Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([C:14](=[O:31])[NH:15][C:16]2([C:19]3[CH:24]=[C:23]([CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[CH:22]=[CH:21][N:20]=3)[CH2:18][CH2:17]2)[CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[N:26]1([CH2:25][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([C:16]3([NH:15][C:14]([C:11]4([NH2:10])[CH2:12][CH2:13]4)=[O:31])[CH2:17][CH2:18]3)[CH:24]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(NC1(C(=O)NC2(c3cc(CN4CCCC4)ccn3)CC2)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC1(C(=O)NC2(c3cc(CN4CCCC4)ccn3)CC2)CC1
Reaction time: 16 h
Yield: 85 %

Procedure:
In a 100 mL one neck round bottom flask, {1-[1-(4-Pyrrolidin-1-ylmethyl-pyridin-2-yl)-cyclopropylcarbamoyl]-cyclopropyl}-carbamic acid benzyl ester (67 mg, 0.154 mmol) was dissolved in MeOH (10 mL). 10 Wt. % Pd/C (15 mg) was then added. Nitrogen gas was bubbled through the suspension for 10 min. The reaction flask was evacuated and then filled with H2. This purging process was repeated twice and then the reaction was allowed to stir for 16 h under H2 (1 atm). The reaction mixture was filtered through celite. The filtrate was concentrated in vacuo to afford 39.3 mg of the title compound as a white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([OH:26])[CH3:25])[CH:19]=3)[N:12]=2)=[CH:9][CH:10]=1)=[O:5].[CH3:28][Mg]Br>C1COCC1>[OH:26][CH:24]([C:20]1[CH:19]=[C:18]([NH:17][C:13]2[N:12]=[C:11]([C:8]3[S:7][C:6]([C:4](=[O:5])[CH3:28])=[CH:10][CH:9]=3)[CH:16]=[CH:15][N:14]=2)[CH:23]=[CH:22][CH:21]=1)[CH3:25]
Reactant: CON(C)C(=O)c1ccc(-c2ccnc(Nc3cccc(C(C)O)c3)n2)s1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2ccnc(Nc3cccc(C(C)O)c3)n2)s1
Temperature: -78 °C
Yield: 0.2 %

Procedure:
5-{2-[3-(1-Hydroxy-ethyl)-phenylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid methoxy-methyl-amide (30 mg, 78 μmol) was dissolved in 5 mL of dry THF and cooled to −78° C. Methylmagnesium bromide (3M in ether, 130 μl, 390 μmol) was added dropwise. The mixture was slowly warmed to room temperature and stirred until all the starting material was consumed (LCMS). The reaction mixture was quenched by addition of a saturated ammonium chloride solution and passed through a Varian Chem Elut cartridge. The crude product was concentrated and purified via flash chromatography (hexanes/ethyl acetate+10% methanol gradient) and preparative HPLC (water/acetonitrile gradient) to give 6.6 mg of 1-(5-{2-[3-(1-Hydroxy-ethyl)-phenylamino]-pyrimidin-4-yl}-thiophen-2-yl)-ethanone as a yellow solid (0.19 μmol, 25%). 1H NMR (500 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.56 (d, J=5 Hz, 1H), 8.07 (d, J=4 Hz, 1H), 7.99 (d, J=4 Hz, 1H), 7.83 (s, 1H), 7.61 (m, 1H), 7.43 (d, J=5 Hz, 1H), 7.25 (t, J=8 Hz, 1H), 6.98 (d, J=8 Hz, 1H), 5.13 (bs, 1H), 4.71 (q, J=6.5 Hz, 1H), 2.57 (s, 3H), 1.36 (d, J=6.5 Hz, 3H). MS: m/z 340 (M+H+).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[OH:9][CH2:10]C1C(O)=C(CO)C=C(C)C=1.O.O.C(O)(=O)C(O)=O.CCOCCOC(C)=O.C=O>O>[C:1]1([CH:10]=[O:9])[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[OH:7]
Reactant: Cc1cccc(O)c1
Reactant: Cc1cc(CO)c(O)c(CO)c1
Agent: C=O
Agent: O=C(O)C(=O)O
Solvent: CCOCCOC(C)=O
Solvent: O
Product: Cc1cccc(O)c1C=O
Temperature: 70 °C

