Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:14]([C:19]([OH:21])=O)[CH2:15][CH:16]([CH3:18])[CH3:17].[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[NH:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:14]([C:19]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:21])[CH2:15][CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
8.43 g (44.0 mmol) of EDCl was added to 100 ml of THF solution of 9.97 g (40.0 mmol) of Boc-Leu-OH (manufactured by Tokyo Chemical Industry Co., Ltd), 3.65 ml (40.0 mmol) of aniline and 4.60 g (40.0 mmol) of HO-Su(hydroxysuccinimide), followed by stirring for 8 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed sequentially with a diluted hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water (one time for each), the organic layer was dried over sodium sulfate. After the drying agent was separated by filtration, the filtrate was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (hexane/ethyl acetate=9/1 to 2/1 (volume ratio)), thereby obtaining 5.43 g of the product with a yield of 44.3%.
Reaction SMILES: CO.[ClH:3].C([O:11][C:12]1[C:13]([C:32]#[N:33])=[C:14]2[C:19](=[CH:20][CH:21]=1)[C@@H:18]([OH:22])[C@@H:17]([N:23](CC1C=CC=CC=1)[CH3:24])[CH2:16][CH2:15]2)C1C=CC=CC=1>[H][H].[Pd]>[ClH:3].[C:32]([C:13]1[C:12]([OH:11])=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][C@H:17]([NH:23][CH3:24])[C@@H:18]2[OH:22])#[N:33]
Reactant: [H][H]
Reactant: CN(Cc1ccccc1)[C@H]1CCc2c(ccc(OCc3ccccc3)c2C#N)[C@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN[C@H]1CCc2c(ccc(O)c2C#N)[C@H]1O

Procedure:
In 30 ml. of methanol are suspended 250 mg. of cis-6-benzyloxy-2-(N-benzyl-N-methylamino)-5-cyano-1-hydroxy-1,2,3,4-tetrahydronaphthalene hydrochloride and 5 % palladium-on-carbon, and the mixture is agitated in hydrogen streams at room temperature for 30 minutes. After the reaction, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The procedure provides cis-5-cyano-1,6-dihydroxy-2-methylamino-1,2,3,4-tetrahydronaphthalene hydrochloride as a white precipitate. Recrystallization from ethanol-ethyl acetate provides colorless crystals melting at 226°-227° C(decomp.). Yield 112 mg.
Reaction SMILES: C([NH:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:8][CH2:7]1)(=O)C.Cl>CC(C)=O>[NH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:8][CH2:7]1
Reactant: CC(=O)NCC1CCC(CCC(=O)O)CC1
Agent: Cl
Solvent: CC(C)=O
Product: NCC1CCC(CCC(=O)O)CC1

Procedure:
Melting point 91-94° C. 13 g of 3-[4-(acetylamino-methyl)-cyclohexyl]-propionic acid are added to 200 ml of semi-concentrated aqueous hydrochloric acid and the resulting solution is refluxed overnight. The mixture is combined with acetone, recrystallised and the precipitate is separated off. When the mother liquor is concentrated step by step further fractions of the crystallin product are isolated. The fractions are combined, recrystallised with isopropanol and then dried.
Reaction SMILES: [C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:14]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][CH:5]1[C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:16])[CH3:15]
Reactant: CC(C)(C)C1Cc2ccccc2N1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1c2ccccc2CC1C(C)(C)C
Reaction time: 2 h

Procedure:
2-t-Butylindoline (20.3 g, 116 mmol) (can be made according to the procedures described in J. Chem Soc. Chem. Commum. 1974, 677-678) and 4-dimethylaminopyridine (10 mg) are dissolved in pyridine (100 ml). Acetic anhydride (11.5 ml, 122 mmol) is added and the solution stirred for 2 hours. The mixture is poured into water (1 L) and the solid filtered and dried in vacuo. The title compound is obtained as white crystals (22.2 g, 88%): mp 75° C.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[CH:2]1.[O:6]1[C:10]2([CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)[O:9][CH2:8][CH2:7]1>>[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:13]1([OH:16])[CH2:14][CH2:15][C:10]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:11][CH2:12]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: c1nncs1
Product: OC1(c2nncs2)CCC2(CC1)OCCO2

