Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[C:16]3[CH:17]=[C:18](Br)[CH:19]=[CH:20][C:15]=3[S:14][N:13]=1)=[O:11])[CH2:2]2.[C:22](=[O:25])(O)[O-].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2[C:40]2C=CC=C[C:41]=2[N:46](C)[CH3:47])CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[C:16]3[CH:17]=[CH:18][C:19]([N:46]4[CH2:47][CH2:22][O:25][CH2:40][CH2:41]4)=[CH:20][C:15]=3[S:14][N:13]=1)=[O:11])[CH2:2]2
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: O=C([O-])O
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1nsc2ccc(Br)cc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Product: O=C(N[C@H]1CN2CCC1CC2)c1nsc2cc(N3CCOCC3)ccc12
Yield: 180.3 %

Procedure:
In a 5 mL microwave reaction vessel was added N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-(bromo)benzo[d]isothiazole-3-carboxamide (133 mg, 0.37 mmol), tris(dibenzylideneacetone)dipalladium (0) (34 mg, 0.04 mmol), caesium bicarbonate (213 mg, 1.1 mmol), and (2′-dicyclohexylphosphanylbiphenyl-2-yl)dimethylamine (30 mg, 0.07 mmol). The vial was then evacuated and back-filled with argon gas. The mixture of solids was then diluted with morpholine (0.7 mL), dioxane (1 mL), and triethylamine (0.5 mL) and the reaction vessel was sealed. The reaction mixture was subjected to microwave irradiation at 120° C. for 1800 s. The reaction mixture was filtered through a plug of celite and concentrated in vacuo. The crude product was purified by chromatography (90/10/1 dichloromethane/methanol/ammonium hydroxide) to provide 47 mg (34%) of 6-morpholin-4-ylbenzo[d]isothiazole-3-carboxylic acid ((3R)-1-azabicyclo[2.2.2]oct-3-yl)amide as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@H:7]([NH2:20])[CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])([CH3:4])([CH3:3])[CH3:2].C[Si](C#N)(C)C.[CH3:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([CH3:37])[C:30]=1[S:38](Cl)(=[O:40])=[O:39].Cl>C(#N)C.C(OCC)(=O)C>[CH3:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([CH3:37])[C:30]=1[S:38]([NH:20][C@H:7]([CH2:8][N:9]1[C:10](=[O:19])[C:11]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]2[C:13]1=[O:14])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])(=[O:39])=[O:40]
Reactant: CC(C)(C)OC(=O)[C@H](N)CN1C(=O)c2ccccc2C1=O
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: C[Si](C)(C)C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(C)c(S(=O)(=O)N[C@H](CN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a stirred solution of tert-butyl-2(R)-amino-3-phthalimido-propionate (5.7 g, 19.63 mmol) in dry acetonitrile (60 ml) was added trimethylsilylcyanide (8.6 ml, 68.7 mmol). After 5 minutes 2,6-dimethyl-4-methoxybenzenesulfonyl chloride (4.84 g, 20.6 mmol) was added in one portion. The material was stirred at ambient temperature for 1 hour and then ethyl acetate (80 ml) was added and the mixture was transferred to a seperatory funnel. The organic phase was partioned with aqueous hydrochloric acid (1.5%, 100 ml), collected and washed with an equal volume of brine. The aqueous phases were back extracted with ethyl acetate (2×80 ml) and the organic phases combined, dried (magnesium sulfate), filtered and condensed. The residue was chromatographed (flash silica gel, 30% ethyl acetate-hexanes) to provide tert-butyl 2(R)-(2,6-dimethyl-4-methoxybenzene sulfonylamino)-3-phthalimido-propionate as white semi-solid (6.9 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:27]=[CH:26][C:6]2[CH:7]([C:17]3[C:18]([S:24][CH3:25])=[N:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].F[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([N:35]([CH3:51])[CH2:36][C:37]([NH:39][C:40]2[S:41][CH:42]=[C:43]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[N:44]=2)=[O:38])[N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[CH2:1]([C:3]1[CH:27]=[CH:26][C:6]2[CH:7]([C:17]3[C:18]([S:24][CH3:25])=[N:19][C:20](=[O:23])[N:21]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([N:35]([CH3:51])[CH2:36][C:37]([NH:39][C:40]5[S:41][CH:42]=[C:43]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[N:44]=5)=[O:38])[N:30]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc(NC(=O)CN(C)c2nccc(F)n2)n1
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)nc1SC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cc1csc(NC(=O)CN(C)c2nccc(-n3cc(C4c5ccc(C)cc5C=Cc5cc(CC)ccc54)c(SC)nc3=O)n2)n1

