Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:20]([N+:21]([O-])=O)=[CH:19][C:5]2[S:6](=[O:18])(=[O:17])[C:7]3[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([Br:16])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[Sn](Cl)Cl.[H][H].CO>[Pd].[Fe].[Zn].C(O)(=O)C.COCCO.C(O)CC.C(O)C>[Br:1][C:2]1[C:20]([NH2:21])=[CH:19][C:5]2[S:6](=[O:18])(=[O:17])[C:7]3[CH:12]=[C:11]([NH2:13])[C:10]([Br:16])=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc2c(cc1Br)-c1cc(Br)c([N+](=O)[O-])cc1S2(=O)=O
Agent: [Fe]
Agent: [Pd]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cc2c(cc1Br)-c1cc(Br)c(N)cc1S2(=O)=O
Reaction time: 2 h

Procedure:
Referring to Scheme II, a mixture of 2,8-dibromo-3,7-dinitrodibenzothiophene-5-oxide 3a and 2,8-dibromo-3-nitrodibenzothiophene-5-oxide 3b was treated in a heterogeneous solvent mixture which include but not limited to acetonitrile, carbon tetrachloride and water, p-dioxane and water, acetonitrile, tetrahydrofuran and water; with an oxidizing agent which include but not limited to sodium periodate and ruthenium(III) chloride; stirred at a temperature range from 15-75° C. until completion as indicated by TLC to yield 2,8-dibromo-3,7-dinitrodibenzothiophene-5,5-dioxide 9 as the isolated product. Treating 2,8-dibromo-3,7-dinitrodibenzothiophen-5,5-dioxide 9 with a reducing agent which include but are not limited to powdered iron, tin (II) chloride, zinc metal or palladium on charcoal with hydrogen in alcoholic solvents which include but are not limited to methyl alcohol, ethyl alcohol, propyl alcohol or 2-methoxy-ethanol and the like; and an organic acid which includes but is not limited to acetic acid; at a temperature range from 50-120° C. for about 2 hours or until completion to give 2,8-dibromo-5,5-dioxo-5H-5λ6 -dibenzothiophene-3,7-diamine 10.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][NH2:18])[CH3:14].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][NH:18][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:3]=1[O:2][CH3:1])[CH3:14]
Reactant: CCOC(CN)OCC
Reactant: COc1cccc(C=O)c1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(CNCc1cccc(OC)c1OC)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,3-dimethoxybenzaldehyde (2 g, 12 mmol) in MeOH (50 mL) was added aminoacetaldehyde diethyl acetal (1.49 mL, 12 mmol) and acetic acid (1.03 mL, 18 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added to a stirred solution of sodium cyanoborohydride (829 mg, 13 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. Then H2O and ethyl acetate were added to the reaction mixture. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was used next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([CH2:15][NH2:16])[CH2:14][CH2:13]1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:16][CH2:15][CH:12]2[CH2:14][CH2:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: NCC1CC1
Product: O=[N+]([O-])c1cc(Br)ccc1NCC1CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
A mixture of 1,4-dibromo-2-nitrobenzene (750 mg, 2.7 mmol) and cyclopropanemethylamine (579 μL, 6.7 mmol) was stirred at 80° C. for 18 h. The mixture was purified by column chromatography on silica gel (ethyl acetate as eluent) to afford the title compound (723 mg, 100%) as an orange solid.
Reaction SMILES: [C:1]([NH:8][C:9]1[C:18]([N+:19]([O-:21])=O)=[CH:17][C:16]([S:22]([NH:25][C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:27])(=[O:24])=[O:23])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14]2)([C:3]([O:5]CC)=O)=[O:2]>C(O)C.[Pt]>[C:26]([NH:25][S:22]([C:16]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]2[NH:8][C:1](=[O:2])[C:3](=[O:5])[N:19]([OH:21])[C:18]=2[CH:17]=1)(=[O:24])=[O:23])([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:27]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(S(=O)(=O)NC(=O)C(=O)OCC)c2c1CCCC2
Agent: [Pt]
Solvent: CCO
Product: CCOC(=O)C(=O)NS(=O)(=O)c1cc2c([nH]c(=O)c(=O)n2O)c2c1CCCC2

