Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[C:8]([C:12]([OH:14])=O)=[CH:7][NH:6][C:5]=2[S:4][N:3]=1.[C:15]([C:19]1[C:27]2[C:22](=[CH:23][C:24]([NH2:28])=[CH:25][CH:26]=2)[NH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1>C(OCC)(=O)C>[C:15]([C:19]1[C:27]2[C:22](=[CH:23][C:24]([NH:28][C:12]([C:8]3[C:9](=[O:11])[C:10]4[C:2]([CH3:1])=[N:3][S:4][C:5]=4[NH:6][CH:7]=3)=[O:14])=[CH:25][CH:26]=2)[NH:21][CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1nsc2[nH]cc(C(=O)O)c(=O)c12
Reactant: CC(C)(C)c1c[nH]c2cc(N)ccc12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1nsc2[nH]cc(C(=O)Nc3ccc4c(C(C)(C)C)c[nH]c4c3)c(=O)c12
Temperature: 45 °C
Yield: 33.2 %

Procedure:
3-Methyl-4-oxo-4,7-dihydroisothiazolo[5,4-b]pyridine-5-carboxylic acid (100.0 mg, 475.7 μmol) and 3-tert-butyl-1H-indol-6-amine (89.56 mg, 0.4757 mmol) were added to a 20-mL vial and suspended in 2-methyl THF (1 mL), followed by propane phosphonic acid anhydride (T3P®, 50% solution in ethyl acetate, 757 mg, 1.19 mmol). Pyridine (75.26 mg, 76.95 μL, 951.4 μmol) was then added and the solution heated at 45° C. for 16 h. The reaction was diluted with 5 mL ethyl acetate and washed with water (1×10 mL). The organic layer was pulled off and concentrated. The residue was dissolved in 6 mL DMF and HPLC purified (RP-C18, 20-99% CH3CN/0.05% TFA). The pooled product fractions were concentrated to approximately 5 mL to provide a suspended white solid. The suspended material was filtered, washed with water and air dried to yield the product N-(3-tert-butyl-1H-indol-6-yl)-3-methyl-4-oxo-4,7-dihydroisothiazolo[5,4-b]pyridine-5-carboxamide (60 mg, 33% yield) as an off-white solid. LC/MS m/z 381.0 [M+H]+, retention time 1.79 min (RP-C18, 10-99% CH3CN/0.05% TFA over 3 min). 1H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 12.27 (s, 1H), 10.73 (s, 1H), 8.92 (s, 1H), 8.11 (d, J=1.7 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.02 (dd, J=9.5, 0.9 Hz, 1H), 6.98 (d, J=2.3 Hz, 1H), 2.79 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: [Cl-].[CH:2]1([CH2:6][NH2+:7][CH2:8][CH2:9]Cl)[CH2:5][CH2:4][CH2:3]1.[Cl:11][C:12]1[C:13]([CH3:21])=[C:14]([N:18]=[C:19]=[S:20])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[C:13]([CH3:21])=[C:14]([N:18]=[C:19]2[N:7]([CH2:6][CH:2]3[CH2:3][CH2:4][CH2:5]3)[CH2:8][CH2:9][S:20]2)[CH:15]=[CH:16][CH:17]=1
Reactant: ClCC[NH2+]CC1CCC1
Reactant: Cc1c(Cl)cccc1N=C=S
Agent: [Cl-]
Product: Cc1c(Cl)cccc1N=C1SCCN1CC1CCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclobutylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3-chloro-2-methylphenyl isothiocyanate to give 2-(3-chloro-2-methylphenylimino)-3-(cyclobutylmethyl)-1,3-thiazolidine.
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][CH:17]=[O:18])[C:3]([NH:5][C:6]1[S:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][N:10]=1)=[O:4].Cl>O>[C:11]([C:8]1[S:7][C:6]([N:5]2[CH:17]([OH:18])[CH2:16][CH2:15][N:2]([CH3:1])[C:3]2=[O:4])=[N:10][N:9]=1)([CH3:13])([CH3:14])[CH3:12]
Reactant: CN(CCC=O)C(=O)Nc1nnc(C(C)(C)C)s1
Agent: Cl
Solvent: O
Product: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O