Procedure:
The product of step (iv) (0.37 g), and the product of step (ii) (0.35 g) was stirred with cesium carbonate (0.32 g) in dry 1-methyl-2-pyrrolidinone (15 ml) at 65-70° C. for 20 hours. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer collected, dried (MgSO4), and solvent evaporated under reduced pressure. Yield 0.61 g.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]([CH2:11][CH2:12]OS(C)(=O)=O)=[CH2:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:10][C:9]([CH2:11][CH2:12][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:8]
Reactant: Oc1ccccc1
Reactant: C=C(C)CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)CCOc1ccccc1
Temperature: 80 °C
Yield: 66.4 %

Procedure:
A mixture of 24.4 g (260 mmol) of phenol, 47.0 g (286 mmol) of 2-methyl-4-methylsulfonyloxy-1-butene, 107 g (780 mmol) of potassium carbonate and 300 ml of N,N-dimethylformamide was stirred and heated at 80° C. for 6 hours, and then it was poured onto 500 ml of ice-water. The resulting mixture was extracted with hexane and the combined extracts were dried (MgSO4) and evaporated in vacuo to give the title compound as an oil (28.0 g, 66% yield).
Reaction SMILES: [OH-].[K+].[O:3]1[C:7]2=[N:8][C:9]([C:17]([O:19]CC)=[O:18])=[C:10]([C:12]([O:14]CC)=[O:13])[CH:11]=[C:6]2[CH:5]=[CH:4]1.CC(C)=O>O.C(O)C>[O:3]1[C:7]2=[N:8][C:9]([C:17]([OH:19])=[O:18])=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=[C:6]2[CH:5]=[CH:4]1
Reactant: CCOC(=O)c1cc2ccoc2nc1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1cc2ccoc2nc1C(=O)O
Temperature: 60 °C

Procedure:
Potassium hydroxide (5.60 g, 85%, 0.087 mol) in water (5 mL) is added to a stirred suspension of diethyl furo[2,3-b]pyridine-5,6-dicarboxylate (9.3 g, 0.035 mol) in absolute ethanol (100 mL). The reaction mixture is heated at 60° C. for one hour, then cooled and anhydrous acetone added. The precipitate is filtered off, dried, suspended in dry acetone and treated with hydrogen chloride to adjust to a pH of 2. Crystallization of the isolated solids from an ethyl acetate-acetone mixture affords furo[2,3-b]pyridine-5,6-dicarboxylic acid mp 189°-192° C.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]2[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:15][O:16][C:11]=2[CH:10]=1)C1C=CC=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].B(Cl)(Cl)Cl.B(Cl)(Cl)Cl>>[CH2:15]1[O:16][C:11]2[CH:10]=[C:9]([OH:8])[CH:26]=[CH:25][C:12]=2[CH:13]=[C:14]1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.[OH:8][C:9]1[CH:26]=[CH:25][C:12]2[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:15][O:16][C:11]=2[CH:10]=1
Reactant: COc1ccc(C2=Cc3ccc(OCc4ccccc4)cc3OC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Product: COc1ccc(C2=Cc3ccc(O)cc3OC2)cc1
Product: Oc1ccc(C2=Cc3ccc(O)cc3OC2)cc1

