Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[O:30])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16].[CH2:31](O)[CH2:32][OH:33].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]2[O:33][CH2:32][CH2:31][O:30]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16]
Reactant: OCCO
Reactant: COc1cc(CCCCCCC=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(CCCCCCC2OCCO2)ccc1OCc1nc(-c2ccccc2)oc1C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
A mixture of 7-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]heptanal (3.8 g), ethylene glycol (1 g), p-toluenesulfonic acid monohydrate and toluene (50 ml) was stirred for 4 hours under reflux. The reaction mixture was cooled, which was then washed with water and dried (MgSO4), followed by distilling off the solvent under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:3), was obtained 2-[6-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]hexyl]-1,3-dioxolan (3.9 g, 94%) as an oily product.
Reaction SMILES: F[C:2]1[C:16]([CH:17]=[O:18])=[CH:15][C:5]2[C:6]([C:9]3[N:13]([CH3:14])[N:12]=[CH:11][N:10]=3)=[N:7][O:8][C:4]=2[C:3]=1[F:19].[CH3:20][C@H:21]1[O:26][C@H:25]([CH3:27])[CH2:24][NH:23][CH2:22]1>>[CH3:27][C@@H:25]1[CH2:24][N:23]([C:2]2[C:16]([CH:17]=[O:18])=[CH:15][C:5]3[C:6]([C:9]4[N:13]([CH3:14])[N:12]=[CH:11][N:10]=4)=[N:7][O:8][C:4]=3[C:3]=2[F:19])[CH2:22][C@@H:21]([CH3:20])[O:26]1
Reactant: Cn1ncnc1-c1noc2c(F)c(F)c(C=O)cc12
Reactant: C[C@@H]1CNC[C@@H](C)O1
Product: C[C@@H]1CN(c2c(C=O)cc3c(-c4ncnn4C)noc3c2F)C[C@@H](C)O1

Procedure:
Starting materials: 6,7-difluoro-3-(1-methyl-1H-1,2,4-triazol-5-yl)benzo[d]isoxazole-5-carbaldehyde (Intermediate 404) and (2R,6R)-2,6-dimethylmorpholine.
Reaction SMILES: Cl[C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([C:9]([N+:13]([O-:15])=[O:14])=[CH:10][C:11]=1[CH3:12])[NH:5][CH:6]([CH3:8])[CH3:7].[CH3:19][O-:20].[Na+]>CO>[CH:6]([NH:5][C:4]1[C:9]([N+:13]([O-:15])=[O:14])=[CH:10][C:11]([CH3:12])=[C:2]([O:20][CH3:19])[C:3]=1[N+:16]([O-:18])=[O:17])([CH3:8])[CH3:7]
Reactant: C[O-]
Reactant: Cc1cc([N+](=O)[O-])c(NC(C)C)c([N+](=O)[O-])c1Cl
Agent: [Na+]
Solvent: CO
Product: COc1c(C)cc([N+](=O)[O-])c(NC(C)C)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a stirred solution of 5.47 g. (0.02 mole) of 3-chloro-N-isopropyl-4-methyl-2,6-dinitroaniline in 100 ml. of methanol is added 1.79 g. (0.033 mole) of sodium methoxide. The reaction mixture is stirred at reflux for three hours, cooled to room temperature and filtered. The filtrate is evaporated at reduced pressure and the residue partitioned between ether and dilute aqueous hydrochloric acid. The organic phase is successively washed with water, saturated sodium bicarbonate and brine. It is then dried over anhydrous magnesium sulfate. Evaporation of the solvent in vacuo gives 5.0 g. of the desired product having a m.p. of 72°-77° C. Two recrystallizations from methanol give the analytical sample, m.p. 77.5°-79° C. Analysis: Calcd. for C11H15N3O5 : C, 49.07; H, 5.62; N, 15.61. Found: C, 49.35; H, 5.66; N, 15.77.
Reaction SMILES: [C-:1]#[N:2].[Na+].C(Cl)(Cl)Cl.[Br:8][C:9]1([C:15]2[O:16][C:17]3[C:25]([CH2:26]Br)=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](=[O:21])[CH:20]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[Br:8][C:9]1([C:15]2[O:16][C:17]3[C:25]([CH2:26][C:1]#[N:2])=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](=[O:21])[CH:20]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: [C-]#N
Reactant: O=c1cc(C2(Br)CCCCC2)oc2c(CBr)cccc12
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: N#CCc1cccc2c(=O)cc(C3(Br)CCCCC3)oc12
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 72.2 %

