Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:27]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:34])[N:27]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
To a mixture of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine, hydrochloride (37.1 g, 0.10 mol, see Example 1b, step 5) and phenyl pyridazin-3-ylcarbamate (21.5 g, 0.10 mol, see Example 39, steps 1 and 2) in acetonitrile (400 mL) was added dropwise diisopropylethyl amine (25.8 g, 0.20 mol). A solution formed after 2 h of stirring. The slightly turbid solution was stirred at ambient temperature for 17 h. It was poured into 2.5 L of stirred ice-water. The resulting mixture was stirred for 1 h. The solid was filtered off, rinsed with 300 mL of water and pressed dry under suction. This was dissolved in 400 mL of dichloromethane. Water was removed using a sep funnel and then the solution was dried over magnesium sulfate and concentrated in vacuo to ˜50 mL. The viscous solution was diluted with 65 mL of ethyl acetate and then with 85 mL of methyl t-butyl ether. A solution formed, and then a solid began separating. The crystallizing mixture was kept at −10° C. for 2 h and filtered. The solid was rinsed with EtOAc:MTBE (40 mL) and pressed dry under suction. Further drying in vacuo at 40° C. for 7 h provided 30.3 g (66%) of product. The mother liquor was concentrated in vacuo to 19 g of a viscous oil. This was dissolved in 15 mL of ethyl acetate. The solution was diluted with 60 mL of methyl t-butyl ether, seeded and kept at 5° C. for 18 h. The solid which crystallized was filtered off, rinsed with 10 mL of methyl t-butyl ether, and pressed dry under suction. 9.0 g (20%) of additional product was obtained. Total yield=39.3 g (86%).
Reaction SMILES: [CH3:1][C:2]1([NH:8][C:9]2[C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:22][C:23]1[CH:24]=[C:25]([CH:29](OS(C)(=O)=O)[CH3:30])[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([CH:29]([N:5]2[CH2:6][CH2:7][C:2]([NH:8][C:9]3[C:10]4[C:17]5[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=5[S:15][C:11]=4[N:12]=[CH:13][N:14]=3)([CH3:1])[CH2:3][CH2:4]2)[CH3:30])[CH:26]=[CH:27][CH:28]=1
Reactant: CC(OS(C)(=O)=O)c1cccc(F)c1
Reactant: CC1(Nc2ncnc3sc4c(c23)CCCC4)CCNCC1
Product: CC(c1cccc(F)c1)N1CCC(C)(Nc2ncnc3sc4c(c23)CCCC4)CC1

Procedure:
The title compound was prepared (97 mg, 81%) from (4-methyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine (150 mg, 0.28 mmol) and methanesulfonic acid 1-(3-fluoro-phenyl)-ethyl ester (61.1 mg, 0.28 mmol) by following the procedure described for preparation 12. 1H NMR (400 MHz, CDCl3): 8 (ppm) 8.38 (s, 1H), 7.20 (s, 1H), 6.89-6.79 (m, 3H), 3.91 (q, 1H), 2.80-2.74 (m, 4H), 2.20-2.09 (M, 2H), 1.90 (m, 2H), 1.89-1.85 (m, 4H), 1.55 (m, 4H), 1.31 (s, 3H); MS (SEI): m/z: Calculated: 424.2; Observed: 425.2 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[F:11][C:12]([F:18])([F:17])[CH2:13][C:14](O)=O>Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:14]([CH2:13][C:12]([F:18])([F:17])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C(O)CC(F)(F)F
Agent: Cl
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 100 °C

Procedure:
To 4,5-dichloro-1,2-phenylenediamine (25 g) was added 3,3,3-trifluoropropionic acid (25 mls) and 4N HCl (90 mL). The resulting mixture was heated to 100° C. overnight. The reaction mixture was quenched with water, basicified with concentrated NH4OH, extracted with EtOAc, and dried over Na2SO4. The crude product was filtered through a plug of silica gel, eluting with 30% EtOAc/hexanes, and collecting the red band. The fractions were concentrated to yield a mixture of the desired title compound and 4,5-dichloro-1,2-phenylenediamine. The crude material was dissolved in small amount of CH2Cl2 and triturated with hexanes to yield the title compound as a tan solid.
Reaction SMILES: Br[CH:2]([CH:11](Br)[CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:14](=[O:17])([O-])[OH:15].[Na+].[CH:19]([NH2:21])=[O:20]>>[CH:14]([O:15][CH2:12][CH2:11][C:2]1[O:20][CH:19]=[N:21][C:3]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:17]
Reactant: NC=O
Reactant: O=C([O-])O
Reactant: CC(Br)C(Br)C(=O)c1ccccc1
Agent: [Na+]
Product: O=COCCc1ocnc1-c1ccccc1

