Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH3:15])[C:6]=2[CH:16]=1.[Br:17]C1CC(=O)NC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:15][C:7]1[C:6]2[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][C:8]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C1CC(Br)C(=O)N1
Reactant: CCOC(=O)c1oc2ccc(Cl)cc2c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1oc2ccc(Cl)cc2c1CBr
Yield: 75.6 %

Procedure:
A mixture of ethyl 5-chloro-3-methyl-2-benzofurancarboxylate (52.5 g, 0.22 mol), N bromosuccinimide (39.15 g, 0.22 mol) and benzoyl peroxide (0.4 g) in carbon tetrachloride (750 ml) was stirred and refluxed for 10 hours. The mixture was cooled, filtered and the filtrate was concentrated. The crude product was recrystallized from hexane to give 52.8 g (76%) of ethyl 3-bromomethyl-5-chloro-2-benzofurancarboxylate: mp 112°-114° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH2:13][C@@:12]3([CH2:18][CH2:17][CH2:16][C@@:15]([CH2:20][N:21]4[C:25]5[CH:26]=[C:27]([C:30]#[N:31])[CH:28]=[CH:29][C:24]=5[N:23]=[CH:22]4)([CH3:19])[CH2:14]3)[O:11][C:10]2=[O:32])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:39][N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1>O1CCOCC1.O.C([O-])(O)=O.[Na+]>[CH3:19][C@:15]1([CH2:20][N:21]2[C:25]3[CH:26]=[C:27]([C:30]#[N:31])[CH:28]=[CH:29][C:24]=3[N:23]=[CH:22]2)[CH2:16][CH2:17][CH2:18][C@:12]2([O:11][C:10](=[O:32])[N:9]([CH2:8][C:4]3[CH:3]=[C:2]([C:43]4[CH:42]=[N:41][N:40]([CH3:39])[CH:44]=4)[CH:7]=[CH:6][N:5]=3)[CH2:13]2)[CH2:14]1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CN(Cc3cc(Br)ccn3)C(=O)O2)C1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccnc(CN3C[C@@]4(CCC[C@](C)(Cn5cnc6ccc(C#N)cc65)C4)OC3=O)c2)cn1
Reaction time: 0.33 h
Yield: 98.9 %

Procedure:
To a microwave vial was added 1-(((5S,7S)-3-((4-bromopyridin-2-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 0.202 mmol), sodium carbonate (64.3 mg, 0.607 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (63.1 mg, 0.303 mmol), and PdCl2(dpV) (14.80 mg, 0.020 mmol) in 1,4-Dioxane (3.0 mL) and Water (1.000 mL). The mixture was subjected to the microwave at 120° C. for 20 minutes. The mixture was diluted with saturated NaHCO3 and extracted with DCM (3×). The combined DCM extracts were passed through a phase separator and concentrated. The residue was purified via reverse HPLC (Waters Sunfire 30×150 mm Acetonitrile:Water TFA 20-60%, 50 mL/min, 15 min). The product was free based with PL-HCO3 resin SPE to yield 1-(((5S,7S)-7-methyl-3-((4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (99 mg, 94%). 1H NMR (400 MHz, DMSO-d6) δ 8.50-8.61 (m, 3H), 8.38 (s, 1H), 8.22 (s, 1H), 7.85 (d, J=8.28 Hz, 1H), 7.73-7.82 (m, 2H), 7.61 (dd, J=8.28, 1.25 Hz, 1H), 4.53 (dd, J=21.83, 16.31 Hz, 2H), 4.07-4.20 (m, 2H), 3.93 (s, 3H), 3.28 (dd, J=19.07, 8.78 Hz, 2H), 1.97 (d, J=13.30 Hz, 1H), 1.79 (d, J=14.56 Hz, 1H), 1.52-1.73 (m, 3H), 1.25-1.49 (m, 3H), 1.05 (s, 3H). MS (m/z) 496.3 (M+H+).
Reaction SMILES: C1(COC2C(C3N(CC4C=CC(CCC(O)=O)=CC=4)C4C=C(F)C(F)=CC=4N=3)=CC=CN=2)CC1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:46]([CH2:47][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=2)=[C:38]([O:60][CH2:61]C2C=CC=CC=2Cl)[CH:37]=1.BrCC1C=CC=C([Cl:77])C=1>>[Cl:77][C:50]1[CH:49]=[C:48]([CH:53]=[CH:52][CH:51]=1)[CH2:47][N:46]1[C:45]2[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=2[N:43]=[C:42]1[C:39]1[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][C:38]=1[O:60][CH3:61]
Reactant: Clc1cccc(CBr)c1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3OCc3ccccc3Cl)n(CC3CCCCC3)c2cc1F
Agent: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Product: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1cccc(Cl)c1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and 1-bromomethyl-3-chloro-benzene (CAS Reg. No. 766-80-3). Brown sticky solid (95%). MS (Turbo Spray): m/z=419.2 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[H-].[Na+].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C>[O:10]=[C:2]1[N:3]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1]1
Reactant: O=c1[nH]c2ccccc2o1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)oc2ccccc21
Reaction time: 1 h
Yield: 103.1 %

