Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH3:31][S:32]([NH:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>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>[CH3:31][S:32]([NH:35][C:36]1[CH:37]=[CH:38][C:39]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][N:6]=[C:5]3[CH:14]2[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[CH:40][CH:41]=1)(=[O:34])=[O:33]
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc(-c2cc(C(N)=O)c3[nH]nc(C4CCN(S(=O)(=O)CCCN5CCCC5)CC4)c3c2)cc1
Yield: 53.1 %

Procedure:
Following the general procedure of Example 66, a mixture of 5-bromo-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 27) (24 mg, 0.048 mmols), {4-[(methylsulfonyl)amino]phenyl}boronic acid (31 mg, 0.144 mmols), potassium carbonate (40 mg), and Pd(PPh3)4 (3 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (15 mg, 53%)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH:23]2[CH:28]([CH:29]([CH3:31])[CH3:30])[CH2:27][CH2:26][CH:25]([CH3:32])[CH2:24]2)=[O:21])=[CH:15][CH:14]=1.Br[CH:34]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.CC(C)([O-])C.[K+].O>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([CH:34]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[C:20]([O:22][CH:23]2[CH:28]([CH:29]([CH3:31])[CH3:30])[CH2:27][CH2:26][CH:25]([CH3:32])[CH2:24]2)=[O:21])=[CH:15][CH:14]=1
Reactant: BrC1CCCCCC1
Reactant: CC1CCC(C(C)C)C(OC(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCC(C(C)C)C(OC(=O)[C@@H](c2ccc(OCc3ccc4ccccc4n3)cc2)C2CCCCCC2)C1
Reaction time: 4 h

Procedure:
1.3 kg of the compound from Example 6 are stirred with exclusion of moisture at -5° C. to +5° C. with 580 g of bromocycloheptane in 2.4 l of DMF. During the course of about 2 hours, a solution of 400 g of potassium tert-butoxide in 1.6 l of DMF is added. The mixture is stirred for a further 4 hours between -20° C. and -10° C. and 7.5 l of water are then added, during the course of which the title compound precipitates as a crude product. The crude product is centrifuged off, dried at 50° C. in vacuo and recrystallised twice using 6 l of ligroin; the solution is filtered hot in the first recrystallisation.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:31]1([CH2:37]Br)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:37][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: BrCC1CCCCC1
Product: Cc1nc2c(ccn2CC2CCCCC2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and cyclohexylmethyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.51-7.43 (m, 1 H), 7.21-7.12 (m, 2 H), 7.00-6.93 (m, 1 H), 6.37 (dd, J=3.4, 7.3 Hz, 1 H), 5.52 (br. s., 1 H), 4.39-4.27 (m, 3 H), 4.25-4.14 (m, 1 H), 2.98-2.77 (m, 5 H), 2.17-2.04 (m, 2 H), 1.96 (td, J=3.7, 7.2 Hz, 1 H), 1.78-1.56 (m, 5 H), 1.31-1.15 (m, 3 H), 0.95 (s, 9 H); LC/MS (m/z) ES+=491.47 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([OH:29])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:34]COC(C)=O.C([O-])(O)=O.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([O:29][CH3:34])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O

Procedure:
To a suspension of 250 mg (0.578 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetic acid (Example 35) in MeOH (3 mL) was added thionyl chloride (78.0 μl, 1070 μmol) dropwise at 0° C. After being stirred at 25° C. for 14h, the reaction was diluted (EtOAc), basified (sat NaHCO3), extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to provide the title compound as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([I:16])=[C:10]3[I:15])[C:6]=2[CH:17]=1.Br[C:19]1C=CC2OC(C)CN3C=CN=C3C=2C=1.IN1C(=O)CCC1=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH:13]([CH3:19])[CH2:12][N:11]3[C:10]([I:15])=[C:9]([I:16])[N:8]=[C:7]3[C:6]=2[CH:17]=1
Reactant: CC1Cn2ccnc2-c2cc(Br)ccc2O1
Reactant: Brc1ccc2c(c1)-c1nc(I)c(I)n1CCO2
Agent: O=C1CCC(=O)N1I
Product: CC1Cn2c(nc(I)c2I)-c2cc(Br)ccc2O1

