Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([NH2:11])=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][C:15]=1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:11][C:7]1[C:6]2[C:2]([C:18]3[CH:17]=[CH:16][C:15]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[C:14]([O:13][CH3:12])[CH:19]=3)=[CH:3][O:4][C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: Nc1nccc2occ(Br)c12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2coc3ccnc(N)c23)ccc1NC(=O)OC(C)(C)C
Yield: 98.3 %

Procedure:
A mixture of 3-bromofuro[3,2-c]pyridin-4-amine (0.443 g, 2.1 mmol) in 1,2-dimethoxyethane (16 mL) and water (8 mL) was treated with tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (0.872 g, 2.5 mmol,), sodium carbonate (0.749 g, 7.1 mmol) and tetrakis triphenylphosphine palladium (0) (0.144 g, 0.12 mmol) at 80° C. for 18 hours. The organic solvent was removed in vacuo and the aqueous mixture was extracted with ethyl acetate (3×10 mL). The combined organic phases were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel using heptane/ethyl acetate (4:1) followed by ethyl acetate as an eluents to give the title compound (0.734 g, 85%) as a tan solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.07 (s, 1H), 7.96 (s, 1H), 7.87 (d, 1H), 7.84 (d, 1H), 7.14 (d, 1H), 7.05 (dd, 1H), 6.94 (d, 1H), 5.55-5.62 (bs, 2H), 3.87 (s, 3H), 1.48 (s, 9H); RP-HPLC (Conditions f) Rt 12.13 min.; MS: MH+ 356.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])[CH3:3].[NH2:19][C:20]1[C:29]2[N:30]=[C:31]([CH2:36][CH2:37][CH2:38][CH3:39])[N:32]([CH2:33][CH2:34][NH2:35])[C:28]=2[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1>>[NH2:19][C:20]1[C:29]2[N:30]=[C:31]([CH2:36][CH2:37][CH2:38][CH3:39])[N:32]([CH2:33][CH2:34][NH:35][C:8](=[O:9])[C:7]3[CH:6]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[C:13]([OH:14])=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=3)[C:28]=2[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 56.9 %

Procedure:
Using the general method of Example 92, 3,5-di-(1,1dimethylethyl)-4-hydroxybenzoyl chloride (0.47 g, 1.7 mmol) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.5 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-di-(1,1-dimethylethyl)-4-hydroxybenzamide as a white powder, m.p. 248-250° C. Analysis: Calculated for C30H40N6O2: %C, 69.74; %H, 7.80; %N, 16.27; Found: %C, 69.65%H, 7.69; %N, 16.42. HRLMS (EI) calcd for C30H40N6O2 (M+) 516.3212 found 516.3226.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CON(C)[C:11](=[O:23])[CH2:12][C:13]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:16][CH2:15][CH2:14]1>O1CCCC1.CCOCC.[NH4+].[Cl-]>[C:17]1([C:13]2([CH2:12][C:11]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[O:23])[CH2:16][CH2:15][CH2:14]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CON(C)C(=O)CC1(c2ccccc2)CCC1
Reactant: Brc1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CC1(c2ccccc2)CCC1)c1ccccn1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromopyridine (1.0 g, 4.3 mmol) in dry tetrahydrofuran (30 mL) 1.6 M n-butyl lithium in hexanes (4.8 mL) was added dropwise at −78° C. The mixture was kept at this temperature for 1 hour, followed by addition of a solution of Example 68D in tetrahydrofuran. At the end of addition, the mixture was allowed to reach ambient temperature and stirred at 60° C. for 2 hours. The mixture was then cooled to 0° C., and diluted with ether (50 mL) and saturated aqueous NH4Cl (60 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated. The crude product was used in the next step without further purification (1.5 g, 5.97 mmol).
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:22][CH:23]([CH3:25])[CH3:24])[C@@H:10]([OH:21])[CH2:11][C@@H:12]([C:17]([OH:20])([CH3:19])[CH3:18])[C:13]([NH:15][CH3:16])=[O:14])=[O:7])(C)(C)C.Cl.[C:27]([O:31][C:32]([NH:34][C@H:35](C(O)=O)[CH2:36][C:37]1[N:38]=[CH:39][S:40][CH:41]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O1CCOCC1>[C:27]([O:31][C:32]([NH:34][C@H:35]([C:6]([NH:8][C@@H:9]([CH2:22][CH:23]([CH3:24])[CH3:25])[C@@H:10]([OH:21])[CH2:11][C@@H:12]([C:17]([OH:20])([CH3:18])[CH3:19])[C:13]([NH:15][CH3:16])=[O:14])=[O:7])[CH2:36][C:37]1[N:38]=[CH:39][S:40][CH:41]=1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(C)(C)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of 274 mg (0.76 mmoles) of (2S, 4S, 5S)-5-(t-butoxycarbonylamino)-4-hydroxy-2-(1-hydroxy-1-methylethyl)-7-methyl-N-methyloctanamide (prepared as described in Preparation 28) in 5 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature and under an atmosphere of nitrogen for 30 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. Diethyl ether was added to the residue, and the solvent was again removed by distillation under reduced pressure. The same operation was repeated, in total, three times. The resulting residue was then dried by evaporation under reduced pressure for 8 hours, after which it was suspended in 5 ml of anhydrous tetrahydrofuran. 248 mg (0.91 mmoles) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were then added to the suspension, after which 0.14 ml (0.92 mmoles) of diethyl cyanophosphate and 0.23 ml (1.65 mmoles) of triethylamine were added to the mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 5 hours, after which the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by medium pressure silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), followed by recrystallization from hexane to give 356 mg (yield 91%) of the title compound as a white amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:18].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.[N:31](OCCC(C)C)=O>C1(C)C=CC=CC=1>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:7]=[C:2]3[C:3](=[CH:4][CH:5]=2)[NH:18][N:31]=[CH:1]3)=[N:10][CH:11]=1)([O-:17])=[O:16]
Reactant: CC(C)CCON=O
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3[nH]ncc3c2)nc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 20.9 %