Procedure:
A solution of 1,3-benzoxazol-2(3H)-one (676 mg, 5.0 mmol) in (5 mL) was added to a suspension of NaH (220 mg, 5.5 mmol) in DMF (5 mL) at room temperature, and the resulting solution was stirred for 1 h. Ethyl bromoacetate (0.55 mL, 5.0 mmol) was added to the reaction mixture, and stirring was continued for 2 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (2×20 mL). The organic extracts were combined and washed with water, brine, and dried (Na2SO4). The solvent was removed under reduced pressure to give the title compound (1.14 g, >100%) as a brown solid. MS (ES) m/e 222 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][NH2:10].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21](OCC)=[O:22])[N:20]=2)[CH:17]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21]([NH:10][CH2:9][C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[O:22])[N:20]=2)[CH:17]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: Cc1cccc(Cl)c1CN
Product: Cc1cccc(Cl)c1CNC(=O)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (2-chloro-6-methylphenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13](O)=[O:14])[CH:9]=[CH:10][CH:11]=1.F[P-](F)(F)(F)(F)F.[N:28]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.N>CN(C=O)C>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([NH2:28])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(C)c1COc1cccc(CC(=O)O)c1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1COc1cccc(CC(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(2,6-Dimethylbenzyloxy)phenylacetic acid (3.08 g, 11.4 mmol) and Benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (5.05 g, 11.4 mmol) in DMF (75 ml) was added triethylamine (2.30 g, 22.8 mmol), and the reaction mixture was stirred for 1 h at room temperature. To this reaction mixture was added liquid ammonia (100 ml) at −40 0° C., the resulting mixture was allowed to warm to ambient temperature over 10-12 hours and concentrated. The residue was taken into ethyl acetate and washed with water (2×), dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (ethyl acetate:hexane, 2.5:1 spiked with acetic acid) to give the title compound.
Reaction SMILES: C(Cl)CCl.[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:45]=[CH:44][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1.[CH2:46]([O:49][CH2:50][CH2:51][C:52](O)=[O:53])[C:47]#[CH:48].ON1C(=O)CCC1=O>C(Cl)Cl>[CH2:46]([O:49][CH2:50][CH2:51][C:52]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:45]=[CH:44][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1)=[O:53])[C:47]#[CH:48]
Reactant: C#CCOCCC(=O)O
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCNc1ccc(C(=O)c2ccc(OCCCN)cc2)cc1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: ClCCCl
Product: C#CCOCCC(=O)NCCCOc1ccc(C(=O)c2ccc(NCCOCCOCCOCCOCCC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
EDC (0.77 g, 4.00 mmol) was added to a solution of tert-butyl 1-((4-(4-(3-aminopropoxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oate (2.00 g, 3.48 mmol), 3-(prop-2-yn-1-yloxy)propanoic acid (0.45 g, 3.48 mmol) and N-hydroxysuccinimide (0.06 g, 0.52 mmol) in DCM (12 mL) at r.t. and the reaction mixture was stirred for 4 hs at room temperature. Upon completion, reaction was concentrated under reduced pressure and purified by silica gel chromatography (EtOAc toEtOAc:MeOH, gradient) to provide 2.12 g (3.10 mmol, 89% yield) of tert-butyl 1-((4-(4-(3-(3-(prop-2-yn-1-yloxy)propanamido)propoxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oate as slightly yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH:18]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:17][CH2:16]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[OH-:27].[Na+]>C(O)C>[NH2:2][C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17][CH:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][CH2:20]2)(=[O:10])=[O:11])=[CH:5][CH:4]=1)=[O:27]
Reactant: CCOC(=O)CC1CCC(CCNS(=O)(=O)c2ccc(C#N)cc2)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc(S(=O)(=O)NCCC2CCC(CC(=O)O)CC2)cc1
Yield: 72 %