Procedure:
10-bromo-2,3-diiodo-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was prepared similarly according to 9-bromo-2,3-diiodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene. 10-bromo-6-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was reacted with N-iodosuccinimide to afford 324 mg (90% yield) of a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[OH:15]O.N>C(O)C>[NH2:1][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)[N:5]=[CH:4][C:3]=1[C:13]([NH2:14])=[O:15]
Reactant: N#Cc1cnn(C2CCOCC2)c1N
Reactant: OO
Agent: N
Solvent: CCO
Product: NC(=O)c1cnn(C2CCOCC2)c1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
A stirred solution of 5-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carbonitrile (˜228 mmol) in ethanol (300 mL) was treated with 35% aqueous H2O2 (100 mL) followed by aqueous ammonia (300 mL). The reaction mixture was stirred for 48 h at ambient temp and then quenched with aq saturated sodium thiosulfate (800 mL) and concentrated under reduced pressure to remove most of the ethanol. The resulting solid was removed by filtration and washed with water (2×200 mL) and ether (2×150 mL). The solid was dried in vacuo to constant weight (31 g, 65% yield for 2 steps). 400 MHz 1H NMR (CD3OD) δ 7.67 (s, 1H), 4.27-4.21 (m, 1H), 4.03 (dd, J=11.6, 4.6 Hz, 2H), 3.28 (t, J=1.7 Hz, 2H), 2.14-2.04 (m, 2H), 1.81-1.78 (m, 2H). MS: (M1H m/z=382.2).
Reaction SMILES: C(O)[C:2]([NH2:7])([CH2:5]O)[CH2:3]O.Cl.[CH3:10][O:11][C:12]1[CH:13]=[C:14](CC(=O)C)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].C1([C@H](N)C)C=CC=CC=1>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:5][C@H:2]([NH2:7])[CH3:3])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(CC(C)=O)cc1OC
Reactant: NC(CO)(CO)CO
Agent: C[C@@H](N)c1ccccc1
Agent: Cl
Product: COc1ccc(C[C@@H](C)N)cc1OC

Procedure:
Using 10 ml of the cell-free extract, the components were reacted in 100 ml of a reaction mixture comprising a 0.1 M Tris-hydrochloric acid buffer (pH 8.5) containing 0.5 g of 1-(3,4-dimethoxyphenyl)-2-propanone and 0.34 g of (R)-1-phenylethylamine at 30° C. for 24 hours. As a result, 0.36 g of (R)-(3,4-dimethoxyphenyl)-2-aminopropane was formed.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.[ClH:32].CCN(C(C)C)[CH:36]([CH3:38])[CH3:37].CC(C)=O>ClCCCl.O1CCOCC1.O.CC(O)=O>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:27][CH2:26][N:25]([CH:36]([CH3:38])[CH3:37])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)[CH:7]=1.[ClH:32]
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1ccccc1F
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CC(C)=O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(C)N1CCC(c2ccc(Nc3cc(NCc4ccccc4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 4-(2-fluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 106) HCl salt (110 mg, 0.24 mmol) was stirred in 5 mL 1,2-dichloroethane (DCE) and 5 mL dioxane. To the slurry were added DIEA (0.21 mL, 1.2 mmol) and acetone (0.18 mL, 2.4 mmol). The mixture was stirred at RT for 1 h. To the mixture were then added HOAc (0.25 mL) and NaBH(OAC)3 (260 mg, 1.2 mmol). The mixture was stirred at RT for overnight. Water (10 mL) was added. The mixture was concentrated in vacuo. The residue was subjected to reverse phase prep HPLC to isolate the title compound as HCl salt. UV=259 nm. M+H found for C27H32FN5O: 462.5. NMR (CD3OD): 8.18 (1H, s), 7.38 (1H, m), 7.30 (2H, d, J=8.8 Hz), 7.09 (3H, m), 7.04 (1H, m), 7.00 (1H, m), 5.82 (1H, s), 4.47 (2H, s), 3.58 (2H, m), 3.22 (3H, m), 2.95 (1H, m), 2.18 (2H, m), 2.01 (2H, m), 1.42 (6H, d, J=6.8 Hz) ppm.
Reaction SMILES: [C:1]([CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:10]=1[O:23][CH3:24])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[H-].[Na+].[CH3:27]I.O>CN(C)C=O>[C:1]([C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:10]=1[O:23][CH3:24])([CH3:27])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)c1cccc(Sc2ccccc2Cl)c1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C#N)c1cccc(Sc2ccccc2Cl)c1OC
Reaction time: 0.33 h
Yield: 102.3 %

Procedure:
A solution of ethyl 2-cyano-2-[2-methoxy-3-(2-chlorophenylthio)phenyl]acetate (3.2 g) in dimethylformamide (10 ml) was added dropwise to a mixture of sodium hydride (65%, 330 mg) and dimethylformamide (20 ml) in 10 minutes at temperature below 10° C. After stirring the mixture at the same temperature for 20 minutes, methyl iodide (2.5 g) was added to the mixture. The mixture was stirred at the same temperature for 15 minutes and then at room temperature for 20 minutes. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water, dried and then evaporated under reduced pressure to give oily ethyl 2-cyano-2-[2-methoxy-3-(2-chlorophenylthio)phenyl]propionate (3.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:36])[C:5]([CH:34]=O)=[N:6][N:7]2[CH2:32][CH3:33].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:36])[C:5]([CH2:34][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)=[N:6][N:7]2[CH2:32][CH3:33]
Reactant: CCn1nc(C=O)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCn1nc(CN2CCCC2)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carbaldehyde (3.5 g, 4.26 mmol) in Dichloromethane (DCM) (80 mL) was added pyrrolidine (0.370 mL, 4.48 mmol) and sodium triacetoxyborohydride (1.355 g, 6.40 mmol). The mixture was stirred at r.t. for 1 h. Then reaction mixture was washed with sat. NaHCO3 (aq.) and brine, dried over sodium sulfate and the solvent was removed in vacuo. The crude product was then purified through normal phase chromatography (CombiFlash Rf), eluting with MeOH/DCM (0-20%) to afford 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-3-(pyrrolidin-1-ylmethyl)cinnolin-4(1H)-one (1.9 g, 3.37 mmol, 79% yield) as an orange solid. The desired product was dissolved in DCM and washed with sat. NaHCO3 (aq.) and brine, concentrated and passed through a flash column chromatography before being used for the next step. LCMS: (M+H)+: 564.4.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(O)(=O)C.[O-]Cl.[Na+]>>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Product: CCOC(=O)C1CCC(=O)CC1
Temperature: 25 °C

Procedure:
To a 3-L 3-neck flask equipped with a mechanical stirrer, a thermometer, and an addition funnel were added 50 g (292 mmol) of the compound of Formula 32.0 from Step 1, 33 mL (584 mmol) of acetic acid and 145 mL of commercial bleach (5.25% NaOCl). To the cooled reaction mixture, at 5° C., was added dropwise 479 mL of more bleach. The reaction was allowed to warm to room temperature for 1 hour and then was extracted with 3×400 mL ethyl acetate. The combined extract was washed with water, dried over MgSO4, and concentrated to give 49 g of crude 33.0 as an oil which was used without purification. The spectrum data are identical to that of literature (see Sanchez, I. H.; Ortega, A.; Garcia, G.; Larraza, M. I.; Flores, H. J. Synthetic comm. 1985, 15, 141).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34](O)=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:60][C:61]1([CH2:65][NH2:66])[CH2:64][O:63][CH2:62]1>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[CH3:60][C:61]1([CH2:65][NH:66][C:34](=[O:35])[CH2:33][CH:30]2[S:29][C:28]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[CH:13][C:12]([O:11][C:8]3[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:20][C:19]=4[O:21][CH:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:32][CH2:31]2)[CH2:64][O:63][CH2:62]1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Reactant: CC1(CN)COC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: CC1(CNC(=O)CC2CN=C(c3cc4cc(Oc5ccc(S(C)(=O)=O)nc5)cc(OC5CCOCC5)c4[nH]3)S2)COC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.1 %

Procedure:
To a solution of {2-[5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (65 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), and 1-(3-methyloxetan-3-yl)methanamine (57 mg), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio), and crystallized from acetonitrile. The obtained crystals were recrystallized from ethyl acetate and diethyl ether to give the title compound (106 mg, yield 61%) as white crystals.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH2:2]>[Pd].CO>[CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: C=Cc1[nH]c2ccccc2c1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCc1[nH]c2ccccc2c1C(=O)OC
Yield: 97.2 %

Procedure:
Methyl 2-vinyl-1H-indole-3-carboxylate (80 mg, 0.4 mmol) and 10% palladium on charcoal (100 mg) in methanol (30 mL) were stirred under hydrogen 0.2 MPa at room temperature for 15 hours. The mixture was filterated the solid and concentrated in vacuum to obtain methyl 2-ethyl-1H-indole-3-carboxylate as a white solid (79 mg, 99%) LRMS (M+H+) m/z: calcd 203.1 found 203.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[CH3:14][C:15]([CH3:17])=[O:16].[OH-].[Na+]>C(O)C>[CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:14][C:15]([CH:17]=[CH:8][C:7]2[CH:10]=[CH:11][C:4]([N:3]([CH2:1][CH3:2])[CH2:12][CH3:13])=[CH:5][CH:6]=2)=[O:16])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)c1ccc(C=CC(=O)C=Cc2ccc(N(CC)CC)cc2)cc1
Yield: 41 %

Procedure:
In 25 ml of anhydrous ethanol were dissolved 17.7 g of p-diethylaminobenzaldehyde and 2.9 g of acetone, and 1.5 ml of 10% aqueous NaOH was added dropwise to the resulting solution, after which the resulting mixture was subjected to reaction under reflux for 8 hours. The reaction mixture was cooled, and the crystals thus precipitated were collected by filtration and then recrystallized from toluene, to obtain 7.7 g of 1,3-bis(4'-diethylaminobenzal)acetone (m.p. 168° C.).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:20][OH:21]>>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15](=[N:20][OH:21])[CH2:14][CH2:13]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCCCCCN1CCC(=O)CC1
Reactant: NO
Agent: Cl
Product: CCCCOCCCCCCN1CCC(=NO)CC1

Procedure:
1-(6-Butoxyhexyl)-4-piperidone oxime is prepared from 1-(6-butoxyhexyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: F[C:2]([F:17])(S(F)(=O)=O)[C:3](F)(F)[C:4](F)(F)[C:5](F)(F)F.O[C@H]1C[C@@]2(C)[C@@H:30]([CH2:31][CH2:32][C:33]2=[O:37])[C@H:29]2[C@H:20]1[C@@H:21]1[C:26]([CH2:27][CH2:28]2)=[CH:25][C:24](=[O:38])[CH2:23][CH2:22]1>C1(C)C=CC=CC=1.N12CCCN=C1CCCCC2.C(OCC)(=O)C>[F:17][C@H:2]1[CH2:3][C@@:4]2([CH3:5])[C@@H:30]([CH2:31][CH2:32][C:33]2=[O:37])[C@H:29]2[C@H:20]1[C@@H:21]1[C:26]([CH2:27][CH2:28]2)=[CH:25][C:24](=[O:38])[CH2:23][CH2:22]1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C[C@]12C[C@H](O)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: C[C@]12C[C@H](F)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reaction time: 0.5 h

Procedure:
4.6 ml of perfluorobutane-1-sulphonyl fluoride are added dropwise at 0° C. to 5.0 g of 11β-hydroxyoestr-4-ene-3,17-dione in 100 ml of toluene and 7.3 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene. After 30 min, the solution is diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated in vacuo. After chromatographing the crude product on silica gel using a hexane-ethyl acetate gradient, 3.8 g of 11β-fluorooestr-4-ene-3,17-dione of melting point 173-174° C. are obtained.
Reaction SMILES: [OH-].[Na+].C([O:6][CH:7]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])(=O)C.S(=O)(=O)(O)O>CO>[OH:6][CH:7]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCCCCCCCC(/C=C/C=C/c1ccccc1CCCCC(=O)O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/C=C/c1ccccc1CCCCC(=O)O
Temperature: 24 °C
Reaction time: 4 h
Yield: 35239.9 %

Procedure:
0.3 ml of a 0.5 normal sodium hydroxide solution is added to a solution of 12 mg of 5-[2-[(1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-phenyl]-pentanoic acid (produced in example 5) in 0.3 ml of methanol at 25° C. and stirred for 4 hours at 24° C. Then, it is cooled to 0° C. and acidified with a 0.5 normal sulfuric acid to pH=6. It is extracted four times with ethyl acetate, the organic phase is washed with water and dried on sodium sulfate. It is concentrated by evaporation in a vacuum, and the residue is chromatographed on silica gel. With ether/hexane (7+3) as a mobile solvent, 3.8 g of the title compound is obtained as a colorless oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:34])[N:10]([CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:11]2=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([N:6]([S:2]([CH3:1])(=[O:4])=[O:3])[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:34])[N:10]([CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:18][S:19]([CH3:22])(=[O:20])=[O:21])[C:11]2=[O:16])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N(S(C)(=O)=O)S(C)(=O)=O)c3C2=O)ccc1OC
Reaction time: 24 h

Procedure:
Methanesulfonyl chloride (0.3 g, 2.62 mmol) was added to a stirred suspension of 4-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl]isoindoline-1,3-dione (0.55 g, 1.31 mmol) and triethylamine (0.4 g, 3.93 mmol) in methylene chloride (60 mL) and the resulting mixture stirred for 24 hours. The mixture was then washed with sat. Sodium bicarbonate (25 mL), 1N hydrogen chloride (25 mL), H2O (25 mL), brine (25 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The residue was slurried in methanol:tetrahydrofuran (2:1) to give after isolation by filtration 4-[bis(methylsulfonyl)amino]-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindoline-1,3-dione (0.53 g, 70%) as a white solid: mp 277-279° C.; 1H NMR (DMSO-d6) δ 8.05-7.95 (m, 3H), 7.11-6.92 (m, 3H), 5.78-5.74 (dd, J=5.5, 9.1 Hz, 1H), 4.31-4.22 (m, 2H), 3.99 (q, J=6.9 Hz, 2H), 3.73 (s, 3H), 3.55 (s, 6H), 2.95 (s, 3H), 1.31 (t, J=7.0 Hz, 3H); 13C NMR (DMSO-d6) δ 166.11, 165.35, 148.96, 147.88, 138.63, 136.05, 132.60, 129.64, 129.31, 129.27, 125.26, 119.89, 112.33, 111.76, 63.73, 55.46, 53.38, 47.92, 43.50, 43.44, 41.15, 14.61; Anal. Calcd. for C22H26N2O10S3: C, 45.95; H, 4.56; N, 4.87; S, 16.74. Found: C, 45.90; H, 4.40; N, 4.75; S, 16.55.