Procedure:
A phenolic resin rich in alternating phenolic copolymer block segments was formed by reacting a mixture of 519.0 g of 99 percent pure m-cresol, 538.2 g 97 percent pure 2,6-bis(hydroxy-methyl)-p-cresol and 20 g oxalic acid dihydrate in a solvent mixture of 40 ml deionized water and 200 ml ethyl cellosolve acetate. The reaction mixture was heated to about 70° C. to initiate the reaction forming the alternating copolymer. At 102° C. 32 6 g of 36 9 percent formaldehyde was added in 8 minutes to the reaction mixture to form substantially m-cresolformaldehyde block segments and to chemically bond these segments to the previously formed alternating copolymer. After heating the mixture at reflux for three hours, the amount of heat was increased to remove the water and solvent by distillation. Partial vacuum was applied at about 220° C. and gradually increased to 4 mm Hg to remove the unreacted monomers. Maximum mixture temperature during vacuum stripping was about 226° C. The copolymer was poured from the reaction kettle and allowed to cool. About 840 g of a block copolymer having a number average molecular weight number, Mn, of 1241 Daltons and a Tg of 112° C. were obtained.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([NH2:22])([CH2:20][OH:21])[CH2:18][OH:19])=[CH:13][CH:14]=1.[ClH:23].[C:24]([OH:28])(=[O:27])[CH2:25][CH3:26]>C(OCC)(=O)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH2:22])([CH2:18][OH:19])[CH2:20][OH:21])=[CH:11][CH:10]=1.[ClH:23].[C:24]([O-:28])(=[O:27])[CH2:25][CH3:26]
Reactant: CCC(=O)O
Agent: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC(=O)[O-]
Temperature: 25 °C

Procedure:
In an alternative procedure, FTY720 free base (2.27 mmol) was dissolved in ethyl acetate (16 ml) at 88-90° C. Then a solution of propionic acid (2.5 eq) in ethyl acetate (3 ml) was added at 70° C., whereupon the product started to crystallize out immediately after addition. The resulting suspension was cooled to room temperature. The product was collected by filtration and was washed with ethyl acetate (2 ml). After drying at 50° C. the product was obtained as white crystals in 96.9% yield.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(OC(=O)C)(=O)C.[Br:16]Br.S([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:16][C:5]1[CH:4]=[CH:3][C:2]([NH2:7])=[C:1]([NH2:8])[CH:6]=1
Reactant: Nc1ccccc1N
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(Br)cc1N
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A mixture of o-phenylenediamine (5 g, 46.2 mmol), acetic acid (40 ml) and acetic anhydride (10.4 g, 102 mmol) was cooled in ice water, to which a solution of bromine (8.9 g, 55.4 mmol) in acetic acid (10 ml) was added and the reaction mixture was stirred for 40 minutes at 50°-55° C. and then the mixture was poured into a solution of sodium hydrogensulfite (1.5 g) in ice water (300 ml).
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:4][C:3]1([CH3:8])[C:5](Cl)=[O:6].[CH2:10]([OH:12])[CH3:11]>S(=O)(=O)(O)O>[F:1][C:2]1([F:9])[CH2:4][C:3]1([CH3:8])[C:5]([O:12][CH2:10][CH3:11])=[O:6]
Reactant: CC1(C(=O)Cl)CC1(F)F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(C)CC1(F)F
Yield: 87 %

Procedure:
35 ml of ethanol are added dr.COPYRGT.pwise at 20° C. to 15.45 g (0.1 mol) of 2,2-difluoro-1-methyl-cyclopropanecarbonyl chloride, with stirring. After the addition of 2 drops of concentrated sulphuric acid, the reaction mixture is refluxed for another hour. Excess ethanol is subsequently distilled off, and the residue is dried and distilled under atmospheric pressure. In this manner, 14.2 g (87% of theory) of ethyl 2,2-difluoro-1-methyl-cyclopropane-carboxylate are obtained in form of a liquid of boiling point 141°-143° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[OH:32]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:26]3[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=3[F:24])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: Oc1ccc(F)cc1F
Product: COc1ccc(-c2cc(Oc3ccc(F)cc3F)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0.613 mmol) and 2,4-difluorophenol were reacted as starting materials at 120° C. for 13 hours and post-treatment was then conducted, whereby the title compound was obtained as a colorless crystalline powder (136 mg, 52.5%). Melting point: 141.7-142.5° C. (diethyl ether-hexane).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.Cl[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O.C(OCC)(=O)C>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])[C:11](=[O:22])[N:10]([CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:8]=2[N:9]=1
Reactant: ClCCCc1ccccc1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(CCCc3ccccc3)c2n1
Temperature: 60 °C
Yield: 57.2 %