Procedure:
To a mixture of 2-methyl-4-(5-nitro-pyridin-2-yloxy)-phenylamine (10 g, 41 mmol), potassium acetate (17 g, 160 mmol), acetic anhydride (17 g, 160 mmol) and toluene (140 mL) at 80° C. was added isoamyl nitrite (9.6 g, 82 mmol) dropwise via an addition funnel. After stirring for 24 h at 80° C., the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was treated with methanol (120 mL) containing 12 mL of concentrated ammonium hydroxide. After refluxing for 2 h, the mixture was cooled to room temperature and was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane to afford 2.2 g of 5-(5-Nitro-pyridin-2-yloxy)-1H-indazole as an orange solid. 1H NMR (CD3OD, 400 MHz): δ 8.96 (d, 1H, J=2.4 Hz), 8.56 (dd, 1H, J=2.8, 9.2 Hz), 8.05 (s, 1H), 7.60 (1H, d, 8.8 Hz), 7.56 (m, 1H), 7.21 (dd, 1H, J=2.0, 8.8 Hz), 7.13 (d, 1H, 9.2 Hz) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][N:14]([CH2:57][CH:58]=O)[C:15](=[O:56])[C:16]1[CH:55]=[CH:54][CH:53]=[C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)=[O:20])[CH:17]=1.CC(O)=O.C([BH3-])#N.[Na+]>C(O)C>[CH3:13][N:14]([CH2:57][CH2:58][N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:12])[C:15](=[O:56])[C:16]1[CH:55]=[CH:54][CH:53]=[C:18]([C:19](=[O:20])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CN(CC=O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CN(CCN1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 47.8 %

