Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=1[CH2:25][CH2:26][CH3:27].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=2[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Br)cc21
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Agent: O=C([O-])[O-]
Agent: On1nnc2cccnc21
Agent: [K+]
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Solvent: ClCCCl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
6-Bromo-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (80 mg, 0.28 mmol), 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (112 mg, 0.38 mmol) and 1-hydroxy-7-azabenzotriazole (57.7 mg, 0.42 mmol) were stirred in 3 mL of DMSO for 10 min under nitrogen. N-Methylmorpholine (0.12 ml, 1.13 mmol) was added along with EDC (81 mg, 0.42 mmol) and the mixture was stirred at room temperature overnight under nitrogen. Ice-water was added and solids crashed out. Then 10% K2CO3 was added to adjust the pH to about 8-9. Then the reaction was stirred at room temperature for 10 min and let stand for 10 min. Solids were filtered off, dissolved in DMF and water was added. Solids that precipitated out were filtered off, air-dried for 15 min and dried in vacuum oven for 2 h to give the title compound (94 mg, 73%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 8.62 (t, J=4.93 Hz, 1H) 8.37 (s, 1H) 8.20 (s, 1H) 7.69 (d, J=1.26 Hz, 1H) 5.91 (s, 1H) 5.06 (dt, J=13.14, 6.57 Hz, 1H) 4.36 (d, J=4.80 Hz, 2H) 2.14 (s, 3H) 1.48-1.56 (m, 2H) 1.47 (s, 3H) 1.45 (s, 3H) 0.89 (t, J=7.33 Hz, 3H); MS (ES) [M+H]+ 445.1, 446.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][C:4]=1[C:14](=[O:16])[CH3:15].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[CH:21]=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[F:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:15][C:14]([C:4]2[CH:5]=[CH:6][C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[CH:8][C:3]=2[O:2][CH3:1])=[O:16])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: COc1cc(-c2cccs2)ccc1C(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1cc(-c2cccs2)ccc1C(=O)C=Cc1ccc(F)c(F)c1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
The 2′-methoxy-4′-(thien-2-yl)acetophenone (0.30 g, 1.3 mmol) from Ex-57A and 3,4-difluorobenzaldehyde 0.19 g, 1.3 mmol) were mixed in tetrahydrofuran (THF, 10 mL). Cesium carbonate (1.2 g, 3.9 mmol) was added, and the mixture was stirred at reflux overnight. Upon cooling to room temperature, the mixture was filtered, the filtrate was treated with 0.5 M HCl, and extracted with dichloromethane. The organic phase was dried and evaporated. Silica gel chromatography gave 0.32 g (69%) of the desired 3-(3,4-difluorophenyl)-1-[2-methoxy-4-(thien-2-yl)phenyl]-2-propen-1-one product, m.p. 73-79° C. 1H-NMR (300 MHz, CDCl3): 7.70 (d, 1H), 7.25-7.40 (m, 2H), 6.98-7.15 (m, 7H), 6.49 (d, 1H), 3.89 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-])=O)[CH:10]=1)[NH:7][C:6]([C:14]1[S:15][CH:16]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:17][N:18]=1)=[CH:5]2.[Cl-].[Ca+2].[Cl-].C(O)C.O1CCCC1>[Fe].O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH2:11])[CH:10]=1)[NH:7][C:6]([C:14]1[S:15][CH:16]([CH2:19][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[CH2:17][N:18]=1)=[CH:5]2
Reactant: O=[N+]([O-])c1cc(Br)cc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(Br)cc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12
Temperature: 80 °C
Yield: 22.4 %

