Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Mg].II.[CH2:12]([N:19]1[CH2:28][CH2:27][C:22]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(I)C.C1C=CC=CC=1.CCOCC>[CH2:12]([N:19]1[CH2:20][CH2:21][C:22]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])([O:26][CH2:25][CH2:24][OH:23])[CH2:27][CH2:28]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCCCCBr
Reactant: c1ccc(CN2CCC3(CC2)OCCO3)cc1
Agent: II
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CCI
Product: CCCCCCCC1(OCCO)CCN(Cc2ccccc2)CC1

Procedure:
A solution of 101.5 g of n-heptyl bromide in 300 ml was added over 1 hour under a nitrogen atmosphere to a flask containing 9.6 g of magnesium turnings, 50 ml of ether, 3 drops of ethyl iodide and an iodine crystal and the mixture was stirred for 1 hour. A solution of 46.6. g of 8-benzyl-1,4-dioxa-8-azaspiro [4,5] decane in 1 liter of anhydrous benzene was added to the resulting solution and after removal of the ether, the mixture was refluxed for 16 hours. The solution was then cooled and 20 ml of water followed by 400 ml of a saturated aqueous ammonium chloride solution was added with stirring. The organic phase was decanted and the solvent was distilled under reduced pressure. The residue was rectified to obtain 40 g of 2-(1-benzyl-4-heptyl-4-piperidyloxy)-ethanol as an oil distilling between 150° to 200° C. The oil was used as is for the next step.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[Br:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH:29][C:30]([CH:32]=[CH:33][C:34](O)=[O:35])=[O:31])[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:15]=[CH:16][CH:17]=1.CCN(C(C)C)C(C)C.[CH2:46]([O:48][C:49]([CH2:51][N:52]([CH2:54][CH2:55][CH2:56][NH2:57])[CH3:53])=[O:50])[CH3:47]>CN(C)C=O.O>[Br:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH:29][C:30](=[O:31])[CH:32]=[CH:33][C:34]([NH:57][CH2:56][CH2:55][CH2:54][N:52]([CH2:51][C:49]([O:48][CH2:46][CH3:47])=[O:50])[CH3:53])=[O:35])[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CN(C)CCCN
Reactant: O=C(O)C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(C)CCCNC(=O)C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
106 mg of benzotriazol-1-yl-N-tetramethyl-uronium-tetrafluoroborate and 68 mg of 1-hydroxybenzotriazole are added to a solution of 200 mg of 4-[(3-bromophenyl)amino]-6-{[(2-carboxyvinyl)carbonyl]amino}-quinazoline in 2.5 ml of dimethyl-formamide. The solution is stirred for 20 minutes at ambient temperature, then 0.5 ml of Hünig's base and 148 mg of 3-{N-[(ethoxycarbonyl)methyl]-N-methylamino}propylamine, dissolved in 0.5 ml of dimethylformamide, are added. The reaction mixture is stirred for a further two hours at ambient temperature before being poured onto 50 ml of water for working king up. The aqueous phase is extracted with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The crude product is purified by chromatography on a silica gel column with methylene chloride/ethanol (20:1 to 9:1). Yield: 106 mg (39% of theory), Melting point: 278-279° C. Mass spectrum (ESI*): m/z=569, 571 [M+H]*
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][C@@H:13]([CH3:15])[C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:23][C:9]2=3)=[CH:4][CH:3]=1.Br[C:34]1[CH:35]=[CH:36][C:37](=[O:41])[NH:38][C:39]=1[CH3:40].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][C@@H:13]([CH3:15])[C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][C:22]([C:34]4[CH:35]=[CH:36][C:37](=[O:41])[NH:38][C:39]=4[CH3:40])=[CH:23][C:9]2=3)=[CH:4][CH:3]=1
Reactant: Cc1[nH]c(=O)ccc1Br
Reactant: Cc1nnc2n1-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1N(c1ccc(Cl)cc1)C[C@H]2C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1[nH]c(=O)ccc1-c1ccc2c(c1)N(c1ccc(Cl)cc1)C[C@@H](C)c1nnc(C)n1-2
Yield: 16.8 %

