Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14](B4OC(C)(C)C(C)(C)O4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.Cl[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[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].O.C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([C:25]4[CH:30]=[C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH:28]=[CH:27][N:26]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(n1)oc1c(B3OC(C)(C)C(C)(C)O3)cccc12
Reactant: Clc1cc(-c2ccccc2)ccn1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(n1)oc1c(-c3cc(-c4ccccc4)ccn3)cccc12
Yield: 77.5 %

Procedure:
A mixture of 2-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuro[2,3-b]pyridine (4.34 g, 14.03 mmol), 2-chloro-4-phenylpyridine (2.66 g, 14.03 mmol), Pd2(dba)3 (0.257 g 0.281 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.582 g, 1.42 mmol), potassium phosphate (8.93 g, 42.1 mmol), toluene (180 mL) and water (28 mL) was degassed with nitrogen and then refluxed overnight. The mixture was concentrated and extracted with ethyl acetate. The ethyl acetate layer was dried on Na2SO4 and then further purified by column chromatography using ethyl acetate in hexanes to give 2-methyl-8-(4-phenylpyridin-2-yl)benzofuro[2,3-b]pyridine (3.66 g, 10.88 mmol, 78% yield).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:11]([C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16](OC)=[O:17])=[C:12]=[S:13]>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:16](=[O:17])[C:15]4[C:14](=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:11][C:12]3=[S:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: COC(=O)c1ccccc1N=C=S
Solvent: C1CCOC1
Product: O=c1c2ccccc2[nH]c(=S)n1-c1ccc2[nH]cnc2c1

Procedure:
1H-benzo[d]imidazol-5-amine (0.14 g, 1.08 mmol) and methyl 2-isothiocyanatobenzoate (0.21 g, 1.08 mmol) were dissolved ind 10 mL of THF. The mixture was stirred by heating under reflux over night. The resulted insoluble solid was separated by suction through a frit and washed with THF to give a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]\[SH:9])[CH:2]=1.[I-].[Na+].[CH:12]1([O:15][N:16]=[C:17]([C:48]2[N:49]=[C:50]([NH:53][CH:54]=[O:55])[S:51][CH:52]=2)[C:18]([NH:20][C@@H:21]2[C:46](=[O:47])[N:23]3[C:24]([C:30]([O:32][CH:33]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])=[C:25]([CH2:28]Cl)[CH2:26][S:27][C@H:22]23)=[O:19])[CH2:14][CH2:13]1.[Cl-].[Na+]>C(#N)C.[Ag].C(OCC)(=O)C>[CH:12]1([O:15][N:16]=[C:17]([C:48]2[N:49]=[C:50]([NH:53][CH:54]=[O:55])[S:51][CH:52]=2)[C:18]([NH:20][C@@H:21]2[C:46](=[O:47])[N:23]3[C:24]([C:30]([O:32][CH:33]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])=[C:25]([CH2:28][S:9]/[CH:8]=[CH:7]\[C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH2:26][S:27][C@H:22]23)=[O:19])[CH2:14][CH2:13]1
Reactant: O=CNc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)cs1
Reactant: S/C=C\c1cccnc1
Agent: [Ag]
Agent: [Cl-]
Agent: [I-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=CNc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CS/C=C\c4cccnc4)CS[C@H]23)cs1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60.2 %

Procedure:
A mixture of silver salt of (Z)-2-(3-pyridyl)ethenethiol (2.03 g) and sodium iodide (3.36 g) in acetonitrile (40 ml) was stirred for 20 minutes at 0° C. in the dark. To the mixture was added benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (2.03 g) at -20° C., and the mixture was stirred at 0° C. for 1.5 hours. The mixture was poured into a mixture of saturated aqueous solution of sodium chloride (200 ml) and ethyl acetate (100 ml). The insoluble material was filtered off and the organic layer was separated. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (1.41 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[CH:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:11][CH2:10]2)(=O)=O.[CH3:24][N:25]1CCCC1=O>CCOC(C)=O.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].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.[Fe+2].[C-]#N.[C-]#N.[Zn+2]>[C:24]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[CH:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:11][CH2:10]2)#[N:25]
Reactant: COC(=O)CC1CCc2cc(OS(=O)(=O)C(F)(F)F)c(C)cc21
Reactant: CN1CCCC1=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)CC1CCc2cc(C#N)c(C)cc21
Temperature: 100 °C

