Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:23])[CH:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][N:12](C(=O)C(F)(F)F)[CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH2:1]([N:8]([CH3:23])[CH:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][NH:12][CH2:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C1C2CCC1CN(C(=O)C(F)(F)F)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(Cc1ccccc1)C1C2CCC1CNC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A mixture of 1-{8-[benzyl(methyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}-2,2,2-trifluoro-1-ethanone (see step (vi) above; 2.1 g, 6.4 mmol) and K2CO3 (3 g, 21.7 mmol) in MeOH/water (110 mL of 10:1) was stirred at rt overnight and then evaporated. DCM and water were added and the layers separated. The water layer was extracted with DCM (3×). The combined organic layers were dried and evaporated to give 1.2 g (81%) of the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13].[NH2:18][C:19]1[N:20]=[CH:21][NH:22][C:23]=1[C:24]#[N:25]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]2[CH:21]=[N:22][C:23]([C:24]#[N:25])=[C:19]2[N:18]=1
Reactant: N#Cc1[nH]cnc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1Cl
Product: N#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3Cl)nc12
Yield: 12 %

Procedure:
Reaction of 1-(2,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (285 mg, 1.0 mmol), prepared from commercially available 2,4-dichloro-acetophenone according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (43 mg, 12%). MS (ISP) 357.0 [(M+H)+]; mp 139° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:23][C:10]2[CH:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:9]=2[CH:8]=1.[CH3:24][S:25]SC>CCCCCC.O1CCCC1>[CH3:16][N:13]1[CH2:14][CH2:15][C:9]2[CH:8]=[C:7]([S:25][CH3:24])[S:23][C:10]=2[CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1
Reactant: CN1CCc2cc(Br)sc2C(c2ccccc2)C1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1cc2c(s1)C(c1ccccc1)CN(C)CC2
Temperature: 25 °C

Procedure:
A solution of n-butyl lithium in n-hexane (1.6M, 0.75 ml) was added dropwise to a stirred solution of 2-bromo-6-methyl-8-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (0.40 g hydrobromide salt converted to free base by aqueous ammonia/dichloromethane extraction) in dry tetrahydrofuran (10 ml) cooled to -70° under nitrogen. After 10 minutes at -70° dimethyl disulphide (0.11 ml) was added dropwise and the mixture allowed to warm to room temperature. After 30 minutes the solution was evaporated, water (10 ml) added to the residue and extracted with dichloromethane (2×5 ml). The extracts were dried, filtered and evaporated to a pale yellow solid. Recrystallisation twice from n-hexane (4 ml) gave white needles (m.p. 90°) of the title product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:17][C:16](=[O:18])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[CH:15]=[C:7]3[C:6]=2[CH:19]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:42])=[O:43])[C:37]([C:2]4[CH:3]=[CH:4][C:5]5[O:17][C:16](=[O:18])[N:8]6[C:9]7[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=7[CH:15]=[C:7]6[C:6]=5[CH:19]=4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1
Reactant: O=c1oc2ccc(Br)cc2c2cc3ccccc3n12
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4oc(=O)n5c6ccccc6cc5c4c3)cc12
Temperature: 100 °C
Yield: 4.4 %

Procedure:
A mixture of 2-bromo-6H-benzo[5,6][1,3]oxazino[3,4-a]indol-6-one (47 mg, 0.15 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (51 mg, 0.1 mmol), K3PO43H2O (80 mg, 0.3 mmol) and Pd(dppf)Cl2 (7 mg, 0.01 mmol) in 2 mL of DMF was heated in a microwave reactor at 100° C. for 20 minutes, and then the mixture was purified using prep-HPLC to provide Compound 53 (2.7 mg, yield: 4.4%). 1H-NMR (CDCl3, 400 MHz) δ 8.52 (d, J=7.6 Hz, 1H), 8.07 (s, 1H), 7.92˜7.96 (m, 3H), 7.70 (d, J=7.6 Hz, 1H), 7.62 (s, 1H), 7.41˜7.54 (m, 4H), 7.21˜7.23 (m, 2H), 7.12 (s, 1H), 5.89 (s, 1H), 3.11 (s, 3H), 3.00 (d, J=4.8 Hz, 3H), 2.88 (s, 3H). MS (M+H)+: 610.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@H:6]([CH:25]([CH3:27])[CH3:26])[C:7]([N:9]1[CH2:14][CH2:13][C@@:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([OH:15])[C:11]([CH3:24])([CH3:23])[CH2:10]1)=[O:8])=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:34][C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38].CS(C)=O>CCOC(C)=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C@@:12]2([OH:15])[CH2:13][CH2:14][N:9]([C:7](=[O:8])[C@H:6]([NH:5][C:3](=[O:4])[CH2:2][O:34][C:35]3[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=3[C:37]([O:39][CH3:40])=[O:38])[CH:25]([CH3:27])[CH3:26])[CH2:10][C:11]2([CH3:23])[CH3:24])=[CH:17][CH:18]=1
Reactant: CC(C)[C@@H](NC(=O)CCl)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1OCC(=O)N[C@@H](C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)C(C)C
Temperature: 25 °C
Yield: 40.5 %

