like aroma.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([CH2:10][C:11]([NH2:13])=[O:12])#[N:9]>>[C:1]1(=[C:10]([C:8]#[N:9])[C:11]([NH2:13])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCC(N)=O
Reactant: O=C1CCCCC1
Product: N#CC(C(N)=O)=C1CCCCC1

Procedure:
Reaction 1. consists of condensing the cyclohexanone (I) with cyanoacetamide, to obtain 2-cyclohexylidene-2-cyanoacetamide (IX); this reaction can be undertaken for example in toluene, in the presence of ammonium acetate and acetic acid, heating to a temperature between 20 and 150° C., and preferably to the reflux temperature of the reaction mixture; the compound IX is separated from the reaction mixture.
Reaction SMILES: CN(C)[C:3]1[S:7][C:6]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[CH:4]=1.Cl.[O:16]1CCCC1>>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:5]2[CH2:4][C:3]([S:7][C:6]=2[CH:8]=1)=[O:16]
Reactant: C1CCOC1
Reactant: COc1ccc2cc(N(C)C)sc2c1
Agent: Cl
Product: COc1ccc2c(c1)SC(=O)C2
Yield: 80 %

Procedure:
To tetrahydrofuran (200 mL) containing 2-dimethylamino-6-methoxybenzo-[b]-thiophene (cf. U.S. Pat. No. 5,420,349) (20.00 g, 96.5 mmol) was added 1N aqueous HCl (200 mL) and the resulting mixture was heated to reflux for 3 h. The mixture was cooled, the layers were separated, and the aqueous layer was extracted with dichloromethane (300 mL). The combined organic layers washed with water (250 mL), dried (MgSO4), filtered and concentrated to give crude product, which was recrystallized from 3A-ethanol, and dried in vacuo at room temperature to afford the title compound (13.89 g, 77.0 mmol, 80%): mp 80°-82° C.; IR (KBr) 1713, 1605, 1485, 1287, 1015, 865, 813 cm-1 ; 1H NMR (DMSO-d6) δ7.22 (d, 1H, J=8.4 Hz), 7.11 (s, 1H), 6.78 (d, 1H, J=8.4 Hz), 4.06 (s, 2H), 3.71 (s, 3H); 13 C NMR (DMSO-d6) δ203.5, 159.0, 136.9, 125.6, 124.6, 112.3, 108.4, 55.3, 46.2. Anal. Calcd. for C9H8O2S: C, 59.98; H, 4.47; S, 17.78. Found: C, 60.19; H, 4.57; S, 18.03.