Procedure:
NaCN (3.88 g, 0.075 mole) was dissolved in water (11 ml) and to the solution was added benzyltrimethylammonium chloride (13.9 g, 0.075 mole). After stirring at 50° C. for 15 minutes, chloroform (120 ml) was added and further 2 -(1-bromocyclohexyl)-8-bromomethyl-4-oxo-4H-[1]-benzopyran (12 g, 0.03 mole) was added. The mixture was stirred for 4 hours. The chloroform layer was washed with water, dried (MgSO4) and then concentrated under reduced pressure to obtain crystals. The crude crystals were recrystallized from ethyl acetate to obtain the title compound (7.5 g) as prisms, m.p. 143°-144° C., yield 72.2%. IR and NMR spectra of this compound were identical with those of the compound obtained in Reference Example 20.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Product: Cc1ccc(S(=O)(=O)OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1

Procedure:
1-Benzhydryl-3-hydroxyazetidine is allowed to react with p-toluenesulfonyl chloride using an acid-removing agent to give 1-benzhydryl-3-(p-toluenesulfonyloxy)azetidine. This compound is allowed to react with diethyl malonate in the presence of a base to give diethyl (1-benzhydryl-3-azetidinyl)malonate.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:16][OH:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.C(N(CC)CC)C.[CH3:25][Si:26](Cl)([CH3:28])[CH3:27]>ClCCl>[CH3:25][Si:26]([CH3:28])([CH3:27])[O:1][CH2:2][C:3]1([CH2:16][O:17][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: OCC1(CO)c2ccccc2-c2ccccc21
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)OCC1(CO[Si](C)(C)C)c2ccccc2-c2ccccc21
Temperature: 0 °C
Yield: 88 %

Procedure:
1 g of 9,9-bis(hydroxymethyl)fluorene (4.4 mmol) was admixed with 20 ml of dichloromethane. The mixture was cooled in ice-water bath, and 1.9 ml of triethyl amine (13.2 mmol) was added thereto. Then 1.4 ml of trimethylsilyl chloride (11 mmol) was added drop-wise, and the mixture was stirred in ice-water bath for further 2 hours. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.14 g of concentrate (yield 88%). MS (EI) m/e: 370(M+).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:13][CH3:14])[C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].BrC1C=CC([N+]([O-])=O)=C(OC)C=1[F:27]>>[F:27][C:7]1[C:8]([O:13][CH3:14])=[C:9]([N+:10]([O-:12])=[O:11])[CH:2]=[CH:3][C:4]=1[C:5]#[N:6]
Reactant: COc1cc(C#N)cc(F)c1[N+](=O)[O-]
Reactant: COc1c([N+](=O)[O-])ccc(Br)c1F
Product: COc1c([N+](=O)[O-])ccc(C#N)c1F

Procedure:
The title compound was prepared according to the procedure for 3-fluoro-5-methoxy-4-nitrobenzonitrile (Compound 146F) using 1-Bromo-2-fluoro-3-methoxy-4-nitrobenzene (Compound 147G). 1H NMR (CDCl3, 400 MHz): δ=4.15 (d, J=2.27 Hz, 3H), 7.45 (dd, J=8.59, 5.56 Hz, 1H), 7.64 (dd, J=8.59, 1.77 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:13][CH2:14][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:20]=2[CH2:21]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: ClCCCN1CCCCC1
Product: CCN(Cc1ccc(OCCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 49.4 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 1-(3-chloropropyl)piperidine (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (13 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[C:8](F)=[CH:7][C:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]=[CH:11]2)=[C:5]([F:21])[CH:4]=1)#[N:2].[CH2:22]([S:24]([NH2:27])(=[O:26])=[O:25])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:1]([C:3]1[C:8]([NH:27][S:24]([CH2:22][CH3:23])(=[O:26])=[O:25])=[CH:7][C:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]=[CH:11]2)=[C:5]([F:21])[CH:4]=1)#[N:2]
Reactant: CCS(N)(=O)=O
Reactant: N#Cc1cc(F)c(-n2cnc(C(F)(F)F)cc2=O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCS(=O)(=O)Nc1cc(-n2cnc(C(F)(F)F)cc2=O)c(F)cc1C#N
Temperature: 60 °C
Reaction time: 6 h
Yield: 1.8 %