Procedure:
To a solution of (R)-6-(4-chlorophenyl)-1,4-dimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (100 mg, 0.22 mmol) in dioxane/water (11 mL, dioxane/water=10:1) was added 5-Bromo-6-methyl-1H-pyridin-2-one (51 mg, 0.27 mmol), cesium carbonate (145 mg, 0.44 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17 mg, 0.022 mmol) under nitrogen atmosphere. The mixture was stirred and heated to reflux overnight. The mixture was cooled down and poured into water (30 mL) and extracted with ethyl acetate (20 ml×3). The combined organic phase was concentrated, and the residue was purified by HPLC (Mobile phase A: water with 0.05% ammonia solution; Mobile phase B: MeCN; column temperature: 30° C., Gradient: 25-55% B, 15 min) to give (R)-5-(6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)-6-methylpyridin-2(1H)-one as a white solid (16 mg, 17%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:31]([O:33]CC)=[O:32].[OH-].[Na+].C1COCC1.Cl>C(OCC)(=O)C.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:31]([OH:33])=[O:32]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCc4ccc(Cl)c(Cl)c4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Yield: 75.6 %

Procedure:
ethyl 6-chloro-7-(4-(3,4-dichlorobenzylcarbamoyl)phenoxy)chroman-4-carboxylate (69.0 mg, 0.129 mmol) was reacted with 1.0 molar sodium hydroxide (516 μL, 0.516 mmol) in a 3:1 THF:Ethanol solution (0.05 M). After 2 hours the reaction was diluted with ethyl acetate, neutralized with 1.0 molar hydrochloric acid (542 μL, 0.542 mmol) and partitioned between saturated aqueous sodium chloride The organic layer was dried with sodium sulfate, filtered, concentrated, and dried under high vacuum to provide the title compound (49.4 mg, 0.0975 mmol, 75.6% yield) as a solid.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[N:5]12[CH2:12][CH2:11][CH:8]([CH2:9][CH2:10]1)[C@@H:7]([NH:13][C:14]([C:16]1[O:17][C:18]3[CH:24]=[C:23](Br)[CH:22]=[CH:21][C:19]=3[CH:20]=1)=[O:15])[CH2:6]2.N1CCCC1.[OH-].[Na+]>[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.C1COCC1>[N:5]12[CH2:12][CH2:11][CH:8]([CH2:9][CH2:10]1)[C@@H:7]([NH:13][C:14]([C:16]1[O:17][C:18]3[CH:24]=[C:23]([C:3]#[C:2][CH2:1][OH:4])[CH:22]=[CH:21][C:19]=3[CH:20]=1)=[O:15])[CH2:6]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2o1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Na+]
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(C#CCO)cc2o1

Procedure:
A mixture of 289 mg (5.15 mmol) of propargyl alcohol, 150 mg (0.43 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzofuran-2-carboxamide (Example 2A), 1.6 mg (0.01 mmol) of copper(I) iodide, 15 mg (0.02 mmol) of bis(triphenylphosphine)palladium(II) chloride, 61 mg (0.86 mmol) of pyrrolidine and 1 ml of THF is heated under reflux overnight. The crude product is mixed with 10 ml of 1N sodium hydroxide solution and extracted three times with a total of 100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate, and the solvent is removed under reduced pressure. The crude product is purified on silica gel 60 (Merck, Darmstadt; eluent: dichloromethane/triethylamine 100:1, then dichloromethane/methanol/triethylamine 100:1:1 to dichloromethane/methanol/triethylamine 100:10:1). The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 40 mg (27% of theory) of the title compound are isolated.
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1.[C:33]([O:37][C:38]([NH:40][NH2:41])=[O:39])([CH3:36])([CH3:35])[CH3:34]>[Cu](I)I.CN(C=O)C>[C:33]([O:37][C:38]([N:40]([C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1)[NH2:41])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Ic1ccc(-n2cccn2)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(N)c1ccc(-n2cccn2)cc1
Temperature: 80 °C
Reaction time: 21 h
Yield: 82.8 %

