Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9](O)[C:5]([N+:6]([O-:8])=[O:7])=[C:4]([NH2:15])[C:3]=1[N+:16]([O-:18])=[O:17].P([O-])([O-])(O)=O.[NH4+:24].[NH4+].O>S1(CCCC1)(=O)=O>[C:9]1([NH2:24])[C:10]([N+:11]([O-:13])=[O:12])=[C:2]([NH2:1])[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([NH2:15])[C:5]=1[N+:6]([O-:8])=[O:7]
Reactant: [NH4+]
Reactant: Nc1c([N+](=O)[O-])c(N)c([N+](=O)[O-])c(O)c1[N+](=O)[O-]
Agent: O=P([O-])([O-])O
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Nc1c([N+](=O)[O-])c(N)c([N+](=O)[O-])c(N)c1[N+](=O)[O-]
Temperature: 177 °C
Reaction time: 2 h

Procedure:
Diaminopicric acid (0.193 g, 0.748 mmol) and diammonium hydrogen phosphate (0.990 g, 7.50 mmol) are suspended in dry sulfolane (3 ml) and stirred in a Teflon® capped glass pressure tube (8 ml). The suspension is heated with stirring from ambient temperature to 177° C. over a 2 hr period. Stirring and heating (177° C.) is continued for an additional 6 hours. The reaction tube is cooled to 4° C. and the resulting suspension is mixed with water (40 ml). The precipitated product is collected, washed with water and dried to yield TATB in the form of a brown solid (0.154 g, 80%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.Cl[CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C.Cl>CN(C=O)C>[F:27][C:24]([F:25])([F:26])[C:20]1[CH:19]=[C:18]([N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][S:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][N:3]=3)[CH2:17][CH2:16]2)[CH:23]=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1cccc(N2CCN(CCCCl)CC2)c1
Reactant: Sc1ccncn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cccc(N2CCN(CCCSc3ccncn3)CC2)c1
Yield: 58.5 %

Procedure:
1.5 g (13.4 mmol) of 4-mercaptopyrimidine, 4.3 g (14 mmol) of 1-(3-chloropropyl)-4-(3-trifluoromethylphenyl) piperazine and 1.5 g (15 mmol) of triethylamine in 5 ml of DMF were stirred at 100° C. for 1 hour. The mixture was then poured into 5% strength hydrochloric acid and extracted with MTB ether. The aqueous phase was made alkaline with sodium hydroxide solution and then extracted with ethyl acetate, and the organic phase was dried over MgSO4 and concentrated. The residue was purified by chromatography (mobile phase: CH2Cl2/CH3OH═98/2). 3.0 g of product were obtained as a yellowish oil (=59% yield).
Reaction SMILES: [CH3:1][NH:2][N:3]=[C:4]([CH3:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7].O1CCCC1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([CH2:41][CH3:42])=[C:34]([C:36](=[O:40])[C:37](Cl)=[O:38])[CH:35]=2)=[CH:26][CH:25]=1>CCCCCC>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([CH2:41][CH3:42])=[C:34]([C:36](=[O:40])[C:37]([N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])=[O:38])[CH:35]=2)=[CH:26][CH:25]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1C(=O)C(=O)Cl
Reactant: CNN=C(C)CS(C)(=O)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C(=O)C(=O)N(C)N=C(C)CS(C)(=O)=O
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a 25 ml volume three-necked flask, 1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine (5-2-1) (670 mg), tetrahydrofuran (anhydrous) (2.25 ml), and triethylamine (390 mg) were added under a nitrogen atmosphere. To the mixture, 2-[5-(4-chlorophenyl)-2-ethylphenyl]-2-oxoacetyl chloride (6-c) (937 mg) was added dropwise at 0° C. and stirred for 2 hours. To hexane (15 ml) in a 50 ml volume three-necked flask, the reaction mixture was added dropwise, stirred for 10 minutes, and filtered. The residue was dried under reduced pressure, dissolved in ethyl acetate, and filtered again. The filtrate was concentrated under reduced pressure to give 853 mg of 1-[2-[5-(4-chlorophenyl)-2-ethylphenyl]-2-oxoacetyl]-1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34)-(1)-67). The filtrate from the first filtration was concentrated under reduced pressure, the residue was subjected to column chromatography (hexane: ethyl acetate=1.5:1) to give 240 mg of additional 1-(2-[5-(4-chlorophenyl)-2-ethylphenyl]-2-oxoacetyl)-1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34)-(1)-67).
Reaction SMILES: COC(C1C(C)=C2C(Cl)=C(C#N)C=NN2C=1)=O.COC1C=CC=CC=1OC1C=CC(N)=CC=1.[CH3:34][O:35][C:36]([C:38]1[C:39]([CH3:74])=[C:40]2[C:45]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=4[O:60][C:61](C(OC(C)(C)C)=O)(C)C)=[CH:49][CH:48]=3)=[C:44]([C:71]#[N:72])[CH:43]=[N:42][N:41]2[CH:73]=1)=[O:37]>>[CH3:34][O:35][C:36]([C:38]1[C:39]([CH3:74])=[C:40]2[C:45]([NH:46][C:47]3[CH:48]=[CH:49][C:50]([O:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=4[O:60][CH3:61])=[CH:51][CH:52]=3)=[C:44]([C:71]#[N:72])[CH:43]=[N:42][N:41]2[CH:73]=1)=[O:37]
Reactant: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)OC(C)(C)C)cc3)c2c1C
Agent: COC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Agent: COc1ccccc1Oc1ccc(N)cc1
Product: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC)cc3)c2c1C
Yield: 85 %