Procedure:
A mixture of 4.3 g (14.3 mmol) of 3-(4-cyano-2,5-difluoro-phenyl)-6-trifluoromethyl-pyrimidin-4-one (cf. Example 1), 1.6 g (14.3 mmol) of ethanesulphonamide, 2.0 g (14.3 mmol) of potassium carbonate and 50 ml of dimethyl sulphoxide is stirred at 60° C. for 6 hours and then concentrated under reduced pressure. The residue is taken up in water and, after acidification, shaken with methylene chloride. The organic phase is dried with sodium sulphate and filtered. The filtrate is concentrated, and the crude product obtained as residue is purified by column chromatography (silica gel, ethyl acetate/chloroform, 1:1 by volume). 100 mg (2% of theory) of 3-(4-cyano-5-ethylsulphonylamino-2-fluoro-phenyl)-6-trifluoromethyl-pyrimidin-4-one of melting point 170° C. are obtained.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[CH:10]2>CN(C=O)C.O>[CH2:1]([S:3][CH2:15][CH2:16][CH2:7][O:6][C:16]1[CH:15]=[C:14]2[C:9]([CH:10]=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:6][CH3:5])[CH3:2]
Reactant: CC[S-]
Reactant: COc1ccc2ncncc2c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSCCCOc1cc2ncncc2cc1OC
Temperature: 70 °C
Yield: 108.4 %

Procedure:
A mixture of sodium ethanethiolate (120 mg, 1.5 mmol) and 4-(4-chloro-2-fluoroanilino)-73chloropropoxy)6-methoxyquinazoline (227 mg, 0.57 mmol) in DMF (10 ml) was stirred and heated at 70° C. for 3 hours. The reaction mixture was allowed to cool, was diluted with water and extracted with ethyl acetate (3×75 ml). The extracts were combined, washed with water (×2), and then brine, and dried (MgSO4). The solvent was removed by evaporation and the residue was recrystallised from ethyl acetate/hexane to give 4-chloro-2-fuoroanilino)-7-(3-(ethylthio)propoxy)6-methoxyquinazoline (86 mg, 40%).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:14])=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A mixture of 4-formylcinnamic acid (7.04 g, 40 mmole), anhydrous potassium carbonate (16.5 g, 120 mmole) and methyl iodide (8.5 g, 60 mmole) in dry N,N-dimethylformamide (50 ml) was stirred overnight at room temperature and the solvent evaporated in vacuo. The product was partitioned between ether and water and the organic phase washed with brine and dried (MgSO4). Evaporation gave 7.32 g (97%) of the title ester of mp (aqueous methanol) 83°-85° C., νmax (mull) 1723, 1683, 1635 cm-1, δ(CDCl3) 3.83 (3H, s, CH3), 6.52 (1H, d, J15 Hz, C=CHCO2), 7.75 (1H, d, J 15 Hz, ArCH=C), 7.79 (4H, ABq, J 6 Hz, Δν16.5 Hz, arom), 10.08 (1H, s, CHO).
Reaction SMILES: [C:1]([NH:3][C:4](S(C)=O)=[N:5][CH3:6])#[N:2].[CH3:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH2:16][S:17][CH2:18][CH2:19][NH2:20]>CC#N>[C:1]([N:3]=[C:4]([NH:20][CH2:19][CH2:18][S:17][CH2:16][C:12]1[N:13]=[CH:14][NH:15][C:11]=1[CH3:10])[NH:5][CH3:6])#[N:2]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CN=C(NC#N)S(C)=O
Solvent: CC#N
Product: CNC(=NC#N)NCCSCc1nc[nH]c1C
Yield: 79.8 %

