Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH:10]12[O:22][CH:13]([CH2:14][CH:15]1[S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17])[CH:12]=[CH:11]2.CCCCCC>ClCCl>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:20]([NH:19][S:16]([CH:15]2[CH:10]3[O:22][CH:13]([CH:12]=[CH:11]3)[CH2:14]2)(=[O:17])=[O:18])=[O:21])[N:3]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)C1CC2C=CC1O2
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)C2CC3C=CC2O3)n1
Temperature: 0 °C
Yield: 90.8 %

Procedure:
30.7 g (0.25 mole) of 2-amino-4,6-dimethylpyrimidine were dissolved in 350 ml of dichloromethane and a solution of 52 g (0.26 mole) of 7-oxabicyclo[2.2.1]hept-2-en-6-ylsulfonyl isocyanate (Diels-Alder adduct of vinylsulfonyl isocyanate and furan) in 100 ml of dichloromethane was added at 0° C. with stirring. The mixture was stirred a further 12 hours at room temperature, cooled to 0° C. and n-hexane was added. The precipitated reaction product was filtered off with suction, washed with n-hexane and dried. 73.6 g (90.8% of theory) of N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-7-oxabicyclo[2.2.1]hept-2-en-6-ylsulfonamide having a melting point of 125°-145° C. were obtained.
Reaction SMILES: [Cl-].[C:2]([O:13][CH3:14])(=[O:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=O)=[CH:5][CH:4]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[N:15]1([C:7]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([O:13][CH3:14])=[O:12])=[CH:11][CH:10]=2)=[O:9])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)N2CCCC2)cc1

Procedure:
29.0 g (0.146 mol) of monomethyl terephthalate chloride was reacted with 14.2 g (200 mmol) of pyrrolidine and 21.0 g (208 mmol) of triethylamine in 350 ml of dichloromethane. After the treatment in an ordinary manner, methyl 4-(1-pyrrolidylcarbonyl)benzoate was obtained. 29.0 g of the ester was hydrolyzed with 12.0 g of sodium hydroxide in a mixed solvent comprising 70 ml of water, 70 ml of methanol and 70 ml of tetrahydrofuran. After the completion of the reaction, the solvent was evaporated. 1 N hydrochloric acid was added to the residue and the obtained mixture was treated with dichloromethane as the extraction solvent in an ordinary manner to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].CCN(CC)CC.N1C=CC=CC=1.[SH2:24].N#N>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4](=[S:24])[NH2:5]
Reactant: N#Cc1c(F)cccc1Cl
Reactant: S
Agent: N#N
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1c(F)cccc1Cl
Temperature: -19 °C
Yield: 71.8 %

