Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][CH:5]=1.[Li].[O:13]1CCC[CH2:14]1>>[CH3:2][O:3][C:4]1[CH2:5][CH:6]=[C:7]([CH2:10][CH2:14][OH:13])[CH2:8][CH:9]=1
Reactant: COc1ccc(CO)cc1
Reactant: C1CCOC1
Agent: N
Agent: [Li]
Product: COC1=CCC(CCO)=CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Liquid ammonia (520 mL) was condensed in a three-necked flask which was fitted with a cold finger and overhead stirrer and kept at -78° C. with a dry ice/isopropanol bath. A solution of 1-methoxy-4-hydroxymethyl-benzene (50 g, 329 mmol) in tetrahydrofuran (140 mL) was added to the reaction flask followed by the addition of small pieces of lithium wire (10.3 g, 1.48 mol) over a period of about 15 min. The reaction mixture was stirred an additional 30 min at -78° C. and then quenched by the slow addition of absolute ethanol (400 mL). After the reaction was completely quenched (white color), it was allowed to warm to room temperature overnight. This allowed most of the NH3 to evaporate. The residue was partitioned between water and diethyl ether, the organic layer collected, dried over anhydrous MgSO4, filtered and evaporated at reduced pressure. The residue, which still contained some water, was dissolved in methylene chloride, dried over anhydrous MgSO4, filtered and evaporated at reduced pressure to give crude 1-methoxy-4-(2-hydroxyethyl)-cyclohexa-1,4-diene (1) as an oil (40.3 g), which was used in the next step without further purification. This crude product was contaminated with the over-reduced product, 1-methoxy-4-(2-hydroxyethyl)-cyclohex-1-ene (2). Compound (1): 1H NMR δ (CDCl3) 2.12 (1H, br s), 2.28 (2H, t, J=7.5 Hz), 2.78 (4H, br s), 3.58 (3H, s), 3.73 (2H, t, J=7.5 Hz), 4.68 (1H, br s), 5.55 (1H, br s).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[C:11]([F:39])[CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:64][C:65]1[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[CH:67][C:66]=1[O:73][CH3:74]>ClCCCl>[C:69]([C:68]1[CH:71]=[CH:72][C:65]([NH:64][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][C:11]=4[F:39])[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:66]([O:73][CH3:74])[CH:67]=1)#[N:70]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)cc(F)c12
Reactant: COc1cc(C#N)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)cc(F)c32)C1c1cccc(Cl)c1F
Yield: 30.6 %

Procedure:
In a manner similar to the method described in Example 27, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 71 (0.95 g, 1.6 mmol), was reacted with diisopropylethylamine (0.82 g, 6.4 mmol), diphenylphosphinic chloride (0.75 g, 3.2 mmol) in 1,2-dichloroethane at room temperature, then reacted with 4-amino-3-methoxy benzonitrile prepared in Example 57 (0.71 g, 4.8 mmol) at 80° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide as a white solid (Yield 0.3 g, 31%).
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[N:20][N:21]3[CH:26]=[CH:25][C:24]([OH:27])=[N:23][C:22]=23)=[CH:14][CH:13]=1.[S:30](Cl)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31].CCN(CC)CC.CCOC(C)=O>O1CCOCC1>[CH3:37][C:36]1[CH:38]=[CH:39][C:33]([S:30]([O:27][C:24]2[CH:25]=[CH:26][N:21]3[N:20]=[CH:19][C:18]([C:15]4[CH:14]=[CH:13][C:12]([C:8]5[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:29])([CH3:28])[CH3:1])[CH:11]=[CH:10][N:9]=5)=[CH:17][CH:16]=4)=[C:22]3[N:23]=2)(=[O:32])=[O:31])=[CH:34][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[Si](C)(C)CCOCn1ccnc1-c1ccc(-c2cnn3ccc(O)nc23)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2ccn3ncc(-c4ccc(-c5nccn5COCC[Si](C)(C)C)cc4)c3n2)cc1
Temperature: 80 °C