Procedure:
2-Chloro-N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)acetamide (35 mg, 0.084 mmol), potassium carbonate (35 mg, 0.253 mmol), methyl 2-hydroxybenzoate (13 mg, 0.084 mmol) and DMSO (3 mL) were mixed with stirring at 25° C. The reaction was stirred for 20 hours, diluted with EtOAc, and then rinsed 4 times with water. The organic layer was dried over sodium sulfate and concentrated in vacuo to give an amber oil which was purified over silica gel in (3:1 to 1:1 hexanes/EtOAc to 100% EtOAc) to obtain methyl 2-(2-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-2-oxoethoxy)benzoate (18 mg, 0.034 mmol, 40% yield) as a white glass. MS found: (M+H)+=531.21.
Reaction SMILES: C([N:8]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](=[O:60])[N:41]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:34])[N:15]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])(OC(C)(C)C)=O.[F:61][C:62]([F:67])([F:66])[C:63]([OH:65])=[O:64]>C(Cl)Cl>[OH:65][C:63]([C:62]([F:67])([F:66])[F:61])=[O:64].[CH3:50][O:49][C:47]([CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][N:41]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])[C:40]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:34])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[O:60])=[O:48]
Reactant: COC(=O)CCCCCN(CCCCCC(=O)OC)C(=O)CCCCCN(CCCCCC(=O)N(CCCCCC(=O)OC)CCCCCC(=O)OC)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCCCCN(CCCCCC(=O)OC)C(=O)CCCCCNCCCCCC(=O)N(CCCCCC(=O)OC)CCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 250 mL round bottom flask, charged with 1.50 g (1.75 mmol) of N-BOC-N,N-bis-(N′,N′-bis(5-methoxycarbonylpentyl)-5-carbamyl pentyl)-amine (17) in 15 mL of methylene chloride, was added 15 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 15 minutes and then concentrated. The residue was diluted with 50 mL of methylene chloride and then concentrated via rotary evaporation. The residue was then diluted with 50 mL of methanol and re-concentrated via rotary evaporation. The residue was again re-diluted with 50 mL of methylene chloride and re-concentrated, first via rotary evaporation and then under full vacuum pump pressure (<0.5 mm Hg).
Reaction SMILES: [N:1]1([CH2:7][CH:8]([C:19]2([OH:23])[CH2:22][CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:24]=O.O.[OH-].[Na+]>C(O)=O>[CH3:24][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH:8]([C:19]2([OH:23])[CH2:22][CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[CH2:2][CH2:3]1
Reactant: OC1(C(CN2CCNCC2)c2cccc(C(F)(F)F)c2)CCC1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: CN1CCN(CC(c2cccc(C(F)(F)F)c2)C2(O)CCC2)CC1
Temperature: 70 °C

Procedure:
A solution of 1-{2-piperazin-1-yl-1-[3-(trifluoromethyl)phenyl]ethyl}cyclobutanol (60 mg, 0.17 mmol), see Example 14, in formic acid (0.33 mL) at 50° C, was treated with an aqueous solution of formaldehyde (37% in water, 0.14 mL, 0.21 mmol). The reaction was heated at 70° C. for 1.5 h, after which time the reaction was poured into water (5 mL) and basified to pH=10 with the addition of a 2 N aqueous solution of sodium hydroxide. The product was then extracted with ethyl acetate (3×4 mL), and the combined organic extracts were dried over magnesium sulfate and concentrated to yield 1-{2-(4-methylpiperazin-1-yl)-1-[3-(trifluoromethyl)phenyl]ethyl}cyclobutanol as a colorless oil. The product was dissolved in methanol (0.5 mL) and the resulting solution was treated with a saturated methanolic solution of hydrochloric acid (0.5 mL) followed by diethyl ether (2 mL). The solution was stored in the refrigerator for 16 h. The resulting precipitate was filtered and washed with diethyl ether to yield 52 mg (69%) 1-{2-(4-methylpiperazin-1-yl)-1-[3-(trifluoromethyl)phenyl]ethyl}cyclobutanol dihydrochloride as a white solid. MS (ESI) m/z 343 ([M+H]+); HRMS: calcd for C18H25F3N2O.2.00 HCl, 414.1453; found (ESI), 343.2007.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=3[N:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.O1CCCCC1[O:30][N:31]1[C:35](=[O:36])[CH2:34][S:33][C:32]1=[O:37]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14](/[CH:16]=[C:34]4/[C:35](=[O:36])[N:31]([OH:30])[C:32](=[O:37])[S:33]/4)=[CH:15][C:10]=3[N:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:21])[F:22])[CH:3]=1
Reactant: O=C1CSC(=O)N1OC1CCCCO1
Reactant: O=Cc1ccc2c(c1)nnn2Cc1ccc(Cl)cc1C(F)(F)F
Product: O=C1S/C(=C\c2ccc3c(c2)nnn3Cc2ccc(Cl)cc2C(F)(F)F)C(=O)N1O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-benzotriazol-5-yl}methylidene)-3-hydroxy-1,3-thiazolidine-2,4-dione was prepared from 1-(4-chloro-2-trifluoromethylbenzyl)-1H-benzotriazole-5-carbaldehyde (from Example 258) and 3-(tetrahydropyran-2-yl)oxy-1,3-thiazolidine-2,4-dione (from Example 288) following General Procedure F.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([N:17]2C(=O)C3C(=CC=CC=3)[C:18]2=[O:27])[C:13](=[O:28])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.[C:31]1([C:37]2[N:42]=[CH:41][C:40](C(Cl)=O)=[CH:39][N:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CO.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([NH:17][C:18]([C:40]2[CH:41]=[N:42][C:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[N:38][CH:39]=2)=[O:27])[C:13](=[O:28])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cnc(-c2ccccc2)nc1
Reactant: O=C(OCc1ccccc1)N1CCN(N2C(=O)c3ccccc3C2=O)C(=O)C1
Agent: NN
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(NN1CCN(C(=O)OCc2ccccc2)CC1=O)c1cnc(-c2ccccc2)nc1
Yield: 183.8 %

Procedure:
A solution of 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-oxo-piperazine-1-carboxylic acid benzyl ester (53 mg, 0.14 mmol) in MeOH (10 mL) is treated with anhydrous hydrazine (0.3 mL, 9.56 mmol). The reaction mixture is stirred at reflux under N2 for 3.5 h. The reaction mixture is concentrated. The residue is dissolved in a mixture of DMF (2 mL) and DCM (2 mL), and treated with 2-phenyl-pyrimidine-5-carbonyl chloride (32 mg, 0.15 mmol). The mixture is stirred under N2 for 16 h, and then diluted with EtOAc (35 mL). The mixture is washed successively with saturated aqueous KHCO3, (15 mL), water (2×15 mL), and saturated aqueous NaCl (15 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue is purified by flash silica gel chromatography (80:20 to 0:100 heptane:EtOAc gradient elution) to afford 3-oxo-4-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-piperazine-1-carboxylic acid benzyl ester as an oil (111 mg, 18%). MS: 432 (M+H); 1H NMR (300 MHz, CDCl3) δ 9.70-10.10 (br, 1H), 9.06 (s, 2H), 8.46 (dd, J=7.8, 1.7 Hz, 2H), 7.44-7.60 (m, 3H), 7.25-7.40 (m, 5H), 5.18 (s, 2H), 4.36 (s, 2H), 3.93 (t, J=5.1 Hz, 2H), 3.69-3.81 (br s, 2H). IC50=103.5 nM.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C@@H:12]([C:13]#[C:14][CH3:15])[CH2:11][CH2:10][C@H:6]1[C:7]([NH2:9])=O)=[O:4].N1C=CN=C1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:5]1[C@@H:12]([C:13]#[C:14][CH3:15])[CH2:11][CH2:10][C@H:6]1[C:7]#[N:9])=[O:4]
Reactant: CC#C[C@H]1CC[C@@H](C(N)=O)N1C(=O)CCl
Agent: c1c[nH]cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reaction time: 1 h

Procedure:
To a stirred solution of (5R)-1-(chloroacetyl)-5-propynyl-L-prolinamide (0.28 g, 1.23 mmol) and imidazole (0.084 g, 1.23 mmol) in dry pyridine (6 mL ) at −35° C. under nitrogen was added POCl3 (0.23 mL, 2.46 mmol) dropwise. The reaction mixture was stirred between −35° C. to −15° C. for 1 hour and evaporated. The residue was diluted with dichloromethane and washed with H2O (2×), dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash chromatography (10% ethyl acetate/hexane) provided the titled compound. MS (DCI) m/z 211 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].C([N-]C(C)C)(C)C.[Li+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([CH:3]([CH2:2][OH:1])[C:4]([O:6][CH3:7])=[O:5])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CCO
Reactant: BrCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COC(=O)C(CO)Cc1ccccc1

