Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:26](=[O:37])[NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=3)=[C:12]([CH:23]([CH3:25])[CH3:24])[N:13]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:9][CH:8]=1)(=O)=O.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+].[N:48]1[CH:53]=[C:52](B(O)O)[CH:51]=[N:50][CH:49]=1>C1(C)C=CC=CC=1.CO.CCOC(C)=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>[F:36][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[F:35])[CH2:28][NH:27][C:26]([C:11]1[C:10]2[C:14](=[CH:15][C:7]([C:52]3[CH:53]=[N:48][CH:49]=[N:50][CH:51]=3)=[CH:8][CH:9]=2)[N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:12]=1[CH:23]([CH3:24])[CH3:25])=[O:37]
Reactant: OB(O)c1cncnc1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OS(=O)(=O)C(F)(F)F)cc2n1Cc1ccccn1
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: [Cl-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(-c3cncnc3)cc2n1Cc1ccccn1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
General Procedure BB. To a solution of 3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indol-6-yl trifluoromethanesulfonate (Compound 202, 33 mg, 0.06 mmol) in toluene (8 ml) and MeOH (1 ml) at 25° C., bubbled with argon then added LiCl (8 mg, 0.18 mmol), Na2CO3 (aqueous) (2M, 0.1 ml), Pd(PPh3)4 (3.4 mg, 0.003 mmol), and 5-pyrimidine boronic acid (11 mg, 0.09 mmol). The reaction was stirred for 12 h at 80° C., diluted with EtOAc, the organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C:9]2=[O:15])=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[C:16]([C:10]1[C:11](=[O:14])[CH2:12][CH2:13][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]=1[OH:15])(=[O:18])[CH3:17]
Reactant: O=C1CCC(c2ccc(F)cc2)C(=O)C1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)C1=C(O)C(c2ccc(F)cc2)CCC1=O

Procedure:
A solution of 4-(4-fluorophenyl)cyclohexane-1,3-dione (4 g), acetic anhydride (6 ml) and 4-(N,N-dimethylamino) pyridine (0.2 g) in toluene (50 ml) was refluxed 3 hours. Evaporation of the toluene in vacuo gave a red oil, which, after purification on a silica gel column using 5% (v/v) diethyl ether-methylene chloride as eluant, gave the title compound as a yeoolw solid (4 g) of m.p. 67°-68° C.
Reaction SMILES: [Br:1][C:2]1[NH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.CC(=O)CC>C(OCC)(=O)C>[Br:1][C:2]1[N:6]([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Brc1ccn[nH]1
Reactant: COC(=O)c1ccc(CBr)cc1
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(Cn2nccc2Br)cc1
Yield: 63.7 %

Procedure:
5-bromo-1H-pyrazole (146 mg, 1 mmol), methyl 4-(bromomethyl)benzoate (242 mg, 2 mmol) and K2C03 (276 mg, 2 mmol) were placed in a 100-mL flask with 2-butanone (20 mL) and heated at reflux temperature for 17 h. The mixture was cooled, filtered and evaporated in vacuuo leaving a residue which was dissolved in ethyl acetate and washed with water. The separated organic layer was dried and concentrated to give desired product as an oil (188 mg, 100% yield). This crude material was used without further purification. LCMS (m/z): 295.1 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[CH:18]=3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:47]2[CH:48]=[C:49]([CH:52]=[CH:53][CH:54]=2)[CH2:50][Cl:51])[CH:40]=[C:41]([O:45][CH3:46])[C:42]=1[O:43][CH3:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:67].Cl>>[ClH:51].[ClH:67].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=4)[CH:18]=3)[CH2:14][CH2:15]2)[CH2:50][C:49]2[CH:52]=[CH:53][CH:54]=[C:47]([C:39]3[CH:40]=[C:41]([O:45][CH3:46])[C:42]([O:43][CH3:44])=[C:37]([O:36][CH3:35])[CH:38]=3)[CH:48]=2)=[CH:5][CH:4]=1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Reactant: COc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1ccc(N(Cc2cccc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1

