Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH2:35][OH:36]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][CH2:32][C@H:31]4[CH2:35][OH:36])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: OC[C@@H]1CCCN1
Product: OC[C@@H]1CCCN1CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 41 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and (S)-2-pyrrolidinemethanol to give the title compound in 41% yield; NMR Spectrum: 1.49-1.53 (m, 1H), 1.60-1.66 (m, 2H), 1.77-1.82 (m, 1H), 2.33-2.36 (m, 1H), 2.58 (br s, 1H), 2.77-2.79 (m, 1H), 3.13-3.15 (m, 1H), 3.26-3.29 (m, 2H), 3.37-3.41 (m, 1H), 4.39 (t, 2H), 4.44 (br s, 1H), 5.28 (s, 2H), 7.24 (d, 1H), 7.36 (t, 1H), 7.56 (s, 1H), 7.58 (s, 1H), 7.87 (t, 1H), 7.93 (d, 1H), 8.29 (s, 1H), 8.40 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 496 (MH+).
Reaction SMILES: Cl[S:2]([C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])=[O:3].[NH2:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].C(=O)(O)[O-].[Na+].C(=O)(O)[O-]>ClCCl.O>[CH3:21][Si:20]([CH3:22])([NH:19][S:2]([C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])=[O:3])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)N
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cccc([N+](=O)[O-])c1S(=O)(=O)N[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 66.3 %

Procedure:
A suspension of ethyl 2-(chlorosulfonyl)-3-nitrobenzoate (14.7 g), amino-t-butyldimethylsilane (15.4 g), and sodium bicarbonate (3.5 g) in dichloromethane (300 mL) was stirred at room temperature in a stoppered flask for 4 days. Water (90 mL) and saturated aqueous bicarbonate (45 mL) were added, and the mixture was stirred. The dichloromethane phase was dried over magnesium sulfate, filtered, concentrated, and chromatographed on silica gel eluted with 20% ethyl acetate in hexanes to give 12.9 g of the title compound as a white solid, m.p. 101-102° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@H:14]([N:20]1[CH:33]=[CH:32][C:23]3[N:24]([CH3:31])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=4[C:22]=3[C:21]1=[O:34])[CH2:13]2>ClCCl>[N:12]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[CH:14]([N@@+:20]1([O-:6])[CH:33]=[CH:32][C:23]3[N:24]([CH3:31])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=4[C:22]=3[C:21]1=[O:34])[CH2:13]2
Reactant: Cn1c2ccccc2c2c(=O)n([C@@H]3CN4CCC3CC4)ccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1c2c(c3ccccc31)C(=O)[N@@+]([O-])(C1CN3CCC1CC3)C=C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
m-Chloroperoxybenzoic acid (1.2 g, 7.0 mmol) was added in small portions at 0° C. to a solution of (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)1,2-dihydro-5-methyl-1-oxopyrido[4,3-b]indole (1.8 g, 5.8 mmol), from Example 3, in dichloromethane (50 mL). The reaction mixture was stirred for additional 0.5 hour at 0° C. The solvent was removed under reduced pressure and the residue was purified by column chromatography (10% methanol in dichloromethane and 1% ammonium hydroxide) to afford 0.75 g (62% yield) of (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-1,2-dihydro-5-methyl-1-oxopyrido[4,3-b]indole N-oxide, as an amorphous solid, m.p 98°-102° C.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.CCOCC>[NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCc2ccccc2N1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCCCN2
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A solution of 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (2.71 g, 16.7 mmol) in THF (40 mL) was added dropwise to a suspension of LAH (1.27 g, 33.4 mmol) in ether (150 mL) at room temperature. The mixture was refluxed for 16 h. Saturated Rochelle's salt solution (15 mL) was added to the mixture cooled with an ice-water bath. The mixture was stirred for 2 hrs and the two layers were separated. The aqueous layer was extracted with ether (2×25 mL). The combined organic layer was dried (Na2SO4), concentrated in vacuo and flash column chromatography (EtOAc:hexane/3:7) gave 2,3,4,5-tetrahydro-1H-1-benzazepine (2.40 g, 98%) as a yellow liquid. 1H NMR (CDCl3, 300 MHz) δ1.58-1.70 (m, 2H), 1.72-1.86 (m, 2H), 2.72-2.82 (m, 2H), 3.00-3.10 (m, 2H), 3.78 (br, 1H), 6.74 (dd, J=1.1, 7.7 Hz, 1H), 6.82 (td, J=7.3, 1.1 Hz, 1H), 7.04 (td, J=7.5, 1.5 Hz, 1H), 7.11 (d, J=7.4 Hz, 1H) ppm.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:14]([N:18]=[C:19]=[O:20])[CH2:15][CH2:16][CH3:17]>C1(C)C=CC=CC=1>[CH2:14]([NH:18][C:19](=[O:20])[NH:6][C:4]([C:3]1[C:2]([CH3:1])=[N:10][CH:9]=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=1)=[O:5])[CH2:15][CH2:16][CH3:17]
Reactant: Cc1ncc([N+](=O)[O-])cc1C(N)=O
Reactant: CCCCN=C=O
Solvent: Cc1ccccc1
Product: CCCCNC(=O)NC(=O)c1cc([N+](=O)[O-])cnc1C
Yield: 43.1 %

