Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]2[C:10]([C:11]#[N:12])=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=3)[C:8]([C:23]#[N:24])=[C:7]([S:25][CH2:26][C:27]3[N:28]=[C:29]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[S:30][CH:31]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:39]([O:43][C:44]([NH:46][C@H:47]([C:59](O)=[O:60])[CH2:48][CH2:49][CH2:50][NH:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[O:45])([CH3:42])([CH3:41])[CH3:40].ClCCl.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.O.C1COCC1>[C:39]([O:43][C:44]([NH:46][C@H:47]([C:59]([O:22][CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[C:8]([C:23]#[N:24])=[C:7]([S:25][CH2:26][C:27]3[N:28]=[C:29]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[S:30][CH:31]=3)[N:6]=[C:5]([N:1]3[CH2:2][CH2:3][CH2:4]3)[C:10]=2[C:11]#[N:12])=[CH:14][CH:15]=1)=[O:60])[CH2:48][CH2:49][CH2:50][NH:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[O:45])([CH3:41])([CH3:40])[CH3:42]
Reactant: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N2CCC2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
75 mg (0.134 mmol) of 2-(azetidin-1-yl)-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 8), 133.53 mg (0.402 mmol) of N2,N5-bis(tert-butoxycarbonyl)-L-ornithine and 8.18 mg (0.067 mmol) of 4-dimethylaminopyridine were initially charged in 1 ml of DMF. 1 ml of dichloromethane and 33.37 mg (0.174 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added, and the reaction solution was then stirred at 40° C. overnight. After cooling, water/THF was added to the reaction solution in such an amount that a clear solution was formed, and the product was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 104 mg (89% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([NH:34]O)=[NH:33])=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]4[O:24][N:34]=[C:32]([C:29]5[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=5)[N:33]=4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: N=C(NO)c1cnc(N)nc1
Product: Nc1ncc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(Cl)c(Cl)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.9) (188 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example B.5) (115 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (180 mg, 73%). MS (EI) 492.0 [(M)+]; mp 300° C.
Reaction SMILES: [C:1]1(=[O:36])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15](=[O:30])[C:16](=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:17]([CH3:19])=O)[C:4](=[O:31])[C:3]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:2]12.[CH3:37][O:38][C:39](=[O:44])/[CH:40]=[C:41](\[NH2:43])/[CH3:42]>C(O)(C)C>[CH3:42][C:41]1[NH:43][C:17]([CH3:19])=[C:16]([C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]2[C:1](=[O:36])[C:2]3=[CH:35][CH:34]=[CH:33][CH:32]=[C:3]3[C:4]2=[O:31])=[O:30])[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:40]=1[C:39]([O:38][CH3:37])=[O:44]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCCCCCCCN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Yield: 84.2 %

Procedure:
6.68 g (13.6 mmol) of 2-(3-nitrobenzylidene)-acetoacetic acid-(8-phthalimidooctyl)ester and 1.57 g (13.6 mmol) of 3-amino-crotonic acid methyl ester are boiled under reflux in 70 ml of isopropanol for 5 hours. The oil obtained after removal of the solvent by evaporation under vacuum is chromatographed on silica gel with dichloromethane/methanol (97:3) as solvent. 6.75 g (85%) of a yellow oil are obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH2:12][CH2:13][C:14]([C:16]2[S:23][C:22]([CH3:24])=[C:21]3[C:17]=2[CH2:18][C@H:19]2[C:25]([CH3:27])([CH3:26])[C@H:20]23)=[O:15])=[CH:7][C:6]=1[CH3:28].CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:28][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][C:14](=[O:15])[C:16]2[S:23][C:22]([CH3:24])=[C:21]3[C:17]=2[CH2:18][C@H:19]2[C:25]([CH3:26])([CH3:27])[C@H:20]23)[CH:9]=[C:10]([CH3:11])[C:5]=1[O:4][CH2:3][CH2:2][O:1][S:39]([CH3:38])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a solution of 3-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (1.55 g, 3.89 mmol) in DCM (60 mL) and DIPEA (1.07 mL, 6.22 mmol) is added methane sulfonylchloride (0.362 mL, 4.67 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. Another portion of methane sulfonylchloride (0.362 mL, 4.67 mmol) is added and stirring is continued for 30 min. The reaction mixture is diluted with DCM, washed with 0.1 N aq. NaOH followed by 10% aq. citric acid solution, dried over MgSO4 and evaporated to give methanesulfonic acid 2-{2,6-dimethyl-4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenoxy}-ethyl ester (1.57 g) as an orange resin; LC-MS: tR=1.14 min, [M+1]+=477.35; 1H NMR (CDCl3): δ 6.86 (s, 2H), 4.57-4.50 (m, 2H), 4.05-4.00 (m, 2H), 3.10 8s, 3H), 3.03-2.85 (m, 5H), 2.79 (d, J=18.8 Hz, 1H), 2.37 8s, 3H), 2.25 (s, 6H), 1.92-1.85 (m, 2H), 1.11 (s, 3H), 0.70 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12](I)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:18]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH3:27])[CH2:19][C:20]#[CH:21].C(#N)C.CC1C=CC(P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C(NC(C)C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].[Cu](I)I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]3[O:16][C:20]([CH2:19][CH2:18][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])=[CH:21][C:12]=3[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCCN1CCC[C@H]1C
Reactant: O=C(c1ccc(F)cc1)c1ccc(O)c(I)c1
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1cc2cc(C(=O)c3ccc(F)cc3)ccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18 %

Procedure:
The product from Example 68A (6.5 g, 18.5 mmol) was sequentially treated with a 0.1 M solution of the product from Example 68B in acetonitrile (230 mL, 23.0 mmol), Pd(OAc)2 (0.127 g, 0.566 mmol), tris(4-methylphenyl)phosphine (0.344 g, 1.130 mmol), and copper iodide (1.08 g, 95.72 mmol). After stirring at 25° C. for 10 minutes, the reaction mixture was treated with diisopropyl amine (26.6 mL, 189 mmol) and then heated at 60° C. in an inert atmosphere for 16 hours. The reaction mixture was allowed to cool to room temperature, filtered through celite, and the filtrate concentrated under reduced pressure. The residue was purified on silica gel using 90% DCM, 9.9% MeOH, 0.1% NH4OH to provide the title compound (1.21 g, 18.0% yield). 1HNMR (300 MHz, CD3OD) δ 1.09 (d, 3H, J=6.1 Hz), 1.46 (m, 1H), 1.81 (m, 2H), 2.02-2.28 (m, 2H), 2.49 (m, 2H) 3.06 (m, 2H), 3.28 (m, 2H), 6.68 (s, 1H), 7.27 (t, 2H), 7.58 (d, 1H, J=8.9 Hz), 7.71 (d, 1H, J=8.9 Hz) 7.86 (t, 2H), 7.97 (s, 1H); MS (ESI) m/z 352 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14])([O-:9])=[O:8].C(OCC)(=O)C.O>ClCCl>[N+:7]([C:10]1[CH:11]=[C:12]([C:13]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:14])[CH:16]=[CH:17][CH:18]=1)([O-:9])=[O:8]
Reactant: C1COCCN1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of morpholine (5.0 ml) in dichloromethane (50 ml) was added 3-nitrobenzoyl chloride (5.05 g). The mixture was stirred at room temperature for 15 minutes, then poured into a mixture of ethyl acetate and water. The organic phase was separated, washed with dilute hydrochloric acid, sodium bicarbonate and brine, dried over magnesium sulfate and concentrated to give 4-(3-nitrophenylcarbonyl)morpholine (6.46 g).
Reaction SMILES: [O:1]=[C:2]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:14][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([F:14])[C:2]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=[O:1])[CH3:8]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)CC(=O)c1ccco1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CCOC(=O)C(F)C(=O)c1ccco1
Reaction time: 90 h
Yield: 79.4 %

Procedure:
Following the method of Banks et al. (J. Chem. Soc., Chem. Commun. 1994, 343), to a stirred solution of 10.0 g (54.9 mmol) ethyl beta-oxo-2-furanpropionate in 500 ml acetonitrile at room temperature was added 19.4 g (54.9 mmol) 1-chloromethyl-4-fluoro-1,4-diazonia-bicyclo[2.2.2]octane bis(tetrafluoroborate) and stirring continued for 90 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue resuspended in ether and washed sequentially with water and with brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo to afford 8.72 g (79%) (RS)-2-fluoro-3-furan-2-yl-3-oxo-propionic acid ethyl ester as a yellow oil which was used in the next step without further purification. EI-MS m/e (%): 200 (M+, 8), 155 ([M—OEt]+, 4), 95 (100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][CH:11]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:10][CH2:9]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Nc1ccncc1C1CCC(=O)CC1
Product: Nc1ccncc1C1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(4-amino-pyridin-3-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [ClH:1].C([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)C1C=CC=CC=1.[H][H]>[Pd].CO>[ClH:1].[CH:10]12[NH:9][CH:14]([CH2:15][CH2:16]1)[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11]2
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2
Reaction time: 4 h
Yield: 97.2 %

Procedure:
Palladium on carbon (10% w/w, 500 mg) was added to a solution of 8-benzyl-3-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (16.5 g, 48.0 mmol, see step (h) above) in methanol (250 mL) under a nitrogen atmosphere at 25° C. The nitrogen atmosphere was exchanged for a hydrogen atmosphere (1 atm of pressure) and the reaction was stirred rapidly. After 4 h the stirring was stopped and the reaction was filtered through a pad of Celite®. The filtrate was concentrated in vacuo to afford an off-white solid (11.6 g). The solid was slurried in acetonitrile, collected and dried in vacuo to afford 10.5 g (86%) of the title compound.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8](=[O:22])[C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[C@@H:3]1[CH2:23][N:24]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>CO>[NH2:24][CH2:23][C@@H:3]1[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:16]1[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=1)=[O:22]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Temperature: 60 °C

Procedure:
A mixture of 2-(((2S,3R)-3-methyl-1-(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoyl)piperidin-2-yl)methyl)isoindoline-1,3-dione (0.67 g, 1.5 mmol) and hydrazine hydrate (0.46 g, 9.27 mmol) in MeOH (10 mL) was heated at 60° C. for 2 h. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with 2 N NaOH (2×), brine, and then dried (Na2SO4). The solvent was removed in vacuo to obtain the title compound which was used without further purification. ESI-MS (m/z): 327 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH:14]=2)[C:6]([N+:16]([O-])=O)=[CH:5][C:4]=1[NH:19][C:20]1[N:25]=[C:24]([C:26]2[CH:27]=[N:28][N:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=23)[C:23]([CH3:35])=[CH:22][N:21]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH:14]=2)[C:6]([NH2:16])=[CH:5][C:4]=1[NH:19][C:20]1[N:25]=[C:24]([C:26]2[CH:27]=[N:28][N:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=23)[C:23]([CH3:35])=[CH:22][N:21]=1
Reactant: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1ncc(C)c(-c2cnn3ccccc23)n1
Yield: 57.6 %

Procedure:
A mixture of N-[2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitrophenyl]-5-methyl-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 2, 279 mg, 0.59 mmol), iron (198 mg, 3.55 mmol) and NH4Cl (22.16 mg, 0.41 mmol) in ethanol (10.5 mL) and water (3.50 mL) was heated at reflux for 0.75 h. Further NH4Cl (22.16 mg, 0.41 mmol) and iron (198 mg, 3.55 mmol) were then added and the mixture was heated at reflux for a further 1.5 h. The mixture was then cooled, filtered, and the filtrate was concentrated in vacuo. Purification by FCC, eluting with 2-10% 7N methanolic ammonia in CH2Cl2 gave the title compound (150 mg, 57%) as a beige crystalline solid after trituration with THF and washing the resulting solid with diethyl ether; 1H NMR: 2.30 (3H, s), 2.40 (5H, m), 2.59 (2H, t), 3.01 (2H, d), 3.73 (3H, s), 4.27 (2H, s), 5.71 (1H, s), 6.63 (1H, s), 7.10 (1H, m), 7.35-7.49 (2H, m), 7.83 (1H, s), 8.27 (1H, s), 8.50-8.63 (2H, m), 8.81 (1H, d); m/z: ES+ MH+ 442.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][C:10](=[O:18])[C:11]3[C:12]([O:17][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[N:13][CH:14]=[CH:15][CH:16]=3.[Cl-].[NH4+].C(OCC)(=O)C.[CH2:27]1[CH2:31]OC[CH2:28]1>>[CH:28]1([C:10]2([OH:18])[C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[O:17][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[CH2:9]2)[CH2:27][CH2:31]1
Reactant: C1CCOC1
Reactant: COc1cccc2c1CC(=O)c1cccnc1O2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1cccc2c1CC(O)(C1CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,11-dihydro-7-methoxy [1]benzoxepino[2,3-b]pyridin-5-one (5.0 g) in THF (50 ml) was added 1.1 M cyclopropylmagnesium bromide THF solution (25 ml) at 0° C. The reaction mixture was warmed to room temperature, and stirred for 30 minutes. Aqueous ammonium chloride and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was filtered and washed with ethyl acetate-hexane (1:2) to give 5-cyclopropyl-5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ol (5.0 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]([CH:19]([CH3:21])[CH3:20])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)(=[O:8])=[O:7].[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:35]=[CH:34][C:31]([O:32][CH3:33])=[C:28]([O:29][CH3:30])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C(C)=CC=CC=1>[CH3:30][O:29][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][N:23]([CH3:22])[CH2:2][CH2:3][CH2:4][N:5]([CH:19]([CH3:21])[CH3:20])[S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)(=[O:8])=[O:7])[CH:35]=[CH:34][C:31]=1[O:32][CH3:33]
Reactant: CC(C)N(CCCCl)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: COc1ccc(CCN(C)CCCN(C(C)C)S(=O)(=O)c2cccc(C(F)(F)F)c2)cc1OC
Reaction time: 48 h

Procedure:
N-(3-chloropropyl)-N-(1-methylethyl)-3-trifluoromethylbenzenesulfonamide (23.4 g, 0.068 mol) and N-methylhomoveratrylamine (13.29 g, 0.068 mol) in xylene (250 mL) containing anhydrous potassium carbonate (4.68 g, 0.034 mol) and cesium carbonate (11.08 g, 0.034 mol) were heated and stirred for 21/2 days. The reaction was cooled, filtered and stripped to provide a gum with a small amount of crystalline material evident. Solution in diethyl ether, filtration of the small amount of solid and concentration of the filtrate provided the crude product (32.91 g). Chromatography first on dry column alumina then silica gel provided the same product as in the preceding example (11.84 g) as a gum.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)=[CH:4][CH:3]=1.Br[CH2:34][CH2:35][CH2:36][N:37]1[C:45](=[O:46])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]1=[O:47].C(=O)([O-])[O-].[K+].[K+]>CCCC[N+](CCCC)(CCCC)CCCC.[I-].CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:34][CH2:35][CH2:36][N:37]4[C:45](=[O:46])[C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:38]4=[O:47])[C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:28])[F:29])[CH:21]=2)=[CH:31][CH:32]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(CCCN2C(=O)c3ccccc3C2=O)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 100 °C
Yield: 100 %

Procedure:
Step 1 7-(4-Chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (1.0 g, 2.14 mmol, intermediate 9), 2-(3-bromopropyl)isoindoline-1,3-dione (0.63 g, 2.36 mmol), potassium carbonate (0.44 g, 3.21 mmol) and TBAI (0.040 g) were combined in DMF (20 mL) and heated at 100° C. for 3 h. The reaction was cooled to room temperature, diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with 1N lithium chloride (2×100 mL), dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to give a clear oil. The oil was purified using an 80 g silica gel flash column eluted with a gradient of 25% to 50% ethyl acetate/hexanes to give 7-(4-chlorobenzyl)-1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (1.4 g, 100% yield) as a white solid. LCMS retention time=4.660 minutes and 100% purity, LCMS MH+ 654. 1H NMR (CDCl3) δ 7.78-7.83 (m, 2H), 7.65-7.70 (m, 2H), 7.41 (t, 1H, J=8 Hz), 7.32 (dd, 4H, J=12 Hz and 28 Hz), 7.10-7.23 (m, 4H), 5.35 (s, 2H), 4.05-4.14 (m, 2H), 3.76 (t, 2H, J=8 Hz), 3.38 (s, 3H), 2.01-2.11 (m, 2H).
Reaction SMILES: C([O:3][C:4]([CH:6]([C:17](OCC)=[O:18])[CH:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C)C)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:7]([CH:6]([CH2:4][OH:3])[CH2:17][OH:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCC(C)C(C(=O)OCC)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCCCC(CO)CO

Procedure:
Quantities: compound from Example 4 (76.5 g, 0.28 mol) and lithium aluminum hydride (23 g, 0.6 mol). The experimental procedure was as described in Example 6. The product was obtained as a colourless solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1.N1C=CN=C1.[C:26]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O.C(Cl)(Cl)Cl.CO>[Si:30]([O:14][CH2:13][C@H:12]1[O:15][C@@H:8]([N:7]2[CH:16]=[C:3]([C:2]([F:1])([F:19])[F:20])[C:4](=[O:18])[NH:5][C:6]2=[O:17])[CH2:9][C@@H:10]1[OH:11])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:32])[CH3:31]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C(F)(F)F)c(=O)[nH]c2=O)C[C@@H]1O
Reaction time: 10 h
Yield: 40.6 %

Procedure:
A 1.0 g quantity of 5-trifluoromethyl-2'-deoxyuridine (3.6 mmoles) was dissolved in 3 ml of N,N-dimethylformamide. To the solution were added 0.49 g (7.2 mmoles) of imidazole and 0.64 g (4.3 mmoles) of tertbutyldimethylsilyl chloride, and the reaction was conducted at room temperature for 10 hours. The reaction mixture was treated in the same manner as in Example 1 with the exception of using chloroform/methanol (30:1) as an eluent for silica gel column chromatography, giving 0.6 g of the title compound as white crystals having a melting point of 199° to 200° C. Yield: 41%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=2)=[C:4]([F:17])[CH:3]=1.[CH3:18][S:19]([CH2:22][C:23]1[N:24]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH:25]=[CH:26][N:27]=1)(=[O:21])=[O:20].[H-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:38][C:35]3[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][N:24]4[CH:25]=[CH:26][N:27]=[C:23]4[CH2:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:37][CH:36]=3)[N:14]=2)=[C:4]([F:17])[CH:3]=1
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Reactant: Fc1cc(Cl)ccc1/C=C/c1nc(CCl)co1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(Cl)cc3F)n2)cc1
Yield: 23.8 %

Procedure:
Using 2-[(E)-2-(4-chloro-2-fluorophenyl)ethenyl]-4-(chloromethyl)-1,3-oxazole (243 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (250 mg) and 65% sodium hydride (35.9 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (105 mg) as a colorless crystal powder.