Procedure:
4-(p-Anisidino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (139 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave the title compound as yellow powder.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH:2]=[CH2:3].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][C:17]=1[Cl:23].C1(C)C=CC=CC=1.C1(N(C)C2CCCCC2)CCCCC1>C(Cl)Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:15][C:16]1[CH:21]=[C:20](/[CH:3]=[CH:2]/[CH2:1][N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:13])[C:5]2=[O:14])[CH:19]=[CH:18][C:17]=1[Cl:23]
Reactant: Clc1ccc(I)cc1Cl
Reactant: C=CCN1C(=O)C(=O)c2ccccc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C1C(=O)N(C/C=C/c2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 80 °C
Yield: 83.9 %

Procedure:
A mixture of 1-allyl-1H-indole-2,3-dione (1.00 g, 5.34 mmol), Pd(P(t-Bu)3)2 (0.0819 g, 0.16 mmol), 1,2-dichloro-4-iodobenzene (1.458 g, 5.34 mmol), dry toluene (10 mL), and N-cyclohexyl-N-methylcyclohexanamine (1.23 mL, 5.86 mmol) in an oven-dried sealed tube under an atmosphere of N2 was heated for 16 h at 80° C. The reaction was cooled, diluted with CH2Cl2, and loaded directly onto a silica gel column that had been packed with CH2Cl2. The column was eluted with a gradient of 100% CH2Cl2 to 95:5 CH2Cl2:EtOAc. The appropriate fractions were combined to provide the title compound as an orange solid (1.489 g, 84%). 1H NMR (600 MHz, CHLOROFORM-D) δ ppm 4.52 (d, J=5.9 Hz, 2H), 6.19 (dt, J=15.9, 5.9 Hz, 1H), 6.56 (d, J=15.6 Hz, 1H), 6.91 (d, J=7.9 Hz, 1H), 7.09-7.20 (m, 2H), 7.37 (d, J=8.2 Hz, 1H), 7.42 (s, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.64 (d, J=7.4 Hz, 1H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]=[CH:12][CH2:13][OH:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18]>>[CH3:15][C:16]([CH3:21])([CH3:20])[C:17]([O:14][CH2:13][CH:12]=[CH:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: O=C(OCC=CCO)c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)OCC=CCOC(=O)c1ccccc1

Procedure:
4-Benzoyloxy-2-butenyl trimethylacetate was prepared by the procedure of Example 1 from 19 gms (0.1 mole) of 4-hydroxy-2-butenyl benzoate and 12 gms (0.1 mole) of trimethylacetyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: [C:1]([C:3]1[C:10]([Cl:11])=[CH:9][C:6]([CH2:7]Br)=[CH:5][C:4]=1[Cl:12])#[N:2].C(C1C=CC(C[N:20]2[C:24]([CH:25]=[O:26])=[CH:23][N:22]=[CH:21]2)=CC=1F)#N>>[C:1]([C:3]1[C:10]([Cl:11])=[CH:9][C:6]([CH2:7][N:20]2[C:24]([CH:25]=[O:26])=[CH:23][N:22]=[CH:21]2)=[CH:5][C:4]=1[Cl:12])#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Reactant: N#Cc1c(Cl)cc(CBr)cc1Cl
Product: N#Cc1c(Cl)cc(Cn2cncc2C=O)cc1Cl

Procedure:
The titled product was prepared from the product of Step C using the same procedures as those described in Example 1, Steps D through G for the preparation of 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC.O.C(O)C>[F:12][C:4]1[CH:3]=[C:2]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)c1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(-c2cccnc2)cc1F

