Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[C:20]([Cl:30])(=[O:29])[C:21]1[C:22]([O:27][CH3:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>C1(C)C=CC=CC=1.[OH-].[Na+]>[ClH:30].[CH3:17][O:16][C:14]1[C:13]([O:18][CH3:19])=[CH:12][C:9]2[CH:10]3[N:5]([CH2:6][CH2:7][C:8]=2[CH:15]=1)[CH2:4][CH2:3][CH:2]([NH:1][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28])[CH2:11]3
Reactant: COc1ccccc1C(=O)Cl
Reactant: COc1cc2c(cc1OC)C1CC(N)CCN1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C1CC(NC(=O)c3ccccc3OC)CCN1CC2
Product: Cl
Yield: 26.7 %

Procedure:
To a cold mixture of 2-amino-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2H-benzo[a]quinolizine, (7 g, 0.026 mole) in 200 ml of toluene and 75 ml of 20% NaOH, was added dropwise 4.8 g of 2-anisoyl chloride in toluene. The mixture was stirred in the cold for 1 hour after which the toluene layer was collected, dried over MgSO4 and concentrated in vacuo. The concentrate was chromatographed over silica gel using ethyl acetate-methanol (4:1) as eluant. The major fraction (6.5 g) was converted to the HCl salt with hydrogen chloride in 2-propanol and the mixture concentrated by removal of the solvent in vacuo. The salt was crystallized from acetone and twice recrystallized from methanol-ethyl acetate to yield 3.0 g of the desired product, m.p. (decomposed at 243°-4°). This compound conforms to Formula II where R1 and R2 are --OCH3, R3 is H and R4 is ##STR27##
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[CH3:3].CCN(C(C)C)C(C)C.[F:31][C:32]1[N:40]=[C:39]2[C:35]([N:36]=[C:37]([NH:47][CH:48]([C:50]3[N:51]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)[C:52](=[O:61])[C:53]4[C:58]([CH:59]=3)=[CH:57][CH:56]=[CH:55][C:54]=4[CH3:60])[CH3:49])[N:38]2[CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)=[CH:34][N:33]=1>CCCCO>[F:31][C:32]1[N:40]=[C:39]2[C:35]([N:36]=[CH:37][NH:38]2)=[C:34]([NH:1][C@H:2]([C:4]2[N:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6](=[O:15])[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:14])[CH3:3])[N:33]=1.[F:31][C:32]1[N:40]=[C:39]2[C:35]([N:36]=[C:37]([NH:47][CH:48]([C:50]3[N:51]([C:62]4[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=4)[C:52](=[O:61])[C:53]4[C:58]([CH:59]=3)=[CH:57][CH:56]=[CH:55][C:54]=4[CH3:60])[CH3:49])[N:38]2[CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)=[CH:34][N:33]=1
Reactant: Cc1cccc2cc(C(C)N)n(-c3ccccc3)c(=O)c12
Agent: Cc1cccc2cc(C(C)Nc3nc4cnc(F)nc4n3C3CCCCO3)n(-c3ccccc3)c(=O)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cccc2cc([C@H](C)Nc3nc(F)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 120 °C
Reaction time: 16 h

Procedure:
3-(1-Aminoethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (200 mg, 0.72 mol) 6-chloro-2fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (compound 5202) (369 mg, 1.44 mmol) and DIPEA (279 mg, 2.16 mmol) were dissolved in n-BuOH (20 mL) in a sealed tube, and the resulting mixture was stirred at 120° C. for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (eluting with 30% to 50% Hex/EA) to afford the desired product, 3-(1-(2-fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 5203) (167 mg, 47% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5](O)=[O:6].C1[CH2:16][N:15]([P+](Br)(N2CCCC2)N2CCCC2)[CH2:14]C1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.CNC>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([N:15]([CH3:16])[CH3:14])=[O:6]
Reactant: O=C(O)c1cc(O)cc(Br)c1
Reactant: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(O)cc(Br)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.4 %