Procedure:
by saponification of the ethyl 4-[2-(4-cyanobenzenesulphonylamino)-ethyl]-cyclohexylacetate with 2N sodium hydroxide solution in ethanol analogously to EXAMPLE 2c). Yield 72% of theory; m.p. 172-174° C. after recrystallisation from isopropanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[N:17]=[CH:16][C:15]([O:18][C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)[CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.I[CH2:48][C:49]([NH2:51])=[O:50].O>CN(C)C=O>[NH2:51][C:49](=[O:50])[CH2:48][N:17]1[C:12](=[N:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:36])[F:34])[CH:28]=3)[CH:22]=[CH:23][CH:24]=2)=[CH:16]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)cn2)cc1
Reactant: NC(=O)CI
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.5 %

Procedure:
To a solution of N-{3-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (2.7 g, 5.12 mmol) in N,N-dimethylformamide (18 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.94 mL, 5.38 mmol), and the mixture was stirred at room temperature for 15 min. 2-Iodoacetamide (995 mg, 5.38 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hr. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with water (100 mL) and saturated brine (100 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→0/100) and recrystallized from ethyl acetate and hexane to give the title compound (1.84 g, 61%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][O:11][C:10](=[O:14])[CH:9]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(C)C)(=O)C>[CH2:1]([N:8]1[CH:13]=[CH:12][O:11][C:10](=[O:14])[C@@H:9]1[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC=CN(Cc2ccccc2)C1c1ccc(F)cc1
Solvent: CC(=O)OC(C)C
Product: O=C1OC=CN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of N-benzyl-4-fluorophenyl-1,4-oxazin-2-one (5 g) in isopropyl acetate (16.76 ml) was diluted with isopropyl acetate (37.6 ml) and a solution of (-)-3-bromocamphor-8-sulphonic acid ((-)-3-BCS) (5.73 g) in isopropyl acetate (20.67 ml) added at room temperature. Crystallisation began after approximately 20 minutes. The mixture was stirred for 1 hour at room temperature and then stirred at 75° C. for 9 days. The mixture was then cooled to room temperature, aged at 0°-5° C. for 1 hour and the solid collected, washed with isopropyl acetate to give the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3-BCS salt: yield 10.5 g, ee 96.5% (S) isomer.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH2:8])(=[O:4])=[O:3].C(=O)([O-])O.[K+].[Cl:20][CH2:21][C:22](Cl)=[O:23].CC(C)=O.C(OC(C)C)(C)C>C(OCC)(=O)C.O>[Cl:20][CH2:21][C:22]([NH:8][C:7]1[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=1)=[O:23]
Reactant: CS(=O)(=O)c1cc(N)cc([N+](=O)[O-])c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: CS(=O)(=O)c1cc(NC(=O)CCl)cc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 42.9 %

