Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[C:5]=2[CH:6]=[O:7])[CH2:3][CH2:2]1.Cl([O-])=[O:21].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C.O>[CH:1]1([C:4]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:17])([F:18])[F:19])[C:5]=2[C:6]([OH:21])=[O:7])[CH2:3][CH2:2]1
Reactant: O=Cc1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude 2-cyclopropyl-4,6-bis-trifluoromethyl-benzaldehyde (intermediate AM, 1.01 g, 3.58 mmol) was dissolved in 8.5 mL tert-butylalcohol and 4.5 mL 2-methyl-2-butene. At 0° C. a solution of sodium chlorite (340 mg, 3.76 mmol) and sodium dihydrogenphosphat (451 mg, 3.76 mmol) in 3 mL water was added. The reaction mixture was stirred at room temperature overnight. The solvents were evaporated off. The residue was taken up in 1N NaOH and extracted twice with tert-butyl methyl ether. The aqueous phase was adjusted to pH 2 by addition of 25% HCl and extracted twice with tert-butyl methyl ether. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude material, off-white solid (1.01 g, 54%) was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1OC
Reactant: c1cn[nH]c1
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc(C(F)(F)F)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with yields 2-chloro-6-trifluoromethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-trifluoromethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH3:11][Si:12]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>O1CCCC1>[O:4]=[C:2]([CH:15]([CH2:14][CH2:13][Si:12]([CH3:21])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:11])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)CCC[Si](C)(C)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(CC[Si](C)(C)c1ccccc1)C(=O)OCC
Temperature: 25 °C
Yield: 92.2 %

Procedure:
In a flask under a nitrogen atmosphere were placed 1.7 g (0.075 mole) metallic sodium and 75 mL of absolute ethanol. When all of the sodium had reacted, the remaining ethanol was evaporated, leaving solid sodium ethoxide. To this solid were added successively 100 mL of dry tetrahydrofuran, 11.0 g (0.075 mole) of diethyl oxalate, and 12.95 g (0.0517 mole) of ethyl 5-methyl-5-phenyl-5-silahexanoate. This mixture was heated at reflux for one hour after which it was cooled to ambient temperature before being poured into 240 mL of 0.5N hydrochloric acid. This mixture was extracted with 200 mL of diethyl ether. The extract was evaporated under reduced pressure, leaving 16.7 g of diethyl 2-oxo-3-(3-methyl-3-phenyl-3-silabutyl)succinate as an oil. This reaction was repeated to provide additional product for subsequent steps in this synthesis.
Reaction SMILES: [CH:1]([C:4]1[NH:14][C:7]2[C:8](=[O:13])[NH:9][CH:10]=[C:11](Br)[C:6]=2[N:5]=1)([CH3:3])[CH3:2].[C:15]([Cu])#[N:16]>CN(C=O)C>[CH:1]([C:4]1[NH:14][C:7]2[C:8](=[O:13])[NH:9][CH:10]=[C:11]([C:15]#[N:16])[C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: N#C[Cu]
Reactant: CC(C)c1nc2c(Br)c[nH]c(=O)c2[nH]1
Solvent: CN(C)C=O
Product: CC(C)c1nc2c(C#N)c[nH]c(=O)c2[nH]1

Procedure:
By reaction of 2-isopropyl-3,5-dihydro-7-bromoimidazo-[4,5-c]pyridin-4-one with CuCN in DMF by customary methods (Ellefson et al., J. Med. Chem. 1976, 19), 2-isopropyl-3,5-dihydro-7-cyanoimidazo[4,5-c]pyridin-4-one is obtained. This is then hydrolysed and alkylated analogously to Examples 1 and 4 and hydrogenated analogously to Example 3. In this process, the carboxylic acid derivatives listed under Example 6 are obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10]CC(C)(C)N=2)=[CH:5][CH:4]=1)[CH3:2].CCCCCC.C([Li])CCC.[CH2:27]([N:34]1[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[ClH:41].[OH-].[Na+]>O1CCCC1>[ClH:41].[CH2:27]([N:34]1[CH2:39][CH2:38][C:37]2([C:7]3[C:6](=[CH:5][CH:4]=[C:3]([CH2:1][CH3:2])[CH:8]=3)[C:9](=[O:10])[O:40]2)[CH2:36][CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCc1ccc(C2=NC(C)(C)CO2)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1ccc2c(c1)C1(CCN(Cc3ccccc3)CC1)OC2=O
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, a solution of 2-(4-ethylphenyl)-4,4-dimethyl-2-oxazoline (1.15 g) in anhydrous tetrahydrofuran (100 mL) was cooled to −78° C. To this solution was added 1.5 M butyl lithium hexane solution (4.53 mL). After being stirred for 1 hour, 1-benzyl-4-piperidone (1.05 mL) was added dropwise. After the reaction temperature was allowed to rise up to room temperature, 2N hydrochloric acid was added to the reaction mixture to make the mixture acidic. The whole was refluxed for 2 hours. After cooling, sodium hydroxide aqueous solution was added to make the reaction mixture basic. The mixture was extracted with ethyl ether. The organic layer was washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the organic solvent left a residue, which was purified by column chromatography on silica gel (hexane/ethyl acetate/=3/2) to give the subject compound (409 mg).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([CH2:23][O:24][CH3:25])=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[NH:4][N:3]=1.N1C=CC=CC=1.[C:32](Cl)([CH3:34])=[O:33].[OH-].[Na+]>C1COCC1>[CH3:25][O:24][CH2:23][C:7]1[C:6]2[C:2]([NH:1][C:32](=[O:33])[CH3:34])=[N:3][NH:4][C:5]=2[CH:10]=[C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[O:13])[N:8]=1
Reactant: COCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2[nH]nc(N)c12
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2[nH]nc(NC(C)=O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (R)-1-(3-amino-4-(methoxymethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (30 mg, 0.088 mmol) in THF (1 ml) was charged with pyridine (72 μl, 0.890 mmol) and AcCl (62 μl, 0.872 mmol). The mixture was stirred at RT for 17 hr before 1N NaOH (1.2 ml, 1.200 mmol) was added and stirred at RT for 2 hr and then heated to 50° C. for 1 hr. The reaction was quenched with sat aq NH4Cl and extracted into EtOAc. The mixture was washed with sat aq NH4Cl followed by brine, dried over MgSO4, filtered, concentrated in vacuo and purified via flash chromatography (0-20% MeOH/DCM) to give (R)—N-(4-(methoxymethyl)-6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide. MS ESI calc'd for C19H23N6O3 [M+H]+ 383. found 383. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.01 (s, 1H), 9.13 (s, 1H), 7.33 (m, 5H), 7.22 (m, 1H), 4.89 (t, J=6.8 Hz), 4.59 (s, 2H), 3.28 (s, 3H), 2.06 (s, 3H), 1.39 (d, 5.1 Hz).
Reaction SMILES: CO/[N:3]=[CH:4]/[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([F:12])[C:6]=1F.O.[NH2:15]N>C1COCC1>[Br:11][C:9]1[CH:10]=[C:5]2[C:6](=[C:7]([F:12])[CH:8]=1)[NH:15][N:3]=[CH:4]2
Reactant: CO/N=C/c1cc(Br)cc(F)c1F
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc(Br)cc2cn[nH]c12
Temperature: 90 °C

Procedure:
A mixture of (E)-5-bromo-2,3-difluorobenzaldehyde O-methyl oxime (19.65 g, 78.6 mmol), hydrazine hydrate (80 mL), and dry THF (80 mL), was heated at 90° C. for 84 h. Work-up: the organic solvent was evaporated. The resulting mixture was diluted with EtOAc (400 mL), washed with water (150 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0=20% EtOAc in petroleum ether) to give 5-bromo-7-fluoro-1H-indazole as a white solid (9.3 g). 1H NMR (300 MHz, CDCl3): δ 13.83 (br, 1H), 8.16 (s, 1H), 7.87 (s, 1H), 7.45 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21]CC)[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][OH:31])[CH:25]=3)=[CH:5][C:4]=2[N:3]=1.B(Br)(Br)Br.CO>ClCCl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][OH:21])[N:14]([CH2:15][C:16]([CH3:17])([OH:18])[CH3:19])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][OH:31])[CH:25]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccc(CO)c4)cnc3c2n1CC(C)(C)O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(C)(O)Cn1c(CO)nc2c(N)nc3cc(-c4cccc(CO)c4)cnc3c21
Temperature: 0 °C
Reaction time: 15 h
Yield: 19.5 %

Procedure:
A suspension of 1-{4-amino-2-(ethoxymethyl)-7-[3-(hydroxymethyl)phenyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (0.800 g, 1.90 mmol) obtained from the filtrate from the trituration in Example 66, in dichloromethane (20 mL) was cooled to 0° C. Boron tribromide (9.5 mL of a 1 M solution in dichloromethane) was added dropwise, and the resulting suspension was stirred at room temperature for 15 hours. Methanol was carefully added, and the resulting solution was stirred at room temperature for one hour and concentrated under reduced pressure. The residue (1.33 g) was dissolved in DMF (15 mL), and potassium acetate was added. The mixture was heated at 50° C. for 18 hours and then concentrated under reduced pressure. The residue was dissolved in methanol (20 mL) and water (10 mL), and lithium hydroxide monohydrate (1.5 g) was added. The reaction was stirred at room temperature for 64 hours and concentrated under reduced pressure. Methanol and silica gel were added, and the mixture was concentrated under reduced pressure. The residue was purified by automated flash chromatography (FLASH 40+M cartridge, eluting with 7% to 20% 1 M methanolic ammonia in dichloromethane) followed by recrystallization from acetonitrile after a hot filtration. The crystals were washed with acetonitrile and dried in a vacuum oven at 65° C. to provide 146 mg of 1-{4-amino-2-(hydroxymethyl)-7-[3-(hydroxymethyl)phenyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as a yellow solid, mp 227-229° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1[C:15]2[N:10]([CH:11]=[CH:12][C:13](=[O:16])[CH:14]=2)[CH2:9][CH:8]=1.C(OC(OCC)CCCN)C.CCOC(CC(CC(OCC)=O)=O)=O.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH:7]1[CH:8]=[CH:9][N:10]2[C:15]=1[CH:14]=[C:13]([OH:16])[CH:12]=[CH:11]2
Reactant: O=c1ccn2c(c1)C=CC2
Agent: CCOC(=O)CC(=O)CC(=O)OCC
Agent: CCOC(CCCN)OCC
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccn2cccc2c1
Yield: 60.7 %

Procedure:
To a suspension of lithium aluminum hydride (2.30 g) in tetrahydrofuran (50 ml) was added dropwise indolizin-7-one (2.80 g), which was prepared from 4,4-diethoxybutylamine and diethyl 1,3-acetonedicarboxylate according to the method described in Heterocycles, 43, 1391 (1996), with stirring under ice-cooling under a nitrogen atmosphere, and the resulting mixture was stirred at the same temperature for 1 hour. After stirring, to the reaction mixture was added sodium sulfate decahydrate, and the resulting mixture was furthermore stirred at room temperature for 1 hour. After removing insoluble materials by filtration, the filtrate was evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of dichloromethane and methanol (4:1) as the eluent to afford the title compound (1.70 g, yield: 59%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:35])([F:34])[C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:8]([N:10]1[CH2:26][CH2:25][C:13]2([N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][NH:15][C:14]2=[O:24])[CH2:12][CH2:11]1)=[O:9].Cl.Cl[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[F:35][C:4]([F:3])([F:34])[C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:8]([N:10]1[CH2:11][CH2:12][C:13]2([N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:16][N:15]([CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[C:14]2=[O:24])[CH2:25][CH2:26]1)=[O:9]
Reactant: ClCCN1CCOCC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN1CCCC1=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCN1CCOCC1)CN2c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
Sodium hydride (34 mg, 60%) was suspended in N-methyl-2-pyrrolidone (2 mL) and 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (200 mg) was added with stirring. After 5 minutes stirring at room temperature 4-(2-chloroethyl)morpholine hydrochloride (79 mg) was added. The mixture was heated to 100° C. with stirring and kept for 1 h at that temperature. After cooling, saturated sodium bicarbonate solution was added and the mixture was extracted with ethylacetate. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. Chromatography on silica gel (ethylacetate) yielded the desired product (180 mg, 73%), MS: m/e=585.1 (M+H+).
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([NH:29][C:30](=[O:37])[C@H:31]([CH2:33][C:34](=[O:36])[NH2:35])[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:30](=[O:37])[C@H:31]([CH2:33][C:34](=[O:36])[NH2:35])[NH2:32])=[O:16])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: NC(=O)C[C@H](N)C(=O)NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)C[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 50.8 %

Procedure:
Using the procedure described previously, a heterogeneous solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (152 mg, 0.52 mmol, 1.0 eq), L-asparagine N-benzylamide (231 mg, 1.04 mmol, 2.0 eq) and dichloromethane (1.5 mL), was treated with triethylamine (436 uL, 3.1 mmol, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (663 uL, 1.04 mL, 2.0 eq), to provide 130.7 mg (51%) of L-asparagine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide as a white foam.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:22]([O:24]CC)=[O:23])=[N:4][N:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[OH-].[K+]>CO>[Br:1][C:2]1[C:3]([C:22]([OH:24])=[O:23])=[N:4][N:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1Br
Temperature: 100 °C
Reaction time: 5 h
Yield: 97.2 %

Procedure:
To a solution of ethyl 4-bromo-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylate (3.5 g, 7.37 mmol) in methanol (50 ml) at room temperature was added potassium hydroxide (830 mg, 14.8 mmol) in one portion. The reaction mixture was warmed to 100° C. and then stirred for 5 hours. The resulting solution was cooled down to room temperature and then evaporated the volatile solvent. The residue was acidified with 10% hydrochloric acid and then filtered using water and hexane. The filtrated solid was dried under vacuum to obtain the title compound (3.2 g, 97%) as pale yellow solid.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:8][CH:7]2[NH:9][CH:3]1[CH2:4][CH:5]([C:10]([O:12]C)=[O:11])[CH2:6]2.Br[CH2:16][C:17]1[NH:22][C:21]([C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[N:20][C@@H:19]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=2[Cl:35])[C:18]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[Cl:35][C:29]1[C:30]([F:34])=[CH:31][CH:32]=[CH:33][C:28]=1[C@H:19]1[C:18]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:17]([CH2:16][N:9]2[CH:3]3[C:2]([F:14])([F:1])[CH2:8][CH:7]2[CH2:6][CH:5]([C:10]([OH:12])=[O:11])[CH2:4]3)[NH:22][C:21]([C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[N:20]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1cccc(F)c1Cl
Reactant: COC(=O)C1CC2CC(F)(F)C(C1)N2
Product: CCOC(=O)C1=C(CN2C3CC(C(=O)O)CC2C(F)(F)C3)NC(c2nccs2)=N[C@H]1c1cccc(F)c1Cl
Yield: 6 %

Procedure:
The title compound was prepared in analogy to Example 1, by using methyl 6,6-difluoro-8-azabicyclo[3.2.1]octane-3-carboxylate 150a (200 mg) and ethyl (4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 98a (400 mg). 30 mg of the title compound was isolated finally after preparative HPLC purification. Preparation of methyl 6,6-difluoro-8-azabicyclo[3.2.1]octane-3-carboxylate 150a:
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[NH2:5][C:6]1[N:14]=[C:13]([O:15][CH2:16][CH2:17][O:18][CH3:19])[N:12]=[C:11]2[C:7]=1[N:8]=[C:9](Br)[N:10]2[CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>CO.C(COC)OC>[NH2:5][C:6]1[N:14]=[C:13]([O:15][CH2:16][CH2:17][O:18][CH3:19])[N:12]=[C:11]2[C:7]=1[N:8]=[C:9]([O:2][CH3:1])[N:10]2[CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1
Reactant: COCCOc1nc(N)c2nc(Br)n(Cc3ccc(C#N)cc3)c2n1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: COCCOC
Solvent: CO
Product: COCCOc1nc(N)c2nc(OC)n(Cc3ccc(C#N)cc3)c2n1
Temperature: 100 °C

Procedure:
Sodium methoxide is generated by reaction of sodium metal (81 mg) in dry methanol (30 mL). The product of example 4 (700 mg) is dissolved in dry dimethoxyethane and the temperature raised to 100° C. After overnight reaction, the mixture is concentrated in vacuo and the residue is chromatographed on silica using 5% methanol in dichloromethane. Yield 120 mg. NMR is consistent with structure assignment.
Reaction SMILES: ClC(Cl)(Cl)C(OC(=O)C(Cl)(Cl)Cl)=O.CS(C)=O.[C:18]([Si:22]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[O:23][CH:24]1[CH:28]([CH2:29][OH:30])[O:27][CH:26]([N:31]2[CH:36]=[CH:35][C:34](=[O:37])[NH:33][C:32]2=[O:38])[CH:25]1[O:39][C:40](=[O:42])[CH3:41])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:18]([Si:22]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[O:23][CH:24]1[CH:28]([CH:29]=[O:30])[O:27][CH:26]([N:31]2[CH:36]=[CH:35][C:34](=[O:37])[NH:33][C:32]2=[O:38])[CH:25]1[O:39][C:40](=[O:42])[CH3:41])([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(=O)OC1C(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(CO)OC1n1ccc(=O)[nH]c1=O
Agent: O=C(OC(=O)C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)OC1C(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(C=O)OC1n1ccc(=O)[nH]c1=O
Reaction time: 0.5 h

Procedure:
To a mixture of trichloroacetic anhydride (1.5 eq.) and dimethylsulfoxide (2.0 eq.) in dichloromethane at −78° C. is added a solution of Compound 9 in dichloromethane. After 30 minutes, triethylamine (4.5 eq.) is added. Subsequently, the mixture is poured into ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The resulting material is carried into the next step without further purification. This procedure has been used to prepare the related 4′-C-α-formyl nucleosides (Nomura, M., et. al., J. Med. Chem. 1999, 42, 2901-2908).
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=[O:8].[Na+].[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C@H:19]1[CH2:25][N:24]2[C:26]([CH:29]=[O:30])=[CH:27][N:28]=[C:23]2[C@H:22]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:21][CH2:20]1.CC(=CC)C>O1CCCC1.O.C(O)(C)(C)C>[C:34]([O:33][C:32]([NH:31][C@@H:22]1[CH2:21][CH2:20][C@@H:19]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=2[F:11])[CH2:25][N:24]2[C:26]([C:29]([OH:8])=[O:30])=[CH:27][N:28]=[C:23]12)=[O:38])([CH3:35])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C=O)cnc21
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(=O)O)cnc21
Reaction time: 3 h

Procedure:
Sodium dihydrogen phosphate (127 mg, 0.92 mmol) and sodium chlorite (42 mg, 0.46 mmol) were added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-formyl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (45 mg, 0.12 mmol) in tetrahydrofuran (0.8 mL), water (0.8 mL), tert-butanol (0.2 mL), and 2-methyl-2-butene (0.2 mL). After 3 h of vigorously stirring, the reaction mixture was quenched with saturated solution of ammonium chloride. The mixture was extracted with ethyl acetate (3×), and the combined organic extracts were washed with water, saturated brine, dried over sodium sulfate, filtered and concentrated. MS 408.1 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[S:17][CH:18]=[CH:19][C:20]=2[S:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[C:6]1[CH3:31].O1CCCC1.[OH-].[Na+].Cl>CO>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:32])=[O:2])[C:6]([CH3:31])=[C:7]2[CH2:15][C:16]1[S:17][CH:18]=[CH:19][C:20]=1[S:21]([C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)(=[O:23])=[O:22]
Reactant: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2ccc(F)cc2)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Cc2sccc2S(=O)(=O)c2ccc(F)cc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 40 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A mixture of {5-fluoro-3-[3-(4-fluorobenzenesulfonyl)thiophen-2-ylmethyl]-2-methylindol-1-yl}acetic acid methyl ester (0.17 g), tetrahydrofuran (2.0 mL) and methanol (1.0 mL) was treated with 5.0 M aqueous sodium hydroxide solution (1.5 mL), and the resulting mixture was stirred at 40° C. overnight. The mixture was acidified by the addition of 5.0 M aqueous hydrochloric acid solution and concentrated to low bulk under reduced pressure. The resulting precipitate was collected by filtration, washed with water and dried to afford the title compound as a cream solid (0.11 g).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]1[CH2:33][OH:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[C:4]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]2[CH2:33][OH:34])[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6]1
Reactant: OC[C@H]1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOC[C@@H]2CO)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 60.6 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.92 g, 2 mmol) was reacted with (S)-morpholin-3-ylmethanol (0.24 g, 2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a pale yellow solid (0.6 g, 61%). The compound was characterized by the following spectroscopic data: