Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN>CO.[Ni]>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:12]=2)=[CH:6][CH:5]=1
Reactant: CC(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccn1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)C(=O)Nc1cc(Oc2ccc(N)nc2)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
A solution of N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)isobutyramide (1.08 g, 3.57 mmol) in MeOH (30 mL) was treated with hydrazine hydrate (1.00 g, 19.98 mmol) followed by Raney Nickel (0.300 g, 5.11 mmol) and stirred at RT for 3 h. The solids were removed via filtration through diatomaceous earth, washed with DCM and MeOH and the filtrate concentrated to dryness to afford N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)isobutyramide (900 mg, 93%) as an off-white solid. MS (ESI) m/z: 273.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=O)[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][CH2:18][Mg+].[Br-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2([CH3:15])[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC[Mg+]
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C2(C)CC2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
Tert-Butyl-4-acetylpiperazine-1-carboxylate (3.90 g, 17.1 mmol) is dissolved in anhydrous THF and cooled to −78° C. in nitrogen atmosphere. To this solution is added MeTi(OiPr)3 (1.0 M in THF, 20.5 mL, 20.5 mmol) over a period of 3 min, followed by EtMgBr (3.0 M in Et2O, 22.0 mL, 66.0 mmol) over a period of 7 min. The reaction mixture is allowed to warm to room temperature during which time it changes from a clear red to a viscous black liquid and gas evolution is observed. The flask can be shaken intermittingly to ensure continuous stirring and LCMS analysis can be used to show the absence of the starting amide. Typically, the reaction is complete after 30 min of stirring. The reaction mixture is then carefully diluted with water (20 mL) and a Rochelle salt solution (20% aq., 50 mL). The mixture is stirred vigorously for 15 min, the upper layer liquid decanted off and the precipitate triturated with EtOAc (3×50 mL). The precipitate is then filtered off using a celite plug (10 g) that has been washed well with EtOAc (20 mL). The initially decanted liquid, the triturates and the filtrate are then combined and extracted with EtOAc (4×50 mL). The combined extracts are dried (MgSO4), filtered and concentrated in vacuo to afford the crude product as a clear oil (4.0 g). Column chromatography (250 g SiO2, hexanes-ethyl acetate 4:1, 2 L) affords tert-butyl-4-(1-methylcyclopropyl)piperazine-1-carboxylate as a white solid (2.46 g, 60%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.29-0.33 (m, 2H), 0.43-0.47 (m, 2H), 0.97 (s, 3H), 1.38 (s, 9H), 2.44-2.48 (m, 4H), 3.17-3.27 (m, 4H); ESI-MS: m/z 229.2 (M+H)+.
Reaction SMILES: C([N:4]1[C:13]2[C:8](=[C:9]([Cl:15])[CH:10]=[C:11]([Cl:14])[CH:12]=2)[C:7](=[O:16])[CH2:6][CH:5]1[C:17]([OH:19])=[O:18])(=O)C>Cl>[C:17]([CH:5]1[CH2:6][C:7](=[O:16])[C:8]2[C:13](=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[NH:4]1)([OH:19])=[O:18]
Reactant: CC(=O)N1c2cc(Cl)cc(Cl)c2C(=O)CC1C(=O)O
Agent: Cl
Product: O=C1CC(C(=O)O)Nc2cc(Cl)cc(Cl)c21
Yield: 95.8 %

Procedure:
1-Acetyl-2-carboxy-5,7-dichloro-4-oxo-1,2,3,4-tetrahydroquinoline (21.17 g) was suspended in 3N hydrochloric acid (500 ml) and heated at reflux overnight. After cooling, the aqueous solution was extracted with ethyl acetate (3×300 ml) and the combined organic layers were washed with brine (1×300 ml), dried (MgSO4), filtered and evaporated in vacuo to give the title compound as a yellow solid (17.45 g, m.p. 218°-219° C.); δ (360 MHz, DMSO) 2.73 (1H, dd, J=15.7 and 6.8 Hz, CHACHBHC), 2.92 (1H, dd, J=15.7 and 6.2 Hz, CHACHBHC), 4.36 (1H, m, CHACHBHC), 6.67 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.96 (1H, d, J=2.0 Hz, 6-H or 8-H), 7.62 (1H, br, s, NH); m/e (FAB) 260 (M+1); Found: C, 46.10; H, 2.85; N, 5.26. C10H7Cl2NO3 requires C, 46.18; H, 2.71; H, 5.39%.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5](=[CH2:8])[C:6]#[N:7])[CH3:3].[OH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C1C=CC=CC=1.CO>[C:6]([CH:5]([CH2:8][N:13]1[CH2:14][CH2:15][CH:10]([OH:9])[CH2:11][CH2:12]1)[CH2:4][N:2]([CH3:3])[CH3:1])#[N:7]
Reactant: C=C(C#N)CN(C)C
Reactant: OC1CCNCC1
Solvent: CO
Solvent: c1ccccc1
Product: CN(C)CC(C#N)CN1CCC(O)CC1
Reaction time: 12 h

Procedure:
2-Dimethylaminomethylpropenenitrile (1.1 g., 0.01 mole) was cooled to 10°-15° C. and to it was added dropwise 4-hydroxypiperidine (1.0 g., 0.01 mole). The evolution of heat is observed. The homogeneous mixture is allowed to stand 12 hours at 15°-20° C. Completion of addition reaction is determined using thin layer chromatography on silica gel with benzene-methyl alcohol (90:10) development. The appearance of a single spot and elimination of reactant spots indicate termination.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])[NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17]>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>[C:16]([NH:9][CH:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])([O:18][CH2:19][CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[C:32]1=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17]
Reactant: CC(C)(C(=O)O)C(N)c1ccccc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C(=O)O)C(NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
The obtained β-phenyl-α,α-dimethyl-β-alanine hydrochloride (2.0 g, 10.8 mmol) was dissolved in a 10% aqueous solution of sodium carbonate (46 ml). To the resulting solution, a solution of Fmoc-Cl (3.35 g, 12.96 mmol) in dioxane (20 ml) was added dropwise under cooling with ice and the mixture was stirred at room temperature overnight. The solvents were distilled off and the residue was dissolved in water and washed with ether. The aqueous layer was adjusted to pH 3 with concentrated HCl under cooling with ice and extracted with ethyl acetate. The collected ethyl acetate layer was washed with a saturated solution of NaCl and dried over anhydrous sodium sulfate. The solvent was distilled off and the obtained oil was applied to a silica gel column (2.5×40 cm) and eluted with a mixed solution (chloroform:methanol=50:1). The desired fractions were collected and the solvents were distilled off to yield a crystal of N-Fmoc-β-phenyl-α,α-dimethyl-β-alanine (1.21 g, 26.6%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[I:10]I>[NH4+].[OH-].O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[I:10]
Reactant: N#Cc1ccc(O)cc1
Reactant: II
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: N#Cc1ccc(O)c(I)c1
Reaction time: 6 h
Yield: 80.1 %

Procedure:
To a solution of 4-hydroxybenzonitrile (0.5 g; 4.18 mmol) in 25% NH4OH (22 ml) a solution of I2 (1.06 g; 4.18 mmol) and KI (3.41 g; 20.54 mmol) in H2O (5 ml) was added at once with stirring. The stirring was continued for 6 h, during which time the mixture turn from black into colourless. The precipitate formed was filtered off and filtrate was evaporated to dryness under reduced pressure. The residue was treated with H2O (3 ml). The precipitate formed was filtered off, washed with cold H2O (3×2 ml), and dried in vacuo to give the title compound (0.82 g; 80%), as colourless solid. 1H-NMR (CDCl3) 6.03 (s, 1H); 7.03 (d, 1H, J=8.5 Hz); 7.53 (dd, 1H, J=1.9 Hz, 8.5 Hz); 7.96 (d, 1H, 1.9 Hz).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:23])[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])=[C:6]2[N:5]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:3]=1.[NH3:30]>CO>[CH3:23][C:9]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=2[CH3:22])=[C:6]2[N:5]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:3]=[C:2]([NH2:30])[N:7]2[N:8]=1
Reactant: Cc1nn2c(Cl)cc(N3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Reactant: N
Solvent: CO
Product: Cc1nn2c(N)cc(N3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Temperature: 0 °C

Procedure:
To a suspension of 7-chloro-2-methyl-3-{{2-methyl-3-(trifluoromethyl)phenyl}methyl}-5-(4-morpholinyl)pyrazolo[1,5-a]pyrimidine (70 mg, 0.16 mmol) in methanol (2 mL) stirred under nitrogen at 0° C. was added a 2 M ammonia solution of in CH3OH (0.82 mL, 1.64 mmol) dropwise. The reaction mixture was stirred at 135° C. for 3 hours. Reaction mixture was concentrated to dryness. Crude product was purified by reverse-phase HPLC to provide titled compound. (16 mg, 24%); LC/MS: MS (ES+) m/e 406 (MH+); 1H NMR (400 MHz, MeOD) δ ppm 2.20 (s, 3H) 2.52 (s, 3H) 3.15 (dt, J=3.28, 1.64 Hz, 1H) 3.50 (dt, J=3.28, 1.64 Hz, 1H) 3.57 (d, J=5.31 Hz, 3H) 3.55 (s, 1H) 3.82 (s, 1H) 3.81 (d, J=5.05 Hz, 3H) 4.10 (s, 2H) 5.59 (s, 1H) 7.12 (s, 1H) 7.26 (s, 1H) 7.55 (s, 1H).
Reaction SMILES: [C:1]([C:3]([CH3:52])([CH3:51])[C:4]1[CH:5]=[C:6]([NH:19][C:20]([NH:22][C@@H:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C@H:26]([O:33][C:34]3[CH:35]=[CH:36][C:37]4[N:38]([C:40]([N:43]5[C@H:48]([CH3:49])[CH2:47][CH2:46][CH2:45][C@@H:44]5[CH3:50])=[N:41][N:42]=4)[CH:39]=3)[CH2:25][CH2:24]2)=[O:21])[N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][OH:18])[CH:10]=2)[N:8]=1)#[N:2].C[C@H]1CCC[C@@H](C)N1C1N2C=C(O[C@H]3C4C(=CC=CC=4)[C@@H](NC(=O)NC4N(C5C=NN(CC[O:96][S:97]([CH3:100])(=O)=[O:98])C=5)N=C(C(C)C)C=4)CC3)C=CC2=NN=1>>[C:1]([C:3]([CH3:51])([CH3:52])[C:4]1[CH:5]=[C:6]([NH:19][C:20]([NH:22][C@@H:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C@H:26]([O:33][C:34]3[CH:35]=[CH:36][C:37]4[N:38]([C:40]([N:43]5[C@H:48]([CH3:49])[CH2:47][CH2:46][CH2:45][C@@H:44]5[CH3:50])=[N:41][N:42]=4)[CH:39]=3)[CH2:25][CH2:24]2)=[O:21])[N:7]([C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[O:15][CH2:16][CH2:17][O:18][S:97]([CH3:100])(=[O:98])=[O:96])[N:8]=1)#[N:2]
Reactant: CC(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5[C@H](C)CCC[C@@H]5C)n4c3)c3ccccc32)n(-c2cnn(CCOS(C)(=O)=O)c2)n1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C#N)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C#N)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12

Procedure:
The title compound was prepared using Intermediate 21a in an analogous fashion to the procedures described for Intermediate A step e. LCMS (Method 3): Rt 3.85 min, m/z 782.5 [MH+].
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=2[N:3]=1.[NH:23]1[CH2:26][CH:25]([C:27]#[N:28])[CH2:24]1.C(=O)([O-])[O-].[K+].[K+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1CCCC1=O>[Cl:22][C:7]1[CH:6]=[CH:5][C:4]2[N:3]=[C:2]([N:23]3[CH2:26][CH:25]([C:27]#[N:28])[CH2:24]3)[CH:11]=[CH:10][C:9]=2[C:8]=1[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:13]
Reactant: N#CC1CNC1
Reactant: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#CC1CN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 130 °C

Procedure:
A mixture of 2,6-dichloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide (example 43(a)) (0.25 g, 0.74 mmol), 3-azetidinecarbonitrile (prepared according to the method of JP 2001172257A), tetra-butylammonium bromide (0.25 g) and potassium carbonate (0.2 g) in N-methylpyrrolidinone were heated at 130° C. in a microwave for 2 hours. Water was added and the reaction mixture was extracted with dichloromethane. The organic fraction was washed with water, dried over magnesium sulfate and concentrated. The residue was purified firstly by C18 cartridge (eluting with 10 to 100% methanol in water) and then by chromatography (SiO2, ethyl acetate:methanol 100:0 to 50:50 as eluant) to give the sub-title compound as a solid (0.082 g).
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([C:13]2[C:14]3[S:20][CH:19]=[C:18]([Br:21])[C:15]=3[S:16][CH:17]=2)[N:10]=[C:9]1[C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1C(OC(C)(C)C)=O)=O)(C)(C)C.Cl.BrC1SC2=NC(N)=CN2C=1>>[Br:21][C:18]1[C:15]2[S:16][CH:17]=[C:13]([C:11]3[N:10]=[C:9]([C@@H:22]4[CH2:26][CH2:25][CH2:24][NH:23]4)[NH:8][CH:12]=3)[C:14]=2[S:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2csc3c(Br)csc23)cn1C(=O)OC(C)(C)C
Agent: Cl
Agent: Nc1cn2cc(Br)sc2n1
Product: Brc1csc2c(-c3c[nH]c([C@@H]4CCCN4)n3)csc12

Procedure:
Compound 77 was synthesized from compound 76 (1.29 mmol), following the procedure as described for compound 11 to give compound 77 in quantitative yield. MS (ESI, EI+) m/z=354.1/356.13 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([Sn](CCCC)(CCCC)CCCC)=[CH:7][CH:6]=1)[CH3:2].FC(F)(F)S(O[C:31]1[CH:32]2[CH2:38][CH:35]([CH2:36][CH:37]=1)[CH2:34][CH2:33]2)(=O)=O>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([C:31]2[CH:32]3[CH2:38][CH:35]([CH2:36][CH:37]=2)[CH2:34][CH2:33]3)=[CH:9][CH:10]=1)[CH3:2]
Reactant: O=S(=O)(OC1=CCC2CCC1C2)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)OCC)cc1
Product: CCOC(=O)c1ccc(C2=CCC3CCC2C3)cc1

Procedure:
4-(Tri-n-butyl-stannyl)-benzoic acid ethyl ester of Example 15, Step A (1.82 g, 4.15 mmol) and bicyclo[3.2.1]oct-2-en-2-yl trifluoromethanesulfonate (1.17 g, 4.57 mmol) were reacted in the manner of Example 15, Step B. Purification by flash column chromatography on silica gel, eluting with a solvent gradient of from 0 to 10% ethyl acetate in hexane afforded the crude title compound a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.CS(O[CH2:17][C:18]([F:21])([F:20])[F:19])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:9]([C:3]1[C:2]([O:1][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:8])([O-:11])=[O:10]
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCC(F)(F)F)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 4 h
Yield: 53.7 %

Procedure:
A mixture of 3-hydroxy-2-nitrotoluene (5 g), 2,2,2-trifluoroethyl methanesulfonate (8.7 g), anhydrous potassium carbonate (9 g) and N,N-dimethylformamide (40 ml) was heated, with stirring, on an oil bath at 80° C. for 4 hours, and then at 100° C. for 4 hours. The reaction solution was extracted with ethyl acetate-water. The organic layer was washed with water, followed by a dilute aqueous potassium carbonate solution and then saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and then filtered through NH silica gel, which was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and subjected to a silica-gel column chromatography with 5 to 10% ethyl acetate/hexane to yield the title compound (4.12 g).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[NH:4][N:3]=1.[C:15]1([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=1>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:4][N:3]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[CH:25][C:24]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([NH:1][C:2]5[CH:6]=[C:5]([C:7]6[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=6)[NH:4][N:3]=5)=[O:23])=[CH:19][CH:20]=4)=[CH:29][CH:28]=3)=[O:32])[CH:6]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: COc1ccc(-c2cc(N)n[nH]2)cc1
Product: COc1ccc(-c2cc(NC(=O)c3ccc(-c4ccc(C(=O)Nc5cc(-c6ccc(OC)cc6)[nH]n5)cc4)cc3)n[nH]2)cc1

Procedure:
Compound 474 was prepared from 3-amino-5-(4-methoxyphenyl)pyrazole and biphenyl-4,4′-dicarboxylic acid. [M+H]+ calcd for C34H29N6O4: 585.23; found: 585.01.
Reaction SMILES: [P:1](Cl)([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][CH3:14])[CH:8]=1)([S:3][CH2:4][CH3:5])=[O:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20]([OH:27])=[C:21]2[C:25]=1[C:24](=[O:26])[CH2:23][CH2:22]2.C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([O:27][C:20]1[CH:19]=[CH:18][C:17]([Br:16])=[C:25]2[C:21]=1[CH2:22][CH2:23][C:24]2=[O:26])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][CH3:14])[CH:8]=1)([S:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C1CCc2c(O)ccc(Br)c21
Reactant: CCSP(=O)(Cl)Oc1cccc(SC)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCSP(=O)(Oc1cccc(SC)c1)Oc1ccc(Br)c2c1CCC2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
S-Ethyl O-(3-methylthiophenyl) chlorothiophosphate (0.015 mole) dissolved in dry toluene (80) is charged into a glass reaction vessel equipped with a stirrer, thermometer and gas inlet tube. The solution is cooled to about 0° C. and a solution of 7-bromo-4-hydroxyindan-1-one (0.015 mole) and triethylamine (0.0175 mole) in toluene (20 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 8 hours. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed solution is then dried and is stripped of solvent leaving a residue. This residue is chromatographed through a 200 ml clay column using ethyl acetate and hexane mixtures as the eluant. Ten separate fractions each containing increasing percentages of ethyl acetate are collected and analyzed by IR for the product. The appropriate fractions are then combined stripped of solvent and subjected to vacuum to yield the desired product S-ethyl O-(3-methylthiophenyl) O-(7-bromoindan-1-on-4-yl) thiophosphate.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([N:9]=[CH:10][N:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[N:3]=1.[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=1)[CH3:19]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([C:19]#[C:18][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][CH:21]=2)=[CH:6][N:5]=[C:4]([N:9]=[CH:10][N:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[N:3]=1
Reactant: C#Cc1ccc(CC)cc1
Reactant: CC(C)N(C=Nc1ncc(I)c(Cl)n1)C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCc1ccc(C#Cc2cnc(N=CN(C(C)C)C(C)C)nc2Cl)cc1
Yield: 63.7 %

Procedure:
A mixture of 6.3 g of 4-chloro-2-diisopropylaminomethyleneamino-5-iodopyrimidine, 33 mL of triethylamine, 2.43 g of 4-ethyl-1-ethynylbenzene, 0.304 g of dichlorobis(triphenyl)phosphine palladium II and 0.21 g copper iodide was magnetically stirred at reflux temperature for 1.5 hrs. The mixture was filtered and the filtrate evaporated in vacuo. Both the precipitate and the evaporated filtrate were dissolved in dichloromethane and washed with water, dried over sodium sulfate, filtered and evaporated. The residues were dissolved in 1:1 dichloromethane-hexanes and separately purified by column chromatography. After initial elution with 1:1 dichloromethane-hexanes, the product was obtained by elution with dichloromethane and 50% ethyl acetate-dichloromethane. Evaporation of the eluates gave 4.04 g of 4-chloro-2-diisopropylaminomethyleneamino-5-(4-ethylphenylethynyl)pyrimidine as a thick amber syrup.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[C:7](=[O:13])[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=1)[CH2:2][CH2:3][CH3:4].[Br:29]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:29][C:8]1[C:7](=[O:13])[N:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:10][C:9]=1[CH2:11][CH3:12]
Reactant: CCCCc1nc(CC)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of 4′-[(2-butyl-4-ethyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1.67 g) in acetic acid (20 mL) was added bromine (0.46 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.26 g, 62%) as a colorless solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[Br:9]Br>C(O)(=O)C>[Br:9][C:5]1[S:1][CH:2]=[C:3]([C:6]([OH:8])=[O:7])[CH:4]=1
Reactant: O=C(O)c1ccsc1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1csc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
To a solution of 3-thiophenecarboxylic acid (7.7 g, 60 mmol) in 70 mL acetic acid was added a solution of 9.6 g bromine in 50 mL acetic acid at RT and stirring was continued at RT for 0.5 h. After that, the reaction mixture was poured into 600 mL ice-water. The precipitate was filtered, washed with water and air-dried to give 7.9 g of 5-bromo-3-thiophenecarboxylic acid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[O:34][N:33]=2)=[CH:28][CH:27]=1)=O.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C.CC(O)=O>[NH:2]1[C:1]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:4][CH:3]1[CH2:24][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[O:34][N:33]=2)=[CH:30][CH:31]=1
Reactant: NC(=O)c1cc(-c2ccc(C=O)cc2)no1
Reactant: c1ccc2c(c1)CNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: NC(=O)c1cc(-c2ccc(CC3Cc4ccccc4N3)cc2)no1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
To a solution of isoindoline (11 μL, 0.097 mmol) in dichloroethane (1 mL) was added Na(OAc)3BH (59 mg, 0.278 mmol). The mixture was stirred at room temperature under argon for 20 min. A slurry of 3-(4-formyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 20; 20 mg, 0.093 mmol) in dichloroethane (1 mL) was added, followed by AcOH (20 μL). The reaction mixture was stirred at room temperature overnight. 1 M Na2CO3 solution was added and the mixture was extracted with CHCl3 (3×25 mL). The organic layer was washed with brine, dried (Na2SO4), evaporated, and purified by chromatography (20-25% acetone/CH2Cl2) to give 3-[4-(1,3-dihydro-indol-2-ylmethyl)-phenyl]-isoxazole-5-carboxylic acid amide (10 mg, 32%) as an off-white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.36 (br. s., 1H), 7.99 (br. s., 1H), 7.88 (d, J=8.2 Hz, 2H), 7.48-7.61 (m, 3H), 7.09-7.26 (m, 4H), 5.74 (s, 2H), 4.07 (br. s., 1H), 3.92 (s, 1H), 3.30 (d, J=3.0 Hz, 2H), 3.15 (d, J=4.8 Hz, 2H).