Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C1(NC(C)(C)C)C=CC=CC=1.NC(N)=O.C(NN[CH2:27][C:28]([C:30]1[CH:31]=[CH:32][C:33]([OH:39])=[C:34]([CH2:36][C:37]#[N:38])[CH:35]=1)=[O:29])(C)(C)C>>[OH:39][C:33]1[CH:32]=[CH:31][C:30]([CH:28]([OH:29])[CH2:27][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:35][C:34]=1[CH2:36][C:37]#[N:38]
Reactant: CC(C)(C)NNCC(=O)c1ccc(O)c(CC#N)c1
Reactant: CC(C)(C)N
Agent: CC(C)(C)Nc1ccccc1
Agent: NC(N)=O
Product: CC(C)(C)NCC(O)c1ccc(O)c(CC#N)c1

Procedure:
The procedure of Example 1(c) is repeated with substitution of an equimolar amount of t-butylamine for phenyl-t-butylamine in that example. The resulting aminoketone, 5-[N-(t-butylamino)glycyl]-2-hydroxyphenylacetonitrile is reduced according to the procedure of Example 1(d) to yield 2-hydroxy-5-[1-hydroxy-2-(t-butylamino)ethyl]-benzeneacetonitrile.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]=[C:5]1[CH3:12])([CH3:3])[CH3:2].[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1.C1C=CC2N(O)N=NC=2C=1.CN(C=O)C>O>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:9]([C:7]3[N:6]=[C:5]([CH3:12])[N:4]([CH:1]([CH3:2])[CH3:3])[CH:8]=3)=[O:11])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: Cc1nc(C(=O)O)cn1C(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1C(C)C
Yield: 79.3 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) using 1-isopropyl-2-methyl-1H-imidazole-4-carboxylic acid (0.303 mmol, 51 mg), (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.253 mmol, 70.4 mg) and only a catalytic amount of HOBt (0.025 mmol, 3.41 mg). DMF (2 ml) was used as the solvent in the reaction. The work up was done by adding water to the reaction mixture and extracting it three times with DCM. The combined organics were washed twice with water. The organic phase was evaporated and the residue was purified by flash chromatography. 86 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.06 (d, 3H), 1.34 (d, 6H), 2.35 (s, 3H), 4.23-4.47 (m, 4H), 7.02 (d, 1H), 7.62 (s, 1H), 7.86 (d, 1H), 7.90-7.96 (m, 1H), 8.00 (s, 1H), 8.04 (d, 1H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.C(Cl)(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH2:29]([N:31]1[C:43]2[CH:42]=[CH:41][C:40]([NH2:44])=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:30]>>[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([NH:44][C:40]1[CH:41]=[CH:42][C:43]2[N:31]([CH2:29][CH3:30])[C:32]3[C:37]([C:38]=2[CH:39]=1)=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:19])(=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: O=C(Cl)c1ccccc1
Product: CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, benzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=469.4.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].[S:10]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11]1>CN(C)C=O.C(OCC)(=O)C>[S:10]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:8][CH3:9])=[O:18])=[CH:11]1
Reactant: O=C(O)/C=C/c1ccsc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccsc1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
11.5 g of potassium carbonate and 6.8 ml of iodoethane are added to 11 g of (E)-3-(3-thienyl)-2-propenoic acid, obtained in step 4.1, in solution in 50 ml of dimethylformamide, and the mixture is stirred for 48 hours at 20° C. The medium is taken up in ethyl acetate and it is washed with water. The organic phase is dried over anhydrous sodium sulfate and it is concentrated to give 12.5 g of oil.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:34])[N:29]([CH3:33])[CH2:30][CH2:31]O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:49]=[N+:50]=[N-:51])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:34])[N:29]([CH2:30][CH2:31][N:49]=[N+:50]=[N-:51])[CH3:33])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CN(CCO)C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN(CCN=[N+]=[N-])C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Yield: 100.8 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[N-methyl-N-(2-hydroxyethyl)carbamoyl]-1,3-thiazol-2-yl}azetidine (997.5 mg, 2.0 mmol) (obtained as described in Reference Example 58(1)) in tetrahydrofuran (50 ml) were added diphenylphosphoryl azide (0.65 ml, 3.02 mmol), triphenylphosphine (793 mg, 3.02 mmol), and a 40% solution of diethylazodicarboxylate in toluene (1.12 g, 3.04 mmol) in an ice bath under an atmosphere of nitrogen, and the mixture was stirred overnight under the same conditions. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using toluene:ethyl acetate (1:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-{4-[N-(2-azidoethyl)-N-methyl-carbamoyl]-1,3-thiazol-2-yl}azetidine (1.05 g, yield 100%) as a colorless and transparent syrup.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[CH2:8]([N:12]=[C:13]=[S:14])[CH:9]([CH3:11])[CH3:10].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:12]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:13]1=[S:14])[CH3:2]
Reactant: CCNCC(=O)O
Reactant: CC(C)CN=C=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CC(=O)N(CC(C)C)C1=S
Yield: 23.2 %