Procedure:
To a solution of L-proline-t-butyl ester (0.096 mmol, 16 mg) in ethanol (0.2 mL) were added (S)—N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)isophthalamide (0.032 mmol, 20 mg) and HOAc (0.064 mmol, 4 mg). The mixture was stirred at room temperature for 25 minutes, and then sodium cyanoborohydride (0.16 mmol, 10 mg) was added. The mixture was stirred for an additional 20 minutes and quenched with water. The yellow solid was collected via filtration and was purified by prep HPLC to give a yellow solid (12 mg, 37%). MS (ES, m/z): 786.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:12]3[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[F:35]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:12]3[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:11]=3[N:10]=2)=[C:6]([CH:7]=1)[O:8][CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[F:35]
Reactant: CCCCCn1c(-c2ccc(Cl)cc2O)nc2cc(F)c(F)cc21
Reactant: N#Cc1ccc(CBr)c(F)c1
Product: CCCCCn1c(-c2ccc(Cl)cc2OCc2ccc(C#N)cc2F)nc2cc(F)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-(5,6-difluoro-1-pentyl-1H-benzoimidazol-2-yl)-phenol and 4-bromomethyl-3-fluoro-benzonitrile (CAS Reg. No. 105942-09-4). Brown powder (41%). MS (Turbo Spray): m/z=484.4 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6](=[S:28])[NH:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(C(=O)Nc2cc(F)ccc2F)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=S)Nc2cc(F)ccc2F)cc1
Yield: 149.3 %

Procedure:
36.7 g of 4-methyl-2',5'-difluorobenzanilide was dissolved in 170 ml of toluene, and 36 g of Lawesson's reagent was added. The mixture was refluxed for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure. The residue was recrystallized from 100 ml of benzene to give 35.0 g of the captioned compound as yellow needle-like crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([O:8][CH3:9])[O:6][CH3:7])=[CH2:4].[O:10]1CCC[CH2:11]1>>[CH3:1][O:2][CH:3]([CH:5]([O:8][CH3:9])[O:6][CH3:7])[CH2:4][CH:11]=[O:10]
Reactant: C=C(OC)C(OC)OC
Reactant: C1CCOC1
Product: COC(CC=O)C(OC)OC
Reaction time: 6 h
Yield: 87 %

Procedure:
A 10 1 magnetic lift stirred autoclave is charged with 1,015 g of 2,3,3-trimethoxyprop-1-ene together with 3,000 g of tetrahydrofuran and 500 mg of Rh2 (COD)2Cl2 as hydroformylation catalyst. The oxo reaction is carried out under a pressure of 500 bar (CO/H2 =1:1) at 40° C. for 6 hours, at 60° C./550 bar for another 6 hours and at 80° C./600 bar for a further 6 hours. According to gas chromatography, this way of carrying out the reaction gives a conversion of 94%. The desired compound 3,4,4-trimethoxybutanal (bp=135° C./110 mbar) is obtained in the yield of 87% following fraction-ation. Preparation of methyl 2-methoxyacrylate
Reaction SMILES: C([O:3][C:4](=[O:30])/[C:5](=[N:25]\[O:26][CH2:27][CH:28]=[CH2:29])/[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)C.[OH-].[Na+]>CO.O1CCCC1>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH2:13][CH2:12][O:11][C:8]1[S:7][C:6](/[C:5](=[N:25]/[O:26][CH2:27][CH:28]=[CH2:29])/[C:4]([OH:30])=[O:3])=[CH:10][CH:9]=1
Reactant: C=CCO/N=C(\C(=O)OCC)c1ccc(OCCOc2ccc3ccccc3c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCO/N=C(\C(=O)O)c1ccc(OCCOc2ccc3ccccc3c2)s1
Temperature: 55 °C
Yield: 63.6 %

Procedure:
As in Example 306 a solution of (E)-5-[2-(2-naphthalenyloxy)ethoxy]-alpha-[(2propenyloxy)imino]-2-thiopheneacetic acid ethyl ester (0.064 g) in methanol (2 mL) and tetrahydrofuran (2 mL) was treated with 4N sodium hydroxide (0.5 mL) and the stirred mixture was heated at 55° C. for 45 minutes. After the normal work up, the product was crystallized from ethyl acetate-hexane to furnish 0.038 g of (E)-5-[2-(2-naphthalenyloxy)ethoxy]-alpha-[(2-propenyloxy)imino]-2-thiopheneacetic acid, mp 106°-108° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Cl-].[Al+3].[Cl-].[Cl-].[C:14](Cl)(=[O:16])[CH3:15]>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([C:14](=[O:16])[CH3:15])[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: CC(=O)Cl
Reactant: Cc1cccc(C)c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C)c(O)c(C)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 2,6-dimethylphenol (12.2 g, 0.1 mmol) in dichloromethane, anhydrous aluminum chloride (14.4 g) was slowly added with stirring, followed by slow addition of acetyl chloride (9.4 g). The reaction mixture was stirred at 10° C. or below for 1 h, then at room temperature for 3 h. Thereafter, the mixture was poured into ice water. Then, the reaction product was extracted with dichloromethane and the extracted layer was washed with water. Further, the extracted layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized with benzene, giving the desired compound, 2,6-dimethyl-4-acetylphenol in an amount of 1.9 g.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.C(N(CC)C(C)C)(C)C.[F:49][C:50]([F:60])([F:59])[C:51]1[CH:58]=[CH:57][C:54]([CH2:55][NH2:56])=[CH:53][CH:52]=1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:56][CH2:55][C:54]2[CH:53]=[CH:52][C:51]([C:50]([F:49])([F:59])[F:60])=[CH:58][CH:57]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)NCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C

