Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>CO.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([S:11]([NH2:14])(=[O:12])=[O:13])=[CH:3][C:2]=1[F:1]
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(S(N)(=O)=O)cc1F
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
To a solution of 1.00 g 3-fluoro-4-nitro-benzenesulfonamide in 10 mL MeOH was added 10 mol % of palladium on carbon. The mixture was hydrogenated for 30 minutes at a H2 pressure of 50 psi. After filtration over Hyflo, concentration in vacuo yielded 630 mg (74%) of a dark-brown oil. 1H NMR (400 MHz, DMSO-d6) δ 6.83 (t, J=8.43 Hz, 1H), 7.42 (dd, J=8.28, 1.96 Hz, 1H), 7.47 (dd, J=10.99, 1.96 Hz, 1H) [NH2's invisible].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH:9]([CH3:11])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl.CCCCCC>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH:9]([CH3:11])[C:8]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: Oc1ccccn1
Reactant: CC(O)C(=O)OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(Oc1ccccn1)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 2-hydroxypyridine (2.9 g, 30 mmol), benzyl lactate (5.0 g, 21 mmol) and triphenylphosphine (12 g, 47 mmol) in 100 mL of methylene chloride was added diethylazodicarboxylate (7.8 mL, 45 mmol) at 0° C. The reaction was allowed to warm to room temperature for 4 h. The resulting mixture was diluted with hexane (100 mL) and concentrated with 20 g of silica gel. The material was loaded onto a silica gel column, which was eluted with 10% ethyl acetate in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.00 (dd, 1H), 7.68 (ddd, 1H), 7.36-7.28 (m, 5 H), 6.94 (dd, 1H), 6.84 (dd, 1H), 5.30 (q, 1H), 5.18 (s, 2H), 1.59 (d, 3H). LC-MS: m/e 258 (M+H)+ (3.3 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH:7]([Br:38])[CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([O:30]C3CCCCO3)[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23]C3CCCCO3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1>O1CCCC1.C(O)(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH:7]([Br:38])[CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([OH:30])[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:23])[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(Br)CCCC(=O)OC)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OC)O[C@H]2C[C@H]1O
Reaction time: 1 h
Yield: 80.3 %

Procedure:
360 mg of (13E)-(5RS,6RS,9α,11α,15S)-5-Bromo-6,9-epoxy-11,15-bis(tetrahydropyran-2-yloxy)prost-13-enoic acid methyl ester (prepared as described in Example 1) were dissolved in a mixture of 0.7 ml of tetrahydrofuran and 7 ml of 65% aqueous acetic acid and the mixture was stirred at 40° to 45° C. for one hour. The reaction mixture was then diluted with ethyl acetate, washed with 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 cyclohexane and ethyl acetate (1:3) as eluent to give 210 mg of the title compound having the following physical characteristics:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]([F:26])([F:25])[CH2:21][C:22](O)=[O:23]>>[F:19][C:20]([F:26])([F:25])[CH2:21][C:22]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:23]
Reactant: O=C(O)CC(F)(F)F
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(CC(F)(F)F)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 3,3,3-trifluoropropanoic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.32 (dd, J=7.9, 1.3 Hz, 1H), 8.04 (dd, J=8.1, 1.3 Hz, 1H), 7.98-8.02 (m, 1H), 7.93 (td, J=7.5, 1.3 Hz, 1H), 3.82-3.84 (m, 4H), 3.53-3.60 (m, 2H), 3.09-3.11 (m, 4H); MS (ESI+) M/Z 357 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([S:26]([F:31])([F:30])([F:29])([F:28])[F:27])[CH:18]=2)=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[H][H]>CC(O)=O.CO.[Pd]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:6]2[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:15])[CH:7]=2)=[CH:18][C:19]=1[S:26]([F:30])([F:31])([F:27])([F:28])[F:29]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Oc2ccc([N+](=O)[O-])c(S(F)(F)(F)(F)F)c2)cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(S(C)(=O)=O)c(Oc2ccc(N)c(S(F)(F)(F)(F)F)c2)cc1C
Yield: 95.3 %

