Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]([SH:18])[CH2:16][SH:17])[CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[O:9][CH2:10]OC.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:33]([O-:35])=[O:34])[C:28]=1[O:29][CH2:30][CH2:31][CH3:32])[CH:24]=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C@H:24]2[S:18][C@H:15]([C:5]3[CH:6]=[C:7]([O:13][CH3:14])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:16][S:17]2)[CH:26]=[C:27]([N+:33]([O-:35])=[O:34])[C:28]=1[O:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCOc1c(OC)cc(C=O)cc1[N+](=O)[O-]
Reactant: COCOc1c(OC)cc(C(S)CS)cc1OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCOc1c(OC)cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1[N+](=O)[O-]

Procedure:
1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (39) (FIG. 19) (0.689 g,2.65 mmole), 3-methoxy-5-nitro-4-propoxybenzaldehyde (40) (0.633 g, 2.65 mmole) and 0.266 g of pyridinium para-toluenesulfonate was added to 50 ml dry benzene and refluxed with Dean-Stark removal of the benzene- water azeotrope for 24 hours. The benzene was removed in vacuo, and the remaining oil redissolved in dichloromethane and was purified by flash column chromatography with 9:1 hex/ethyl acetate as eluent. The product mixture contains a 1/1 cis/trans ratio (0.600 g, 47%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18]>>[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=[C:4]([CH:3]=2)[C:14]([OH:16])=[O:15])=[CH:21][CH:20]=1)#[N:18]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Product: N#Cc1ccc(-c2cc(C(=O)O)cnc2OCC(F)(F)F)cc1

Procedure:
The title compound was synthesized in analogy to Example BQ using 5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1211586-75-2) and B-(4-cyanophenyl)-boronic acid, (CAN 126747-14-6) as starting materials; MS (ESI): 321.2 (M−H).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[CH2:29][C:28]([CH3:32])([CH3:31])[CH2:27][CH2:26][C:25]=5[N:24]([CH3:33])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[CH2:29][C:28]([CH3:31])([CH3:32])[CH2:27][CH2:26][C:25]=5[N:24]([CH3:33])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4c3CC(C)(C)CC4)nc12)C(=O)N1CC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4c3CC(C)(C)CC4)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 53.7 %

Procedure:
In a round-bottomed flask, 5-(2-trimethylsilanyl-ethoxymethyl)-2-(1,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (112 mg, 0.19 mmol) was dissolved in dichloromethane (0.9 ml) and trifluoroacetic acid (0.6 ml, 7.5 mmol) was added. The yellow solution was stirred at room temperature for 2.5 h then concentrated. The residue was redissolved in dichloromethane (0.9 ml) and ethylenediamine (0.8 ml, 11.4 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 47 mg (51%) of 2-(1,5,5-Trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a white powder. MS: (M+H)+=461; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.61 (br. s., 1H), 8.94 (s, 1H), 8.27-8.41 (m, 2H), 4.43-4.80 (m, 3H), 3.94-4.24 (m, 2H), 3.80 (s, 3H), 3.72-3.91 (m, 1H), 2.89 (d, J=15.9 Hz, 1H), 2.59-2.71 (m, 3H), 1.59 (t, J=6.2 Hz, 2H), 1.40 (dd, J=6.8, 3.0 Hz, 3H), 1.00 (s, 6H).
Reaction SMILES: P(Br)(Br)Br.Br[CH2:6][C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])=[CH:10][CH:11]=1.[NH:21]1[CH:28]=[CH:27][C:25](=[O:26])[NH:24][C:22]1=[O:23].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C=O)C>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[O:8][C:7]([CH2:6][N:21]2[CH:28]=[CH:27][C:25](=[O:26])[NH:24][C:22]2=[O:23])=[CH:11][CH:10]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CBr)o1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1ccn(Cc2ccc(-c3ccccc3[N+](=O)[O-])o2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.8 %

