Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:8][N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH3:26])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: Cc1ccccc1B(O)O
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+]
Product: Cc1ccccc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-methylphenyl)boronic acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 210 mg, 68%). More specifically, a suspension of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-methylphenyl)boronic acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg) in 1,2-dimethoxyethane (10 mL) and water (7.5 mL) was stirred at 105° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:1→3:1) to give the title compound as a pale-yellow oil (yield 210 mg, 68%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=3[CH3:20])[C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: Cc1ccc(C)c(B(O)O)c1
Reactant: CCCNC(=O)c1nnc2c(I)c(Cl)ccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(C)ccc3C)c(Cl)ccc2c1N
Yield: 44.7 %

Procedure:
Using method A, 4-amino-7-chloro-8-iodo-N-propyl-cinnoline-3-carboxamide (78 mg, 0.20 mmol) and (2,5-dimethylphenyl)boronic acid (63 mg, 0.417 mmol) were reacted to afford the title compound (33 mg, 45% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.48 (bm, 1H), 7.85 (bm, 1H), 7.75 (m, 1H), 7.15-7.24 (m, 2H), 6.98 (s, 1H), 3.43 (apparent q, J=6.7 Hz, 2H), 2.36 (s, 3H), 1.95 (s, 3H), 1.63 (apparent sextet, J=7.2 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H). MS APCI, m/z=369 (M+H) HPLC 2.15 min.
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[C:8]([NH2:10])=[O:9].Cl[CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=1>>[NH2:2][C:3]1[N:7]([CH2:12][C:13]2[CH:14]=[C:15]([C:23]([F:25])([F:26])[F:24])[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=2)[CH:6]=[N:5][C:4]=1[C:8]([NH2:10])=[O:9]
Reactant: FC(F)(F)c1cc(CCl)cc(C(F)(F)F)c1
Reactant: NC(=O)c1nc[nH]c1N
Agent: Cl
Product: NC(=O)c1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Wash sodium hydride (2.71 g of a 60% solution in mineral oil, 67.66 mmol) three times with hexanes, then dilute with 85 mL of DMF. To this mixture add the HCl salt of 5-amino-1H-imidazole-4-carboxylic acid amide (5.0 g, 30.75 mmol) neat in four portions. The mixture generates gas and remains cloudy and turns a slightly green color. After mixing for 40 min., add 1-chloromethyl-3,5-bis-trifluoromethyl-benzene (8.88 g, 33.83 mmol). (The mixture again generates gas and darkens). Stir at RT for 2 days, then pour through a plug of Celite and wash with DMF (50 mL) and xylenes (50 mL). Remove the DMF via azeotropic distillation with xylenes under reduced pressure (5×50 mL), and then concentrate the residue under a steady stream of nitrogen for 18 h to provide the title compound as a dark purple solid. MS (ES) 351.1, 353.1 (M+1); 1H NMR (300 MHz, CDCl3) δ 7.70 (s, 1H), 7.58 (s, 2H), 7.31 (s, 2H), 6.96 (s, 1H), 5.46 (s, 2H), 5.10 (s, 2H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.[N+](C1C=CC(OC(=O)[NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[CH:47][CH:46]=2)=CC=1)([O-])=O>>[N:51]1([C:48]2[CH:47]=[CH:46][C:45]([NH:44][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([N:26]6[CH2:31][CH2:30][O:29][CH2:28][CH2:27]6)=[C:21]([O:24][CH3:25])[CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)=[O:7])=[CH:50][CH:49]=2)[CH2:52][CH2:53][O:54][CH2:55][CH2:56]1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2c(C3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1N1CCOCC1
Agent: Cl
Product: COc1cc2c(C3CCN(C(=O)Nc4ccc(N5CCOCC5)cc4)CC3)ncnc2cc1N1CCOCC1

