Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[O:17][CH:18]([F:20])[F:19])[C:10]([O:12]C)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[O:17][CH:18]([F:19])[F:20])[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(OC(F)F)c(OC2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OC(F)F)c(OC2CCCC2)c1

Procedure:
A solution of methyl 3-cyclopentyloxy-4-difluoromethoxybenzoate (0.6 g; that is prepared as described in Reference Example 41) in methanol (10 mL) is treated with potassium carbonate (0.35 g) and water (4 mL), and then it is heated at reflux for 3 hours. Methanol is evaporated off under reduced pressure, and the residue is dissolved in water (40 mL). The solution is washed with diethyl ether (40 mL), acidified with concentrated hydrochloric acid, and extracted with ethyl acetate (3×40 mL). The combined ethyl acetate extracts are dried over magnesium sulfate and evaporated under reduced pressure, to give 3-cyclopentyloxy-4-difluoromethoxybenzoic acid (0.47 g), in the form of a white solid, m.p. 126-128° C.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[N:31]1([CH2:36][CH2:37][CH2:38][NH2:39])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:36][CH2:37][CH2:38][NH:39][C:8](=[O:7])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27]([NH2:28])=[O:29])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: NCCCN1CCCC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCN3CCCC3)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 3-pyrrolidin-1-yl-propylamine by the procedure analogous to Example 1. MS (APCl, m/z): 472 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)C=C[CH:4]=[CH:3][CH:2]=1.[NH:21]1C=CC=C1B(O)O>>[NH:21]1[CH:4]=[CH:3][CH:2]=[C:1]1[C:7]1[NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=1[C:14]=23
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1ccc[nH]1
Product: O=C1NCCc2c(-c3ccc[nH]3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 1-)t-butoxycarbonyl)pyrrole-2-boronic acid (263 mg, 1.24 mmol) were coupled with concomitant removal of the BOC group to yield 2-(1H-pyrrol-2-yl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 81 mg (28% as a greenish grey solid: m.p. >400° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 3.02 (m, 2H), 3.42 (m, 2H), 6.22 (m, 1H), 6.44 (m, 1H), 6.97 (m, 1H), 7.14 (t, J=7.5 Hz, 1H), 7.49 (dd, J=8.1, 0.9 Hz, 1H), 7.64 (dd, J=7.5, 0.6 Hz, 1H), 7.98 (br t, 1H), 11.01 (br s, 1H), 11.13 (br s, 1H). MS (electrospray, MH+) 252. Anal. (C15H13N3O.0.4 H2O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[CH3:12][S-:13].[Na+].O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([S:13][CH3:12])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: C[S-]
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1nc(Cl)nc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.12 g, 5.96 mmol) in DMSO (8 mL), sodium thiomethoxide (0.500 g, 7.14 mmol) was added. The mixture was stirred at room temperature for 2 h. H2O was added to induce precipitation. The precipitate was collected and dried on vacuum to give 2-chloro-4-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine as a solid (0.90 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13]C)=[C:11]2[C:6]([CH:7]=[CH:8][C:9](C(O)=O)=[N:10]2)=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[OH:13][C:12]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: COc1ccc2ccc(C(=O)O)nc2c1OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2cccnc2c1O
Yield: 53.1 %

Procedure:
Finely ground 7,8-dimethoxyquinoline-2-carboxylic acid (1.00 g, 4.3 mmol) (W. Ried, A. Berg and G. Schmidt, Chem. Ber., 85, 204 (1952)) was heated under nitrogen in a flask submerged in an oil bath at 185° until the evolution of gases had ceased from the melt. The reaction was cooled and 75% aqueous sulfuric acid (8.1 mL) was carefully added. The resulting solution was heated at 105°-125° for 2 hr, cooled, poured over ice and taken to pH 5 with 5N sodium hydroxide. The mixture was filtered, and the filtrate was extracted with methylene chloride (4×50 mL). The extracts were dried (MgSO4) and concentrated in vacuo to give 8-hydroxy-7-methoxyquinoline (0.40 g, 53%), mp 113°-115° after recrystallization from 95% ethanol. Anal. Calcd for C10H9NO2 : C, 68.56; H, 5.18; N, 8.00. Found: C, 68.33; H, 5.17; N, 7.97.
Reaction SMILES: [CH2:1]([N:8]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2[CH:13]=[C:12]([C:23]#N)[CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=[O:26]>[Ni]>[CH2:1]([N:8]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2[CH:13]=[C:12]([CH:23]=[O:26])[CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: N#Cc1ccc2c(c1)c1ccccc1c(=O)n2Cc1ccccc1
Agent: [Ni]
Product: O=Cc1ccc2c(c1)c1ccccc1c(=O)n2Cc1ccccc1
Yield: 80 %