Procedure:
To a suspension of NaH (60% in mineral oil, 58 mg) in 10 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (320 mg, 1.04 mmol). The mixture was heated to 60° C. resulting in a clear solution. 1-Chloro-3-phenylpropane (260 μL, 1.81 mmol) was added, and the reaction mixture was heated at 60° C. for 35 minutes, then poured onto ice water. The resulting gummy solid was dissolved in ethyl acetate, washed with water, and dried over magnesium sulfate. Filtration, followed by concentration in vacuo, gave an oil that was purified by flash chromatography, eluting with 1:3 hexane:ethyl acetate to provide 345 mg of crude product. Recrystallization from ethyl acetate and hexane followed by drying in vacuo provided 253 mg (57%) of 2-amino-6-(2,6-dichlorophenyl)-8-(3-phenylpropyl)-8H-pyrido[2,3-d]pyrimidin-7-one; mp 161°-163° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[C:23]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)(=[O:25])[CH3:24].C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:3]=[C:2]([C:30]4[CH:31]=[CH:32][C:27]([NH:26][C:23](=[O:25])[CH3:24])=[N:28][CH:29]=4)[CH:7]=[CH:6][CH:5]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
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: COCCOC
Solvent: O
Product: CC(=O)Nc1ccc(-c2cccc(-n3c4c(c5cc(C)ccc53)CN(C)CC4)c2)cn1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 2-acetamidopyridine-5-boronic acid pinacol ester (147 mg, 0.560 mmol) and K2CO3 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield N-(5-(3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)pyridin-2-yl)acetamide. 1H NMR (TFA salt, CD3OD) d (ppm): 8.6 (s, 1H), 8.18 (s, 2H), 7.8 (d, 1H), 7.62-7.77 (m, 2H), 7.42 (d, 1H), 7.3 (s, 1H), 7.17 (d, 1H), 7.03 (d, 1H), 4.7 (d, 1H), 4.42 (d, 1H), 3.8 (m, 1H), 3.58 (m, 1H), 3.0-3.2 (m, 5H), 2.41 (s, 3H), 2.2 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26](C)[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([CH2:38][S:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([CH2:38][S:39]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[O:55])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4ccccn4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)c4ccccn4)cc2)CCN3CCC)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 17.4 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyridinylsulfanyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.40 g) was dissolved in methylene chloride (12 ml), and m-chloroperbenzoic acid (217 mg) was added to the solution at 0° C., and the mixture was stirred at 0° C. for 20 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(2-pyridinylsulfinyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 185) (70 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[C:21]([O:32][CH2:33][CH3:34])=[CH:22][C:23]([Cl:31])=[C:24]([S:26]([NH:29][CH3:30])(=[O:28])=[O:27])[CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:35](Cl)([Cl:37])=[O:36].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:31][C:23]1[C:24]([S:26](=[O:28])(=[O:27])[NH:29][CH3:30])=[CH:25][C:20]([C:10]2[N:9]([C:35]([Cl:37])=[O:36])[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]=2)=[C:21]([O:32][CH2:33][CH3:34])[CH:22]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc(Cl)c(S(=O)(=O)NC)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In an analogous manner as described in example 29, 5-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-2-chloro-4-ethoxy-N-methyl-benzenesulfonamide was treated with phosgene and diisopropylethylamine in methylene chloride to give 2-(4-chloro-2-ethoxy-5-methylsulfamoyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride. The crude carbamoyl chloride was then reacted with 1-hydroxybenzotriazole hydrate and diisopropylethylamine in methylene chloride to give the racemic 2-(4-chloro-2-ethoxy-5-methylsulfamoyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carboxylic acid benzotriazol-1-yl ester after purification by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:12][C:13]1[C:14]([CH3:24])=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([O:18][CH3:19])=[O:17].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[C:14]([CH3:24])=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([O:18][CH3:19])=[O:17])=[O:9]
Reactant: COC(=O)c1ccc(C)c(N)c1C
Reactant: O=C(O)c1cc(Br)ccc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(Br)ccc2F)c1C
Reaction time: 0.17 h
Yield: 51.9 %