Procedure:
The title compound was prepared from 4-(6-methoxy-7-morpholin-4-yl-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester, prepared in Example 211a, and (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride, prepared as described in Example 66a, using essentially the protocol given for Example 170c. 1H-NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 7.37 (s, 1H), 7.28 (m, 2H), 7.25 (s, 1H), 6.89 (m, 2H), 6.35 (s, 1H), 4.27 (m, 2H), 4.06 (s, 3H), 3.94 (m, 4H), 3.86 (m, 4H), 3.59 (tt, 1H), 3.29 (m, 4H), 3.16 (td, 2H), 3.11 (m, 4H), 2.21-2.08 (m, 2H), 2.03-1.95 (m, 2H). LC/MS (ESI): calcd mass, 532.3, found 533.3 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])=[CH:18][CH:17]=1
Reactant: COc1cccc2cc(C(=O)O)oc12
Reactant: Nc1ccc(Cl)cc1
Product: COc1cccc2cc(C(=O)Nc3ccc(Cl)cc3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and 4-chloroaniline to give N-(4-chlorophenyl)-7-methoxybenzofuran-2-carboxamide (Compound 379a). Successively, it was formylated to give N-(4-chloropheny)-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 379b), then compound 379b was reacted with cyclobutylamine to give compound 379 as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[CH2:9][NH:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[CH:14]1([C:17](=[O:23])[CH2:18][C:19](OC)=[O:20])[CH2:16][CH2:15]1.N1(C2C=CN=CC=2)CCCC1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[CH2:9][N:8]([C:19](=[O:20])[CH2:18][C:17]([CH:14]3[CH2:16][CH2:15]3)=[O:23])[CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: Cc1cc(Cl)nc2c1CNCC2
Agent: Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)nc2c1CN(C(=O)CC(=O)C1CC1)CC2
Temperature: 25 °C
Yield: 52.4 %

Procedure:
Microwave was used to irradiated a suspension of 2-chloro-4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (1.00 g, 4.56 mmol), methyl 3-cyclopropyl-3-oxopropanoate (1.298 g, 9.13 mmol), 4-pyrrolidinopyridine (0.068 g, 0.456 mmol) and DIPEA (1.20 mL, 6.85 mmol) in toluene (10 mL) at 150° C. for 45 min. The mixture was cooled to rt and diluted with 1 M HClaq (10 mL) and EtOAc. The products were extracted twice with EtOAc. The combined organic layer was washed with a mixed solution of 1M HClaq/brine (1 mL/2 mL), dried over Na2SO4, filtered, and concentrated to give crude. The residue was purified by flash column chromatography on 12 g of silica gel (eluent: DCM/EtOAc=90:10 to 0:100) to give crude 1-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-3-cyclopropylpropane-1,3-dione (0.70 g): MS (ESI+) m/z 293.31 (M+H)+. The obtained material was used without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][C:4]([C:6]1[C:11]([OH:12])=[C:10]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:9]([OH:18])=[C:8]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[C:7]=1[OH:24])=[O:5]>C(O)C.[C].[Pd]>[CH3:1][CH:2]([CH3:25])[CH2:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]([CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[C:9]([OH:18])=[C:10]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]=1[OH:12])=[O:5]
Reactant: CC(C)=CCc1c(O)c(CC=C(C)C)c(O)c(C(=O)CC(C)C)c1O
Agent: [Pd]
Solvent: CCO
Product: CC(C)CCc1c(O)c(CCC(C)C)c(O)c(C(=O)CC(C)C)c1O
Yield: 86.8 %

Procedure:
In 22.0 ml of ethanol, 1.50 g (4.34 mmol) of {3,5-bis(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone (15) was dissolved. The solution was stirred with 924 mg (0.217 mmol, 5% equivalent) of 5% palladium carbon catalyst (water content up to 50%) under hydrogen atmosphere under ordinary pressure at room temperature for two hours. The solution was filtered and concentrated under a reduced pressure to form a brown oil. This oil was subjected to silica gel chromatography (using 100 g of Wako Gel C-200, eluted with hexane:ethyl acetate=10:1) to obtain 1.32 g (yield 86.6%) of the product (37) in the form of a colorless oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[NH2:11][CH2:12][C:13]1[NH:17][N:16]=[C:15]([CH3:18])[C:14]=1[O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[C:23]#[N:24].S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>CO.ClCCl>[Cl:28][C:26]1[CH:25]=[C:22]([CH:21]=[C:20]([O:19][C:14]2[C:15]([CH3:18])=[N:16][NH:17][C:13]=2[CH2:12][NH:11][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:27]=1)[C:23]#[N:24]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: Cc1n[nH]c(CN)c1Oc1cc(Cl)cc(C#N)c1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: Cc1n[nH]c(CNCc2ccc(C#N)cc2)c1Oc1cc(Cl)cc(C#N)c1
Reaction time: 0.5 h
Yield: 20.1 %