Procedure:
2-Chloro-6-fluorobenzonitrile, (99.1%, 62.2 g, 0.40 mol) was weighed into a 1-L three-necked roundbottom flask equipped with a condenser and an overhead electric stirrer, along with Et3N (78 mL, 56.6 g, 0.56 mol) and 180 mL (176.04 g, 2.23 mol) of pyridine. The reactor was purged with a slow stream of N2 and vented to a 13% bleach solution. The stirring solution was cooled to −19° C. in a CCl4/dry ice bath, and H2S gas (33.6 g, 0.99 mol) was sparged below the liquid surface at a rate of 0.4 g/min over a period of 82 min. During the gas addition, the solution temperature rose to −11° C. The yellow-green solution was allowed to gradually warm to 25° C. and stir overnight with a slow N2 purge of the reactor head space into bleach solution. The solution was poured into 1.6 L of ice water, stirred, and the resulting white crystals were collected on a buchner funnel and rinsed with additional water. After 2 h of air drying, the moist filter cake was vacuum oven dried for 5 h at 65° C. to give 54.5 g of 2-Chloro-6-Fluorobenzthioamide (72% wt. % yield), mp 155-160° C., having a GC area % purity of 98.8% and containing 1.2% 2-Chloro-6-fluorobenzonitrile.
Reaction SMILES: [CH2:1]1[C:5]2=[CH:6][C:7]3[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1.[H-].[Na+].[CH2:16](I)[CH3:17]>CN(C)C=O>[CH2:16]([O:13][C:9]1[CH:10]=[CH:11][C:12]2[N:4]3[CH2:3][CH2:2][CH2:1][C:5]3=[CH:6][C:7]=2[CH:8]=1)[CH3:17]
Reactant: CCI
Reactant: Oc1ccc2c(c1)cc1n2CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)cc1n2CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
a solution of 64.00 g 2,3-dihydro-1H-3a-aza-cyclopenta[a]inden-6-ol in 240 mL N,N-dimethylformamide was added over 10 min to a cooled (0° C.) suspension of 17.73 g (0.406 mol) sodium hydride (55% in oil) in 400 mL N,N-dimethylformamide. The mixture was stirred at 0° C. for 30 min. To the resulting mixture was added 32.84 mL (63.39 g, 0.406mol) ethyl iodide dropwise over 10 min. The mixture was stirred at room temperature for 1 h. The mixture was partitioned between ice-water and ethyl acetate. The phases were separated and the organic phase was washed with 10% citric acid, 10% sodium bicarbonate solution and brine. The aqueous phases were re-extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated to dryness. The solid residue was stirred with 600 mL n-hexane for 1 h and the product collected by filtration. The filtrate was concentrated to obtain a second crop of product, to afford a combined yield of 66.4 g (89.3%) of the title compound as white crystals melting at 101-102° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20]CC)=O)=[CH:8][C:9]=1[NH:10]2.[CH2:23]([Mg]Cl)[CH3:24]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[Br:1][C:2]1[C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:18]4([OH:20])[CH2:24][CH2:23]4)=[CH:6][CH:5]=3)[NH:10][C:11]=2[C:12]([C:15]([NH2:16])=[O:17])=[CH:13][CH:14]=1
Reactant: CC[Mg]Cl
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Product: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C3(O)CC3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
Step 1 A solution of ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (Intermediate 48-1, 0.275 g, 0.761 mmol) was treated with titanium (IV) isopropoxide (0.31 mL, 1.07 mmol), followed by ethylmagnesium chloride (2 M in THF, 3.81 mL, 7.61 mmol). The mixture was stirred at rt for 1 h, then was cooled on ice and treated with water (10 mL). After 30 min, the solid was removed by filtration and rinsed with ether (150 mL). The organic layer was dried and concentrated to give 4-bromo-7-(1-hydroxycyclopropyl)-9H-carbazole-1-carboxamide as a yellow solid (0.220 g, 79%). 1H NMR (400 MHz, DMSO-d6) δ 11.65 (1 H, s), 8.52 (1 H, d, J=8.4 Hz), 8.25 (1 H, br. s.), 7.84-7.89 (2 H, m), 7.61 (1 H, br. s.), 7.45 (1 H, d, J=8.1 Hz), 7.13 (1 H, dd, J=8.5, 1.7 Hz), 6.11 (1 H, s), 1.21-1.27 (2 H, m), 1.06-1.11 (2 H, m).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C1COCC1>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: C1CNCCN1
Reactant: BrCc1ccccc1I
Solvent: C1CCOC1
Product: Ic1ccccc1CN1CCNCC1

Procedure:
Synthesized according to General Procedure A: 2-iodobenzyl bromide (4{27}, 4.92 g, 16.8 mmol, 1 equiv.), piperazine (8.70 g, 101.0 mmol, 6 equiv.), THF (36.7 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{27} (4.43 g, 89%) as a light yellow liquid. 1H-NMR (400 MHz, CDCl3): δ 7.80 (dd, 1H, J=1.2, 8.0 Hz) 7.39 (dd, 1H, J=1.2, 7.6 Hz), 7.30-7.26 (m, 1H), 6.91 (dt, 1H, J=1.2, 7.2 Hz), 3.47 (s, 2H), 2.86 (t, 4H, J=4.8 Hz), 2.46 (br s, 4H), 1.76 (br s, 1H). 13C-NMR (100 MHz, CDCl3): δ 140.4, 139.3, 130.2, 128.6, 127.8, 100.6, 66.9, 54.3, 46.0.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].C(O[CH:10](OCC)[N:11]([CH3:13])[CH3:12])C>>[CH3:10][N:11]([CH3:13])[CH:12]=[CH:4][C:3](=[O:5])[CH:2]([CH3:6])[CH3:1]
Reactant: CC(=O)C(C)C
Reactant: CCOC(OCC)N(C)C
Product: CC(C)C(=O)C=CN(C)C
Yield: 80 %

Procedure:
3-Methylbutan-2-one (2.5 g, 1 eq.) and dimethylformamide diethylacetal (7.46 mL, 1.5 eq.) were heated at 100° C. for 4 days to give compound 85 as yellow viscous oil in 80% yield, which was used directly without further purification in the next step.
Reaction SMILES: [CH2:1]([N:8]1[C@H:17]2[C@@H:12]([CH2:13][CH2:14][C:15](=O)[CH2:16]2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21]>C(O)C.N1C=CC=CC=1>[CH2:1]([N:8]1[C@H:17]2[C@@H:12]([CH2:13][CH2:14][C:15](=[N:20][OH:21])[CH2:16]2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC[C@H]2CCCN(Cc3ccccc3)[C@@H]2C1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C1CC[C@H]2CCCN(Cc3ccccc3)[C@@H]2C1
Yield: 88 %

