Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].O.[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([F:38])[C:25]([F:26])=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH:36]=[O:37])=[CH:29][CH:28]=3)[CH:23]=[CH:22][CH2:21]2)=[CH:16][CH:15]=1)(=[O:7])[CH:5]=[CH2:6]>O1CCOCC1>[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([F:38])[C:25]([F:26])=[C:24]([C:27]3[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][OH:37])=[CH:31][CH:32]=3)[CH:23]=[CH:22][CH2:21]2)=[CH:16][CH:15]=1)(=[O:7])[CH:5]=[CH2:6]
Reactant: C=CC(=O)OCCCCOc1ccc(C2(F)CC=CC(c3ccc(CCCC=O)cc3)=C2F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=CC(=O)OCCCCOc1ccc(C2(F)CC=CC(c3ccc(CCCCO)cc3)=C2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A mixture of 0.119 g of sodium borohydride and 10 ml of water was treated dropwise at 0° C. with a solution of 5.00 g of 4-[2',3'-difluoro-4"-(4-oxo-butyl)-1,2':4',1"-terphenyl-4-yloxy]-butyl acrylate in 50 ml of dioxan. The mixture was subsequently stirred at room temperature for 1 hour. The reaction mixture was poured into 50 ml of water, the phases were separated and the aqueous phase was extracted twice with 25 ml of ethyl acetate each time. The combined organic phases were washed twice with 50 ml of water each time, dried over magnesium sulphate, filtered and concentrated. Chromatographic purification of the residue on silica gel with cyclohexane/ethyl acetate (vol. 8:2) gave 4.49 g of 4-[2',3'-difluoro-4"-(4-hydroxy-butyl)-1,2':4',1"-terphenyl -4-yloxy]-butyl acrylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[C:13]1([C:19]([C:21]2[C:26]([F:27])=[CH:25][C:24](F)=[CH:23][C:22]=2[F:29])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:19]([C:21]1[C:22]([F:29])=[CH:23][C:24]([O:8][C:6]2[CH:5]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:3]=[C:2]([Cl:1])[CH:7]=2)=[CH:25][C:26]=1[F:27])(=[O:20])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(c1ccccc1)c1c(F)cc(F)cc1F
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Product: O=C(O)Cc1cc(Cl)cc(Oc2cc(F)c(C(=O)c3ccccc3)c(F)c2)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 18 step (iv) and the product from step (i).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:26]([F:29])([F:28])[F:27])([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.[NH2:38][CH2:39][C:40]([NH:42][CH2:43][C:44]([F:47])([F:46])[F:45])=[O:41].C(N(CC)CC)C>CN(C=O)C.C1COCC1>[OH:6][N:5]=[C:4]([NH:38][CH2:39][C:40]([NH:42][CH2:43][C:44]([F:47])([F:46])[F:45])=[O:41])[C:3]1[CH:7]=[CH:8][C:9]([C:11]2[CH2:15][C:14]([C:26]([F:29])([F:27])[F:28])([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[O:13][N:12]=2)=[CH:10][C:2]=1[CH3:1]
Reactant: Cc1cc(C2=NOC(c3cccc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C=NO
Reactant: NCC(=O)NCC(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(c3cccc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=NO)NCC(=O)NCC(F)(F)F
Temperature: 75 °C
Yield: 42.6 %

Procedure:
To a solution of 2-Methyl-4-[5-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-4,5-dihydro-isoxazol-3-yl]-benzaldehyde oxime (250 mg) in DMF (8 mL) was added N-chloro succinimide (84 mg) and heated to 75° C. for 1 h. After cooling, the reaction mixture was poured onto water and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to ¼ of the original volume to obtain the crude hydroxamic acid chloride. This mixture was added to a solution of 2-amino-N-(2,2,2-trifluoro-ethyl)-acetamide (116 mg) and triethylamine (0.30 mL, 0.21 g) in THF (8 mL) and stirred at room temperature over night. After concentration in vacuo, the mixture was purified by chromatography on silica gel to obtain the title compound (146 mg, 43%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][N:4]1[C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1N1N=CC=N1)=[O:12].CC1C=CC([C:35]2[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][N:4]1[C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[C:35]1[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=1)=[O:12]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CCCC3C2CN)c1
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CC3CCCC3C2CN)c1