Procedure:
To a solution of 3-bromo-5-hydroxy-benzoic acid (2.0 g, 9.25 mmol), PyBroP (7.7 g, 18.5 mmol) and diisopropylethylamine (6.4 mL, 37 mmol) in DMF (50 mL) was added dimethylamine hydrochloride (1.51 g, 18.5 mmol). The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (Isco™ 120 g) using ethyl acetate as eluting solvent to give the title compound (1.5 g, 67%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3=[CH:19][CH:20]=[CH:21][C:22]([C:23](OC)=[O:24])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.O.[NH2:28][NH2:29]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3=[CH:19][CH:20]=[CH:21][C:22]([C:23]([NH:28][NH2:29])=[O:24])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1nc(Nc1cccc(Cl)c1)c1ccncc12
Reactant: NN
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: NNC(=O)c1cccc2c1nc(Nc1cccc(Cl)c1)c1ccncc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Methyl 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-7-carboxylate (47 mg) was mixed with Methanol (1 ml) and Hydrazine hydrate (1 ml). 2-3 drops of DMF were added and the mixture was stirred at 60° C. for 2 hours. The volatiles were removed and another amount of reagent Methanol (1 ml) and Hydrazine (1 ml) were added, and the mixture was stirred at 60° C. for an extra 2 hours. The volatiles were removed in vacuo and the material was crashed out using AcOEt/hexanes. Filtration and drying afforded 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-7-carbohydrazide as a solid (29 mg, 62% yield). LCMS (ES): >85% pure, m/z 364 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:33])[CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([O:31][CH3:32])=[C:24]([O:29][CH3:30])[CH:25]=3)[CH2:20]2)=[O:13])=[C:5]([N+:34]([O-])=O)[CH:4]=1>CO.[Pd]>[NH2:34][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][C:6]=1[CH2:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:33])[CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][C:23]([O:31][CH3:32])=[C:24]([O:29][CH3:30])[CH:25]=2)[CH2:20]1)=[O:13]
Reactant: COc1cc2c(cc1OC)CC(N(C)CCCNC(=O)Cc1cc(OC)c(OC)cc1[N+](=O)[O-])CC2
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)c(CC(=O)NCCCN(C)C2CCc3cc(OC)c(OC)cc3C2)cc1OC

Procedure:
Here, 1-[2-(4,5-dimethoxy-2-nitro-phenyl)-1-oxo-ethylamino]-3-[N-methyl-N-(6,7-dimethoxy-1,2,3,4-tetrahydronaphth-2 yl)-amino]-propane (8.5 g, 0.017 mol) is dissolved in methanol (100 ml), mixed with 10% palladium on charcoal (9.8 g) and hydrogenated for one hour at 20° C. under hydrogen pressure (5 bar). The catalyst is filtered off and the filtrate is concentrated by rotary evaporation. Yield: 7.8 g. Rf value: 0.2 (alumina, eluant: 98 parts by volume of methylene chloride+2 parts by volume of ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:32])[C:9]=1[C:10]#[C:11][CH2:12][C:13]([CH2:19][C:20]1([CH3:31])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=2)[O:23][CH2:22][CH2:21]1)([OH:18])[C:14]([F:17])([F:16])[F:15])[C:5]#[N:6].FC(F)(F)C(OC(=O)C(F)(F)F)=O.CN(C)C(=N)N(C)C>ClCCl>[CH3:32][C:8]1[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]2[C:9]=1[CH:10]=[C:11]([CH2:12][C:13]([CH2:19][C:20]1([CH3:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[O:23][CH2:22][CH2:21]1)([OH:18])[C:14]([F:15])([F:16])[F:17])[NH:1]2
Reactant: Cc1cc(C#N)cc(N)c1C#CCC(O)(CC1(C)CCOc2ccc(F)cc21)C(F)(F)F
Agent: CN(C)C(=N)N(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C#N)cc2[nH]c(CC(O)(CC3(C)CCOc4ccc(F)cc43)C(F)(F)F)cc12
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 16.3 %