Procedure:
A mixture of 0.9 g of 2-methyl-5-nitronicotinamide and 0.9 g of n-butylisocyanate in 40 ml of anhydrous toluene was refluxed for 18 hours. Unreacted nicotinamide (0.2 g) was filtered off and the filtrate was chromatographed over silica gel to give 0.6 g of the desired product. mp 111° - 112° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27]>>[NH2:1][C:2]1[C:11]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([O:22][CH3:21])[CH:24]=3)[CH:15]=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: COC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Product: COC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3cccc(OC)c3)c2)c1

Procedure:
In a manner similar to that described in Example 1, methyl 6-amino-5-((3-aminophenyl)ethynyl)nicotinate and 3-methoxybenzoic acid are converted to the title compound.
Reaction SMILES: [F:1][C@H:2]1[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]1([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[CH3:10].[N+:18]([O-])([OH:20])=[O:19].[OH-].[Na+]>S(=O)(=O)(O)O>[F:1][C@H:2]1[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]1([C:11]1[CH:16]=[C:15]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:13][C:12]=1[F:17])[CH3:10]
Reactant: O=[N+]([O-])O
Reactant: C[C@]1(c2ccccc2F)N=C(N)COC[C@@H]1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@]1(c2cc([N+](=O)[O-])ccc2F)N=C(N)COC[C@@H]1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5R,6R)-6-fluoro-5-(2-fluorophenyl)-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (1.2 mmol) in sulfuric acid (5.0 ml) was added at 0° C. red fuming nitric acid (1.9 mmol) over a period of 20 min and stirring was continued for 30 min. The solution was dropped slowly into ice/water (60 ml), the pH was adjusted to 9 by addition of aqueous 4 N NaOH and extracted with ethyl acetate. The organic layer was dried, evaporated and the residue purified by chromatography on silca-NH2 using n-heptane/ethyl acetate to give (5R,6R)-6-fluoro-5-(2-fluoro-5-nitro-phenyl)-5-methyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine as a pale yellow solid. MS (ISP): m/z=286.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[CH:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:17]([NH:16][C:14](=[O:15])[NH:13][C:4]1[CH:3]=[C:2]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1)[CH3:18]
Reactant: CCNC(=O)Nc1cc(Cl)c(C(=O)OCC)cn1
Reactant: Nc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cc(Nc2cccnc2)c(C(=O)OCC)cn1
Temperature: 80 °C
Yield: 66 %