Procedure:
To a solution of 5-bromo-2-fluoro-benzoic acid (500 mg, 2.28 mmol) in CH2Cl2 (15 mL) at 0° C. are added methyl 3-amino-2,4-dimethylbenzoate (409 mg, 2.28 mmol, see preparation 10) and N,N-diisopropylethylamine (737.6 mg, 5.71 mmol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 1.74 g, 2.74 mmol) is added via syringe and stirred at 50° C. After 16 hours, the solvent is removed under reduced pressure and the residue is triturated with MeOH to give the title compound as a white solid (450 mg, 51.8%). Mass spectrum (m/z): 380.2 (M+1).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:10](Cl)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:10]2=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)Cl)(c2ccccc2Sc2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)N1CCC2(CC1)C(=O)c1ccccc1Sc1ccccc12

Procedure:
A solution of 14 g of 1-acetyl-4-(2-phenylthiophenyl)piperidine-4-carbonyl chloride in 500 ml of methylene chloride is slowly added with stirring to 7.5 g of aluminum chloride. After total addition, the reaction mixture is refluxed for 2 hours. Thereafter, ice is added before extracting thrice with chloroform. The combined chloroform extracts are successively washed with dilute alkali, washed with water, dried and the solvent is removed under vacuum, providing 10,11-dihydro-1'-acetyl-11-oxospiro[dibenz(b,f)thiepin-10,4'-piperidine].
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1>C(O)C>[NH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][N:2]([CH3:13])[CH3:1])=[CH:9][CH:8]=1
Reactant: CN(C)Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CN(C)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.7 %

Procedure:
In ethanol (100 ml) was dissolved dimethyl-4-nitrobenzylamine (20.7 g), and to the mixture was added dried 10% palladium on carbon (1.00 g). Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 20 hours. The palladium was filtered off, and the filtrate was concentrated. The residue was separated and purified with column chromatography (ethyl acetate) to give 4-aminobenzyldimethylamine (8.75 g) as pale yellow oil.
Reaction SMILES: P(Br)(Br)([Br:3])=O.O=[C:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]#[N:18])[C:11]=2[CH:10]=[CH:9][NH:8]1>ClCCCl>[Br:3][C:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]#[N:18])[C:11]=2[CH:10]=[CH:9][N:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: N#Cc1cccc2c(=O)[nH]ccc12
Solvent: ClCCCl
Product: N#Cc1cccc2c(Br)nccc12

Procedure:
Phosphorus oxybromide (6.7 g) was added to a suspension of 1-oxo-1,2-dihydro-5-isoquinolinecarbonitrile (2 g) in 1,2-dichloroethane (100 ml). The resulting suspension was heated under reflux overnight. The solvent was removed in vacuo and the residue was washed with aq NaHCO3 (2N, 2×15 ml) to afford, after drying, the title compound (2.27 g). δH (DMSO-d6, 400 MHz): 7.99 (2H, m), 8.54 (3H, m).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH3:9])[C:5](=[O:10])[CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([NH:17]C(=O)C)=[CH:13][CH:12]=1.Cl>>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([N:3]2[CH2:4][C:5](=[O:10])[N:6]([CH2:7][CH2:8][CH3:9])[C:2]2=[O:1])=[CH:16][CH:15]=1
Reactant: CCCN1C(=O)CN(c2ccc(NC(C)=O)cc2)C1=O
Agent: Cl
Product: CCCN1C(=O)CN(c2ccc(N)cc2)C1=O
Yield: 90 %