Procedure:
To (±)-1-benzyl-trans-decahydro-7-quinolinone (D.11) (1.17 g), dissolved in ethanol (20 ml) and pyridine (0.8 ml), was added hydroxylamine hydrochloride (0.4 g), and the mixture was heated under reflux for 1 hr. On cooling, the ethanol was removed under reduced pressure and the residue was treated with dilute potassium carbonate solution. The product was extracted with chloroform and dried (K2CO3). Removal of the solvent afforded crude (±)-1-benzyl-trans-decahydro-7-quinolinone oxime (D.12) (1.1. g, ca 88%).
Reaction SMILES: [F:1][CH:2]1C(=O)[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:3]1.[CH3:18][O:19][CH:20](OC)[O:21][CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:18][O:19][C:20]1([O:21][CH3:22])[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:3][CH:2]1[F:1]
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1F
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC1(OC)CCN(c2ccc([N+](=O)[O-])cc2)CC1F
Temperature: 45 °C
Yield: 91 %

Procedure:
The mixture of 4-(3-fluoro-4-oxo-piperidin-1-yl)-nitrobenzene (51 mmol), trimethylorthoformate (103 mmol), p-toluene-sulphonic acid monohydrate (51 mmol) in methanol (100 ml) was heated at 45° C. for 24 hours. Solvent was removed and residual mass was taken into ethyl acetate and saturated sodium bicarbonate solution mixture. The organic layer was dried and removal of the solvent afforded title compound as a solid in 91% yield.
Reaction SMILES: [ClH:1].C(O[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:15])[CH3:14])[CH:8]=1)=[NH:6])C.C(=O)([O-])[O-].[NH4+:20].[NH4+]>C(O)C>[ClH:1].[C:13]([C:9]1[CH:8]=[C:7]([C:5](=[NH:6])[NH2:20])[CH:12]=[CH:11][CH:10]=1)(=[O:15])[CH3:14]
Reactant: [NH4+]
Reactant: CCOC(=N)c1cccc(C(C)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CC(=O)c1cccc(C(=N)N)c1

Procedure:
A mixture of 14 g. (0.08 mole) of 3-acetylbenzenecarboximidic acid ethyl ester, hydrochloride of A. above and 14 g. (0.15 mole) of finely ground ammonium carbonate in 100 ml. of ethanol is heated at boiling temperature in an open flask for 3 hours. The solution is cooled and the first small amount of precipitate is collected and is discarded. The filtrate is further cooled to precipitate 6.7 g. of product with a melting point of 193° (dec.).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[O:10])[C:6]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)=[C:15]([CH3:32])[CH:14]=2)=[N:5][C:4]=1[C:33]1[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=1)[CH3:2].C(O)C>[Pd].O1CCCC1>[CH2:1]([C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[O:10])[C:6]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][CH:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)[CH2:23][CH2:24]3)=[C:15]([CH3:32])[CH:14]=2)=[N:5][C:4]=1[CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH3:2]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1C1=CCNCC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1C1CCNCC1
Yield: 86.7 %

Procedure:
A mixture of 6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazine-2-carboxamide (100 mg), ethanol (3.9 mL), and tetrahydrofuran (1 mL) was reacted using a continuous hydrogenation reaction device (H-Cube (registered trademark); manufactured by ThalesNano) under the conditions of CatCart (registered trademark) 10% palladium-supported carbon (manufactured by ThalesNano), a flow rate of 1 mL/min, a temperature of 70° C., and a pressure of 1015 psi. The solvent was evaporated under reduced pressure to obtain 6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(piperidin-4-yl)pyrazine-2-carboxamide (87 mg) as a yellow solid.
Reaction SMILES: [CH:1]([C:3]1[C:19]2[CH:18]=[C:17](C(OCC)=O)[O:16][C:15]=2[C:14]2[CH:13]=[CH:12][C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]=2[CH:4]=1)=[O:2].[OH-].[Na+].C1COCC1.Cl>O>[CH:18]1[C:19]2[C:3]([CH:1]=[O:2])=[CH:4][C:5]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[CH:12]=[CH:13][C:14]=3[C:15]=2[O:16][CH:17]=1
Reactant: CCOC(=O)c1cc2c(C=O)cc3c4ccccc4ccc3c2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc2c3ccccc3ccc2c2occc12
Yield: 37 %