Procedure:
To a chilled (0° C.) solution of 500 mg (1.1 mmol) of 3-amino-5-methyl-4-[5,5,5-trifluoro-4-(6-fluoro-4-methylchroman-4-ylmethyl)-4-hydroxypent-1-ynyl]benzonitrile in 20 mL of dichloromethane was added 460 μL (3.3 mmol) of trifluoroacetic anhydride. After 15 minutes, the reaction was concentrated in vacuo and the residue three times diluted with ether and concentrated. The resulting oil was dissolved in 1.5 mL of DMSO, and then 0.4 mL (3.2 mmol) of tetramethylguanidine was added and the mixture was warmed at 140° C. in a microwave oven. After 10 minutes, the mixture was cooled and poured onto crushed ice. The resulting solid was collected by filtration, air dried, and chromatographed on silica gel eluting with ethyl acetate-hexanes (gradient: 0-30% EtOAc) to afford two diastereomers. Further purification of the separated diastereomers by preparatory TLC (silica gel, ethyl acetate-hexanes (7:3)) gave first 82 mg (17%) of the title compound as a single diastereomer (M−1=445) and second 80 mg (17%) of the title compound as the opposite diastereomer (M−1=445).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:8][N:7]=1.[Sn](Cl)(Cl)(Cl)Cl.O>Cl>[F:16][C:15]([F:18])([F:17])[C:9]1[CH:8]=[N:7][C:6]2[O:5][CH2:4][C:3](=[O:2])[NH:12][C:11]=2[CH:10]=1
Reactant: COC(=O)COc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: O=C1COc2ncc(C(F)(F)F)cc2N1
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
In a 10 ml flask, (3-nitro-5-trifluoromethyl-pyridin-2-yloxy)-acetic acid methyl ester (84 mg, 0.30 mmol) was dissolved in concentrated hydrochloric acid (1.5 ml) and then tin tetrachloride (227 mg, 1.2 mmol) was added thereto. The mixture was stirred for 30 minutes at 80□. After completion of the reaction, water was added thereto at room temperature and the mixture was extracted with a solvent of methanol: dichloromethane=1:9. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of methanol:dichloromethane=1:50. The fractions containing the product were collected and evaporated to obtain white solid (40 mg, 62%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22]C)=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([N:11]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[N:13]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CN(c2nc3cc(OC)ccc3n2C)C2CCC(C(C)(C)C)CC2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(CN(c2nc3cc(O)ccc3n2C)C2CCC(C(C)(C)C)CC2)cc1
Temperature: 25 °C

Procedure:
To a stirring solution of the title compound of Example 14 Step C (1 mmol, 464 mg) in 5 mL of DCM at −78° C. under N2 was added dropwise BBr3 (5 mmol, 5 mL of a 1M solution in DCM). The reaction was allowed to warm to ambient temperature. After 15 min the reaction was poured into stirring NaHCO3 (gas evolution), and the product was extracted with DCM. The organic layer was dried with Na2SO4 and concentrated under reduced pressure, affording the product as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.90 (d, 2H), 7.44 (d, 2H), 7.28 (unres. m, 1H), 7.01 (d, 1H), 6.83 (dd, 1H), 4.64 (s, 2H), 3.89 (s, 3H), 3.58 (s, 3H), 3.20 (m, 1H), 2.10 (m, 2H), 1.89 (m, 2H), 1.59 (m, 2H), 0.98-1.14 (overlapping m, 3H), 0.86 (s, 9H). MS (ESI): m/z 450 (M+H). HPLC A: 2.30 min.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]([NH:8][C:9]1([C:12](=[O:34])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[C:30]([F:33])([F:32])[F:31])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:7].[OH-].[Na+].Cl>C1COCC1>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:12]([C:9]3([NH:8][C:6](=[O:7])[CH2:5][CH2:4][C:3]([OH:35])=[O:2])[CH2:11][CH2:10]3)=[O:34])=[CH:20][CH:19]=2)=[C:23]([C:30]([F:31])([F:33])[F:32])[CH:24]=1
Reactant: COC(=O)CCC(=O)NC1(C(=O)NCc2ccc(Oc3ccc(OC)cc3C(F)(F)F)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)CCC(=O)O)CC3)cc2)c(C(F)(F)F)c1