Procedure:
A mixture of 4-cyanobenzaldehyde (60 mg, 0.460 mmol), the amine of Example 77 (120 mg, 0.460 mmol), magnesium sulphate (500 mg) and dichloromethane (5 ml) was stirred under nitrogen at room temperature for 3 days. The mixture was concentrated under reduced pressure and the crude product was purified by flash column chromatography on silica gel eluting with methanol:ethyl acetate (5:95, by volume) to provide a foam. The foam was dissolved in methanol (5 ml), sodium borohydride (50 mg, 1.31 mmol) was added in one portion at room temperature and the reaction was stirred for 30 minutes. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (20 ml). The resulting solution was washed with 1M aqueous sodium carbonate solution (10 ml) and brine (10 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:4:1, by volume) to provide the title compound (35 mg) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:21]([O:23][CH3:24])=[O:22]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C(N)c1ccc(OC)cc1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccc(OC)cc1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(4-methoxyphenyl)acetate hydrochloride (prepared by the Bucherer Modification of the Strecker procedure as described in J. P. Greenstein et al., “The Chemistry of Amino Acids”, Vol. 1, p. 698, Wiley, New York (1961)), the title compound was prepared as a solid (mp=170-174° C.). The reaction was monitored by tlc (Rf=0.1 in 98:2 CHCl3/MeOH) and the product was purified by silica gel chromatography using 98:2 CHCS3/MeOH as the eluent.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:14]2=[C:15]3[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]3=[CH:5][C:4]=1[NH:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1.Br[CH2:29][CH:30]1[CH2:32][CH2:31]1.[Cl-].[NH4+]>CN(C)C=O>[CH:30]1([CH2:29][N:16]([C:4]2[CH:3]=[C:14]3[C:15]4[CH:10]([CH2:11][CH2:12][CH2:13]3)[CH2:9][CH2:8][CH2:7][C:6]=4[CH:5]=2)[C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)[CH2:32][CH2:31]1
Reactant: CCOC(=O)c1ccc(Nc2cc3c4c(c2)CCCC4CCC3)cc1
Reactant: BrCC1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N(CC2CC2)c2cc3c4c(c2)CCCC4CCC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
A suspension of sodium hydride (60%, 0.009 g) in N,N-dimethylformamide (2 ml) was added with ethyl 4-[(5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)amino]benzoate (0.033 g) dissolved in N,N-dimethylformamide (1 ml), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was added with bromomethylcyclopropane (0.02 ml), the mixture was stirred at room temperature for 2 hours, and then added with saturated aqueous ammonium chloride, and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:50) to obtain the title compound (0.037 g, yield: 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:15]([O:17][CH3:18])=[O:16])=[C:11]([CH2:13]O)[N:12]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[Cl:21][CH2:13][C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:9][C:10]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1oc(-c2ccc(Cl)cc2)nc1CO
Product: COC(=O)c1oc(-c2ccc(Cl)cc2)nc1CCl

Procedure:
100 mg (0.43 mmol) of the compound from Example 44A, together with 0.24 ml (3.24 mmol) of thionyl chloride, are stirred at RT for 8 h. The excess thionyl chloride is removed under reduced pressure and the residue is taken up in about 5 ml of ethyl acetate. The mixture is washed once with 2 ml of sat. aqueous sodium bicarbonate solution. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The product obtained is used without further purification in the subsequent reactions.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([CH:27]=[C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:29]=1[OH:30])[CH:9]=[C:10]1[C:15](=[O:16])[N:14]([CH2:17][C:18]([O:20]CC)=O)[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[S:11]1)([CH3:5])([CH3:4])[CH3:3].[NH3:35]>CO>[C:18]([CH2:17][N:14]1[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[S:11][C:10](=[CH:9][C:8]2[CH:27]=[C:28]([C:31]([CH3:33])([CH3:32])[CH3:34])[C:29]([OH:30])=[C:6]([C:2]([CH3:3])([CH3:5])[CH3:4])[CH:7]=2)[C:15]1=[O:16])(=[O:20])[NH2:35]
Reactant: N
Reactant: CCOC(=O)CN1C(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)Sc2ccccc21
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(C=C2Sc3ccccc3N(CC(N)=O)C2=O)cc(C(C)(C)C)c1O
Temperature: 80 °C
Reaction time: 96 h
Yield: 37.3 %