Procedure:
To a solution of alcohol in dichloromethane at 0° C. was added neat PBr3 in ice bath. The solution was allowed to warm to 25° C. and then stirred for 12 h. The reaction was quenched with ice and extracted with ethyl acetate. The combined organic layers were washed with H2O, sat. NaHCO3 and brine, and dried over anhydrous Na2SO4. After the solution was filtered and concentrated under reduced pressure, the crude compound was used for the subsequent alkylation without further purification. To a solution of 2-(bromomethyl)-5-(2-nitrophenyl)furan 11a (120 mg, 0.43 mmol) and uracil (476 mg, 4.3 mmol) in anhydrous DMF (2.0 mL) was added anhydrous potassium carbonate (235 mg, 1.7 mmol) at 25° C. The resulting solution was then heated at 50° C. for 8 h. After removal of DMF under reduced pressure, the residue was diluted with CHCl3 and washed three times with water. The organic layer was dried over anhydrous MgSO4 and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate to afford 90 mg (68%) of the uracil 13a as a white solid. 1H NMR (DMSO) δ: 11.29 (1H, s), 7.82 (1H, d, J=8.1 Hz), 7.77 (1H, d, J=7.5 Hz), 7.68 (1H, t, J=7.2 Hz), 7.60 (1H, d, J=7.8 Hz), 7.52 (1H, t, J=8.1 Hz), 6.83 (1H, d, J=3.6 Hz), 6.53 (1H, d, J=3.3 Hz), 5.57 (1H, dd, J=7.8, 1.5 Hz), 4.88 (2H, s); 13C NMR (DMSO) δ: 164.08, 151.69, 151.07, 148.39, 147.33, 145.33, 132.91, 129.70, 129.04, 124.36, 122.84, 110.38, 111.18, 102.01, 43.74.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH3:26][C@H:27]([NH2:36])[C@H:28]([OH:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][NH:36][C@@H:27]([CH3:26])[C@H:28]([OH:35])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@@H](C)[C@H](O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
(2′-Formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.094 g, 0.27 mmol), (1R,2S)-(−)-norephedrine (0.054 g, 0.35 mmol), and sodium triacetoxyborohydride (0.113 g, 0.53 mmol) were combined in dichloroethane (1 mL). Acetic acid (1 drop) was added, and the reaction was stirred at room temperature for 40 minutes. Analytical tlc showed that only starting material was present, so the reaction was heated to 50° C. and stirred overnight. Analytical LCMS showed that some starting material was still present, so additional (1R,2S)-(−)-norephedrine (0.057 g, 0.38 mmol), and sodium triacetoxyborohydride (0.115 g, 0.53 mmol) were added, and the reaction was stirred for 3.5 hours at 50° C. After cooling to room temperature, the mixture was diluted with CH2Cl2 and saturated aqueous NaHCO3, and the aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]([CH2:13][CH3:14])[C@H:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:11]C1)=[O:7].N[C@@H:16](CCC)CO.[N+](CC)#[C-]>>[ClH:1].[ClH:1].[NH2:3][C@@H:4]([CH2:13][CH2:14][CH3:16])[C@H:5]([OH:12])[C:6]([NH:8][CH2:9][CH3:11])=[O:7]
Reactant: CCC[C@H](N)CO
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Agent: Cl
Agent: [C-]#[N+]CC
Product: CCC[C@H](N)[C@H](O)C(=O)NCC

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide dihydrochloride, Representative Procedure A, starting with (S)-2-aminopentan-1-ol in the first step (A1), and using isocyanoethane in the third step (A3).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.[OH-].[Na+]>C(O)C>[CH3:11][N:12]1[CH2:17][CH2:16][C:15]2[N:1]=[C:2]3[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]3=[CH:4][C:14]=2[CH2:13]1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ccc(C=O)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCc2nc3cc(N)ccc3cc2C1
Yield: 42.5 %

