Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].Cl.[NH2:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:22][C@H:23]1[C:29]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:28]=2[CH2:27][CH2:26][CH2:25][NH:24]1>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:22][C@H:23]1[C:29]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:28]=2[CH2:27][CH2:26][CH2:25][N:24]1[CH2:2][C:3]([NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:4]
Reactant: NC1Cc2ccccc2C1
Reactant: COc1ccc(C[C@@H]2NCCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(Br)CBr
Agent: Cl
Product: COc1ccc(C[C@H]2c3cc(OC)c(OC)cc3CCCN2CC(=O)NC2Cc3ccccc3C2)cc1OC

Procedure:
prepared according to general procedure A, by reaction of 2-bromoacetyl bromide with 2-aminoindane hydrochloride and 1-(S)-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[O:12][C:11]([CH2:13][NH:14][CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][NH:19][C:18]3=[C:22]([C:25]#[N:26])[C:23]#[N:24])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].CO>N1C=CC=CC=1>[C:27]([N:14]([CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][NH:19][C:18]1=[C:22]([C:23]#[N:24])[C:25]#[N:26])[CH2:13][C:11]1[O:12][C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: N#CC(C#N)=C1NCCN1CCNCc1ccc(CN2CCCCC2)o1
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)N(CCN1CCNC1=C(C#N)C#N)Cc1ccc(CN2CCCCC2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
In 12 ml of pyridine was dissolved 0.6 g (1.69 mmol) of Compound 28, and 260 mg (2.55 mmol) of acetic anhydride was added dropwise. The reaction mixture was stirred at room temperature for 0.5 hour and, after addition of 1 ml of methanol, the solvent was distilled off. The residue was diluted with 20 ml of water, adjusted to pH 13 with 5N sodium hydroxide solution and extracted with methylene chloride. The extract was washed with saturated aqueous sodium chloride solution twice and dried over anhydrous magnesium sulfate. Finally the solvent was distilled off to give 0.66 g (97.9%) of Compound 44 as colorless oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].C[C:28]1[CH:33]=[CH:32][C:31](B(O)OOCC)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:28]2[CH:29]=[CH:30][C:31]([O:4][CH:5]([CH3:18])[CH3:6])=[CH:32][CH:33]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: CCOOB(O)c1ccc(C)cc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccc(OC(C)C)cc2)c1

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-methylethoxy-phenylboronic acid, 5-[4-(1-methylethoxy)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=55%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:11])[NH:8]2)=[C:4](NC(=O)C)[CH:3]=1.Cl.[NH:18]([C:20]1[CH:31]=[CH:30][C:23]([CH2:24][S:25]([NH:28][CH3:29])(=[O:27])=[O:26])=[CH:22][CH:21]=1)[NH2:19]>>[OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[N:19][NH:18][C:20]3[CH:31]=[CH:30][C:23]([CH2:24][S:25](=[O:27])(=[O:26])[NH:28][CH3:29])=[CH:22][CH:21]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[NH:8][C:7](=[O:11])[CH3:6]
Reactant: CNS(=O)(=O)Cc1ccc(NN)cc1
Reactant: CC(=O)Nc1cc(O)cc2c1C(=O)C(=O)N2
Agent: Cl
Product: CNS(=O)(=O)Cc1ccc(NN=C2C(=O)Nc3cc(O)c(NC(C)=O)cc32)cc1
Yield: 4 %

Procedure:
Condensation of N-(6-hydroxy-2,3-dioxo-2,3-dihydro-1H-indol-4-yl)acetamide and 4-hydrazino-N-methyl-benzylsulfonamide hydrochloride according to Procedure G gave the title compound in 4% yield: 1H NMR (DMSO-d6): δ2.04 (s, 3H), 2.51 (d, J=4.8 Hz, 3H), 4.24 (s, 2H), 6.45 (s,1H), 6.84 (t, J=4.8 Hz, 1H), 7.30 (s, 4H), 7.82 (s, 1H), 9.12 (s, 1H), 10.20 (s, 1H), 10.77 (s, 1H), 12.50 (s, 1H); APCI−MS m/z416 (M−H)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH2:10][CH3:11])[C:8]#[N:9].[C:12]1([C:18]#[N:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1.O1[CH2:24][CH2:23][CH2:22]C1>>[C:18]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH2:10][CH2:11][N:1]([CH:2]([CH3:7])[CH3:3])[CH:23]([CH3:24])[CH3:22])[C:8]#[N:9])#[N:19]
Reactant: CCC(C#N)c1ccccn1
Reactant: N#CC1=CCCCC1
Reactant: C1CCOC1
Product: CC(C)N(CCC(C#N)(c1ccccn1)C1CCCCC1C#N)C(C)C
Temperature: 20 °C