Procedure:
A solution of 82 mg (0.166 mmol) of N-{1-[4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylcarbamoyl]-cyclopropyl}-succinic acid-monoamide-methylester (product from Example 132) and 2 mL sodium hydroxide solution (1 N) in 10 mL THF was stirred for two hours at ambient temperature, then neutralised with 0.1 N hydrochloric acid and evaporated down. The solid residue was stirred in approx. 3 mL dichloromethane, filtered off and evaporated down again.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]([OH:17])([CH3:16])[P:8]([O:13][CH2:14][CH3:15])(=[O:12])[O:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.ClCCl.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([O:17][C:7]([CH3:16])([P:8]([O:9][CH2:10][CH3:11])(=[O:12])[O:13][CH2:14][CH3:15])[CH2:6][S:5][C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:28])[CH3:27]
Reactant: CCOP(=O)(OCC)C(C)(O)CSC(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(C)(CSC(C)(C)C)OC(C)=O
Temperature: 20 °C
Reaction time: 8 h

Procedure:
25.2 g (88.6 mmol) of diethyl 2-t-butylthio-1-hydroxy-1-methylethanephosphonate in 130 ml of acetic anhydride are treated with 1 ml of concentrated sulfuric acid, during which process the temperature of the solution rises from 20 to about 30° C. The mixture is subsequently stirred for 8 hours at 20° C., treated with 100 ml of dichloromethane and poured onto 300 ml of ice/water. The organic phase which is separated off is washed in succession with dilute hydrochloric acid, sodium hydrogen carbonate solution and water and dried over sodium sulfate, and the solvent is distilled off in vacuo.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:20])[C@@H:10]([OH:19])[C:11]([F:18])([F:17])[C:12](OCC)=[O:13])=O)(C)(C)C>Cl.C(OCC)(=O)C>[F:17][C:11]1([F:18])[C@H:10]([OH:19])[C@H:9]([CH3:20])[NH:8][C:12]1=[O:13]
Reactant: CCOC(=O)C(F)(F)[C@H](O)[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H]1NC(=O)C(F)(F)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
Ethyl 4-[(tert-butoxycarbonyl)amino]-2,4,5-trideoxy-2,2-difluoro-L-threo-pentonate (5.45 g) was dissolved in a 4 mol/L solution (100 mL) of hydrogen chloride/ethyl acetate, and the mixture was stirred at room temperature for 1.5 hr. The reaction solution was concentrated under reduced pressure, THF (.200 mL) and diisopropylethylamine (9.9 mL) were added thereto, and the mixture was heated under reflux for 3 hr. The reaction solution was concentrated under reduced pressure and water (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (100 mL×5) and ethyl acetate/THF=2/1 (100 mL×3). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound as a white powder (yield: 1.55 g, 46%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:38]1[CH:42]=[C:41]([CH2:43]O)[CH:40]=[N:39]1)=O)(C)(C)C>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[C:18]([N:20]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:43][C:41]1[CH:42]=[N:38][NH:39][CH:40]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)n1cc(CO)cn1
Reactant: COc1ccc(NC(=O)C2CCc3c(OCc4ccccc4)cccc32)c(OC)c1
Product: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCc3c(OCc4ccccc4)cccc32)c(OC)c1