Procedure:
A mixture of α,β-dibromobutyrophenone (30.6 g) and formamide (50 ml) was heated on an oil bath at 120° C.-130° C. for an hour. Then, saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the oily residue was further distilled under reduced pressure to give an oil of 5-(2-formyloxyethyl)-4-phenyloxazole, yield 12.9 g (59.4%), b.p. 136°-137° C./0.4 mmHg.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][C@@H:11]([C@@H:19]([OH:22])[CH2:20][CH3:21])[CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[C:23]([N:27]=[C:28]=[S:29])([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:23]([NH:27][C:28]([NH:10][C@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C@@H:19]([OH:22])[CH2:20][CH3:21])=[S:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC[C@H](O)[C@H](N)Cc1ccncc1
Reactant: CC(C)(C)N=C=S
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC[C@H](O)[C@@H](Cc1ccncc1)NC(=S)NC(C)(C)C
Temperature: 50 °C

Procedure:
4.3 cm3 of triethylamine are added to a solution of 3.6 g of (2R,3S)-2-amino-1-(4-pyridyl)-3-pentanol dihydrochloride in 60 cm3 of ethanol, followed by addition of 2.6 cm3 of tert-butyl isothiocyanate. The mixture is heated at a temperature in the region of 50° C. for 18 hours. After cooling, the reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. and the residue is taken up in 50 cm3 of water and 100 cm3 of dichloromethane. The organic phase is washed with 30 cm3 of water, dried over sodium sulfate, filtered and concentrated under the above conditions. 4.3 g of N-tert-butyl-N′-[(1R,2S)-1-(4-pyridylmethyl)-2-hydroxybutyl]thiourea are obtained in the form of a thick colorless oil [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 0.80 (t, J=7.5 Hz: 3H); from 1.25 to 1.55 (mt: 2H); 1.37 (s: 9H); 2.72 (dd, J=14 and 9 Hz: 1H); 2.93 (dd, J=14 and 4.5 Hz: 1H); 3.37 (mt: 1H); 4.60 (mt: 1H); 4.88 (unresolved complex: 1H); 7.11 (s: 1H); 7.16 (d, J=8.5 Hz: 1H); 7.26 (broad d, J=5.5 Hz: 2H); 8.43 (broad d, J=5.5 Hz: 2H)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[C:14]([O:16][CH3:17])=[O:15]>CO>[CH3:17][O:16][C:14](=[O:15])[CH:13]([C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:22][CH:23]=1)[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Oc1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Oc1ccc(F)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 1.87 g of p-fluorophenol in 50 ml of methanol is added 1.07 g of sodium methoxide. To this solution is added 5.4 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate and the mixture is refluxed for 18 hours. The mixture is concentrated to 1/2 volume and poured into 150 ml of ice and water. The mixture is extracted with ether and the cold extracts washed with 50 ml of 2 N NaOH and with saline. After drying (MgSO4), the extracts are concentrated under vacuum to give the product as an amber colored oil.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[CH2:23][NH2:24]>>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:24]([CH2:23][C:17]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=2[F:15])[CH:10]=1
Reactant: NCc1cc(F)ccc1F
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Product: Cl
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(F)ccc1F

Procedure:
According to the method of Example 160, 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide was reacted with 1-(2,5-difluorophenyl)methanamine to give the title compound.
Reaction SMILES: [C:1](O[O:10][C:11](=[O:18])[C:12]1[CH:17]=CC=C[CH:13]=1)(=O)[C:2]1C=CC=[CH:4][CH:3]=1.[CH2:19]1[CH2:23]O[CH2:21][CH2:20]1>>[CH3:17][C:12]([C:11]([O:10][CH3:19])=[O:18])=[CH2:13].[CH2:21]=[CH:20][C:19]1[CH:23]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: C1CCOC1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: C=C(C)C(=O)OC
Product: C=Cc1ccccc1
Reaction time: 72 h