Procedure:
The dimethyl acetal of 3-[1-methyl-3-(5-t-butyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde (16 grams), concentrated hydrochloric acid (10 ml) and water (500 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is filtered while hot and the filtrate is then cooled, resulting in the formation of a precipitate. The precipitate is recovered by filtration, dried and is recyrstallized to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:31]=[C:30]([CH3:32])[C:14]([O:15][CH:16]4[CH2:19][CH:18]([C:20]([O:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:21])[CH2:17]4)=[C:13]([CH3:33])[CH:12]=3)[O:8][C:6]=2[N:7]=1.[CH3:34][S:35]([O-:37])=[O:36].[Na+]>CN(C)C=O>[CH3:34][S:35]([C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:31]=[C:30]([CH3:32])[C:14]([O:15][CH:16]4[CH2:19][CH:18]([C:20]([O:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:21])[CH2:17]4)=[C:13]([CH3:33])[CH:12]=3)[O:8][C:6]=2[N:7]=1)(=[O:37])=[O:36]
Reactant: CS(=O)[O-]
Reactant: Cc1cc(-c2nc3cnc(Cl)nc3o2)cc(C)c1OC1CC(C(=O)OCc2ccccc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cnc(S(C)(=O)=O)nc3o2)cc(C)c1OC1CC(C(=O)OCc2ccccc2)C1

Procedure:
A solution of 200 mg of benzyl 3-[4-(5-chlorooxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]cyclobutanecarboxylate and 48 mg of sodium methylsulfinate in 4 ml of N,N-dimethylformamide was heated in a microwave reactor at 100° C. for 60 min. At room temperature, the mixture was filtered and then washed with DMF. The filtrate was concentrated and the resulting residue was purified by preparative HPLC. This gave 71 mg (32%) of the title compound.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:34]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:33])[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][S:39](=[O:43])(=[O:42])[CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCCl>[CH2:1]([S:8][CH:9]([CH2:34][N:36]1[CH2:41][CH2:40][S:39](=[O:43])(=[O:42])[CH2:38][CH2:37]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:33])[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1cccc2cc(C(=O)NCC(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Reactant: O=S1(=O)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(c1cccc2cc(C(=O)NCC(CN3CCS(=O)(=O)CC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.9 %

Procedure:
To a mixture of N-[2-(benzylthio)-3-oxopropyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (0.30 g), thiomorpholine 1,1-dioxide (0.15 g) and 1,2-dichloroethane (12 mL) was added sodium triacetoxyborohydride (0.25 g), and the mixture was stirred at room temperature for 2 days. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=25:75-40:60) to give the title compound (0.37 g, yield: 100%) as a colorless oil. MS: 628 (MH+).
Reaction SMILES: [C:1]([CH2:3][C:4]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:5](OCC)=[O:6])#[N:2]>C(O)(=O)C.O=[Pt]=O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:3][CH2:1][NH:2][C:5]2=[O:6])=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(CC#N)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=C1NCCC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of the product from Example 14A (20 mg, 0.063 mmol) in acetic acid (4 mL) was added to PtO2 (4.00 mg, 0.018 mmol) in a 50 mL pressure bottle and stirred at room temperature for 12 hours under hydrogen (30 pounds per square inch). The mixture was filtered through a nylon membrane and then concentrated to obtain solid. The solid was slurried in 5% ethyl acetate/hexanes, filtered and dried to give the title compound. MS (DCI+) m/z 274 (M+H)+.
Reaction SMILES: [C@]12(C)C(C)(C)C(CC1)CC2C([O:12][CH:13]([C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26])[C:14]([CH3:17])([CH3:16])[CH3:15])=O.C([O-])([O-])=O.[K+].[K+].O.Cl>CO>[I:24][C:21]1[CH:22]=[CH:23][C:18]([CH:13]([OH:12])[C:14]([CH3:15])([CH3:16])[CH3:17])=[C:19]([N+:25]([O-:27])=[O:26])[CH:20]=1
Reactant: CC(C)(C)C(OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccc(I)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)C(O)c1ccc(I)cc1[N+](=O)[O-]
Yield: 98.2 %