Procedure:
A suspension of 5-ethoxalylamino-8-ethoxalylaminosulfonyl-1,2,3,4-tetrahydro-6-nitronaphthalene (0.61 g, 1.3 mmol) in 100 ml of ethanol was hydrogenated at room temperature and atmospheric pressure in the presence of 60 mg of 5% platinum on carbon. After the theoretical absorption, the mixture was filtered and the filtrate was evaporated to dryness. The crude product (0.51g) was triturated with 50 ml of water, filtered off and then washed with water and a small amount of cold ethanol affording 0.28 g (53%) of the title compound. M.p. 267° C. decomp. (DSC); IR (KBr): 1725 cm-1 ; 1H-NMR (DMSO-d6): 1.23 (t,J=7Hz, 3H, CH3), 1.57-1.93 (m, 4H, 2CH2), 2.63-3.20 (m, 4H, 2CH2), 4.20 (q,J=7Hz, 2H, CH2), 7.98 (s, 1H, ArH), 11.5 (broad s, 1H, NH, only one exchangeable proton could be seen).
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]([CH3:21])=[C:8]2[CH2:22][C:23]([NH:25]N)=[O:24])=[O:4])N>[Ni].CCO>[NH2:1][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]([CH3:21])=[C:8]2[CH2:22][C:23]([NH2:25])=[O:24])=[O:4]
Reactant: Cc1c(CC(=O)NN)c2cc(C(=O)NN)ccc2n1Cc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: Cc1c(CC(N)=O)c2cc(C(N)=O)ccc2n1Cc1ccccc1

Procedure:
Using the method described in Example 3, Part D, 40 mg (0.11 mmol) of 5-hydrazinocarbonyl-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid hydrazide was hydrogenolized using approximately 1 g of Raney nickel in 50 mL of EtOH to give after chromatography on silica (gradient, CH2Cl2→8% MeOH/CH2Cl2) 17 mg (50% yield) of 5-aminocarbonyl-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[OH:22])=[O:20])=[CH:14][CH:13]=1)[CH:7]=[CH:6]2.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35](=[O:36])[NH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([N:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[OH:22])=[O:20])=[CH:16][CH:17]=1)[CH:7]=[CH:6]2)[CH3:39]
Reactant: Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1

Procedure:
The title compound can be synthesized from 1-[4-(5-aminoindol-1-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea hydrochloride and ethyl chloroformate by using the same techniques as in Example 41.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1F)[CH:21]=[O:22].[OH-].[Na+]>CS(C)=O>[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:9][CH3:10])[CH:4]=1)[CH:21]=[O:22]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CCc1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1cc(Oc2ccc(C=O)cc2Br)ccc1Cl
Temperature: 50 °C
Reaction time: 0.02 h

Procedure:
To a solution of DMSO (10 mL) was added 4-chloro-3-ethylphenol (5 g, 31.9 mmol), followed by potassium carbonate (11.0 g, 79.8 mmol). After 1 minute, 3-bromo-4-fluorobenzaldehyde (6.48 g, 31.9 mmol) was added in one portion, and the reaction heated to 50° C. for 5 hours. The reaction was diluted by addition of 1M NaOH solution (100 mL), and extracted into ethyl acetate (3×100 mL). The combined organic layers were then dried over magnesium sulfate, filtered, and concentrated in vacuo to leave a crude pink oil. The crude material was purified by column chromatography (silica), eluting with 4:1 heptane:ethyl acetate, the title compound as a white solid (8.22 g, 76%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1(=[O:23])[O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[CH2:21]([OH:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][OH:23]
Reactant: O=C1CCCCCCCCCCCCCCO1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCCCCCCCCCCCCCO
Reaction time: 1 h