Procedure:
As shown in Scheme 2, 7-benzyloxy-3-(4-methoxyphenyl)-2H-1-benzopyran (compound 1) was reacted with n-Bu4NI/BCl3 and BCl3 to give haginin E (compound 2a) at a yield of 79% and 7-hydroxy-3-(4-methoxyphenyl)-2H-1-benzopyran (4′-O-methyl haginin E, compound 2b) at a yield of 81%, respectively. Treatment of compound 1 with Pd(OH)2/C (Pearlman's reagent) and cyclohexene in refluxing ethanol promoted O-debenzylation and reduction of the chromene ring in one step, giving 7-hydroxy-3-(4-methoxyphenyl)-1-benzopyran (compound 3a) at a yield of 94%. Compound 3a was subsequently demethylated by use of n-Bu4NI/BCl3 to give equol (compound 3b) at a yield of 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[CH3:33])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=3[CH3:33])[CH2:23][CH2:22]2)=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)C1(c2ccc(F)cc2Cl)CCCC1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(F)cc3Cl)CCCC2)CC1

Procedure:
Example 135 was prepared from 1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.56 (dd, 1H, J=8.7, 6.3 Hz), 7.32 (s, 1H), 7.22–7.15 (m, 2H), 7.06 (dd, 1H, J=8.7, 3.0 Hz), 7.05–6.95 (m, 2H), 5.90–5.84 (m, 1H), 3.21 (q, 2H, J=5.7 Hz), 2.87–2.80 (m, 2H), 2.59–2.49 (m, 1H), 2.44 (septet, 1H, J=6.5 Hz), 2.41–2.40 (m, 2H), 2.26 (t, 2H, J=5.7 Hz), 2.19 (s, 3H), 2.04–1.96 (m, 2H), 1.93–1.85 (m, 2H), 1.82–1.71 (m, 3H), 1.64–1.48 (m, 7H), 1.17 (d, 6H, J=6.5 Hz); ESMS m/e: 542.2 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[C:6]([NH:9][C:10]1[S:11][C:12]([S:16](Cl)(=[O:18])=[O:17])=[C:13]([CH3:15])[N:14]=1)(=[O:8])[CH3:7].C(N(CC)CC)C>C1COCC1>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[S:16]([C:12]1[S:11][C:10]([NH:9][C:6](=[O:8])[CH3:7])=[N:14][C:13]=1[CH3:15])(=[O:17])=[O:18]
Reactant: CNCCO
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)N(C)CCO)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 80.9 %