Procedure:
5-Benzyl-6-oxo-5,6-dihydrophenanthridine-2-carbonitrile (1.24 g) and Raney nickel (0.8 g) were suspended in 75% formic acid (25 ml). The suspension was heated under reflux for 1 hour and 40 minutes, and filtered while hot. The filtrate was concentrated and purified by silica gel chromatography (methylene chloride:methanol=50:1) to thereby obtain 1.08 g (yield: 80%) of the title compound as a colorless crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:6][S:7]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])(=[O:9])=[O:8])[CH2:4][CH3:5].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>CN(C=O)C>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][N:6]([CH2:3][CH2:4][CH3:5])[S:7]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])(=[O:9])=[O:8]
Reactant: CCCNS(=O)(=O)c1c(C)cc(C)cc1C
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCCCBr)S(=O)(=O)c1c(C)cc(C)cc1C
Yield: 95.5 %

Procedure:
NaH (60%, 0.70 g, 17 mmol), 65 (3.5 g, 14.5 mmol), and 1,4-dibromobutane (37.6 g, 174 mmol) in DMF (40 mL) were combined and worked up by the method of 43. Excess 1,4-dibromobutane was removed by a Kugelrohr apparatus under high vacuum. Column chromatography (7:1 hexane/EtOAc) produced 5.21 g (95%) of 67 as an oil: NMR δ 0.79 (t, 3 H, J=7), 1.46-1.54 (m, 2 H), 1.64-1.78 (m, 4 H), 2.30 (s, 3 H), 2.60 (s, 6 H), 3.11 (t, 2 H, J=7), 3.21 (t, 2 H, J=7), 3.31 (t, 2 H, J=7), 6.93 (s, 2 H). Anal. (C16H26BrNO2S) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=[O:4].Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:11][CH:12]=1
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)C=Cc1ccc(OCCCCCCO)cc1
Temperature: 90 °C
Reaction time: 32 h
Yield: 71.9 %

Procedure:
Methyl 4-hydroxy cinnamate (40 g, 225 mmol) was dissolved in 1-methyl-2-pyrrolidinone (NMP, 300 mL). 6-Chlorohexanol (269 mmol, 36.8 g), anhydrous K2CO3 (37.2 g, 269 mmol) and catalytic amount of KI were added. The batch was stirred at 90° C. for 32 hours. Water was added to the cooled solution, which was subsequently extracted with ethyl acetate (EtOAc, 3×200 mL). The combined organics were washed with 10% KOH (2×100 mL), brine solution and then dried over MgSO4. The concentrated product was then recrystallized from a 1:1 mixture of EtOAc/hexanes to give 45 g (72% yield) of an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][C:10]#[CH:11])=[CH:4][CH:3]=1.N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])[CH2:9][C:10]#[CH:11])=[CH:6][CH:7]=1
Reactant: C#CCC(O)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Reaction time: 0.08 h
Yield: 31.7 %