Procedure:
The title compound was prepared following the same general protocol as described for (1-(aminomethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone in Example A68 using 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid. MS (ESI) 339 (M+H).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:18][C:19]([O:22][C:23]([N:25]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:26]1[N:27](C(OC(C)(C)C)=O)[CH:28]=[C:29]([CH:31](OC)[O:32]C)[N:30]=1)=[O:24])([CH3:21])[CH3:20].O>CC(C)=O>[CH3:21][C:19]([O:22][C:23]([N:25]([C:26]1[NH:27][CH:28]=[C:29]([CH:31]=[O:32])[N:30]=1)[C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])=[O:24])([CH3:18])[CH3:20]
Reactant: COC(OC)c1cn(C(=O)OC(C)(C)C)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(C=O)c[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.8 %

Procedure:
A catalytic amount of pyridinium p-toluenesulfonate was added to a solution of 1,1-dimethylethyl 2-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-[bis(methyloxy)methyl]-1H-imidazole-1-carboxylate (1.520 g, 3.32 mmol) in acetone:water/3:2 (25 mL). The mixture was stirred at RT for 3 days. The solvent was evaporated and the residue was purified by chromatography (EtOAc:hexanes) to give 0.680 g of the title compound (0.680 g, 66%). 1H NMR (400 MHz, chloroform-d) δ ppm 10.57 (br. s., 1H), 9.57 (s, 1H), 7.61 (s, 1H), 1.51 (s, 18H). ES MS: m/z 310 (M−H), 334 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1>CC#N>[CH2:24]([O:11][C:3]1[CH:4]=[C:5]([CH2:8][C:9]#[N:10])[CH:6]=[CH:7][C:2]=1[Cl:1])[C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: N#CCc1ccc(Cl)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCc1ccc(Cl)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a solution of (4-chloro-3-hydroxy-phenyl)acetonitrile (6.2 g, 37 mmol) in CH3CN (80 mL) was added K2CO3 (10 g, 74 mmol) and BnBr (7.6 g, 44 mmol). The mixture was stirred at room temperature overnight. The solids were filtered off and the filtrate was evaporated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 50:1) to give 2-(3-(benzyloxy)-4-chlorophenyl)-acetonitrile (5.6 g, 60%). 1H NMR (400 MHz, CDCl3) δ 7.48-7.32 (m, 6H), 6.94 (d, J=2 Hz, 2H), 6.86 (dd, J=2.0, 8.4 Hz, 1H), 5.18 (s, 2H), 3.71 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:21][C:22]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O.CC([O-])=O.[Na+]>CC(O)=O>[Cl:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]2[CH:1]=[CH:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=2[OH:21])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccc(Cl)c(Cl)c1
Reactant: COc1cccc(C=O)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(C=Cc2nc3ccccc3c(=O)n2-c2ccc(Cl)c(Cl)c2)c1O
Yield: 41.7 %

Procedure:
Compound 63 (1 g, 0.028 mol), 2-hydroxy-3 methoxybenzaldehyde (9, 0.4 g, 0.003 mol) and NaOAc (0.233 g, 0.002 mol) in AcOH were heated under reflux for 10 hours. After cooling the precipitate formed was washed with water, filtered off, dried and recrystallized from EtOH to yield 64 (0.55 g, 71%). M. Wt. 439. LCMS [M+H]+=440.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18](O)[C:13]=3[C:12]3[CH:22]=[C:23]([F:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:28]>ClC1C=CC=CC=1.ClCCl>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([Cl:28])[C:13]=3[C:12]3[CH:22]=[C:23]([F:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N#Cc1ncc2c(c1O)c1cc(F)cnc1n2S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: N#Cc1ncc2c(c1Cl)c1cc(F)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
A solution of 9-benzenesulfonyl-3-fluoro-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (500 mg, 1.36 mmol) and phosphorus pentachloride (708 mg, 3.4 mmol) in chlorobenzene (1.5 mL) was heated at 110° C. for 1 hour. The reaction mixture was cooled to ambient temperature and then the solvent removed in-vacuo to afford a residue. The resultant residue was dissolved in dichloromethane (50 mL) and then the solution was diluted with ice/water (50 mL). The layers were separated and the aqueous layer further extracted with dichloromethane (50 mL). The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The resultant residue was triturated with diethyl ether and dried to afford the title compound as a tan solid (320 mg, 65%). 1H NMR (400 MHz, CDCl3): 9.81 (s, 1H), 8.69 (d, J=2.8 Hz, 1H), 8.50 (dd, J=7.6, 2.8 Hz, 1H), 8.24 (d, J=8.0 Hz, 2H), 7.65 (t, J=7.5 Hz, 1H), 7.53 (t, J=7.8 Hz, 2H).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[N:24]1([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([C:29]2[CH:35]=[CH:34][C:32]([NH:33][C:1]([C:4]34[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]5[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]5[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]3)[CH2:6][CH2:5]4)=[O:2])=[CH:31][CH:30]=2)[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccc(N2CCCC2)cc1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(N4CCCC4)cc3)(CC1)CC2
Yield: 18.9 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-(pyrrolidin-1-yl)aniline (50.2 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-[4-(pyrrolidin-1-yl)phenyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (13.7 mg).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])#[N:2]>CO.[Pd]>[C:1]([CH2:3][CH2:4][C:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])#[N:2]
Reactant: COC(=O)C=CCC(CCC#N)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCC(CCC#N)(c1ccccc1)c1ccccc1
Reaction time: 21 h
Yield: 96 %

Procedure:
To a solution of methyl 7-cyano-5,5-diphenyl-hept-2-enoate (1.4 1 g, 4.41 mmol) in MeOH (di00 mL) was added Pd/C (0.714 g). The reaction mixture was hydrogenated at 4 atm for 21 hr. 5 The catalyst was filtered and the filtrate was evaporated in vacuo. The oily residue (2 g) was purified by a silica gel column chromatography (eluting with 15:85 mixture of ethyl acetateihexane) to yield the desired product as a colorless oil (96 %): MS showed (M+H)+ e 322;H-NMR (CDCl3, δ): 1.25-1.36 (mn, 2H), 1.98-2.13 (m,. 4H), 2.26 (t, 2H, J =7.1 Hz). 2.49-2.58 (mn, 2H) 3 .65 (s, )H), 7.10-7.17 (mn, 4H), 7.21-7.36 (mn, 6H); IR (MIC) u 2951, 2247, 1735, 1444, 1196 cm-1 ; Anal. Calcd for C2 1H21N02 : C, 78.47; H, 7.2 1; N, 4.3 6; Found: C, 78.58; H, 7.12; N, 4.14.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:7]=[C:6]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH3:4].[CH2:24]=[O:25]>C(O)(=O)C>[CH2:1]([N:5]1[C:9]([CH2:24][OH:25])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:7]=[C:6]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=O
Reactant: CCCCn1cc(-c2ccc(OC)cc2)nc1-c1ccccc1
Solvent: CC(=O)O
Product: CCCCn1c(-c2ccccc2)nc(-c2ccc(OC)cc2)c1CO
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a 150 ml sealed flask is added 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazole (10.72, 35 mmol) followed by the addition of 24 ml of acetic acid and 24 ml of 37% formaldehyde, the resulting mixture is stirred at 70° C. for 8 h, then cooled to room temperature. The organic solvents is evaporated, the residue is diluted 100 ml of water and basified with sodium hydroxide solution, the mixture is extracted with ethyl acetate (100 ml×4), washed with water and brine, dried over Na2SO4 Concentration and purification through silica gel chromatography (hexanes/ethyl acetate, from 8:1 to 1:1) affords 10.0 of 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethanol as white solid. 1H NMR (400 MHz, CDCl3) δ 7.58 (2H, dd, J=8.7 Hz), 7.354˜7.51(2H, m), 7.44˜7.38 (3H, m), 6.87 (2H, d, J=8.7 Hz), 4.59 (2H, s), 3.95 (2H, t, J=7.5 Hz), 3.784 (3H, s), 1.60 (2H, m), 1.16 (2H, m), 0.77 (3H, t, J=7.2 Hz); MS (+VE) m/z 337(M+1).
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10](Cl)=[O:11])[CH2:2]1.[OH:14][CH2:15][CH:16]([CH2:18][OH:19])[OH:17]>O>[CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10]([O:14][CH2:15][CH:16]([CH2:18][OH:19])[O:17][C:10]([CH:3]2[CH:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:6][CH:1]([CH3:13])[CH2:2]2)=[O:11])=[O:11])[CH2:2]1
Reactant: OCC(O)CO
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Solvent: O
Product: CC1CCC(C(C)C)C(C(=O)OCC(CO)OC(=O)C2CC(C)CCC2C(C)C)C1