Procedure:
A mixture of EXAMPLE 50A (5 g), 3-pyridinylboronic acid (4 g) and dichlorobis(triphenylphosphine)-palladium (II) (1.1 g) in 7:3:2 DME/water/ethanol (200 mL) and 2M aqueous Na2CO3 solution (1 mL) at 80° C. was stirred 18 hours, cooled and filtered. The filtrate was partitioned between ethyl acetate and water, and the ethyl acetate layer washed with water and concentrated. The concentrate was flash chromatographed on silica gel with 1:2 ethyl acetate/hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22]C2CCCCO2)[CH:5]=[CH:4][C:3]=1[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37])=[O:30].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22])[CH:5]=[CH:4][C:3]=1[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37])=[O:30]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2COCCOCCOC2CCCCO2)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2COCCOCCO)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 149 (5.68 g, 10.8 mmol) was dissolved in MeOH (100 mL) and p-toluenesulfonic acid (3.09 g, 16.3 mmol) was added. The solution was stirred at room temperature for 2 h. Aqueous NaHCO3 (5%, 100 mL) was added and the water phase was extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The crude product was purified by flash chromatography using EtOAc/Petroleum ether 1:1–3:2 as the eluent to afford the title compound as an orange oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[NH:7][C:6](=[O:11])[C:5]=1[C:12]#[N:13].N>CO.[Ni]>[NH2:13][CH2:12][C:5]1[C:6](=[O:11])[NH:7][C:8]([CH3:10])=[CH:9][C:4]=1[CH2:3][O:2][CH3:1]
Reactant: COCc1cc(C)[nH]c(=O)c1C#N
Agent: [Ni]
Agent: N
Solvent: CO
Product: COCc1cc(C)[nH]c(=O)c1CN
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of 4-(methoxymethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (0.165 g, 0.927 mmol) in methanol (10 mL), Raney Ni and ammonia (1 mL) were added and reaction stirred under hydrogen balloon pressure for 3 h. On completion, reaction mass was filtered through celite bed and filtrate concentrated to obtain the desired compound (0.13 g, 80%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](O)=[N:8][C:7]([CH:12]([CH3:14])[CH3:13])=[N:6][C:5]=2[C:4]([CH3:15])=[N:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>P(Cl)(Cl)(Cl)=O>[Cl:17][C:9]1[C:10]2[N:2]([CH3:1])[N:3]=[C:4]([CH3:15])[C:5]=2[N:6]=[C:7]([CH:12]([CH3:14])[CH3:13])[N:8]=1
Reactant: Cc1nn(C)c2c(O)nc(C(C)C)nc12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn(C)c2c(Cl)nc(C(C)C)nc12
Yield: 97.4 %

Procedure:
A mixture of 10 g (0.048 mol) of 1,3-dimethyl-5-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7-ol and 10.2 g (0.049 mol) of phosphorus pentachloride in 70 ml of phosphorus oxychloride is stirred under reflux five hours and evaporated in vacuo. The residue is dissolved in 150 ml of methylene dichloride and stirred with 100 ml of a saturated solution of sodium bicarbonate. The organic layer is separated, dried over MgSO4, and evaporated in vacuo to to give 10.5 g of 7-chloro-1,3-dimethyl-5-isopropyl-1H-pyrazolo[4,3-d]pyrimidine, mp 87°-89° C. from pet ether.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7](Cl)[C:6]=12.[NH3:16].O>CC(O)C>[Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:16])[C:6]=12
Reactant: Clc1nccn2c(C3CCC3)nc(Br)c12
Reactant: N
Solvent: O
Solvent: CC(C)O
Product: Nc1nccn2c(C3CCC3)nc(Br)c12
Temperature: 100 °C

Procedure:
A suspension of 1-bromo-8-chloro-3-cyclobutylimidazo[1,5-a]pyrazine (341 mg, 1.2 mmol) in IPA (3 mL) was saturated with NH3(g) at 0° C. for 3 min. The tube was sealed and heated at 100° C. for 17 h. H2O (10 mL) was added and the mixture was extracted with EtOAc (3×30 mL). The organic phase was washed with brine and concentrated under reduced pressure to provide the title compound as a white solid; 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J=4.8 Hz, 1H), 6.97 (d, J=5.2 Hz, 1H), 5.65 (br, 2H), 3.70 (qud, J=0.8 Hz, 8.4 Hz, 1H), 2.55-2.35 (m, 4H), 2.18-1.93 (m, 2H); MS (ES+): m/z 267.1 (100), 269.1 (100) [MH+]; HPLC: tR=1.70 min (OpenLynx, polar—5 min).
Reaction SMILES: CS([Cl:5])(=O)=O.C(N(CC)CC)C.[I:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:5][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[I:13]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccccc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCc1ccccc1I
Temperature: 0 °C
Reaction time: 19 h
Yield: 100.7 %