Procedure:
A mixture of 3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-ol (15.0 mg, 0.0368 mmol), tosyl chloride (7.0 mg, 0.0368 mmol) and NEt3 (5.13 μL, 0.037 mmol) in dioxane (2 mL) was heated at 80° C. for 18 hours. Additional portions of tosyl chloride (7.0 mg, 0.037 mmol) and NEt3 (5.1 μL, 0.037 mmol) were added and the mixture continued to heat at 80° C. for 12 hours. The cooled reaction mixture was poured into EtOAc and extracted with 10% HCl. The organic extract was dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography, eluting with 1-2% MeOH/dichloromethane, afforded 3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl 4-methylbenzenesulfonate as a brown-yellow film (19.0 mg, 92%). LCMS (APCI+) m/z 562 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OCCCC)=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:3]=1.Br[C:26]1[C:27]([C:32]#[N:33])=[N:28][CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:7]=1)=[C:26]1[C:27](=[C:32]([NH2:33])[N:8]=2)[N:28]=[CH:29][CH:30]=[CH:31]1
Reactant: N#Cc1ncccc1Br
Reactant: CCCCOC(=O)Nc1ccc(Cl)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: Nc1nc2ccc(Cl)cc2c2cccnc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-carbamate (from step 2) (1.0 eq.) and 3-bromopicolino-nitrile (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-50% ethyl acetate in hexane and then re-purified using 0-5% methanol in dichloromethane to give a solid. 1H NMR (acetone d-6): δ 9.08 (d, 1H), 8.96 (d, 1H), 8.45 (s, 1H), 7.86-7.89 (dd, 1H), 7.60 (d, 1H), 7.54 (d, 1H), 6.78 (br, 2H). LRMS [M+H]=230.1
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1.C([Mg]Cl)(C)C.[CH2:21]([Sn:25]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])Cl)[CH2:22][CH2:23][CH3:24]>C1COCC1>[CH3:14][S:11]([C:7]1[CH:6]=[C:5]2[C:10]([C:2]([Sn:25]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:21][CH2:22][CH2:23][CH3:24])=[N:3][N:4]2[CH3:15])=[CH:9][CH:8]=1)(=[O:13])=[O:12]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1nc(I)c2ccc(S(C)(=O)=O)cc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(S(C)(=O)=O)ccc12
Temperature: -16 °C
Reaction time: 1 h

Procedure:
In a round-bottomed flask, 3-iodo-6-methanesulfonyl-1-methyl-1H-indazole (120 mg, 0.36 mmol) was dissolved in THF (2 ml). The colorless solution was cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0 M in THF, 0.25 ml, 0.50 mmol) was added dropwise. The reaction mixture was stirred at −16° C. for 1 h then tributylchlorostannane (0.12 ml, 0.44 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature over 2.5 h then quenched with saturated NH4Cl-solution and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to afford 6-methanesulfonyl-1-methyl-3-tributylstannanyl-1H-indazole as a light yellow oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](Br)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([Br:28])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(Br)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2,6-dibromo-pyridine.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11]CC1C=CC=CC=1)=[O:4].Cl.Cl.[NH2:36][C@@H:37]([CH3:45])[CH2:38][CH2:39][NH:40][CH:41]1[CH2:44][CH2:43][CH2:42]1.O=C1N2CCCNC2CN2C=C(C(N)=O)C(=O)C(OCC3C=CC=CC=3)=C12>>[CH:41]1([N:40]2[CH2:39][CH2:38][C@H:37]([CH3:45])[N:36]3[C:3](=[O:4])[C:5]4[N:6]([CH:7]=[C:8]([C:20]([NH:21][CH2:22][C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)=[O:30])[C:9](=[O:19])[C:10]=4[OH:11])[CH2:31][C@@H:32]23)[CH2:44][CH2:43][CH2:42]1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Reactant: C[C@H](N)CCNC1CCC1
Agent: Cl
Agent: NC(=O)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1CCCNC1C2
Product: C[C@H]1CCN(C2CCC2)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(O)c3C(=O)N12

Procedure:
In a similar manner to that described in example Z-35a, from 16 (18 mg, 0.39 mmol) and [(3S)-3-Aminobutyl]cyclobutylamine bis-hydrochloride (23 mg, 0.107 mmol), (4S,12aS)-1-cyclobutyl-N-[(4-fluorophenyl)methyl)-4-methyl]-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide was prepared as a white solid. This material was deprotected in a second step similar to that described in example Z-37 to give the title compound as a white solid after purification by HPLC (4.5 mg, 25% 2 steps). 1H NMR (CDCl3) δ 12.54 (s, 1H), 10.48 (s, 1H), 8.20 (s, 1H), 7.31 (m, 2H), 6.08 (m, 2H), 5.02 (m, 1H), 4.61-4.57 (m, 2H), 4.26-4.14 (m, 3H), 3.05 (m, 1H), 2.90 (m, 1H), 2.49 (m, 1H), 2.12 (m, 1H), 2.05-1.87 (m, 8H), 1.84-1.61 (m, 3H), 1.46 (m, 1H), 1.32 (m, 3H); ES+MS: 455 (M+1).
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.[NH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:6]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: NCc1cccnc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(Br)cc1C(=O)NCc1cccnc1
Yield: 87.2 %

