Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C@:17]3([CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[C:16]2=[O:25])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:26][C:27]1[CH:32]=[CH:31][C:30](I)=[C:29]([Cl:34])[CH:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)CCC.[Cu]I>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([N:21]2[CH2:22][CH2:23][CH2:24][C@@:17]3([C:16](=[O:25])[N:15]([C@H:12]4[CH2:13][CH2:14][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:10][CH2:11]4)[CH2:19][CH2:18]3)[CH2:20]2)=[C:29]([Cl:34])[CH:28]=1
Reactant: Clc1cc(Br)ccc1I
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CC[C@]3(CCCNC3)C2=O)CC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CCCCO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CC[C@]3(CCCN(c4ccc(Br)cc4Cl)C3)C2=O)CC1
Temperature: 100 °C

Procedure:
A mixture of (5S)-2-(cis-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (0.282 g, 0.000769 mol), 4-bromo-2-chloro-1-iodobenzene (0.293 g, 0.000922 mol) (Lancaster, cat #: 19245), copper(I) iodide (0.015 g, 0.000077 mol), potassium phosphate (0.490 g, 0.00231 mol) and 1,2-ethanediol (0.0857 mL, 0.00154 mol) in 1-butanol (0.75 mL) was heated at 100° C. under nitrogen for 2 d. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by flash chromatography on a silica gel column (eluting with 0 to 50% ethyl acetate in hexanes) to afford the desired product.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)[CH:4]([CH2:5][C:6]2=[O:17])[CH2:3]1.[CH3:18][C:19]([CH3:24])([CH2:22]O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>CCOCC>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C:7]23[C:6]4([O:21][CH2:20][C:19]([CH3:24])([CH3:22])[CH2:18][O:17]4)[CH2:5][CH:4]2[CH2:3][N:2]([CH3:1])[CH2:8]3)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(C23CN(C)CC2CC3=O)c1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cccc(C23CN(C)CC2CC32OCC(C)(C)CO2)c1

Procedure:
A mixture of 1.18 g. of 3-methyl-5-(m-methoxyphenyl)-3-azabicyclo[3.2.0]heptan-6-one, 0.78 g. of 2,2-dimethyl-1,3-propanediol and 1.05 g. of p-toluenesulfonic acid in 25 ml. of toluene was heated at reflux under a Dean-Stark trap for 29 hours. The mixture was cooled, diluted with ether, washed with 10% sodium hydroxide, and then with water giving a brown oil. This oil was distilled in a Kugelrohr apparatus at 175° C. and 0.10 mm., giving the desired product as a colorless oil.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Zn]CC)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[C:20]=2/[CH:25]=[N:26]/[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[C:20]=2[CH:25]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:15][CH:14]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1noc(-c2ccc(Br)cc2)c1/C=N/S(C)(=O)=O
Agent: CC[Zn]CC
Solvent: Cc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(C#C[Si](C)(C)C)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(Trimethylsilyl)acetylene (0.6926 mL, 5 mmol) and diethylzinc (1.1M in toluene, 4.54 mL, 5 mmol) were dissolved in toluene (15.5 mL) and stirred for 1 hour at room temperature. Then, N-[1-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-meth-(E)-ylidene]-methanesulfonamide (1 g, 0.291 mmol) was added and the reaction was heated to 60° C. for 20 hours. The reaction was quenched with H2O and submitted to aqueous workup then purified via silica gel chromatography to yield the title compound which was brought directly to the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C[C:14]([N:16](C)C)=O.C(OCC)(=O)C>CO>[CH:5]([C:4]1[CH:3]=[C:2]([C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=1)[C:14]#[N:16])=[O:6]
Reactant: CC(=O)N(C)C
Reactant: COc1cc(C=O)cc(Br)c1O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C=O)cc(C#N)c1O

