Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].N12CCCN=C1CCCC[CH2:13]2>CCOC(C)=O.O>[CH3:10][O:9][C:5]1[C:4]([O:11][CH3:13])=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(OC)c1O
Reactant: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(OC)c1OC
Temperature: 90 °C

Procedure:
To a solution of 2,6-dimethoxyphenol (1.0 g, 6.49 mmol) in DMC (10 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)(0.99 g, 6.49 mmol) was added and the resulting solution was heated to reflux (90° C.) for 4.5 hours. The reaction was cooled to ambient temperature and diluted with EtOAc (50 mL) and H2O (40 mL). The organic layer was separated and washed in sequence with H2O (40 mL), 2M HCl (2×40 mL), 2M NaOH (2×40 mL) and H2O. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give trimethoxybenzene as a solid. The yield of trimethoxybenzene as deteremined by HPLC was 99%.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:9][C:4]=2[CH2:3]1.[CH3:17][O:18][C:19]1[CH:23]=[CH:22][NH:21][C:20]=1[CH:24]=O>N1CCCCC1.CC(O)C>[CH3:17][O:18][C:19]1[CH:23]=[CH:22][NH:21][C:20]=1/[CH:24]=[C:3]1/[C:4]2[CH:9]=[C:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[S:7][C:5]=2[NH:6][C:2]/1=[O:1]
Reactant: COc1cc[nH]c1C=O
Reactant: CC(C)(C)OC(=O)c1cc2c(s1)NC(=O)C2
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2sc(C(=O)OC(C)(C)C)cc21
Temperature: 75 °C
Yield: 40.3 %

Procedure:
tert-Butyl 5,6-dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxylate (915 mg, 3.8 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (10 ml). 3-Methoxypyrrole-2-carboxaldehyde (3.8 mmol, 480 mg) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (15 ml) and the precipitated solid was collected by filtration and washed with water to give 530 mg of tert-butyl (Z)-5,6-dihydro-4-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-oxo-4H-thieno [2,3-b]pyrrole-2-carboxylate as a red solid. MS(ES): m/e 347 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH:29]=1)[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.[C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)#[N:36]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:35]([C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:3]=[C:4]([CH2:5][O:6][CH2:7][C:8]3([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[CH:27]=[C:28]([C:30]([N:31]([CH3:32])[CH3:33])=[O:34])[CH:29]=2)=[CH:39][CH:38]=1)#[N:36]
Reactant: CN(C)C(=O)c1cc(Br)cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(COCC2(c3ccccc3)CCNCC2)cc(-c2ccc(C#N)cc2)c1
Temperature: 120 °C

Procedure:
tert-Butyl 4-((3-bromo-5-(dimethylcarbamoyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (41.2 mg, 0.08 mmol), 4-cyanophenylboronic acid (34.3 mg, 0.23 mmol), and tetrakis(triphenylphosphine) palladium(0) (12.1 mg, 0.01 mmol) were combined in dry tetrahydrofuran (3 mL) in a microwave tube and sealed. After flushing with nitrogen, 0.28 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated and treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol and concentrated to afford 29 mg (66%). 1H-NMR (CD3OD, 500 MHz) δ 7.81-7.84 (m, 2H), 7.76 (s, 1H), 7.74 (s, 1H), 7.59 (s, 1H), 7.49 (s, 1H), 7.42-7.44 (m, 2H), 7.32-7.35 (m, 2H), 7.17-7.22 (m, 2H), 4.51 (s, 2H), 3.52 (s, 2H), 3.15 (s, 3H), 2.99 (s, 3H), 2.88-2.95 (m, 2H), 2.67-2.72 (m, 2H), 2.24-2.27 (m, 2H), 1.91-1.97 (m, 2H). 13C-NMR (CD3OD, 126 MHz) δ 172.2, 144.9, 144.2, 140.9, 139.9, 137.3, 132.9, 128.4, 128.1, 127.4, 127.2, 126.2, 125.7, 124.7, 118.7, 111.5, 79.9, 72.2, 42.1, 41.8, 39.1, 34.7, 32.7. Mass spec.: 454.31 (MH)+. Accurate mass spec.: m/z 454.2496 [MH]+, Δ=0.3 ppm.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[CH3:19][CH:20]1[NH:24][C:23](=O)[CH2:22][CH2:21]1.P(Cl)(Cl)(Cl)=O>>[CH3:19][CH:20]1[N:24]=[C:23]([N:6]2[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:16]=[CH:15][C:14]=3[O:13][C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:22][CH2:21]1
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1O2
Reactant: CC1CCC(=O)N1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCC(N2c3ccccc3Oc3ccc(C(F)(F)F)cc32)=N1