Procedure:
0.1N hydrochloric acid in methanol (3 ml) was added to a solution of 2-(3,5-di-tert.-butyl-4-hydroxybenzylidene)-3,4-dihydro-4-ethoxycarbonylmethyl-3-oxo-2H-1,4-benzothiazine (Compound No. 1-1, 0.4 g) in 17.85 N ammonia in methanol (15 ml). After the addition, the mixture was stirred for 4 days at 80° C. in a sealed tube and followed by concentration in vacuo. To the residue, dilute hydrochloric acid was added and the whole was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give 0.14 g (37.3%) of the titled compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.[H-].[Na+]>>[Br:1][C:2]1[N:7]=[C:6]([N:8]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Nc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cccc(Br)n2)cc1
Reaction time: 2 h
Yield: 106.7 %

Procedure:
To a solution of 6-bromo-pyridin-2-ylamine (1.00 g, 5.78 mmol) under a nitrogen atmosphere at room temperature was added 4-methoxybenzyl chloride (1.96 mL, 14.5 mmol) in one portion. To this mixture was added NaH (60% suspension in mineral oil, 694 mg, 17.3 mmol) in one portion. The reaction was stirred for 2 h then partitioned between aqueous NaHCO3 and CH2Cl2. The layers were separated and the aqueous layer was further extracted with CH2Cl2. The combined organic layers were dried with MgSO4 and concentrated in vacuo to give a light yellow oil. This oil was purified by flash chromatography on silica gel (1→15% EtOAc/hexanes) to give 2.55 g of the title compound as a colorless oil, m/z 413.9 [M−H]+.
Reaction SMILES: [CH3:1][CH:2]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].Br[CH2:20][C:21]#[C:22][CH2:23][CH3:24]>>[CH2:20]([O:15][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([O:9][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])=[CH:18][CH:17]=1)[C:21]#[C:22][CH2:23][CH3:24]
Reactant: CC(C)CCCC(C)Oc1ccc(C(=O)O)cc1
Reactant: CCC#CCBr
Product: CCC#CCOC(=O)c1ccc(OC(C)CCCC(C)C)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(1,5-dimethylhexyl)oxy]benzoic acid with 1-bromo-2-pentyne, there is obtained p-[(1,5-dimethylhexyl)oxy]benzoic acid-2-pentynyl ester; nD24 = 1.5078.
Reaction SMILES: [H-].[Na+].[CH3:3][Si:4]([C:7]#[CH:8])([CH3:6])[CH3:5].CS(O[CH:14]1[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1)(=O)=O>O1CCCC1>[CH3:3][Si:4]([C:7]#[C:8][CH:14]1[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1)([CH3:6])[CH3:5]
Reactant: C#C[Si](C)(C)C
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC1CCC2(CC1)OCCO2
Temperature: 0 °C