Procedure:
A solution of 2,4-diaminobenzaldehyde (1.00 g, 7.34 mmol), 1-methyl-4-piperidinone (1.08 ml, 8.81 mmol) and 4N aqueous sodium hydroxide solution (11 ml) in ethanol (70 ml) was stirred at 60° C. for 16 hrs, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The obtained crude product was purified by NH-silica gel chromatography (elute solvent; ethyl acetate) and treated with ethyl acetate-isopropyl ether (1:5) to give the title compound (666 mg) as a powder.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.CN.C(O)(=O)C.[B-][C:44]#[N:45].[Na+]>O1CCCC1.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][NH:45][CH3:44])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: [B-]C#N
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCOC1
Product: CNCc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (1.0 g), methylamine (2M tetrahydrofuran solution, 3.2 mL), acetic acid (0.13 g), ethanol (20 mL) and tetrahydrofuran (20 mL) was stirred at room temperature for 2 hrs. Sodium cyanotrihydroborate (0.20 g) was added to the reaction mixture, and the mixture was further stirred at room temperature for 3 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give N-({3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methyl)-N-methylamine as colorless crystals (0.15 g, yield 14%) from a fraction eluted with ethyl acetate-methanol (10:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 103-104° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](C=O)[C:5]([Cl:10])=[CH:4][N:3]=1.[CH:11](OC)([O:14][CH3:15])[O:12][CH3:13]>CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C:5]([Cl:10])=[CH:4][N:3]=1
Reactant: COC(OC)OC
Reactant: O=Cc1cc(Br)ncc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(OC)c1cc(Br)ncc1Cl
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a sol. of 2-bromo-5-chloro-pyridine-4-carbaldehyde (43.9 g, 199 mmol) in MeOH (800 mL) were successively added at rt trimethyl orthoformate (65.3 mL, 597 mmol) and p-toluenesulfonic acid monohydrate (1.90 g, 10.0 mmol). This reaction mixture was then heated to reflux for 3 h. The mixture was allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and this mixture was washed with aq. 10% K2CO3. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying under high vacuum yielded the title compound (51.7 g, 97%). LC-MS: tR=0.92 min; ES+: 309.06.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([C:26]([F:29])([F:28])[F:27])[O:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([F:25])[CH2:24][NH:23][CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.[CH3:30][S:31]([CH2:34][C:35]([OH:37])=O)(=[O:33])=[O:32]>>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([C:26]([F:27])([F:29])[F:28])[O:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([F:25])[CH2:22][N:23]([C:35](=[O:37])[CH2:34][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:24]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:6]=[C:7]([Cl:9])[C:8]=1[Cl:1]
Reactant: FC1(c2ccc(C3=COC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)CNC1
Reactant: Cl
Reactant: CS(=O)(=O)CC(=O)O
Product: CS(=O)(=O)CC(=O)N1CC(F)(c2ccc(C3=COC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1

Procedure:
Example 3 was prepared similarly to that of Example 1, except that Example 3, Intermediate 3 was reacted with methane sulfonyl acetic acid. Yield: 0.170 g (29.74%). 1H NMR (400 MHz, DMSO-d6) δ: 3.11 (s, 3H), 3.22 (d, J=17.24 Hz, 1H), 3.70 (d, J=17.16 Hz, 1H), 4.24 (s, 2H), 4.34 (d, J=21.64 Hz, 2H), 4.70 (d, J=21.6 Hz, 2H), 7.28 (d, J=8.12 Hz, 2H), 7.47 (d, J=8.24 Hz, 2H), 7.58 (s, 1H), 7.92 (s, 2H). LC-MS (m/z): =583.8 (M−H). HPLC purity: 99.64%.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:34])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5([C:32]#[N:33])[CH2:31][CH2:30]5)[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[N:10][N:9]2[CH:35]=1)=[O:4].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(=O)([O-])O.[Na+]>C(#N)C>[C:32]([C:29]1([C:25]2[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=2)[C:22]([NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:11]3[CH:12]=[CH:13][C:8]4[N:9]([CH:35]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:40]5[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]5)[N:7]=4)[N:10]=3)[CH:16]=2)=[O:34])[CH2:31][CH2:30]1)#[N:33]
Reactant: CN1CCNCC1
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)CCl)cn5n4)c3)c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN1CCN(CC(=O)Nc2cn3nc(Oc4cccc(NC(=O)c5cccc(C6(C#N)CC6)c5)c4)ccc3n2)CC1
Temperature: 80 °C
Yield: 41 %