Procedure:
A mixture of single diastereomer (R or S)-1-(4-iodo-2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate (409 mg, 0.79 mmol) and K2CO3 (110 mg, 0.8 mmol) in methanol (15 mL) was heated to reflux for 30 minutes. Water (5 mL) was added and the solution was neutralized to pH 7 with 1M HCl. Solvent was removed in vacuo and the residue was taken into a mixture of ethyl acetate (30 mL) and water (10 mL). The organic phase was separated, dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography to yield single enantiomer (R or S)-1-(4-iodo-2-nitrophenyl)-2,2-dimethyl-1-propanol (260 mg, 98%) as a light yellow oil. 1H NMR was identical to that of the racemic alcohol. The absolute configuration of the single enantiomer alcohol is not determined.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[F:11].[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[Br:1][C:2]1[C:3]([F:11])=[C:4]2[C:5]([CH:12]=[CH:13][NH:8]2)=[CH:6][CH:7]=1
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Solvent: C1CCOC1
Product: Fc1c(Br)ccc2cc[nH]c12
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-2-fluoro-3-nitrobenzene (2.5 g, 11.3 mmol) in THF (25 mL) at −50° C. was added vinyl magnesium bromide (34 mL, 34 mmol) and the mixture was stirred at −40° C. for 1 h. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to yield a gum, which was purified by column chromatography over silica gel eluting with EtOAc/hexane to afford pure 6-bromo-7-fluoro-1H-indole. 1H NMR (400 MHz, CDCl3) δ=6.53-6.62 (m, 1H), 7.16-7.25 (m, 2H), 7.29 (d, J=8.34 Hz, 1H) and 8.36 (br. s., 1H); MS (ES+): m/z 214.08 [MH+].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(=O)(O)[O-].[Na+]>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[O:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:31][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCCCCCCOCCCCOc1ccc2ccccc2c1
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: c1ccc(CNCCCCCCOCCCCOc2ccc3ccccc3c2)cc1
Yield: 95.6 %

Procedure:
2-[4-[(6-Bromohexyl)oxy]butoxy]naphthalene (2.25 g) and benzylamine (3.88 g) were stirred under nitrogen at ca. 125° for 2 h. The solution was diluted with 8% sodium bicarbonate (100 ml) and extracted with diethyl ether (2×100 ml), dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System C (98:2:1) gave the title compound as a yellow oil (2.3 g), t.l.c. (System C 40:10:1) Rf 0.71.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH:6]=[CH:5][C:4](=[O:8])[CH2:3]1>[Pd]>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1
Reactant: CC1(C)CC=CC(=O)C1
Agent: [Pd]
Product: CC1(C)CCCC(=O)C1

Procedure:
(a') A catalytic hydrogenation of 3,3-dimethyl-cyclohex-5-en-1-one was carried out according to the usual techniques in the presence of palladium on charcoal and yielded 3,3-dimethylcyclohexanone. The subsequent ethylination by means of acetylene in a basic medium gave 1-ethynyl-1-hydroxy-3,3-dimethyl-cyclohexane in about 50% yield.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[C:10]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1
Reactant: COC(=O)COc1nc(C)ncc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)COc1nc(C)ncc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.9 %

Procedure:
A mixture of 0.21 g of 5-benzyloxy-4-(methoxycarbonyl)methoxy-2-methylpyrimidine, 16 mg of 10% palladium/carbon and 1.5 ml of ethyl acetate was stirred for 3 hours at room temperature under hydrogen atmosphere. The reaction system was purged with nitrogen, then, the reaction solution was filtrated through Celite, and the filtrate was concentrated to obtain 0.15 g of 5-hydroxy-4-(methoxycarbonyl)methoxy-2-methylpyrimidine.
Reaction SMILES: Br[CH2:2][C:3](=[O:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC(C)=O>[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3](=[O:5])[CH3:4])[CH2:24][CH2:23]1
Reactant: CC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
Bromoacetone (0.336 ml, 4.00 mmol) and potassium carbonate (1.38 g, 10.00 mmol) were added to a solution of 1-(2-fluoro-4-nitrophenyl)piperazine (compound of Reference Example 52; 0.390 g, 2.00 mmol) in acetone (10 ml) under ice cooling, and the mixture was stirred at room temperature for 18 hours. The residue obtained by evaporation of the solvent under reduced pressure was washed with water to give the title compound (0.467 g, 83%) as a yellow solid.
Reaction SMILES: [CH2:1]([Zn]CC)C.C1(C)C=CC=CC=1.ClCI.[CH3:16]/[C:17](=[CH:20]/[CH:21]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH3:22])/[CH2:18][OH:19].S(=O)(=O)(O)O>>[CH3:16][C@:17]1([CH2:18][OH:19])[CH2:1][C@H:20]1[C@H:21]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH3:22]
Reactant: C/C(=C/C(C)c1ccc(C)cc1)CO
Reactant: CC[Zn]CC
Agent: ClCI
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1ccc([C@H](C)[C@@H]2C[C@]2(C)CO)cc1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 9.4 g, 11.4 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to −15° C. Chloroiodomethane (4.02 g, 22.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept at −15° C. After completion of the dropwise addition, the mixture was stirred at −10 to −15° C. for 20 minutes, and then cooled to −25° C. (Z)-2-Methyl-4-(4-methylphenyl)pent-2-en-1-ol (1.08 g, 5.7 mmol) was added dropwise at −20 to −25° C. over a period of 20 minutes. After completion of the dropwise addition, the stirring was continued at −15 to −25° C. for 60 minutes. Next, a 20% aqueous sulfuric acid solution (4.2 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1S*,2S*)-1-Methyl-2-((R*)-1-(4-methylphenyl)ethyl)cyclopropyl]methanol (0.79 g, 3.8 mmol, 68% yield) was obtained as the main isomer, and [(1S*,2S*)-1-methyl-2-((S*)-1-(4-methylphenyl)ethyl)cyclopropyl]methanol (0.21 g, 1.0 mmol, 18% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:6][C:4]=1[NH2:5].[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[C:30]=1[N:37]1[C:41](=[O:42])[CH2:40][C:39](OCC)=[N:38]1>C(O)C>[Cl:36][C:31]1[CH:32]=[C:33]([Cl:35])[CH:34]=[C:29]([Cl:28])[C:30]=1[N:37]1[C:41](=[O:42])[CH2:40][C:39]([NH:5][C:4]2[CH:6]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:8]([Cl:10])=[CH:9][C:3]=2[Cl:2])=[N:38]1
Reactant: CCOC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Reactant: CCCCCCCCCCCCCCCCOc1cc(N)c(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOc1cc(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c(Cl)cc1Cl
Temperature: 150 °C

