Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24]CC5C=CC=CC=5)=[CH:20][CH:19]=4)=[N:14][C:13]=3[CH:32]=2)[S:3]1.Br.C(OCC)(=O)C.O>C(O)(=O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)=[N:14][C:13]=3[CH:32]=2)[S:3]1
Reactant: O=C1NC(=O)C(Cc2ccc3oc(Cc4ccc(OCc5ccccc5)cc4)nc3c2)S1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc3oc(Cc4ccc(O)cc4)nc3c2)S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
A mixture of 0.95 g of 5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-(4-benzyloxybenzyl)benzoxazole, 10 ml of a 25% hydrogen bromide solution in acetic acid and 10 ml of acetic acid is stirred at room temperature overnight. Ethyl acetate and water are added to the reaction mixture. The ethyl acetate layer is washed with water, dried and evaporated to remove the solvent. The residue is crystallized with n-hexane, and recrystallized from a mixture of ethyl acetate and n-hexane, whereby 0.42 g of 5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-(4-hydroxybenzyl)benzoxazole is obtained as colorless needles.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[S:31][CH:32]=[CH:33][N:34]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[S:31][CH:32]=[CH:33][N:34]=2)=[O:25])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCNCc1nccs1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CCN(Cc1nccs1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=1.C(N(CC)CC)C>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.C(O)C>[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:17])[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Br:1])[OH:5])[CH:11]=1
Reactant: O=Cc1ccccc1Br
Reactant: O=Cc1cccnc1
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(c1cccnc1)C(O)c1ccccc1Br

Procedure:
146 g (0.8 mol) of 2-bromobenzaldehyde, 85.6 g (0.8 mol) of 3-pyridinealdehyde, 20 g (0.08 mol) of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazoliumbromide and 40.4 g (0.4 mol) of triethylamine in 500 ml of ethanol were heated at 75° C. for 16 hours. Thereafter, the ethanol was distilled off and the residue was taken up in methylene chloride. The solution was washed twice with water and then extracted twice with 300 ml of 4N hydrochloric acid. The acidic aqueous phase was then rendered slightly alkaline with 4N sodium hydroxide solution and extracted three times with methylene chloride. After the solvent had been distilled off, the crude product was stirred with isopropanol, filtered off under suction and dried to give a product of melting point 105°-108° C.
Reaction SMILES: [CH:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].Cl>O1CCCC1CO>[OH:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][OH:2])=[CH:22][CH:21]=2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(OCCCCOc2ccc(C=O)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: OCC1CCCO1
Product: OCc1ccc(OCCCCOc2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.8 %

Procedure:
1,4-Bis(4-formylphenoxy)butane (3.98 g) was dissolved in 10.5 ml of tetrahydrofuran-methanol (5:1), 1.23 g of sodium borohydride was added to the solution which was cooled on ice-water, and the resulting mixture was stirred for 1.5 hours at room temperature. Then, 100 ml of 1N hydrochloric acid was added and the mixture was again stirred at room temperature to collect the thus formed precipitate by filtration. The thus obtained crude product was washed with water and methanol in that order and dried under a reduced pressure to obtain 3.38 g of 1,4-bis(4-hydroxymethylphenoxy)butane.
Reaction SMILES: ClP(C(C)(C)C)C(C)(C)C.Br[C:12]1[C:17]2=[CH:18][CH:19]=[C:20]3[C:29]([CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]4)=[CH:21]3)=[C:16]2[CH:15]=[CH:14][CH:13]=1.[CH3:30][C:31]1[CH:32]=[C:33]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[CH:39]=2)[CH:34]=[CH:35][CH:36]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:44][C:40]1[CH:39]=[C:38]([N:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([CH3:30])[CH:32]=2)[C:12]2[C:17]3=[CH:18][CH:19]=[C:20]4[C:29]([CH:28]=[C:27]5[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]5)=[CH:21]4)=[C:16]3[CH:15]=[CH:14][CH:13]=2)[CH:43]=[CH:42][CH:41]=1
Reactant: Cc1cccc(Nc2cccc(C)c2)c1
Reactant: Brc1cccc2c1ccc1cc3ccccc3cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(Cl)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(N(c2cccc(C)c2)c2cccc3c2ccc2cc4ccccc4cc23)c1
Temperature: 60 °C

