Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si](C)(C)C)=[CH:14][C:13]=2[F:22])=[N:9][C:8]([CH2:23][NH:24][CH:25]=[O:26])=[CH:7][N:6]=1)=[O:4].[I:27]Cl>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:27])=[CH:14][C:13]=2[F:22])=[N:9][C:8]([CH2:23][NH:24][CH:25]=[O:26])=[CH:7][N:6]=1)=[O:4]
Reactant: ClI
Reactant: COC(=O)c1ncc(CNC=O)nc1Nc1ccc([Si](C)(C)C)cc1F
Solvent: ClCCl
Product: COC(=O)c1ncc(CNC=O)nc1Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
To a cold (0° C.) solution of 3-(2-fluoro-4-trimethylsilanyl-phenylamino)-5-formylaminomethyl-pyrazine-2-carboxylic acid methyl ester (480 mg, 1.28 mmol) in dichloromethane (13 mL) under N2 was added dropwise a solution of 1M iodine monochloride in dichloromethane (3.0 mL, 3.0 mmol, 2.4 eq), and the mixture was stirred at 0° C. for 1.5 hour. The reaction was quenched by addition of a saturated aqueous solution of sodium thiosulfate (˜3 mL). After stirring for 10 minutes the reaction mixture was poured into ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried (Na2SO4), filtered and evaporated in vacuo to afford the desired product as a yellow solid (548 mg, 99%). LCMS (method C): RT=2.65 min, [M+H]+=431.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:11][CH3:12])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][CH2:31][O:32][C:33]([CH2:35]Br)=[O:34]>CN(C=O)C>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH2:35][C:33]([O:32][CH2:31][CH3:30])=[O:34])=[CH:15][CH:14]=2)[CH2:11][CH3:12])=[CH:5][CH:4]=1
Reactant: CCC(=NOCc1ccc(C(F)(F)F)cc1)c1ccc(N)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccc(C(CC)=NOCc2ccc(C(F)(F)F)cc2)cc1
Yield: 55.5 %

Procedure:
To a solution of the product of step 2 (3.5 g, 0.0097 moles) in DMF (35 mL), potassium carbonate (4 gm, 0.0291 moles) and Ethyl bromo acetate (1.8 gm, 0.0107 moles) were added and reaction mixture was srirred at 100° C. for over night. The reaction mixture was poured into ice cold water and extracted by ethyl acetate. The combined ethyl acetate extract was washed with water and brine, dried over sodium sulphate and evapourated under reduced pressure to yield 2.2 gm (55%) of product as solid.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([NH:15][CH2:16][CH2:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=O)(C)(C)C>C(Cl)Cl>[ClH:1].[ClH:1].[NH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CC(C)(C)OC(=O)NCCNc1ccccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCNc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
4 N HCl/dioxane (54 mL) was added in a stream to a solution of 2-[[2-(tert-butoxycarbonyl)amino-1-ethyl]amino]pyridine (5.09 g, 21.45 mmole) in anhydrous CH2Cl2 (54 mL) at 0° C. under argon, then the mixture was warmed to RT. After 2 hr, the mixture was cooled to 0° C. and suction filtered. The solid was washed extensively with anhydrous Et2O and dried in high vacuum at 40° C. to afford the title compound (4.27 g, 95%) as an off-white, somewhat hygroscopic solid: 1H NMR (400 MHz, CD3OD) δ7.99-8.07 (m, 1 H), 7.92-7.98 (m, 1 H), 7.19 (d, J=9.1 Hz, 1 H), 6.98-7.04 (m, 1 H), 3.76 (t,J=6.2 Hz, 2 H). 3.27 (t, J=6.2 Hz, 2 H, partially obscured by residual solvent signal); MS (ES) m/e 138 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:12]([CH3:13])=[N:11][NH:10][C:9]=2[O:14][CH:15]([CH3:27])[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[CH3:26])=O)[N:3]=1>ClCCCl.CCOCC.CCCC(C)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:12]([CH3:13])=[N:11][N:10]3[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=4[CH3:26])=[C:15]([CH3:27])[O:14][C:9]=23)[N:3]=1