Procedure:
To a RB flask equipped with magnetic stirring bar, condenser, and N2 inlet line with bubbler was added ethyl 11-formyl-phenanthro[1,2-b]furan-2-carboxylate (15A, 2.5 g, 7.8 mmol), 1N NaOH solution (25 mL), THF (50 mL) and H2O (25 mL). The mixture was refluxed for 2 h until it became homogeneous. The mixture was acidified with 1N HCl and the solvent removed by rotary evaporation. The crude solid was then heated to 150° with copper powder (0.9 g) and quinoline (Aldrich, 25 mL) for 1 h. The reaction mixture was cooled and the quinoline removed under vacuum to give a crude dark green solid. After chromatography and crystallization (CH2Cl2 /hexane) 0.71 g (37% yield) of phenanthro[1,2-b]furan-11-carbaldehyde, mp 145°-150°, (C,H).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([O:23][CH3:24])(=[O:22])[C@@H:19]([CH3:21])[OH:20].[CH:25]([O:27][CH2:28][CH3:29])=[CH2:26]>C(OCC)(=O)C>[CH2:25]([O:27][CH:28]([O:20][C@H:19]([CH3:21])[C:18]([O:23][CH3:24])=[O:22])[CH3:29])[CH3:26]
Reactant: C=COCC
Reactant: COC(=O)[C@@H](C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Product: CCOC(C)O[C@H](C)C(=O)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 139 %

Procedure:
A catalytic amount of pyridinium para-toluenesulfonate was added to 20.8 g (0.2 mole) of methyl (R)-(-+)-lactate (98.9% e.e) and 18.7 g (0.26 mole) of ethyl vinyl ether. The resulting mixture was stirred at room temperature for 6 hours. After the reaction, thereto was added 100 ml of ethyl acetate, followed by washing with 70 ml of a saturated aqueous sodium hydrogen carbonate solution, 70 ml of water and 70 ml of a saturated aqueous sodium chloride solution in this order. The washed material was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent. The resulting concentrate was subjected to distillation to obtain 49.0 g (yield: 97.8%) of an oily title compound (diastereomixture).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[Cl:19])=[CH:16][CH:15]=[CH:14][CH:13]=2.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:8][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: CCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A solution of valeryl chloride (13.3 mL, 112 mmol) in dichloromethane (35 mL) was added dropwise to a stirred solution of 3-amino-4-chloroquinoline (10.0 g, 56 mmol) and triethylamine (2.1 mL, 15 mmol) in dichloromethane (100 mL), and the reaction was stirred overnight at room temperature and then stirred for one hour with saturated aqueous sodium bicarbonate (150 mL). The aqueous layer was separated and extracted with dichloromethane (2×50 mL). The combined organic fractions were washed with saturated aqueous sodium bicarbonate (50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure. The residue was recrystallized from toluene/hexane to provide 11.1 g of N-(4-chloroquinolin-3-yl)pentanamide as a light brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[N:6][CH:7]=1.CC1(C)C(C)(C)[O:24][B:23](B2OC(C)(C)C(C)(C)O2)[O:22]1.C([O-])(=O)C.[K+]>O1CCOCC1>[O:19]=[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17](=[O:18])[N:9]1[CH2:8][C:5]1[N:6]=[CH:7][C:2]([B:23]([OH:24])[OH:22])=[CH:3][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(Br)cn1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(B(O)O)cn1
Temperature: 70 °C
Yield: 99.3 %

Procedure:
To a mixture of 2-((5-bromopyridin-2-yl)methyl)isoindoline-1,3-dione (317 mg, 1.000 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (381 mg, 1.499 mmol) in dioxane (10 mL) at rt under nitrogen was added potassium acetate (294 mg, 3.00 mmol), followed by PdCl2(dppf)-CH2Cl2Adduct (82 mg, 0.100 mmol). At this time, the reaction mixture was heated to 70° C. under nitrogen for 5 hr. After cooling to rt, the solvent was removed on the rotovap and the residue was taken up in EtOAc (30 ml). The mixture was filtered through celite and the filter cake was thoroughly washed with EtOAc. The EtOAc filtrate was concentrated to afford (6-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-3-yl)boronic acid (280 mg, 0.993 mmol, 99% yield) as a brown oil. This material was used as is in the next step. MS (ES+) m/z: 283.1 (M+H); LC retention time: 0.54 min (analytical LCMS Method B).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19]CC)=[O:18])=[C:4]2[CH2:3]1.[OH-].[Na+].Cl>C(O)C.O>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([OH:19])=[O:18])=[C:4]2[CH2:3]1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1Cc2c(C(=O)O)ncn2-c2ccccc2C1=O