Procedure:
3.80 g of methyl 5-methanesulfonyl-4-(4-nitro-3-pentafluorosulfanyl-phenoxy)-2-methylbenzoate (example 1) were dissolved in 30 ml of HOAc and 30 ml of MeOH, admixed with 200 mg of Pd/C (10%) and hydrogenated under 6 bar of hydrogen pressure for 24 h. Since the reaction was not yet complete, a further 300 mg of Pd/C (10%), 30 ml of HOAc and 30 ml of MeOH were added and the mixture was hydrogenated under 6 bar of hydrogen pressure for a further 24 h. Subsequently, the catalyst was filtered off and the solvents were removed under reduced pressure. 3.4 g of a light gray solid were obtained, mp 175° C. (with decomposition).
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[OH:11]O.[CH3:13][O:14][C:15]1[C:16]([CH3:40])=[C:17]([C:31]([O:38][CH3:39])=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH:28]([CH3:30])[CH3:29])=[C:23]([CH:26]=1)[CH:24]=[O:25]>O.C(#N)C>[CH3:13][O:14][C:15]1[C:16]([CH3:40])=[C:17]([C:31]([O:38][CH3:39])=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH:28]([CH3:30])[CH3:29])=[C:23]([CH:26]=1)[C:24]([OH:11])=[O:25]
Reactant: COc1c(C)c(Cc2ccc(OC(C)C)c(C=O)c2)c(OC)c(OC)c1OC
Reactant: OO
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: COc1c(C)c(Cc2ccc(OC(C)C)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
An aqueous solution (5 ml) of sodium dihydrogenphosphate (1.28 g, 10.65 mmol), an aqueous solution (7 ml) of sodium chlorite (0.533 g, 6.15 mmol) and aqueous hydrogen peroxide (0.18 ml, 30%) were added to an acetonitrile solution (5 ml) of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-isopropoxybenzaldehyde (0.530 g, 1.37 mol) and the resulting solution was stirred at room temperature for 5 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium hydrosulfite (Na2S2O4) solution and saturated brine, then dried and concentrated to obtain the titled compound (0.475 g, 1.18 mmol, 86%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][CH2:5][CH:6]=[O:7].[CH2:10]([Mg]Cl)[CH:11]=[CH2:12].O.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][CH2:5][CH:6]([OH:7])[CH2:12][CH:11]=[CH2:10]
Reactant: C=CC[Mg]Cl
Reactant: COC(CCC=O)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCC(O)CCC(OC)OC
Reaction time: 3 h

Procedure:
4,4-Dimethoxybutyraldehyde (Org. Biomol. Chem. 4 (2006) 2158) (5.47 g) was dissolved in THF (55 mL), and the solution was cooled in an ice bath under a nitrogen atmosphere. Then, a solution of allylmagnesium chloride in THF (62.1 mL, 1 M) was slowly added. After completion of the addition, the mixture was stirred for three hours. After slowly adding water, ethyl acetate and a saturated ammonium chloride solution were added, followed by further stirring. The aqueous layer was separated and then the organic layer was sequentially washed with a saturated ammonium chloride solution, water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain the title compound (5.55 g).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[CH:13]1[CH:14]=[CH:15][N:16]2[CH2:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[NH:19][CH2:18][C:17]=12.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O.ClCCl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:19]2[C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[CH2:22][N:16]3[CH:15]=[CH:14][CH:13]=[C:17]3[CH2:18]2)=[O:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: COc1cc(I)ccc1C(=O)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(I)ccc1C(=O)N1Cc2cccn2Cc2ccccc21
Reaction time: 2 h
Yield: 90 %