Procedure:
A mixture of 23.1 g of 3-bromo-4-hydroxy-5-methoxy benzaldehyde, 9.3 g of cuprous cyanide and 140 ml of dimethyl acetamide (DMA) was refluxed for 2 hours with stirring. After cooling, the mixture was poured over ice and extract&d with an ethyl acetate--methanol mixture (90-10). The organic phase was washed and dried and the solvents were eliminated to obtain 18 g of crude product, which was used as is for the following step. It melted at 180° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl.[C:19]1([C:25]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:33]1[CH2:34][CH2:35][N:30]([C:28]2[S:27][N:26]=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:29]=2)[CH2:31][CH2:32]1)=[O:18]
Reactant: O=C(Nc1nc2ccccc2s1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1nc2ccccc2s1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 26.1 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl 1,3-benzothiazol-2-ylcarbamate (240 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 81.4 mg (26.1%) of the desired product as a solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1([CH3:19])[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[NH2:4].[C:20](OC(=O)C)(=O)[CH3:21]>ClCCl>[CH3:10][C:7]1([CH3:11])[N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]([CH3:19])([C:3]2[N:4]=[C:20]([CH3:21])[O:1][N:2]=2)[CH2:9][O:8]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OCC1(C)C(N)=NO
Solvent: ClCCl
Product: Cc1nc(C2(C)COC(C)(C)N2C(=O)OC(C)(C)C)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 146 mg of tert-butyl 4-(N′-hydroxycarbamimidoyl)-2,2,4-trimethyl-1,3-oxazolidine-3-carboxylate in 4 ml of dichloromethane was added 55 μl of acetic anhydride, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and to the obtained residue were added 4 ml of DMF, followed by stirring at 110° C. for 15 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 113 mg of tert-butyl 2,2,4-trimethyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)-1,3-oxazolidine-3-carboxylate.
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].[CH2:9]([O:16][NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][N:17]([CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCCC(Br)CCC
Reactant: O=C(NOCc1ccccc1)Nc1ccccc1
Product: CCCC(CCC)N(OCc1ccccc1)C(=O)Nc1ccccc1
Yield: 38.9 %

Procedure:
Using the general method of Compound 42 Part B, 4-bromoheptane (5.84 g, 32.6 mmole) was reacted with 1-benzyloxy-3-phenylurea (7.3 g, 30.2 mmole) to provide about 4 g of 1-benzyloxy-1-(1-propylbutyl)-3-phenylurea.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]2=[O:17].[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]1([C:24]#[C:25][C:2]2[CH:3]=[C:4]3[C:14](=[CH:15][CH:16]=2)[O:13][C:7]2([CH2:12][CH2:11][CH2:10][O:9][CH2:8]2)[CH2:6][C:5]3=[O:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CC2(CCCOC2)Oc2ccc(Br)cc21
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1CC2(CCCOC2)Oc2ccc(C#Cc3ccccc3)cc21
Temperature: 80 °C
Yield: 90.5 %