Procedure:
A mixture of 16 g of the 2,4-dichloro-5-hexadecyloxyaniline hydrochloride obtained in Step (2) described above and 12 g of 1-(2,4,6-trichlorophenyl)-3-ethoxy-2-pyrazolin-5-one was heated to 150° C. and melted. Thereafter, the mixture was reacted at 150 to 160° C. for an hour under a reduced pressure (approximately 20 mm Hg) with stirring while removing the ethanol formed. The reaction mixture was allowed to cool to 100° C. and then 100 ml of ethanol was added thereto. After heating with stirring, the mixture was allowed to cool to room temperature. The precipitate was recovered by filtration. After drying, the precipitate was recrystallized from 100 ml of ethyl acetate to obtain 16 g of the desired coupler. The melting point thereof was 107 to 108° C.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH:8]=[CH:9][C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[CH3:22][Al](C)C.O>O1CCOCC1.C1(C)C=CC=CC=1.[Cu]Br>[CH3:22][C@@H:14]1[C@@:15]2([CH3:16])[C:10]([CH:9]=[CH:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][C:3]2=[O:21])=[CH:11][C:12](=[O:20])[CH2:13]1
Reactant: C[C@]12C=CC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[Al](C)C
Agent: [Cu]Br
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1CC(=O)C=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
2.82 g (10 mmol) of androsta-1,4,6-triene-3,17-dione is dissolved in 20 ml of dioxane at 20° C. and mixed with 143.3 mg (1 mmol) of copper(I) bromide. 9.4 ml (11 mmol) of a 10% solution of trimethyl aluminum in toluene is added to the reaction at room temperature under nitrogen atmosphere and stirred for 10 minutes at 20° C. For hydrolysis, 1 ml of water dissolved in 5 ml of dioxane is carefully added to the reaction. It is stirred for 10 minutes more and the inorganic precipitate filtered off with dioxane is washed again. The dioxane solution is concentrated by evaporation on a rotary evaporator and the residue is chromatographed on silica gel with ethyl acetate/hexane as eluent. After concentration by evaporation of the fractions, 2.97 g of 1α-methyl-androsta-4,6-diene-3,17-dione (99% of theory) of a melting point of 171° C. is obtained.
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[Cl:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:28])[C:12]=1[NH:13][C:14]1[C:23]2[C:18](=[C:19]([OH:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[O:17][C:16](=[O:27])[CH:15]=1>>[Cl:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:28])[C:12]=1[NH:13][C:14]1[C:23]2[C:18](=[C:19]([O:26][CH2:2][C:3]([OH:5])=[O:4])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[O:17][C:16](=[O:27])[CH:15]=1
Reactant: O=C(O)CBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCC(=O)O