Procedure:
To a solution of methyl (5-trifluoromethylsulfonyloxy-6-methylindan-1-yl)acetate (405 mg, 1.15 mmol, from Step E) in N-methylpyrrolidinone (5 mL), Pd2dba3 (5.00 mg, 0.00546 mmol), dppf (7 mg, 0.0127 mmol) and Zn(CN)2 were added under Ar. The reaction mixture was heated to 100° C. for 15 hr, cooled to ambient temperature and diluted with EtOAc. The organic layer was washed several times with H2O, dried (brine, MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (10% EtOAc/hexanes) on SiO2 afforded the 176 mg of the title compound as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.71-1.90 (m, 1H), 2.36-2.60 (m, 5H), 2.71-2.82 (m, 1H), 2.82-2.96 (m, 2H), 3.55-3.68 (m, 1H), 3.76 (s, 3H), 7.11 (s, 1H), 7.47 (s, 1H).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[CH3:5][CH:6]1[CH2:12][C:11]2[CH:13]=[C:14]3[O:19][CH2:18][O:17][C:15]3=[CH:16][C:10]=2[C:9]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[N:8][NH:7]1>C(O)(=O)C>[CH3:5][CH:6]1[CH2:12][C:11]2[CH:13]=[C:14]3[O:19][CH2:18][O:17][C:15]3=[CH:16][C:10]=2[C:9]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[N:8][N:7]1[C:2](=[S:1])[NH2:3]
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Temperature: 105 °C
Reaction time: 6 h
Yield: 76.1 %

Procedure:
A mixture of 0.90 g (9.26 mmol) of potassium thiocyanate, 2.00 g (6.15 mmol) of (±)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine and 40 ml of acetic acid was stirred at 100-110° C. for 6 h. After cooling, the precipitated crystals were filtered off, washed with water and dried to yield 1.80 g (76%) of the title compound. Mp.: 242-243° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:30][CH3:31])[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18](F)[CH:17]=3)[N:13]=[C:12]3[NH:24][N:25]=[C:26]([CH3:27])[C:11]=23)[C:6]([CH3:29])([CH3:28])[CH2:5][NH:4]1)[CH3:2].[Cl:32]C1C=C(O)C=CC=1B1OCC(C)(C)CO1>>[Cl:32][C:17]1[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=1[C:14]1[N:13]=[C:12]2[NH:24][N:25]=[C:26]([CH3:27])[C:11]2=[C:10]([CH2:9][N:7]2[CH2:8][C:3]([CH2:30][CH3:31])([CH2:1][CH3:2])[NH:4][CH2:5][C:6]2([CH3:29])[CH3:28])[CH:15]=1
Reactant: CC1(C)COB(c2ccc(O)cc2Cl)OC1
Reactant: CCC1(CC)CN(Cc2cc(-c3ccc(O)c(F)c3)nc3[nH]nc(C)c23)C(C)(C)CN1
Product: CCC1(CC)CN(Cc2cc(-c3ccc(O)cc3Cl)nc3[nH]nc(C)c23)C(C)(C)CN1

Procedure:
The title compound was synthesized in a similar manner as Example 58 (4-[4-(5,5-Diethyl-2,2-dimethyl-piperazin-1-ylmethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl]-2-fluoro-phenol) employing 3-chloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenol in step (b).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([NH2:17])=[O:16])[CH:10]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]1[C:23]([CH3:24])=[C:22]([C:25](O)=[O:26])[C:21](=[O:28])[N:20]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.O>[CH3:18][N:19]1[C:23]([CH3:24])=[C:22]([C:25]([NH:1][C:2]2[N:7]=[CH:6][C:5]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]([C:15]([NH2:17])=[O:16])[CH:10]=3)=[CH:4][CH:3]=2)=[O:26])[C:21](=[O:28])[N:20]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NC(=O)c1cc(Oc2ccc(N)nc2)ccn1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 28 h
Yield: 25 %