Procedure:
Copper iodide (18 mg, 0.05 eq, 0.09 mmol), 1,10-phenanthroline (67 mg, 0.2 eq, 0.37 mmol) and caesium carbonate (0.84 g, 1.4 eq, 2.6 mmol) were mixed in a RB flask, placed under vacuum and purged with N2 (g). 1-(4-Iodo-phenyl)-1H-pyrazole (0.5 g, 1.0 eq, 1.85 mmol), hydrazine carboxylic acid tert-butyl ester (0.3 g, 1.2 eq, 2.22 mmol) and DMF (25 ml) were added to the mixture which was then heated to 80° C. with stirring under an inert atmosphere for 21 hours. The reaction mixture was allowed to cool and was then filtered through a silica pad, which was then washed with ethyl acetate. The filtrate was then concentrated to dryness in vacuo. The resultant residue was purified by column chromatography using heptane/ethyl acetate (3:1) as eluent to yield impure title compound (0.42 g). LCMS: [M+H]+=275, rt=1.25 min, 48% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:8]=2)=[C:4]([F:27])[CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[C:43]1([CH2:49][C:50]([N:52]=[C:53]=[S:54])=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(OCC)C>C(O)C.CCCCCC>[F:27][C:4]1[CH:3]=[C:2]([NH:1][C:53]([NH:52][C:50](=[O:51])[CH2:49][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[S:54])[CH:26]=[CH:25][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:8]=1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: CCOCC
Solvent: CCCCCC
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ncn2)CC1
Reaction time: 0.08 h
Yield: 16.8 %

Procedure:
3-[6-(4-Amino-2-fluorophenoxy)pyrimidin-4-yl}-1-methyl-1-(1-methylpiperidin-4-yl)urea (50 mg) was dissolved in ethanol (1 ml), and then D-10-camphorsulfonic acid (62.3 mg) was added thereto, followed by stirring for 5 min. Phenylacetyl isothiocyanate (toluene solution, 0.355 M, 0.565 ml) was added thereto, followed by stirring further for 1 hr. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (0.5 ml)-hexane (2.0 ml) was then added to suspend a solid. The solid was filtered off and dried under aeration to provide the titled compound (12.4 mg, 16.8%) as pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([O:13][C@H:14]2[CH2:19][CH2:18][NH:17][CH2:16][C@H:15]2[O:20][CH3:21])=[O:12])=[CH:4][C:3]=1[Cl:22].Cl[CH2:24][CH2:25][CH2:26][C:27]([C:29]1[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=1)=[O:28].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CC(C)CC(=O)C>[NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([O:13][C@H:14]2[CH2:19][CH2:18][N:17]([CH2:24][CH2:25][CH2:26][C:27](=[O:28])[C:29]3[CH:30]=[C:31]([O:39][CH3:40])[C:32]([O:37][CH3:38])=[C:33]([O:35][CH3:36])[CH:34]=3)[CH2:16][C@H:15]2[O:20][CH3:21])=[O:12])=[CH:4][C:3]=1[Cl:22]
Reactant: CO[C@@H]1CNCC[C@@H]1OC(=O)c1cc(Cl)c(N)c2c1OCC2
Reactant: COc1cc(C(=O)CCCCl)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COc1cc(C(=O)CCCN2CC[C@H](OC(=O)c3cc(Cl)c(N)c4c3OCC4)[C@H](OC)C2)cc(OC)c1OC
Yield: 27.8 %

Procedure:
A mixture of intermediate (6) (2.3 g), 4-chloro-1-(3,4,5-trimethoxyphenyl)-1-butanone (2 g), sodium carbonate (2.1 g) and potassium iodide (catalytic quantity) in 4-methyl-2-pentanone (150 ml; previously dried over MgSO4) was stirred and refluxed overnight. The reaction mixture was cooled, washed with water, dried over MgSO4, filtered and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2, upgrading to CH2Cl2 /(CH3OH/NH3) 97/3). The pure fractions were collected and the solvent was evaporated. The residue was dissolved in methanol and converted into the ethanedioic acid salt with ethanedioic acid (0.6 g). The mixture was boiled, then cooled and the precipitate was filtered off and recrystallized from 2-propanol. The precipitate was dissolved in aqueous NH4OH/CH2Cl2. The organic layer was separated, dried over MgSO4, filtered and the solvent was evaporated. The residue was stirred in boiling diisopropylether, cooled and the resulting precipitate was filtered off and dried (vacuum; 80° C.), yielding 1.10 g of (±)-cis-3-methoxy-1-[4-oxo-4-(3,4,5-trimethoxyphenyl)butyl]-4-piperidinyl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate (28%); mp. 132.3° C. (compound 1). In a similar manner there were also prepared:
Reaction SMILES: [CH2:1](O)[CH3:2].[Br:4][C:5](=[CH:9][OH:10])[C:6](=[O:8])[CH3:7]>C1(C)C=CC=CC=1>[Br:4][C:5](=[CH:9][O:10][CH2:1][CH3:2])[C:6](=[O:8])[CH3:7]
Reactant: CC(=O)C(Br)=CO
Reactant: CCO
Solvent: Cc1ccccc1
Product: CCOC=C(Br)C(C)=O
Yield: 100 %