Procedure:
A mixture of 5-bromo-2-[5-(morpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-7-nitro-1H-indole (2.4 g), iron (1.7 g), calcium chloride (310 mg), ethanol (50 mL), tetrahydrofuran (25 mL) and water (5 mL) was stirred under heating at 80° C. for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (MgSO4), and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the title compound (500 mg, yield 22%) as yellow crystals from a fraction eluted with ethyl acetate:hexane=50:50. MS: 396 (MH+).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].N1C=CC=CC=1>ClCCl.CN(C1C=CN=CC=1)C>[F:11][C:12]([F:20])([F:21])[C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccccc1C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Benzenesulfonyl chloride (400 g, 2.26 moles) was dissolved in dichloromethane (2 L). To this was added o-trifluoromethylaniline (250 mL, 320 g, 1.99 mol), pyridine (222 mL), and DMAP (7.5 g). The resulting solution was stirred at room temperature for 3 days (72 h), then heated to reflux for 1 hour. The cooled solution was then concentrated on the rotary evaporator, with the bath temperature gradually raised to 70° C. The residue was taken up in ether (3 L) and 1N HCl (1.5 L). The ether layer was separated, washed 2×500 mL with 1N HCl, 1×1 L with brine, 1×1 L with saturated sodium bicarbonate, and once more with 1 L of brine. It was then dried over magnesium sulfate, filtered with suction, and concentrated on the rotary evaporator without heat. The product formed fine crystals as the ether evaporated, and when most of the ether was gone, the crystals were slurried with hexane (2 L), collected with suction and dried. Yield 571 g, 84%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(OCC)C.CCCCCC>[Cl:19][CH2:20][C:21]([NH:14][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([O:7][C:6]2[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(Oc2ccc(C(N)=O)cc2)cc1
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccc(Oc2ccc(C(=O)NC(=O)CCl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-Methoxyphenoxy)benzamide (8.34 g, 34.3 mmol) and chloroacetyl chloride (19.4 g, 171 mmol) were heated together at 100° C. for 2 hours. The cooled mixture was diluted with ethyl ether and hexane. After stirring for 1 hour at room temperature the solid was collected yielding 8.98 g of N-(2-chloroacetyl)-4-(4-methoxyphenoxy)benzmide as a light orange solid. MS (m/z, APCI): 320 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21](CO)=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CNC(=O)C=1)C1C=CC=CC=1.ClCC(C1C=C2C(=CC=1)[CH2:51][N:50]([C:55](=[O:60])[C:56]([F:59])([F:58])[F:57])[CH2:49]2)=O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16](=[O:17])[C:18]2[CH:19]=[C:20]3[C:21](=[CH:22][CH:23]=2)[CH2:51][N:50]([C:55](=[O:60])[C:56]([F:59])([F:58])[F:57])[CH2:49]3)[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCl)c1ccc2c(c1)CN(C(=O)C(F)(F)F)C2
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Agent: O=c1cc(OCc2ccccc2)cc[nH]1
Solvent: CS(C)=O
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)C2

Procedure:
4-Benzyloxy-1-{2-oxo-2-[2-(2,2,2-trifluoro-acetyl)-2,3-dihydro-1H-isoindol-5-yl]-ethyl}-1H-pyridin-2-one is prepared following preparation 15b from 1.50 g (7.45 mmol) 4-benzyloxy-1H-pyridin-2-one and 2.28 g (7.83 mmol) 1-[5-(2-chloro-acetyl)-1,3-dihydro-isoindol-2-yl]-2,2,2-trifluoro-ethanone (see preparation 23) in DMSO as solvent.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].IC1C=CC=CC=1C(NCCN1C(=O)CC(=O)NC2C3C(C=CC1=2)=CC=CC=3)=O>>[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:29]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(CCNC(=O)c2ccccc2I)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3F)cc2)c2ccc3ccccc3c2N1
Yield: 67.6 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.101 mmol) obtained in Example 1, (3), and 2-fluorobenzoyl chloride (32 mg, 0.202 mmol), the title compound (30 mg, yield 67%) was obtained as white crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Br)cc1C(=O)O
Yield: 86.5 %