Procedure:
In 238 ml of dimethylformamide were dissolved 23.8 g of 2-amino-5-bromobenzoic acid, 13.1 g of 3-aminomethylpyridine and 24.5 g of triethylamine, and the solution was chilled with ice. To this solution was dropwise added 33.3 g of diphenylphosphoryl azide in 10 minutes, and the resultant mixture was stirred at room temperature for 18 hours. The reaction mixture was poured onto ice water. The precipitated solid was filtered, washed with water and dried to give 29.4 g of the titled compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].F[C:12]1[CH:25]=[CH:24][C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:21]1[CH:22]=[CH:23][C:18]([C:16]([C:15]2[CH:24]=[CH:25][CH:12]=[CH:13][CH:14]=2)=[O:17])=[CH:19][CH:20]=1)=[CH:2][CH3:3]
Reactant: C=CCc1ccccc1O
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: CC=Cc1ccccc1Oc1ccc(C(=O)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
o-Allylphenol (33.5 g), 4-fluorobenzophenone (50.05 g), potassium carbonate (24.20 g), dry N-methylpyrrolidone (160 ml) and toluene (60 ml) are placed in a 3-necked 500 ml flask fitted with a stirrer, reflex condensor and thermometer and the mixture is heated under nitrogen to a temperature between 155°-160° C. and stirred for 3 hours. Water and toluene are separated via a Dean Stark trap and finally after 3 hours the reaction mixture reaches a temperature of 160° C. The mixture is cooled to 100° C. and a 1:1 mixture of toluene/water (400 ml) is added while stirring. After phase separation the aqueous layer is washed with toluene (50 ml) and the combined toluene layers are washed 4 times with water (150 ml). The toluene phase is dried over sodium sulphate and toluene distilled off by use of a rotary evaporator finally in vacuum leaving 4-[o-(1-propenyl)phenoxy]benzophenone as a light yellow melt. The yield is 73 g.
Reaction SMILES: Cl[C:2]1[C:3]([O:16][CH2:17][C:18]2([C:24]#[N:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:26]1(B(O)O)[CH2:28][CH2:27]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Pd]>[C:24]([C:18]1([CH2:17][O:16][C:3]2[C:2]([CH:26]3[CH2:28][CH2:27]3)=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:5]([F:15])[CH:4]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)#[N:25]
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(C#N)CCCCC2)cc1F
Agent: [Pd+2]
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C#N)CCCCC2)cc1F
Temperature: 150 °C
Yield: 86.4 %

Procedure:
To an argon-degassed solution of tert-butyl 5-chloro-4-((1-cyano-cyclohexyl)methoxy)-2-fluorobenzoate (0.571 g, 1.55 mmol) in toluene (8 mL) and water (1 mL) was added cyclopropylboronic acid (0.66 g, 7.71 mmol), tribasic potassium phosphate (1.02 g, 4.80 mmol), tricyclohexylphosphine tetrafluoroborate (0.28 g, 0.92 mmol), and palladium acetate trimer (0.11 g, 0.47 mmol Pd). The mixture was heated at 150° C. in a microwave reactor for 0.5 hour, then diluted with ethyl acetate (150 mL), washed with a 3:1 mixture of saturated aqueous ammonium chloride and water (2×150 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to dryness. The residue was purified by column chromatography with a gradient of ethyl acetate in hexanes from 0-10% to afford the title compound as a yellow syrup (0.50 g, 86%): 1H NMR (300 MHz, CDCl3) δ 7.41 (d, J=8.3 Hz, 1H), 6.46 (d, J=12.2 Hz, 1H), 3.93 (s, 2H), 2.18-2.13 (m, 2H), 2.07-1.98 (m, 1H), 1.82-1.63 (m, 5H), 1.55 (s, 9H), 1.48-1.39 (m, 2H), 1.29-1.21 (m, 1H), 0.94-0.88 (m, 2H), 0.65-0.60 (m, 2H); MS (ES+) m/z 374.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([NH:5][NH:6][C:7]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:23])[CH:13]=2)[N:8]=1)=O.O.N>>[F:1][C:2]([F:25])([F:24])[C:3]1[N:8]2[C:9]3[C:14]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:16][C:7]2=[N:6][N:5]=1)=[CH:13][C:12]([Cl:23])=[CH:11][CH:10]=3
Reactant: O=C(NNc1nc(-c2ccccc2)c2cc(Cl)ccc2n1)C(F)(F)F
Agent: N
Solvent: O
Product: FC(F)(F)c1nnc2nc(-c3ccccc3)c3cc(Cl)ccc3n12
Temperature: 0 °C