Procedure:
The title compound was prepared by the procedure described in Example 4 using 9.2 g of N-ethyl glycine, 5.7 g of isobutyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved by flash chromatography on silica gel (methylene chloride). Title compound (2.3 g) was obtained as an oil. Anal. Calcd. for. C9 H16N2O S: C, 53.97; H, 8.05; N, 13.99. Found: C, 54.01; H, 8.21; N, 14.00. Mass spectrum (EI, M.+) m/z 200.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[S:10][CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](OB(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>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(O)C>[N+:14]([C:13]1[CH:12]=[CH:11][S:10][C:9]=1[C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccsc1Br
Reactant: OB(O)Oc1ccc(Cl)cc1
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: O=[N+]([O-])c1ccsc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.5 %

Procedure:
To 50 ml of toluene, 1 g of 2-bromo-3-nitrothiophene, 0.75 g of 4-chlorophenylboric acid, 5 ml of a 2M-aqueous potassium carbonate solution and 2 ml of ethanol were added and stirred at room temperature for 30 minutes in a nitrogen atmosphere. Successively 0.28 g of Pd(PPh3)4 was added and heat-refluxed for 2 hours. The aqueous layer was separated from the reaction mixture and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue thus obtained was purified by silica gel column chromatography to obtain 1.1 g of the product as a yellow crystal. The yield was 98%. 1H-NMR(CDCl3, δ value):7.29(1H, d, J=5.9), 7.43(4H, s), 7.66(1H, d, J=5.9)
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([F:27])[CH:33]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OB(O)c1cccc(F)c1
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: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccc(F)c4)cc23)CC1
Yield: 117.2 %

Procedure:
Following the general procedure of Example 65, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidine carboxylate (Intermediate 5) (400 mg, 0.545 mmols), 3-fluorophenyl boronic acid (397 mg, 2.84 mmols), potassium carbonate (782 mg, 5.67 mmol), and Pd(PPh3)4 (218 mg, 0.189 mmol) in dioxane/water (7 mL/1 mL) were reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (280 mg, 68%)
Reaction SMILES: Br.[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13])[CH3:3].C(N(CC)CC)C.[C:24]12([C:34](Cl)=[O:35])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>O1CCCC1>[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH:13][C:34]([C:24]12[CH2:33][CH:28]3[CH2:27][CH:26]([CH2:32][CH:30]([CH2:29]3)[CH2:31]1)[CH2:25]2)=[O:35])[CH3:3]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
2.93 g (0.010 mol) of L-alanyl-L-proline ethylamide hydrobromide were dissolved in 50 ml of tetrahydrofuran and the mixture was cooled to 0° C. There were then added 2.8 ml (0.020 mol) of triethylamine followed by 2.15 g (0.010 mol) of 1-adamantoyl chloride. The mixture was stirred at 0° C. for 0.5 hour and at room temperature for 2 hours and then evaporated to dryness. The oily residue was dissolved in ethyl acetate and the solution washed successively with 0.5-N hydrochloric acid, water, 5% sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. The resulting oil was crystallised from ethyl acetate/petroleum ether to yield 2.2 g (59%) of N-(1-adamantylcarbonyl)-L-alanyl-L-proline ethylamide of melting point 116°-118° C; [α]D20 =-88.1° (c=0.99% in methanol).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:24]([NH:26][C:27](=[O:45])[C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[C:31]([CH3:43])=[C:30]([F:44])[CH:29]=1)[CH3:25].C(=O)([O-])O.[Na+].O>C(O)(C)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.C(Cl)Cl>[CH2:24]([NH:26][C:27]([C:28]1[CH:29]=[C:30]([F:44])[C:31]([CH3:43])=[C:32]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([N:11]4[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]4)=[N:7][NH:8]3)=[CH:4][CH:3]=2)[CH:33]=1)=[O:45])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCN(c2n[nH]c3cc(Br)ccc23)CC1
Reactant: CCNC(=O)c1cc(F)c(C)c(B2OC(C)(C)C(C)(C)O2)c1
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: O
Solvent: ClCCl
Solvent: CC(C)O
Product: CCNC(=O)c1cc(F)c(C)c(-c2ccc3c(N4CCN(C(=O)OC(C)(C)C)CC4)n[nH]c3c2)c1
Temperature: 150 °C
Yield: 45.2 %

Procedure:
A mixture of 1,1-dimethylethyl 4-(6-bromo-1H-indazol-3-yl)-1-piperazinecarboxylate (Intermediate 6, 28 mg), N-ethyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 5, 27 mg), tetrakis(triphenylphosphine)palladium (2 mg) and aqueous sodium hydrogen carbonate (0.125 ml) in isopropanol (0.5 ml) was heated at 150° C. in a microwave oven for 15 min. Water and DCM were added and the organic phase was separated using a hydrophobic filter tube. The solvent was evaporated and the residue was purified by reverse phase preparative HPLC to give the title compound (16 mg).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#N)=[CH:7][C:6]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])(=O)C.Cl.[OH2:24].[CH2:25]([OH:27])[CH3:26]>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:27][CH2:25][CH3:26])=[O:24])=[CH:7][C:6]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21]
Reactant: O
Reactant: CCO
Reactant: CC(=O)Nc1ccc(CC#N)cc1C(=O)c1ccccc1Cl
Agent: Cl
Product: CCOC(=O)Cc1ccc(N)c(C(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
32.2 g (0.1 mol) of 4-acetamido-3-(2-chlorobenzoyl)-phenylacetonitrile are dissolved in 340 ml of absolute ethanol. While cooling in ice, dry gaseous hydrogen chloride is passed in for one hour. The mixture is subsequently refluxed for 30 minutes and then stirred at room temperature for 24 hours. Five times the amount of water is added to the reaction mixture, which is left to stand for 15 minutes. Extraction with dichloromethane, drying and concentration of the organic phase is followed by working out by chromatography on silica gel results in 20.9 g (64% of theory) of the title compound as an oil.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH:5](/[Mg]Br)=[CH:6]\[CH3:7].CON(C)[C:13](=[O:45])[CH2:14][N:15]([C@@H:23]([C:33](=[CH2:44])[CH2:34][CH2:35][O:36][Si:37]([CH3:43])([CH3:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:24][O:25][Si:26]([CH3:32])([CH3:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[CH3:28][C:27]([CH3:30])([Si:26]([CH3:31])([CH3:32])[O:25][CH2:24][C@@H:23]([N:15]([CH2:14][C:13](=[O:45])[CH:5]=[CH:6][CH3:7])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:33](=[CH2:44])[CH2:34][CH2:35][O:36][Si:37]([CH3:42])([CH3:43])[C:38]([CH3:39])([CH3:40])[CH3:41])[CH3:29]
Reactant: C/C=C/[Mg]Br
Reactant: C=C(CCO[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C(CCO[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)C=CC)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
A suspension of cerium (III) chloride (47.6 g, 193.26 mmol) in THF (200 mL) 3 at room temperature was stirred vigorously for 2 hours. The suspension was cooled to −78° C. and (E)-prop-1-enylmagnesium bromide (0.5 M in THF) (387 mL, 193.26 mmol) was added dropwise. The mixture was stirred at −78° C. for 1.5 hours. (5)-tert-butyl (2-(methoxy(methyl)amino)-2-oxoethyl)(2,2,3,3,11,11,12,12-octamethyl-7-methylene-4,10-dioxa-3,11-disilatridecan-6-yl)carbamate (Intermediate 278, 13.55 g, 24.16 mmol) in THF (50 mL) was then added dropwise at −78° C. The reaction was stirred at −78° C. for 1 hour and then warmed to 0° C. for 30 minutes. The reaction was quenched with 10% citric acid, diluted further with water and extracted twice with ether. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the title compound (10 g, 76%) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[CH3:14])=O)[CH:2]=1.O.NN.[OH-].[K+]>C(O)CO>[Br:19][C:16]1[CH:17]=[CH:18][C:11]2[O:10][C:9]([CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[C:13]([CH3:14])[C:12]=2[CH:15]=1
Reactant: Cc1c(C(=O)c2cccnc2)oc2ccc(Br)cc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1c(Cc2cccnc2)oc2ccc(Br)cc12
Temperature: 120 °C
Yield: 78.4 %

Procedure:
A mixture of 5-bromo-3-methylbenzofuran-2-yl pyrid-3-yl ketone free base (2.67 g) and hydrazine hydrate (1.80 g) in ethylene glycol (30 ml) was heated at 120° C. for 2.5 hours. The mixture was cooled, potassium hydroxide (1.80 g) was added and the temperature was raised to 120° again and maintained at this temperature for 1 hour. Dilution with water and ether extraction gave an oil which was chromatographed on silica gel. Elution with chloroform gave a solid which was crystallised from petrol (b.p. 80°-100°) to give 5-bromo-3-methyl-2-(3-pyridylmethyl)benzofuran (2.00 g), m.p. 57°-58°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10][CH2:9][C:8]=2[CH:18]=1)([O-])=O.S1C=CC=C1.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10][CH2:9][C:8]=2[CH:18]=1
Reactant: [H][H]
Reactant: CCOC(=O)C1CCc2cc([N+](=O)[O-])ccc2O1
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: CCOC(=O)C1CCc2cc(N)ccc2O1
Yield: 90 %

Procedure:
A mixture of 59.8 parts of ethyl 3,4-dihydro-6-nitro-2H-1-benzopyran-2-carboxylate, 3 parts of a solution of thiophene in methanol 1% and 480 parts of methanol was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 48 parts (90%) of ethyl 6-amino-3,4-dihydro-2H-1-benzopyran-2-carboxylate as a residue (intermediate 24).
Reaction SMILES: [N:1]([CH2:4][CH:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]([CH3:8])[CH3:7])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(OCC)(=O)C>C1COCC1>[NH2:1][CH2:4][CH:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C(CN=[N+]=[N-])NC(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)C(CN)NC(=O)OCc1ccccc1
Reaction time: 20 h