Procedure:
2-Amino-5-bromobenzoic acid (4.0 g, 0.018 mol) was dissolved in DMF (90 mL) and treated with carbonic acid di-tert-butyl ester (4.44 g, 0.020 mol), 4-dimethylamino-pyridine (0.219 g, 0.0018 mol) and triethylamine (2.8 mL, 0.020 mol) for 16 h at 70° C. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed twice with saturated aqueous sodium bicarbonate, then twice with 1 N hydrochloric acid, dried over sodium sulfate. The organic layers were concentrated to afford 5-bromo-2-tert-butoxycarbonylamino-benzoic acid as a yellow solid (4.92 g, 86.7%). 1H NMR (500 MHz, DMSO-d6) δ 1.46 (s, 9H), 7.72 (dd, J=2.5, J=8.5 Hz, 1H), 8.01 (d, J=2.5 Hz, 1H), 8.22 (d, J=8.5 Hz, 1H), 10.44 (s, 1H). MS: m/z 316 (M+H+).
Reaction SMILES: Br.C([N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)C#C.Cl.N([O-])=O.[Na+].[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH:22]([S:10][C:9]1[NH:5][N:6]=[N:7][N:8]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccccc1
Reactant: C#CCn1nnnc1S
Agent: Br
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: c1ccc(C(Sc2nnn[nH]2)c2ccccc2)cc1
Reaction time: 1.5 h

Procedure:
To a mixture of the crude product of 3-benzhydrylisothiosemicarbazide hydrobromide from (1) above, water (2.3 l), conc. hydrochloric acid (126 g) and toluene (900 ml) was dropwise added a solution of sodium nitrite (83.5 g) in water (200 ml) and the resulting mixture was stirred for 1.5 hours at 10° to 15° C. The reaction mixture was extracted with ethyl acetate. The organic layer was added to water (1 l) and adjusted to pH 9.5 with 4 N aqueous solution of sodium hydroxide. The separated aqueous layer was then adjusted to pH 2.5 with 10% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and evaporated to give a residue, which was washed with a mixture of n-hexane and isopropyl ether (2:1) and air-dried to give 5-benzhydrylthio-1H-tetrazole (127.22 g), mp 132° to 134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=O)[C:16]2[C:11](=[N:12][C:13]([S:19][CH3:20])=[N:14][CH:15]=2)[N:10]2[CH:21]=[CH:22][N:23]=[C:9]12.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[S:33])[C:16]2[C:11](=[N:12][C:13]([S:19][CH3:20])=[N:14][CH:15]=2)[N:10]2[CH:21]=[CH:22][N:23]=[C:9]12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CSc1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Solvent: Cc1ccccc1
Product: CSc1ncc2c(=S)n(-c3ccccc3Cl)c3nccn3c2n1

Procedure:
A solution of Example 1D (0.730 g, 2.123 mmol) and Lawesson's reagent (0.515 g, 1.274 mmol) in toluene (40 mL) was heated to reflux for 4 hours. The reaction mixture was concentrated and purified on a 40 g column using the ISCO Companion flash system eluting with hexane/ethyl acetate (1:1 to 4:6) to provide the title compound.
Reaction SMILES: Cl.[C:2]1([NH:8]N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:11]([CH2:17][CH3:18])[CH2:12][CH2:13][C:14]([OH:16])=[O:15]>>[CH2:17]([C:11]1[NH:8][C:2]2[C:7]([C:12]=1[CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:18]
Reactant: CCC(=O)CCC(=O)O
Reactant: NNc1ccccc1
Agent: Cl
Product: CCc1[nH]c2ccccc2c1CC(=O)O
Yield: 10 %

Procedure:
Reaction was conducted in the same manner as Reference Example 86, except that phenylhydrazine hydrochloride was used instead of 3-tolylhydrazine hydrochloride and 4-oxohexanoic acid was used instead of levulinic acid, to obtain the title compound (10% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8](=O)[NH:9][CH:10]=[CH:11][CH:12]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:8]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cccc1-c1ccccn1
Product: Clc1ncccc1-c1ccccn1
Temperature: 25 °C