Procedure:
Compound 430C (1.81 g, 85%) was prepared from 4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid methyl ester (prepared using the procedure of Example 1D) (1.25 g, 5.0 mmol) and 430B (1.08 g, 5.0 mmol) by a route analogous to that used for the preparation of compound 388D. It is a white solid, and has a retention time of 6.74 min (∠Cl, 8 min run). MS found, (M+H)+=429.2
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]1[C:19]2([CH2:24][CH2:23][N:22](C(OCCCC)=O)[CH2:21][CH2:20]2)[NH:18][CH:17]([CH2:32][CH2:33][S:34][CH3:35])[C:16]1=[O:36])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:8]([N:15]1[C:19]2([CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[NH:18][CH:17]([CH2:32][CH2:33][S:34][CH3:35])[C:16]1=[O:36])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCCCOC(=O)N1CCC2(CC1)NC(CCSC)C(=O)N2Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCCC1NC2(CCNCC2)N(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trifluoroacetic acid (7.8 g, 68.0 mmol) was added dropwise to a solution of tert 1-butyl benzyl-3-(2-methylsulfanylethyl)-2-oxo-1,4,8-triazaspiro[4,5]decane-8-carboxylate (1.5 g, 3.5 mmol) in CH2Cl2 (10 ml) at 0° C. and the mixture was stirred for 15 min at this temperature. After warming to RT, the reaction solution was stirred for a further 2.5 h. Subsequently, the reaction solution was adjusted to pH 7 to 8 using saturated aqueous NaHCO3 solution, the organic phase was separated off, and the aqueous phase was extracted with CH2Cl2 (2×10 ml). The combined organic phase was dried over Na2SO4, filtered and the solvent was removed by distillation. Workup was carried out by means of column chromatography to give 1-benzyl-3-(2-methylsulfanyl-ethyl)-1,4,8-triazaspiro[4,5]decan-2-one in a yield of 655 mg (58% of theory).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].Cl.[CH2:11]([C@H:18]1[CH2:23][NH:22][CH2:21][CH2:20][NH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:11]([C@@H:18]1[NH:19][CH2:20][CH2:21][N:22]([S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])[CH2:23]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: c1ccc(C[C@H]2CNCCN2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1cccs1)N1CCN[C@@H](Cc2ccccc2)C1
Reaction time: 3 h
Yield: 110.8 %