Yield: 37.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 82 using 4-benzyloxy-N-(2,4-dimethoxyphenyl)indan-1-carboxamide (0.96 g) and 1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)pyrazole (0.47 g) as starting materials, 4-benzyloxy-N-(2,4-dimethoxyphenyl)-N-[(pyrazol-4-yl)methyl]indan-1-carboxamide (0.43 g) was obtained. By the reaction and treatment in the same manner as in Example 271 using this compound (0.43 g) and ethyl iodide (0.28 mL), 4-benzyloxy-N-(2,4-dimethoxyphenyl)-N-[(1-ethylpyrazol-4-yl)methyl]indan-1-carboxamide (0.36 g) was obtained. By the reaction and treatment in the same manner as in Example 17 using this compound (0.36 g), N-(2,4-dimethoxyphenyl)-N-[(1-ethylpyrazol-4-yl)methyl]-4-hydroxyindan-1-carboxamide (0.21 g) was obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:13]=[CH:12][C:11]3[C:10](=O)[NH:9][CH:8]=[N:7][C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.C([N:18](CC)C(C)C)(C)C.O(Cl)Cl.[P+5]>>[CH:1]1([C:4]2[N:13]=[CH:12][C:11]3[C:10]([NH2:18])=[N:9][CH:8]=[N:7][C:6]=3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=c1[nH]cnc2cc(C3CC3)ncc12
Reactant: CCN(C(C)C)C(C)C
Agent: ClOCl
Agent: [P+5]
Product: Nc1ncnc2cc(C3CC3)ncc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 7-cyclopropyl-3H-pyrido[4,3-d]pyrimidin-4-one (7, 1.0 g, 5.34 mmol) in a round bottom flask under a nitrogen atmosphere was added N,N-diisopropylethylamine (9.45 mL, 53.42 mmol) at 0° C. To this stirred mixture was slowly added phosphorus(V) oxychloride (7.48 mL, 80.13 mmol). The reaction mixture was stirred at room temperature for 2-3 h until a clear solution was obtained. The solution was concentrated under reduced pressure under inert conditions, taken up in excess toluene and reconcentrated. This process was repeated sev N,N-diisopropylethylamine eral times. The residue was dissolved in acetonitrile to it was added 30% aqueous ammonia (30 mL). The mixture was heated to 120° C. for 16 h in sealed tube. The reaction mixture was diluted with 10% methanol in dichloromethane and extracted from the aqueous ammonia. The organic layers were separated, dried over Sodium sulfate, filtered and concentrated to dryness. The crude residue was given Methanol washing. The solid obtained was dried to afford 7-cyclopropylpyrido[4,3-d]pyrimidin-4-amine (8) as a brown solid. Yield: 0.60 g, 60%; MS (ESI) m/z 375.8 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.43 (s, 1H), 8.26-7.99 (m, 2H), 7.39 (s, 1H), 1.75 (s, 1H), 1.01-0.84 (s, 4H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[OH:11][C:12]1[CH:16]=[C:15]([N:17]2[C:21]3[CH:22]=NC=[CH:25][C:20]=3[N:19]=[CH:18]2)[S:14][C:13]=1[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+].[CH3:36][N:37](C=O)C>>[C:5]([C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[CH2:2][O:11][C:12]1[CH:16]=[C:15]([N:17]2[C:21]3[CH:22]=[CH:36][N:37]=[CH:25][C:20]=3[N:19]=[CH:18]2)[S:14][C:13]=1[C:26]([O:28][CH3:29])=[O:27])#[N:6]
Reactant: CN(C)C=O
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1C#N

Procedure:
In a similar manner as described for example B18, 171.7 mg of 2-(bromomethyl)benzonitrile, 200 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate, 110.9 mg of potassium carbonate in 6 ml anhydrous DMF yield the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][NH2:7])=[O:5])#[N:2].[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([N:6]([C:4](=[O:5])[CH2:3][C:1]#[N:2])[NH2:7])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CCC(=O)NN
Reactant: O=C(Cl)c1ccccc1
Product: N#CCC(=O)N(N)C(=O)c1ccccc1

Procedure:
treating said cyanoacetic hydrazide of step (a) with benzoyl chloride in the presence of a buffer system to form an N-benzoylcyanoacetic hydrazide, and thereafter;
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12][NH:11]1)([O-])=O.[CH3:23][O:24]CCOC>[Pd]>[C:17]1([N:14]2[CH2:15][CH2:16][N:10]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[NH:1][C:23](=[O:24])[N:11]3[CH2:12][CH2:13]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1ccccc1N1CCN(c2ccccc2)CCN1
Reactant: COCCOC
Agent: [Pd]
Product: O=C1Nc2ccccc2N2CCN(c3ccccc3)CCN12

Procedure:
Hexahydro-1-(2-nitrophenyl)-5-phenyl-1H-1,2,5-triazepine (10.0 g) in 1,2-dimethoxyethane (500 ml) was hydrogenated over 10% palladium on carbon (2 g) at atmospheric pressure and room temperature until theoretical uptake was achieved. The mixture was filtered through Celite and the filter pad was washed with 1,2-dimethoxyethane. The filtrate was evaporated to approximately 100 ml and 1,1'-carbonyl-dimidazole (11 g) was added. The mixture, protected from moisture, was swirled and heated under reflux on a steam bath for 4 hours. The solution was evaporated to dryness. The residue in chloroform was applied to a column (75×5.4 cm) of dry column grade neutral alumina prepacked in chloroform. Elution was with chloroform and monitoring of fractions was by t.l.c. on Alox-25 uv254 plates (Brinkmann) with chloroform-methanol (9:1) as developer. The fractions containing the major component were evaporated to dryness and the residue was crystallized from chloroform-ether; wt. 7.45 g (75%), mp=196°-198°. Three crystallizations from the same solvent system gave titled product, mp=198°-199°.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:11][C:12]([F:18])([F:17])[C:13]#[C:14][CH2:15][OH:16].C(N(CC)CC)C>ClC(Cl)C.ClCCl>[C:4]1([C:3]2[C:13]([C:12]([F:18])([F:17])[F:11])=[C:14]([CH2:15][OH:16])[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCC#CC(F)(F)F
Reactant: O/N=C(\Cl)c1ccccc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCc1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a pale yellow, homogeneous mixture of (Z)—N-hydroxybenzimidoyl chloride (Intermediate I-3B, 5.50 g, 35.4 mmol) and 4,4,4-trifluorobut-2-yn-1-ol (Intermediate I-3A, 5.46 g, 39.6 mmol) in dichloroethane (85 mL) in a 250 mL round bottom flask at 70° C. was added triethylamine (9.85 mL, 70.7 mmol) in 22 mL of dichloroethane over 2.5 h via an addition funnel (the first ˜50% over 2 h and the remaining 50% over 0.5 h). The reaction mixture was stirred at room temperature overnight, diluted with dichloromethane (100 mL), washed with water (100 mL), and the organic layer was collected. The aqueous layer was extracted with dichloromethane (2×50 mL), and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. Analysis indicated that the product mixture was composed of a 86:14 mixture of the desired regioisomer, (3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)methanol, and the undesired regioisomer, (3-phenyl-5-(trifluoromethyl)isoxazol-4-yl)methanol. The mixture was purified by silica gel chromatography using a mixture of ethyl acetate and hexane to afford (3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)methanol (5.34 g, 21.96 mmol, 62.1% yield) as a pale yellow oil. The compound had an HPLC ret. time=1.91 min. (condition A); LC/MS M+1=244.2; 1H NMR (500 MHz, CDCl3) δ ppm 2.21 (br. s., 1H), 4.97 (s, 2H), 7.47-7.56 (m, 3H), and 7.65 (d, J=6.60 Hz, 2H).