Procedure:
To a mixture of p-aminobenzoic acid (5.0 g, 36 mmol) and HBTU (14 g, 36 mmol) in DMF (50 mL, 600 mmol) at 0° C. were added N,N-diisopropylethylamine (19 mL, 110 mmol) and 4-(trifluoromethyl)benzylamine (6.2 mL, 44 mmol). The reaction mixture was slowly warmed to ambient temperature. The reaction mixture was quenched with an equal volume of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic layers were washed successively with water, aqueous lithium chloride, and brine, dried over sodium sulfate, filtered and concentrated in vacuo (8.2 g, 70%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10].[O-:19][C:20]#[N:21].[K+].Cl>O.CO>[C:20]([NH:1][CH2:2][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10])(=[O:19])[NH2:21]
Reactant: CC(C)(C)OC(=O)NC(CN)c1ccccc1Cl
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(CNC(N)=O)c1ccccc1Cl
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Of the compound from Example 113A, 330 mg (1.15 mmol) in 12 ml of water/methanol 1:1 were admixed at RT with 279 mg (3.44 mmol) of potassium cyanate. The mixture was heated at 40° C. for 1 h and then admixed with 1.15 ml of 1M hydrochloric acid (1.15 mmol) and stirred overnight at RT. A further 93 mg (1.14 mmol) of potassium cyanate were added and the mixture was stirred further at RT for 3 h. The entire reaction mixture was purified by preparative HPLC [Method 10]. The product fraction was freed from the solvents on a rotary evaporator. Drying of the residue in an HV gave 292 mg (80% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6](=O)[C:7]=1[NH:8][C:9](=O)[CH3:10].P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[C:7]=1[N:8]=[C:9]([CH3:10])[NH:1]2
Reactant: CC(=O)Nc1c(N)nc[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc2c(Cl)ncnc2[nH]1
Yield: 6 %

Procedure:
A solution of N-(4-amino-6-oxo-1,6-dihydropyrimidin-5-yl)acetamide (330 mg, 1.92 mmol, 1.00 equiv, 98%) in phosphorus oxychloride (5 mL) was refluxed overnight. The resulting mixture was concentrated under vacuum. The residue was redissolved in 10 mL of ethyl acetate, washed with 10 mL of saturated aqueous sodium bicarbonate solution, 1×10 mL of water and 1×10 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 20 mg (6%) of 6-chloro-8-methyl-9H-purine as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])=[N:3][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-amino-5-chloropyridine (10.0 g, 0.078 mol) (Aldrich) and triethylamine (12 mL, 0.086 mol) in methylene chloride (200 mL), at 0° C, was added dropwise trimethylacetyl chloride in methylene chloride (15 mL). The reaction was allowed to warm to room temperature while stirring overnight. The resulting mixture was washed with water, brine, and was dried over MgSO4 and filtered. Concentration of the filtrate in vacuo provided a colorless oil (19.2 g). The oil was dissolved in hexanes and cooled causing the precipitation of a solid. The solid was collected by filtration affording the amide as a white solid (14.96 g, 90%): mp 51.4–53.4° C. 1H NMR (CDCl3/300 MHz) 8.25–8.15 (m, 2H), 8.00 (br s, 1H), 7.68–7.60 (m, 1H), 1.28 (s, 9H). Anal. Calc'd for C10H13N2OCl: C, 56.47; H, 6.16; N, 13.17 Found: C, 56.72; H, 6.34; N, 12.88.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([N+:10]#[C-:11])=[CH:6]N(C)C)[CH3:2].C(N(CC)CC)C.[SH2:20]>O1CCCC1>[C:4]([C:5]1[N:10]=[CH:11][S:20][CH:6]=1)([O:3][CH2:1][CH3:2])=[O:12]
Reactant: [C-]#[N+]C(=CN(C)C)C(=O)OCC
Reactant: S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cscn1