Procedure:
A 5.9 g portion of 3-(2-pyridinyl)-2(1H)-pyridinone in 100 ml of phosphorus oxychloride was heated on a steam bath for 18 hours, then concentrated under vacuum. The residue was stirred with crushed ice and chloroform and adjusted to pH 7 with 10N sodium hydroxide. The organic layer was separated, dried, filtered through a short pad of hydrous magnesium silicate and the filtrate concentrated under vacuum to an oil. This oil was heated with hexane, filtered while hot and the filtrate cooled to room temperature, giving 3.5 g of 2'-chloro-2,3'-bipyridine as white needles, mp 50° C.
Reaction SMILES: C([C@H]1CC[C@H](OC2C=C3C(=CC=2)C=C(C([N+]([O-])=O)(C)CCC(O)=O)C=C3)CC1)(C)(C)C.[C:32]([C@H:36]1[CH2:41][CH2:40][C@H:39]([O:42][C:43]2[C:44]([C:64]([F:67])([F:66])[F:65])=[C:45]3[C:50](=[CH:51][CH:52]=2)[CH:49]=[C:48]([C:53]([N+:61]([O-:63])=[O:62])([CH3:60])[CH2:54][CH2:55][C:56]([O:58]C)=[O:57])[CH:47]=[CH:46]3)[CH2:38][CH2:37]1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C@H:36]1[CH2:37][CH2:38][C@H:39]([O:42][C:43]2[C:44]([C:64]([F:65])([F:66])[F:67])=[C:45]3[C:50](=[CH:51][CH:52]=2)[CH:49]=[C:48]([C:53]([N+:61]([O-:63])=[O:62])([CH3:60])[CH2:54][CH2:55][C:56]([OH:58])=[O:57])[CH:47]=[CH:46]3)[CH2:40][CH2:41]1)([CH3:33])([CH3:34])[CH3:35]
Reactant: COC(=O)CCC(C)(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Agent: CC(CCC(=O)O)(c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Product: CC(CCC(=O)O)(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]

Procedure:
4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-4-nitropentanoic acid was synthesized as per 4-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)-4-nitropentanoic acid (Example 206) in 10% yield using methyl 4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-4-nitropentanoate as starting material.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][CH:5]=1>>[CH3:1][NH:2][CH2:10][C:7]1[CH:8]=[N:9][C:4]([CH3:3])=[CH:5][CH:6]=1
Reactant: CN
Reactant: Cc1ccc(CCl)cn1
Product: CNCc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 16.6 g of 40% aqueous MeNH2 solution and 52 ml of CH2CN was cooled with ice and 6.08 g (0.043 mole in terms of pure product) of crude (6-methyl-3-pyridyl)methyl chloride was added dropwise with constant stirring. After completion of dropwise addition, the mixture was stirred at room temperature for 1.5 hours, at the end of which time the solvent was distilled off. The solid residue was extracted with CH2Cl2 and the CH2Cl2 layer was dried over MgSO4. The CH2Cl2 was distilled off and the residue was diluted with 70 ml of Et2O and filtered to remove the insoluble matter. Finally the filtrate was concentrated to recover 4.60 g of the title compound as a crude oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].COCCOCCN(CCOCCOC)CCOCCOC>CN(C=O)C.O.Cl[Cu]>[O:1]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCCc2c(O)cccc21
Reactant: Ic1ccccc1
Agent: Cl[Cu]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCc2c(Oc3ccccc3)cccc21
Temperature: 50 °C
Yield: 18 %

Procedure:
To a solution of 5-hydroxy-1-tetralone (4.5 g, 28.0 mmol) and iodobenzene (24.0 g, 168.0 mmol) in DMF (50 mL) was added NaH (1.2 g, 30.0 mmol) at room temperature. The mixture was heated to 50° C. until the solid was dissolved and then cooled. To the mixture was added CuCl (2.8 g, 28.0 mmol); followed by tris(dioxa 3,6-heptyl)amine (2.7 g, 8.4 mmol). The mixture was heated at 145° C. overnight. The reaction was diluted with water, extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated. Purification by silica gel chromatography (20:1 PE/EtOAc) gave 1.2 g (18%) of the title compound as a yellow oil. [M+H] calc'd for C16H14O2, 239; found 239.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C@@H:7]([NH2:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:25]1([C:32]([NH:34][C@@H:35]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:36](O)=[O:37])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:1]([O:5][C:6](=[O:24])[CH:7]([NH:23][C:36](=[O:37])[CH:35]([NH:34][C:32]([N:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:33])[CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCc2ccncc2)cc1
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2ccncc2)cc1)C(=O)OC(C)(C)C