Procedure:
190 μl (1 mmol) of chloro-di-tert-butylphosphine and then 112 mg (0.5 mmol) of palladium(II) acetate are added to a suspension of 15.4 g (50 mmol) of 4-bromobenz[a]anthracene, 11.8 g (60 mmol) of bis(3-methylphenyl)amine and 7.7 g (80 mmol) of sodium tert-butoxide in 500 ml of toluene, and the mixture is subsequently heated under reflux for 5 h. After the mixture has been cooled to 60° C., 500 ml of water are added, the organic phase is separated off, filtered through silica gel, evaporated virtually to dryness at 80° C. in vacuo, and 300 ml of ethanol are then added. After cooling, the solid is filtered off with suction. Recrystallisation five times from dioxane (about 8 ml/g); sublimation (p=5×10−5 mbar, T=280° C.). Yield: 11.9 g (28 mmol), 56.1%, purity 99.9% (HPLC).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[C@H:20]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[C:35]([C:40]6[CH:61]=[CH:60][C:43]7[NH:44][C:45]([C@@H:47]8[CH2:52][C@@H:51]9[C@@H:49]([CH2:50]9)[N:48]8C(OC(C)(C)C)=O)=[N:46][C:42]=7[CH:41]=6)[CH:36]=5)[N:31]=4)[CH:28]=[CH:29][C:23]=3[N:22]=2)[CH2:19][C@@H:18]2[C@H:16]1[CH2:17]2)=O)(C)(C)C.[ClH:62]>O1CCOCC1>[ClH:62].[C@@H:16]12[CH2:17][C@@H:18]1[CH2:19][C@@H:20]([C:21]1[NH:25][C:24]3[CH:26]=[C:27]([C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[C:35]([C:40]6[CH:61]=[CH:60][C:43]7[N:44]=[C:45]([C@@H:47]8[CH2:52][C@@H:51]9[C@@H:49]([CH2:50]9)[NH:48]8)[NH:46][C:42]=7[CH:41]=6)[CH:36]=5)[N:31]=4)[CH:28]=[CH:29][C:23]=3[N:22]=1)[NH:15]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2cc(-c3ccc4nc(-c5ccc6nc([C@@H]7C[C@H]8C[C@H]8N7C(=O)OC(C)(C)C)[nH]c6c5)ccc4c3)ccc2[nH]1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: c1cc2nc(-c3ccc4nc([C@@H]5C[C@H]6C[C@H]6N5)[nH]c4c3)ccc2cc1-c1ccc2nc([C@@H]3C[C@H]4C[C@H]4N3)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 187.4 %

Procedure:
A TFA salt of tert-butyl (1R,3S,5R)-3-(5-(2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-6-yl)-6-quinolinyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (51 mg, 0.054 mmol) was mixed with a dioxane solution of HCl (0.5 mL, 2.00 mmol), and stirred at rt for 2 h. The volatiles were removed to yield an HCl salt of 2,6-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoline (53 mg) as yellow solid. LC-MS retention time 1.20 min; m/z 524 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water: 10% methanol: 0.1% TFA. Solvent B=10% water: 90% methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([CH3:22])[C:13](=[O:14])[N:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11](=[O:20])[N:10]2[CH3:21])=[CH:5][CH:4]=1)#[N:2].[ClH:23].[CH2:24]([OH:26])[CH3:25]>>[ClH:23].[CH2:24]([O:26][C:1](=[NH:2])[C:3]1[CH:4]=[CH:5][C:6]([C@@:9]2([CH3:22])[C:13](=[O:14])[N:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11](=[O:20])[N:10]2[CH3:21])=[CH:7][CH:8]=1)[CH3:25]
Reactant: COC(=O)CN1C(=O)N(C)[C@@](C)(c2ccc(C#N)cc2)C1=O
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc([C@@]2(C)C(=O)N(CC(=O)OC)C(=O)N2C)cc1