Procedure:
A suspension of 4-iodo-2-methoxybenzoic acid of Step B (2.5 g, 9.0 mmol) in thionyl chloride (10 mL) was heated at reflux for 1 hour. After cooling, the thionyl chloride was removed in vacuo. The residue was dissolved in toluene and concentrated in vacuo to give the crude acid chloride as a brown solid. The acid chloride was then dissolved in dichloromethane (10 mL) and slowly added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.75 g, 9.5 mmol) and N,N-diisopropylethyl amine (3.4 mL, 19.5 mmol) in dichloromethane (20 mL). After stirring for 2 hours, the reaction was quenched with water. The organic layer was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography on silica gel using a solvent gradient of 15 to 25% ethyl acetate in hexane provided 3.6 g of title product as a white foam, which was redissolved in dichloromethane and evaporated to dryness prior to use in the next step.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](CC(=O)C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1.[CH2:29]1[CH2:42][O:41][C:36]23[O:37][CH2:38][CH2:39][O:40][C:31]2([C@:32]2([CH2:55][CH2:54][C@H:53]4[C@@H:43]([CH2:44][C:45](=[CH2:56])[CH:46]5[C@:51]4([CH3:52])[CH2:50][CH2:49][CH2:48][CH2:47]5)[C@@H:34]2[CH2:35]3)[CH3:33])[O:30]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH2:39]1[CH2:38][O:37][C:36]23[O:41][CH2:42][CH2:29][O:30][C:31]2([C@:32]2([CH2:55][CH2:54][C@H:53]4[C@@H:43]([CH2:44]/[C:45](=[CH:56]\[CH3:1])/[CH:46]5[C@:51]4([CH3:52])[CH2:50][CH2:49][CH2:48][CH2:47]5)[C@@H:34]2[CH2:35]3)[CH3:33])[O:40]1
Reactant: C[C@]12CCCCC1C(=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C/C=C1\C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Yield: 96 %

Procedure:
17,17-Bis(ethylendioxy)-6(E)-ethylidenandrostane was prepared in 96% yield from 3,3:17,17-bis(ethylendioxy)androstane-6-one and (ethyl)triphenylphosphonium bromide by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-6-methyleneandrostane (Prepn. 8). The mixture was purified by flash chromatography (SiO2, cyclohexane/EtOAc 85/15). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 4.91 (m, 1H), 3.93-3.78 (m, 8H), 2.69 (m, 1H), 2.10-0.85 (m, 22H), 0.81 (s, 3H), 0.66 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[C:19]2[O:18][CH:17]([CH2:20]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:16][C:15]=2[CH:14]=[C:13]([O:32][CH3:33])[CH:12]=1.[CH3:34][NH2:35]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[C:19]2[O:18][CH:17]([CH2:20][NH:35][CH3:34])[CH2:16][C:15]=2[CH:14]=[C:13]([O:32][CH3:33])[CH:12]=1
Reactant: CN
Reactant: COc1ccc(OC)c(-c2cc(OC)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1
Product: CNCC1Cc2cc(OC)cc(-c3cc(OC)ccc3OC)c2O1

Procedure:
The title compound was prepared (0.032 g, 27%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,5-dimethoxyphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.152 g, 0.32 mmol) and methylamine (0.100 g, 3.2 mmol). mp 144-145° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)([OH:31])=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:16]=[C:17]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([C:29]([OH:31])=[O:30])[CH:37]=4)[CH:18]=[CH:19][CH:20]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1N(c2ccccc2)C(c2cccc(Br)c2)CN1S(=O)(=O)c1ccccc1
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cccc(-c2cccc(C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3)c2)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-phenyl-imidazolidin-2-one (example 5, step 2) was reacted with 3-carboxyphenylboronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 3′-(1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl)-biphenyl-3-carboxylic acid as an off-white solid. MS: 497.2 ([M−H]−)
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C@H:10]([C:13]1[O:14][CH:15]=[C:16]([C:18](=[O:20])[NH2:19])[N:17]=1)[CH2:11][CH3:12])[CH3:9])(C)(C)C.[ClH:22]>ClCCl>[ClH:22].[NH2:7][C@@H:8]([C@H:10]([C:13]1[O:14][CH:15]=[C:16]([C:18]([NH2:19])=[O:20])[N:17]=1)[CH2:11][CH3:12])[CH3:9]
Reactant: CC[C@@H](c1nc(C(N)=O)co1)[C@@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: CC[C@@H](c1nc(C(N)=O)co1)[C@@H](C)N
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of tert-butyl((2R,3R)-3-(4-carbamoyloxazol-2-yl)pentan-2-yl)carbamate (677 mg, 2.28 mmol) in anhydrous dichloromethane (6 mL) was treated with HCl (4M HCl in 1,4-dioxane, 12 mL, 48.0 mmol) and allowed to stir at room temperature overnight. The reaction was then evaporated in vacuo to give 2-((2R,3R)-2-aminopentan-3-yl)oxazole-4-carboxamide hydrochloride (532 mg, 2.28 mmol, 100% yield) which was used immediately in the next reaction.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([O-])([O-])=O.[Cs+].[Cs+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:29][N:15]1[C:16]2[C:12](=[CH:11][C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])=[CH:18][CH:17]=2)[C:13]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[CH:14]1
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2ccc(S(=O)(=O)c3ccccc3)cc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: Cn1cc(CCNC(=O)OC(C)(C)C)c2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 67.7 %

