Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([O:14][C:15]2[C:16]([O:35][CH3:36])=[CH:17][CH:18]=[C:19]3[C:24]=2[NH:23][C:22](=[O:25])[CH:21]=[C:20]3[NH:26][C:27]2[C:32]([Cl:33])=[CH:31][N:30]=[CH:29][C:28]=2[Cl:34])[CH2:13][CH2:12][CH2:11][CH2:10]1.CN(C)C=O>O>[Br:1][C:21]1[C:22](=[O:25])[NH:23][C:24]2[C:19]([C:20]=1[NH:26][C:27]1[C:32]([Cl:33])=[CH:31][N:30]=[CH:29][C:28]=1[Cl:34])=[CH:18][CH:17]=[C:16]([O:35][CH3:36])[C:15]=2[O:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OC1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)c(Br)c(=O)[nH]c2c1OC1CCCC1
Reaction time: 4 h

Procedure:
N-Bromosuccinimide (0.104 g, 0.585 mmol) was added to a solution of 4-(3,5, -dichloropyridin-4-ylamino)-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one (0.246 g, 0.585 mmol, Example 1) and anhydrous dimethylformamide (3 mL) at 0° C. After 4 h at 0° C., the mixture was poured into water, and the precipitate was filtered. Saturated sodium thiosulfate solution (1 mL) was added to a solution of the filter cake and methanol (5 mL). After the dibromo intermediate was consumed, as monitored by LCMS, the mixture was diluted with water and extracted with ethyl acetate. The organic extract was dried, filtered, and concentrated to give 3-bromo-8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one: 1H NMR (400 MHz, DMSO-d6): δ 10.56 (s, 1H), 8.88 (br s, 1H), 8.42 (s, 2H), 7.62 (d, 1H), 7.04 (d, 1H), 4.98 (m, 1H), 3.89 (s, 3H), 1.84-1.51 (m, 8H); MS (ESI): 497.8.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24](I)=[CH:23][C:3]=1[CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]1[CH2:21][CH3:22])=[O:7].C([Li])CCC.C(O)(=[O:35])C.OO>O1CCCC1>[F:1][C:2]1[CH:26]=[CH:25][C:24]([OH:35])=[CH:23][C:3]=1[CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]1[CH2:21][CH3:22])=[O:7]
Reactant: CC(=O)O
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1cc(I)ccc1F
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1cc(O)ccc1F
Temperature: -78 °C
Yield: 43 %

Procedure:
(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(2-fluoro-5-iodo-benzyl) ester (8.9 g, 18 mM) was dissolved in tetrahydrofuran (150 mL), trisopropylborate (6.7 g, 36 mM) was added and the mixture was cooled to −78° C. At this low temperature n-butyllithium (16.9 mL, 1.6N) was added drop by drop with stirring. The mixture was stirred for 45 min at −78° C., for another 45 min at −50° C. and for 15 min at 0° C. Acetic acid (9.5 mL, 50%) was added slowly with stirring (0–5° C.), followed by hydrogen peroxide (2.75 mL, 35%). Stirring continued with cooling for another 45 min and for 1 h at room temperature. The mixture was partitioned between water and diethylether, organic phases were pooled, washed with water, sodium thiosulfate solution (5%), brine and dried with Na2SO4 to yield after evaporation a light yellow oil (8.5 g). This residue was purified by column chromatography (silica gel; n-hexane/ethylacetate 1:1) to yield 3.0 g (43%) of the product as a yellowish oil. MS (ISP): 400.5 (M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][N:14]([CH2:25][CH2:26]Cl)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:26][CH2:25][N:14]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:13][CH2:12]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Reactant: C[C@H](N)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N2CCN([C@@H](C)c3ccc(Br)cc3)CC2)cc1
Temperature: 125 °C
Reaction time: 20 h
Yield: 76.4 %