Procedure:
A solution of 2.56 g of methyl (S)-(4-(4-cyanophenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetate (8.5 mmol) in 40 ml of absolute ethanol was cooled to 0° C. Dry hydrogen chloride gas was passed into the solution, the temperature always being kept below 10° C., until the nitrile band was no longer present in the IR spectrum. The ethanolic solution was concentrated to 20 ml and treated with 200 ml of diethyl ether. The suspension was concentrated and dried in a high vacuum.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14]2=[O:19])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:20]1([C:24]([C:26]2[CH:31]=[CH:30][C:29](F)=[C:28]([Cl:33])[CH:27]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].C[Si](C=[N+]=[N-])(C)C>CC(N(C)C)=O.C(O)(=O)C.CO>[N:20]1([C:24]([C:26]2[CH:31]=[CH:30][C:29]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][N:15]([CH3:18])[C:14]4=[O:19])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[C:28]([Cl:33])[CH:27]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1
Reactant: O=C(c1ccc(F)c(Cl)c1)N1CCC1
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCN(C)C2=O)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2Cl)cc(O[C@H]2CCN(C)C2=O)c1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A mixture of methyl 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 8) (265 mg, 1 mmol), azetidin-1-yl-(3-chloro-4-fluoro-phenyl)methanone (CAS no. 863454-79-9) (320 mg, 1.5 mmol) and potassium carbonate (276 mg, 2.0 mmol) in DMA (10 mL) was stirred at 120° C. for 16 hours. The solution was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with water (3×20 mL), dried (MgSO4), filtered and the solvent removed under reduced pressure. The combined aqueous extracts were acidified with 2N hydrochloric acid, extracted with a mixture of ethyl acetate and DCM (1:1, 3×20 mL), washed with brine, dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue from this was dissolved in THF (2 mL) and methanol (1 mL) and treated with 2M (trimethylsilyl)diazomethane (0.240 mL, 0.48 mmol) and stirred for 30 minutes. The solution was treated with acetic acid (1 drop), evaporated under reduced pressure. This residue was combined with that from the initial ethyl acetate extraction and purified by flash chromatography on silica eluting with 20-100% ethyl acetate in isohexane to afford the product (380 mg, 83%). m/z 459 (M+H)+
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24][C@@H:23]1[OH:35])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(Cl)(Cl)Cl.CCO>N1C=CC=CC=1>[CH3:36][S:37]([O:35][C@@H:23]1[C@@H:22]([CH2:21][O:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:26][C@@H:25]([N:27]2[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24]1)(=[O:39])=[O:38]
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)O[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 4 °C
Reaction time: 24 h

Procedure:
The product of Example 1 (59 g, 0.13 mol) was dissolved at room temperature in 120 mL of pyridine. The solution was put into an ice bath and 29 mL of methanesulfonyl chloride (0.34 mol) was added dropwise. The resulting solution was allowed to stir at 4° C. for 24 hours. The reaction mixture was added in three portions at a slow flow rate into a blender as described previously. The pea-green solid was collected by filtration, washed twice with 2 L of water, and dried to yield 58 g (93%). The compound started to soften at 85° C. and melted at 106-108° C. Rf =0.62 (CHCl3 --EtOH, 10:1). Anal. (C29H28N2O7S).
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[CH:3]=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]([Cl:6])([Cl:5])[CH:3]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)[OH:4]
Reactant: Clc1ccccc1
Reactant: O=CC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: OC(c1ccc(Cl)cc1)C(Cl)(Cl)Cl
Temperature: 1 °C

Procedure:
A mixture of chlorobenzene (1400 g) and trichloro-acetaldehyde (384 g) is stirred at 0-2° C. Aluminium chloride (274 g) is added in portions over 110 minutes at the same temperature. Occasionally cooling is necessary. The reaction mixture is stirred at 0-5° C. for 5 hours. The reaction mixture is poured into ice/water (3000 g). The organic phase is separated, washed three times with water (500 g each), dried (sodium sulfate) and evaporated. 2,2,2-Trichloro-1-(4-chloro-phenyl)-ethanol is obtained as oil.
Reaction SMILES: [CH2:1]([CH:3]1[C:8]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:14])[O:4]1)[CH3:2].[Cl:15][C:16]1[CH:17]=[C:18]([S:23]([CH2:25][CH2:26][CH2:27][CH2:28]Br)=[O:24])[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([S:23]([CH2:25][CH2:26][CH2:27][CH2:28][O:13][C:10]2[CH:11]=[CH:12][C:7]3[NH:6][C:5](=[O:14])[O:4][CH:3]([CH2:1][CH3:2])[C:8]=3[CH:9]=2)=[O:24])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CCC1OC(=O)Nc2ccc(O)cc21
Reactant: O=S(CCCCBr)c1ccc(Cl)c(Cl)c1
Product: CCC1OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 4 from 4-ethyl-6-hydroxy-4H-3,1-benzoxazin-2-one and 4-(3,4-dichlorophenylsulfinyl)butylbromide.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]2[CH2:8][CH:9]=[C:10]([CH:12]=O)[CH:11]=[C:5]2[O:4][CH2:3]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:12][C:10]3[CH:9]=[CH:8][C:6]4[NH:7][C:2](=[O:1])[CH2:3][O:4][C:5]=4[CH:11]=3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: O=CC1=CCC2NC(=O)COC2=C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1ccc(N2CCN(Cc3ccc4c(c3)OCC(=O)N4)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.8 %