Procedure:
To the solution of 36.75 g of 4-diisopropylamino 2-(2-pyridyl butyronitrile (Example 1a) in 300 ml of tetrahydrofuran are added at ambient temperature 71.7 g of Triton B then 15.9 g of 1-cyclohexene carbonitrile dissolved in 100 ml of tetrahydrofuran. The mixture is left for one night with stirring at ambient temperature (about 20° C.), then the solvent is evaporated to dryness. The residue is taken up in water and extracted 3 times with ether. The solvent is evaporated and the residue is chromatographed over a column of alumina. By eluting with a pentane-ethyl acetate (80-20) vol/vol mixture, 20 g of the expected product are obtained, used as such for cyclization.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][C:4]1[N:5]([CH2:18][CH2:19][CH3:20])[N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17]>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl.CO.[Pt](=O)=O>[CH3:1][CH:2]([CH3:21])[CH2:3][C:4]1[N:5]([CH2:18][CH2:19][CH3:20])[N:6]=[C:7]2[C:16]=1[C:15]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[N:9]=[C:8]2[NH2:17]
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)C
Agent: O=[Pt]=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCn1nc2c(N)nc3c(c2c1CC(C)C)CCCC3
Reaction time: 24 h
Yield: 64 %

Procedure:
A solution of 1-(2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (0.8 g, 3 mmol), prepared as described in Example 1, in trifluoroacetic acid (10 mL) was treated with platinum (IV) oxide (0.5 g) and shaken under hydrogen pressure (50 psi, 3.4×105 Pa) for 24 hours on a Parr apparatus. The reaction mixture was diluted with chloroform (20 mL) and methanol (10 mL) and filtered through a layer of CELITE filter agent. The filtrate was concentrated under reduced pressure. The residue was suspended in 6 M aqueous hydrochloric acid (5 mL), stirred for 30 minutes, and treated with 50% aqueous sodium hydroxide to adjust the mixture to pH 13. A precipitate formed and was isolated by filtration, washed with water, and dried. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 0-35% CMA in chloroform) to yield 0.55 g of 1-(2-methylpropyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine as an off-white powder, mp 167-168° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].N1C=CC=CC=1.[CH3:18][S-:19].[Na+]>CO.ClCCl>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([S:19][CH3:18])[CH:7]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a mixture of compound 2,4-difluoro-1-nitro-benzene (10 g, 62.9 mmol), pyridine (10 ml, 124 mmol) in MeOH (30 ml) was added the solution of sodium thiomethoxide(20%, 300 mmol) in methanol drop-wise at 0° C. The mixture was stirred for 2 hour and then diluted with dichloromethane. The mixture was washed with brine, dried over MgSO4 and evaporated under reduced pressure. The resulting residue was recrystallized from ethyl acetate to give titled compound (10 g, yield 85%)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[S:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2sc3ncccc3c2n1
Reactant: C1COCCN1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2sc3ncccc3c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To 4 (34.3 mg, 0.14 mmol) in methanol (1.5 mL) was added morpholine (25 μL, 0.29 mmol) dropwise, and the resulting reaction was stirred for 1 h at rt. The mixture was then filtered, washed with water and then methanol, and the remaining solid was dissolved in CH2Cl2 and concentrated in vacuo to furnish 5 as a pale brown solid (30.1 mg, 0.098 mmol, 73%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>CC#N>[Br:8][C:5]1[N:4]=[C:3]([C:9]2[O:18][C:13]([C:14]([CH3:15])([CH3:16])[CH3:17])=[N:12][N:11]=2)[C:2]([NH2:1])=[N:7][CH:6]=1
Reactant: CC(C)(C)C(=O)NNC(=O)c1nc(Br)cnc1N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nnc(-c2nc(Br)cnc2N)o1
Temperature: 67.5 °C
Reaction time: 1 h
Yield: 1.7 %

Procedure:
To 3-amino-6-bromo-N′-pivaloylpyrazine-2-carbohydrazide (2301 g, 7.28 mol) in MeCN (10.8 L) was added DIPEA (3.044 L, 17.48 mol) and p-toluenesulfonyl chloride (1665 g, 8.73 mol) portion-wise (˜280 g×6) at 50° C. over a period of 30 mins. The reaction temperature was maintained between 65-70° C. by controlling the rate of addition. After the addition was complete, the reaction mixture was stirred at 70° C. for 1 h. The mixture was cooled to room temperature and quenched with 5% NaHCO3 (aqueous, 24.2 L). The resulting suspension was stirred for 30 mini then filtered. The product was washed with water (14.8 L), pulled dry and dried at 50° C. for 16 h. The product was dissolved in DCM (12 L) and the phases separated. The organic phase was loaded onto a silica pad (6 kg) and the product was eluted with 20% EtOAc/DCM (8×10 L). Concentration of the product containing fractions gave 1987 g (92% yield) with a purity of 99.8% by HPLC of 5-bromo-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (36 g, 17%): 1H NMR Spectrum: (DMSO-d6) 1.43 (9H, s), 7.70 (2H, s), 8.39 (1H, s): Mass Spectrum [M+H]+=298.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN(C)C=O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[O:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CN1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(N)nc2)CC1
Temperature: 70 °C