Reactant: COc1ccc(C(=O)C(C)Oc2[nH]nc(C)c2-n2nc(C)nc2C)c(C)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: ClCCCl
Solvent: CCCC(C)C
Product: COc1ccc(-c2c(C)oc3c(-n4nc(C)nc4C)c(C)nn23)c(C)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a dispersion of 2-[4-(3,5-dimethyl-[1,2,4]triazol-1-yl)-5-methyl-2H-pyrazol-3-yloxy]-1-(4-methoxy-2-methyl-phenyl)-propan-1-one (step 1) (0.905 g, 2.45 mmol) in 1,2-dichloroethane (20 ml) was added titanium tetrachloride (0.675 ml, 6.12 mmol). The reaction mixture was heated to 85° C. for 2.5 hours and left at RT overnight. The mixture was quenched carefully with sat. NH4Cl (50 ml) and extracted with EtOAc (2×50 ml). The combined organic extracts were washed with NaHCO3 (50 ml), brine, dried (MgSO4) and concentrated in vacuo to afford a dark brown oil. The crude oil was then taken up in 10% Et2O/iso-hexane (50 ml) and the brown solution was sonicated. The resulting solid was collected and washed with iso-hexane to give a cream coloured solid. Purification of this solid by recrystallisation from hot Et2O (˜40 ml) yielded the title compound as tan crystals; LC-MS Rt 3.7 mins; MS m/z 352.1 [M+H]+; Method=10minLC_v001.
Reaction SMILES: C([N:4]([CH2:8][CH3:9])[CH:5]([CH3:7])C)(C)C.Cl.[SH:11]N.ClC[SiH3].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18]>CC#N.CCOC(C)=O>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:17]([N:4]2[CH2:5][CH2:7][C@@H:9]([SH:11])[CH2:8]2)=[O:18])=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: NS
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [SiH3]CCl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC[C@@H](S)C1

Procedure:
N,N-Diisopropylethylamine 496 l, 2.85 mmol) was added to a suspension of mercaptoamine hydrochloride 7* (173 mg, 1.24 mmol) in anhydrous MeCN (0.93 ml) and the resulting mixture was stirred under a N2 atmosphere with ice bath cooling for 5 minutes. Chloromethyl silane (204 l, 1.61 mmol) was added and the mixture was stirred at 0° for 10 minutes. A solution of p-nitrobenzyl chloroformate (267 mg, 1.24 mmol) in MeCN (0.31 ml) and more N,N-diisopropylethylamine (216 l, 1.24 mmol) were added and the resulting mixture was stirred at 0° for 30 minutes and at room temperature for 60 minutes. The mixture was diluted with EtOAc, washed with H2O, 1N HCl, 5% aq. NaHCO3, and brine, dried with MgSO4, filtered and evaporated i.v., to a pale yellow oil. The crude product was chromatographed on a EM silica gel 60 column (20 g) that was eluted with 2:1 hexane-ethyl acetate at a rate of 8 ml fractions/3.5 minutes. Fractions 16-22 gave the product 25* (198 mg) as a pale yellow oil which crystallized to an off-white solid on storage in a refrigeration.