Procedure:
A solution containing 19 g (84.5 mmol) of the semi-purified reaction product of Example 1 dissolved in 50 ml of DMF was cooled to 0° C. (ice bath) and 12.9 g (190 mmol) of imidazole was added in one portion. The reaction mixture was stirred 10 minutes until all the imidazole dissolved and then was added in one portion 14.3 g (95 mmol) of t-butyldimethylchlorosilane. After stirring for 5 minutes, the ice bath was removed and the reaction mixture was stirred for an additional 2 hr. at R.T. The reaction was then poured into 500 ml of ether and washed 3× with 50 cc of H2O and 1× with 100 ml of brine. The organic layer was then separated, dried (MgSO4), and removal of all solvent yielded 29.32 g of crude product. Separation by reverse phase HPLC (gradient elution with acetonitrile-water) yielded 9.1 g of the titled product.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]=[C:7]([OH:13])[CH:6]=[CH:5]2.[CH3:21][CH:22]([Si:24](Cl)([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH3:23].C1CCN2C(=NCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]=[C:7]([O:13][Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:23])[CH3:21])[CH:6]=[CH:5]2
Reactant: Cc1cc2cc(O)ccc2c(-c2ccc(Cl)cc2)c1Br
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc2c(-c2ccc(Cl)cc2)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
6-Bromo-5-(4-chlorophenyl)-7-methylnaphthalen-2-ol (4.5 g, 12.9 mmol) was taken up in DCM (65 mL). Added to this solution were TIPSCl (4.1 mL, 19.4 mmol), DBU (3.5 mL, 23.2 mmol), and DMAP (0.16 g, 1.3 mmol). After stirring at room temperature overnight, the DCM was removed in vacuo and the residue taken up in hexane (200 mL). This solution was washed with 1 M HCl (100 mL) and the layers separated. Following extraction of the aqueous layer with hexanes, the combined organics were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The resulting residue was purified by Yamazen column chromatography (2-5% DCM/Hex) to afford 5.12 g (79%) of the title compound as a colorless syrup. 1H-NMR: 400 MHz, (CDCl3) δ: 7.61 (s, 1H); 7.49 (br d, J=8.4 Hz, 2H); 7.23 (br d, J=8.4 Hz, 2H); 7.17 (d, J=8.8 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H); 6.95 (dd, J=8.8, 2.4 Hz; 1H); 2.60 (s, 3H); 1.30 (hep, J=7.2 Hz, 3H); 1.12 (d, J=7.2 Hz, 18H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:11])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[Cl-].[Cl-].[Cl-].[Al+3].[Br:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24](Cl)=[O:25])[CH:20]=[CH:21][CH:22]=1.Cl>C(Cl)Cl>[Br:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24]([C:5]2[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([CH3:1])[NH:3][C:4]=2[CH3:11])=[O:25])[CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1cc(C)[nH]c1C
Reactant: O=C(Cl)Cc1cccc(Br)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1c(C)[nH]c(C)c1C(=O)Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of methyl 2,5-dimethyl-1H-pyrrole-3-carboxylate (0.295 g, 1.93 mmol) in anhydrous DCM (5 mL) was added dropwise to a stirred suspension of aluminum trichloride (0.714 g, 5.35 mmol) in anhydrous DCM (10 mL) at 0° C., under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes. A solution of 2-(3-bromophenyl)acetyl chloride (48) (0.500 g, 2.14 mmol) in anhydrous DCM (5 mL) was added dropwise to the stirred suspension at 0° C. The resulting suspension was allowed to warm to room temperature and then stirred at room temperature for a further 18 hours. The reaction mixture was poured onto ice (50 mL) and conc HCl (2 mL). The layers were separated and the aqueous layer extracted with DCM (2×50 mL). The combined organics were washed sequentially with 2M HCl (2×75 mL), water (50 mL), and saturated NaHCO3 (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product, which was used directly in the next stage; m/z (LC-MS, ESI−), RT=2.46 min (M−H=350.00).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][C:25]=1[N+:32]([O-:34])=[O:33])[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[C:1]([O:5][C:6]([N:8]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][CH3:35])=[CH:26][C:25]=1[N+:32]([O-:34])=[O:33])[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[CH:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(N(C(=O)OC(C)(C)C)c2ccc(CO)cc2[N+](=O)[O-])ncn1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COCc1ccc(N(C(=O)OC(C)(C)C)c2cc(N(C)C(=O)OC(C)(C)C)ncn2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 17.6 %

Procedure:
To a solution of tert-butyl (6-((tert-butoxycarbonyl)(4-(hydroxymethyl)-2-nitrophenyl)amino)pyrimidin-4-yl)(methyl)carbamate (1.5 g, 3.488 mmol) in acetone (20 mL) under an argon atmosphere at 0° C., was added potassium carbonate (0.48 g, 6.97 mmol) followed by dimethyl sulfate (0.87 g, 6.97 mmol). The resulting reaction mixture was then refluxed for 24 h and then allowed to cool to rt. The reaction mixture was concentrated under vacuum to obtain a crude residue. The residue was purified by silica gel column chromatography to afford the title compound (0.3 g, yield: 19%) as a solid. MS (ESI): 490.55 [M+H]+.
Reaction SMILES: COS([O:6][CH3:7])(=O)=O.O[N:9]=[C:10]1[NH:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[S:12][CH2:11]1.[OH-].[Na+]>C(O)C>[CH3:7][O:6][N:9]=[C:10]1[NH:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[S:12][CH2:11]1
Reactant: ON=C1CSc2ccccc2CN1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=C1CSc2ccccc2CN1
Reaction time: 24 h