Procedure:
In the next place, a mixture of 1.0 g of 2-(2-trifluoroacetylhydrazino)-4-phenyl-6-chloroquinazoline thus obtained and 20 g of polyphosphoric acid was heated at 150° C for 2 hours. The mixture was then poured into ice-water and made alkaline with concentrated ammonia water. The resulting crystals were collected by filtration, washed with water, dried and dissolved in chloroform, and purified by chromatography on silica gel using chloroform as an eluent to give 1-trifluoromethyl-5-phenyl-7-chloro-s-triazolo[4,3-a]quinazoline, m.p. 241° - 242° C.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5](=[C:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]3=[O:33])=[CH:19][C:18]=2[F:34])[CH2:13][CH2:12]1)[C:6](OCC)=[O:7])#[N:4].Cl>CO>[C:3]([CH:5]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]3=[O:33])=[CH:19][C:18]=2[F:34])[CH2:13][CH2:12]1)[CH2:6][OH:7])#[N:4]
Reactant: CCOC(=O)C(C#N)=C1CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C(C#N)CO)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
The mixture of sodium borohydride (5.26 mmol), (S)-N-{3-[4-(4-(1-cyano-1-ethoxycarbonyl-methylidene)-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.34 mmol) in methanol (15 ml) was stirred for 0.5 hours at room temperature. The reaction mixture was neutralized with dilute hydrochloric acid. The solid was filtered and purified on silica gel column chromatography recrystallized from chloroform:methanol to provide tile compound in 76% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[CH:13]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:14]([C:17]([O:19][CH2:20][CH2:21]Br)=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8].[I-].[Na+].CC(C)=O.S1C=CC=C1CC(NC1S[C@@H]2CC(=O)N2C(C([O-])=O)C=1C(OCC[I:67])=O)=O>C(Cl)(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[CH:13]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:14]([C:17]([O:19][CH2:20][CH2:21][I:67])=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(=O)OCCBr)=CS[C@H]12
Reactant: O=C(Cc1cccs1)NC1=C(C(=O)OCCI)C(C(=O)[O-])N2C(=O)C[C@H]2S1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(=O)OCCI)=CS[C@H]12
Reaction time: 16 h

Procedure:
Benzhydryl 7-(2-thienylacetamido)-3-(2-bromoethoxycarbonyl)-2-cephem-4-carboxylate (7.61 g., 12 mmol.) was combined with sodium iodide (6.75 g., 45 meq.) in 100 ml. acetone. The reaction mixture was degassed and then heated to 35° with stirring for 16 hours. The reaction mixture was filtered and evaporated to dryness. The residue was dissolved in ethyl acetate and washed with water (3X) and brine and dried (Na2SO4). Evaporation in vacuo to dryness provided 7.78 g. (95.5%) of benzhydryl 7-(2-thienylacetamido-3-(2-iodoethoxycarbonyl)-2-cephem-4-carboxylate: ir (CHCl3) 1785 cm-1 (β-lactam C = O); nmr (CDCl2) δ 2.96 (t, 2, J = 7.0 Hz, --OCH2 --), 3.80 (s, 2, side chain CH2), 4.24 (t, 2, J = 7.0 Hz, --OCH2 --), 4.95 (d, 1, J = 4.0 Hz, C6 --H), 5.24 (q, 1, J = 4.0 Hz, C7 --H, rest of the signal covered by C4 --H), 5.50 (s, 1, C4 --H), and 7.80 (s, 1, C2 --H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH2:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH2:13])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: NC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: NC(=O)Nc1cccc(N)c1
Reaction time: 2 h