Procedure:
To a stirred solution of 2-(methylamino)-ethanol (0.44 g, 5.86 mmol) in THF (12 ml) was added at 0° C. (ice water bath) commercially available 2-acetamido-4-methylthiazole-5-sulfonyl chloride (1.0 g, 3.92 mmol) and triethylamine (0.6 ml, 4.32 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by flash chromatography on silica gel (dichloromethane/MeOH) and subsequent crystallization (dichloromethane/MeOH/hexane) to yield 2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-ethyl)-methyl-amide (0.93 g, 81%) as a white solid. MS (ISP) 294.0 [(M+H)+]; mp 189° C.
Reaction SMILES: [C:1]1([C:7]#[C:8]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)=[O:16]>C1COCC1.CCCCCC>[OH:16][CH:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC#Cc1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)C#Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred solution of 4.40 mL (40.0 mmol) of phenylpropyne in 30 mL of THF under nitrogen at -75° C. was added a solution of 16 mL (40 mmol) of 2.5M n-butyllithium in hexane over 20 min. The resulting light yellow solution was warmed to 0° C. and stirred for 30 min. This solution was added via syringe to a slurry of 6.25 g (38.0 mmol) of methyl 4-formylbenzoate in 30 mL of THF at -30° C. over 20 min. The resulting light yellow solution was warmed to room temperature and stirred for 30 min. The reaction was quenched with saturated ammonium chloride solution, extracted twice with ether, dried (MgSO4) and evaporated. Purification by flash chromato-graphy (5×15 cm column, 1:19 ether/dichloromethane as elutent) gave title compound as a white solid, mp 48°-50° C., 9.36 g, 88% yield.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:13]2)(=O)C(C)(C)C.CO[CH:43](OC)[CH2:44][NH2:45].C[O:49]C(OC)[C@@H](N)C(C)C>>[C:37]([O:36][C@@H:9]([C:10]1[C:11]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]1[CH:43]=[CH:44][N:45]=[C:15]1[CH:14]=[CH:13]2)[C:8]([OH:49])=[O:7])([CH3:40])([CH3:38])[CH3:39]
Reactant: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: COC(OC)[C@@H](N)C(C)C
Reactant: COC(CN)OC
Product: Cc1cc2c(ccc3nccn32)c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(6-(4-chlorophenyl)-8-methylimidazo[1,2-a]quinolin-7-yl)acetic acid (62) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-isopropyl-8-methylimidazo[1,2-a]quinolin-7-yl)acetic acid of Example 60 except using (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate and 2,2-dimethoxyethanamine instead of (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate and (S)-1,1-dimethoxy-3-methylbutan-2-amine. 1H-NMR 400 MHz (CD3OD) δ 8.92 (m, 1 H), 8.45 (m, 1 H), 8.10 (m, 1 H), 7.7-7.6 (m, 5 H), 7.38 (m, 1 H), 5.21 (s, 1 H), 2.80 (s, 3 H), 0.99 (s, 9 H); LCMS-ESI+ (m/z): [M+H]+ calcd for C24H24ClN2O3: 423. Found: 423.2; LCMS-ESI+ (m/z): [M+H]+ calcd for C24H22ClN2O3: 421.1. Found: 421.0.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH3:6].[Cl:7][C:8]1[C:13]2[S:14][CH:15]=[C:16]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1.O>CN(C=O)C.C(OCC)(=O)C>[ClH:7].[Cl:7][C:8]1[C:13]2[S:14][CH:15]=[C:16]([N:17]([CH2:4][CH2:5][CH3:6])[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CCCBr
Reactant: Clc1cccc2c(Nc3ccncc3)csc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCN(c1ccncc1)c1csc2c(Cl)cccc12
Product: Cl
Reaction time: 2 h
Yield: 168.3 %

Procedure:
To a suspension of NaH (452 mg, 11.29 mmole, washed with pentane) in dry DMF (15 mL) was added 1-bromopropane (1.03 mL, 11.29 mmole), and thereafter a solution of 7-chloro-3-[(4-pyridinyl)amino]benzo[b]thiophene (2.8 g, 10.75 mmole) in warm DMF (20 mL) was added so that the reaction mixture was warm to the touch. After the addition, the reaction mixture was stirred for two hours, distributed between water and ethyl acetate, and the organic phase was washed with water, dried (MgSO4) and concentrated to afford 3.07 g of a dark brown oil. This was flash chromatographed twice (silica, 5% MeOH/EtOAc then 10% MeOH/EtOAc; alumina, Et2O) to yield 2.36 g of product. The hydrochloride salt was formed in methanol with ethereal hydrogen chloride, the solution was concentrated to a solid and the solid was recrystallized from methanol and diethyl ether. The resulting pale yellow solid was dried for four hours under high vacuum over P2O5 and refluxing toluene to yield 1.77 g, mp 249° C. (dec.).
Reaction SMILES: BrCCO[Si](C(C)(C)C)(C)C.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].[CH3:22][C:23]1[CH:27]=[C:26]([N:28]2[CH2:32][CH2:31][NH:30][C:29]2=[O:33])[S:25][C:24]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH3:22][C:23]1[CH:27]=[C:26]([N:28]2[CH2:32][CH2:31][N:30]([CH2:13][C:14](=[O:15])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:29]2=[O:33])[S:25][C:24]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)cc1C
Agent: CC(C)(C)[Si](C)(C)OCCBr
Product: CCOC(=O)c1sc(N2CCN(CC(=O)c3ccccc3)C2=O)cc1C
Yield: 39 %