Procedure:
The title compound was prepared as a white solid from [1,3,4]thiadiazole (3B Scientific) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 33.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:21]=1)=[O:4].[Cl:22][S:23](O)(=[O:25])=[O:24]>>[CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:16]=[CH:17][C:18]([S:23]([Cl:22])(=[O:25])=[O:24])=[CH:19][CH:20]=3)=[CH:10][N:9]2[CH:21]=1)=[O:4]
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)Nc1cn2cc(Sc3ccccc3)ccc2n1
Product: COC(=O)Nc1cn2cc(Sc3ccc(S(=O)(=O)Cl)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4.5 gms. (0.015 mole) of 2-methoxycarbonylamino 6-(phenylthio) imidazo [1,2-a] pyridine is added portionwise to 45 ml. of chlorosulfonic acid at 0° to -5° C. The reaction mixture is stirred at room temperature for 24 hours. The solution is poured onto ice and the solids are collected by filtration. After repeated washes with water, the crude chlorosulfonic acid derivative is dried at room temperature in vacuo.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2].[CH:27]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=[O:37])=[CH:31][CH:30]=1)=O>>[C:36]([CH2:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:27][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C@@H:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:14]=[CH:13][C:12]=3[CH2:11]2)=[CH:30][CH:31]=1)([OH:38])=[O:37]
Reactant: CCNc1ccccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=Cc1ccc(CC(=O)O)cc1
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)CC[C@@H](c1ccccc1NCCCc1ccc(CC(=O)O)cc1)C2
Yield: 87.7 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylaminophenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (182 mg) and (4-formylphenyl)acetic acid (420 mg) according to an analogous synthetic method to Example 212, the title compound (227 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C[O:12][P:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([P:13](=[O:12])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: COP(c1ccccc1)c1ccccc1
Product: Cc1ccccc1C(=O)P(=O)(c1ccccc1)c1ccccc1
Yield: 84 %

Procedure:
134 parts of 2-methylbenzoyl-diphenylphosphine oxide are prepared from 77 parts of 2-methyl-benzoyl chloride and 108 parts of methoxydiphenylphosphine by a method similar to that described for compound XI. Yield 84% of theory.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:12])[CH3:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:21][CH:22]([C:24]1[N:29]=[CH:28][N:27]=[C:26](Cl)[C:25]=1[Cl:31])[CH3:23]>C1(C)C=CC=CC=1>[Cl:31][C:25]1[C:26]([NH:12][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:13])[F:1])=[CH:9][CH:8]=2)[CH3:11])=[N:27][CH:28]=[N:29][C:24]=1[CH:22]([Cl:21])[CH3:23]
Reactant: CC(Cl)c1ncnc(Cl)c1Cl
Reactant: CC(N)c1ccc(OC(F)F)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Cl)c1ncnc(NC(C)c2ccc(OC(F)F)cc2)c1Cl

Procedure:
In 50 ml of toluene were dissolved 3.8 g of 1-(4-difluoromethoxyphenyl)ethylamine and 2.3 g of triethylamine, and to the mixture was added 3.5 g of 6-(1-chloroethyl)-4,5-dichloropyrimidine. The mixture was refluxed under heating for 5 hours.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O-:9])=[O:8].[CH3:10]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])CCCCCBr
Reactant: CO
Product: COC(=O)CCCCCBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To a 2 liter round bottomed flask, charged with 99.7 g (0.511 mol) of 6-bromohexanoate (Aldrich Chemical Co., Milwaukee, Wis.) and 1 liter of methanol, was bubbled hydrogen chloride gas for 1-2 minutes. The mixture was stirred at 20-30° C. for 18 h and then concentrated via rotary evaporation. The residue was diluted with 500 mL of diethyl ether and washed with 150 mL of de-ionized water, 200 mL of saturated sodium bicarbonate, and then once again with 200 mL of de-ionized water. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated via rotary evaporation. The residue was distilled under vacuum to afford 99.6 g of the product (1) as a colorless oil (93%): b.p.=93-96° C. at 3 mm Hg: 1H NMR (d6-DMSO) d 3.57 (3H, s), 3.51 (2H, t), 2.30 (2H, t), 1.78 (2H, pentet) and 1.62-1.28 (4H, m) ppm.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([OH:8])=[C:4]([CH3:9])[O:3]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl>[C:18](=[O:19])([O:7][C:6]1[C:5](=[O:8])[CH:4]([CH3:9])[O:3][C:2]=1[CH3:1])[O:20][CH2:21][CH3:22]
Reactant: CC1=C(O)C(=O)C(C)O1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1=C(C)OC(C)C1=O
Yield: 72.5 %