Procedure:
A solution of N-cyano-N'-methyl-methylsulfinylformamidine (493 mg) and 2-(5-methylimidazol-4-ylmethylthio)ethylamine (684 mg) in CH3CN (20 ml) was stirred for 4 hrs. at room temperature. After concentration under a reduced pressure, the residue was subjected to chromatography on SiO2 [eluant: CH3CN-CH3OH (4:1)]. The product obtained was recrystallized from CH3CN to give N"-cyano-N-methyl-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]guanidine (684 mg). Yield 79.7%, m.p. 136°-138° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.[Li]CCCC.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(NC1C(C([O-])=O)=CC=C(F)N=1)(=O)C(C)(C)C>C1COCC1.O>[F:1][C:2]1[C:3]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4][CH:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[N:7]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(F)n1
Reactant: CCOC(=O)Cl
Agent: CC(C)(C)C(=O)Nc1nc(F)ccc1C(=O)[O-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NC(=O)C(C)(C)C)nc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 6-fluoro-2-pivaloylaminopyridine (2 g) in THF (30 ml) was cooled to -78° C. and BuLi (15 mL of 1.6M in hexane) was added and the reaction stirred at 0° C. for 2 h. On re-cooling to -78° C., ethyl chloroformate (2 mL) was added and the reaction allowed to warm slowly to room temperature over 1 h. Water (10 ml) was added and the products extracted into Et2O (3×50 ml) and dried (Na2 SO4). Concentration afforded an oil which was triturated with petrol to give a solid, the isomeric 2-pivaloylamino-6-fluoropyridine-3-carboxylate (1H NMR [CDCl3 ] δ1.36 (s, 9H), 1.43 (t, 3H), 4.41 (q, 2H), 6.64 (dd, 1H), 8.45 (t, 1H), 11.34 (brs, 1H). The mother liquors were concentrated and purified by flash column chromatography (SiO2, Petrol to 5% Et2O/petrol to give ethyl 2-fluoro-6-pivaloylaminopyridine-3-carboxylate (1.2 g).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][C:27]([CH3:32])([CH3:31])[C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][C:27]([CH3:32])([CH3:31])[C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: CC(C)(CN)C(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Yield: 50 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (82 mg, 0.26 mmol) and 3-amino-2,2-dimethyl-propionic acid (90 mg, 0.77 mmol) (ChemBridge) in 0.5 M NaOMe/MeOH (1.0 mL, 0.5 mmol) was microwaved at 120° C. for 40 min. Reaction mixture was concentrated and the residue was dissolved in water (70 mL). It was acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried. Crude product was triturated with MeOH (2 mL). solid was collected and dried to provide the title compound 54.4 mg (0.13 mmol) in 51% yield. LC-MS ESI−: 404.03 (M−1)−.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([O-])=O.[N+](C1C=CC=C2C=1C(C(=O)C1C=CC=CC=1)=NN2)([O-])=O>>[NH2:11][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([OH:10])=[N:2]2)=[O:19])=[CH:16][CH:15]=1
Reactant: Oc1n[nH]c2ccccc12
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C(c1ccccc1)c1n[nH]c2cccc([N+](=O)[O-])c12
Product: Nc1ccc(C(=O)n2nc(O)c3ccccc32)cc1

Procedure:
Reaction of 1H-indazol-3-ol with p-nitrobenzoyl chloride and subsequent catalytic reduction of the nitrobenzoyl indazol derivative according to the general procedure B above afforded the desired amine as a colorless solid in 49.1% overall yield; m.p. 233°-235° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C[Al](C)C.[NH:23](/[C:27](/[CH3:33])=[CH:28]\[C:29](OC)=[O:30])[C:24]([CH3:26])=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:29](=[O:30])[CH:28]=[C:27]([CH3:33])[N:23]=[C:24]2[CH3:26])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: Nc1ccc(NCCCN2CCOCC2)c(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(NCCCN3CCOCC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.7 %

Procedure:
To a solution of 2-fluoro-N1-(3-morpholinopropyl)benzene-1,4-diamine (1.60 g, 6.23 mmol) in CH2Cl2 (30 mL) was added trimethylaluminum (22 mL, 44 mmol, 2 M in toluene) slowly at rt. The reaction mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (1.98 g, 12.59 mmol) in CH2Cl2 (10 mL). The reaction was stirred at rt overnight, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as a pale yellow solid (0.60 g, 27%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=O)[C:19]([CH2:24]OC)=[CH:20]N(C)C)[CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:28][C:29]([NH2:31])=[S:30].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[C:19]([CH3:24])=[CH:20][N:31]=[C:29]([SH:30])[N:28]=2)[CH:17]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COCC(=CN(C)C)C(=O)c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1
Reactant: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cnc(S)nc1-c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1
Temperature: 90 °C
Yield: 48.1 %