Procedure:
A solution of 14.26 g (0.05 mol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate and 2.2 g (0.055 mol) of sodium hydroxide in 100 ml of ethanol and 20 ml of water is heated to boiling under reflux for 45 minutes and subsequently treated with 55 ml of 1 N hydrochloric acid and 50 ml of water. After distillation of the ethanol, the resulting crystal slurry is filtered off under suction, washed with water and dried. There is obtained 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid of melting point 287°.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1.[C:28]([O:32][CH3:33])(=[O:31])[NH:29][NH2:30]>CO.ClCCl>[CH3:33][O:32][C:28]([NH:29][N:30]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:6][CH2:7]1)=[O:31]
Reactant: O=C1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Reactant: COC(=O)NN
Solvent: CO
Solvent: ClCCl
Product: COC(=O)NN=C1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.4 %

Procedure:
3-(4-(4-Oxopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (125 mg, 0.33 mmol) was dissolved in MeOH (5 ml) and dichloromethane (5 ml), methyl carbazate (34 mg, 0.37 mmol) added, and the mixture stirred at ambient temperature under nitrogen for 18 hours. The mixture was evaporated, and the residue purified by chromatography on a 5 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 1% MeOH in dichloromethane. Relevant fractions were combined to give the desired product (98 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:18])=[N:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[NH2:19][C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.I([O-])(=O)(=O)=O.[Na+].CO>O>[OH:9][CH:8]1[C@H:7]([N:6]2[CH:16]=[C:2]([F:1])[C:3]([NH2:18])=[N:4][C:5]2=[O:17])[O:15][C@H:12]([CH2:13][OH:14])[CH:10]([OH:11])[N:19]1[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: Nc1nc(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1F
Reactant: Nc1ncccn1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: Nc1nc(=O)n([C@@H]2O[C@H](CO)C(O)N(c3ncccn3)C2O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of 5-fluorocytidine (2.42 g) and 2-aminopyrimidine (0.95 g) in water (50 ml) was added sodium metaperiodate (2.13 g) under cooling with an ice-water bath. The solution was stirred at ambient temperature for 8 hours. To the reaction mixture was added methanol (50 ml). The precipitate was filtered off and the filtrate was evaporated in vacuo. The residue was triturated with acetone and air-dried to give 1-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]-5-fluorocytosine (2.3 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][OH:11])[CH:8]=1)([O-])=O>CCOC(C)=O.CCO.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][OH:11])[CH:8]=1
Reactant: O=[N+]([O-])c1cnn(CCO)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cnn(CCO)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(4-nitro-1H-pyrazol-1-yl)ethanol (9.12 g, 58.07 mmol) in EtOAc (20 mL, degassed) and EtOH (60 mL, degassed), PtO2 (1.13 g, 5.81 mmol) was added and the reaction mixture was stirred at rt under a H2-atmosphere for 18 h. The mixture was diluted with EtOH, filtered over celite and the filter cake was rinsed with EtOH. The filtrate was concentrated to obtain 2-(4-amino-1H-pyrazol-1-yl)ethanol as a red oil, which was used in the next step without further purification. LC-MS conditions A: tR=0.14 min, [M+H]+=128.24.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:19]I>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:16])[CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:19])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C(=O)Cc2ccccc2)ccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)C(C)c2ccccc2)ccn1
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
1-(2-Methyl-pyridin-4-yl)-2-phenyl-ethanone (233 mg, 1.1 mmol, solution in 5 mL DMF) was added over 15 min to a suspension of NaH (55% in mineral oil, 58 mg, 1.3 mmol) in DMF (2 mL). After 30 min, methyl iodide (0.07 mL, 1.2 mmol) was added slowly drop by drop. The mixture was poured onto ice and extracted with ethyl acetate. The combined organic layers were washed (brine), dried (Na2SO4), and the solvent was evaporated. Purification by column chromatography (silica gel, heptane:ethyl acetate=100:0-50:50) afforded the title compound (142 mg, 54%). 1H NMR (300 MHz, DMSO-D6) 8.56 (1H, d), 7.68 (1H, s), 7.61 (1H, d), 7.30-7.27 (4H, m), 7.20-7.18 (1H, m), 4.92 (1H, q), 1.40 (3H, d); MS (m/e)=226.3 [MH+].