Procedure:
Lithium aluminium hydride (1.52 g, 40.0 mmol, 2.0 eq.) was suspended in dry THF (80 mL) under an argon atmosphere. A solution of 15-pentadecanolide (4.80 g, 20.0 mmol) in dry THF (200 mL) was added at 0° C. Stirring was continued at this temperature for 1 h and for 3 more hours at r.t. Potassium sodium tartrate solution (20%, 50 mL) was added dropwise to the stirred reaction mixture. The phases were separated and the aqueous phase was extracted with diethyl ether (3×100 ml). The combined organic layers were dried over MgSO4. The solvent was removed in vacuo and the product was isolated as a white solid, which was used for the next step without purification. Yield: 4.68 g (96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH2:33][CH2:34][C:35]1[S:36][CH:37]=[CH:38][CH:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:32][CH2:33][CH2:34][C:35]4[S:36][CH:37]=[CH:38][CH:39]=4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCCc1cccs1
Product: O=C(NCCc1cccs1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(2-aminoethyl)thiophene as in General Procedure 10 to give the title compound. LCMS: m/z=556.91 (M+H™); retention time=0.92 minutes.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:5]([C:4](=[O:22])[C:3]([OH:23])=[O:2])=[CH:6][CH:7]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)C(=O)c1ccc(OCCCc2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCCc2ccc(F)cc2)cc1
Yield: 77.6 %

Procedure:
A mixture of 4-[[3-(4-fluorophenyl)propyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.58 g) in methanol and 0.5N sodium hydroxide (8 mL) was treated as in Example 19. Extraction provided 0.55 g which solidified and was crystallized from diethyl etherhexane to give 0.43 g of colorless 4-[[3-(4-fluorophenyl)propyl]oxy]-alpha-oxobenzeneacetic acid, mp 77°-78° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:16]=[C:15]3[NH:40][C:41](=[O:58])[C:42]2[CH:47]=[CH:46][C:45]([N:48]([CH2:50][CH2:51][N:52]([CH3:54])[CH3:53])[CH3:49])=[CH:44][C:43]=2[N+:55]([O-])=O)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C1CCCCC=1>[Pd].O1CCOCC1>[NH2:55][C:43]1[CH:44]=[C:45]([N:48]([CH2:50][CH2:51][N:52]([CH3:54])[CH3:53])[CH3:49])[CH:46]=[CH:47][C:42]=1[C:41]([NH:40][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([S:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)(=[O:11])=[O:10])[CH:13]=2)[N:17]([C:21]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:16]=1)=[O:58]
Reactant: CN(C)CCN(C)c1ccc(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: C1=CCCCC1
Product: CN(C)CCN(C)c1ccc(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)c(N)c1
Temperature: 85 °C
Reaction time: 5 h
Yield: 94.4 %

Procedure:
A mixture of N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-2-nitro-benzamide (1.0 g, 1.25 mmol), cyclohexene (2 mL), 1,4-dioxane (50 mL) and 10% Pd/C (0.1 g) was stirred at 85° C. for 5 hours. More cyclohexene (3 mL) and 10% Pd/C (0.2 g) were then added and the mixture stirred at 90° C. for additional 6 hours. The reaction mixture was then cooled to room temperature and filtered over celite washing thoroughly with ethanol. The filtrate was evaporated to dryness affording the title compound as a pale brown solid (910 mg, 94% yield).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:12]1[CH:13]=[CH:14][C:15]([OH:23])=[C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=1)[O:4][Si:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7].[Br:24][C:25]1[CH:42]=[CH:41][C:28]([O:29][CH2:30][C:31](ON2C(=O)CCC2=O)=[O:32])=[CH:27][CH:26]=1>O1CCCC1>[Br:24][C:25]1[CH:42]=[CH:41][C:28]([O:29][CH2:30][C:31]([NH:1][CH2:2][C@@H:3]([C:12]2[CH:13]=[CH:14][C:15]([OH:23])=[C:16]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])[CH:17]=2)[O:4][Si:5]([CH2:6][CH3:7])([CH2:10][CH3:11])[CH2:8][CH3:9])=[O:32])=[CH:27][CH:26]=1
Reactant: O=C(COc1ccc(Br)cc1)ON1C(=O)CCC1=O
Reactant: CC[Si](CC)(CC)O[C@@H](CN)c1ccc(O)c(NS(C)(=O)=O)c1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)O[C@@H](CNC(=O)COc1ccc(Br)cc1)c1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of N-[5-((R)-2-azido-1-triethylsilyloxyethyl)-2-benzyloxyphenyl]methanesulfonamide (1.84 g) and 10% palladium-carbon (0.18 g) in methanol (15 mL) /methylene chloride (15 mL) was stirred at room temperature for 5 hrs under an atmosphere of hydrogen. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to afford N-[5-((R)-2-amino-1-triethylsilyloxyethyl)-2-hydroxyphenyl]methanesulfonamide as a crude product. The crude N-[5-((R)-2-amino-1-triethylsilyloxyethyl)-2-hydroxyphenyl]methanesulfonamide was dissolved in tetrahydrofuran (40 mL), and 2,5-dioxopyrrolidin-1-yl (4-bromophenoxy)acetate (1.39 g) was added to the solution. After being stirred at room temperature for 3 hrs, the reaction mixture was concentrated in vacuo, and the residue was purified by medium-pressure silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to afford the title compound (1.01 g).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][N+:7]([O-])=O>CO.[Ni]>[C:10]1([CH:5]2[CH2:6][NH:7][C:3](=[O:2])[CH2:4]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccccc1
Agent: [Ni]
Solvent: CO
Product: O=C1CC(c2ccccc2)CN1

Procedure:
A solution of 4-nitro-3-phenyl-butyric acid methyl ester (4.02 g, 18 mmol) and Raney-Nickel (6 ml, slurry in water) in methanol (30 ml) was stirred under hydrogen atmosphere for 3 hours. After filtration using celite and removal of the solvent under reduced pressure, residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, and then dried over sodium sulfate. The solvents were removed under reduced pressure, and the residue was dissolved in toluene (50 ml) and the resulting solution was refluxed for 6 hours. Removal of the solvent afforded crude 4-phenyl-pyrrolidin-2-one. A solution of crude 4-phenyl-pyrrolidin-2-one in tetrahydrofuran (20 ml) was added to a solution of lithium aluminum hydride (1.34 g, 35.3 mmol) and the mixture was refluxed for 6 hours. After quenching the reaction with 20% aqueous sodium hydroxide, a solution of di-tert-butyl dicarbonate (4.14 g, 19 mmol) was added and the mixture was stirred for 3 hours. Aqueous citric acid and aqueous potassium hydrogen sulfate was added to acidify the solution, and the solution was extracted with toluene. The organic layer was washed with water, aqueous sodium bicarbonate, brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified with silica gel column chromatography (eluent; hexane/ethyl acetate=9/1) to afford 1-tertbutoxycarbonyl-3-phenyl-pyrrolidine (1.84 g, 42%).
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16]C(=O)[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([N:35]5[CH2:39][CH2:38][NH:37][C:36]5=[O:40])[CH:30]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1>C1COCC1>[CH3:1][C:2]1([CH3:41])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:16])[CH2:13][NH:14][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[C:31]([N:35]4[CH2:39][CH2:38][NH:37][C:36]4=[O:40])[CH:32]=[CH:33][CH:34]=3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCc4cccc(N5CCNC5=O)c4)C(=O)O3)ccc2O1
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3cccc(N4CCNC4=O)c3)ccc2O1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 36.2 %

Procedure:
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-(6-{4-[3-(2-oxoimidazolidin-1-yl)phenyl]butoxy}hexyl)-1,3-oxazolidin-2-one (113 mg) was stirred in THF (8 ml) while purging with a vigorous stream of nitrogen for 3 min. Potassium trimethylsilanolate (285 mg) was added and the mixture was stirred at 80° C. under nitrogen for 0.75 h. MeOH (10 ml) was added and then the solvents were removed under reduced pressure. The residue was dissolved in MeOH and applied to a silica Bond Elut cartridge (10 g) which was preconditioned in CH2Cl2 eluting with CH2Cl2, 5% MeOH—CH2Cl2, 2% increasing to 10% 2M NH3 in MeOH—CH2Cl2 to give the title compound (39 mg). LCMS RT=2.94 min
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:20]=[C:11]2[N:12]([CH2:16][C:17]([OH:19])=O)[CH2:13][CH2:14][CH2:15][N:10]2[C:9](=[O:21])[N:8]=1.CCN(C(C)C)C(C)C.CN(C(O[N:43]1N=N[C:45]2[CH:46]=CC=N[C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)CC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:20]=[C:11]2[N:12]([CH2:16][C:17]([NH:43][CH2:44][CH2:45][CH3:46])=[O:19])[CH2:13][CH2:14][CH2:15][N:10]2[C:9](=[O:21])[N:8]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)CN1CCCn2c1cc(OCc1ccc(F)c(F)c1)nc2=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCN
Product: CCCNC(=O)CN1CCCn2c1cc(OCc1ccc(F)c(F)c1)nc2=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 5.7 %

Procedure:
To a solution of 2-(8-((3,4-difluorobenzyl)oxy)-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidin-1-yl)acetic acid (300 mg, 0.854 mmol), Hunig's base (0.597 mL, 3.42 mmol) and HATU (487 mg, 1.281 mmol) in tetrahydrofuran (10 mL) was added propan-1-amine (76 mg, 1.281 mmol). The reaction mixture was stirred at 20° C. for 2 hours. The solution was concentrated and purified by MDAP, to afford title compound (20 mg, 0.049 mmol, 5.69% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:18]([CH3:24])[CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[C@H:13]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:12][C@@H:11]1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:61].N1C=CC=CC=1>CCOCC.CCCCCC.C(#N)C>[CH3:1][O:2][C:3](=[O:40])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:18]([CH3:24])[CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[C@H:13]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:12][C@H:11]1[Cl:61]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](OC2CCCCO2)C(C)CC=C(C)C)[C@H](OC2CCCCO2)C[C@@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](OC2CCCCO2)C(C)CC=C(C)C)[C@H](OC2CCCCO2)C[C@H]1Cl
Reaction time: 0.17 h

Procedure:
A solution of 1.09 g of (5Z,13E)-(8R,9S,11R,12R,15S,16RS)-9-hydroxy-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-5,13,18-prostatrienoic acid methyl ester, 760 mg of triphenylphosphine, and 14.5 ml of a solution of 0.97 ml of carbon tetrachloride, 0.79 ml of pyridine, and 48 ml of acetonitrile were agitated under argon at room temperature for 69 hours. The mixture was then diluted with 15 ml of ether and 30 ml of hexane, further stirred for 10 minutes, and filtered. The residue from the evaporation was extracted with a mixture of 5 ml of ether and 95 ml of hexane, filtered, and evaporated to dryness under vacuum. The residue was purified by column chromatography on silica gel with hexane/20-33% ethyl acetate as the eluent, thus isolating 1.04 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[NH:22][C:21](=[O:28])[C:20]2=[CH:29]OC.CCOC(C)=O.O>CN(C)C=O>[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[NH:22][C:21](=[O:28])[C:20]2=[CH:29][NH:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([CH3:15])=[N:4]2)=[CH:9][CH:10]=1
Reactant: Cc1nn(-c2ccc(N)cc2)c(C)c1Cl
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)c(C)c1Cl
Yield: 31.6 %

Procedure:
The 4-(4-Chloro-3,5-dimethyl-pyrazol-1-yl)-phenylamine (130 mg, 0.58 mmol) and 6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (120 mg, 0.43 mmol) is heated in N,N-dimethylformamide (10 mL) at 100° C. for 4 h. EtOAc (100 mL) and H2O (20 mL) is then added. The EtOAc layer is washed with H2O (3×20 mL) and brine (15 mL) and dried over MgSO4. Upon removal of EtOAc, precipitate formed and the precipitate is collected and washed with MeOH and Et2O and dried to provide the title compound (64 mg, 32%). 1H NMR (400 MHz, DMSO) δ 12.56(1H, d, J=12.4 Hz), 11.46 (1H, s), 8.98 (1H, d, J=12.4 Hz), 8.50 (1H, s), 7.43-7.94 (6H, m), 2.30 (3H, s), 2.21 (3H, s); MP: 290-291° C.; Anal. Cacl. for C21H16BrClN4O2: C, 53.47; H, 3.42; N, 11.88. Found: C, 51.49; H, 2.94; N, 11.31.