Procedure:
An oven dried 3-necked round bottom flask equipped with condenser was charged with 6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (223 mg, 0.75 mmol), TEA (3 mL) and DEA (0.8 mL) under N2 atmosphere. To this solution was added CuI (5.7 mg, 0.03 mmol), PdCl2(PPh3)2 (21 mg, 0.03 mmol) and PPh3 (16 mg, 0.06 mmol). The system was degas once again, then phenylacetylene (0.41 mL, 3.75 mmol) was added and the mixture was heated to 80° C. (oil bath) with stirring. The reaction was evaporated after 12 h and the residue was purified by flash chromatography (12 g silica gel, eluted with EA in hexane in a gradient of 0-25%, v/v) to afford 6-(phenylethynyl)-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (216 mg, yield: 90%). MS ESI+ve m/z 319 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]([CH2:11]O)=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.Cl>[Zn].O>[CH3:11][C:5]1[O:4][C:3]([CH2:2][OH:1])=[CH:8][C:7](=[O:9])[C:6]=1[OH:10]
Reactant: O=c1cc(CO)oc(CO)c1O
Agent: Cl
Agent: [Zn]
Solvent: O
Product: Cc1oc(CO)cc(=O)c1O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
2,6-Dihydroxymethyl-5-hydroxy-4-pyrone, 10 g, was added to 50 ml of water to dissolve at 70° C. To the solution was added 8 g of zinc powders and, 28 ml of conc. hydrochloric acid (12 N) was dropwise added to the mixture over an hour. The mixture was stirred at the same temperature for 30 minutes. Insoluble matters (zinc powders) were removed and the reaction solution was cooled to 5° C. After adjusting its pH to 2 with 50% aqueous sodium hydroxide solution, the mixture was stirred at the same temperature for an hour and the resulting crystals were taken out by filtration, washed with a small quantity of chilled water and dried to give 5.15 g of the title compound.
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[O:12](S(C(F)(F)F)(=O)=O)[S:13]([C:16]([F:19])([F:18])[F:17])(=O)=[O:14].O>ClCCl>[F:17][C:16]([F:19])([F:18])[S:13]([O:4][CH2:3][CH2:2][F:1])(=[O:14])=[O:12]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCCF
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(OCCF)C(F)(F)F
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a solution of 2-fluoroethanol (3.2 g, 50 mmol) and triethylamine (5.5 g, 55 mmol) in dichloromethane (60 mL) was added dropwise (CF3SO2)2O (15.5 g, 55 mmol) at −78° C. under N2. The mixture was stirred at 10˜20° C. for 1 h, and treated with water (100 mL). The organic layer was washed with satd aq NaHCO3 (100 mL) and brine (100 mL), dried, and concentrated to give 2-fluoroethyl trifluoromethanesulfonate (8 g, yield 82%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(NC([N:25]1[C:33]2[C:28](=[CH:29][C:30]([O:34][C:35]3[C:36]4[CH:43]=[C:42]([C:44]5[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:52]6[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=6)=[CH:46][CH:45]=5)[N:41](COCC[Si](C)(C)C)[C:37]=4[N:38]=[CH:39][N:40]=3)=[CH:31][CH:32]=2)[CH:27]=[CH:26]1)=O)C>O1CCCC1>[CH2:51]([O:50][C:47]1[CH:48]=[CH:49][C:44]([C:42]2[NH:41][C:37]3[N:38]=[CH:39][N:40]=[C:35]([O:34][C:30]4[CH:29]=[C:28]5[C:33](=[CH:32][CH:31]=4)[NH:25][CH:26]=[CH:27]5)[C:36]=3[CH:43]=2)=[CH:45][CH:46]=1)[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CCNC(=O)n1ccc2cc(Oc3ncnc4c3cc(-c3ccc(OCc5ccccc5)cc3)n4COCC[Si](C)(C)C)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(COc2ccc(-c3cc4c(Oc5ccc6[nH]ccc6c5)ncnc4[nH]3)cc2)cc1
Yield: 13.3 %

Procedure:
After dissolving 1.5 ml of tetrahydrofuran in 22 mg of 5-[6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-indole-1-carboxylic ethylamide, a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran was added and the mixture was refluxed for 2 hours. After returning it to room temperature, water was added and the precipitated crystals were filtered out and subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain 2 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:10]([Si:17]1(C2C=CC=CC=2)[CH2:22][CH2:21][CH:20]([C:23](O)=[O:24])[CH2:19][CH2:18]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:10]([Si@H:17]1[CH2:18][CH2:19][C@H:20]([C:23]([O:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[O:24])[CH2:21][CH2:22]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Reactant: Oc1ccc(F)c(F)c1
Product: CCCCCCC[Si@H]1CC[C@H](C(=O)Oc2ccc(F)c(F)c2)CC1

Procedure:
The general procedure of Example 3 was repeated using 3,4-difluorophenol and 4-n-heptyl-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1ccc(F)cc1
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(F)cc2)CC1

Procedure:
4-Fluorobenzylamine (2.5 g) and N-tert-butoxycarbonyl-4-piperidone (4 g) were reacted as described in Example 98 (step 2), to give the title product as a yellow oil which crystallised (6.2 g). δH (250 MHz, CDCl3) 1.22-1.37 (2H, m), 1.43 (9H, s), 1.82-1.94 (2H, m), 2.60-2.72 (1H, m), 2.74-2.84 (2H, m), 3.80 (2H, s), 3.94-4.10 (2H, m), 6.97 (2H, m), 7.26-7.31 (2H, m).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][OH:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][O:31][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CCO)cc1OC
Product: COc1ccc(CCOC(=O)NC(=O)C(c2ccccc2)c2ccccc2)cc1OC

Procedure:
The title compound, white solid, m.p. 144° C. and MS: m/e=419.5 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and 2-(3,4-dimethoxy-phenyl)-ethanol.
Reaction SMILES: C([C@H:5]1[C@H:10]2[C@H:11]3[C:20]([CH2:21][CH2:22][C@:8]2([CH3:9])[C:7](=[O:24])[CH2:6]1)=[C:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)CCC.C1(SCl)C=CC=CC=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:9][C@:8]12[CH2:22][CH2:21][C:20]3[C@@H:11]([CH2:12][CH2:13][C:14]4[C:19]=3[CH2:18][CH2:17][C:16](=[O:23])[CH:15]=4)[C:10]1=[CH:5][CH2:6][C:7]2=[O:24]
Reactant: CCCC[C@@H]1CC(=O)[C@@]2(C)CCC3=C4CCC(=O)C=C4CC[C@H]3[C@H]12
Agent: ClSc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3C1=CCC2=O
Reaction time: 0.17 h
Yield: 100.6 %