Procedure:
A solution of tert-butyl 2-[5-(phenylsulfonyl)-1H-indol-3-yl]ethylcarbamate (0.58 g, 1.46 mmol) in acetone (25.0 mL) was treated with Cs2CO3 (1.85 g, 5.68 mmol) and dimethyl sulfate (0.80 mL, 8.45 mmol). The reaction was stirred at room temperature for 3.5 hours then filtered. The filtrate was concentrated in vacuo and subjected to column chromatography (silica gel, 30% EtOAc/hexane) to give 0.41 g (68%) of a colorless solid as the title compound: mp 127.4-130.6° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.93 (d, J=7.1 Hz, 1H), 7.65-7.55 (m, 5H), 7.35 (s, 1H), 6.93 (br, 1H), 3.77 (s, 3H), 3.20-3.18 (m, 2H), 2.86-2.82 (m, 2H), 1.37 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 155.5, 142.7, 138.3, 132.8, 130.5, 130.0, 129.4, 127.0, 126.7, 119.7, 119.3, 113.4, 110.7, 77.4, 41.1, 32.5, 28.1, 24.9; IR (diffuse reflectance) 1676, 1531, 1450, 1366, 1316, 1303, 1286, 1177, 1152, 1144, 1103, 797, 726, 692, 626 cm−1; HRMS (FAB) calcd for C22H26N2O4S+H 414.1613, found 414.1619; Anal. Calcd for C22H26N2O4S: C, 63.74; H, 6.32; N, 6.76. Found: C, 63.78; H, 6.39; N, 6.80.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=2[N:10]=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.CN(C=O)C>CC(O)C>[C:22]([O:26][C:27](=[O:28])[NH:29][CH:30]1[CH2:34][CH2:33][N:32]([C:9]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]3[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=3[N:10]=2)[CH2:31]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: Cn1c(=O)c2c(nc(N3CCC(NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2)n(C)c1=O