Procedure:
A mixture of 400 ml absolute ethanol and 60 ml toluene was heated to reflux and 20 ml of azeotrope was removed via a Dean Stark trap. To the ethanol-toluene solution was added 33.0 g (0.2 mol) of 3-bromo-4-hydroxy-3-buten-2-one and reflux was continued for 2 hours during which period three aliquots of 20 ml of ethanol-toluene were removed via the trap. The solution was concentrated in vacuo to give 38.6 g (100%) of 3-bromo-4-ethoxy-3-buten-2-one as a mobile oil. nmr (DMSOd-6) (δ): 8.21 (s, 1H); 4.23 (q, 2H); 2.33 (s, 3H); 1.31 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][NH:13][C@@H:12]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.CCOC(C)=O>[Br:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][N:13]([C:24]3[N:25]=[CH:26][C:27]([C:30]([OH:39])([C:31]([F:32])([F:33])[F:34])[C:35]([F:37])([F:38])[F:36])=[CH:28][N:29]=3)[C@@H:12]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:11]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(c1ccc(Br)s1)N1CCN[C@@H](CC2CCOCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(Br)s1)N1CCN(c2ncc(C(O)(C(F)(F)F)C(F)(F)F)cn2)[C@@H](CC2CCOCC2)C1
Temperature: 100 °C
Reaction time: 16 h
Yield: 46.2 %

Procedure:
A mixture of (3S)-1-((5-bromo-2-thiophenyl)sulfonyl)-3-(tetrahydro-2H-pyran-4-ylmethyl)piperazine (190 mg, 0.464 mmol, Example 133, Step 1), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (156 mg, 0.557 mmol, Intermediate D), and potassium carbonate (128 mg, 0.928 mmol) in DMF was heated at 100° C. and stirred for 16 h. The mixture was diluted with water (20 mL) and EtOAc (20 mL). The layers were separated and the organics were washed with water (20 mL) and brine (20 mL). The organic extracts were dried over MgSO4, filtered, and concentrated. The crude material was absorbed onto silica gel and purified via column chromatography (40 g silica gel, 0 to 100% EtOAc in hexanes) to give (S)-2-(2-(4-(5-bromothiophen-2-ylsulfonyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)pyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (140 mg).
Reaction SMILES: [CH2:1]([CH:3]([CH2:35][CH3:36])[CH:4]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:25])=[CH:20][CH:19]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2].O1CCCC1.[OH-].[Na+]>C(O)C>[CH2:35]([CH:3]([CH2:1][CH3:2])[CH:4]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[CH:22][CH:23]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:36]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2C)C(CC)CC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(CC)C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a mixture of ethyl 3-{[(4-{[2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butyl]amino}phenyl)carbonyl](methyl)amino}propanoate (261 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (231 mg, 94%) as a pale-brown solid.
Reaction SMILES: C(OC1C=C(C(F)=CC=1Cl)[NH2:8])C=C.[CH2:14]1[CH:19]2[C:20](O[C:23](=[O:24])[CH:18]2[CH2:17][CH:16]=[CH:15]1)=[O:21].C(O)(=O)C>O>[C:23]1(=[O:24])[NH:8][C:20](=[O:21])[C:19]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]1=2
Reactant: O=C1OC(=O)C2CC=CCC12
Reactant: C=CCOc1cc(N)c(F)cc1Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)C2=C1CCCC2
Temperature: 25 °C