Procedure:
Methanesulfonyl chloride (2.0 ml, 29 mmol) and triethylamine (3.6 ml, 26 mmol) were added to a solution of o-iodobenzyl alcohol (5.0 g, 21 mmol) in methylene chloride (50 ml) cooled to 0° C., and the mixture was stirred at that temperature for 19 hours. A 5% aqueous sodium hydrogencarbonate solution was added, and the resulting mixture was extracted with methylene chloride. The methylene chloride layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (5.34 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=2)[CH:9]=[N:8]1.[OH-].[Na+].CN([CH:25]=[O:26])C>>[CH:25]([C:9]1[C:10]2[C:15](=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)[N:7]([CH3:6])[N:8]=1)=[O:26]
Reactant: COC(=O)c1ccc2cnn(C)c2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(C=O)nn(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a dry flask under nitrogen is added dry DMF (1.6 mL) and the solution cooled to −5 C in an ice/ethanol bath. Phosphorous oxychloride (530 uL, 5.7 mmol) is added via syringe and the solution is allowed to stir for 30 minutes in the bath. Methyl 1-methyl-1H-indazole-6-carboxylate, (500 mg, 2.84 mmol, prepared as in Jadhav et al, U.S. Pat. No. 5,760,028) dissolved in DMF (3 mL) is added slowly to the cold solution. The reaction is then warmed to 35 C, stirred for four hours, and then poured onto crushed ice. The resulting slurry is neutralized with 1N NaOH to pH=7, heated rapidly to boiling for 1 minute, cooled quickly to room temperature, and the solution extracted with ethyl acetate. The combined organics are washed with water and brine, dried, filtered and concentrated. The resulting oil is purified by flash chromatography to afford the product.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]#[N:12])[CH2:2][CH3:3].C([O-])(=O)C.[Na+].C(O)(=O)C.[Br:22]Br>ClCCl.[Cl-].[Na+].O>[Br:22][C:8]1[CH:7]=[CH:6][C:5]([NH:10][C:11]#[N:12])=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=1
Reactant: BrBr
Reactant: CCCc1ccccc1NC#N
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CCCc1cc(Br)ccc1NC#N
Reaction time: 2.5 h
Yield: 24.4 %

Procedure:
(2-propylphenyl)cyanamide (0.550 g, 3.43 mmol), sodium acetate (0.278 g, 3.4 mmol), and catalytic acetic acid were combined in dichloromethane (25 mL). Bromine (0.17 mL, 3.43 mmol) was added dropwise and allowed to stir 2.5 hours. The mixture was then poured into brine and extracted with diethylether. The solvent was dried over magnesium sulfate and evaporated in vacuo. The solid was triturated with 9/1 Hexane/acetone, filtered, and dried to give 4-bromo2-propylphenylcyanamide (0.200 g, 24%) an off white solid. HRMS: calcd for C10H11BrN2+H+, 239.01783; found (ESI-FTMS, [M+H]+), 239.01782.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:3].CN(C)C=O.[N:29]([CH2:32][CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[N+:30]=[N-:31]>[Cu]I.CO>[CH3:3][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[N:31]=[N:30][N:29]([CH2:32][CH2:33][NH:34][C:35]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:41])[CH:18]=3)[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:1]
Reactant: CC(C)(C)OC(=O)NCCN=[N+]=[N-]
Reactant: C#Cc1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3cn(CCNC(=O)OC(C)(C)C)nn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A flask was charged with 1-methylethyl[(2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 58) (80 mg, 0.254 mmol) and copper(I) iodide (2.423 mg, 0.013 mmol) then filled with N,N-dimethylformamide (DMF) (1.8 mL) and methanol (0.200 mL). 1,1-Dimethylethyl (2-azidoethyl)carbamate (for a preparation, see Intermediate 78) (95 mg, 0.509 mmol) was added and the resulting mixture was stirred under microwave irradiation at 100° C. for 2 h then cooled to room temperature. The reaction mixture was partitioned between EtOAc and brine and the layers were separated. The aqueous phase was extracted with EtOAc (3×) and the combined organic phases were washed with brine, dried over a Na2SO4 cartridge and concentrated in vacuo. Purification of the residue on SP4 using a 10 G silica cartridge (gradient: 5 to 25% (10% MeOH in DCM) in DCM) gave 1-methylethyl((2S,4R)-1-acetyl-6-{1-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1H-1,2,3-triazol-4-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (108 mg, 0.216 mmol, 85% yield) as a pale yellow foam. LCMS (method A): Retention time 0.95 min, [M+H]+=501.26
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C@H:14]2[CH2:19][O:18][C:16](=[O:17])[CH2:15]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH:25]=O.[H-].[Na+].CO.Cl>C1(C)C=CC=CC=1>[CH3:33][O:32][C:28]1[CH:27]=[C:24]([CH:23]=[C:22]([O:21][CH3:20])[C:29]=1[O:30][CH3:31])/[CH:25]=[C:15]1/[C:16]([O:18][CH2:19][C@@H:14]/1[CH2:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:17]
Reactant: COc1cc(C[C@H]2COC(=O)C2)cc(OC)c1OC
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(/C=C2/C(=O)OC[C@@H]2Cc2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 45 h
Yield: 32.1 %