Procedure:
Poly(styrene-co-methyl methacrylate) is synthesized by free radical polymerization. Benzoyl peroxide was used as initiator, 0.1 wt % of total volume of monomers. Reaction took place in a round bottom flask equipped with a magnetic stirrer at 110° C. for 5 hours under a nitrogen environment. After reaction, THF (60 ml per 10 ml of monomer) was added into the round bottom flask and kept with stirring for 2-4 days to dissolve the product. The dissolved polymer solution was then precipitated in excess amount of methanol and then dried in oven at 40° C. for at least 24 hrs.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.C[O:9][CH:10](OC)[C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1>CN(C=O)C.C(Cl)(Cl)Cl.O.[Cu]>[N:3]1([C:14]2[CH:15]=[CH:16][C:11]([CH:10]=[O:9])=[CH:12][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: COC(OC)c1ccc(Br)cc1
Reactant: c1c[nH]cn1
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of sodium hydride (60% in oil: 0.82 g, 20.5 mmol) in dry DMF (4.5 ml) under nitrogen atmosphere is added imidazole (1.37 g, 20.1 mmol) with stirring at room temperature. After being stirred for 20 min. 4-bromobenzaldehyde dimethyl acetal (4.63 g, 20 mmol) and copper powder (0.13 g, 2.0 mmol) are added and the reaction mixture is stirred at 130° C. for 2 h, then at 150° C. for 2.5 h. The mixture is cooled to room temperature, diluted with chloroform and water. The solution is stirred for 1 h and filtered on Celite. The organic layer is separated, washed wit water, dried over sodium sulfate, and concentrated in vacuo. The residue is dissolved in 1N hydrochloric acid (20 ml) and stirred at room temperature for 4 h. The reaction mixture is diluted with 5N NaOH (4 ml), and extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and concentrated in vacuo. The solid obtained is washed with hexane and dried in vacuo to give 4-(1-imidazolyl)benzaldehyde.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:9][C@@H:8]2[C@@H:4]([C@@H:5]([CH2:11][OH:12])[O:6][CH:7]2[OH:10])[O:3]1.[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[O:9][C@@H:8]2[C@@H:4]([C@@H:5]([CH2:11][O:12][C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:6][CH:7]2[OH:10])[O:3]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)O[C@@H]2[C@@H](CO)OC(O)[C@@H]2O1
Solvent: c1ccncc1
Product: CC1(C)O[C@@H]2[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)OC(O)[C@@H]2O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2,3-O-Isopropylidene-D-ribofuranose (15.7 g, 83.1 mmol) was dissolved in pyridine (100 mL) and trityl chloride (27.8 g, 0.1 mol) was added. The mixture was stirred at room temperature for 24 h. The solvent was evaporated and the residue purified by column chromatography on silicagel using hexanes/ethyl acetate (v.v=4:1) as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:17]([CH2:19][CH2:20][O:21][CH3:22])[CH3:18])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[NH2:24][CH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([N:17]([CH2:19][CH2:20][O:21][CH3:22])[CH3:18])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]2[OH:32])=[O:15])=[CH:6][CH:7]=1
Reactant: COCCN(C)c1ncc(C(=O)O)cc1-c1ccc(Cl)cc1
Reactant: NC[C@H]1CCCC[C@H]1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C)c1ncc(C(=O)NCC2CCCCC2O)cc1-c1ccc(Cl)cc1

Procedure:
In analogy to example 1f, 5-(4-chloro-phenyl)-6-[(2-methoxy-ethyl)-methyl-amino]-nicotinic acid was coupled with cis-2-aminomethyl-1-cyclohexanol hydrochloride using TBTU and N,N-diisopropyl ethyl amine in N,N-dimethylacetamide to give racemic 5-(4-chloro-phenyl)-N-((1RS,2RS)-2-hydroxy-cyclohexylmethyl)-6-[(2-methoxy-ethyl)-methyl-amino]-nicotinamide as an off-white solid. MS (ISP) 432.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:16][F:17])[NH:14][C:13](=[S:15])[CH2:12][O:11][CH2:10]2)[C:5]([Cl:8])=[N:6][CH:7]=1.[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:25]([C:22]2[CH:21]=[CH:20][C:19]([Br:18])=[CH:24][N:23]=2)=[O:26])=[CH:3][C:4]=1[C:9]1([CH2:16][F:17])[CH2:10][O:11][CH2:12][C:13](=[S:15])[NH:14]1
Reactant: Nc1cnc(Cl)c(C2(CF)COCC(=S)N2)c1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(Nc1cnc(Cl)c(C2(CF)COCC(=S)N2)c1)c1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-amino-2-chloro-pyridin-3-yl)-5-fluoromethyl-morpholine-3-thione (33 mg, 0.12 mmol), 5-bromo-pyridine-2-carboxylic acid (36 mg, 0.18 mmol) and HOAt (29 mg, 0.215 mmol) in DMF (0.4 ml) was cooled to 0° C. and DIPEA (0.042 ml, 0.24 mmol) and EDC (34 mg, 0.18 mmol) were added, the reaction mixture was stirred at 0° C. for 10 min, then allowed to warm to room temperature over night. At 0° C. aq. 1M KHCO3 was added and the mixture extracted with toluene. The combined organic layers were washed with water, dried with Na2SO4 and evaporated. The residue was taken up in DCM/MeOH 65/35 from which the product started to crystallize. Filtration, rinsing of the crystallized material with DCM and drying provide the title compound as yellow crystals.
Reaction SMILES: [C:1]([O:10]OC(C)(C)C)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(C)C.C([O:21]O)(CC)(C)C.O(C(C)(CCC(OO)(C)C)C)O.O([C:37]([CH3:48])([CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:46][OH:47])(C)C)C)O.C1(C(C2C=CC=CC=2)OO)C=CC=CC=1.C(OO)C1C=CC=CC=1>>[C:1]([O:47][O:46][C:43](=[O:21])[C:42]1[CH:48]=[CH:37][CH:39]=[CH:40][CH:41]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(CCCCC(C)(C)OO)OO
Reactant: CC(C)(C)OOC(C)(C)c1ccccc1
Reactant: CCC(C)(C)OO
Agent: CC(C)(CCC(C)(C)OO)OO
Agent: OOC(c1ccccc1)c1ccccc1
Agent: OOCc1ccccc1
Product: O=C(OOC(=O)c1ccccc1)c1ccccc1

Procedure:
t-butyl cumyl peroxide; di(cumylperoxide); t-amyl hydroperoxide, 2,5-di(hydroperoxy)-2,5-dimethylhexane, 3,3-dimethyl-2-methylhydroperoxybutene-1;2,7-di(hydroperoxy)-2,7-dimethyloctane, diphenylhydroperoxymethane; benzylhydroperoxide;
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[CH:27]=[C:26]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[N:25]=1.[CH:43]1([NH:46][C:47](=[O:64])[NH:48][C:49]2[CH:54]=[CH:53][C:52](B3OC(C)(C)C(C)(C)O3)=[CH:51][CH:50]=2)[CH2:45][CH2:44]1>>[CH:43]1([NH:46][C:47]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([C:24]3[N:29]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]4[CH3:36])[CH:27]=[C:26]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)[N:25]=3)=[CH:51][CH:50]=2)=[O:64])[CH2:45][CH2:44]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1cc(-c2ccccn2)nc(Cl)n1
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: C[C@H]1COCCN1c1cc(-c2ccccn2)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1

Procedure:
Method as described for intermediate 5 using (S)-4-(2-chloro-6-(pyridin-2-yl)pyrimidin-4-yl)-3-methylmorpholine (intermediate 21) and 4-(3-cyclopropylureido)phenyl boronic acid pinacol ester. Material was purified by prep HPLC (low pH) to afford a light orange solid.
Reaction SMILES: [CH:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].N1C=CC=CC=1.[CH2:24]([O:30][C:31](Cl)=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CC(N(C)C)=O>[CH2:24]([O:30][C:31]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]2[OH:3])[C:11](=[O:12])[N:13]=1)=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCOC(=O)Cl
Reactant: Nc1ccn(C2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CCCCCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.5 %

Procedure:
To a solution of 4.0 g of arabinofuranosylcytosine dissolved in 50 ml of dimethylacetamide, there are added 3.0 g of pyridine and 4.06 g of n-hexylchloroformate. The reaction is carried out by stirring the mixture at room temperature for 3 hours. After the reaction is over, dimethylacetamide is evaporated under reduced pressure. The residue is diluted with 100 ml of cold water and the mixture is stirred under ice-cooling for one hour. The precipitated solids are filtrated and dried. The resultant white powders are washed with ethyl ether to obtain 2.9 g of N4 -hexyloxycarbonyl-1-β-D-arabinofuranosylcytosine (Yield:47%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:11]2[C:16]([CH3:17])=[CH:15][S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:11]3[C:16]([CH3:17])=[CH:15][S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1csc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c12
Reactant: Cc1ncc[nH]1
Product: Cc1csc2nc(-n3ccnc3C)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13]2[C:14]([CH2:24][N:25]([CH3:36])[CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)=[CH:15][N:16](C3CCCCO3)C=2)[CH:5]=[C:6]([CH3:12])[C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O.C(O)(C(F)(F)F)=O.CC#[N:47]>Cl>[CH:9]([O:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:13]2[C:14]([CH2:24][N:25]([CH3:36])[CH2:26][CH2:27][NH2:28])=[CH:15][NH:16][N:47]=2)=[CH:5][C:6]=1[CH3:12])([CH3:11])[CH3:10]
Reactant: CC#N
Reactant: Cc1cc(-c2cn(C3CCCCO3)cc2CN(C)CCNC(=O)OC(C)(C)C)cc(C)c1OC(C)C
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2n[nH]cc2CN(C)CCN)cc(C)c1OC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
A solution of tert-butyl N-[2-[([4-[3,5-dimethyl-4-(propan-2-yloxy)phenyl]-1-(oxan-2-yl)-1H-pyrrol-3-yl]methyl)(methyl)amino]ethyl]carbamate (650 mg, 1.30 mmol, 1.00 equiv) in 3N hydrochloric acid (20 mL) was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-Waters 2767-2(HPLC-08)): Column, Xbridge Shield RP 18, 5 um, 19*150 mm; mobile phase, water with 50 mmol CF3COOH and CH3CN (10.0% CH3CN up to 28.0% in 2 min, up to 46.0% in 10 min, up to 100.0% in 1 min, down to 10.0% in 1 min); Detector, UV 254 nm to give 269 mg (38%) of N1-((3-(4-isopropoxy-3,5-dimethylphenyl)-1H-pyrazol-4-yl)methyl)-N1-methylethane-1,2-diamine as a light yellow oil. 1H-NMR (300 MHz, D2O): δ 7.88 (s, 1H), 7.17 (s, 2H), 4.42 (s, 2H), 4.35-4.26 (m, 1H), 3.30-3.10 (m, 4H), 2.57 (s, 3H), 2.23 (s, 6H), 1.23 (d, J=6.3 Hz, 6H) ppm. LCMS (method J, ESI): RT=1.57 min, m/z=317.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([O:11]C)=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=1.[OH-].[Na+].C(OCC)(=O)C.O>CO>[Cl:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(Cl)cnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=C(O)c1nc(Cl)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
In 10 mL of methanol was dissolved 2.0 g of methyl 3,6-dichloro-2-pyrazinecarboxylate. Then, 10.2 mL of 1 mol/L aqueous solution of sodium hydroxide was added at an ice-cooled temperature and stirred at room temperature for one hour. The reaction mixture was poured into a mixture of 200 mL of ethyl acetate and 200 mL of water, and the organic layer was separated. The organic layer was washed successively with 50 mL of water and 50 mL of saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was washed with hexane to obtain 1.6 g of 3,6-dichloro-2-pyrazinecarboxylic acid as a white-colored solid product.