Procedure:
A mixture of (S)-1-(4-bromophenyl)ethanamine (0.36 ml, 2.50 mmol) and N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (864 mg, 2.62 mmol) in DIPEA (0.873 ml, 5.0 mmol) was heated at 125° C. and stirred for 20 h. The reaction mixture was cooled to RT then diluted into DCM (30 ml) and washed with Na2CO3 2M in water (40 ml). The aqueous phase was further extracted with DCM (3×20 ml) and the combined organic fractions were dried over Na2SO4, filtered and evaporated to dryness. AcOEt was added in small portions into a hot mixture of the crude in heptane until complete dissolution. The mixture was allowed to cooled to RT during which time precipitation occurred. The mixture was cooled to 0° C. (ice bath) for 30 min then filtered. The solid was washed with heptane, dried under air and finally under high vacuum to yield the title compound (810 mg, 1.91 mmol, 77% yield) as a brownish solid. HPLC: AtRet=1.66 min; LC-MS: m/z 425.4 [M+H]+; 1H NMR (400 MHz, CDCl3): 1.29 (d, J=6.8, 3H), 2.41-2.50 (m, 5H), 2.52-2.61 (m, 2H), 2.93-3.05 (m, 4H), 3.34 (q, J=6.7, 1H), 7.09-7.16 (m, 2H), 7.31-7.37 (m, 2H), 7.39-7.44 (m, 2H), 7.61-7.66 (m, 2H).
Reaction SMILES: [C:1]1(=O)CCCC1.P([O-])([O-])([O-])=O.[BH4-].[Na+].[C:14]([O:17][CH:18]1[CH:22]([CH2:23][C:24]([OH:26])=[O:25])[CH:21]([C:27]([O:29][CH3:30])=[O:28])[CH:20]([OH:31])[CH2:19]1)(=[O:16])[CH3:15]>O.CO>[CH3:1][O:25][C:24](=[O:26])[CH2:23][CH:22]1[CH:18]([O:17][C:14](=[O:16])[CH3:15])[CH2:19][CH:20]([OH:31])[CH:21]1[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)C1C(O)CC(OC(C)=O)C1CC(=O)O
Reactant: O=C1CCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CC1C(OC(C)=O)CC(O)C1C(=O)OC
Reaction time: 2 h

Procedure:
The cyclopentanone VI (8.6 g.), obtained according to the previous example, is dissolved in 50 ml. of methanol and added to 500 ml. of a phosphate buffer adjusted to a pH of 5.3. Then 20 ml. of an aqueous solution containing an excess of sodium borohydride (1.25 g.) is added at 5° C. After two hours at room temperature, 200 ml. of water is added to the reaction mixture which is then extracted several times with ethyl acetate. The combined organic layers are dried on MgSO4 and then evaporated to dryness giving 8.4 g. (98%) of crude methylester of 5-acetoxy-2-carbomethoxy-3-hydroxycyclopentaneacetic acid. This product examined by gas chromatography exhibits an 80% purity. The product which may be further purified by column chromatography has all the substituent groups with the desired orientation. The compound may not be distilled without decomposition. The principal absorption peaks in the N.M.R. spectrum in CDCl3 occur at the following frequencies expressed in δ units: 2.05 (3H, singlet), 3.65 (3H, singlet), 3.72 (3H, singlet), 4.30-4.70 (1H, multiplet, 5.18-5.43 (1H, multiplet).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[N:24]1[CH2:28][C:27](=[O:29])[NH:26][S:25]1(=[O:31])=[O:30])[CH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16])C1C=CC=CC=1>CCO.O.[Pd]>[NH2:16][CH2:15][C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[CH2:12][C:11]1[CH:21]=[CH:22][C:23]([N:24]2[S:25](=[O:31])(=[O:30])[NH:26][C:27](=[O:29])[CH2:28]2)=[C:9]([OH:8])[CH:10]=1
Reactant: N#Cc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: NCc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
A solution of 2-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl]-benzonitrile in EtOH/water (1:1) is hydrogenated at 1 atm over 10% Pd/C for 40 min. The catalyst is filtered, the solvent evaporated and the residue purified by preparative HPLC to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O.Cl>[OH-].[Na+].CS(C)=O>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCBr
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCOc1ccc2cc(C(=O)O)ccc2c1
Temperature: 80 °C

