Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[CH:27]=[C:28]([F:44])[C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:50](O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:50])[C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[CH:27]=[C:28]([F:44])[C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:47][CH2:48]1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)cc(F)c1-c1cccc-3c1
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1C)-c1cccc(c1)-c1c(F)cc(F)cc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 7.2 %

Procedure:
Prepared in 7.2% yield from Methyl(2S)-2-(tert-butoxy)-2-[(22S)-16,18-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.09 (d, J=7.7 Hz, 1H), 7.93 (s, 1H), 7.74 (s, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.25 (d, J=7.3 Hz, 1H), 7.01 (d, J=12.1 Hz, 1H), 6.92-6.84 (m, 1H), 6.08 (br. s., 1H), 4.69 (br. s., 1H), 3.87-3.78 (m, 1H), 3.70 (t, J=10.3 Hz, 1H), 3.50-3.40 (m, 2H), 2.89 (br. s., 1H), 2.69 (d, J=9.5 Hz, 1H), 2.49 (s, 3H), 2.33 (s, 3H), 1.93-1.46 (m, 10H), 1.20 (s, 12H), 1.13 (d, J=5.9 Hz, 3H); LCMS (ESI, M): 675.3.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH:8]([O:12][CH2:13][C:14]([O:16]C)=O)[C:9](=[O:11])[CH3:10]>C(O)(C)(C)C.CCOCC>[CH3:7][CH:8]1[C:9](=[O:11])[CH2:10][C:14](=[O:16])[CH2:13][O:12]1
Reactant: COC(=O)COC(C)C(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: CC1OCC(=O)CC1=O

Procedure:
Potassium tert-butoxide in tert-butanol (1 M, 203 mL) and the product from Example 44B (15.5 g, 97 mmol) in ether (55 mL) were processed as described in Example 43C. The residue was purified on silica gel eluting with ethyl acetate:formic acid:water:hexane (200:1:1:200) provided the title compound. 1H NMR (CDCl3) δ 1.48 (d, 3H), 3.43 (d, 1H), 3.92 (d, 1H), 3.97 (q, 1H), 4.04 (d, 1H), 4.44 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13]2[C:18]([C:19]3[N:27]=[CH:26][N:25]=[C:24]4[C:20]=3[N:21]=[CH:22][N:23]4C3CCCCO3)=[CH:17][CH:16]=[CH:15][N:14]=2)=[C:10]2[C:5]([C:6](SC)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1>C(O)(C(F)(F)F)=O.O1CCOCC1>[N:27]1[C:19]([C:18]2[C:13]([NH:12][C:11]3[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]4[C:10]=3[N:9]=[CH:8][N:7]=[C:6]4[NH:43][C:40]3[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=3)=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: CSc1ncnc2c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c(C)ccc12
Reactant: Nc1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(Nc3ccc(Cl)cc3)ncnc2c1Nc1ncccc1-c1ncnc2[nH]cnc12
Temperature: 160 °C

Procedure:
A clear microwave vial was charged with 7-methyl-4-(methylthio)-N-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)quinazolin-8-amine (0.200 g, 0.413 mmol) and 4-chlorobenzenamine (0.105 g, 0.825 mmol) and 5 ml of dioxane. A few drops of TFA was added to the mixture and the reaction vial was capped. The vial was heated in a microwave reactor at 160° C. for 12 minutes. The solid that crashed out of the reaction mixture was filtered off and washed with ethyl acetate. The solid was dissolved in DMSO (3 ml) and purified by RP-HPLC using a gradient of 5% ACN 0.1% TFA to 95% ACN 0.1% TFA in water 0.1% TFA. The pure fractions were neutralized with ammonium hydroxide and the volatiles were removed under reduced pressure. The solid that crashed out of the aqueous layer was filtered off, washed with water and dried in a vacuum oven at 45 degrees to give N8-(3-(9H-purin-6-yl)pyridin-2-yl)-N4-(4-chlorophenyl)-7-methylquinazoline-4,8-diamine as a yellow solid. MS Found: (ESI pos. ion) m/z 480 (M+H+).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:7]([Sn:11]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12]I)[CH2:8][CH2:9][CH3:10].CN(C)C=O>O1CCCC1>[CH2:18]([Sn:11]([CH2:7][CH2:8][CH2:9][CH3:10])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][O:4][CH:1]([CH3:3])[CH3:2])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COC(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32 %