Procedure:
2-Thiophenesulfonyl chloride (2.6 g, 14 mmol, Sigma-Aldrich, St. Louis, Mo.) was added to a stirring solution of (2S)-2-benzylpiperazine hydrochloride (4.5 g, 18 mmol), Hünig's base, (16 mL, 90 mmol), and CH2Cl2 (90 mL) at room temperature. After 3 h, silica gel (29 g) was added to the reaction mixture and the volatiles were removed in vacuo. The residue was subjected to column chromatography (120 g of silica, 2% MeOH in CH2Cl2) to give (3S)-3-benzyl-1-(2-thiophenylsulfonyl)piperazine (5.0 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([CH3:13])[CH:4]=1.[Br:14]Br.OS([O-])=O.[Na+].O>C(O)(=O)C.C(Cl)Cl>[Br:14][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH3:13])=[C:6]([NH:9][C:10](=[O:12])[CH3:11])[CH:7]=1
Reactant: COc1ccc(NC(C)=O)c(C)c1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)c(NC(C)=O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To a solution of N-(4-methoxy-2-methylphenyl)acetamide (130 g, 0.73 mol) in acetic acid (800 mL) is added bromine (42 mL, 0.8 mol) dropwise at 0° C. After addition, the resulting mixture is stirred at RT overnight. Saturated aqueous NaHSO3 is added until a clear solution is obtained, and then a large amount of water (2.0 L) is added forming a precipitate. The precipitated solid is collected and washed with water to give the crude product (thin layer chromatography (TLC) solvent: DCM:EtOAc=10:1). The solid is dissolved in minimum amount of refluxing DCM, and then PE (about 10-20% volume of DCM used) is added. The resulting solution is cooled to RT. After 2 hours, the precipitated solid is collected and washed with PE to give a white product (108 g, 57% yield). MS (m/z): 260.0 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](O)=[O:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:35]=1[CH2:36][NH:37][C:38](=[O:44])[C@@H:39]1[CH2:43][CH2:42][CH2:41][NH:40]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C1C=C2N=NN(O)C2=CC=1.O.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:24])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:15]([N:40]2[CH2:41][CH2:42][CH2:43][C@H:39]2[C:38]([NH:37][CH2:36][C:35]2[CH:45]=[C:46]([Cl:49])[CH:47]=[CH:48][C:34]=2[CH2:33][NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:31])=[O:44])=[O:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(C(O)(C(=O)O)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)C(O)(c1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of (4-tert-butoxycarbonylphenyl)(hydroxy)phenylacetic acid from the previous step (0.030 g, 0.09 mmol, HPLC RT=2.53 min), L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide (0.037 g, 0.1 mmol) and HOBT hydrate (0.015 g, 0.1 mmol) in DMF (1 mL) was added EDC (0.021 g, 0.1 mmol). Diisopropylethylamine was then added in portions (˜0.06 mL total) to bring the pH of the solution to 6-7 as measured on wetted E. Merck pH indicator strips. The mixture was stirred at ambient temperature for 2 days, at which time HPLC analysis indicated complete consumption of the proline starting material. The DMF was removed under reduced pressure and the residue was partitioned between EtOAc (40 mL) and saturated aqueous NaHCO3 (10 mL). The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed under reduced pressure and the oil residue was purified by preparative on a Waters PrepPak using 10-100% CH3CN in H2O with 0.1% TFA as eluant over 60 min. Product-containing fractions were combined and the acetonitrile was removed under reduced pressure. The water layer was basicified with saturated aqueous NaHCO3, extracted with 4×20 mL CH2Cl2, dried over Na2SO4 and filtered. The filtrate solvent was removed under reduced pressure to give 1-(2-(4-tert-butyloxycarbonylphenyl)-2-hydroxy-2-phenylethanoyl)-N-(2-tert-butyloxycarbonylaminomethyl-5-chlorobenzyl)-L-prolinamide as a white solid. (0.030 g, 46%; HPLC RT=3.25 min, method B; LC-MS M+H=678).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:15][NH2:16]>CN(C=O)C.CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:16][CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1
Reactant: CN
Reactant: CC(C)c1csc2c(Cl)nc(Cl)nc12
Solvent: CO
Solvent: CN(C)C=O
Product: CNc1nc(Cl)nc2c(C(C)C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To 10 ml of a solution of 100 mg (0.41 mmol) of 2,4-dichloro-7-isopropylthieno[3,2-d]pyrimidine in DMF was added 40% methylamine solution in methanol under ice cooling. The reaction mixture was stirred at the same temperature for one hour and then allowed to resume room temperature, followed by stirring for further 2 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/2) to give 90 mg (yield: 92.0%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([CH2:26][C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[C:9]([NH:11][C@H:12]([CH:15]([OH:25])[C:16]2[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)[CH2:13][CH3:14])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:1]1([CH2:7][C@H:8]([CH2:26][C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[C:9]([NH:11][C@H:12]([C:15]([C:16]2[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)=[O:25])[CH2:13][CH3:14])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC[C@H](NC(=O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1)C(O)c1noc(C(F)(F)F)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC[C@H](NC(=O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1)C(=O)c1noc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of (R)-2-Cyclohexylmethyl-N-{(S)-1-[hydroxy-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-methyl]-propyl}-4-morpholin-4-yl-4-oxo-butyramide (324 mg, 0.661 mmol) in methylene chloride (10 ml) was treated with Dess Martin periodinane (308 mg, 0.726 mmol) and stirred at room temperature for 90 minutes. The reaction mixture was washed with an aqueous solution of Na2S2O3 (0.26M), saturated aqueous bicarbonate solution and water, dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude was purified by flash chromatography eluting with a mixture of ethyl acetate and heptane to give (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-N-[(S)-1-(5-trifluoromethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide as an off white solid (10 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([O:11]C)[C:6]([O:9]C)=[CH:7][CH:8]=1)[CH3:2].C(O)(=O)C.Br>O>[CH2:1]([C:3]1[CH:4]=[C:5]([OH:11])[C:6](=[CH:7][CH:8]=1)[OH:9])[CH3:2]
Reactant: CCc1ccc(OC)c(OC)c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CCc1ccc(O)c(O)c1
Yield: 89 %