Procedure:
A solution of (R)-3-[1-(3,4,5-trimethoxyphenyl)-methyl]butanolide [10.52 g, 0.04 mol; K. Lalami, D. Dhai, and E. Brown, Heterocycles, 27, 1131 (1988)] and 3,4,5-trimethoxybenzaldehyde (11.4 g, 0.058 mol) in toluene (150 ml) was cooled to 0° C. under an argon stream. The solution was added with 4.0 g of sodium hydride (60%, 0.1 mol) and 0.15 ml (0.0037 mol) of methanol, followed by stirring at room temperature for 45 hours. The reaction mixture was ice-cooled and then added with 100 ml of 2N-HCl. After the removal of the water layer, the organic layer was washed successively with water, saturated NaHCO3 and saturated NaCl and then dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue thus obtained (20 g) was purified by column chromatography on a silica gel column (silica gel: "MERCK #9385", 500 g, eluent: 1:2 mixed solvent of ethyl acetate and hexane), whereby 5.71 g of the title compound were obtained as pale yellow oil (yield: 33%). [α]27D : -75.64° (C=0.55, CHCl3)
Reaction SMILES: C([O:8][C@@H:9]([C@@H:11]1[N:16]2[C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:19]([NH2:27])[C:18]=3[N:28]=[C:15]2[CH2:14][O:13][CH2:12]1)[CH3:10])C1C=CC=CC=1.Cl>CO.[Pd].C(O)C>[NH2:27][C:19]1[C:18]2[N:28]=[C:15]3[CH2:14][O:13][CH2:12][C@H:11]([C@H:9]([OH:8])[CH3:10])[N:16]3[C:17]=2[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: C[C@@H](O)[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Reaction time: 24 h
Yield: 90.6 %

Procedure:
(11R)-11-[(1R)-1-(Benzyloxy)ethyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (512 mg, 1.37 mmol) was dissolved in 30 mL of methanol and the solution was placed in a pressure bottle. Palladium on carbon (10%, 200 mg) and 2.5 mL of 3 M HCl in ethanol were then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 24 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with methanol and the combined filtrates were concentrated under reduced pressure. The residue was dissolved in H2O and the solution was made basic by the addition of concentrated aqueous NH4OH solution. The aqueous solution was extracted with 10% MeOH/CHCl3 several times and the combined organic layers were concentrated under reduced pressure. Chromatography (SiO2, 25-50% CMA/CHCl3) gave an off-white powder. Crystallization from ethyl acetate and methanol gave 353 mg of the title compound as white needles, mp 215.3-218.6° C.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]#[N:13])[CH:8]=[CH:9][CH:10]=1.I[CH3:15]>C1COCC1>[CH3:15][N:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([S:4][CH3:3])[CH:6]=1)[C:12]#[N:13]
Reactant: CI
Reactant: CSc1cccc(NC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cccc(N(C)C#N)c1
Temperature: 70 °C
Yield: 72.6 %

Procedure:
A flame-dried Schlenk flask under a nitrogen atmosphere was charged with sodium hydride (60% in mineral oil, 0.14 g, 3.5 mmol), 3-Methylsulfanyl-phenyl-cyanamide (0.493 g, 3.00 mmol) and anhydrous THF (5 ml). The mixture was stirred rapidly and heated to 70° C. for circa 0.5 hours. On cooling to room temperature, iodomethane (0.37 ml, 6.00 mmol) was added drop wise and the mixture stirred at room temperature over night. The resulting clear, colourless solution was concentrated under vacuum before water (30 ml) and diethylether (40 ml) were added. The organic phase was separated, dried over Na2SO4 and the diethylether solvent removed under vacuum to yield a crude residue. Purification by column chromatography on silica gel using dichloromethane as mobile phase afforded the title compound as a pale yellow oil (0.388 g, 73%).