Reaction SMILES: [C:1]([N:4]([CH2:21][C@@H:22]1[O:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]3)=[C:30]([F:42])[CH:29]=2)[CH2:23]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:20])[CH2:11][NH:12]C(OC(C)(C)C)=O)=[O:6])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.C1COCC1.[ClH:56]>O1CCOCC1>[ClH:56].[C:1]([N:4]([CH2:21][C@@H:22]1[O:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:39][CH2:38][S:37](=[O:40])(=[O:41])[CH2:36][CH2:35]3)=[C:30]([F:42])[CH:29]=2)[CH2:23]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:20])[CH2:11][NH2:12])=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: COc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)CN
Yield: 72 %

Procedure:
Following General procedure G, except that the entire reaction is performed at RT. (R)-Tert-butoxycarbonylamino-acetic acid (acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamoyloxy)-methyl ester (12a) (0.24 g, 0.39 mmol), anisole (0.5 mL), THF (7.3 mL), and 4 M HCl in dioxane (3 mL) gave the title compound in 72% yield (0.16 g). 1H NMR (400 MHz, DMSO): δ 8.39 (br d, 3H), 7.47 (dd, 1H), 7.39 (t, 1H), 7.28 (dd, 1H), 5.93 (m, 2H), 4.80 (m, 1H), 4.14 (m, 2H), 3.92 (m, 3H), 3.82 (m, 1H), 3.37 (m, 2H), 3.20 (m, 1H), 3.10 (m, 2H), 2.47 (s, 3H), 2.16 (m, 2H), 2.04 (m, 2H). MS-APCI (m/z+): 516, 616.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=3)[C:15]([C:23]3[N:24]=[C:25]4[C:31]([C:32](O)=[O:33])=[CH:30][N:29]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:26]4=[N:27][CH:28]=3)=[N:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:43][C:44]([NH2:47])([CH3:46])[CH3:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>CN(C)C=O>[C:44]([NH:47][C:32]([C:31]1[C:25]2[C:26](=[N:27][CH:28]=[C:23]([C:15]3[C:16]4[C:21](=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[N:13]([CH2:12][CH:10]4[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9]4)[N:14]=3)[N:24]=2)[N:29]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:41])[CH3:42])[CH:30]=1)=[O:33])([CH3:46])([CH3:45])[CH3:43]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1CC(Cn2nc(-c3cnc4c(n3)c(C(=O)O)cn4COCC[Si](C)(C)C)c3ccc(F)cc32)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CN(C(=O)OC(C)(C)C)C4)c4cc(F)ccc34)nc12
Yield: 91.7 %

Procedure:
2-(1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-6-fluoro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (150 mg, 251 μmol), 2-methylpropan-2-amine (18.4 mg, 251 μmol), HATU (105 mg, 277 μmol) and diisopropylamine (97.5 mg, 754 μmol) in dimethylformamide (12 mL) were stirred at room temperature for 15 h. The mixture was partitioned between ethyl acetate and water then the organic phase was washed with water then dried, filtered and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-6-fluoro-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (150 mg, 91.5%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13](=[O:19])[C@H:14]([C@@H:16]([CH3:18])[OH:17])[NH2:15].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:19])[C@H:14]([C@@H:16]([CH3:18])[OH:17])[NH:15][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H](NC(=O)c1ccccc1)[C@@H](C)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
A solution of benzoyl chloride (17 g) in ethyl acetate (40 ml) is added dropwise, with stirring, in an ice-cold mixture of L-threonine methyl ester, hydrochloride (16.5 g), water (100 ml), sodium bicarbonate (21.8 g), and ethyl acetate (100 ml). After stirring for 2 hours, the organic phase is separated, dried over sodium sulfate, and evaporated to give crystalline N-benzoyl-L-threonine methyl ester (21.5 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH2:15][C:16]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:23](OCC)[N:24]([CH3:26])[CH3:25])C>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[CH:23][N:24]([CH3:26])[CH3:25])[C:16]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2ccc(OCc3ccccc3)cc21
Reactant: CCOC(OCC)N(C)C
Product: CN(C)C=C1CCc2ccc(OCc3ccccc3)cc2C1=O

Procedure:
7-Benzyloxy-3,4-dihydro-2-dimethylaminomethylene-1(2H)naphthalenone was prepared from 7-benzyloxy-3,4-dihydro-1(2H)naphthalenone (6.0 g, 23.8 mmol) and N,N-dimethylformamide diethylacetal (20 ml, 119.4 mmol) to give the desired compound as a pale yellow solid (4.56 g) m.p. 85-86°. MS(ES+) 308 (MH+, 100%).
Reaction SMILES: [CH3:1][N:2]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:3](=[O:28])[CH2:4][N:5]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:6](=[O:21])[CH2:7][NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)=[O:10].[ClH:35]>C(O)C.C(#N)C.C(OC(C)C)(C)C.C(OC(C)C)(C)C.[Pd]>[ClH:35].[NH2:18][C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[NH:8][CH2:7][C:6]([N:5]([CH2:4][C:3]([N:2]([CH3:1])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[CH:17]=[CH:16][CH:15]=1
Reactant: CN(C(=O)CN(C(=O)CNC(=O)Nc1cccc([N+](=O)[O-])c1)c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CC(C)OC(C)C
Solvent: CC#N
Product: CN(C(=O)CN(C(=O)CNC(=O)Nc1cccc(N)c1)c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
0.3 g of 5% palladium-on-charcoal is added to a solution of 1.8 g of N-methyl-2-{2-[3-(3-nitrophenyl)ureido]-N-phenylacetamido}-N-phenylacetamide in 100 cm3 of ethanol. The suspension obtained is stirred for 2 hours at a temperature close to 50° C under a hydrogen atmosphere (100 kPa). After cooling, the catalyst is separated off by filtration and the solution is concentrated to dryness under reduced pressure (2.7 kPa) at 35° C. The residue obtained is dissolved in 60 cm3 of an acetonitrile/diisopropyl ether mixture (20/80 by volume) and 5 cm3 of a 3.5N solution of hydrochloric acid in diisopropyl ether are added. The insoluble product formed is separated off by filtration, air-dried and recrystallization from ethanol. 0.9 g of 2-{2-[3-(3-aminophenyl)ureido]-N-phenylacetamido}-N-methyl-N-phenylacetamide hydrochloride melting at 220° C is thus obtained.
Reaction SMILES: C(ON=O)CC(C)C.N[C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][N:16]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][C:26]=3[C:27]([F:30])([F:29])[F:28])[C:17]2=[O:20])=[CH:12][C:11]=1[F:31].CO.C(Cl)(Cl)(Cl)[Cl:35]>C(Cl)(Cl)Cl>[Cl:35][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][N:16]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][C:26]=3[C:27]([F:30])([F:29])[F:28])[C:17]2=[O:20])=[CH:12][C:11]=1[F:31]
Reactant: Nc1cc2c(cc1F)CCN(c1cnccc1C(F)(F)F)C2=O
Reactant: ClC(Cl)(Cl)Cl
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1c2cc(Cl)c(F)cc2CCN1c1cnccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
Isoamylnitrite (107.7 mg, 0.91 mmol) was added to the stirred solution of 7-amino-6-fluoro-2-(4-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-79b: 100 mg, 0.306 mmol) in CCl4 (10 mL). The resulting mixture was stirred for 1 hour at 70° C. The reaction was monitored by TLC (5% methanol in CHCl3). The reaction mixture was concentrated to yield the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3), followed by preparative HPLC afforded 10 mg of the product (10% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([OH:17])([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:8][CH:7]1[CH3:18])=[O:5])[CH3:2].C1C(=O)N([Br:26])C(=O)C1.O.CCOC(C)=O>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[S:13][C:14]([Br:26])=[CH:15][N:16]=2)([OH:17])[CH2:8][CH:7]1[CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(O)(c2nccs2)CC1C
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(O)(c2ncc(Br)s2)CC1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a solution of the product of Step 1 (20 g, 74.3 mmol) in DMF (140 mL) was added NBS (15.9 g, 89 mmol). After the initial exotherm had subsided the reaction mixture was heated to 50° C. and stirred for 1 h. It was then cooled to room temperature and water (280 mL containing 7 g of sodium sulfite) was added followed by EtOAc. The layers were cut and the aqueous layer was back extracted with EtOAc (2×), and then the combined organics washed with H2O. The organic layer was dried with MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography to afford 4-(5-bromo-thiazol-2-yl)-4-hydroxy-2-methyl-cyclohexanecarboxylic acid ethyl ester (20 g, 57.4 mmol), MS ESI: [M+H]+ m/z 347.9.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](O)(=O)[CH3:12]>>[CH3:11][C:12]1[NH:10][C:1](=[O:9])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1
Reactant: CC(=O)O
Reactant: NC(=O)c1ccccc1N
Product: Cc1nc2ccccc2c(=O)[nH]1

Procedure:
A solution of anthranilamide (13.6 g; 100 mmol) in acetic acid (100 ml) was refluxed for 60 h. The reaction mixture was evaporated to dryness, suspended in H2O, filtered and washed thoroughly with NaHCO3 until the filtrate had a pH of 8–8.5.
Reaction SMILES: [C:1]1([O:7][P:8](Cl)(Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:12].[NH2:13][C:14]([CH3:20])([CH3:19])[C:15]([O:17][CH3:18])=[O:16].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:12][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[O:7][P:8](=[N:13][C:14]([CH3:20])([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[O:9]
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: COC(=O)C(C)(C)N
Reactant: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(C)(C)N=[P+]([O-])Oc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of phenylphosphorodichloridate (1.0 eq., 13.0 mmol, 1.9 mL) and methyl α-aminoisobutyrate hydrochloride (1.0 eq., 13.0 mmol, 2.0 g) in CH2Cl2 (80 mL) was cooled to −80° C. Dry N,N-diisopropylethylamine (DIPEA; 2.0 eq., 26.0 mmol, 4.3 mL) was added dropwise. After 2 hours, the reaction was warmed to room temperature and the solvent was removed under reduced pressure. Dry diethylether was added and the precipitate was filtered off and washed twice with dry diethylether under an argon atmosphere. The filtrate was evaporated to dryness to give 11 which was stored as a 0.90 M solution in dry tetrahydrofuran (THF) at −18° C.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:10]1[S:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[K+].O>C(O)(=O)C>[CH2:3]([C:10]1[S:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([OH:31])=[C:29]([Br:1])[CH:30]=2)=[CH:21][CH:20]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrBr
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Yield: 26.6 %

Procedure:
Bromine (1.47 mL, 28.69 mmol) in acetic acid (50 mL) was added dropwise over a 30 minutes period into a cold (5° C.) mixture of 4′-(2-benzyl-benzo[b]thiophen-3-yl)-biphenyl-4-ol (7.5 g, 19.13 mmol), potassium acetate (18.6 g, 190.13 mmol), and acetic acid (200 mL). After the addition the mixture was poured into water, and extracted with ethyl ether. The organic extracts were washed with aqueous sodium bisulfite and dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexanes/EtAOc/CH2Cl2 3:1:1) gave 4′-(2-benzyl-benzo[b]thiophen-3-yl)-3-bromo-biphenyl-4-ol as a light yellow solid (2.4 g): mp 54-56° C. MS m/e 477 (M+);
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:47]1[O:48][CH:49]=[CH:50][CH:51]=1)CCC>COCCOC.C(Cl)(Cl)Cl.CO>[O:48]1[CH:49]=[CH:50][CH:51]=[C:47]1[C:2]1[CH:3]=[C:4]2[CH2:10][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Brc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Cl-]
Agent: [Li+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: c1coc(-c2cnc3c(c2)CC2(CN4CCC2CC4)O3)c1
Yield: 89.2 %

Procedure:
A solution containing 5′-bromospiro[1-azabicyclo[2.2.2] octane-3,2′(3′H)-furo[2,3-b]pyridine] (103.5 mg, 0.351 mmol), tris(dibenzylidineacetone)dipalladium (0) (14 mg, 0.015 mmol), tri(o-tolyl)phosphine (44.4 mg, 0.146 mmol), lithium chloride (62 mg, 1.46 mmol), and 2-(tri-n-butylstannyl)furan (0.17 g, 0.476 mmol) in 1,2-dimethoxyethane (1 ml) was heated under reflux for 2 h. The solution was evaporated, and the residue was taken up in chloroform and filtered. The filtrate was evaporated then purified by HPLC using a gradient of 0-25% 1:1:2 7M methanolic ammonia:methanol:chloroform and chloroform to obtain the title compound (89 mg, 0.313 mmol, 89%) as a pale solid: electrospray MS (m/z, relative intensity) 283 ([MH]+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>CS(C)=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH:12]=[CH:13][CH:14]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1C=CCCC1
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1C=CC(c2cccnc2)CC1
Temperature: 100 °C
Yield: 6.1 %

Procedure:
A solution of 1-benzyloxycarbonyl-1,2,3,4-tetrahydropyridine (8.69 g) in dimethylsulfoxide (50 mL) was treated with 3-bromopyridine (6.32 g), triethylamine (5.6 mL) and palladium(II) acetate (0.499 g). The reaction mixture was heated to 100° C. for 16 hours, cooled to the room temperature, diluted with water, and extracted with ether. The organic layer was washed with water; the combined organic layers were dried and evaporated to produce the crude product. This material was distilled under reduced pressure and the volatile material distilling at 120° C. (66.7 Pa) was removed. The remaining residue was chromatographed, with hexane:ethyl acetate (1:1) as eluent, to afford the coupled product (0.714 g); NMR (CDCl3): 1.7 (broad s, 2), 2.16 (broad m, 1), 3.5-3.7 (m, 2), 4.9-5.1 (d of m, 2), 5.2 (m, 2), 7.0-7.5 (m, 8), 8.5 (m, 2); MS: m/z=295(M+1).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[N+]=[N-])[C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@:22]2([C:23]([O:25][CH3:26])=[O:24])[CH2:8][C:7]2([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:18][CH:17]=1
Reactant: C=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(Br)cc1
Product: COC(=O)[C@@]1(c2ccc(Br)cc2)CC1(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 88 %

Procedure:
To a flame-dried round bottom flask kept under a dry atmosphere of argon, was added Rh2(RDOSP)4 (0.01 equiv., 382 mg), 1,1-diphenylethlyene 11 (2.32 equiv., 8.16 mL), and dry degassed pentane (100 mL). A solution of freshly prepared methyl 2-(4-bromophenyl)-2-diazoacetate 12 (1.0 equiv., 5.1 g) in dry, degassed pentane (150 mL) was added to the former solution drop-wise over 3 hours at room temperature. The mixture was allowed to stir overnight, and then concentrated in vacuo. The crude material was purified using flash column chromatography eluting with a 50:1 mixture of hexanes/ethyl acetate to provide the desired product as a white foam (7.2 g, 88% yield, 98% ee). mp: 82-85° C.; Rf=0.55 (hexanes/ethyl acetate=7/1); [α]20 D −289.2° (c=1.17, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.48-7.47 (m, 2H), 7.35-7.31 (m, 2H), 7.27-7.18 (m, 5H), 7.02-6.97 (m, 5H), 3.34 (s, 3H), 2.68 (d, J=5.5 Hz, 1H), 2.39 (d, J=5.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 170.9, 141.7, 139.1, 134.8, 133.5, 130.6, 129.8, 128.5, 128.3, 127.7, 126.9, 126.3, 121.1, 52.2, 44.6, 42.4, 22.6; IR (neat): 3057, 3024, 2947, 1724, 1490, 1217; HRMS (APCI) calcd for C23H20BrO2 (M+H)+ 407.06412. found 407.06432; HPLC (S,S-Whelk, 5% isopropanol in hexane, 0.8 mL/min, 1 mg/mL, 60 min, UV 254 nm) retention times of 10.6 min (major) and 50.9 min (minor), 98% ee. (S)-methyl 1-(4-bromophenyl)-2,2-diphenylcyclopropanecarboxylate was prepared by the same procedure with Rh2(S-DOSP)4 as the catalyst, [α]20D: 219.6° (c=1.32, CHCl3).