Procedure:
A solution of 1.5 g of 15 α-hydroxy-4,9-estradiene-3,17-dione in 20 ml of methylene chloride and 1.2 ml of triethylamine is mixed with a solution of 0.83 g of phenylsulfenyl chloride in 5 ml of methylene chloride drop by drop at -20° C. After addition, stirring is performed for 10 minutes at -20° C., the reaction solution is then diluted with 100 ml of methylene chloride, washed, one after the other, with saturated sodium hydrogen carbonate solution and saturated ammonium chloride solution, dried with sodium sulfate and concentrated. Crystallization of the crude product from ethyl acetate/diisopropyl ether yields 1.24 g (88.2% of theory) of 4,9,14-estratriene-3,17-dione with a melting point of 143° to 144° C.
Reaction SMILES: CO.[CH3:3][N:4]([CH3:18])[C:5]1[C:14]([CH2:15]O)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:17])[CH:11]=2)[N:6]=1.O=S(Cl)[Cl:21]>C(Cl)Cl>[ClH:21].[Cl:21][CH2:15][C:14]1[C:5]([N:4]([CH3:18])[CH3:3])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH3:17])=[CH:9][CH:8]=2
Reactant: Cc1ccc2nc(N(C)C)c(CO)cc2c1
Reactant: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc2nc(N(C)C)c(CCl)cc2c1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.5 %

Procedure:
To a stirred solution of 2-(dimethylamino)-6-methylquinolin-3-yl)methanol RBO 40152 (900 mg, 4.16 mmol) in dry CH2Cl2 (30 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (3 mL, 42 mmol). The mixture was stirred for 3 h at RT then concentrated to dryness at 40° C. under vacuum. The residue was coevaporated twice with CH2Cl2 (20 mL) at 40° C. under vacuum to give of 3-(chloromethyl)-N,N,6-trimethylquinolin-2-amine hydrochloride RBO 35154 as a yellow solid (558 mg, 50% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:22]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=2[Cl:31])=[C:21]([F:32])[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH2:13][C:14](=[O:20])[N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O.CCOC(C)=O>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:22]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]3[N:11]([CH2:12][CH2:13][C:14](=[O:20])[N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[CH:10]=[N:9][C:8]=3[C:21]=2[F:32])=[C:25]([Cl:31])[CH:26]=1
Reactant: COC(=O)c1cc2c(ncn2CCC(=O)N2CCCC2)c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(ncn2CCC(=O)N2CCCC2)c(F)c1Nc1ccc(Br)cc1Cl
Reaction time: 16 h
Yield: 104.3 %

Procedure:
To a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-(3-oxo-3-pyrrolidin-1-yl-propyl)-3H-benzoimidazole-5-carboxylic acid methyl ester (41 mg, 0.079 mmol) in THF/H2O (1.5 mL/0.75 mL) is added 0.20 mL (0.20 mmol) of 1 N aqueous LiOH at room temperature. The resulting solution is stirred 16 hours. The reaction mixture is acidified with 1 N aqueous HCl (pH ˜2 to 3) and diluted with EtOAc. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give a crude product (42 mg) which is directly used without further purification.
Reaction SMILES: ClC1C=CC(CN2C(=O)C(COS(C)(=O)=O)=CC(C3C=CC4OCCC=4C=3)=N2)=CC=1.[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([C:40]3[CH:41]=[C:42]([C:47]([O:49]C)=[O:48])[C:43](=[O:46])[NH:44][N:45]=3)=[CH:39][C:34]=2[CH2:33][CH2:32]1.[Cl:51][C:52]1[CH:61]=[CH:60][C:55]([CH:56]=[CH:57][CH2:58]Cl)=[CH:54][CH:53]=1>>[C:47]([C:42]1[C:43](=[O:46])[N:44]([CH2:58][CH:57]=[CH:56][C:55]2[CH:60]=[CH:61][C:52]([Cl:51])=[CH:53][CH:54]=2)[N:45]=[C:40]([C:38]2[CH:37]=[CH:36][C:35]3[O:31][CH2:32][CH2:33][C:34]=3[CH:39]=2)[CH:41]=1)([OH:49])=[O:48]
Reactant: ClCC=Cc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(-c2ccc3c(c2)CCO3)n[nH]c1=O
Agent: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccc(Cl)cc2)c1=O
Product: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(CC=Cc2ccc(Cl)cc2)c1=O
Yield: 44.4 %