Procedure:
A mixture of 10.0 g (60.2 mM) of 4-ethylveratrole, 38.4 g (639 mM) of acetic acid and 115.0 g (668 mM) of 47% hydrobromic acid was heated under reflux for 4 hours with stirring. After cooling to the room temperature, 100 ml of water was added and the resultant mixture was extracted three times with each 110 ml of ether. The ether extract was successively washed with 110 ml of water, 150 g of 5% aqueous sodium thiosulfate solution and further twice with each 110 ml of water. The resulting ether solution was dried with anhydrous sodium sulfate, filtered, concentrated and distilled under vacuum to obtain 7.4 g (53.6 mM) of 4-ethylcatechol as a light yellow liquid having a boiling point of 111°-112° C./4 mmHg.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:3][CH2:2]1.Cl.[NH2:23][C:24]([CH2:31][CH3:32])([CH2:29][CH3:30])[C:25]([O:27][CH3:28])=[O:26]>>[CH3:28][O:27][C:25](=[O:26])[C:24]([CH2:31][CH3:32])([NH:23][C:15]([C:13]1[CH:12]=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[C:9]([O:8][CH2:7][CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[N:14]=1)=[O:17])[CH2:29][CH3:30]
Reactant: CCC(N)(CC)C(=O)OC
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CCOCC2)n1
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CCOCC2)n1)C(=O)OC

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)picolinic acid (Example 230 b) and methyl 2-amino-2-ethylbutanoate hydrochloride (CAN 92398-54-4) as starting materials, MS (EI): m/e=433.5 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20]CC)=[O:19])=[CH:16][C:3]1=2.CO>O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2
Reactant: CCOC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CN2
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CN2
Yield: 68.4 %