Procedure:
A mixture of 3-oxo-dihydro-2H-benzo[1,4]oxazine-7-carbaldehyde (0.5 g, 2.8 mmol), 1-(4-methyl-phenyl)-piperazine (0.5 g, 2.8 mmol), acetic acid (0.17 g, 2.8 mmol) and sodium triacetoxyborohydride (1.2 g, 5.9 mmol) in 20 mL of 1,2-dichloroethane is stirred at room temperature for 3 hours. The reaction is quenched with 50 mL of water, and the layers are separated. The aqueous phase is extracted with ethyl acetate (3×50 mL). The organic phases are combined and dried over sodium sulfate. Evaporation of the solvent gives a solid which is recrystallized twice from acetonitrile to give 0.31 g (33% yield) of 7-[4-(4-methyl-phenyl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazine-3-one; mp 208-210° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6](=[O:43])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([O:28]C2CCCCO2)[CH:21]([CH3:27])[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C@H:16]([O:35]C2CCCCO2)[CH2:15][C@H:14]1[Cl:42])(=[O:4])=[O:3]>C(O)(=O)C.O.O1CCCC1>[CH3:1][S:2]([NH:5][C:6](=[O:43])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([OH:28])[CH:21]([CH3:27])[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C@H:16]([OH:35])[CH2:15][C@H:14]1[Cl:42])(=[O:3])=[O:4]
Reactant: CC(C)=CCC(C)[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)NS(C)(=O)=O)[C@H](Cl)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)=CCC(C)[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)NS(C)(=O)=O)[C@H](Cl)C[C@H]1O
Yield: 53.8 %

Procedure:
156 mg of (5Z,13E)-(8R,9R,11R,12R,15S,16RS)-9-chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-5,13,18-prostatrienoic acid methylsulfonylamide was stirred for 16 hours under argon at room temperature with 3 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10). The mixture was then evaporated under vacuum and the residue purified by column chromatography on silica gel with methylene chloride/5-30% isopropanol as the eluent, thus obtaining 62 mg of the desired compound.
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=O)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[F:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([NH:24][NH2:25])=[O:23])=[CH:20][CH:19]=1>C(O)C.O.Cl>[F:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([NH:24]/[N:25]=[C:14](/[C:11]2[NH:12][CH:13]=[C:9]([C@@H:2]([OH:1])[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6])[N:10]=2)\[CH3:15])=[O:23])=[CH:20][CH:19]=1
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Agent: Cl
Solvent: CCO
Solvent: O
Product: C/C(=N\NC(=O)c1ccc(F)cc1)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Temperature: 55 °C
Reaction time: 48 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (172 mg, 0.74 mmol) was suspended in ethanol (4 ml) and water (1 ml). 4-fluorobenzoic acid hydrazide (131 mg, 0.85 mmol, 1.1 eq.) and hydrochloric acid (one drop, 12 N) were added, and the suspension was stirred at 55° C. for 48 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The reaction mixture was cooled to room temperature, and partially concentrated in vacuo. The resulting white precipitate was collected and washed with ethanol to yield the product, as one apparent isomer, as a white solid: 97 mg (35%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1.[ClH:63]>C(Cl)Cl.C(Cl)Cl.CO>[ClH:63].[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:55][CH2:56][N:57]4[CH2:62][CH2:61][O:60][CH2:59][CH2:58]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: OCCN1CCOCC1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Diethyl azodicarboxylate (209 mg, 1.2 mmol) was added dropwise to a suspension of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (146 mg, 0.4 mmol), (prepared as described for the starting material in Example 24), triphenylphosphine (314 mg, 1.2 mmol) and 4-(2-hydroxyethyl)morpholine (79 mg, 0.6 mmol) in methylene chloride (5 ml). The mixture was stirred for 1 hour at ambient temperature and purified by column flash chromatography eluting with methylene chloride/methanol (95/5 followed by 90/10) to give a white solid. The solid was dissolved in methylene chloride/methanol and 2M ethereal hydrogen chloride (0.5 ml) was added. The mixture was concentrated by evaporation and the resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-morpholinoethoxy)quinazoline hydrochloride (155 mg, 70%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.Cl.[OH-].[NH4+]>CO>[C:22]([C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:21]=[CH:20][N:19]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccnc(C#N)c2)CC1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1cc(CCN2CCNCC2)ccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
1-Boc-4-[2-(2-cyanopyridin-4-yl)ethyl]piperazine (4.0 g, 12.64 mmol) was dissolved in methanol (60 mL) and cooled to 0° C. Concentrated hydrochloric acid (10.4 mL, 126 mmol) was added and the mixture stirred for 1 h. The solvents were removed under vacuum and co-evaporated twice with methanol, a 1:1 mixture of methanol/toluene, and finally with methanol. The residue was dried under vacuum overnight to provide crude product (4.5 g). Half of the product was dissolved in methanol, concentrated ammonium hydroxide was added, and solvents were removed under vacuum. The residue was purified by chromatography (SiO2, 100:10:1 CH2Cl2:methanol:concentrated ammonium hydroxide) to provide 1-[2-(2-cyanopyridin-4-yl)ethyl]piperazine (1.05 g, 69%).
Reaction SMILES: [CH3:1][C@@:2]([O:20]S(C)(=O)=O)([CH2:7][CH2:8][C:9]1[C:14](=O)[C:13]([CH3:16])=[C:12]([CH3:17])[C:11](=[O:18])[C:10]=1[CH3:19])[C:3]([O:5][CH3:6])=[O:4].[BH4-].[Na+].C[O-].[Na+].Cl>CO.[Cl-].[Na+].O.CCOCC>[CH3:6][O:5][C:3]([C@:2]1([CH3:1])[CH2:7][CH2:8][C:9]2[C:10]([CH3:19])=[C:11]([OH:18])[C:12]([CH3:17])=[C:13]([CH3:16])[C:14]=2[O:20]1)=[O:4]
Reactant: COC(=O)[C@@](C)(CCC1=C(C)C(=O)C(C)=C(C)C1=O)OS(C)(=O)=O
Agent: C[O-]
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 0.5 g (1.4 mmoles) of (R)-(-)-methyl 2-methyl-2-[(methylsulfonyl)oxy]-4-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1yl)butanoate in 30 ml of methanol, at room temperature, was added a solution of 20.2 mg (0.53 mmole) of sodium borohydride in 10 ml of methanol, dropwise, with stirring. After stirring at room temperature for 50 min, 5.77 ml (7.73 mmoles) of 1.34 M methanolic sodium methoxide was added and stirring was continued for 2 hr, at room temperature. The resulting solution was acidified with 1 N aqueous hydrochloric acid then poured into saturated brine and worked-up with ether in the usual manner. The crude, crystalline produce (0.34g) was chromatographed on 20 g of silica gel. Elution with 19:1 parts by volume and 9:1 parts by volume toluene-ethyl acetate gave 0.311g (84.1%) of (S)-(-)-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester as a colorless solid, mp 131°-134°; [α]D25 -60.46° (c 3.88, CH3OH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]2[C:17]([CH:18]3[CH2:28][CH:19]3[CH2:20][O:21]2)=[CH:16][CH:15]=1>N1C=CC=CC=1.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]2[C:17]([CH:18]3[CH2:28][CH:19]3[CH2:20][O:21]2)=[CH:16][CH:15]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2F)ccc2c1OCC1CC21
Reaction time: 2 h
Yield: 96.3 %

Procedure:
2,4-Difluorobenzenesulphonyl chloride (0.468 g) was added to a solution of methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylater (Intermediate 42, 0.438 g) in pyridine (2 mL) and DCM (4 mL) and the solution was left at room temperature for 2 hours. The mixture was diluted with DCM, washed with 2M hydrochloric acid, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-30% to give methyl (1aRS,7bSR)-5-(2,4-difluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.761 g) as a light coloured gum.