Procedure:
Following the procedure as described in Example 50, making variations as required to replace (2-bromoethoxy)(tert-butyl)dimethylsilane with 2-bromoacetophenone to react with ethyl 3-methyl-5-(2-oxoimidazolidin-1-yl)thiophene-2-carboxylate, the title compound was obtained as a colorless solid in 39% yield: 1H NMR (300 MHz, CDCl3) δ 7.95 (d, J=8.3 Hz, 2H), 7.60-7.56 (m, 1H), 7.52-7.44 (m, 2H), 6.18 (s, 1H), 4.73 (s, 2H), 4.24 (q, J=7.1 Hz, 2H), 3.94-3.86 (m, 2H), 3.76-3.68 (m, 2H), 2.48 (s, 3H), 1.30 (t, J=7.1 Hz, 3H); MS (ES+) m/z 373.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:28][C@@H:24]1[C@@H:25]([OH:27])[CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
3-Bromo-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 7.1, 60 mg, 0.13 mmol), pyrimidin-5-ylboronic acid (66.6 mg, 0.325 mmol), Pd(PPh3)2Cl2 (9.13 mg, 0.013 mmol) and Na2CO3 (68.9 mg, 0.650 mmol) were added to a MW vial. The vial was sealed, evacuated/purged with argon, and DME (552 μL), water (158 μL), EtOH (79 μL) were added. The RM was then subjected to MW irradiation at 120° C. for 10 min. The RM was diluted with DME (2 mL), treated with Si-Thiol (Silicycle, 1.27 mmol/g, 102 mg, 0.130 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 12, from 20% to 50% in 18 min) to yield the title compound as a white solid. UPLC-MS (condition 1) tR=2.10 min, m/z=461.0 [M+H]+, m/z=459.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.75 (d, J=10.27 Hz, 2H) 3.27 (dd, J=10.39, 3.55 Hz, 2H) 3.88 (br. s, 2H) 5.07 (d, J=3.42 Hz, 2H) 6.97 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.82-7.90 (m, 3H) 7.94 (dd, J=8.80, 2.45 Hz, 1H) 8.85 (s, 2H) 9.17 (s, 1H) 10.10 (s, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-])=O)[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([OH:30])[CH2:25]1.C(N(CC)C(C)C)(C)C.[H][H]>CO.[Pd]>[NH2:20][C:17]1[C:18]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([OH:30])[CH2:25]2)=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: N[C@@H]1CCC[C@@H](O)C1
Agent: [Pd]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCC[C@@H](O)C1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A stirred suspension of 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (24.5 g, 72.6 mmol) in methanol (120 ml) was treated with (1R,3R)-3-Amino-cyclohexanol* (8.9 g, 76.3 mmol) and N,N-diisopropylethylamine (13.3 mL, 76.3 mmol), and stirred at 65° C. for three hours. The mixture was then cooled and 10% palladium on carbon (7.6 g, 3.6 mmol) was added. The mixture was pressurized to 100 psi with hydrogen and stirred at 50° C. for 18 h. Filtration and concentration afforded the desired product which was carried on directly into the next step. LCMS (Method P, ESI): RT=2.17 min, m+H=387.1. *Prepared following the procedures described in: P. Bernardelli et al./Tetrahedron: Asymmetry 15 (2004) 1451-1455
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]=[CH:10][C:11]1[CH:19]=[CH:18][C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:17][C:16]1[CH:18]=[CH:19][C:11]([CH:10]=[O:9])=[CH:12][C:13]=1[O:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C=O)ccc1OCc1ccccc1
Yield: 62.5 %