Procedure:
3-(Methylsulfonyl)-5-nitro-aniline (4.3 g; 19.89 mmol) was diluted in 60 ml of ethyl acetate and a solution of potassium hydrogen carbonate (219 g, 21.87) in 10 ml of water was added. The reaction mixture was stirred at 0° C. and chloroacetylchloride (2.47 ml; 21.87 mmol) was added dropwise. The reaction mixture was allowed to reach room temperature and stirred for 2 h. Then, the phases were separated. The organic phase was dried on MgSO4 and concentrated under vacuum. The oil obtained was treated with acetone/di-isopropyl ether (1/5) and the solid obtained was filtered. 2.5 g (8.54 mmol; 43% yield) of the desired 2-Chloro-N-(3-methanesulfonyl-5-nitro-phenyl)-acetamide were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([OH:17])=[O:16])=[O:8])=[CH:3][CH:2]=1>[OH-].[Na+]>[N:1]1[CH:6]=[CH:5][C:4]([C:7]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[C:15]([OH:17])=[O:16])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(c1ccncc1)[C@H]1CCCC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H]1CCCC[C@H]1C(=O)c1ccncc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Cis-2-(4-pyridylcarbonyl)cyclohexanecarboxylic acid was dissolved in 10% sodium hydroxide (300 mL) and stirred at 20° C. for 16 h. The aqueous solution was extracted with diethyl ether (200 mL) and then acidified to pH=4 by addition of 6 M hydrochloric acid. The resulting precipitate was collected and recrystallized from hot water, to give (1S, 2R)-2-(4-pyridylcarbonyl)cyclohexanecarboxylic acid, as a white solid (4.8 g, 40% from cis-1,2-cyclohexanedicarboxylic anhydride).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][CH:40]([N:43]([CH3:45])[CH3:44])[CH2:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.C(Cl)(Cl)Cl>CO.C(OCC)(=O)C.[C].[Pd]>[CH3:45][N:43]([CH3:44])[CH:40]1[CH2:39][CH2:38][N:37]([C:34]2[CH:35]=[CH:36][C:9]([OH:8])=[C:10]([CH:33]=2)[C:11]([NH:13][C:14]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][C:15]=2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])[CH2:42][CH2:41]1
Reactant: CN(C)C1CCN(c2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)C1CCN(c2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(4-(dimethylamino)piperidin-1-yl)benzamido)-4-phenylbenzoate (0.13 g) in methanol (1.5 mL) and ethyl acetate (1.5 mL), 10% palladium-carbon (0.13 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. Chloroform was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0.066 g of tert-butyl 2-(5-(4-(dimethylamino)piperidin-1-yl)-2-hydroxybenzamido)-4-phenylbenzoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].Cl[C:28]1[C:37]([CH3:38])=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1.[H-].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:26])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][O:25][C:28]3[C:37]([CH3:38])=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6]
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(CO)cc2)cc1)C(C)C
Reactant: Cc1cc2ccccc2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(COc3nc4ccccc4cc3C)cc2)cc1)C(C)C
Temperature: 100 °C
Reaction time: 5 h
Yield: 12.2 %