Procedure:
A solution of 3-dimethylamino-2-isocyano-acrylic acid ethyl ester (1.0 g) and triethylamine (3.0 g) in tetrahydrofuran (30 mL) is treated with gaseous hydrogen sulfide until all starting material is consumed. The mixture is concentrated to an oil and purified by column chromatography using silica and 25% ethyl acetate-hexanes as the eluant. The purified material (0.61 g) is isolated as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:10]=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[CH:13]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Fe]>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([N:12]2[CH:13]=[C:9]([O:8][C:7]3[CH:21]=[CH:22][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH:10]=[N:11]2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(-n2cc(Oc3ccc([N+](=O)[O-])cc3)cn2)cc1
Agent: [Fe]
Solvent: CCO
Product: Cc1ccc(-n2cc(Oc3ccc(N)cc3)cn2)cc1
Temperature: 27.5 °C
Reaction time: 6 h

Procedure:
4-(4-Nitro-phenoxy)-1-p-tolyl-1H-pyrazole (600 mg, 2.03 mml) was taken in ethanol and iron powder (1.13 g, 20.33 mmol) was added and stirred at 20-35° C. for 6 hours. Iron powder was removed and ethanol was evaporated under vacuum. Residue was taken up in water and pH was adjusted to 7 using saturated NaHCO3 solution. The aqueous layer was extracted with ethyl acetate, was washed with brine solution and dried over anhydrous Na2SO4. The solvent was evaporated under vacuum at 50° C. and the product was dried in high vacuum.
Reaction SMILES: Br[C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2.[CH2:25]([Sn](CCCC)(CCCC)C#C)[CH2:26]CC.C(OCC)(=O)C>CN(C)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>[CH:14]1([C:12]([N:8]2[C:9]3[C:4](=[C:3]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:2]([C:25]#[CH:26])=[CH:11][CH:10]=3)[CH2:5][CH2:6][C@@H:7]2[CH3:17])=[O:13])[CH2:16][CH2:15]1
Reactant: C[C@H]1CCc2c(ccc(Br)c2Oc2ccccc2)N1C(=O)C1CC1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#Cc1ccc2c(c1Oc1ccccc1)CC[C@H](C)N2C(=O)C1CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.030 g, 0.08 mmol), tributyl(ethynyl)stannane (0.030 g, 0.09 mmol), and tetrakis(triphenylphosphine)palladium (O) (0.037 g, 0.03 mmol) in N,N-dimethylformamide (1.5 mL) stirred overnight at 120° C. The reaction mixture was cooled to room temperature, poured into ethyl acetate (15 mL), washed with water (2×5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 1:5, ethyl acetate/petroleum ether). The product was further purified by preparative-HPLC with the following conditions (Waters III): Column, Xbridge RP C18, 19×150 mm, 5 um; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (50% to 100% acetonitrile in 10 min, flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded (S)-cyclopropyl(6-ethynyl-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone (0.004 g, 16%) as a brown semi-solid. 1H NMR (300 MHz, CD3OD) δ ppm 0.65-0.85 (m, 1H), 0.87-1.04 (m, 2H), 1.05-1.25 (m, 4H), 1.38-1.52 (m, 1H), 1.85-2.02 (m, 1H), 2.11-2.47 (m, 2H), 2.62-2.85 (m, 1H), 3.47 (m, 1H), 4.75-4.82 (m, 1H), 6.79 (d, J=8.10 Hz, 2H), 6.95-7.05 (m, 1H), 7.19-7.39 (m, 3H), 7.45 (d, J=8.40 Hz, 1H). MS (ESI, pos. ion) m/z 332 [M+H]+.