Procedure:
A mixture of 9.0 g of 19A, 6.8 g of THPA and 100 mL of glacial acetic acid was heated at reflux temperature for 4 hours. The resulting mixture was cooled to room temperature, poured into 450 mL of water and extracted with ether. The extract phase was washed with water, dried (Na2SO4), and filtered, and the solvent was evaporated from the filtrate. The residue was flash-chromatographed on silica gel, with a 15:85 v:v mixture of ethyl acetate and hexane as eluent, to give N-(3-allyloxy)-4-chloro-6-fluorophenyl)-3,4,5,6-tetrahydrophthalimide (19B), as an orange oil.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]([CH2:8][C:9]([OH:11])=O)(C(O)=O)[OH:4].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[Na].[Na].COC(C1C=CC(O)=CC=1)=O.C(OC(C1C=CC(O)=CC=1)=O)C.C[C:60]1[C:65]2O[C@@:67](CCC[C@@H](CCC[C@@H](CCCC(C)C)C)C)([CH3:70])[CH2:68][CH2:69][C:64]=2C(C)=[C:62](OC(C)=O)[C:61]=1C>O>[CH:61]1[CH:60]=[C:65]2[CH2:64][C:69]3[CH:68]=[CH:67][CH:70]=[C:1]([OH:13])[C:2]=3[C:3](=[O:4])[C:8]2=[C:9]([OH:11])[CH:62]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Agent: CCOC(=O)c1ccc(O)cc1
Agent: COC(=O)c1ccc(O)cc1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: O
Product: O=C1c2c(O)cccc2Cc2cccc(O)c21
Temperature: 50 °C
Yield: 0.2 %

Procedure:
Separately, 1,646 g of deionized water are heated to approximately 90° C. and 18 g of citric acid are dissolved therein. To this is added 1.2 g of disodium ethylenediamine tetracetic acid and 5g of a 1.5:1 mixture of methylparaben and ethylparaben. When this aqueous mixture, which will weigh about 1,670 g and will constitute approximately 83.5% of the final composition, is homogenous, it is combined with the above hydrocarbon component in a homogenizer. When the emulsion is thoroughly blended, it is cooled to 50° C. and 0.6 g of tocopherol acetate are added. This mixture is further blended to produce 2,000 g of a 0.2% homogenous anthralin cream which maintains its formulation stability and in which the anthralin does not appear to undergo excessive degradation, e.g. less than 10% as determined by HPLC.
Reaction SMILES: C[CH2:2][N:3](C(C)C)[CH:4](C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1C2C(COC([N:54]3[CH2:62][C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[CH:55]3[C:63]([OH:65])=O)=O)C3C(=CC=CC=3)C=2C=CC=1.CNC>C(Cl)Cl.CCO>[CH3:2][N:3]([CH3:4])[C:63]([CH:55]1[C:56]2[C:61](=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH2:62][NH:54]1)=[O:65]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C1c2ccccc2CN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: CN(C)C(=O)C1NCc2ccccc21
Reaction time: 0.25 h
Yield: 204.6 %

Procedure:
1.66 g of DIPEA and then 5.73 g of BOP are added to a solution of 5 g of 2-(9-fluorenylmethoxycarbonyl)isoindoline-1-carboxylic acid (commercial) in 100 ml of DCM and the mixture is left stirring for 15 minutes at AT. 4.6 ml of a 5.6M solution of dimethylamine in EtOH are subsequently added and the mixture is left stirring for 30 minutes at AT. The reaction mixture is concentrated under vacuum, the residue is taken up in water and extracted with DCM, the organic phase is washed with a 5% KHSO4 solution and dried over Na2SO4, and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, elution being carried out with a DCM/AcOEt (70/30, v/v) mixture. 5 g of the expected product are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([CH3:23])=[N:20][C:19]=2[CH:24]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:23][C:21]1[O:22][C:18]2[CH:17]=[CH:16][C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])=[CH:24][C:19]=2[N:20]=1
Reactant: Cc1nc2cc(Br)ccc2o1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nc2cc(N3CCN(c4cnccc4C)C3=O)ccc2o1
Yield: 16.5 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 0.1 g, 0.00057 mol) was reacted with 5-bromo-2-methyl-benzooxazole (0.119 g, 0.000597 mol), 1,4-dioxane (20 mL), copper iodide (0.01 g, 0.000057 mol), trans-1,2-diamino cyclohexane (0.019 g, 0.00017 mol) and potassium phosphate (0.242 g, 0.00114 mol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3), followed by preparative HPLC afforded 29 mg of the product (16% yield).