Procedure:
A solution of 6-hydroxy-2-naphthoic acid (1.04 g) in a mixture of 10% sodium hydroxide aqueous solution (4.44 ml) and dimethyl sulfoxide (18 ml) was stirred for half an hour at 80° C. Then heptyl bromide (0.872 ml) was added thereto and stirred for 5 hours at 60° C. The reaction mixture was added to water (50 ml) and the mixture was adjusted to pH 3 with conc. hydrochloric acid. The resultant precipitate was collected by filtration and dried to give 6-heptyloxy-2-naphthoic acid (1.39 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([C@@H:13]2[CH2:21][C:16]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:15][N:14]2[C:22](=[O:32])[C@@H:23]([NH:27][C:28](=[O:31])[O:29][CH3:30])[CH:24]([CH3:26])[CH3:25])=O)=[CH:4][CH:3]=1.O1CCOCC1.C([O-])(=O)C.[NH4+:44]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:44][C:11]([C@@H:13]3[CH2:21][C:16]4([O:17][CH2:18][CH2:19][O:20]4)[CH2:15][N:14]3[C:22](=[O:32])[C@@H:23]([NH:27][C:28](=[O:31])[O:29][CH3:30])[CH:24]([CH3:26])[CH3:25])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1)OCCO2)C(C)C
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(Br)cc3)[nH]1)OCCO2)C(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
In a 5 mL seal tube, methyl (S)-1-((S)-8-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate (75 mg, 142 μmol) was combined with 1,4-dioxane (2 ml) to give a light yellow solution. Ammonium acetate (110 mg, 1.42 mmol) was added and it was stirred at 110° C. overnight. It was cooled and diluted with EtOAc(10 ml), filtered and concentrated in vacuo to afford methyl (S)-1-((S)-8-(5-(4-bromophenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate as a light brownish solid (70 mg, 96.8%). ESI-LRMS m/e calcd for C22H27BrN4O5 [M+] 507. found 508 [M+H+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C1COCC1.C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=2)[CH2:10][CH2:11]1)=[O:29]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)c3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-chlorobenzoyl chloride: ESMS m/e: 456.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16]([NH:17][C@H:18]([CH3:23])[C:19]([F:22])([CH3:21])[CH3:20])=[C:15]([C:24]([NH2:26])=[O:25])[CH:14]=[N:13][N:12]3[CH:27]=2)[CH:6]=[CH:7][CH:8]=1.[CH:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1.C(N(CC)CC)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>CN(C=O)C>[CH:28]1([C:31]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[C:11]4[C:16]([NH:17][C@H:18]([CH3:23])[C:19]([F:22])([CH3:21])[CH3:20])=[C:15]([C:24]([NH2:26])=[O:25])[CH:14]=[N:13][N:12]4[CH:27]=3)[CH:6]=[CH:7][CH:8]=2)=[O:32])[CH2:30][CH2:29]1
Reactant: O=C(O)C1CC1
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3cccc(CN)c3)cc12)C(C)(C)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3cccc(CNC(=O)C4CC4)c3)cc12)C(C)(C)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To a solution of 6-(3-(aminomethyl)phenyl)-4-(((1R)-2-fluoro-1,2-dimethylpropyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 68, 15 mg, 0.041 mmol), cyclopropanecarboxylic acid (3.40 μl, 0.041 mmol) and triethylamine (8.49 μl, 0.061 mmol) in DMF (0.5 mL) was added BOP (17.96 mg, 0.041 mmol) and the resulting mixture was stirred at rt for 30 minutes. The reaction mixture was purified by reverse-phase preparative HPLC (condition C) to yield the title compound (9.6 mg, 53%). HPLC (condition J): retention time=2.140 minute. LC/MS (M+H)+=438.2. 1H NMR (500 MHz, MeOD) δ ppm 8.08 (1 H, s), 7.86 (1 H, d, J=1.7 Hz), 7.50-7.57 (2 H, m), 7.35 (1 H, t, J=7.6 Hz), 7.19 (1 H, d, J=7.5 Hz), 7.09 (1 H, d, J=1.7 Hz), 4.39-4.49 (3 H, m), 1.54-1.61 (1 H, m), 1.51 (3 H, d, J=3.6 Hz), 1.44-1.48 (6 H, m), 0.89-0.95 (2 H, m), 0.72-0.78 (2 H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=[C:13]2[N:12]=[C:11]([CH3:23])[C:10]=1[C:24]([O:26]C(C)(C)C)=[O:25].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=[C:13]2[N:12]=[C:11]([CH3:23])[C:10]=1[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(C(=O)OC(C)(C)C)c(C)nc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(C(=O)O)c(C)nc2n1
Temperature: 60 °C
Yield: 100.3 %