Procedure:
4-(3-Dimethylamino-2-methoxymethyl-acryloyl)-1H-pyrrole-2-carboxylic acid (2-hydroxy-1-(S)-phenyl-ethyl)-amide (17.6 mmol, 6.0 g) was combined with thiourea (39 mmol, 3.0 g) and potassium carbonate (53 mmol, 7.3 g) in ethanol (50 mL) and the resulting suspension was heated at 90° C. for 24 hrs. The solvent was removed in vacuo and the resulting black solid was diluted with water and the solid was removed by filtration. The solid was washed with ethyl acetate twice and the aqueous solution was acidified to pH 5–6 with HCl (2N). The solid formed was removed by filtration and the aqueous solution was then extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate. The solvent was removed under vacuum to afford the title compound as a brown solid (3.0 g, 48% yield). HPLC Method B, Rt=3.7 minutes, 1H NMR consistent with structure.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.[O:24]1[CH2:29][CH2:28][CH2:27][CH:26]([NH2:30])[CH2:25]1.CCN(C(C)C)C(C)C>>[CH3:22][C:3]1[C:2]([NH:30][CH:26]2[CH2:27][CH2:28][CH2:29][O:24][CH2:25]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: NC1CCCOC1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CCCOC1
Temperature: 100 °C
Yield: 75 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 44 mg, 0.148 mmol), rac-tetrahydro-2H-pyran-3-amine hydrochloride (40.9 mg, 0.297 mmol, Matrix Scientific, Columbia, S.C.), and DIPEA (129 μl, 0.742 mmol), heating at 100° C. for 1 h. Purification by silica gel (100% DCM to 6% MeOH/DCM) provided rac-2-(2-methyl-3-((tetrahydro-2H-pyran-3-yl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (75% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72-1.83 (m, 3H) 2.13-2.21 (m, 1H) 2.56 (s, 3H) 2.91 (t, J=6.85 Hz, 2H) 3.35-3.42 (m, 2H) 3.45 (td, J=6.85, 2.35 Hz, 2H) 3.87 (d, J=10.76 Hz, 1H) 4.01-4.08 (m, 1H) 4.12-4.20 (m, 1H) 6.86 (d, J=7.24 Hz, 1H) 6.94 (br. s., 1H) 7.08 (d, J=2.15 Hz, 1H) 7.35 (t, J=7.82 Hz, 1H) 7.59 (dd, J=8.12, 1.27 Hz, 1H) 7.91 (dd, J=7.53, 1.27 Hz, 1H) 12.07 (br. s., 1H). MS (ESI, pos. ion) m/z: 378.2 (M+1). Chiral purification [SFC: Chiralpak OH-J (30×150 mm), A: liquid CO2, B: 20 mM NH3 in MeOH/EtOH/isopropanol (1:1:1), isocratic: 70:30 (A:B), 70 mL/min] separately afforded 2-(2-methyl-3-((tetrahydro-2H-pyran-3-yl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (first eluting enantiomer, 208) and 2-(2-methyl-3-((tetrahydro-2H-pyran-3-yl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (second eluting enantiomer, 209).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)=[C:9]([CH:11]([OH:14])[CH2:12][CH3:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O>CS(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)=[C:9]([C:11](=[O:14])[CH2:12][CH3:13])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(O)c1cc(C(C)(C)C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Solvent: O
Solvent: CS(C)=O
Product: CCC(=O)c1cc(C(C)(C)C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
1-{5-(Tert-butyl)-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-propanol was dissolved in anhydrous dimethylsulfoxide (1 ml) to prepare a solution. A sulfur trioxide trimethylamine complex (70 mg) was added to the solution at 0° C., and the mixture was stirred at room temperature for 18 hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (37 mg, yield 19%).
Reaction SMILES: [C:1](Cl)(=O)C.[NH2:5][C@H:6]([C:10]([OH:12])=[O:11])[CH2:7][CH2:8][CH3:9]>CO>[CH3:1][O:11][C:10](=[O:12])[C@H:6]([CH2:7][CH2:8][CH3:9])[NH2:5]
Reactant: CC(=O)Cl
Reactant: CCC[C@H](N)C(=O)O
Solvent: CO
Product: CCC[C@H](N)C(=O)OC

Procedure:
To 20 mL of methanol was slowly added 2.6 mL acetyl chloride. Then 2.0 g (17.1 mmole) of L-norvaline was added. The solution was heated to reflux and monitored by thin-layer chromatography (TLC) until complete. The methanol was stripped off by rotary evaporation and the resulting oil was pumped under high vacuum overnight to give the title compound. NMR(300 MHZ, CD3OD): δ 4.03 (t, Nva-α, 1H), 3.81 (s, COOCH3, 3H), 1.87 (m, CH2CH2CH3, 2H), 1.44 (m, CH2CH2CH3, 2H), 0.98 (t, CH2CH2CH3, 3H).