Procedure:
β-Propiolactone (A) is dissolved in methanol and treated with 1 equivalent of triethylamine to produce methyl 3-hydroxypropionate (B). Compound B is converted to the dianion with 2 equivalents of lithium diisopropylamide and alkylated with 1 equivalent of benzyl bromide to produce methyl 2-benzyl-3-hydroxypropionate (C). Compound C is protected as the t-butyldimethylsilyl ether (D). Compound D is then saponified with potassium hydroxide and carefully acidified to produce the acid (E). The acid (E) is then dissolved in tetrahydrofuran, treated with 1 equivalent of N-methylmorpholine and cooled to -20° C. One equivalent of isobutyl chloroformate is added, followed by 1 equivalent of 5,6-diamino-1,3-dipropyluracil in dimethyl-formamide to produce the amide. The amide is then treated with aqueous potassium hydroxide at 70° C. to produce the cyclized, deprotected 3,7-dihydro-8[(R)-1-methyl-2-phenyl-ethyl]1, 3-dipropyl-1H-purine-2,6-dione. ##STR8##
Reaction SMILES: [CH:1](OC)(OC)OC.[CH2:8]([O:15][C:16]1[CH:31]=[CH:30][C:29]([C:32]([NH:34][NH2:35])=[O:33])=[CH:28][C:17]=1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:15][C:16]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][CH:1]=[N:35][N:34]=2)=[CH:28][C:17]=1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(OC)OC
Reactant: NNC(=O)c1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Product: O=C(OCc1ccccc1)c1cc(-c2nnco2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A trimethyl orthoformate (2 mL) suspension of the obtained benzyl 2-(benzyloxy)-5-(hydrazinocarbonyl)benzoate (0.20 g) was heated to reflux for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue, and 0.16 g of the solid substance was collected by filtration. The obtained solid substance (0.11 g) was stirred at 200° C. for 15 minutes. The reaction mixture was cooled to room temperature and then purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-50% hexane/ethyl acetate] to obtain 0.079 g of benzyl 2-(benzyloxy)-5-(1,3,4-oxadiazol-2-yl)benzoate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:6]2[CH3:11].[C:17](O)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:6]2[CH3:11])(=[O:19])[CH3:18]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1cc2c(N)cccc2n1C
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2c(NC(C)=O)cccc2n1C
Temperature: 25 °C
Yield: 97.9 %

Procedure:
In 20 ml of pyridine was dissolved 1.2 g (5.52 mmol) of ethyl 4-amino-1-methyl-2-indolecarboxylate. While stirring at room temperature, 10 ml of anhydrous acetic acid was added to the solution. After stirring for 2 hours at room temperature, the reaction mixture was poured onto ice water. The mixture was extracted three times with ethyl acetate. The combined extracts were washed with 1N hydrochloric acid and then with saturated sodium hydrogencarbonate solution. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography to give 1.40 g (97.9%) of ethyl 4-acetamido-1-methyl-2-indolecarboxylate.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([OH:22])=[CH:16][C:15]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][C:24]=1[O:32][CH3:33])[CH:8]1[CH2:34][C:35]3[C:40]([CH:7]21)=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[NH:3])[NH2:2].[CH:41]1([NH2:44])[CH2:43][CH2:42]1>>[CH:41]1([NH:44][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:15]3[CH:16]=[C:17]([OH:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[CH:9]3[CH:8]4[CH2:34][C:35]5[C:40]([CH:7]4[C:6]4[C:11](=[CH:12][CH:13]=[C:4]([C:1](=[NH:2])[NH2:3])[CH:5]=4)[NH:10]3)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[C:24]([O:32][CH3:33])[CH:25]=2)=[O:30])[CH2:43][CH2:42]1
Reactant: NC1CC1
Reactant: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)O)cc2OC)cc1O
Product: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)NC3CC3)cc2OC)cc1O

Procedure:
Example 239 was prepared according to the protocol described for example 235 from 2′-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5′-hydroxy-2,4′-dimethoxy-biphenyl-4-carboxylic acid (example 235 step a) and cyclopropylamine. Mass Spectrum: 575 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>O1CCOCC1>[F:18][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)[CH:16]=[CH:15][C:14]=1[F:17]
Reactant: COC(=O)c1ccc(-c2ccc(F)c(F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccc(F)c(F)c2)cc1
Temperature: 60 °C
Yield: 12 %

Procedure:
Combine 3,4-difluorobenzeneboronic acid (1.0 g, 5.2 mmol), methyl-4-bromobenzoate (0.241 g, 1.73 mmol), Pd(OAc)2 (0.019 g, 0.086 mmol), tetrabutylammonium bromide (0.111 g, 0.345 mmol), and potassium phosphate (0.733 g, 3.454 mmol). Purge the reaction vessel with argon and add anhydrous DMF (20 ml) to the reaction mixture. Heat the sealed reaction vessel to 120° C. with stirring until completion. Cool the reaction to room temperature, dilute with ethyl acetate, and filter through a short plug of celite with additional ethyl acetate. Wash organics with water, dry over MgSO4, filter, and evaporate. Purification by flash column chromatography yields 3′,4′-difluorobiphenyl-4-carboxylic acid methyl ester as a yellow solid. Dissolve the purified ester in dioxane (45 ml) and add an equal volume of 1 M aqueous NaOH. Heat the reaction vessel to 60° C. with stirring until completion. Remove the solvent by evaporation. Dissolve the residue in dichloromethane and wash with 1N aqueous hydrochloric acid. Dry the organics over MgSO4, filter and evaporate to yield 0.048 g (12%) of the title compound. MS (m/e): 235 (M+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[NH:13][NH:12][C:11]2=[O:16])=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[CH2:18]([O:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.O1CCOCC1>C(O)C>[CH2:18]([O:25]/[N:26]=[C:1](/[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[NH:13][NH:12][C:11]2=[O:16])=[CH:6][CH:5]=1)\[CH3:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc(-n2c(=O)[nH][nH]c2=O)cc1
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: C/C(=N\OCc1ccccc1)c1ccc(-n2c(=O)[nH][nH]c2=O)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
To 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione (500 mg, 2.281 mmol) in ethanol (6.91 mL) was added O-benzylhydroxylamine hydrochloride (728 mg, 4.56 mmol) and HCl 4N in dioxane (0.277 mL, 9.12 mmol). The mixture was stirred at 65° C. for 1 hour, filtered, and then concentrated in vacuo. Saturated sodium bicarbonate added to the residue, extracted with ethyl acetate twice, dried over MgSO4, filtered, and concentrated in vacuo. Methanol/CH2Cl2 (50/50) was added, then the precipitate was filtered and dried, giving (E)-4-(4-(1-(benzyloxyimino)ethyl)-phenyl)-1,2,4-triazolidine-3,5-dione (I-5a: 167 mg, 23%) as a white solid. LC-MS (M+1) 325.1, t=1.77 minutes. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.60 (s, 3 H) 7.68 (d, J=8.84 Hz, 2 H) 8.05 (d, J=8.59 Hz, 2 H) 10.65 (s, 2 H). 1H NMR (400 MHz, CD3CN) δ ppm 2.29 (s, 3 H) 5.26 (s, 2 H) 7.37 (d, J=7.07 Hz, 1 H) 7.42 (t, J=7.33 Hz, 2 H) 7.45-7.50 (m, 2 H) 7.53 (d, J=8.59 Hz, 2 H) 7.75-7.93 (m, 4 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12](F)=[C:11]([CH:16]=O)[CH:10]=1.O.O.[NH2:20][NH2:21]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[NH:21][N:20]=[CH:16]2
Reactant: NN
Reactant: O=Cc1cc(-c2c(F)cccc2F)ccc1F
Solvent: O
Product: Fc1cccc(F)c1-c1ccc2[nH]ncc2c1
Temperature: 120 °C
Yield: 25.4 %

Procedure:
2′,4,6′-trifluorobiphenyl-3-carbaldehyde (160 g, 695.01 mmol) was taken in hydrazine hydrate (800 mL) and heated to 120° C. for 8 h. The reaction mixture was cooled to RT. Water was added to the reaction mixture and extracted with EtOAc (2×500 mL). Organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated and purified by column using silica (100-200 mesh) and 0-15% EtOAc-hexane to provide 5-(2,6-difluoro-phenyl)-1H-indazole (40.8 g, 25.4% yield). MS (ESI, pos. ion) m/z: 231.1 (M+1).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)OC1.[C:13](=[O:16])(O)[O-].[Na+]>>[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:13](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:16]1
Reactant: NC1COc2ccccc2C1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: NC1CCc2ccccc2O1

Procedure:
3-aminochroman hydrochloride (0.37 g, 2 mmol) was neutralized with aqueous sodium bicarbonate, extracted with diethyl ether, dried with magnesium sulfate, and the solvent evaporated to give 2-aminochroman.