Procedure:
Step 1C [Intermediate 3: 2-(4′-Hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester (1.2 g, 3.2 mmol, 1.0 equiv.), 2-chloro-3-methyl quinoline (2.26 g, 12.7 mmol, 4 equiv.) were dissolved in DMF (30 mL) followed by the addition of NaH (382 mg, 60% in oil, 9.54 mmol, 3 equiv.). The mixture was stirred at 100° C. for 5 hrs, then at room temperature overnight. The reaction mixture was then poured into cold water, solid precipitated from the mixture was collected by filtration and washed with water. Regular column chromatography (Silica gel, 1% MeOH/CH2Cl2) to yield 203 mg of 3-Methyl-2-[4′-(3-methyl-quinolin-2-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid methyl ester in 12% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:27][O:28][C:29]1[N:30]=[CH:31][C:32]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:10])=[O:11])=[C:4]([C:23]([F:25])([F:26])[F:24])[CH:3]=2)=[CH:33][CH:34]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(C(F)(F)F)c2)cn1
Yield: 76.4 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.10 g) and 2-methoxy-5-pyridineboronic acid (0.065 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (0.8 ml) with tetrakis(triphenylphosphine)palladium (0.012 g) to obtain the title compound (0.081 g) as a colorless solid. MS (ISP): 497.3 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][C@H:5]([C:25]1[S:26][C:27](Br)=[CH:28][CH:29]=1)[NH:6][C:7]([C:9]1[C:10](=[O:24])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)=[O:8].[C:32]1([S:38]([N:41]2[C:45]3=[N:46][CH:47]=[CH:48][CH:49]=[C:44]3[C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42]2)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.ClCCl.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>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]>[CH3:1][O:2][C:3](=[O:31])[CH2:4][C@H:5]([C:25]1[S:26][C:27]([C:43]2[C:44]3[C:45](=[N:46][CH:47]=[CH:48][CH:49]=3)[N:41]([S:38]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)(=[O:40])=[O:39])[CH:42]=2)=[CH:28][CH:29]=1)[NH:6][C:7]([C:9]1[C:10](=[O:24])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: COC(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(Br)s1
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)s1
Temperature: 100 °C

Procedure:
Into a Vial was dissolved (R)-3-(5-Bromo-thiophen-2-yl)-3-{[1-(3,4-difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-propionic acid methyl ester (0.080 g, 0.16 mmol;), 1-Benzenesulfonyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.1 mmol;) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (17 mg, 0.021 mmol; Strem;) in 1,4-Dioxane (2.21 mL, 28.4 mmol; Acros;). To this was added 2.0 M of Sodium carbonate in water (0.55 mL). The reaction was purged with Argon and sealed. The reaction was heated at 100° C. under an atmosphere of Argon for 2 hours. LC-MS showed the formation of product at 1.97 with the correct mass 689.16. The reaction was worked up by dissolving in methylene chloride then washing 1× with citric acid, 1× with saturated bicarbonate, and 1× with brine before drying with magnesium sulfate and concentrating to give the crude product. The crude was dissolved in dichloromethane and the purified by combiflash using a 0-100 percent hexanes/ea gradient to give the pure product. ES (+) MS m/e=689.16
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:4]=1[CH2:5][N:6]1[C:11]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]([CH2:22][CH2:23]OS(C)(=O)=O)=[CH:15]3)=[C:10]([CH2:29][CH3:30])[CH:9]=[C:8]([C:31]([O:33][CH3:34])=[O:32])[C:7]1=[O:35].[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1.C([O-])(O)=O.[Na+]>CC#N>[CH3:1][O:2][C:3]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:4]=1[CH2:5][N:6]1[C:11]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]([CH2:22][CH2:23][N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:15]3)=[C:10]([CH2:29][CH3:30])[CH:9]=[C:8]([C:31]([O:33][CH3:34])=[O:32])[C:7]1=[O:35]
Reactant: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CCOS(C)(=O)=O)n2C
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CCN1CCCC1)n2C
Temperature: 80 °C
Yield: 62.8 %

Procedure:
To solution of methyl 1-(2,4-dimethoxybenzyl)-5-ethyl-6-(1-methyl-2-(2-(methylsulfonyloxy)ethyl)-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (0.233 g, 0.40 mmol) in CH3CN (2 mL) was added pyrrolidine (0.15 mL, 1.83 mmol). Reaction mixture was heated at 80° C. for 1.5 h until complete consumption of starting material was observed. Then NaHCO3 (aqueous saturated, 5 mL) was added to the reaction and product was extracted with DCM (3×10 mL). Combined organics were washed with NaCl (aqueous saturated, 5 mL) and dried over Na2SO4. Upon solvent removal residue was purified by column chromatography using MeOH/DCM (gradient 0-10%) to afford methyl 1-(2,4-dimethoxybenzyl)-5-ethyl-6-(1-methyl-2-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (0.140 g) in 62% yield.