Procedure:
A solution of 2,5-dimethyl-4-hydroxy-3(2H)-furanone (pineapple ketone, 133.0 g, 1.0 mole) and triethylamine (152.0 g, 1.5 moles) in methylene chloride (665 g) is cooled to 5° C. under nitrogen atmosphere. To the cooled solution is added over a period of 2.5 hours, a solution of ethyl chloroformate (127.7 g, 1.18 moles) in methylene chloride (600 g) stirred at 5°-8° C. for two additional hours. The reaction mixture is filtered through a Buchner funnel to remove the triethylamine hydrochloride. The salt is washed with methylene chloride (200 ml). The combined organic layers are washed twice with 100 ml portions of water and dried over sodium sulfate. The solvent is removed in vacuo and the crude product distilled (<0.1 torr) through a Goodloe column to yield 72.5% of ethyl 2,5-dimethyl-3-oxo-4(2H)-furyl carbonate product b.p. 87° C. (0.08 torr), IR (neat film) 2980(M), 1770(S), 1715(S), 1640(S), 1250(S) cm-1, 'H NMR δ 1.58(t,J=8 Hz,3), 1.65 (d,J=7 Hz,3), 2.32 (s,3), 4.45 (q,J=7 Hz,2), 4.75 (q,J=7 Hz,1), and 3.3% of the diadduct, diethyl 2,5-dimethyl-3,4-furyl dicarbonate, b.p. 110° C. (0.08 torr), IR (neat film 2980(M), 1770(S), 1250(S), 'H NMR δ=1.50 (t,J=6 Hz,6) 2.3 (S,6) 4.45 (q,J=8 Hz,4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH2:18][CH3:19])([CH3:17])[C:13](=[O:16])[NH:14][N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC1C=CC(S(O[CH:31]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH2:18][CH3:19])([CH3:17])[C:13](=[O:16])[N:14]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CCC1(C)C(=O)NN=C1c1ccc(OC)c(OC)c1
Product: CCC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
Prepared analogous as described for the example B1 (Alternative 1) using 5-(3,4-dimethoxyphenyl)-4-ethyl-4-methyl-2,4-dihydro-3H-pyrazol-3-one (compound C9) and tert-butyl 4-(Toluene-4-sulfonyloxy)piperidine-1-carboxylate (compound E1) as starting compounds resulting in the hydrochloride salt of the title compound. (compound B9*HCl)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=[O:18])=[N:9]2)=[CH:4][CH:3]=1.[CH:22]([Mg]Br)=[CH2:23].C1(C)C=CC=CC=1.C1COCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:17]([OH:18])[CH:22]=[CH2:23])[CH:19]=[CH:20][CH:21]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC(O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a degassed suspension of 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde (U.S. Pat. No. 4,851,409, Example 24, Step 1) (100 g, 0.34 mol) in toluene (700 mL) at 0° C. was slowly added 1.0M vinylmagnesium bromide in toluene/THF (370 mL, 0.37 mol). After stirring for 1 hour at 0° C., the reaction was quenched by the slow addition of saturated NH4Cl solution (150 ml), followed by H2O (500 mL) and HOAc (50 mL). The product was extracted with EtOAc and the two-phase system was filtered through celite to remove an insoluble precipitate. The aqueous phase was then re-extracted with EtOAc (100 mL) and the combined organic layer was washed with H2O, followed by brine. The solution was dried (MgSO4), and evaporated to give a dark yellow residue which was purified by flash chromatography (EtOAc:hexane 1:5, then 1:3). The product was filtered from the column fractions to give a beige solid (67.6 g, mp=110°-112° C.). The filtrate was concentrated and the resulting residue was recrystallized from EtOAc/hexane 1:4 to give a second crop of 15.1 g.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[CH:21]([CH3:22])[CH2:20][CH:19]([C:23]([NH:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1F)#[N:2].O.[NH2:35][NH2:36]>CCO>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:9]3[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]4[C@H:21]([CH3:22])[CH2:20][C@H:19]([C:23]([NH:25][CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])[CH2:18]4)[CH:10]=3)=[CH:7][CH:8]=2)[NH:36][N:35]=1
Reactant: NN
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2CC(C(=O)NCc3ccccc3)CC2C)n1
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)C[C@H]2C)n1
Temperature: 100 °C