Procedure:
To a solution of ethyl 4-chloro-6-(3-ethylureido)nicotinate, i (1.0 g, 3.70 mmol), in 1,4-dioxane (25 mL) was added 3-aminopyridine (0.435 g, 4.81 mmol) followed by Cs2CO3 (1.80 g, 5.55 mmol). The resulting solution was purged with nitrogen for 15 min followed by addition of Pd(OAc)2 (0.025 g, 0.11 mmol) and Xantphos (0.13 g, 0.22 mmol). The reaction mixture was again purged with nitrogen for 15 min and then heated at 80° C. overnight. The reaction mixture was cooled to room temperature, filtered through a celite bed, and the bed washed with EtOAc. The combined filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product thus obtained was triturated with a mixture of 10% MeOH-Et2O to obtain compound ii as an off-white solid (0.80 g, 66%). 1H NMR (DMSO-d6, 400 MHz): δ 9.62 (s, 1H), 9.17 (s, 1H), 8.63 (s, 1H), 8.56 (d, J=2.4 Hz, 1H), 8.41 (d, J=4.4 Hz, 1H), 7.77 (m, 1H), 7.75 (br s, 1H), 7.48 (m, 1H), 7.20 (s, 1H), 4.32 (q, J=6.8 Hz, 2H), 3.11 (q, J=7.20 Hz, 2H), 1.33 (t, J=6.8 Hz, 3H) and 1.03 (t, J=7.20 Hz, 3H). [M+H]+ m/z=330.12.
Reaction SMILES: ClC1C(NC2N=C3C(N(C)C(=O)CCN3C3CCCC3)=CN=2)=CC(F)=C(C=1)C(O)=O.[Cl:31][C:32]1[C:33]([F:65])=[C:34]([CH:42]=[C:43]([Cl:64])[C:44]=1[NH:45][C:46]1[N:56]=[C:55]2[C:49]([N:50]([CH3:63])[C:51](=[O:62])[CH2:52][CH2:53][N:54]2[CH:57]2[CH2:61][CH2:60][CH2:59][CH2:58]2)=[CH:48][N:47]=1)[C:35]([O:37]C(C)(C)C)=[O:36]>>[Cl:31][C:32]1[C:33]([F:65])=[C:34]([CH:42]=[C:43]([Cl:64])[C:44]=1[NH:45][C:46]1[N:56]=[C:55]2[C:49]([N:50]([CH3:63])[C:51](=[O:62])[CH2:52][CH2:53][N:54]2[CH:57]2[CH2:61][CH2:60][CH2:59][CH2:58]2)=[CH:48][N:47]=1)[C:35]([OH:37])=[O:36]
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3c(Cl)cc(C(=O)OC(C)(C)C)c(F)c3Cl)ncc21
Agent: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3Cl)ncc21
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3c(Cl)cc(C(=O)O)c(F)c3Cl)ncc21

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 219, utilising tert-butyl 3,5-dichloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-2-fluoro-benzoate (Intermediate 222; 236 mg, 0.45 mmol), as an off-white solid (180 mg, 87%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[N:19]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[N:19]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: NCC1CCCCC1N(Cc1ccccc1)Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(NCC2CCCCC2N(Cc2ccccc2)Cc2ccccc2)cc1

Procedure:
In a manner similar to Preparation 2, react 1-fluoro-4-nitrobenzene with N-[2-(aminomethyl)cyclohexyl]-N-(phenylmethyl)benzenemethanamine to obtain the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Br[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>C1COCC1.C(Cl)Cl.[NH4+].[Cl-].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>[C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1ccncc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnc(-c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: c1ccc(-c2cc(-c3ccncc3)cnn2)cc1
Temperature: 150 °C
Yield: 69.4 %

Procedure:
3-Phenyl-5-(tri-n-butylstannyl)pyridazine (110 mg, 0.247 mmol), 4-bromopyridine hydrochloride (72 mg, 0.370 mmol) and Pd(PPh3)4 (10 mg) in THF (2 ml) were combined and heated to 150° C. for 60 min in a Smith Synthesiser microwave reactor (Personal Chemistry, Uppsala, Sweden). The reaction was diluted with CH2Cl2 (6 ml) and NH4Cl (2 ml) then poured into PTFE (5 μM) fritted syringe barrels. The organic phase was collected and concentrated while loading onto silica. The compound was purified by dry flash column chromatography to give the title compound as a white solid (40 mg). δH (400 MHz, d6 DMSO) 7.36-7.63 (3H, m), 8.10 (2H, dd, J 1.8 and 4.5), 8.32 (2H, m), 8.62 (1H, d, J 2.0), 8.80-8.82 (2H, dd, J 1.8 and 4.5), 9.71 (2H, d, J 2.0); m/z (ES+) 234 (MH+).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][CH:5]1[CH3:22])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:29]([C:31]1[CH:32]=[C:33](B(O)O)[O:34][CH:35]=1)=[O:30].C1(C)C=CC=CC=1>C(O)C.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>[CH3:19][CH:18]([O:17][C:16](=[O:21])[NH:15][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:33]3[O:34][CH:35]=[C:31]([CH:29]=[O:30])[CH:32]=3)[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:22])[CH2:6]1)[CH3:20]
Reactant: O=Cc1coc(B(O)O)c1
Reactant: CC(=O)N1c2ccc(Br)cc2C(NC(=O)OC(C)C)CC1C
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: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3cc(C=O)co3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C