Procedure:
A mixture of N-[3-({2-[(chloroacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(1-cyanocyclopropyl)benzamide (140 mg, 0.287 mmol), 1-methylpiperazine (1 mL) and acetonitrile (2 mL) was stirred with heating at 80° C. for 4 hr. After the reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=0/100→100/0) to give the title compound (65 mg, 41%) as a white powder.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[C:4]([C:15]2[N:20]=[C:19]3[C:21]([C:32]([O:34]C)=[O:33])=[CH:22][N:23](COC(=O)C(C)(C)C)[C:18]3=[N:17][CH:16]=2)=[N:3]1.[OH-].[K+]>O1CCOCC1.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:13])([F:14])[F:12])[CH:9]=2)[C:4]([C:15]2[N:20]=[C:19]3[C:21]([C:32]([OH:34])=[O:33])=[CH:22][NH:23][C:18]3=[N:17][CH:16]=2)=[N:3]1
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4cc(C(F)(F)F)ccc34)nc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(C(F)(F)F)cc21
Yield: 155.7 %

Procedure:
A mixture of methyl 2-(1-methyl-6-(trifluoromethyl)-1H-indazol-3-yl)-5-(pivaloyl oxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (200 mg, 0.409 mmol) and KOH (229 mg, 4.09 mmol) in 1,4-dioxane (5 mL) and water (2 mL) was heated to reflux for 4 hours. Dioxane was concentrated and the residual aqueous layer was adjusted to pH=4 with 1.0 M HCl. The precipitate was collected by filtration and dried to afford 2-(1-methyl-6-(trifluoromethyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (230 mg, crude) as a yellow solid. LCMS: (M+H)+=362.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][C:15](O)=[O:16].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH:43]1([NH2:50])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>CN(C)C=O>[CH:43]1([NH:50][C:15](=[O:16])[CH2:14][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:12][C:13]=3[CH:1]=2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: NC1CCCCCC1
Reactant: O=C(O)Cc1ccc2c(c1)Cc1ccccc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cc1ccc2c(c1)Cc1ccccc1-2)NC1CCCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
In dimethylformamide (50 ml) was dissolved 2-fluoreneacetic acid (2.24 g) followed by addition of 1-hydroxybenztriazole (2.0 g) and, then, dicyclohexylcarbodiimide (3.1 g) with constant stirring and ice-cooling. The mixture was further stirred at room temperature for 15 minutes. Cycloheptylamine (1.7 g) was then added under ice-cooling and the mixture was stirred at room temperature for 8 hrs. The resulting solid was filtered off and the filtrate was distilled under reduced pressure. The residue was extracted with 50 ml of chloroform and the extract was washed with 1N aqueous sodium hydroxide solution, 1N hydrochloric acid and water in the order mentioned and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography to give 2.1 g of N-cycloheptyl-2-fluoreneacetamide as a solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:15][C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.P(Cl)(Cl)([Cl:19])=O.CN(C)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O.C(Cl)(Cl)Cl>[Cl:19][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2ccco2)nc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Clc1nc(-c2ccco2)nc2ccccc12
Reaction time: 0.25 h

Procedure:
A 2.12 g portion of 2-(2-furyl)quinazolin-4(3H)-one was stirred into 25 ml of phosphorus oxychloride and to this mixture was slowly added 1.21 g of dimethylaniline. This mixture was stirred for 15 minutes. The entire mixture was added slowly to 1 liter of cold water containing 25 ml of chloroform. Solid sodium bicarbonate was added as required to keep the water solution basic. The chloroform extract was separated and the water extracted with an additional 25 ml of chloroform. The chloroform extracts were combined and concentrated to give a yellow solid. The solid was recrystallized from cyclohexane to give 1.4 g of 4-chloro-2-(2-furyl)quinazoline, m.p. 116°-118°; ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][N:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4]1.[CH2:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24](O)=[O:25])=[CH:16]1)[CH3:14]>>[CH2:4]1[CH:5]2[N:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:11][CH2:12][CH:3]1[CH2:2][O:1][C:24]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]([CH2:13][CH3:14])[CH:16]=1)=[O:25]
Reactant: CCn1cc(C(=O)O)c2ccccc21
Reactant: OCC1CCN2CCCCC2C1
Product: CCn1cc(C(=O)OCC2CCN3CCCCC3C2)c2ccccc21