Procedure:
To a suspension of 4-((6-aminopyridin-3-yl)oxy)picolinamide (230 mg, 1 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (237 mg, 1.02 mmol) in DCM (5 mL) was added EDCI (230 mg, 1.2 mmol) and HOAT (27 mg, 0.2 mmol). The reaction was stirred at 45° C. for 28 hours, then cooled to rt and diluted with water (10 mL) and DCM (20 mL). The organic phase was concentrated in vacuo and the residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=40/1) to give the title compound as a light grey solid (111 mg, 25%).
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:3]2[N:2]=[N:1][C:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4]2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)Cc1nnn[nH]1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nnn(Cc2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.8 %

Procedure:
Ethyl 2-(1H-1,2,3,4-tetrazol-5-yl)acetate (5.0 g, 32.0 mmol) was dissolved in dimethylformamide (20 ml), added with potassium carbonate (5.75 g, 41.6 mmol). The mixture was further added dropwise with 4-methoxybenzyl chloride (5.21 ml, 38.4 mmol) under ice cooling and stirred at the same temperature for 1 hour and 30 minutes and at room temperature for 15 hours. The solvent was evaporated, and the residue was diluted with toluene, washed with water and saturated brine, and dried over anhydrous sodium sulfate. Then, the solvent was evaporated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1, v/v) to obtain the title compound (3.78 g, 42.7%) as colorless oil.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:18]3[C:13](=[C:14]([OH:32])[C:15]4[C:24](=[O:25])[C:23]5[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=5[C:20](=[O:21])[C:16]=4[C:17]=3[OH:19])[CH2:12][C@@:11]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([NH2:38])[C@@H:3]1[O:39][CH:40]1[O:45][CH2:44][CH2:43][CH2:42][CH2:41]1.C[C@@H]1O[C@@H](O[C@@H]2C3=C(O)C4C(=O)C5C(=CC=CC=5OC)C(=O)C=4C(O)=C3C[C@@](O)(C(CO)=O)C2)C[C@H](N)[C@@H]1O[C@@H]1OCCCC1>>[CH3:1][CH:2]1[O:7][CH:6]([O:8][C@@H:9]2[C:18]3[C:13](=[C:14]([OH:32])[C:15]4[C:24](=[O:25])[C:23]5[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=5[C:20](=[O:21])[C:16]=4[C:17]=3[OH:19])[CH2:12][C@@:11]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:10]2)[CH2:5][CH:4]([NH2:38])[CH:3]1[O:39][CH:40]1[O:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](OC2CCCCO2)[C@H](C)O1
Agent: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O[C@H]2CCCCO2)[C@H](C)O1
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3OC1CC(N)C(OC2CCCCO2)C(C)O1

Procedure:
Therarubicin for injection: generic name “pirarubicin”, manufactured by Meiji Seika Kaisha, Ltd.
Reaction SMILES: [N+:1]([O-:14])([O:3][C@H:4]1[CH2:8][C@H:7]([C:9](=O)[NH2:10])[CH2:6][C@@H:5]1[O:12][CH3:13])=[O:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.Cl.N[NH:39][C:40]([NH2:42])=[O:41].[OH-].[Na+]>ClCCl>[N+:1]([O-:14])([O:3][C@H:4]1[CH2:8][C@H:7]([C:9]2[NH:42][C:40](=[O:41])[NH:39][N:10]=2)[CH2:6][C@@H:5]1[O:12][CH3:13])=[O:2]
Reactant: CO[C@H]1C[C@@H](C(N)=O)C[C@@H]1O[N+](=O)[O-]
Reactant: NNC(N)=O
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@H]1C[C@@H](c2n[nH]c(=O)[nH]2)C[C@@H]1O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h