Procedure:
To a suspension of racemic (3S,5R)-1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-N-(phenylmethyl)-3-pyrrolidinecarboxamide (360 mg total, 0.81 mmol) in EtOH (50 mL) at room temperature was added hydrazine monohydrate (2 mL) in one portion. The suspension was heated in an oil bath to 100° C. for 20 hours. LCMS showed there was still 40% starting material remaining. To the mixture was added 2 mL of hydrazine monohydrate, followed by heating to 100° C. for another 24 h. LCMS showed conversion complete. The mixture was cooled to room temperature, and filtered through celite. The filtrate was concentrated in vacuo, and the resulting residue was taken up in 8 mL of water to form a suspension, which was briefly sonicated. The mixture was filtered. The solids collected were combined with another run starting with 190 mg of racemic (3S,5R)-1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-N-(phenylmethyl)-3-pyrrolidinecarboxamide. The combined crude products were purified by silica gel column chromatography using gradient elution of 1% A in CHCl3 to 75% A in CHCl3. A was a mixture of 800/80/3200 CH3OH/NH4OH/CHCl3. Trituration of the purified material in a mixture of CHCl3 (2 mL) and hexane (8 mL), followed by drying under vacuum at 65° C. for 14 hours afforded the title compound (228 mg) as a beige powder. LC-MS (ES) m/z=457 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.42 (d, J=6.1 Hz, 3H), 2.00-2.06 (m, 1H), 2.52-2.58 (m, 1H), 2.99 (s, 3H), 3.00-3.10 (m, 1H), 3.68-3.73 (m, 1H), 3.95-4.10 (bs, 1H), 4.21-4.33 (bs, 1H), 4.39-4.47 (m, 2H), 6.23 (s, 1H), 7.25-7.37 (m, 5H), 7.52 (dd, J=8.5, 1.1 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.85 (s, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][CH2:12][C:13]([OH:15])=O)([CH3:3])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>FC(F)(F)C(O)=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:5]=1[S:10][CH2:11][CH2:12][C:13]2=[O:15])([CH3:2])[CH3:3]
Reactant: CC(C)c1ccccc1SCCC(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cccc2c1SCCC2=O
Temperature: 25 °C
Reaction time: 64.2 h
Yield: 17 %

Procedure:
3-(2-Isopropylphenylthio)propanoic acid from Step 1 (6.85 g, 30 mmol) was dissolved in trifluoroacetic acid (20 mL), treated with trifluoroacetic anhydride (12 mL) and stirred at room temperature (64.2 hours). The reaction was concentrated in vacua, and the residue dissolved in ethyl acetate, extracted with 5% NaOH, washed with brine, dried over MgSO4, and concentrated in vacua to give a brown oil which was passed through a column of silica gel eluted with 12% ether/hexane to give 8-isopropylthiochroman-4-one as a brown oil (1.05 g, 17%): 1H NMR (CDCl3) 300 MHz 8.01 (d, J=7.0 Hz, 1H) 7.38 (d, J=7.5 Hz, 1H) 7.17 (t, J=7.8 Hz, 1H) 3.19 (m, 3H) 2.96 (m, 2H) 1.25 (d, J=7.0 Hz 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].O.[C:13](Cl)(Cl)=[O:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[O:7][C:13](=[O:14])[NH:11][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
4-Chloroanthranilic acid (10.0 g, 56.5 mmol) was dissolved at room temperature with stirring in 190 mL of distilled water containing 8.98 g (84.7 mmol) Na2CO3. When the 4-chloroanthranilic acid was completely dissolved, a 20% w/v solution of phosgene in toluene (84 mL) was added dropwise via a dropping funnel over 45 minutes. The resulting suspension was stirred at room temperature overnight under nitrogen. The product was collected by filtration and washed well with water. The resulting gray-white solid was dried in a vacuum oven at 60° C. overnight to provide 7-chloro-1,4-dihydro-2H-3,1-benzoxazine-2,4-dione (10.3 g, 52.3 mmol, 93%): 1H NMR (DMSO-d6): δ 11.93 (br s, 1H), 7.17 (d, J=1.5 Hz, 1H), 7.28 (dd, J=1.6 and 8.2 Hz, 1H), 7.91 (d, J=8.2 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[N:32]=[CH:31][C:30](Br)=[CH:29][N:28]=1>>[F:13][C:12]([F:15])([F:14])[C:11]1[N:6]2[CH:5]=[N:4][C:3]([C:1]#[C:2][C:30]3[CH:29]=[N:28][C:27]([NH2:26])=[N:32][CH:31]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: Nc1ncc(Br)cn1
Reactant: C#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Nc1ncc(C#Cc2ncn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 8-ethynyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.18) (178 mg, 0.5 mmol) and commercially available 2-amino-5-bromo-pyrimidine (87 mg, 0.5 mmol) according to general procedure II. Obtained as a dark red solid (92 mg, 41%). MS (EI) 447.1 [(M+)]; mp 294° C.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:4]12[CH2:5][C:6]([OH:8])=[O:7])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[N:14]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:13]3)=[O:2].[CH2:30]([Mg]Br)[CH:31]([CH3:33])[CH3:32]>C1COCC1>[OH:2][CH:1]([C@H:3]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:4]12[CH2:5][C:6]([OH:8])=[O:7])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[N:14]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:13]3)[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)C[Mg]Br
Reactant: CC(C)(C)N1C[C@H]2[C@@H]3CC[C@H](C=O)[C@@]3(CC(=O)O)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Solvent: C1CCOC1
Product: CC(C)CC(O)[C@H]1CC[C@H]2[C@@H]3CN(C(C)(C)C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12CC(=O)O