Procedure:
In a manner similar to that described in Example 25, the product from Example O and the product from Example Z were coupled to give the title compound.
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.O=P(Cl)(Cl)[Cl:16]>ClC(Cl)C>[Cl:16][C:2]1[N:3]=[C:4]2[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1(C)Cn2c(nc(O)cc2=O)N1
Solvent: CC(Cl)Cl
Product: CC1(C)Cn2c(nc(Cl)cc2=O)N1
Temperature: 60 °C
Yield: 83 %

Procedure:
18.5 g of 7-hydroxy-2,2-dimethyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are suspended in 200 mL of dichloroethane. 48 mL of POCl3 are added and the mixture is heated to 60° C. for 3 h. After returning to RT, the solvents are dry evaporated. The residue is taken up in water and AcOET, 30% NaOH is added until pH=12. The product precipitates, it is filtered and then dried. 16.9 g (yield=83%) of 7-chloro-2,2-dimethyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are obtained as a yellow solid and including the following characteristics:
Reaction SMILES: C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](C=O)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[C:30]([C@@H:32]1[CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33]1)#N>>[CH:30]([C@@H:32]1[CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33]1)=[O:2]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12CCCCC1[C@@H](C=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1[C@@H](C=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
6α-Formylandrostane-3,17-dione was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-6α-formylandrostane (Prepn. 11) by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness to give 6α-formylandrostane-3,17-dione. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 9.50 (d, 1H), 2.56-0.82 (m, 21H), 1.16 (s, 3H), 0.88 (s, 3H).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([S:11][CH3:12])[N:5]=1.[CH2:13]([OH:15])[CH3:14]>>[CH2:13]([O:15][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([S:11][CH3:12])[N:5]=1)[CH3:14]
Reactant: CSc1nc(C)cc(Cl)n1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Product: CCOc1cc(C)nc(SC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To sodium hydride (2.75 g (60% in mineral oil), 0.046×1.5 mmol) dissolved in ethanol (20 ml), 4-chloro-6-methyl-2-methylmercaptopyrimidine (Compound IV-7) (8.0 g, 0.046 mmol) was added and the solution was stirred for about 1 hour at room temperature.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12](=[O:19])[NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:6]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C.[OH-].[Na+]>O1CCOCC1>[CH2:21]([O:20][C:6]1[C:7]([C:12](=[O:19])[NH:13][CH2:14][C:15]([F:16])([F:17])[F:18])=[CH:8][C:9]([F:11])=[CH:10][C:5]=1[C:4]([OH:28])=[O:3])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1cc(F)cc(C(=O)NCC(F)(F)F)c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cc(F)cc(C(=O)NCC(F)(F)F)c1OCc1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
10.78 g (27 mmol) of 2-benzyloxy-5-fluoro-(2,2,2-trifluoroethylcarbamoyl)-benzoic acid ethyl ester is dissolved in 60 ml of dioxane, the solution is mixed with 17.5 ml (35 mmol) of 2N sodium hydroxide solution, stirred for 1 hour at room temperature and 1 hour at 40° C. The reaction mixture is concentrated by evaporation under reduced pressure, the residue is taken up in 80 ml of water, acidified to pH 1 with concentrated hydrochloric acid. In this case, the acid precipitates mostly at amorphous solid. It is suctioned off and washed with a little water. The aqueous phase is shaken out several times with ethyl acetate. The ethyl acetate extract is concentrated by evaporation and the residue is combined with the precipitate from the water. It is dried in a vacuum for 48 hours at 50° C. Yield: 8.38 g (22.57 mmol) =83.6% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH3:13][O:14][C:15](=[O:29])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[NH:19][C:18]=1[CH3:28]>>[CH3:13][O:14][C:15](=[O:29])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]([C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([N:1]=[N+:2]=[N-:3])=[CH:5][CH:6]=2)[C:18]=1[CH3:28]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Product: COC(=O)Cc1c(C)n(C(=O)c2ccc(N=[N+]=[N-])cc2)c2ccc(OC)cc12

Procedure:
The title compound is prepared by condensing 18.16 g (0.1 mole) of p-azidobenzoyl chloride with 0.1 mole of methyl-5-methoxy-2-methyl-3-indolylacetate following the procedure described in Example 2.