Procedure:
(1S,2S,4R)-4-carbamoyl-2-methoxycyclopentyl nitrate (example 14, 0.14 g, 0.68 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.19 g, 0.75 mmol) were stirred for 10 minutes in dichloromethane (5 mL) and triethylamine (0.29 mL, 2.1 mmol). Semicarbazide hydrochloride (0.082 g, 0.73 mmol) was added and stirred at room temperature for 4 days. The solution was concentrated in vacuo and brought up in 1 M sodium hydroxide (3 mL, 3.0 mmol) to reflux for 8 hours. Purification of the crude product by reversed-phase mass-directed high-performance liquid chromatography afforded the title compound as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 1.93-1.98 (m, 1H), 2.34 (dd, J=4.1, 8.3 Hz, 2H), 2.40-2.47 (m, 1H), 2.40-2.47 (m, 1H), 3.42 (quintet, J=6.2 Hz, 1H), 3.50 (s, 3H), 3.93-3.96 (m, 1H), 5.40-5.43 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 85 %

Procedure:
As described for example 105, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol) was converted, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (105 mg, 85%) which was obtained as a white solid. MS: m/e=412.5 [M+H]+.
Reaction SMILES: C[Si](Cl)(C)C.BrCCBr.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20](I)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[Cl:24][C:25]1[CH:30]=[C:29](I)[CH:28]=[C:27]([Cl:32])[N:26]=1>CN(C)C(=O)C.CCOC(C)=O.O.[Zn].C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].[Cu]I>[Cl:24][C:25]1[CH:30]=[C:29]([CH:20]2[CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:18][CH2:19]2)[CH:28]=[C:27]([Cl:32])[N:26]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe]
Solvent: BrCCBr
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)nc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
Under a nitrogen atmosphere, zinc dust (4.06 g, 62.1 mmol) was suspended in N,N-dimethylacetamide (5 mL) and a mixture of trimethylsilylchloride (0.946 mL, 7.30 mmol) and 1,2-dibromoethane (0.636 mL, 7.30 mmol) was added cautiously over 10 min. After stirring for a further 15 min, a solution of N-(tert-butoxycarbonyl)-4-iodopiperidine (16.74 g, 51.11 mmol) in N,N-dimethylacetamide (20 mL) was added over 30 min and stirring was continued for an additional 30 min. In the open atmosphere, this mixture was filtered through Celite as quickly as possible, rinsing with a small amount of N,N-dimethylacetamide. The resulting yellow solution was injected into a separately prepared, nitrogen flushed suspension of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.35 g, 1.83 mmol), copper(I) iodide (695 mg, 3.65 mmol) and 2,6-dichloro-4-iodopyridine (10.0 g, 36.5 mmol) in N,N-dimethylacetamide (30 mL) and this mixture was stirred at 80° C. for 16.5 hr. After cooling to rt, the mixture was diluted with EtOAc and water and partitioned. Filtration through Celite was necessary to break the emulsion, following which, the organics were washed with water and then dried over MgSO4. After being freed of volatiles, the resultant residue was purified by flash column chromatography (100:0-70:30 heptanes/EtOAc) to afford tert-butyl 4-(2,6-dichloro-4-pyridyl)piperidine-1-carboxylate as a white solid (7.49 g, 62%); 1H NMR (400 MHz, CDCl3) δ 7.11 (s, 2H), 4.19 (m, 2H), 2.78 (m, 2H), 2.71 (m, 1H), 1.81 (m, 2H), 1.65 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2.[CH:22]([C:25]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:26]=1[NH2:27])([CH3:24])[CH3:23].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C1(C)C=CC=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].O>[CH:32]([C:28]1[CH:29]=[CH:30][CH:31]=[C:25]([CH:22]([CH3:24])[CH3:23])[C:26]=1[NH:27][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2)([CH3:34])[CH3:33]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: Brc1cccc2ccc(-c3cccc4ccccc34)nc12
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1Nc1cccc2ccc(-c3cccc4ccccc34)nc12
Temperature: 105 °C
Reaction time: 8 h