Procedure:
To a mixture of isopropanol (2 mL) and tetrahydrofuran (2 mL) was added sodium hydride (66%, 58 mg, 1.6 mmol) on an ice bath, then, the solution was stirred for 20 minutes at room temperature. To the reaction solution was added a solution of tributyl-iodomethyl-stannane (230 mg, 0.53 mmol), synthesized according to the document (Synthetic Communications, Vol. 24, No. 8, pp. 1117-1120), in tetrahydrofuran (1 mL) dropwise on an ice bath, then, N,N-dimethylformamide (0.5 mL) was added thereto, followed by stirring overnight at room temperature. The reaction solution was partitioned into water (20 mL) and diethyl ether (50 mL). The organic layer was separated, washed with brine, and then, evaporated in vacuo. The residue was purified by neutral silica gel column chromatography (heptane:ethyl acetate=30:1), and the title compound (63 mg, 0.17 mmol, 32%) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29](O)=[O:30])[CH:25]=[CH:26][CH:27]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: COc1cccc(CC(=O)Nn2nc(-c3ccc(Cl)cc3)c3ccccc3c2=O)c1

Procedure:
The product of Example 86A and 2-(3-methoxyphenyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.41-8.43 (m, 1H), 7.96-8.01 (m, 2H), 7.72-7.74 (m, 1H), 7.60-7.67 (m, 4H), 7.27 (t, J=7.9 Hz, 1H), 6.98 (d, J=2.4 Hz, 1H), 6.96 (d, J=7.6 Hz, 1H), 6.85 (dd, J=8.2, 2.6 Hz, 1H), 3.76 (s, 3H), 3.67-3.67 (bs, 2H; MS (ESI−) M/Z 418 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH3:14])/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.CO[CH2:24][N:25]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][Si](C)(C)C.CCN(CC)CC>C(Cl)Cl>[CH3:13][O:12][C:10]([C:9]1([CH3:14])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:24][N:25]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:26]1)=[O:11]
Reactant: COC(=O)/C(C)=C/c1ccc(Cl)cc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(C)CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
A mixture of 8.8 g (41.8 mmol) (E)-methyl 3-(4-chlorophenyl)-2-methylacrylate (freshly distilled) 0.476 g (4.18 mmol) TFA, and 12.4 g (52 2 mmol) N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine in 100 mL DCM was stirred at 0-5° C. for 1 h and at room temperature. NEt3 was added and the mixture was concentrated. The residue was purified by column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to yield after evaporation of the product containing fractions 7.55 g (53%) of the title compound as colorless oil. MS m/e: 344.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[N:4][N:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[N:22]=[C:23]=[O:24].CN(C)C=O>ClCCCl.O>[CH3:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH3:14])[C:16]=1[NH:22][C:23]([NH:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[N:4][N:3]=1)=[O:24]
Reactant: Cc1cccc(C)c1N=C=O
Reactant: Nc1nnnn1Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: Cc1cccc(C)c1NC(=O)Nc1nnnn1Cc1ccccc1

Procedure:
5-Amino-1-benzyltetrazole (3.25 g, 0.0186 mol) was suspended in 15 mL of 1,2-dichloroethane after which 2,6-dimethylphenylisocyanate (3.5 mL, 0.025 mol) was added. The mixture was refluxed for 6 hours, 10 mL of dimethylformamide was added, and the mixture was refluxed for an additional 6 hours. The reaction mixture was diluted twice with 50 mL water and the water decanted from the precipitate then concentrated in vacuo adding ethanol as the azeotropic solvent. The precipitate was washed with ether, dried in a vacuum oven, washed with hot water and hot ethyl acetate, extracted with hot 9:1 methanol/methylene chloride, and concentrated to give the title compound, m.p. 220-230° C. dec.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[O:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([OH:14])=[O:13].[CH:16](NC(=NC(C)C)OC(C)C)([CH3:18])[CH3:17]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[O:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([O:14][CH:16]([CH3:18])[CH3:17])=[O:13]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C1\CCOC1=O
Reactant: CC(C)N=C(NC(C)C)OC(C)C
Solvent: c1ccccc1
Product: CC(C)OC(=O)[C@@H]1[C@H](/C=C2\CCOC2=O)C1(C)C
Yield: 49.2 %

Procedure:
Using the procedure of Example 17, 8.4 g of (1R,cis) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-furanylidene)-methyl]-cyclopropane-1-carboxylic acid and 7.45 g of isopropyl N,N'-diisopropylcarbamimidate were reacted to obtain 4.96 g of isopropyl (1R,cis) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-furanylidene)-methyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+41°±2.5° (c=0.5% in benzene).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[C:16]2[N:15]3[CH:17]=[CH:18][N:19]=[C:14]3[C:13](=[O:20])[NH:12][C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2.C[Si](C)(C)Cl.Cl.Cl[CH2:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1>CN(C)C=O.O.C(O)(=O)C>[CH3:3][C:4]1([CH2:28][C:29]2[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=2)[C:16]2[N:15]3[CH:17]=[CH:18][N:19]=[C:14]3[C:13](=[O:20])[NH:12][C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: CC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reactant: Cn1ccnc1CCl
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: Cn1ccnc1CC1(C)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 0.17 h
Yield: 33.4 %

Procedure:
0.4 g of 80% sodium hydride is added over 5 minutes to a stirred solution, under an argon atmosphere, of 0.6 g of 10-methyl-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one in 30 ml of dimethylformamide. The stirring is continued for 10 minutes at a temperature in the region of 20° C., then 0.35 ml of trimethylchlorosilane is added and the stirring is continued for 10 minutes. 82 mg of sodium hydride are then added and the stirring is continued for 1 hour. 0.5 g of 2-chloromethyl-1-methylimidazole hydrochloride is then added and the stirring is continued for 2 hours. The reaction mixture is treated with 6 ml of acetic acid and 200 ml of water. The solution obtained is washed with ethyl acetate (2×200 ml) and the aqueous phase is concentrated on a rotary evaporator. The evaporation residue is triturated with 20 ml of isopropanol and filtered, and the filtrate is concentrated on a rotary evaporator. A pasty residue is obtained which is purified by chromatography on a column of silica (80 g), eluting with a dichloromethane/methanol mixture (85/15 by volume). 0.28 g of 10-methyl-10-[(l-methylimidazol-2-yl)methyl]-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is obtained in the form of a cream-coloured solid melting above 260° C. (Analysis, % calculated C: 68.87, H: 5.17, N: 21.13, O: 4.83, % found C: 68.8, H: 5.2, N: 21.2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([O:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[Br:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(O)c(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.6 %

Procedure:
To a solution of 2-bromo-4-methylphenol (1.5 g, 8.0 mmol) in N,N-dimethylformamide (40 mL), potassium carbonate (1.32 g, 9.6 mmol) was added and furthermore benzyl bromide (1.05 mL, 8.8 mmol) was added thereto. The mixture solution was stirred at room temperature for 12 hours, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (1.72 g, 77%).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][CH2:5][N:4]=[C:3]1[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]1>CN(C)C=O>[O:2]1[CH2:7][CH2:6][CH2:5][N:4]=[C:3]1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:22][CH2:23][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:10][CH:9]=1
Reactant: Oc1ccc(C2=NCCCO2)cc1
Reactant: CCOC(=O)N1CCC(CCCCl)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(CCCOc2ccc(C3=NCCCO3)cc2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A mixture of 15 parts of 4-(5,6-dihydro-4H-1,3-oxazin-2-yl)phenol hydrochloride, 29 parts of potassium carbonate and 180 parts of N,N-dimethylformamide was stirred for 1 hour at about 80° C. Then there were added 16.4 parts of ethyl 4-(3-chloropropyl)-1-piperidinecarboxylate and stirring was continued overnight at about 95° C. The reaction mixture was poured into ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98.5:1.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 18.8 parts (71.7%) of ethyl 4-[3-[4-(5,6-dihydro-4H-1,3-oxazin-2-yl)phenoxy]propyl]-1-piperidinecarboxylate; mp. 128.5° C. (int. 59).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][C:11](=[O:14])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:15]=[C:16]1[O:20][C:18](=[O:19])[CH2:17]1>CN(C)C=O>[O:14]=[C:11]1[NH:10][N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:18](=[O:19])[CH2:17][C:16]([CH3:15])=[O:20])=[CH:7][CH:6]=2)[CH2:13][CH2:12]1
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: C=C1CC(=O)O1
Solvent: CN(C)C=O
Product: CC(=O)CC(=O)Nc1ccc(C2=NNC(=O)CC2)cc1

Procedure:
20 g (0.106 mole) of 3-(4-aminophenyl)-6-oxo-1,4,5,6-tetrahydropyridazine in 250 ml of dimethylformamide are stirred with 9.47 g (0.113 moles) of diketene for 12 hours at room temperature. After the mixture has been concentrated, the residue is boiled up with 100 ml of ethanol, and the product is filtered off after cooling.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11](O[C:14](=[O:29])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][CH:17]=2)=[O:12])=[CH:2]1.C([O-])(=O)C.[NH4+:34]>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11]([NH:34][C:14](=[O:29])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][CH:17]=2)=[O:12])=[CH:2]1
Reactant: COc1cc2[nH]cc(C3=C(c4c[nH]c5ccccc45)C(=O)OC3=O)c2cc1OC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Product: COc1cc2[nH]cc(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c2cc1OC
Yield: 40.1 %

Procedure:
3.0 g (7.72 mmol) 2-(1H-indol-3-yl)-3-(5,6-dimethoxy-1H-indol-3-yl)-maleic acid anhydride, together with 75 g ammonium acetate, are heated to 140° C. for 1 hour. After cooling, the reaction mixture is mixed with 1.5 l of water and the dark red precipitate is filtered off with suction. There is obtained a crude yield of 2.61 g. For purification, 1.75 g thereof is chromatographed on silica gel with dichloromethane/ethyl acetate (8:1 v/v) as elution agent. There are obtained 1.20 g 2-(1H-indol-3-yl)-3-(5,6-dimethoxy-1H-indol-3-yl)-maleinimide×0.5 ethyl acetate in the form of dark red crystals; m.p. 120° C. (decomp.); RF=0.32 (dichloromethane/ethyl acetate 3:1 v/v). Yield 54% of theory.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:37][CH:38]([C:45]2([CH3:50])[CH2:49][CH2:48][CH2:47][CH2:46]2)[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)=[N:6][CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[C:3]([NH:37][CH:38]([C:45]2([CH3:50])[CH2:46][CH2:47][CH2:48][CH2:49]2)[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][N:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)CC(Nc1nc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(F)cc23)ncc1F)C1(C)CCCC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(Nc1nc(-c2n[nH]c3ncc(F)cc23)ncc1F)C1(C)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of racemic ethyl 3-[[5-fluoro-2-(5-fluoro-1-trityl-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl]amino]-3-(1-methylcyclopentyl)propanoate, 148a, (0.240 g, 0.357 mmol) in dichloromethane (20 mL) was added triethylsilane (0.285 mL, 1.784 mmol) followed by trifluoroacetic acid (0.275 mL, 3.567 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the resulting crude residue was purified by silica gel chromatography (5% MeOH/CH2Cl2) to afford the desired product: 1H NMR (400 MHz, CDCl3) δ 11.80 (s, 2H), 8.59 (d, J=12.3 Hz, 2H), 8.48 (d, J=7.9 Hz, 1H), 6.60 (d, J=8.3 Hz, 1H), 5.07 (s, 1H), 4.09 (q, J=7.0 Hz, 2H), 2.97-2.59 (m, 2H), 1.70 (dd, J=27.7, 13.9 Hz, 6H), 1.57-1.33 (m, 2H), 1.16 (dd, J=18.1, 11.1 Hz, 6H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.97 minutes (M+H) 431.24.
Reaction SMILES: [CH:1]1([N:4]([CH3:21])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([C:17]#[CH:18])[CH:8]=[C:7]([O:19][CH3:20])[C:6]2=3)[CH2:3][CH2:2]1.[CH2:22]([O:29][C:30](=[O:40])[CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1)C1C=CC=CC=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:29][C:30](=[O:40])/[CH:31]=[CH:32]/[C:33]1[CH:34]=[CH:35][C:36]([C:18]#[C:17][C:9]2[CH:8]=[C:7]([O:19][CH3:20])[C:6]3[CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:21])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=3[CH:10]=2)=[CH:37][CH:38]=1
Reactant: C#Cc1cc(OC)c2c(c1)C(C)(C)CCC2N(C)C1CC1
Reactant: O=C(C=Cc1ccc(O)cc1)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.095 g, 0.336 mmol), methyl-4-iodocinnamate (Reagent 4, 0.097 g, 0.336 mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-15% ethyl acetate in hexane as the eluent, the title compound was obtained as a white solid (0.12 g, 80%).
Reaction SMILES: [CH2:1]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]CC)=[O:20])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[Na+].Cl>CO.O1CCCC1>[CH2:1]([C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCc1ccc(CC(=O)OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCc1ccc(CC(=O)O)cc1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 26.9 %