Procedure:
Dimethylsulphate (1.26 g) was added dropwise to a vigorously stirred suspension of 3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine (2 g, prepared in a similar manner to Example 25 above) in a mixture of a 10% aqueous solution of sodium hydroxide (4 ml) and ethanol (150 ml). The reaction mixture was kept at room temperature for 24 hours and then extracted with dichloromethane. The organic layer was dried and the solvent was removed by evaporation. Purification of the solid residue by flash chromatography using dichloromethane as eluent gave 3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from hexane. Yield 1.51 g (m.p. 101°-102° C.).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.Cl[P:12](=[O:20])(Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>BrCCBr.O1CCCC1>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([P:12](=[O:20])([C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:5]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1ccc(P(=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 70 °C
Yield: 92.6 %

Procedure:
A slurry of magnesium (133.7 g, 5.50 mol), tetrahydrofuran (988 g), and 1,2-dibromoethane (0.1 g, 0.5 mmol) was refluxed for 20 min. under a blanket of nitrogen. 4-Bromoanisole (1002 g, 5.357 mol) was added by drop over 6 h at a rate to maintain 70° C. The reaction mixture was heated for an additional hour. Dichlorophenylphosphine oxide (479.4 g, 2.459 mol) was added by drop to maintain a temperature of 35° C. over 5 h. The reaction mixture was worked up to give bis(4-methoxyphenyl)phenylphosphine oxide (770.8 g, 93% yield) as a viscous amber oil. 31P NMR: (d6-DMSO) δ 30.2 (s).
Reaction SMILES: CS(Cl)(=O)=O.C(O[C@H:15]1[C@H:20]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])[C@@H:19]([N:26]=[N+:27]=[N-:28])[CH:18]=[C:17]([C:29]([O:31][CH3:32])=[O:30])[CH2:16]1)(=O)C1C=CC=CC=1.[CH2:33](N(CC)CC)[CH3:34]>ClCCl>[N:26]([C@@H:19]1[C@@H:20]([O:21][S:22]([CH3:25])(=[O:23])=[O:24])[C@H:15]([CH:33]=[CH2:34])[CH2:16][C:17]([C:29]([O:31][CH3:32])=[O:30])=[CH:18]1)=[N+:27]=[N-:28]
Reactant: COC(=O)C1=C[C@H](N=[N+]=[N-])[C@@H](OS(C)(=O)=O)[C@H](OC(=O)c2ccccc2)C1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: C=C[C@@H]1CC(C(=O)OC)=C[C@H](N=[N+]=[N-])[C@H]1OS(C)(=O)=O
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride can be added dropwise to a 0° C. solution of Example 13H and triethylamine in dichloromethane. The reaction mixture can be stirred for 2 hours, washed with saturated NaHCO3 solution, brine, dried (MgSO4), filtered and concentrated. The concentrate can be purified by flash chromatography to afford the desired product.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][CH:19]2[S:23][CH3:24])[C@H:15]2[C@@:6]1([F:27])[C@:7]1([CH3:26])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:25])[CH:9]=[CH:8]1)(=[O:3])[CH3:2].[CH2:28]([SH:30])[CH3:29].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>ClCCl>[C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2([S:30][CH2:28][CH3:29])[S:23][CH3:24])[C@H:15]2[C@@:6]1([F:27])[C@:7]1([CH3:26])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:25])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]
Reactant: CSC1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@]12C
Reactant: CCS
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCSC1(SC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Reaction time: 1 h