Procedure:
A mixture of 19.5 parts of N-[4-(2,4-dioxo-3-propyl-1-imidazolidinyl)phenyl]acetamide and 480 parts of concentrate hydrochloric acid was stirred and refluxed for 5 hours. The reaction mixture was cooled, the precipitated product was filtered off and dissolved in a mixture of methanol and water. The solution was neutralized with a sodium hydrogen carbonate solution and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated, yielding 15 parts (90%) of 1-(4-aminophenyl)-3-propyl-2,4-imidazolidinedione; mp. 133.2° C. (23).
Reaction SMILES: [C:1]([C@:3]1([OH:25])[C:8](=[CH2:9])[CH2:7][C@H:6]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:4]12[CH3:5])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:23])[CH2:16][CH2:17]1)[C:12](=[CH2:24])[CH2:11]3)#[CH:2].[O:26]=[Si]=O.C([O-])(=O)C.[Na+]>O>[C:1]([C@:3]1([OH:25])[C:8](=[CH2:9])[CH2:7][C@H:6]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:4]12[CH3:5])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:23])[CH2:16][CH2:17]1)[C:12](=[CH2:24])[CH2:11]3)(=[O:26])[CH3:2]
Reactant: C#C[C@]1(O)C(=C)C[C@H]2[C@@H]3CC(=C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: O=[Si]=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC(=C)[C@@]3(O)C(C)=O)[C@@]2(C)CCC(=O)C=C12
Temperature: 45 °C

Procedure:
9.0 Kg of 17α-ethynyl-17β-hydroxy-6,16-dimethyleneandrost-4-en-3-one is added to a reactor vessel, flushed with nitrogen until the oxygen content is less than 4%. 108 Liters (85.3 Kg) of acetone is added and the solution heated to 45° C. A catalyst solution (prepared by the addition of 0.72 liters conc. sulfuric acid to 10.8 liters of deionized water, followed by the addition of 576 grams of mercuric oxide, red powder to the dilute acid) is added to the reaction mixture and stirred at 45° C. until the reaction is complete, as monitored by TLC. The reaction mixture is cooled to less than 25° C. and 2.3 Kg Celite 545, 2.2 Kg sodium acetate and 20 liters of water added and mixture stirred for 15 min. The resulting crude product is filtered using a pot filter coated with Celite 545. The reactor is rinsed with 50 liters of acetone and filtered. The combined filtrate is concentrated under vacuum to about 50 liters, cooled to below 20° C. and stirred for 15 min. The slurry is filtered and the filter cake washed with 10 liters of acetone and 20 liters of water. The filter cake is dried in a vacuum oven at 50° C. to yield 17α-acetyl-17β-hydroxy-6,16-dimethyleneandrost-4-en-3-one (mercury content 10,500 ppm).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].NC1C=CC(CN2CCN(C(OC(C)(C)C)=O)[C@@H](C)C2)=CC=1.[OH-].[K+]>>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:6]2[CH2:5][CH2:4][N:3]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([CH3:1])[CH2:7]2)=[CH:10][CH:11]=1
Reactant: C[C@@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C
Agent: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Product: C[C@@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Reaction time: 0.67 h

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2R)-2-methyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D4) using a method similar to that described for D2 in Description 2 although aq. 2M KOH solution was used in place of solid KOH and the reaction time was 40 minutes. MS (ES): MH+ 306.2, MNa+ 328.2.
Reaction SMILES: Br[CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[CH3:10][O:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=1[OH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][O:20][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=1[O:11][CH3:10])[CH3:6]
Reactant: CCOC(CBr)OCC
Reactant: COc1cccc(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(COc1cccc(OC)c1OC)OCC
Temperature: 140 °C
Reaction time: 24 h
Yield: 87.7 %

Procedure:
2-bromo-1,1-diethoxyethane (0.097 mol) was added to a mixture of 2,3-dimethoxyphenol (0.097 mol) and potassium carbonate (0.097 mol) in N,N-dimethylacetamide (200 ml). The reaction mixture was stirred for 24 hours at 140° C. The solvent was evaporated. The residue was partitioned between 1,1'-oxybisethane and a solution of NaOH in water. The organic layer was separated, washed with a saturated NaCl solution, dried (MgSO4), filtered and the solvent was evaporated, yielding 23 g (87.7%) of 1-(2,2-diethoxyethoxy)-2,3-dimethoxybenzene (interm. 1).