Procedure:
Benzyl bromide (1.2 mL, 9.9 mmol) was added to a suspension of vanillin (1.0 g, 6.6 mmol) and potassium carbonate (2.7 g, 20 mmol) in acetone (10 mL) and treated according to Procedure 3. The crude product was recrystallised from EtOH to give 4-benzyloxy-3-methoxybenzaldehyde (1.0 g, 64%) as a colourless crystalline solid; mp 61-62° C.; δH (400 MHz, CDCl3) 3.95 (s, 3H, OCH3), 5.25 (s, 2H, OCH2), 6.99 (d, J5,6=8.0 Hz, 1H, H5), 7.32-7.45 (m, 7H, H2, H6, Ph), 9.84 (s, 1H, CHO); δC (100 MHz, CDCl3) 56.1, 70.8 109.3, 112.4, 126.6 127.2, 128.2, 128.7, 130.3, 136.0, 150.1, 153.6, 190.9; vmax 988, 1133, 1259, 1505, 1583, 1672 cm−1.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=P([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22]C=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])[CH3:2].[CH:26](N=C=S)(C)C.BrC(C)C(=O)C(OC)=O.O>C1COCC1>[CH3:20][CH2:25][CH2:24][CH:23]([CH3:22])[CH3:26].[C:4]([O:3][CH2:1][CH3:2])(=[O:5])[CH3:6]
Reactant: CC(C)N=C=S
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COC(=O)C(=O)C(C)Br
Solvent: C1CCOC1
Solvent: O
Product: CCCC(C)C
Product: CCOC(C)=O
Temperature: -78 °C

Procedure:
Ethoxycarbonylmethylene triphenyl phosphorane (33.8 g) in dry THF (200 ml) was treated with isopropyl isothiocyanate (10.1 g) at 65° C. for 16 h under nitrogen. The mixture was cooled to −78° C. and methyl 3-bromo-2-oxo-butanoate was added. The reaction was allowed to warm slowly to room temperature. After 24 h at room temperature more methyl 3-bromo-2-oxo-butanoate (2.8 g) was added and the mixture was warmed to 60° C. for 16 h. The cooled reaction was poured into water (1.5 L) and extracted into ether. Drying and evaporation gave an oil which was chromatographed (SiO2/10:1 isohexane-ethyl acetate then 5:1 isohexane-ethyl acetate) to afford the sub-title compound (23.5 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[C:24]([F:29])[C:23]([F:30])=[C:22](F)[C:21]=1[F:32].C(=O)([O-])[O-].[K+].[K+]>C1(=O)OCCC1>[N+:26]([C:25]1[C:24]([F:29])=[C:23]([F:30])[C:22]([O:15][C:13]2[CH:12]=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:14]=2)=[C:21]([F:32])[C:20]=1[F:19])([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1c(F)c(F)c(F)c(F)c1F
Reactant: O=[N+]([O-])c1ccc(O)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C1CCCO1
Product: O=[N+]([O-])c1ccc(Oc2c(F)c(F)c([N+](=O)[O-])c(F)c2F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
24.5 g of 2-benzyloxy-4-hydroxynitrobenzene (0.1 mol) and 21.3 g of pentafluoronitrobenzene (0.1 mol) are dissolved in 300 ml of γ-butyrolactone in a three-neck flask fitted with stirrer. 30 g of potassium carbonate (0.22 mol) are then added in portions, and the mixture is stirred at room temperature for 24 hours. The reaction solution is then filtered via a fluted filter, and the crude product is extracted by shaking with 200 ml of ethyl acetate and 300 ml of water. The organic phase is washed three times with water, dried over sodium sulfate and evaporated to half in a rotary evaporator. The precipitated crude product is then recrystallized from a mixture of methylene chloride and petrol ether (volume ratio 1:1) and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet.