Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11]=2[F:13])[C:6](=[O:34])[C:5]([CH:35]=O)=[CH:4]1)[CH3:2].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl.C(Cl)Cl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)=[C:10]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C:11]=2[F:13])[C:6](=[O:34])[C:5]([CH2:35][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:4]1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCn1cc(C=O)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c(F)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCn1cc(CN2CCCC2)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c(F)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.5 %

Procedure:
To a solution of 1-ethyl-8-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (6.5 g, 13.22 mmol) in 1,2-Dichloroethane (DCE) (100 mL) was added pyrrolidine (1.637 mL, 19.84 mmol), sodium triacetoxyborohydride (5.61 g, 26.4 mmol) and AcOH (0.076 mL, 1.322 mmol). The reaction mixture was stirred at 25° C. for 3 h. LCMS indicated completion of the reaction. The mixture was diluted with DCM and washed with brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The crude material was purified by normal phase automatic silica column chromatography (Combiflash RF, 40 g golden column) eluting with MeOH/DCM (0-20%), and purified again with reverse phase automatic silica column chromatography (Combiflash RF, 150 g golden column) eluting with acetonitrile/Water (0-60%) to afford 1-ethyl-8-fluoro-6,7-bis((4-methoxybenzyl)oxy)-3-(pyrrolidin-1-ylmethyl)quinolin-4(1H)-one (4.3 g, 7.87 mmol, 59.5% yield) as a pale yellow solid.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH2:19][C:20](Cl)=[O:21])[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>>[C:1]12([C:11]3[CH:12]=[C:13]([CH2:19][C:20]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=4)=[O:21])[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(CC(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1ccc(N)cc1
Product: COC(=O)c1ccc(NC(=O)Cc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1

Procedure:
In a manner similar to Example 1(d), by reaction of 3.8 g (11.9 mmol) of 3-(1-adamantyl)-4-methoxyphenylacetyl chloride with 1.81 g (12 mmol) of methyl 4-aminobenzoate, 3.2 g (63%) of the expected methyl ester, melting point 146°-147° C., are obtained.
Reaction SMILES: Br[CH:2]([C:4]1[C:5]([F:27])=[CH:6][C:7]2[O:16][CH2:15][CH2:14][N:13]3[C:9](=[N:10][C:11]([C:17]4[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=4)=[CH:12]3)[C:8]=2[CH:26]=1)[CH3:3].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>O1CCOCC1>[F:27][C:5]1[C:4]([CH:2]([N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)[CH3:3])=[CH:26][C:8]2[C:9]3[N:13]([CH:12]=[C:11]([C:17]4[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=4)[N:10]=3)[CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(C(C)Br)c(F)cc2OCC3)n(C(C)C)n1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2cc(C(C)N4CCN(C)CC4)c(F)cc2OCC3)n(C(C)C)n1
Yield: 63.3 %

Procedure:
A solution of 9-(1-bromoethyl)-8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 374 (99 mg, 0.23 mmol), N-methylpiperazine (28 μL, 0.25 mmol) and DIPEA (60 μL, 0.35 mmol) in dioxane (1 mL) was stirred at RT for 72 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (Si-PPC, gradient 0-8% 2 M NH3/MeOH in DCM) to give 66 mg of a pale yellow oil. The compound was further purified by reverse phase column chromatography (C18, gradient 2-50% MeOH in 1% TFA/H2O) and then loaded in MeOH onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2 M NH3 in MeOH. The basic fraction was concentrated in vacuo to afford 373 (47 mg, 40% over 2 steps) as a white solid. LCMS (Method K): RT 2.70 min [M+H]+ 454.2. 1H NMR (CD3OD, 400 MHz): δ 8.54 (1H, d, J=8.6 Hz), 7.68 (1H, s), 6.76 (1H, d, J=11.0 Hz), 5.83 (1H, sept., J=6.7 Hz), 4.49 (4H, br s), 3.84 (1H, q, J=6.8 Hz), 2.47 (8H, br s), 2.33 (3H, s), 2.22 (3H, s), 1.53 (3H, d, J=6.7 Hz), 1.52 (3H, d, J=6.7 Hz), 1.40 (3H, d, J=6.8 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]#N)=[CH:10]2)=[CH:5][CH:4]=1.[OH-:15].[K+].Cl.[OH2:18]>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]([OH:18])=[O:15])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(C#N)cc2c1
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: COc1ccc2ccc(C(=O)O)cc2c1
Temperature: 70 °C
Yield: 98 %

Procedure:
A solution of 7-methoxy-2-naphthonitrile (501 mg, 2.74 mmol) and KOH (503 mg, 9.0 mmol) in 95% ethanol (5 mL) is heated to reflux for 24 hours. The reaction mixture is allowed to cool, diluted with water and then acidified to pH<2 with concentrated HCl. The resulting precipitate is collected by filtration, washed with water and dried by heating at 70° C. under vacuum to give 7-methoxy-2-naphthoic acid as a white solid (540 mg, 98%). HRMS (FAB) calculated for C12H10O3+H+: 203.0708, found 203.0701.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:14])[C:7]2=[O:12].[F:21][C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:32][C:33](O)=[O:34].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:21][C:22]1[C:27]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:32][C:33]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:14])[C:7]2=[O:12])=[O:34]
Reactant: CC(c1ccccn1)n1ccc2c(N)cccc2c1=O
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccccn1)n1ccc2c(NC(=O)Cc3cccc(C(F)(F)F)c3F)cccc2c1=O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 5-amino-2-(1-(pyridin-2-yl)ethyl)isoquinolin-1(2H)-one (100 mg, 0.0004 mol) in N,N-Dimethylformamide (1 mL, 0.01 mol) was added 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid (178 mg, 0.000801 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (468.3 mg, 0.001232 mol) and N,N-diisopropylethylamine (300 uL, 0.002 mol). The reaction mixture was stirred for 16 hours at 50° C. LC/MS indicated that the reaction was completed. The DMF reaction solution was directly applied to prep. HPLC. The final product was obtained as a solid (102.4 mg). MS m/z=470.3 (M+1). 1H NMR (DMSO) δ 10.17 (s, 1 H), 8.54 (d, J=6.4 Hz, 1 H), 8.10 (d, J=8.0 Hz, 1 H), 7.82 (dd, J=7.8, 0.7 Hz, 1 H), 7.78 (td, J=9.5, 1.8 Hz, 2 H), 7.70 (t, J=7.1 Hz, 1 H), 7.55 (d, J=7.8 Hz, 1 H), 7.48 (t, J=7.9 Hz, 1 H), 7.40 (t, J=7.7 Hz, 1 H), 7.35 (d, J=8.0 Hz, 1 H), 7.31 (qd, J=4.8, 0.9 Hz, 1 H), 6.74 (d, J=7.8 Hz, 1 H), 6.28 (q, J=7.2 Hz, 1 H), 3.98 (s, 2 H), 1.78 (d, J=7.2 Hz, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[O:18][C:17](C=O)=[CH:16][CH:15]=3)[S:13][C:6]=12.[CH3:28][O:29][CH2:30][CH2:31][NH2:32].[BH-](OC(C)=O)(OC(C)=O)O[C:35](C)=O.[Na+].C(O)(=O)C>ClCCl>[F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[O:18][C:17]([CH2:35][NH:32][CH2:31][CH2:30][O:29][CH3:28])=[CH:16][CH:15]=3)[S:13][C:6]=12
Reactant: COCCN
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)o1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)o1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A suspension of 107 (2.00 g, 5.20 mmol), 2-methoxyethylamine (1.954 g, 26.02 mmol), NaBH(OAc)3 (5.52 g, 26.02 mmol) and acetic acid (1.49 ml, 26.02 mmol) in anhydrous dichloromethane was stirred at room temperature under nitrogen for five days. The reaction mixture was then carefully quenched with a saturated solution of NaHCO3 (pH 8-9), and extracted with DCM. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the title compound 108 as a yellow-orange sticky oil. The material was used in the next step without further purification. MS (m/z): 444.2 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]2[C:7]3[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9](S)[C:8]=3[CH:15]=[CH:16][CH:17]=2)(=[O:4])=[O:3].[N:18]1([CH2:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][N:20]=[CH:19]1>C(O)C>[N:18]1([CH2:23][CH2:24][CH2:25][NH:26][C:9]2[C:8]3[CH:15]=[CH:16][CH:17]=[C:6]4[C:7]=3[C:11](=[CH:12][CH:13]=[C:5]4[S:2]([CH3:1])(=[O:4])=[O:3])[N:10]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: NCCCn1ccnc1
Reactant: CS(=O)(=O)c1ccc2c3c(cccc13)C(S)=N2
Solvent: CCO
Product: CS(=O)(=O)c1ccc2c3c(cccc13)C(NCCCn1ccnc1)=N2

Procedure:
The reaction of molecular equivalents of 6-methylsulfonylbenz(cd)indol-2-thiol, 3-(1H-imidazol-1-yl)propanamine, mercuric acetate, and sufficient refluxing ethanol to permit stirring, by the procedure of Example 55 gives the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[Mg].[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15].[Cl-].[Zn+2:26].[Cl-]>C1C=CC=CC=1.C1COCC1>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([Zn:26][C:20]2[CH:21]=[CH:22][C:17]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:18][CH:19]=2)=[CH:3][CH:4]=1)[CH:9]([CH3:11])[CH3:10]
Reactant: [Zn+2]
Reactant: CC(C)Cc1ccc(Br)cc1
Reactant: CC(C)Cc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC(C)Cc1ccc([Zn]c2ccc(CC(C)C)cc2)cc1

Procedure:
Under a nitrogen atmosphere, a solution of 10.2 g of p-bromoisobutylbenzene in 30 ml of benzene was added dropwise slowly to 1.2 g of magnesium turnings in 20 ml of THF at the refluxing temperature. To the resulting p-isobutylphenyl magnesium bromide solution was added 3.14 g of anhydrous zinc chloride in an atmosphere of nitrogen. When the temperature of the resulting mixture was maintained at 25° to 30° C. for 1 hour, a solution of di-(p-isobutylphenyl) zinc formed.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.C([Li])CCC.CCCCCC.CN([CH:31]=[O:32])C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[N:10]=[C:9]([CH:31]=[O:32])[S:8][C:6]=2[N:7]=1
Reactant: CN(C)C=O
Reactant: Clc1nc(N2CCOCC2)c2ncsc2n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(5-chlorothiazolo[5,4-d]pyrimidin-7-yl)morpholine 14 (1.75 g, 6.85 mmol) in dry THF at −78° C. was added a 2.5M solution of n-butyllithium (nBuLi) in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h, dry DMF (796 uL, 1.5 eq.) was added. The reaction mixture was stirred for 1 h at −78° C. and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture was poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air-dried to yield 5-chloro-7-morpholinothiazolo[5,4-d]pyrimidine-2-carbaldehyde 44.
Reaction SMILES: [O:1]=[C:2]([C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[S:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=2)=[CH:12][CH:11]=1)[CH3:9])[CH2:3][C:4](OC)=[O:5].[OH-].[Na+].Cl.[NH2:29]O.Cl>CO.CO.O>[F:23][C:22]([F:24])([F:25])[C:20]1[N:21]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([C@H:8]([C:2]3[O:1][N:29]=[C:4]([OH:5])[CH:3]=3)[CH3:9])=[CH:15][CH:14]=2)[S:18][CH:19]=1
Reactant: NO
Reactant: COC(=O)CC(=O)[C@H](C)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1cc(O)no1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To a cooled (−30° C.) solution of the intermediate 7a, methyl (4R)-3-oxo-4-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)pentanoate, (372 mg, 1 mmol) in CH3OH (0.5 ml), a solution of NaOH (42 mg, 1.05 mmol) in CH3OH (4 ml) was added by dripping. The resulting mixture was stirred for 10 min, then a mixture of hydroxylamine hydrochloride (133 mg, 2 mmol) and NaOH (83 mg, 2 mmol) in CH3OH/water (4 ml/0.5 ml) was added at the same temperature. After stirring for 2 h at −30° C., the reaction mixture was poured into 37% HCl (1.5 ml) and the resulting mixture was heated at 80° C. for 2 h. After cooling at room temperature and solvents evaporation, the crude was diluted with water and extracted with EtOAc (3×10 ml). The combined organic extracts were dried over anhydrous Na2SO4, evaporated and purified by flash chromatography (n-hexane/EtOAc 8:2; 1% AcOH) to afford pure 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]isoxazol-3-ol (10) (202 mg, 0.57 mmol) as a pale yellow solid (57%). [α]D=−40 (c=1.4; CH3OH); 1H-NMR (CDCl3): δ 10.70 (bs, 1H, OH), 9.15 (bs, 1H, NH), 7.40 (d, 2H, J=7 Hz), 7.25 (d, 2H, J=7 Hz), 7.00 (s, 1H), 5.70 (s, 1H), 3.80 (q, 1H, J=7 Hz), 1.55 (d, 3H, J=7 Hz).
Reaction SMILES: [Li].[NH2:2][C:3]1[N:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.[O:15]([C:22]1[S:26][C:25]([CH2:27][NH2:28])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[NH2:2][C:3]1[N:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([NH:28][CH2:27][C:25]1[S:26][C:22]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:23][CH:24]=1)=[O:7]
Reactant: Nc1ncc([N+](=O)[O-])cc1C(=O)O
Reactant: NCc1ccc(Oc2ccccc2)s1
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ncc([N+](=O)[O-])cc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
Then, the resulting lithium salt of 2-amino-5-nitro-nicotinic acid, C-(5-phenoxy-thiophen-2-yl)-methylamine (60 mg, 0.29 mmol), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (162 mg, 0.367 mmol) and triethylamine (103 μl, 0.735 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), and the solution was stirred for 6 hours at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate, and the organic layer was washed with water and brine. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and the title compound (87 mg, 0.24 mmol, 96%) was obtained as a pale yellow solid.
Reaction SMILES: C(O[C@H:5]1[C@H:10]2[C@H:11]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@:7]([CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:8][O:9]2)[O:6]1)(=O)C.[C:29]([NH:37][C:38]1[N:46]=[CH:45][N:44]=[C:43]2[C:39]=1[NH:40][CH:41]=[N:42]2)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>C(#N)C>[C:29]([NH:37][C:38]1[N:46]=[CH:45][N:44]=[C:43]2[C:39]=1[N:40]=[CH:41][N:42]2[C@@H:5]1[C@H:10]2[C@H:11]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@:7]([CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:8][O:9]2)[O:6]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Nc1ncnc2nc[nH]c12)c1ccccc1
Reactant: CC(=O)O[C@@H]1O[C@@]2(COCc3ccccc3)CO[C@@H]1[C@@H]2OCc1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: O=C(Nc1ncnc2c1ncn2[C@H]1O[C@@]2(COCc3ccccc3)CO[C@@H]1[C@@H]2OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
A solution of furanose 207 (167 mg, 0.434 mmol) and 6-N-benzoyladenine (194 mg, 0.813 mmol) in anhydrous acetonitrile (5.3 mL) was added BSA (0.43 mL, 1.76 mmol) and stirred at room temperature for 1 h. The solution was cooled to 0° C. and trimethylsilyl triflate (0.16 mL, 0.86 mmol) was added dropwise. After stirring at 65° C. for 2 h, the reaction was quenched with a saturated aqueous solution of sodium hydrogen carbonate (40 mL) and the mixture was extracted with dichloromethane (2×50 mL). The combined extract was dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by chromatography over silica gel with dichloromethane:methanol (98:2) as eluent to give the product 208 as a solid (111 mg, 45%); 1H NMR (CDCl3): δ 8.82 (1H, s, H-8), 8.14 (1H, s, H-2), 7.59-7.26 (15H, m, Bz, Bn), 6.74 (1H, s, H-1′), 4.92 (1H, s, H-2′), 4.74-4.39 (4H, m, Bn), 4.42 (1H, s, H-3′), 4.19-4.10 (2H, m, H-5″), 3.92 (1H, d, J 11.8 Hz, H-5′), 3.88 (1H, d, J 11.5 Hz, H-5′); MS FAB: 564 (M+H, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[O:3]1.[Br:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[BrH:17].[CH2:22]([O:21][C:19](=[O:20])[CH2:18][N:13]1[CH:14]=[C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)[CH:10]=[CH:11][C:12]1=[NH:15])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Br
Product: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5.0 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylamine in 7.6 ml of ethyl 2-bromoacetate are placed in a round-bottomed flask and the mixture is stirred at ambient temperature for 20 h. A precipitate forms, and is recovered by filtration, washed with diethyl ether and then with ethanol, and oven-dried under reduced pressure. 8.78 g of compound are obtained.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.Cl.Cl.C(OC([N:20]1[C:24]([NH:25][C:26](=[O:40])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)=[C:23]2[CH2:41][NH:42][C:43]([CH3:45])([CH3:44])[C:22]2=[N:21]1)=O)C.C(N(CC)C(C)C)(C)C.[F:55][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([F:62])[C:57]=1[NH2:63]>C(Cl)Cl>[F:55][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([F:62])[C:57]=1[NH:63][C:5]([N:42]1[CH2:41][C:23]2[C:22](=[N:21][NH:20][C:24]=2[NH:25][C:26](=[O:40])[C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:31][CH:32]=2)[C:43]1([CH3:44])[CH3:45])=[O:11]
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1)CNC2(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(F)cccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Nc3[nH]nc4c3CN(C(=O)Nc3c(F)cccc3F)C4(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.7 %

Procedure:
To a solution of triphosgene (195 mg, 0.65 mmol, 0.56 eq) in DCM (15 mL) was added a solution of 6,6-Dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester dihydrochloride (0.60 g, 1.15 mmol) in DCM (30 mL) followed by N,N-diisopropylethylamine (760 microL, 4.31 mmol, 3.75 eq). After 3 hours, a solution of 2,6-Difluoro-phenylamine (0.22, 1.72 mmol, 1.5 eq) and diisopropylethylamine (300 microL, 1.72 mmol, 1.5 eq) in DCM (8 mL) was added. The reaction was stirred overnight at room temperature. The solution was washed with brine, the organic phase was dried over sodium sulphate and concentrated. The residue was dissolved in methanol (16 mL), treated with TEA (1.6 mL, 11.5 mmol, 10 eq) and stirred overnight at room temperature. After evaporation of the solvent, the solid was purified by flash chromatography (CH2Cl2/MeOH/NH3 95/5/01). The solid was treated with diisopropylether and filtered to afford 0.37 g of the title compound in 64% yield.
Reaction SMILES: [CH:1]([N:4]=[C:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:15](Cl)([Cl:17])=[O:16]>C(Cl)Cl>[C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:15]([Cl:17])=[O:16])([CH3:7])=[CH2:6]
Reactant: CC(C)=NC(C)C
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)N(C(=O)Cl)C(C)C

Procedure:
99 parts of acetone isopropylimine and 94 parts of triethylamine are dissolved in 400 parts of methylene chloride, and the whole reacted with 120 parts of phosgene at a temperature of 30° to 40° C., as described in Example 1. After isolation, 131 parts (81% of the theory) of N-isopropenyl-N-isopropylcarbamyl chloride is obtained having a boiling point of 69° C. at 3 mm.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:4].C([Li])CCC.CCCCCC.Cl.[C:26](=O)([O-])[O-:27].[K+].[K+]>O1CCCC1.CN(C)C=O>[CH:26]([C:11]1[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1])=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:27]
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncccc1C=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
2,2-Dimethyl-N-pyridin-2-yl-propionamide (20.3 g) was dissolved in tetrahydrofuran (230 ml) to prepare a solution which was then cooled to −78° C. A 2.44 M n-butyllithium/n-hexane solution (100 ml) was gradually added dropwise thereto, and the mixture was stirred at −78° C. for 15 min. The reaction solution was stirred at 0° C. for 2 hr and was then again cooled to −78° C. A solution of N,N-dimethylformamide (25.0 g) in tetrahydrofuran (25 ml) was gradually added dropwise thereto. The temperature of the mixture was raised to room temperature. The reaction solution was then poured into a mixture of ice (50 g) and 6 N hydrochloric acid (150 ml), and the mixture was stirred at room temperature for 20 min. The aqueous layer was neutralized with potassium carbonate powder and was extracted with diethyl ether. The diethyl ether layer was then washed with water and saturated brine and was dried over magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give N-(3-formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (11.8 g, yield 50%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH2:22][CH2:21][CH2:20][N:12]3[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.B(Br)(Br)[Br:24].O>C(Cl)Cl>[BrH:24].[BrH:24].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]3[CH2:22][CH2:21][CH2:20][N:12]3[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Br
Product: Oc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 3g (10.3 mmoles) of 2-(4-methoxyphenyl)-3-(4-pyridyl)-6,7-dihydro [5H]pyrrolo [1,2-a]imidazole of Part c) above in 150 ml of dry methylene chloride was treated dropwise at -80° C. with a solution of 17.7 g (30.9 mmoles) of boron tribromide in methylene chloride and allowed to warm to room temperature overnight. The reaction mixture was chilled in an ice bath, 5 to 10 ml of water added, and the solvent removed in vacuo. The residue was recrystallized from hot water containing 0.5 ml. of 48% hydrobromic acid and dried in vacuo to afford the titled compound as bright yellow crystals, mp 257-258° C. Anal. Calcd. for C1H15N3O2HBr.1/3H20: C, 45.87; H, 4.00; N, 9.44. Found: C,45.66; H, 3.69; N,9.67.