Procedure:
A mixture of p-menth-3-oyl chloride (2 g.) and glycerol (20 ml.) was heated at 100° for 4 hours. The mixture was then poured into water (600 ml.) and extracted 3 times with ether. The extracts were dried (MgSO4) and the solvent removed under reduced pressure to leave 1,2-bis-(p-menth-3-oyl)glycerol as a colourless oil (1.2 g.).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:24][CH2:23][C:22]2[C:21]3=[N:25][N:26]=[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:20]3[N:19]=[C:18]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[C:17]=2[CH2:16]1)=O)(C)(C)C>ClCCl>[C:28]1([C:27]2[N:20]3[N:19]=[C:18]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[C:17]4[CH2:16][NH:15][CH2:24][CH2:23][C:22]=4[C:21]3=[N:25][N:26]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(OCc3ccccn3)nn3c(-c4ccccc4)nnc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2nnc3c4c(c(OCc5ccccn5)nn23)CNCC4)cc1
Yield: 96.2 %

Procedure:
Trifluoroacetic acid (3 ml) was added to a solution of 3-phenyl-5-(pyridin-2-ylmethoxy)-8,9-dihydro-6H-1,2,3a,4,7-pentaazacyclopenta[α]-naphthalene-7-carboxylic acid tert-butyl ester (217 mg, 0.47 mmol) in dry dichloromethane (3 ml) at 0° C. under nitrogen. After 1 hour the volatiles were removed in vacuo and the residue was partitioned between dichloromethane and saturated aqueous potassium carbonate. The aqueous was further extracted with dichloromethane (×2). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with dichloromethane/methanol/ammonia (60:8:1) to afford the title amine (162 mg, 96%) as a colourless solid, m.p.=157-159° C. 1H NMR (360 MHz, d6-DMSO) δ2.92-2.96 (2H, m), 3.07 (2H, t, J=5.8 Hz), 3.84 (2H, s), 5.56 (2H, s), 7.36 (1H, dd, J=6.7, 4.9 Hz), 7.52-7.60 (4H, m), 7.87 (1H, td, J=7.8, 1.7), 8.23 (2H, dd, J=6.3, 1.9 Hz), 8.62-8.64 (1H, m). MS (ES+) m/e 359 [MH]+. Anal. Found C, 64.93; H, 5.31; N, 22.30. C20H18N6O.0.75 H2O requires C, 64.59; H, 5.29; N, 22.60%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C@@H:7]([CH:12]([CH3:14])[CH3:13])[C@H:6]([OH:15])[CH2:5]2.[H-].[Na+].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:21]=1.O>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C@@H:7]([CH:12]([CH3:13])[CH3:14])[C@H:6]([O:15][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:21]=1)[CH2:5]2
Reactant: BrCc1cccc(Oc2ccccc2)n1
Reactant: CC(C)[C@@H]1c2cc(Cl)c(Cl)cc2C[C@H]1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H]1c2cc(Cl)c(Cl)cc2C[C@H]1OCc1cccc(Oc2ccccc2)n1
Reaction time: 0.67 h
Yield: 83.9 %

Procedure:
A solution of trans-5,6-dichloro-1-isopropyl-2-indanol (0.73 g), in anhydrous tetrahydrofuran (7 ml) was added to a suspension of sodium hydride (0.24 g, oil free) in anhydrous tetrahydrofuran (10 ml). The mixture was stirred for 40 minutes and a solution of 2-(bromomethyl)-6-phenoxypyridine (0.84 g) in anhydrous tetrahydrofuran was added, followed by a catalyst amount of tetra-n-butylammonium iodide, The mixture was stirred at room temperature for 18 hours, mixed with water (100 ml) and extracted with diethyl ether (3×50 ml). The combined ether extracts were dried (MgSO4) and condensed under reduced pressure to give an oil which was purified by flash chromatography to give trans-5,6-dichloro-1-isopropyl-2-((6-phenoxypyridin-2-yl)-methoxy)-indane (1.07 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]5[O:37][C:38]([CH3:41])=[N:39][N:40]=5)[CH:31]=4)=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]5[O:37][C:38]([CH3:41])=[N:39][N:40]=5)[CH:31]=4)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1nnc(-c2cccc(-c3cn(COCC[Si](C)(C)C)c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)c2)o1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc(-c2cccc(-c3c[nH]c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)c2)o1
Yield: 21.2 %