Procedure:
To benzyl N-[1-(azidomethyl)-2-methyl-propyl]carbamate 6.9 g (0.0263 mole) in THF (100 mL) was added triphenyl phosphine 7.59 g (1.1 eq). The contents were stirred for 20 hrs. After addition of water (10 mL), and stirring for an additional 6 hrs, ethyl acetate was added and the layers separated. After drying with magnesium sulfate and concentration under vacuum, the crude product was columned using DCM/MeOH (0-10%) to afford benzyl N-[1-(aminomethyl)-2-methyl-propyl]carbamate as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:3]=1[NH:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1B1OC(C)(C)C(C)(C)O1.Br[C:32]1[N:37]=[C:36]([C:38]([NH:41][C:42]2[C:47]([CH2:48][CH3:49])=[CH:46][CH:45]=[CH:44][C:43]=2[CH2:50][CH3:51])([CH3:40])[CH3:39])[CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].O>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.C1(C)C=CC=CC=1.CO>[CH2:50]([C:43]1[CH:44]=[CH:45][CH:46]=[C:47]([CH2:48][CH3:49])[C:42]=1[NH:41][C:38]([C:36]1[N:37]=[C:32]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[CH:15][C:6]=2[CH2:5][NH:4][C:3]2[C:2]([CH3:1])=[CH:28][C:27]([CH3:29])=[CH:26][C:25]=2[CH3:30])[CH:33]=[CH:34][CH:35]=1)([CH3:40])[CH3:39])[CH3:51]
Reactant: Cc1cc(C)c(NCc2ccc3ccccc3c2B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CCc1cccc(CC)c1NC(C)(C)c1cccc(Br)n1
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: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCc1cccc(CC)c1NC(C)(C)c1cccc(-c2c(CNc3c(C)cc(C)cc3C)ccc3ccccc23)n1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 2.43 g (6.00 mmol) of 2,4,6-trimethyl-N-{[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}aniline, 2.10 g (6.00 mmol) of N-[1-(6-bromopyridin-2-yl)-1-methylethyl]-2,6-diethylaniline, 4.33 g (15.10 mmol) of Na2CO3×10H2O, 65 ml of water, 18 ml of methanol, and 80 ml of toluene was purged with argon for 30 min. To this solution 0.35 g (0.30 mmol) of Pd(PPh3)4 was added. In argon atmosphere, this mixture was stirred for 12 h at 80° C. Then, it was cooled to room temperature, the organic layer was separated, the aqueous layer was extracted with 3×200 ml of ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel 60 (40-63 um, eluent: dichloromethane-ethyl acetate=20:1, vol.). Yield 2.66 g (82%) of yellow oil. Anal. calc. for C39H43N3: C, 84.24; H, 8.00; N, 7.76. Found: C, 84.36; H, 8.15; N, 7.61. 1H NMR (CDCl3): δ 7.87 (m, 1H. 8-H in naphtalene), 7.82 (d, J=8.4 Hz, 1H, 4-H in naphtalene), 7.78 (t, J=7.7 Hz, 1H, 4-H in pyridine), 7.70 (dd, J=7.7 Hz, J=0.6 Hz, 1H, 5-H in pyridine), 7.35-7.47 (m, 4H, 3, 5, 6, 7-H in naphtalene), 7.21 (dd, J=7.7 Hz, J=0.6 Hz, 1H, 3-H in pyridine), 6.93-7.00 (m, 3H, 3, 4, 5-H in 2, 6-Et2C6H3), 6.74 (s, 2H, 3, 5-H in mesityl), 3.96 (m, 2H, CH2N), 3.70 (br.s, 2H, NH), 2.47 (sep, J=7.6 Hz, 1H, CHMe2), 2.43 (sep, J=7.6 Hz, 1H, CHMe2), 2.21 (s, 3H, 4-Me in mesityl), 2.03 (s, 6H, 2, 6-Me in mesityl), 1.54 (s, 3H, CMeMe′), 1.47 (s, 3H, CMeMe′), 1.02 (t, J=7.6 Hz, 6H, CHMe2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14]Cl)[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][CH2:28][NH2:29].C(N(CC)CC)C.O>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][NH:29][CH2:28][CH2:27][CH2:26][C:20]3[C:19]4[C:23](=[CH:24][CH:25]=[C:17]([F:16])[CH:18]=4)[NH:22][CH:21]=3)[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2
Reactant: NCCCc1c[nH]c2ccc(F)cc12
Reactant: Fc1cc2c(c(OCCCl)c1)OCCC2
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Fc1cc2c(c(OCCNCCCc3c[nH]c4ccc(F)cc34)c1)OCCC2
Temperature: 90 °C
Reaction time: 14 h

Procedure:
A solution 2-(6-fluorochroman-8-yloxy)ethylchloride (0.25 g, 7.1 mmol), 3-(5-fluoro-1H-indol-3-yl)-propylamine (0.42 g, 2.2 mmol) and triethylamine (0.22 g, 2.2 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to stir for 14 hours at 90° C. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) afforded 0.25 g (60%) as a white solid: mp 137-138.5° C.