Procedure:
To a solution of 11β-acetyloxy-9-fluoro-17-(methylthio)androsta-1,4-diene-3-one (632 mg) in dry dichloromethane (20 ml) containing dry ethanethiol (0.6 ml) is added boron trifluoride etherate (0.25 ml). After one hour, the mixture is added to a NaHCO3 solution and extracted with chloroform. The chloroform solution is washed with water, dried (MgSO4 anhydrous), and evaporated to afford the title compound (620 mg) contaminated with a small amount of 11β-acetyloxy-9-fluoroandrosta-1,4-diene-3,17-dione. This material is used in the next step without further purification. A specimen crystallized from acetone-hexane shows melting point 140°-142° C. and a consistent nmr spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH2:15][OH:16])=[CH:13][N:12]=[C:11]([NH:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)[N:10]=1>FC(F)(F)C(O)=O>[NH2:20][CH2:19][CH2:18][NH:17][C:11]1[N:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:14]([CH2:15][OH:16])=[CH:13][N:12]=1
Reactant: CC(C)(C)OC(=O)NCCNc1ncc(CO)c(-c2ccc(Cl)cc2Cl)n1
Solvent: O=C(O)C(F)(F)F
Product: NCCNc1ncc(CO)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(2-{[4-(2,4-dichlorophenyl)-5-(hydroxymethyl)pyrimidin-2-yl]amino}ethyl)(tert-butoxy)carboxamide (372 mg, 0.90 mmol) was dissolved in 2 mL of anhdyrous trifluoroacetic acid and stirred at room temperature for 2 h. Evaporation of the solvent afforded {2-[(2-aminoethyl)amino]-4-(2,4-dichlorophenyl)pyrimidin-5-yl}methan-1-ol, as its trifluoracetate salt, in quantitative yield.
Reaction SMILES: [O:1]1[CH2:5][CH:2]1[CH2:3]Cl.[OH:6][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].O>C(O)C>[O:1]1[CH2:5][CH:2]1[CH2:3][O:6][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1c(-c2ccccc2)oc2c(O)cccc2c1=O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(OCC3CO3)cccc2c1=O
Reaction time: 6 h

Procedure:
7 ml of 2,3-epoxypropyl chloride was added dropwise at 20-25° C. to a stirred mixture of 5 g of 8-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 9.7 ml of 2N aqueous sodium hydroxide solution in 10 ml of ethanol. After 6 hours at 20°-25° C., the reaction mixture was poured into 100 ml of water and the precipitate which formed was collected by suction filtration. After drying and purifying by flash chromatography on silica gel (eluant petroleum ether: ethyl acetate (65:35), there was obtained 4.45 g of the title compound, m.p. 128°-129° C.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH3+:16].[CH3:17][C:18]1[O:22][C:21]([C:23](=O)[CH3:24])=[CH:20][CH:19]=1>>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH:16][CH:23]([C:21]1[O:22][C:18]([CH3:17])=[CH:19][CH:20]=1)[CH3:24]
Reactant: CC(=O)c1ccc(C)o1
Reactant: [NH3+]CCOc1ccc2ccccc2c1Cl
Agent: [Cl-]
Product: Cc1ccc(C(C)NCCOc2ccc3ccccc3c2Cl)o1
Yield: 34 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)oxy]ethanaminium chloride and 1-(5-methylfuran-2-yl)ethanone in 34% yield as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:33](=[CH:34][CH:35]=2)[O:32][C:31]([CH3:37])([CH3:36])[C:27]2([CH2:30][O:29][CH2:28]2)[C@@:14]23[CH2:18][O:17][C:16]([NH:19]C(=O)OC(C)(C)C)=[N:15]2)=[O:9])=[N:6][CH:7]=1>C1(C)C=CC=CC=1>[NH2:19][C:16]1[O:17][CH2:18][C@@:14]2([N:15]=1)[C:27]1([CH2:28][O:29][CH2:30]1)[C:31]([CH3:36])([CH3:37])[O:32][C:33]1[C:13]2=[CH:12][C:11]([NH:10][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:9])=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1OC(C)(C)C21COC1
Solvent: Cc1ccccc1
Product: CC1(C)Oc2ccc(NC(=O)c3ccc(Cl)cn3)cc2[C@@]2(COC(N)=N2)C12COC2
Temperature: 120 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
A mixture of tert-butyl [(4S)-6′-{[(5-chloropyridin-2-yl)carbonyl]amino}-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]carbamate (1.02 g, 1.93 mmol), silica gel (neutral; 3.06 g) and toluene (20.4 mL) was stirred for 3 hours at 120° C. The reaction mixture was cooled down to ambient temperature and concentrated at reduced pressure. The residue was purified with column chromatography on silica gel (CHCl3-EtOH, a linear gradient of EtOH from 0 to 15%) and then with NH-silica gel (Hexane-EtOAc, a linear gradient of EtOAc from 50 to 100%). The purified product was recrystallized from EtOH/H2O (1:1), and the solid was collected by filtration and dried at reduced pressure to give a hydrate of N-[(4S)-2-amino-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-6′-yl]-5-chloropyridine-2-carboxamide (547 mg) as a crystal.