Procedure:
The general procedure of Example 1 (3) was carried out by use of 6-(2,3-dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorocinnamyl chloride, to thereby yield the title compound as an orange powder (yield: 44.4%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26](C)[C:27](=O)OC(C)(C)C)[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10]([C:35]1[CH:40]=[C:39]([Cl:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].O.[ClH:45]>C1COCC1>[ClH:41].[ClH:45].[ClH:41].[Cl:41][C:39]1[CH:40]=[C:35]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[C:13]3[NH:14][C:15]2[CH:20]=[N:19][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26][CH3:27])[CH2:22]3)=[CH:17][CH:16]=2)[CH:36]=[C:37]([Cl:43])[C:38]=1[OH:42]
Reactant: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CNC1CCN(c2ccc(Nc3c(C(C)=O)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Temperature: 65 °C
Yield: 257 %

Procedure:
To a solution of tert-butyl (1-(5-((3-acetyl-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-4-yl)amino)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (94 mg, 0.15 mmol) in THF (5 mL) was added water (3 mL) and HCl (6 M in water, 2 mL, 12 mmol). The reaction mixture was heated at 65° C. for 4 h, cooled to room temperature and concentrated. The resultant residue was purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TEA). The residue was dissolved in methanol (5 mL) and HCl (6 M in water, 1.0 mL, 6 mmol) was added. The resultant solution was concentrated to give the desired product (81.2 mg, 85%) as an orange solid. 1H NMR (500 MHz, MeOD) δ 9.32 (s, 1H), 8.32-8.25 (m, 2H), 8.13-8.05 (m, 2H), 8.03-7.97 (m, 1H), 7.37 (s, 2H), 7.22 (d, J=9.1 Hz, 1H), 4.17-4.07 (m, 2H), 4.00-3.90 (m, 2H), 3.86-3.77 (m, 1H), 2.84 (s, 3H), 2.79 (s, 3H), 2.71-2.60 (m, 1H), 2.48-2.38 (m, 1H). ESI MS m/z 522 [C27H25Cl2N5O2+H]+; HPLC 97.5% (AUC), tR=10.00 min.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=O.C([O:32]CC)C>>[CH2:23]([CH:20]1[CH2:21][CH2:22][N:17]([CH:15]([NH:1][C:2]2[CH:12]=[CH:11][C:5]3[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=3[CH:3]=2)[CH:14]=[O:32])[CH2:18][CH2:19]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOCC
Reactant: Nc1ccc2c(c1)OCC(=O)N2
Reactant: O=C(CCl)N1CCC(Cc2ccccc2)CC1
Product: O=CC(Nc1ccc2c(c1)OCC(=O)N2)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 7-amino-4H-benzo[1,4]oxazine-3-one and 2-chloro-1-(4-benzyl-piperidin-1-yl)-ethanone (Example 200a) according to the method described in Example 142b. Melting Point: 172-175° C. (diethylether).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CCN(C(C)C)C(C)C.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C1C=CN=CC=1)C.CS(C)=O.O>[NH2:1][C:2]1[C:3]([C:9]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: Nc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Nc1ncc(Br)nc1C(=O)Nc1ccccc1
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
A mixture of 3-amino-6-bromo-pyrazine-2-carboxylic acid (3.5 g, 16.05 mmol), 1,1′-carbonyldiimidazole (5.205 g, 32.10 mmol), DIPEA (2.282 g, 3.075 mL, 17.66 mmol) and DMAP (98.04 mg, 0.8025 mmol) were combined in DMSO (131 mL) and stirred for 30 min. Aniline (1.495 g, 1.463 mL, 16.05 mmol) was then added and the resulting solution stirred at RT for 18 hours. After this time water was added and the product collected by filtration to give a brown powder (3.5 g, 74% Yield).