Procedure:
A mixture of 8-bromo-2-(1-naphthyl)quinoline (2.03 g, 6 mmol), 2,6-diisopropylaniline (1.3 ml, 7 mmol), Pd(dba)2 (72 mg, 0.12 mmol), L=(N-[2′-(dicyclohexylphosphino)[1,1′-biphenyl]-2-yl]-N,N-dimethylamine (94 mg, 0.24 mmol), NadtBu (0.72 g, 7.2 mol) and toluene (15 mL) is stirred for 8 h under an argon atmosphere at 105° C. in an oil bath. The mixture is then poured into water and extracted with benzene (3×50 mL). The combined organic phase is washed with water and brine, and is then concentrated. The residue is purified by column chromatography (silica gel 40, hexane/toluene 2:1). Yield: 1.7 g (66%).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:8]([O:10]CC)=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH-].[K+].CCOC(C)=O.Cl>CCO>[CH2:6]([O:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:1])[C:8]([OH:10])=[O:9])[CH3:7]
Reactant: CCOC(=O)C(C)(C)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)C(=O)O
Yield: 77.4 %

Procedure:
Diethyl dimethylpropanedioate (10 g, 53 mmol) in 170 mL EtOH was treated with 3.00 g (53 mmol) KOH at ambient temperature for 4 days. The reaction mixture was concentrated to dryness and partitioned between EtOAc and water. The aqueous phase was isolated, combined with fresh EtOAc and the pH adj to 2 with 6N HCl. The organic phase was isolated and the aqueous portion extracted twice with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated to give 6.56 g (41 mmol) 3-(ethyloxy)-2,2-dimethyl-3-oxopropanoic acid as a clear oil. 1H NMR (300 MHz, CDCl3) d 4.20 (q, J=7.1 Hz, 2H), 1.46 (s, 6H), 1.26 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[C:19]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=3[OH:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:28])#[N:2].[CH3:29][CH:30]([CH3:33])[CH2:31]O.C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[C:19]([S:24]([NH2:27])(=[O:25])=[O:26])[CH:20]=[CH:21][C:22]=3[O:23][CH2:29][CH:30]([CH3:33])[CH3:31])=[O:16])[CH2:13][CH2:14]2)=[CH:5][C:4]=1[F:28])#[N:2]
Reactant: CC(C)CO
Reactant: N#Cc1ccc(N2CCN(C(=O)c3cc(S(N)(=O)=O)ccc3O)CC2)cc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)COc1ccc(S(N)(=O)=O)cc1C(=O)N1CCN(c2ccc(C#N)c(F)c2)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To 0.1 mmol (3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-hydroxy benzenesulfonamide (compound 6.38), 0.5 mmol 2-methyl-1-propanol and 0.3 mmol diphenyl-2-pyridylphosphine in 4 ml THF was added 0.3 mmol di-tert-butyl azodicarboxylate, and the mixture was stirred at 60° C. for 4 h. The mixture was then diluted with ethyl acetate and washed twice with 5 M aq HCl and then with saturated aq NaCl solution. The organic phase was then dried with Na2SO4, and concentrated in vacuo. The residue was triturated in ether to afford the title compound. MS (m/e): 459.2 ([M−H]−, 100%)
Reaction SMILES: FC(F)(F)C(O)=[O:4].CON=[C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[CH:21]=[C:22]([C:31]([OH:33])=[O:32])[O:23][C:24]=3[C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.O1CCOCC1.[ClH:40]>CC(C)=O>[ClH:40].[O:4]=[C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[CH:21]=[C:22]([C:31]([OH:33])=[O:32])[O:23][C:24]=3[C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)=[CH:17][CH:18]=2)[CH2:13][CH2:12]1
Reactant: O=C(O)C(F)(F)F
Reactant: CON=C1CCc2cc(-c3cc(C(=O)O)oc3-c3ccncc3)ccc21
Agent: Cl
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2ccc3c(c2)CCC3=O)c(-c2ccncc2)o1
Reaction time: 1.5 h

Procedure:
The product from Step 3 (5.46 g, 11.7 mmol) was suspended in 5M hydrochloric acid (50 ml), dioxane (50 ml) and acetone (10 ml). The suspension was heated to reflux for 30 minutes, whereupon the suspended solids dissolved. The heating was continued for a further 90 minutes before the mixture was cooled, diluted with acetone (100 ml) and evaporated in vacuo to a wet solid. The solid was dried by repeatedly (×3) suspending in toluene and evaporating to dryness.