Procedure:
1-methylethyl (1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation see Example 61) (150 mg, 0.406 mmol) was mixed with potassium carbonate (112 mg, 0.812 mmol), tetrakis(triphenylphosphine)palladium(0) (23.47 mg, 0.020 mmol) and (4-formyl-2-furanyl)boronic acid (68.2 mg, 0.487 mmol, available from Frontier scientific), dissolved in ethanol (1 mL) and toluene (1 mL) and stirred under nitrogen at 90° C. for 2.5 days. The reaction A was partitioned between distilled water (20 mL) and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (2×60 mL) and the organic fractions were combined, washed (brine (50 mL)), dried (sodium sulfate) and evaporated to dryness to give a dark brown solid (184 mg) which was purified using MDAP. Product-containing fractions were evaporated to dryness to give a yellow/brown solid (32 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24](I)=[C:25]([CH:34]=1)[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].C(NCC)C.[CH2:41]([N:44]1[C:48](=[O:49])[C:47]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:46]2[C:45]1=[O:54])[C:42]#[CH:43]>[Pd](Cl)Cl.C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:43]#[C:42][CH2:41][N:44]2[C:48](=[O:49])[C:47]3=[CH:50][CH:51]=[CH:52][CH:53]=[C:46]3[C:45]2=[O:54])=[C:25]([C:26](=[O:27])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1I
Reactant: C#CCN1C(=O)c2ccccc2C1=O
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCNCC
Product: O=C(c1ccccc1)c1cc(Cl)ccc1C#CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 0.71 g (4.0 mmole) of palladium chloride, 2.1 g (8.0 mmole) of triphenylphosphine, 0.80 g (4.2 mmole) of cuprous iodide, 68.8 g (0.21 mole) of 5-chloro-2-iodobenzophenone, 200 ml of diethylamine, and 400 ml of methylene chloride was stirred at room temperature under argon until complete solution was obtained. In one portion, 40.0 g (0.22 mole) of N-propargyl-phthalimide was added to the solution and the resulting mixture stirred for 20 hr. The volatiles were removed at reduced pressure and the residue was triturated with 200 ml of isopropanol. The resulting precipitate was collected by filtration to give the crude product mp 130°-133° C. Recrystallization from acetone gave cream colored prisms, mp 148°-150° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#N)=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1.C([O-])(=[O:14])C.[Na+].CO>[Ni].O>[Cl:1][C:2]1[C:7]([CH:8]=[O:14])=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc(C#N)c(Cl)nc1C
Reactant: CC(=O)[O-]
Agent: [Ni]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(C=O)c(Cl)nc1C
Yield: 60.5 %

Procedure:
A mixture of 2-chloro-3-cyano-5,6-dimethylpyridine (21.5 g) semicarbazide hydrochloride (24.0 g), sodium acetate (42.3 g), water (225 ml) and methanol (475 ml) was hydrogenated at 344 kPa at 50° using Raney nickel catalyst (5 g). The mixture was added to water (750 ml) and filtered. The solid filtered off was suspended in water (130 ml) and concentrated hydrochloric acid (70 ml) was added and the mixture was heated at 100° for 1 hour, formalin (40% w/w, 120 ml) was added and the mixture was heated at 100° for a further 0.5 hour and allowed to cool. Sodium acetate (95 g) and water (250 ml) were added and the mixture was extracted with ether and the extracts were washed with 5% aqueous potassium carbonate and evaporated to give 2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde (13.24 g, 60%) m.p. 69°-70°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH3:17])[C:12](Br)=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH3:17])[C:12]([B:29]([OH:34])[OH:30])=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2)cc(C)c1B(O)O
Temperature: -78 °C
Yield: 60.1 %

Procedure:
To a solution (100 mL) of 5-(benzyloxy)-2-bromo-1,3-dimethylbenzene (8.78 g, 30.2 mmol) in tetrahydrofuran was added n-butyllithium hexane solution (1.6 M, 22.6 mL, 36.2 mmol) under stirring at −78° C. The reaction mixture was stirred at the same temperature for 1.5 hr, and triisopropyl borate (20.9 mL, 90.6 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added 2 M hydrochloric acid (150 mL) and the mixture was stirred for 2.5 hr. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Cold hexane was added to the residue to allow crystallization. The precipitated crystals were collected by filtration, washed with cold hexane and dried to give the title compound (4.65 g, yield 60%) as colorless crystals.
Reaction SMILES: [CH:1]([O:4][CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:3])[CH3:2].[CH2:26]([OH:29])[C:27]#[CH:28].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.[Cu](I)I.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>[OH:29][CH2:26][C:27]#[C:28][C:14]1[CH:13]=[C:12]([CH2:11][CH:5]([O:4][CH:1]([CH3:3])[CH3:2])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:17]=[CH:16][CH:15]=1
Reactant: C#CCO
Reactant: CCOC(=O)C(Cc1cccc(OS(=O)(=O)C(F)(F)F)c1)OC(C)C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc(C#CCO)c1)OC(C)C
Reaction time: 4 h
Yield: 44.3 %