Procedure:
Reaction of 2-(trifluoromethyl)phenoxazine, 5-methyl-2-pyrrolidinone and phosphorous oxychloride according to the procedure of Example 1 provides the free base 10-(5-METHYL-1-PYRROLIN-2-YL)-2-(TRIFLUOROMETHYL)PHENOXAZINE as a distillable oil, b.p. 145-152° C. at 0.03 mm Hg. Conversion of the free base to the hydrochloride salt affords 10-(5-METHYL-1-PYRROLIN-2-YL)-2-(TRIFLUOROMETHYL)PHENOXAZINE HYDROCHLORIDE, m.p. 192.5-195.5° C. (dec.) (corr.), in a 45% overall yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](Br)=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]([N:35]2[C:43]3[C:38](=[CH:39][C:40](B4OC(C)(C)C(C)(C)O4)=[CH:41][CH:42]=3)[CH2:37][CH2:36]2)=[O:34])[CH:29]=[CH:30][CH:31]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:40]3[CH:39]=[C:38]4[C:43](=[CH:42][CH:41]=3)[N:35]([C:33](=[O:34])[CH2:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=3)[CH2:36][CH2:37]4)=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cccc(CC(=O)N2CCc3cc(B4OC(C)(C)C(C)(C)O4)ccc32)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c3c(N)ncnc32)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4cn(C5CCN(C(=O)OC(C)(C)C)CC5)c5ncnc(N)c45)ccc32)c1
Temperature: 100 °C
Yield: 80.4 %

Procedure:
To 1,1-dimethylethyl 4-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (200 mg, 0.505 mmol), and 1-[(3-methylphenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (228 mg, 0.606 mmol) dissolved in 1,4-Dioxane (4 mL) was added saturated aqueous NaHCO3 (2 mL). The mixture was then bubbled with N2 gas for 10 minutes and then Pd(Ph3P)4 (58.3 mg, 0.050 mmol) was added and then bubbled for 5 additional minutes. Then reaction was then capped and heated at 100° C. overnight. The mixture was allowed to cool then diluted with water (10 mL) then extracted with EtOAc (3×20 ml). The organics were combined, washed with brine, dried over MgSo4, filtered and concentrated to isolate a amber color oil. The oil was then purified on a 25 g Biotage SNAP column conditioned with Hexane and eluting with a gradient of 0 to 10% MeOH in DCM for 30 minutes to afford 1,1-dimethylethyl 4-(4-amino-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (230 mg, 80% yield) as a amber color oil. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.13 (s, 1H), 7.45 (s, 1H), 7.32 (s, 1H), 7.20-7.26 (m, 2H), 7.12 (s, 1H), 7.09 (t, J=7.58 Hz, 2H), 4.71-4.83 (m, 1H), 4.20 (t, J=8.46 Hz, 2H), 4.08-4.15 (m, 2H), 3.94 (s, 2H), 3.82 (s, 2H), 3.20 (t, J=8.46 Hz, 2H), 2.95 (br. s., 2H), 2.31 (s, 3H), 1.86-1.97 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[NH:5][C:6](=[O:25])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([C:21](=[NH:23])[NH2:22])=[CH:17][CH:16]=2)[CH:8]=1.C(Cl)Cl.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([NH:5][C@H:4]([C:3]([O:2][CH3:1])=[O:34])[CH2:26][C:27]([OH:29])=[O:28])=[O:25])=[O:24])=[CH:20][CH:19]=1)(=[NH:22])[NH2:23]
Reactant: COC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c1cccc(NC(=O)c2ccc(C(=N)N)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CC(=O)O)NC(=O)c1cccc(NC(=O)c2ccc(C(=N)N)cc2)c1
Reaction time: 3 h
Yield: 75 %