Procedure:
A solution of N-(3-nitrophenyl)-urea (1.0 g, 5-5 mmol) and methanol (40 mL) was treated with 10% Pd/C (250 mg) and placed under H2 (45 psi) for 2 h. The mixture was then filtered through celite and concentrated to afford N-(3-aminophenyl)-urea (828 mg, 5.5 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[C:11](=[NH:13])[NH2:12])[CH3:2].[S:14](N1C=CN=C1)(N1C=CN=C1)(=[O:16])=[O:15]>O>[NH2:13][C:11]1[C:5]2[C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][S:14](=[O:16])(=[O:15])[N:12]=1
Reactant: O=S(=O)(n1ccnc1)n1ccnc1
Reactant: CCOc1cccc(O)c1C(=N)N
Solvent: O
Product: CCOc1cccc2c1C(N)=NS(=O)(=O)O2

Procedure:
0.25 g (1.39 mmol) of 2-ethoxy-6-hydroxybenzenecarboximidamide is stirred without solvent with 0.65 g (3.28 mmol) of 1,1′-sulphonyldiimidazole at 130° C. for 18 hours. Cooling is followed by stirring the mixture with water and removing with dichloromethane. The organic phase is dried over magnesium sulphate and concentrated under reduced pressure. This gives 0.2 g of a pale yellow, crystalline material.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:16][CH2:17]Cl)=[C:11]([CH2:13][CH2:14][CH3:15])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1.C([O-])(=O)C([O-])=O>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:16][CH2:17][N:31]3[CH2:30][CH2:29][CH:28]([C:25]4[C:24]5[CH:34]=[CH:35][C:21]([F:20])=[CH:22][C:23]=5[O:27][N:26]=4)[CH2:33][CH2:32]3)=[C:11]([CH2:13][CH2:14][CH3:15])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CCCc1sc2c(c1CCCl)CCN(C(C)=O)C2
Agent: Cl
Agent: O=C([O-])C(=O)[O-]
Product: CCCc1sc2c(c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCN(C(C)=O)C2
Yield: 38.3 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.7 g of 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-propylthieno[2,3-c]pyridine and 1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.7 g of 6-acetyl-2-propyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil, m.p. 178°-180° C. (decomposition) as oxalate 1/2hydrate thereof.
Reaction SMILES: CO[C:3]1[CH:10]=[CH:9][C:8]([CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH3:12])=[CH:7][C:4]=1[CH:5]=O.[ClH:17].Cl.[C:19]1([C@H:25]2[C@@H:30]([NH2:31])[CH2:29][CH2:28][CH2:27][NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.Cl.C(C1(C2C=CC(OC)=C(C=2)CN[C@H]2CCCN[C@H]2C2C=CC=CC=2)CC1)#N>>[ClH:17].[ClH:17].[CH3:16][O:15][C:13]([CH:11]([C:8]1[CH:9]=[CH:10][CH:3]=[C:4]([CH:7]=1)[CH2:5][NH:31][C@H:30]1[CH2:29][CH2:28][CH2:27][NH:26][C@H:25]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:12])=[O:14]
Reactant: COC(=O)C(C)c1ccc(OC)c(C=O)c1
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Agent: COc1ccc(C2(C#N)CC2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: Cl
Product: COC(=O)C(C)c1cccc(CN[C@H]2CCCN[C@H]2c2ccccc2)c1

Procedure:
This compound was prepared from Compound 33 and Compound 3 in the same manner of Compound 5.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1.S([C:27]1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>COC(OC)(C)C.C(OCC)(=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9](=[CH:10][C@H:11]2[CH3:21])[CH:8]=[C:7]([O:22][CH3:27])[CH2:6][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: c1cc[nH+]cc1
Solvent: COC(C)(C)OC
Solvent: CCOC(C)=O
Product: COC1=CC2=C[C@@H](C)[C@@H]3[C@H]([C@@H](F)C[C@]4(C)C(=O)CC[C@@H]34)[C@H]2CC1
Yield: 789.2 %

Procedure:
A solution of 2 g of 11β-fluoro-7α-methylestr-4-ene-3,17-dione in 20 ml 2,2-di-methoxypropane was stirred with 200 mg of pyridinium tosylate for 6.5 hours at 80° C. Then, it was diluted with ethyl acetate, washed with sodium bicarbonate solution and sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. 2 g of crude 11β-fluoro-3-methoxy-7α-methylestra-3,5-dien-17-one was obtained.