Procedure:
To the solution of ethyl 4-undecylphenylacetate (7.2 g, 0.023 mol) in a mixture of methanol (40 ml) and tetrahydrofuran (40 ml) was added sodium hydroxide (2.2 g, 0.055 mol) and stirred at 50° C. for 20 minutes. The reaction mixture was adjusted to pH 4 with 2N hydrochloric acid after concentration. The resultant mixture was extracted with ethyl acetate, and the organic layer was washed with water, dried and concentrated under reduced pressure. The resulting crude crystals were recrystallized from hexane to obtain 4-undecylphenylacetic acid (3-x, 1.8 g, 27%). m.p. 83°-84° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].[CH3:13][S:14]([NH2:17])(=[O:16])=[O:15].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5]([NH:17][S:14]([CH3:13])(=[O:16])=[O:15])=[O:6]
Reactant: COc1cc(C)ccc1C(=O)O
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C)ccc1C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 63 %

Procedure:
2-Methoxy-4-methyl-benzoic acid (1.0 g. 6 mmol), methanesulphonamide (1.14 g. 12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.31 g. 12 mmol), 4-dimethylaminopyridine (1.47 g. 12 mmol) and DCM (50 mL) were combined and stirred at room temperature under nitrogen for 18 hours. The reaction mixture was concentrated in vacuo and the residue suspended in water and acidified with aqueous potassium hydrogen sulphate (0.5 M). The mixture was extracted with EtOAc (1×30 mL). The organic layer was separated, washed with brine (2×20 mL), dried over sodium sulfate, filtered and evaporated to give a solid, which was triturated with hexane: diethyl ether (4:1) to yield the title compound as a white solid (0.92 g, 63%).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=O)[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.NN.[OH-].[K+]>C(O)COCCO.C(O)CCC>[CH3:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:14]([CH2:13][CH2:12][C:11]4[CH:10]=[C:9]([OH:20])[CH:8]=[CH:7][C:6]=43)[C@@H:15]1[CH2:16][CH2:17][CH2:18]2
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: OCCOCCO
Product: C[C@@]12CCC[C@H]1[C@@H]1CCc3cc(O)ccc3[C@H]1CC2
Temperature: 50 °C
Yield: 97.5 %

Procedure:
Into a stirring suspension of estrone (8.1 g, 30 mmols) in 60 mL diethylene glycol, 20 mL 1-butanol and 2 mL hydrazine anhydrous (60 mmols) were added. The reaction mixture was heated under reflux for 1 hour to get clear solution. After cooling reaction mixture to 50 ° C., 5.04 g KOH pellets (90 mmols) were added and butanol was distilled. The reaction mixture was heated at 50° C. for 2 hours and then cooled to RT. On pouring in to ice (50 g), 20 mL 6N HCl was added and the reaction mixture stirred to give white solid product. The product was separated by filtration, washed with cold water and dried under vac. to give 7.5 g (90%) product. The product was purified on silica gel column eluted with CHCl3/MeOH 99:1. 1H NMR in CDCl3 confirmed the product as estra-1,3,5(10)-triene-3-ol.