Procedure:
7-Benzyl-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (2A) (100 mg, 0.33 mmol), (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (305 mg, 1.64 mmol), and triethylamine (0.46 ml, 3.28 mmol) was dissolved in 20 ml of 2-propanol and 5 ml of DMF and the mixture was subjected to microwaves (method F, 130° C., 300 W) for three hours. The solvent was evaporated and the crude product was purified by preparative HPLC (method A1, Rt=11.75 min.). Evaporation of the solvent afforded compound (3A) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25][N:26]2[CH2:34][CH2:33][CH2:32][C@H:27]2[C:28]([O:30][CH3:31])=[O:29])=[C:20]([F:35])[CH:19]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:39]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:37]=[CH:36][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:8])[S:25][N:26]2[CH2:34][CH2:33][CH2:32][C@H:27]2[C:28]([O:30][CH3:31])=[O:29])=[C:20]([F:35])[CH:19]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: COC(=O)[C@@H]1CCCN1SNc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CCCN1SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
A solution of 2,6-difluorobenzoylisocyanate (2.8 g) in a 1:1 mixture of toluene and petroleum ether (10 ml) was added at room temperature over 30 minutes to a stirred solution of the compound of Example 4 (6.5 g) in the same solvent (20 ml). After stirring at room temperature for 3 hours, the solvent was stripped and the residue purified by chromatography over silica using dichloromethane as eluant, to give 5.5 g of the desired product, melting point 65°-68° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][CH:12]([CH3:28])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=1)=[O:14]>>[CH3:11][CH:12]([CH3:28])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:27][CH2:26][N:25]([CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:24][CH2:23]2)[CH:17]=1)=[O:14]
Reactant: OCCCc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure O and Scheme W using 3-phenyl-1-propanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 365.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH2:5][C:6](=[CH:10]Br)[CH:7]=[CH:8][CH:9]=1.[C-]#N.[K+].[C:16](#[N:18])C.CO>ClCCl.C1OCCOCCOCCOCCOCCOC1.CO.ClCCl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:16]#[N:18])[CH:5]=1
Reactant: CC#N
Reactant: COC(=O)C1=CC=CC(=CBr)C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
Methyl-3-bromomethylenebenzoate (5.0 g, 0.022 mol, Ryan Chemicals (Maybridge)), dry potassium cyanide (2.9 g, 0.044 mol), and 18-crown-6 (0.5 g, 0.0018 mol) was added to ~50 mL acetonitrile in a 100-mL round-bottom flask. The mixture was vigorously stirred for 24 h at room temperature. The reaction was monitored by TLC (Bakerflex) in dichloromethane, 2% methanol, and 5% methanol/dichloromethane. A heavy white precipitate (KBr) was removed by filtration. The filtrate was concentrated to 1/3 of the original volume and water was added until the final volume was ~100 mL. The yellow solution was added to a 250-mL separatory funnel and was extracted with dichloromethane until the organic phase was colorless and then twice more. The organic layers were combined and dried with magnesium sulfate. The drying agent was removed by filtration and the solvent was concentrated to a light yellow oil. The oil was dissolved into an equal volume of ether and was added to a 15×2.5 cm column of TLC grade silica gel and eluted with ether. The progress of the column was followed with a hand-held UV lamp. When the faster-running impurities had eluted, the product was collected and the solvent was concentrated leaving a light yellow oil. Though this oil was pure by TLC, the product was distilled (101.5° C. at 0.05 mm Hg) leaving 3.5 g (92%) of methyl-3-cyanomethylbenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.COCCOC.CO.[CH3:18][O:19][C:20]([NH:22][C:23](=NC(OC)=O)SC)=[O:21]>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:23]([NH:22][C:20](=[O:21])[O:19][CH3:18])[NH:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: COCCOC
Solvent: CCOCC
Solvent: CO
Product: COC(=O)Nc1nc2ccc(Br)cc2[nH]1
Temperature: 105 °C
Yield: 77.4 %

Procedure:
To a slurry of 4-bromobenzene-1,2-diamine (2.1 g, 11 mmol), 1,2-dimethoxyethane (20 mL) and methanol (5 mL) was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (4.0 g, 19 mmol). The reaction mixture was heated (105° C.) for 12 h and then diluted with ethyl ether (100 mL). The resulting precipitate was collected by filtration and rinsed with ethyl ether (2×25 mL) to provide methyl 6-bromo-1H-benzo[d]imidazol-2-ylcarbamate (2.3 g, 77% yield). MS (EI) for C9H8BrN3O2: 271 (MH+).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:5][C:6]=1[Cl:7].C([O-])(=O)C.[Na+].[H][H]>[Pd].C(O)C>[Cl:7][C:6]1[CH:5]=[C:4]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[S:3][CH:2]=1
Reactant: [H][H]
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)c(Br)s1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(c1ccc(F)cc1)c1cc(Cl)cs1
Reaction time: 3 h

Procedure:
A slurry of 5% palladium on charcoal (20 g) in ethanol (100 ml) was added under nitrogen gas to a solution of the above 2-bromo3-chloro-5-(4-fluorobenzoyl)-thiophene (299.4 9 ) in ethanol (3.400 ml), containing sodium acetate (77.0 g),and the mixture was hydrogenated for 3 hours at room temperature and pressure (total uptake of hydrogen was 22,994 ml). The reaction mixture was filtered through a dicalite pad and the pad was washed with ethanol (2×200 ml). The filtrate was taken to low volume (approximately 2 l) and added to water (17 l). The precipitate was filtered and while damp it was dissolved in dichloromethane (1 l) which was then reduced in volume to approximately 500 ml. Methanol (500 ml) was added and the remainder of the dichloromethane was removed by distillation. The resultant crystals were filtered and dried to give 4-chloro-2-(4-fluorobenzoyl)thiophene as a white solid (169 g). A second crop (19.2 g) was obtained and recrystallised from dichloromethane/methanol to give more of the purified product (12.9 g). The crops were combined and used in the next stage.