Procedure:
To a stirred solution of 6-tert-butyl 2-ethyl 5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2,6-dicarboxylate (1.14 g, 2.53 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL). The reaction was heated to 60° C. for 30 h and concentrated under reduced pressure to obtain 5-(2,4-dichlorophenyl)-2-(ethoxycarbonyl)-7-methylimidazo[1,2-a]pyrimidine-6-carboxylic acid (1 g, 100% crude yield) as a yellow oil.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[C:27](/[CH3:31])=[CH:28]\[CH2:29][OH:30])[C:21]=1[CH3:32])([C:14]([CH3:17])([CH3:16])[CH3:15])([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.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[C:27](/[CH3:31])=[CH:28]\[CH2:29][O:30][S:41]([CH3:40])(=[O:43])=[O:42])[C:21]=1[CH3:32])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C/C(=C/CO)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/C(=C/COS(C)(=O)=O)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a mixture of 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((Z)-3-hydroxy-1-methyl-1-propenyl)benzene (120 mg) and triethylamine (32.8 mg) in dichloromethane (1.2 ml) was dropwise added methanesulfonyl chloride (34 mg) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. The mixture was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacua to give 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((Z)-3-methanesulfonyloxy-1-methyl-1-propenyl)benzene (132 mg) as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH3:9].[Br:10]Br>[W]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: Cc1cc(Br)ccc1Br
Reactant: BrBr
Agent: [W]
Product: BrCc1cc(Br)ccc1Br
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
33 g (0.1 mole) 2,5-dibromo toluene is placed in a 100 ml three-necked flask, fitted with a reflux condenser, a sealed mechanical stirrer, and a separatory funnel with the stem reaching nearly to the bottom of the flask. The flask is illuminated with two 300-watt tungsten lamps during the reaction. The flask is heated in an oil bath to 150° C., and 18.4 g (5.9 ml, 0.115 mole) bromine is added over two hours. The mixture is stirred for an additional 10 minutes, and the contents, while still liquid, are poured into a 500 ml round-bottom flask containing 300 ml of hot light petroleum ether and 2 g decolorizing carbon. A reflux condenser is attached, and the mixture is heated to reflux until the material dissolves, then rapidly filtered through a pre-heated Buchner funnel. The filtrate is cooled and washed with cold light petroleum.
Reaction SMILES: C([O:5][P:6]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:7][CH2:8][CH2:9][CH2:10][CH3:11])CCC.Cl[C:18]([O:20][CH3:21])=[O:19]>>[CH3:21][O:20][C:18]([P:6](=[O:5])([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:19]
Reactant: COC(=O)Cl
Reactant: CCCCOP(OCCCC)OCCCC
Product: CCCCOP(=O)(OCCCC)C(=O)OC

Procedure:
From 26.6 g (0.10 mole) of tri-n-butylphosphite and 18.9 g (0.20 mole) of methyl chloroformate (80° C., 6 hours).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=[O:8].[CH3:12][OH:13]>>[CH3:12][O:13][C:7]([C:3]1[C:2]([C:10]([OH:9])=[O:11])=[N:1][CH:6]=[CH:5][N:4]=1)=[O:8]
Reactant: O=C1OC(=O)c2nccnc21
Reactant: CO
Product: COC(=O)c1nccnc1C(=O)O
Temperature: 25 °C

Procedure:
A solution of 12.0 g (79.95 mmol) of 2,3-pyrazine dicarboxylic anhydride in 282 mL of MeOH was heated to 65° C. overnight. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. To the obtained residue was added water followed by slow addition of solid NaHCO3. After gas evolution ceased, the aqueous layer was extracted with EtOAc (1×). The aqueous layer was then acidified to pH 2 by addition of conc. HCl. The aqueous layer was extracted with EtOAc (2×) and the combined organics from the second extraction washed with brine (1×). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to yield 12.41 g (85% crude yield) of 3-(methoxycarbonyl)pyrazine-2-carboxylic acid (Compound 6) as a white powder that was used without further purification: 1H NMR (DMSO, 300 MHz): δppm 8.91 (d, J=2.7 Hz, 1H), 8.89 (d, J=2.7 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[C:7]([CH3:24])[C:6]=2[C:5]([OH:25])=[CH:4][CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][C:39](=[O:42])[CH2:40]Br>C(OCC)(=O)C>[CH3:37][O:38][C:39](=[O:42])[CH2:40][O:25][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:24])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][CH:15]=1)[C:9]([CH3:12])=[N:10]2
Reactant: COC(=O)CBr
Reactant: Cc1nc2c(Cl)ccc(O)c2c(C)c1Cc1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(S(C)(=O)=O)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 8-chloro-3-(4-methanesulfonylbenzyl)-2,4-dimethylquinolin-5-ol (0.31 g), N,N-dimethylformamide (5.0 mL), potassium carbonate (0.46 g) and bromoacetic acid methyl ester (0.35 g) was stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate and this solution washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of toluene, dichloromethane and ethyl acetate (1:1:0 to 0:1:0 and 0:1:1 by volume) gave title compound as a white solid, 0.20 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][OH:11])=[O:9])[CH:3]=1.B([O-])([O-])[O-].[Na+].[Na+].[Na+].FC(F)(F)C(O)=O.C(OC(=O)C)(=O)C.OO>>[CH:3]1[C:4]([C:8]([O:10][OH:11])=[O:9])=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: OO
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: O=C(OO)c1ccccc1
Reaction time: 4.5 h

Procedure:
m-Chloroperbenzoic acid (MCPBA), a mixture of sodium borate and trifluoroacetic acid or a mixture of acetic anhydride and H2O2 is preferably used for the oxidation. If desired, a commercially available wetting agent can additionally be added to the oxidizing agent. The reaction times lie in a wide range and range from about 0.5 to about 15 hours, preferably 1 to 8 hours. The reaction temperature ranges from −20 to about 100° C., preferably from 0 to about 85° C.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[O:14]1[CH:16]([CH2:17][CH2:18][CH3:19])[CH2:15]1>>[ClH:1].[OH:14][CH:16]([CH2:17][CH2:18][CH3:19])[CH2:15][NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: CCCC1CO1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: CCCC(O)CNCc1ccc(S(N)(=O)=O)cc1

Procedure:
In the same manner as in Example 452, Step 1, the title compound was synthesized from 4-aminomethylbenzenesulfonamide hydrochloride and 1,2-epoxypentane.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:27]=O)=[N:18][CH:19]=[C:20]([N:22]([CH3:26])[CH2:23][CH2:24][CH3:25])[N:21]=1.[CH2:29]([NH:36][CH2:37][CH2:38][OH:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:29]([N:36]([CH2:27][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]([CH3:26])[CH2:23][CH2:24][CH3:25])=[CH:19][N:18]=1)[CH2:37][CH2:38][OH:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OCCNCc1ccccc1
Reactant: CCCN(C)c1cnc(C=O)c(Cl)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCN(C)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.9 %

Procedure:
Sodium triacetoxyborohydride (0.74 g) was added to a solution of 3-chloro-5-[methyl(propyl)amino]pyrazine-2-carbaldehyde (0.50 g), N-benzylethanolamine (0.42 g) and acetic acid (0.40 mL) in acetonitrile (8 mL), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→40% ethyl acetate/hexane) to give the title compound (0.75 g, 91%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[CH2:4][CH2:5][CH2:6][CH:7]([Se]C1C=CC=CC=1)[CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1.OO.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:1][O:2][C:3](=[O:45])[CH2:4][CH2:5]/[CH:6]=[CH:7]/[CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(C(CCCC(=O)OC)[Se]c3ccccc3)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(/C=C/CCC(=O)OC)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of 560 mg of (13E)-(5RS,6RS,9α,11α,15S)-5-phenylseleno-6,9-epoxy-11,15-bis(tetrahydropyran-2-yloxy)prost-13-enoic acid methyl ester (prepared as described in Example 6) in a mixture of 6 ml of ethyl acetate and 3 ml of tetrahydrofuran was added 0.5 ml of 30% hydrogen peroxide and 100 mg of sodium bicarbonate, and the reaction mixture was then stirred for one hour. Afterwards it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium carbonate, water and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of benzene and ethyl acetate (6:1) as eluent to give 380 mg of the title compound having the following physical characteristics: