Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:12]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25](O)=[O:26])=[CH:22][CH:23]=2)[C:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:28])[CH2:17][C:16]1([CH3:36])[CH3:35])(=[O:14])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:12]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([NH:11][CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:26])=[CH:22][CH:23]=2)[C:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:28])[CH2:17][C:16]1([CH3:36])[CH3:35])(=[O:14])[CH3:13]
Reactant: COc1ccc(CCN)cc1
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)c2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)cc1

Procedure:
Condensation of 2-(4-methoxyphenyl)ethylamine (6.1 mg) with 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylic acid (10 mg), under the agency of HATU (23 mg) and N,N-diisopropylethylamine (19 l)) in dichloromethane (2 ml) was performed according to the method described in example 11.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[C:20]([C:22]1[N:26]([CH3:27])[C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].[F-].[K+]>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].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:27][N:26]1[C:25]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)(=[O:10])=[O:9])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=2)=[CH:24][CH:23]=[C:22]1[C:20]#[N:21]
Reactant: O=S(=O)(c1ccc(Br)cc1C(F)(F)F)N1CCCC1
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)N2CCCC2)c(C(F)(F)F)c1
Reaction time: 16 h
Yield: 54.5 %

Procedure:
In analogous manner to general procedure B, 1-{[4-bromo-2-(trifluoromethyl)phenyl]sulfonyl}pyrrolidine (200 mg, 0.56 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100 mg, 0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (83 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 1-methyl-5-[4-(pyrrolidin-1-ylsulfonyl)-3-(trifluoromethyl)phenyl]-1H-pyrrole-2-carbonitrile (117 mg, 54%) was provided after purification. HRMS: calcd for C17H16F3N3O2S+H+, 384.09881; found (ESI, [M+H]+), 384.0991, HPLC purity 100.0% at 210-370 nm, 10.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[C:12]2[C:7]=1[N:8]=[C:9]([O:20][CH3:21])[C:10]([O:18][CH3:19])=[N:11]2)(=[O:4])=[O:3].C(=O)(OCC=C)O[CH2:24][CH:25]=[CH2:26].C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.ClCCl.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]>[CH3:1][S:2]([CH:5]([C:6]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[C:12]2[C:7]=1[N:8]=[C:9]([O:20][CH3:21])[C:10]([O:18][CH3:19])=[N:11]2)[CH2:26][CH:25]=[CH2:24])(=[O:4])=[O:3]
Reactant: C=CCOC(=O)OCC=C
Reactant: COc1nc2cc(Cl)c(Cl)c(CS(C)(=O)=O)c2nc1OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C=CCC(c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of (6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methyl methyl sulphone (50 mg, 0.142 mmol) (Preparation 29) and diallyl carbonate (41 μl, 40 mg, 0.285 mmol) in dry tetrahydrofuran (0.8 ml) was added via cannula to a mixture of tris(dibenzylideneacetone)dipalladium (0 ml).chloroform adduct (7.4 mg, 0.007 mmol) and 1,2-bis(diphenylphosphino)ethane (11.3 mg, 0.028 mmol) in dry tetrahydrofuran (0.6 ml) under nitrogen at room temperature. The mixture was stirred at room temperature for 5 minutes and then at reflux for 2 hours. The mixture was allowed to cool, was diluted with dichloromethane and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 3:1 hexane:ethyl acetate) to give 1-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-3-butenyl methyl sulphone as a mixture of diastereoisomers (approximately 20:1 by
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[N+:17]([O-])([OH:19])=[O:18].[N+]([O-])([O-])=O.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(CCc2ccccc2)cc(C)n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(CCc2ccc([N+](=O)[O-])cc2)cc(C)n1
Temperature: 50 °C

Procedure:
Compound (2) (20 g, 88.9 mmols) was dissolved in THF (150 ml), and nitric acid (6.7 ml, 60% aq. solution, 1 eq) was added. Diethylether was added to the clear solution until it remained turbid, and the mixture was left in the freezer for crystallization. The white crystals of nitrate (quantit. yield) were added in small portions to well-chilled sulfuric acid (150 ml), never allowing the temperature to reach 10° C., whereafter the mixture was warmed at 50° C. for 10 min. The resulting brown solution was poured onto ice and neutralized with solid sodium hydrogen carbonate. The organic material was extracted with chloroform (3×200 ml), and after drying over sodium sulphate, the chloroform extract was flash chromatographed using 4% ethanol/chloroform as a solvent. The appropriate fractions were collected and evaporated yielding a pure yellow solid
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:13]([OH:15])=O)[CH:10]=[CH:11][CH:12]=3)[N:8]=2)[CH2:3][CH2:2]1.Cl.Cl.[NH2:18][C@H:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:21]12[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22]1)[C@H:19]([NH:18][C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:6]3[O:5][C:4]([CH:1]4[CH2:2][CH2:3]4)=[N:8][C:7]=13)=[O:15])[CH2:20]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: O=C(O)c1cccc2oc(C3CC3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(C3CC3)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.2 %

Procedure:
A mixture of 2-cyclopropylbenzoxazole-4-carboxylic acid (65 mg, 0.32 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (64 mg, 0.32 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (123 mg, 0.64 mmol) and 1-hydroxybenzotriazole (86 mg, 0.64 mmol) in DMF (2 mL) was stirred at room temperature for 5 min, then triethylamine (0.17 mL, 1.28 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylbenzoxazole-4-carboxamide (43 mg, 43%) as a colorless semisolid: 1H NMR (500 MHz, CDCl3) δ 9.43 (d, J=7.0 Hz, 1H), 8.10 (dd, J=7.5, 1.0 Hz, 1H), 7.56 (dd, J=8.0, 2.0 Hz, 1H), 7.36 (t, J=8.5 Hz, 1H), 4.28-4.22 (m, 1H), 3.49 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.10-2.85 (m, 4H), 2.75 (dd, J=14.0, 4.5 Hz, 1H), 2.28-2.20 (m, 1H), 2.12-2.06 (m, 1H), 2.00-1.90 (m, 1H), 1.75-1.69 (m, 2H), 1.60-1.50 (m, 1H), 1.35-1.22 (m, 4H); MS (ESI+) m/z 312 (M+H); HPLC>99% (AUC), tR=12.31 min.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].O.NN.Cl>C(O)COCCO.O>[CH:1]1([CH2:6][C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(c1cccs1)C1CCCC1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Product: c1csc(CC2CCCC2)c1

Procedure:
The material from step 33a above (12.28 g ) was dissolved in 100 mL of diethylene glycol. KOH (11.20 g, 200 mmol) was added and dissolved. Hydrazine hydrate (8.25 mL, 170 mmol) was added, and the reaction was heated to gentle reflux for 18 hours. After cooling, the reaction was diluted with water, neutralized with 66 mL of 3 N HCl and extracted with 3×100 mL of hexane. The extract was dried over MgSO4, filtered through a pad of silica gel and evaporated on a rotary evaporator to give 6.58 g of the title product. NMR (CDCl3) δ:1.21 (m, 2H), 1.61 (m, 4H), 1.81 (m, 2H), 2.14 (septet, 1H), 2.81 (d, 2H), 6.79 (dd, J=4 Hz, 1H), 6.91 (dd, J=4, 5 Hz, 1H), 7.11 (dd, J=1, 5 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH2:39]/[C:40](=[N:54]\O)/[C@@H:41]1[CH2:46][CH2:45][CH2:44][CH2:43][N:42]1[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48]>C(Cl)Cl.O>[NH2:54]/[C:40](=[N:39]\[O:10][C:9](=[O:11])[C@@H:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)/[C@@H:41]1[CH2:46][CH2:45][CH2:44][CH2:43][N:42]1[C:47]([O:49][C:50]([CH3:52])([CH3:51])[CH3:53])=[O:48]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1/C(N)=N/O
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O/N=C(\N)[C@@H]1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (2R)-2-(2-tert-butoxy-2-oxoethyl)-5-cyclohexylpentanoic acid (preparation 168) (500 mg, 1.67 mmol) in DCM (20 ml) was treated with HOBt (227 mg, 1.67 mmol), NMM (203 μl, 1.85 mmol) and WSCDI (354 mg, 1.85 mmol) followed by tert-butyl(2S)-2-[(Z)-amino(hydroxyimino)methyl]-1-piperidinecarboxylate (WO 9945006) (406 mg, 1.67 mmol) and stirred at room temperature, under a nitrogen atmosphere for 18 hours. H2O (10 ml) was added and after 10 minutes the reaction mixture was separated in a 5 micron filter cartridge. The solvent was removed under reduced pressure to afford the title compound as a colourless foam.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]2=[N:23][C:24]3[C:37]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[N:31]([CH3:38])[C:30]4[C:25]=3[C:26]([CH:27]=[C:28](O)[CH:29]=4)=[C:19]2[CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]2=[N:23][C:24]3[C:37]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[N:31]([CH3:38])[C:30]4[C:25]=3[C:26]([CH:27]=[C:28]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:29]=4)=[C:19]2[CH:18]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CN1c2ccccc2-c2nc3ccc(Cl)cc3c3cc(O)cc1c23
Solvent: ClCCl
Product: CN1c2ccccc2-c2nc3ccc(Cl)cc3c3cc(OS(=O)(=O)C(F)(F)F)cc1c23
Temperature: 25 °C
Yield: 67 %

Procedure:
(Method L) Under an atmosphere of nitrogen, trifluoromethanesulphonic acid anhydride (1.14 ml, 6.4 mmol, 1 eq) was added dropwise to a stirred cold (0° C.) suspension of 3-chloro-6-hydroxy-8-methyl-8H-quino[4,3,2-kl]acridine, 36 (2.23 g, 6.4 mmol) in DCM (1 L). On warming to RT a green solution was formed. Aqueous work-up (water, 500 mL), separation of the organic layer, drying (MgSO4), filtering, adsorption onto silica, and column chromatography (85:15 hexane:ethyl acetate) gave the title compound as a yellow solid, (2 g, 4.3 mmol, 67%).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:6])=[CH:3]/[C:4]#[N:5].C[O:8][C:9](=O)[C:10]#[CH:11].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>CN(C=O)C>[CH3:6][C:2]1[NH:1][C:9](=[O:8])[CH:10]=[CH:11][C:3]=1[C:4]#[N:5]
Reactant: C/C(N)=C\C#N
Reactant: C#CC(=O)OC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1[nH]c(=O)ccc1C#N

Procedure:
A solution of (E)-3-amino-but-2-enenitrile (100 g) and propynoic acid methyl ester in DMF (200 ml) was stirred at 25° C. for 2 h and refluxed for additional 1 h. Dowtherm (100 ml) was added and the temperature was rised to 230° C. DMF and MeOH were distilled off. The reaction mixture was cooled down, EtOAc (200 ml) was added and the resulting crystals were filtered off and washed with EtOAc and ether affording the title compound (44.8 g, FP>250° C.).
Reaction SMILES: [CH2:1]([Mg])[CH3:2].[F:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH:26]=[O:27])[CH:24]=4)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[Cl-].[NH4+].C(OCC)(=O)C>CCOCC.O1CCCC1>[F:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH:26]([OH:27])[CH2:1][CH3:2])[CH:24]=4)[CH2:19][CH2:18]3)[CH2:15][CH2:16]2)=[CH:7][CH:6]=1
Reactant: O=Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reactant: CC[Mg]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCC(O)c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Temperature: 25 °C
Yield: 66 %

Procedure:
A 3 M solution (1.4 ml) of ethylmagnesium in ether was added dropwise at −78° C. into a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindoline (1.0 g) in tetrahydrofuran (30 ml) and the resultant mixture was allowed to warm to room temperature. Then a saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution and the layers were separated. The organic layer was washed with brine and dried over magnesium sulfate. After removing the solvent, the residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (710 mg) as a colorless oil (yield: 66%).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:21])[CH2:16][C:17](=[O:20])[CH2:18]Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=[O:23].[Na+]>CO>[C:1]1([CH:7]([O:14][C:15](=[O:21])[CH2:16][C:17](=[O:20])[CH2:18][OH:23])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C[O-]
Reactant: O=C(CBr)CC(=O)OC(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CO
Product: O=C(CO)CC(=O)OC(c1ccccc1)c1ccccc1
Yield: 47.1 %

Procedure:
To a solution of 4-bromo-3-ketobutyric acid diphenylmethyl ester (2b, 11.4 g, 32.8 millimoles) in methanol dried with Molecular Sieves is added sodium formate (3.40 g, 50.0 millimoles), and the mixture is refluxed for 4 hours. The reaction mixture is filtered to remove solid material concentrated under reduced pressure, and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and evaporated to remove the solvent. The residue is purified by chromatography over Lobar® column B using a mixture of benzene and ethyl acetate (3:1) as eluting solvent to afford the title compound (3b, 4.39 g, 47%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH:20]([N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])=[CH2:21].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C>[OH:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:21]=[CH:20][N:22]2[C:23](=[O:32])[C:24]3[C:25](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:27])=[CH:3][CH:4]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: C=CN1C(=O)c2ccccc2C1=O
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1C=Cc1ccc(CCO)cc1
Temperature: 90 °C
Reaction time: 21 h

Procedure:
To a solution of 2-(4-bromophenyl)ethanol (48.3 g) in acetonitrile (480 mL) was added diisopropylethylamine (46.6 g), N-vinylphthalimide (43.7 g) and tri-o-tolylphosphine (7.31 g) and the mixture was purged with nitrogen gas three times. Palladium acetate (2.7 g) was added and the mixture was stirred at 90° C. for 21 hr under nitrogen. The reaction was cooled and the precipitated product collected by filtration. The resulting solid was re-dissolved in dichloromethane and ethyl acetate and filtered through silica gel. The filtrate was concentrated in vacuo to give the title compound, 24 g.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:15]>C1COCC1.CCOC(C)=O>[CH3:15][N:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][N:10]=[CH:9]1
Reactant: CI
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cncc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.2 %

Procedure:
To a solution of 4-phenylimidazole (500 mg, 3.47 mmol) in 10 mL THF at rt, was added 60% NaH (146 mg, 3.64 mmol). The mixture was stirred at rt for 5 min, then iodomethane (238 μL, 3.82 mmol) was added. The mixture was stirred at rt for 30 min, then was diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (column #1: 0 to 10% MeOH/CH2Cl2 gradient, column #2: 1 to 2 to 5% MeOH/EtOAc, stepwise gradient) to afford 352 mg of Intermediate 13.1 and 166 mg of Intermediate 13.2.
Reaction SMILES: [Br:1][C:2]1[C:6]([N:7]([CH3:9])[CH3:8])=[C:5](Br)[S:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(O)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:6]([N:7]([CH3:9])[CH3:8])=[C:5]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)[S:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1sc(Br)c(N(C)C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(N(C)C)c1Br
Temperature: 25 °C
Yield: 76.6 %

Procedure:
To a solution of Ethyl 3,5-dibromo-4-(dimethylamino)thiophene-2-carboxylate (compound 34c, 3.0 g, 8.40 mmol) in a mixture of toluene:ethanol (5 ml:30 ml) was added (4-chlorophenyl)boronic acid [1.44 g, 9.24 mmol] and potassium carbonate (2.32 g, 16.80 mmol) at 25° C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.48 g, 0.42 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 95 to 100° C. for 3 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite, the celite cake was then washed with ethyl acetate (50 ml). The filtrate so obtained was then concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 12% ethyl acetate in hexanes as an eluent to obtain the title compound (2.5 g, 76.56%).
Reaction SMILES: [N:1]1([C:16]([O:18][CH:19]2[CH:26]3[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:28][CH:20]2[CH2:21]4)[CH2:25]3)=[O:17])[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8][CH2:7]2)[CH2:3][CH2:2]1.[CH2:29]([O:31][C:32]([C@@H:34]1[CH2:36][C@H:35]1[C:37](O)=[O:38])=[O:33])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.C(Cl)Cl>[CH2:29]([O:31][C:32]([C@@H:34]1[CH2:36][C@H:35]1[C:37]([N:8]1[CH2:7][C:4]2([CH2:5][CH2:6][N:1]([C:16]([O:18][CH:19]3[CH:20]4[CH2:28][CH:24]5[CH2:23][CH:22]([CH2:27][CH:26]3[CH2:25]5)[CH2:21]4)=[O:17])[CH2:2][CH2:3]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:38])=[O:33])[CH3:30]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
Reactant: O=C(OC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNCc1ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1C(=O)N1Cc2ccccc2C2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)C1
Reaction time: 1 h
Yield: 69.1 %

Procedure:
2-Adamantyl 2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate (12 mg, 0.025 mmol), trans-2-(ethoxycarbonyl)cyclopropanecarboxylic acid (8 mg, 2.5 equiv), HATU (11 mg, 1.15 equiv), DIEA (13 μL, 3 equiv) were mixed with CH2Cl2 (2 mL) and put on shaker for 1 h at rt. The mixture was diluted with EtOAc (8 mL), washed with 3% aq HCl (2×3 mL), concentrated and purified by preparative HPLC to afford 2-adamantyl 2-((1R,2R)-2-(ethoxycarbonyl)cyclopropanecarbonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate (9 mg, 69%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.CN(CCN(C)C)C.[Li]CCCC.[Sn](Cl)(C)(C)C.Br[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=[O:30].[F-].[K+]>C1COCC1.C(OCC)(=O)C.O1CCOCC1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=[O:30]
Reactant: Cn1cccc1
Reactant: O=Cc1cccc(Br)c1
Agent: CN(C)CCN(C)C
Agent: C[Sn](C)(C)Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1cccc1-c1cccc(C=O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
EX-602A) To solution of N-methylpyrrole (0.97 mL, 11 mmol) in Et20 (20 mL) was added neat TMEDA (1.5 mL. 10 mmol) and 1.6 M n-BuLi in hexanes (6.3 mL, 10 mmol). The solution was heated to reflux under N2 for 1 h and then cooled to −78° C. A 1.0 M solution of Me3SnCl in THF was added over 15 min, and the resulting solution stirred for 30 min at −78° C. After warming to room temperature, 3-bromo-benzaldehyde (0.70 mL, 6.0 mmol), Pd(PPh3)2C2 (0.25 g, 0.35 mmol) and dioxane (10 mL) were added. The slurry was heated to reflux for 18 h. The cooled mixture was poured into a mixture of saturated KF and ethyl acetate and stirred 15 min. The slurry was filtered through celite. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 5% ethyl acetate in hexane gave 0.45 g (24%) of the desired 3-(1-methyl-1H-pyrrol-2-yl)benzaldehyde product as a yellow oil. MS: m/z=186.2 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]([CH3:11])[CH2:8][CH2:9][NH2:10].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:6][N:7]([CH3:11])[CH2:8][CH2:9][NH:10][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)CCNS(C)(=O)=O
Reaction time: 1.5 h

Procedure:
Methanesulfonyl chloride (Compound 19, 2.6 ml, 34.0 mmol) was added to a mixture of N,N-dimethylethylenediamine (3.7 ml, 34.0 mmol) and diisopropylethylamine (5.93 ml, 34.0 mmol) in tetrahydrofuran (30 ml) at 0° C. After 1.5 hours stirring at 0°, the mixture was quenched with water and extracted thoroughly with ethyl acetate. Evaporation of the dried (magnesium sulfate) extract gave an oil, which was purified by flash chromatography on silica using 20% methanol/chloroform to give the title sulfonamide. 1HNMR(CDCl3): 2.24 (s, 6H), 2.48 (t, 2H, J=5.9 Hz), 2.97 (s, 3H), 3.18 (t, 2H, J=5.6 Hz). 13CNMR(CDCl3): 39.3, 39.9, 44.5 and 57.8.