Procedure:
A solution of N-[m-(p-amidinobenzamido)benzoyl]-3-(t-butoxycarbonyl)-L-alanine methyl ester hydroidide in CH2Cl2 /trifluoroacetic acid is left to stand at room temperature for 3 hours. After removal of the solvent and recrystallization of the residue from ethanol/ether there is obtained (S)-3-[m-(p-amidinobenzamido)benzamido]-3-(methoxycarbonyl)propionic acid trifluoroacetate in the form of a colourless solid. Yield: 75%, m.p. 132°-134° C. (decomposition). MS: 413 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[C:12](O)([C:14]([F:17])([F:16])[F:15])=O>Cl>[F:15][C:14]([F:17])([F:16])[C:12]1[NH:11][C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Product: O=C(O)c1ccc2[nH]c(C(F)(F)F)nc2c1
Temperature: 0 °C

Procedure:
50 g (0.329 mol) of 3,4-diaminobenzoic acid, dissolved in 300 ml of 4N HCl, are heated under reflux with 40.5 g (0.355 mol) of TFA for 5 hours. The solution is then cooled to 0° C., and the precipitated product is filtered off with suction, washed with water and dried at 40° C. in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([CH3:23])([NH2:22])[CH3:21])=[CH:15][C:14]=1[F:24].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:22][C:20]([CH3:23])([CH3:21])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[C:14]([F:24])[CH:15]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CC(C)(N)Cc1ccc(Cl)c(F)c1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(Cc1ccc(Cl)c(F)c1)Nc1ccc([N+](=O)[O-])cc1Cl
Temperature: 90 °C
Reaction time: 38.5 h
Yield: 57.2 %

Procedure:
A mixture of 3-chloro-4-fluoro-1-nitrobenzene (421 mg, 2.40 mmol) and 1-(4-chloro-3-fluorophenyl)-2-methylpropan-2-amine (484 mg, 2.40 mmol) in DMSO (10 mL) was heated at 90° C. under N2 for 3 h. The mixture was cooled to rt and stirred at rt for 38.5 h. It was then heated and stirred further at 90° C. for 81.5 h. The mixture was cooled to rt and 80 mL of water was added. The resulting mixture was extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 (10 g) and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/DCM (V/V)=20:1) to give the title compound as yellow oil (490 mg, 57.2%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH2:15])[CH:7]=[C:8]([S:11]([OH:14])(=[O:13])=[O:12])[CH:9]=2)[CH:4]=[C:3]([S:16]([OH:19])(=[O:18])=[O:17])[CH:2]=1.[OH-].[Na+:21].C(O)C>O>[Na+:21].[Na+:21].[NH2:15][C:6]1[C:5]2[C:10](=[CH:1][CH:2]=[C:3]([S:16]([O-:19])(=[O:18])=[O:17])[CH:4]=2)[CH:9]=[C:8]([S:11]([O-:14])(=[O:13])=[O:12])[CH:7]=1
Reactant: Nc1cc(S(=O)(=O)O)cc2ccc(S(=O)(=O)O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(S(=O)(=O)[O-])cc2ccc(S(=O)(=O)[O-])cc12

Procedure:
A 45.0 g amount of (62.5%) 1-naphthylamine-3,7-disulfonic acid is suspended in 200 ml of water and 30 ml of 5 N sodium hydroxide is added to it. The solution is warmed and absolute ethyl alcohol is added until a cloudy precipitate forms. The solution is cooled and the solid is collected by filtration and is washed with 85% ethyl alcohol, ethyl alcohol and ether. The product is dried in vacuo at 110° C. to give 21.0 g of 4-amino-2,6-naphthalenedisulfonic acid disodium salt.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].B([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)(O)O.C(N(CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:2]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH:3]=1)=[O:6]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(C)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)c(-c2ccc(C(=O)O)cc2)c1
Temperature: 100 °C
Yield: 71.3 %

Procedure:
A stirred solution of methyl 3-bromo-4-methylbenzoate (2.6 g, 0.011 mole) in dry DMF (20 ml) under argon was treated with 4-boronobenzoic acid (1.85 g, 0.011 mole) and tetrakis (triphenylphosphine) palladium (O) (400 mg), followed by triethylamine (4.68 ml, 0.046 mole). The mixture was heated at 100° C. for 18 hours, then concentrated in vacuo. The residue was treated with ethyl acetate and extracted with 10% NaHCO3 solution. The basic extract was acidified with dil. HCl and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a light orange solid (2.12 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: C1CCNCC1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCCCC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and piperidine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=371.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:25]2[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 4-(trifluoromethoxy)benzene boronic acid according to the general procedure B. Obtained as an orange solid (569 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5](O)=[O:6].[Cl:15]CCl.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([Cl:15])=[O:6]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C(=O)Cl)cc1Cl
Temperature: 0 °C

Procedure:
A round bottom flask was charged with 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (available from Paragos Product List, 10.2 g, 47.5 mmol), dichloromethane (158 ml) and oxalyl chloride (8.29 ml, 95 mmol). The reaction mixture was cooled to 0° C. in an ice/water bath prior to the addition of N,N-dimethylformamide (0.158 ml). The solution was allowed to warm to ambient temperature overnight. The solvent was evaporated to yield the title compound as a cream solid (11.4 g). δH (CDCl3, 400 MHz): 1.44 (6H, d), 4.73 (1H, septet), 6.98 (1H, d), 8.0 (1H, dd), 7.98 (1H, d).
Reaction SMILES: [C:1](OC[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@@H](O)CC4)CC=C1C[C@@H](O)CC2)(=[O:3])[CH3:2].[CH3:26][Si:27]([CH3:59])([CH3:58])[O:28][C@H:29]1[CH2:46][CH2:45][C@@:44]2([CH2:47][O:48][Si](C)(C)C)[C:31](=[CH:32][CH2:33][C@@H:34]3[C@@H:43]2[CH2:42][CH2:41][C@@:39]2([CH3:40])[C@H:35]3[CH2:36][CH2:37][C@@H:38]2[O:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH2:30]1>>[C:1]([O:48][CH2:47][C@@:44]12[C@@H:43]3[C@H:34]([C@H:35]4[C@@:39]([CH2:41][CH2:42]3)([CH3:40])[C@@H:38]([O:53][Si:54]([CH3:56])([CH3:57])[CH3:55])[CH2:37][CH2:36]4)[CH2:33][CH:32]=[C:31]1[CH2:30][C@@H:29]([O:28][Si:27]([CH3:59])([CH3:26])[CH3:58])[CH2:46][CH2:45]2)(=[O:3])[CH3:2]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O[Si](C)(C)C)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CC[C@@H]2O[Si](C)(C)C
Reactant: CC(=O)OC[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Product: CC(=O)OC[C@]12CC[C@H](O[Si](C)(C)C)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O[Si](C)(C)C)CC[C@@H]12

Procedure:
Following essentially the same procedure but substituting 17α-methyl-5-androstene-3β,17β,19-triol 3,17-diacetate, androst-5-ene-3β,17β,19-triol 19-acetate, and 4α-methyl-17β,19-di(2'-tetrahydropyranyloxy)-5-androsten-3β-ol for the androst-5-ene-3β,17β,19-triol above results in the formation of 17α-methyl-3β,17β,19-tri(trimethylsiloxy)androst-5-ene, 3β,17β-di(trimethylsiloxy)-5-androsten-19-ol acetate and 4α-methyl-17β,19-di(2'-tetrahydropyranyloxy)-3β-trimethylsiloxy-5-androstene, respectively.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=2[Cl:18])=[C:4]([CH3:19])[N:3]=1>C(O)(=O)C.O=[Pt]=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=2[Cl:18])=[C:4]([CH3:19])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1cc([N+](=O)[O-])ccc1Cl
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Cc1nc(N)nc(N)c1-c1cc(N)ccc1Cl

Procedure:
A solution of 2,4-diamino-5-(2-chloro-5-nitrophenyl)-6-methyl pyrimidine (13.9 g) in acetic acid (500 ml) was reduced under an atmosphere of hydrogen in the presence of PtO2 (0.28 g). The mixture was filtered through hyflo and the filtrate was concentrated. The residue was neutralised with saturated NaHCO3 solution and the product was extracted with ethyl acetate, bulked, dried (MgSO4) and evaporated. Chromatography on SiO2 gel, eluting with CHCl3 to 40% MeOH/CHCl3, gave the desired product, 6 g, mp. 117°-121° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]([NH:19][P:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)([CH3:3])[CH3:2].[CH2:27]([Li])CCC.CI>C(OCC)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]([N:19]([P:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH3:27])[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: Cc1ccc(C(=Nc2ccccc2C(C)C)NP(C(C)C)C(C)C)cc1
Solvent: CI
Solvent: CCOCC
Product: Cc1ccc(C(=Nc2ccccc2C(C)C)N(C)P(C(C)C)C(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
N′-(2-isopropylphenyl)-N-(diisopropylphosphino)-4-methylbenzamidine (1.40 g, 3.0 mmol) was dissolved in 25 mL of diethylether and cooled to 0° C. Butyllithium (1.50 mL of 2.0 M solution in pentane, 3.0 mmol) was added dropwise, producing a cloudy yellow suspension. The slurry was warmed to room temperature and stirred for 2 hours. Methyliodide (1.5 mL of 2.0 M solution in THF) was added dropwise at room temperature and stirred continued for 1 hour. The solution became clear yellow. The solvent was removed under vacuum and replaced with 20 mL of diethylether. A small amount of solid (presumably LiI) was removed by filtration and the filtrate was taken to dryness, yielding 0.94 g (65%) of sticky yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:12]O>[Pd]>[CH3:12][C:2]1[C:3]([NH2:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: Nc1c(Cl)ccc2[nH]ncc12
Reactant: CO
Agent: [Pd]
Product: Cc1ccc2[nH]ncc2c1N
Yield: 6 %

Procedure:
Analogously to the production of 5-chloro-1H-indazol-4-ylamine, the regioisomeric mixture of the previous reaction (1.0 g, 5.64 mmol)) is reacted with 100 mg of palladium on carbon in methanol under hydrogen atmosphere for 16 hours at room temperature. After purification on silica gel with hexane/ethyl acetate (33% hexane, then 100% ethyl acetate), 53 mg (6% of theory) of 5-methyl-1H-indazol-4-ylamine is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C:4](=[N:8]O)[C:5](=[O:7])[CH3:6].[C:11](O)(=[O:13])[CH3:12]>C(OC(=O)C)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:10])[CH:4]([NH:8][C:11](=[O:13])[CH3:12])[C:5](=[O:7])[CH3:6]
Reactant: COC(=O)C(=NO)C(C)=O
Reactant: CC(=O)O
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(NC(C)=O)C(C)=O
Reaction time: 20 h
Yield: 60 %

Procedure:
Part B: Crude 2-hydroxyimino-3-oxo-butyric acid methyl ester (24 gram, ˜0.15 mol) dissolved in a magnetically stirred mixture of acetic acid (293 ml), acetic acid anhydride (110 ml) and Pd/C (4 gram) was hydrogenated for 20 hours at room temperature at 1 atmosphere H2 pressure. After filtration over hyflo, the acetic acid and acetic acid anhydride were removed by concentration in vacuo. The resulting crude mixture was purified by flash chromatography (dichloromethane/methanol=95/5 (v/v)) to give 2-acetylamino-3-oxo-butyric acid methyl ester (16.7 gram, 60% yield) as a white solid. Rf (dichloromethane/methanol=95/5 (v/v))=0.4. 1H-NMR (400 MHz, CDCl3): 2.08 (s, 3H), 2.40 (s, 3H), 3.83 (s, 3H), 5.29 (d, J˜7, 1H), 6.71 (br s, 1H).
Reaction SMILES: Cl.[CH:2]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:43]=[CH:42][CH:41]=[CH:40][C:27]=1[C:28]([NH:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)=[O:29]>ClCCl>[CH:2]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH2:8][N:7]([C:35]([C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:40]=[CH:41][CH:42]=[CH:43][C:26]=4[CH3:25])=[CH:39][CH:38]=3)=[O:36])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)CCc1ccccc1NC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To a mixture of 0.245 g (1 mmol) of 5,6,11,12-tetrahydrodibenz[b,f]azocine hydrochloride and 30 μl (2.2 mmol) of triethylamine in 2 ml of dichloromethane is added a solution of 0.281 g (1.1 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 4 ml of dichloromethane. The mixture is stirred overnight at room temperature, washed with water 2N HCl (3×2 ml) and 1N sodium bicarbonate (3×2 ml). The organic layer is dried (MgSO4) and filtered through a thin pad of hydrous magnesium silicate (pad washed with 3 volumes of CH2Cl2). The filtrate is concentrated to give 200 mg of a foam; Mass Spec.-FAB 447 (M+H).