Procedure:
eq-2-Hydroxymethylquinolizidine (N. J. Leonard et al, J. Org. Chem., 1957, 22, 1445) was reacted with the acid chloride of 1-ethylindole-3-carboxylic acid using the method of Example 1. The product was chromatographed on silica gel eluting with ethyl acetate to afford the title compound (E16) as a pale yellow oil. This was converted to its hydrochloride salt mp 168°-172° C.
Reaction SMILES: CN(C)C=O.[CH:6]1([N:12]2[C:20]3[C:19](=[O:21])[NH:18][C:17]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:24][C:23]=4[O:35][CH3:36])=[N:16][C:15]=3[C:14]([CH3:37])=[N:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:38](N(CC)CC)[CH3:39].C(I)C>C(OCC)(=O)C>[CH:6]1([N:12]2[C:20]3[C:19](=[O:21])[NH:18][C:17]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:34][CH2:33][CH2:32][N:31]([CH2:38][CH3:39])[CH2:30][CH2:29]5)=[CH:24][C:23]=4[O:35][CH3:36])=[N:16][C:15]=3[C:14]([CH3:37])=[N:13]2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COc1cc(N2CCCNCC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCI
Product: CCN1CCCN(c2ccc(-c3nc4c(C)nn(C5CCCCC5)c4c(=O)[nH]3)c(OC)c2)CC1
Reaction time: 3 h
Yield: 60.8 %

Procedure:
To a 4 ml N,N-dimethylformamide solution of 102 mg (0.23 mmol) of the compound obtained in Example 125, 49 μl (0.35 mmol) of triethylamine and 23 μl (0.29 mmol) of ethyl iodide were added at room temperature, and the mixture was stirred for 3 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and a saturated aqueous solution of sodium chloride in this order. The washed system was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1˜10/1) to obtain 65 mg (60%) of the captioned compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9](=O)[C:10]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:11]=1[F:18])=[O:5])[CH3:2].[C:20]1([CH3:31])[CH:25]=[CH:24][C:23]([S:26]([NH:29]N)(=[O:28])=[O:27])=[CH:22][CH:21]=1.[CH2:32](O)C>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]([C:10]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:11]=1[F:18])=[CH:32][NH:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:31])=[CH:21][CH:22]=1)(=[O:28])=[O:27])=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: CCO
Reactant: CCOC(=O)C1CC1C(=O)c1cc(C#N)ccc1F
Product: CCOC(=O)C1CC1C(=CNS(=O)(=O)c1ccc(C)cc1)c1cc(C#N)ccc1F
Yield: 66 %

Procedure:
2-(5-cyano-2-fluoro-benzoyl)-cyclopropanecarboxylic acid ethyl ester (1.62 g, 6.2 mmol) and p-toluenesulfonhydrazide (2.31 g, 12.4 mmol) were refluxed in 50 mL ethanol for 36 h. The reaction was concentrated in vacuo, then purified by flash chromatography on silica gel using ethyl acetate/hexane (0-25%) as the eluent to give 2-[1-(5-cyano-2-fluoro-phenyl)-2-(toluene-4-sulfonylamino)-vinyl]-cyclopropanecarboxylic acid ethyl ester (1.77 g, 66%) as a mixture of cis and trans isomers. 1H NMR (500 MHz, CDCl3) 7.87 (1H, d, J=8.24 Hz), 7.78 (0.5H, m), 7.76 (1H, d, J=8.24 Hz), 7.65 (0.5H, m), 7.61 (0.5H, dd, J 2.14, 6.71 Hz), 7.44 (0.5H, dd, J=2.14, 5.80 Hz), 7.36 (2H, dd, J=3.96, 7.93 Hz), 7.31 (0.5H, t, J=8.54 Hz), 7.18 (0.5H, t, J=8.54 Hz), 4.22 (1H, m), 4.12 (2H, dq, J=7.32, 4.27 Hz), 2.46 (3H, 2s), 2.20 (0.5H, m), 1.99 (0.5H, m), 1.66 (0.5H, mn), 1.43 (0.5H, m), 1.31 (2H, m), 1.27 (3H, dt, J=7.02, 3.67 Hz). MS m/e 430.13 (M+H)+.