Procedure:
(S)-5-Methyl-2-(1-((5-(3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (90 mg, 0.13 mmol) was treated with trifluoroacetic acid (2 ml, 25 mmol) and a solution of ammonia (7N in methanol, 2 ml, 100 mmol) according to the method described in Example 27 to give 15 mg (20% yield) of the title compound. Purity 95%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][CH:20]=2)=[N:10]1.C(=O)([O-])[O-:29].[K+].[K+].OO.O>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH2:27])=[O:29])=[CH:21][CH:20]=2)=[N:10]1
Reactant: O=C([O-])[O-]
Reactant: N#CCc1ccc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cc1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)Cc1ccc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.9 %

Procedure:
To a solution of (4-(1-(2,6-difluorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (80.0 mg) obtained in Example 39 in DMSO (0.8 mL) was added potassium carbonate (36.6 mg), and then 30% aqueous hydrogen peroxide (0.068 mL) was added thereto. The reaction mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the white precipitate was collected by filtration, washed with water, and dried in vacuum to give the title compound (7.5 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([CH:29]=O)[CH:26]=[C:25]([CH:31]=[O:32])[CH:24]=2)[N:20]=[N:19][C:18]=1[O:33][CH3:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN.C(O)(=O)C.[C:41]([BH3-])#[N:42].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([CH2:29][NH:42][CH3:41])[CH:26]=[C:25]([CH2:31][OH:32])[CH:24]=2)[N:20]=[N:19][C:18]=1[O:33][CH3:34])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1nnc(-c2cc(C=O)cc(C=O)c2)cc1-c1cc2ccccc2n1C(=O)OC(C)(C)C
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cc(CO)cc(-c2cc(-c3cc4ccccc4n3C(=O)OC(C)(C)C)c(OC)nn2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
170 mg of 2-[6-(3,5-diformyl-phenyl)-3-methoxy-pyridazin-4-yl]-indole-1-carboxylic acid tert-butyl ester is dissolved in 5 ml of methanol and 0.093 ml of methylamine solution in THF is added. The solution is stirred for 5 min at RT then 22 mg of acetic acid and 26 mg of sodium cyanoborohydride is added. The reaction is stirred for 4 h at 60° C. The product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 19 mg. LC-MS (ES+) 475 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1([N:13]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:14](=[O:25])[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)=O.C[O-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH:27]1([O:26][N:13]2[C:5]3([CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]3)[C:3]([OH:2])=[C:15]([C:16]3[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=3[CH3:22])[C:14]2=[O:25])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COC(=O)C1(N(OC2CCCCC2)C(=O)Cc2c(C)cc(C)cc2C)CCN(OC)CC1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CON1CCC2(CC1)C(O)=C(c1c(C)cc(C)cc1C)C(=O)N2OC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{cyclohexyloxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester (600 mg, 1.34 mmol) in dimethylformamide (10 ml) at 0° C. was added sodium methoxide (217 mg, 4.02 mmol) in one portion and the mixture was stirred at room temperature overnight. The reaction mixture was poured on cold saturated aqueous ammonium chloride and thoroughly extracted with ethyl acetate (4×25 ml). The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/cyclohexane 1:1). Yield: 329 mg of 1-cyclohexyloxy-4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (title compound P2ii.26) as a slight tan foam. Trituration with hexane gave a white solid, mp 115-118° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][OH:6])[CH3:2].[H-].[Na+].Cl[C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1.O>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1)[CH3:2]
Reactant: CCOCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-ethoxyethanol (1.08 g, 12 mmol) and sodium hydride (410 mg, 12 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (790 mg, 4 mmol) in dry tetrahydrofuran. The mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.