Procedure:
A mixture of ethyl 5,6-dihydro-11-oxodibenz[b,e]azepine-2-acetate (0.333 g), methanol (20 ml) sodium hydroxide (1 g) and water (20 ml) was heated under refluxing for 3 hours. After removal of the solvent by distillation, water was added to the mixture, and then, 5% sulfuric acid was added. The precipitated crystals were collected by filtration, washed in water, and dried to obtain 5,6-dihydro-11-oxodibenz[b,e]azepine-2-acetic acid (0.206 g). m.p.: 135°-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]3[CH2:21][C:20](=O)[N:19]([CH2:23][O:24]CC[Si](C)(C)C)[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40](C=O)[CH:39]=1.Cl>C1(C)C=CC=CC=1.CO>[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH:20]=[C:21]2[C:15]3[C:16](=[N:17][CH:18]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:14]=3)[NH:19][C:23]2=[O:24])[CH:39]=1
Reactant: COc1cc(-c2cnc3c(c2)CC(=O)N3COCC[Si](C)(C)C)cc(OC)c1OC
Reactant: O=Cc1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(-c2cnc3c(c2)C(=Cc2cccnc2)C(=O)N3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
To a solution of 5-(3,4,5-trimethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (157 mg, 0.365 mmol) in toluene (2 mL) was added triethylamine (56 μl, 0.365 mmol), molecular sieves 4 Å (100 mg), and 3-pyridinecarboxaldehyde (38 μl, 0.401 mmol). The resulting mixture was stirred overnight at room temperature, after which it was filtered and partitioned between DCM and H2O. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 40-70% EtOAc:Hexanes to yield the SEM-protected precursor as a mixture of cis and trans isomers (101 mg, 53%). 41 mg (0.079 mmol) of this material was dissolved in MeOH (1.5 ml), 6 N HCl (3 ml) was added, and the mixture was stirred for 3 hours at 45° C. The reaction was quenched with 1 N NaOH (15 ml), neutralized by the addition of saturated NaHCO3 and extracted with DCM. Silica gel chromatography eluting with 0-5% MeOH:DCM yielded the title compound (22 mg, 72%) as a cis/trans-mixture. 1H NMR (CDCl3, 300 MHz): δ 9.15 (d, J=4.8 Hz, 1H), 9.11 (bs, 1H), 9.02 (d, J=1.2 Hz, 1H), 8.98 (d, J=1.1, 1H), 8.69 (dd, J=0.9, 2.9 Hz, 1H), 8.66 (dd, J=0.9, 2.8 Hz, 1H), 8.39 (d, J=1.2 Hz, 1H), 8.37 (d, J=1.2 Hz, 1H), 7.95 (m, 1H), 7.93 (s, 1H), 7.87 (d, J=1.1 Hz, 1H), 7.44 (m, 1H), 6.75 (s, 2H), 6.59 (s, 2H), 3.97 (s, 6H), 3.91 (s, 3H), 3.90 (s, 6H), 3.86 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[N:10])=[C:4]([O-])[CH:3]=1.[Na+].P(Cl)(Cl)[Cl:14].O=P(Cl)(Cl)Cl>[OH-].[Na+]>[NH2:1][C:2]1[CH:3]=[C:4]([Cl:14])[C:5]([C:9]#[N:10])=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(N)cc([O-])c1C#N
Reactant: ClP(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(N)cc(Cl)c1C#N
Temperature: 25 °C

Procedure:
A suspension of sodium 6-amino-3-cyano-2-methylpyridin-4-olate (690 mg, 4.03 mmol, prepared in analogy to WO2001062233A2 and isolated as sodium salt) in PCl3 (3.50 ml, 40.3 mmol) and POCl3 (0.94 ml, 10.1 mmol) was heated to reflux for 12 h. After cooling to room temperature, the reaction mixture was carefully given onto 2N NaOH (200 ml) and 50 g ice. The mixture was extracted with DCM (7×50 ml), and the combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was used without additional purification. LCMS RtM=1.45 min, [M+H]+=168.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][N:30]([CH3:35])[C:31](=[O:34])[CH:32]=[CH2:33])=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][N:30]([CH3:35])[C:31](=[O:34])/[CH:32]=[CH:33]/[C:2]2[CH:11]=[N:10][C:9]3[NH:8][C:7](=[O:12])[CH2:6][CH2:5][C:4]=3[CH:3]=2)=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=CC(=O)N(C)Cc1cn(Cc2ccccc2)c2ccccc12
Reactant: O=C1CCc2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CN(Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 33.8 %

Procedure:
A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (1.05 g, 4.60 mmole), N-(1-benzyl-1H-indol-3-ylmethyl)-N-methyl-acrylamide (1.40 g, 4.60 mmole), Pd(OAc)2 (0.10 g, 0.46 mmole), tri-ortho-tolylphosphine (0.28 g, 0.92 mmole) and diisopropylethylamine (1.20 mL 6.90 mmole) in propionitrile (75 mL) was deoxygenated, then was and heated to reflux under a N2 overnight. The dark mixture was filtered through a pad of Celite®, and the filter pad was rinsed with acetonitrile (300 mL). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (5% MeOH/CHCl3). The title compound (0.70 g. 35%) was obtained as a light yellow solid after drying in vacuo: MS (ES) m/e 451 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH2:10]2)=[CH:5][N:4]=1)#[N:2]>N.CO.[Ni]>[CH:9]1([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][NH2:2])=[N:4][CH:5]=2)[CH2:11][CH2:10]1
Reactant: N#Cc1ccc(C2CC2)cn1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ccc(C2CC2)cn1

Procedure:
To a solution of 2-cyano-5-cyclopropylpyridine (210 mg, 1.4 mmol) in 20 mL of 7.0 M ammonia in MeOH was added a small spoon of Raney Ni slurry. The mixture was hydrogenated at 50 psi overnight. The catalyst was filtered off and the filtrate was concentrated to yield a dark oil which was used for the next step reaction without further purification.