Procedure:
A solution of 17β-formyl-6-t-butylcarboxy-6-azaandrost-4-en-3-one (550 mg, 1.37 mmol), prepared in part B above, in THF (10 mL) is treated with isobutylmagnesium bromide (2.0M in diethyl ether, 2.0 mL, 4.0 mmol) at 0° C. After 20 minutes the reaction is quenched with saturated aqueous NaHSO4, extracted with ethyl acetate (2×40 mL), dried over MgSO4, concentrated and chromatographed on silica gel (50% ethyl acetate/hexanes) to give crude 17β-(1-hydroxy-3-methylbutyl)-6-t-butylcarboxy-6-azaandrost-4-en-3-one of sufficient purity to carry on to the following steps; yield: 168 mg (26%); FAB mass spec. MH+ 460.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[NH:11][CH2:10]2.[H-].[Na+].Br[CH2:23][C:24]([NH2:26])=[O:25]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([CH2:23][C:24]([NH2:26])=[O:25])[CH2:10]2
Reactant: NC(=O)CBr
Reactant: O=C1NCc2cc(OCc3cccc(F)c3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)CN1Cc2cc(OCc3cccc(F)c3)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 67 %

Procedure:
A mixture of 5-(3-fluoro-benzyloxy)-2,3-dihydro-isoindol-1-one (400 mg, 1.6 mmol), sodium hydride (55% in mineral oil, 75 mg, 1.7 mmol) in THF (20 mL) was stirred at RT for 45 min, and then 2-bromoacetamide (75 mg, 1.9 mmol) was added and the resulting mixture heated at 50° C. for 16 h. After cooling to RT the mixture was half-evaporated and diluted with water. The mixture was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulfate. After filtration and evaporation the residue was purified by chromatography (SiO2, CH2Cl2:2N NH3-MeOH 98:2 to 85:15) to afford the title product (337 mg, 67%) as a white solid. MS m/e=315.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[N:10][C:9]2[NH:8][C:7](=[O:12])[CH2:6][O:5][C:4]=2[CH:3]=1.[Li]N([Si](C)(C)C)[Si](C)(C)[CH3:16].COS(OC)(=O)=O>C1COCC1>[CH3:16][N:8]1[C:7](=[O:12])[CH2:6][O:5][C:4]2[CH:3]=[C:2]([Br:1])[CH:11]=[N:10][C:9]1=2
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Reactant: O=C1COc2cc(Br)cnc2N1
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: CN1C(=O)COc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 5 g of 7-bromo-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (0.022 mole) in 90 ml of THF is added 24 ml of LiN(TMS)2 (0.024 mole) in THF. The homogenous solution is maintained under nitrogen at room temperature for 20 min., 3.03 g (0.024 mole) of dimethylsulfate is added and the reaction mixture allowed to stir overnight. The reaction mixture is then quenched with 20 ml of sat. ammonium chloride and extracted with 3×80 ml ethyl acetate. The ethyl acetate is then washed with 3×30 ml sat. ammonium chloride, dried over sodium sulfate and concentrated to obtain off white product which is used directly in the next step.