Procedure:
Under a nitrogen atmosphere, a mixture of 3.2 grams (0.08 mole) of sodium hydride (60% in mineral oil) in 25 mL of tetrahydrofuran is stirred, and a solution of 7.9 grams (0.08 mole) of trimethylsilylacetylene in 15 mL of tetrahydrofuran is added dropwise. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about one hour. The reaction mixture is then cooled to 0° C., and a solution of 18.9 grams (0.08 mole) of 8-methylsulfonyloxy-1,4-dioxaspiro[4.5]decane in 25 mL of tetrahydrofuran is added dropwise. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature where it is stirred during about 18 hours. After this time the reaction mixture is concentrated under reduced pressure to a residue. The residue is stirred in water, and the mixture is extracted with three 50 mL portions of diethyl ether. The combined extracts are washed with water and dried with magnesium sulfate. The mixture is filtered, and the filtrate is concentrated under reduced pressure, yielding 8-trimethylsilylethynyl-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:7]12[CH3:8])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[NH:14][CH2:13]3)=[O:5])[CH3:2].[H-].[Na+].CI.[C:32](OCC)(=O)C>CN(C=O)C>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:7]12[CH3:8])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[N:14]([CH3:32])[CH2:13]3)=[O:5])[CH3:27]
Reactant: CCN(CC)C(=O)[C@H]1CC[C@H]2[C@@H]3CNC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)[C@H]1CC[C@H]2[C@@H]3CN(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
To a solution of 17β-N,N-diethylcarbamoyl-6-azaandrost-4-en-3-one (24 mg, 0.065 mmol) in DMF (2 mL) at room temperature is added NaH (16 mg, 80% oil dispersion, 0.5 mmol) and, after 30 min, methyl iodide (50 μL, excess). After stirring for 30 min ethyl acetate (30 mL) is added, the solution washed with H2O and saturated aqueous NACl, dried over MgSO4, concentrated and flash chromatographed on silica gel (100% ethyl acetate to 5% methanol/chloroform) to give 17β-N,N-diethylcarbamoyl-6-methyl-6-azaandrost-4-ene-3-one as a white solid; yield 19 mg (76%). This material is then recrystallized from hexanes/methylene chloride to give 14 mg pure white solid; m.p. 158°-159° C. Anal. Calcd. for C24H38N2O2 ; C, 74.57; H, 9.91; N, 7.25. Found: C, 74.38; H, 9.84; N, 7.18.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:6]
Reactant: Nc1cccnc1
Reactant: Nc1c(Br)cccc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(Br)cccc1C(=O)Nc1cccnc1
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a solution of 2-amino-3-bromobenzoic acid (Aldrich; 2.00 g, 9.26 mmol) and 3-aminopyridine (Aldrich; 0.871 g, 9.26 mmol) in 10 mL EtOAc was added DIPEA (1.93 mL, 11.11 mmol) followed by 1-propanephosphonic acid cyclic anhydride (T3P) (50 wt. % solution in EtOAc; Matrix Scientific; 6.00 mL, 10.18 mmol). The reaction became warm and after 5 min a thick precipitate formed. The reaction was stirred overnight. The reaction was treated with sat'd aq. NaHCO3 and EtOAc. The organic layer was washed 1× sat'd aq. NaHCO3, 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 2-amino-3-bromo-N-(pyridin-3-yl)benzamide (2.13, 7.29 mmol, 79% yield) as a yellow solid used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.37 (1H, s), 8.87 (1H, d, J=2.2 Hz), 8.31 (1H, dd, J=4.6, 1.5 Hz), 8.08-8.14 (1H, m), 7.71 (1H, dd, J=7.8, 1.4 Hz), 7.62 (1H, dd, J=7.8, 1.4 Hz), 7.39 (1H, dd, J=8.2, 4.7 Hz), 6.57-6.71 (1H, m), 6.36 (2H, s). m/z (ESI, +ve) 291.9/293.9 (M+H)+.
Reaction SMILES: C(C[N:10]1[CH:14]=[C:13](C2C=CC=CC=2)[N:12]=[CH:11]1)(=O)C1C=CC=CC=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:12]1[C:13]2[N:10]=[CH:14][CH:13]=[N:12][C:14]=2[NH:10][CH2:11]1
Reactant: O=C(Cn1cnc(-c2ccccc2)c1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cnc2c(n1)NCN2
Temperature: 20 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
A solution of 2-[1(S)-{1,1-dimethylethoxy)carbonylamino}-2-(3-indolyl)ethyl]-1-(benzoylmethyl)-4-phenyl-1H-imidazole (prepared as described previously) (100 mg) in a mixture of 10% TFA in DCM (1.3 mL) was stirred for about 3 hours at about 20° C. and concentrated under reduced pressure to yield the expected dihydro-imidazo-pyrazine (yield=95%). LC/MS: calculated MW: 402.19, m/z=403.2 (M+H).