Procedure:
550 mg of Ethyl 2-isopropoxy-3-(3-[(trifluoromethyl)sulfonyl]oxyphenyl)propanoate was dissolved in 5 ml of N,N-dimethylformamide, and 160 mg of propargyl alcohol, 13 mg of copper iodide, 83 mg of tetrakis(triphenylphosphine)palladium and 1 ml of triethylamine were added. After stirring was continued at 50° C. for 4 hours under nitrogen atmosphere, the reaction mixture was diluted with ethyl acetate and washed with water and 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off. Then, the residue was purified by silica gel column chromatography, to give 184 mg of the title compound in the 4:1→2:1 hexane-ethyl acetate fraction.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](N)[CH:5]=[CH:4][C:3]=1[Cl:9].C(ON=O)(C)(C)C.[FH:17].N1C=CC=CC=1>ClCCl>[Br:1][C:2]1[C:3]([Cl:9])=[CH:4][CH:5]=[C:6]([F:17])[N:7]=1
Reactant: F
Reactant: Nc1ccc(Cl)c(Br)n1
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Fc1ccc(Cl)c(Br)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-5-chloropyridin-2-amine (1 g, 4.82 mmol) in dichloromethane (10 mL) at 0° C. added tert-butylnitrite (1.145 mL, 9.64 mmol) followed by pyridine hydrofluoride (3 mL, 9.64 mmol) and the mixture was stirred at 0° C. for 30 minutes. The mixture was quenched with water and extracted with dichloromethane. The organic layer was washed with water and brine (25 mL each), dried over sodium sulfate, filtered, and concentrated to afford of the title compound. 1H NMR (400 MHz, CDCl3): δ 6.90-6.93 (m, 1H), 7.80-7.84 (m, 1H).
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].[F:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:16]=O)=[CH:12][NH:13]2)=[CH:9][C:8]=1[O:18][CH3:19].C([O-])(=O)C.[NH4+]>>[F:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH3:5])=[CH:12][NH:13]2)=[CH:9][C:8]=1[O:18][CH3:19]
Reactant: CC[N+](=O)[O-]
Reactant: COc1cc2c(C=O)c[nH]c2cc1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1cc2c(C=C(C)[N+](=O)[O-])c[nH]c2cc1F
Temperature: 100 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
A mixture of nitroethane (44 ml, 611 mmol), 6-fluoro-5-methoxy-1H-indole-3-carbaldehyde (11.8 g, 61 mmol), and ammonium acetate (1.78 g, 23 mmol) is stirred at 100° C. for 3 hours, allowed to cool, and is filtered to give 14 g of 6-fluoro-5-methoxy-3-(2-nitro-propenyl)-1H-indole (92%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9](O)(=[O:13])[C:10]([CH3:12])=[O:11].N1C=CC=CC=1.COC(Cl)Cl>C(Cl)Cl>[C:9]([O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1)(=[O:13])[C:10]([CH3:12])=[O:11]
Reactant: Cc1ccc(O)cc1
Reactant: CC(=O)C(=O)O
Agent: COC(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)C(=O)Oc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
p-Tolyl pyruvate was prepared as follows. p-cresol (540 mg, 5 mmol) and pyruvic acid (440 mg, 5 mmol) were dissolved in methylene chloride (30 mL) and cooled on an ice bath. Pyridine (790 mg. 1 mL, 12.4 mmol) was added, followed by addition of 1,1-dichloromethyl methyl ether (690 mg, 0.53 mL, 6 mmol). The reaction mixture was stirred for 1 h on an ice bath, warmed to room temperature and washed with 30 mL of 5% aqueous HCl and 30 mL of saturated aqueous NaHCO3. The organic layer was dried over anhydrous MgSO4, filtered and solvent removed on a rotary evaporator. The residue was purified by flash silica gel chromatography (20:1→15:1 hexanes-ethyl acetate) to give 450 mg of p-tolyl pyruvate as a clear oil. 1H NMR (400 MHZ, CDCl3) δ 7.21 (d, J=4 Hz, 2H), 7.05 (d, J=4 Hz, 2H), 2.59 (s, 3H), 2.36 (s, 2H). 13C NMR (100 MHZ, CDCl3) δ 191.3, 159.5, 148.1, 136.6, 130.4, 120.8, 27.0, 21.1. HRMS (ESI-12 Tesla FT-MS) [M+H]+ calcd. 179.0708, found 179.0709.