Procedure:
The title compound was prepared from 2-bromoacetic acid and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 12.90 (br, 1H), 9.56 (br s, 1H), 8.83 (s, 2H), 7.97 (d, 1H), 7.23 (d, 1H), 4.66 (s, 1H), 4.65 (s, 2H), 3.94 (s, 3H); MS (ESI): 410.8.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:17]3[CH2:22][NH:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][C:9]=1[F:30])=[O:6])[CH3:3].CN1CCOCC1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:52]([N:55]1[CH2:60][CH2:59][CH:58]([C:61](O)=[O:62])[CH2:57][CH2:56]1)(=[O:54])[CH3:53]>CN(C=O)C>[C:52]([N:55]1[CH2:56][CH2:57][CH:58]([C:61]([N:21]2[CH2:22][C:17]3[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])=[N:15][C:14]([C:11]4[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH2:2][CH3:3])=[O:6])=[C:9]([F:30])[CH:10]=4)=[N:19][C:18]=3[CH2:20]2)=[O:62])[CH2:59][CH2:60]1)(=[O:54])[CH3:53]
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)C2CCN(C(C)=O)CC2)C3)cc1F
Temperature: 25 °C
Yield: 6.8 %

Procedure:
A stirred solution of (S)-1-ethyl-3-(2-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (intermediate 18) (133 mg, 0.25 mmol) and N-methylmorpholine (55 μL, 0.5 mmol) in DMF (5 mL, anhydrous) was added EDC (53 mg, 0.275 mmol), HOBT (37 mg, 0.275 mmol), and 1-acetylpiperidine-4-carboxylic acid (43 mg, 0.25 mmol). The reaction mixture was stirred at room temperature until analysis by LCMS deemed reaction complete. Solvent was then removed in vacuo. Purified by prep. HPLC (low pH) Then further purified using a TsOH cartridge to remove residual formic acid from HPLC (loaded in MeOH eluted with 2M methanolic ammonia). Yielding a light pink solid (9.6 mg, 0.017 mmol, 7%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].S(Cl)([Cl:23])(=O)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([Cl:23])[C:6](=[O:18])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)CCCOCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C(Cl)C(=O)CCCOCc1ccccc1
Temperature: 0 °C

Procedure:
To a stirred solution of 13.9 g of crude 6-Benzyloxy-3-oxo-hexanoic acid ethyl ester in 50 ml dichloromethane were added dropwise 4.3 ml sulfuryl chloride. The reaction mixture was stirred at 0° C. and then at room temperature for thirty minutes. The reaction mixture was poured on ice and extracted three times with portions of 150 ml dichloromethane. The combined organic layers were washed with water, dried over MgSO4 and then the solvent was evaporated in vacuo to obtain 14.9 g of crude 6-Benzyloxy-2-chloro-3-oxo-hexanoic acid ethyl ester as a yellow oil.
Reaction SMILES: [Ce].[N+]([O-])(O)=O.[N+]([O-])([O-])=[O:7].[NH4+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[O:7])=[CH:13][CH:14]=1
Reactant: COc1ccc(C)cc1
Reactant: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O=[N+]([O-])O
Product: COc1ccc(C=O)cc1
Yield: 94.8 %

Procedure:
The same procedure as in Example 1 is repeated except that the cerium salt is electrolyzed with 100 ml of 2 to 3% by weight aqueous solution of nitric acid placed into the cathode chamber in place of ammonium nitrate. p-Methyl anisole is oxidized with the solution withdrawn from the anode chamber to give anisaldehyde in a yield of 94.8%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9].C(OC(=O)[C@H](CC1C=CC=CC=1)N)(C)(C)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:13]([OH:15])=[O:14])(=[O:9])=[O:10]
Reactant: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1F
Agent: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Product: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1F

Procedure:
Following the 14a synthetic method, using B1 (110.65 mg, 0.5 mmol) instead of A1 gave 14b as a colorless oil; (102.01 mg, 63.1%). [α]D25: +16.3 (c=0.39, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 7.82 (dd, J=1.8, 7.8 Hz, 1H), 7.59-7.52 (m, 1H), 7.26-7.21 (m, 4H), 7.15-7.08 (m, 3H), 5.27 (d, J=9 Hz, 1H), 4.43 (m, 1H), 3.20-3.05 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 171.53, 160.51, 157.15, 136.55, 134.91, 134.79, 129.48, 129.31, 128.18, 126.68, 124.15, 117.04, 116.75, 57.32, 38.37; HRMS (ESI): calcd for C15H14FNO4S: [M+Na]+=346.0508, obsd [M+Na]+=324.0520.