Procedure:
3.00 g 6-amino-nicotinic acid are dissolved in 30 ml of dimethylformamide and 4.05 g of N,N-carbonyldiimidazole are added. The mixture is briefly heated to 70° C. and then stirred for a further hour at ambient temperature. After this time 4.85 ml of N-methylpiperazine are added and the mixture is stirred for 12 hours at ambient temperature. The solvent is eliminated and the residue is purified through a silica gel column with methylene chloride/ethanol/ammonia 7:1:0.1 as eluant.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][F:11])=[CH:6][C:5]([O:12][CH3:13])=[CH:4][C:3]=1[CH:14]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:38]=C(C)O[N:35]=2)=[CH:30][CH:29]=1)[C:15]1[NH:16][C:17](=[O:26])[N:18]([C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:19]=1.O.[C:41]([OH:44])(=[O:43])[CH3:42]>CO.[Fe]>[C:41]([OH:44])(=[O:43])[CH3:42].[F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][F:11])=[CH:6][C:5]([O:12][CH3:13])=[CH:4][C:3]=1[CH:14]([NH:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([NH2:38])=[NH:35])=[CH:32][CH:33]=1)[C:15]1[NH:16][C:17](=[O:26])[N:18]([C:20]2[N:21]=[CH:22][CH:23]=[CH:24][N:25]=2)[N:19]=1
Reactant: COc1cc(OCCF)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(OCCF)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1

Procedure:
After adding 1.2 g of iron powder to a solution of 1.2 g of 5-{[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one in 18 ml of a methanol:water:acetic acid=1:1:1 mixed solvent, the mixture was stirred at 65° C. for 24 hours and 30 minutes under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (750 mg) as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][Cl:15])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.CO.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([S:11][CH2:12][CH2:13][CH2:14][Cl:15])=[CH:10][C:4]=1[NH2:1]
Reactant: Nc1ccc(SCCCCl)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc(SCCCCl)cc1N

Procedure:
6 G of 2nitro-4-(3-chloropropylthio)aniline is treated in 120 ml. methanol and 120 ml. of water with 30 g. of sodium hydrosulfite (Na2S2O4) on the steam bath for about 5 minutes. The reaction mixture is concentrated under vacuum and extracted well with chloroform. Evaporation of the dried extract affords 1,2-diamino-4-(3-chloropropylthio)benzene.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:11]([O:17][CH2:18][CH2:19][Cl:20])(=[O:16])[CH2:12][C:13]([CH3:15])=O.[NH2:21]/[C:22](/[CH3:28])=[CH:23]\[C:24]([O:26][CH3:27])=[O:25]>C(O)(C)C>[CH3:27][O:26][C:24]([C:23]1[CH:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[N:8]=2)[C:12]([C:11]([O:17][CH2:18][CH2:19][Cl:20])=[O:16])=[C:13]([CH3:15])[NH:21][C:22]=1[CH3:28])=[O:25]
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)CC(=O)OCCCl
Reactant: N#Cc1cccc(C=O)n1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCl)C1c1cccc(C#N)n1
Reaction time: 14 h
Yield: 33.7 %

Procedure:
6-Cyano-2-pyridine aldehyde (1.613 g, 12.2 mmol), chloroethyl acetoacetate (2.009 g, 12.2 mmol) and methyl 3-aminocrotonate (1.364 g, 12.2 mmol) were dissolved in 16 ml of isopropanol, and the solution was stirred at 35° to 40° C. under a nitrogen gas stream for 14 hours. The reaction solvent was distilled off under reduced pressure, and the residue was purified by column chromatography [silica gel; ethyl acetate-n-hexane (5:6)]. The crude product thus obtained was recrystallized from isopropyl ether-methanol to obtain 1.546 g (34% yield) of the above-captioned compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[C:5]2[C:13]([NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+].O.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[OH:12][C:7]1[CH:6]=[C:5]([C:13]([NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:14])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:3]=2)[N:8]=1
Reactant: O=C(Nc1cccnc1)c1cc(O)nc2ccc(Br)cc12
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccnc1)c1cc(O)nc2ccc(-c3ccccc3)cc12
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To a round-bottomed flask under argon atmosphere was added 6-bromo-2-hydroxy-N-(pyridin-3-yl)quinoline-4-carboxamide (3.00 g) in DMF (50 ml), and the vessel was purged with argon under stirring for 5 minutes. After 5 minutes, 2N solution of potassium carbonate in water (11 eq) was added and the flask was purged with argon under stirring for 5 minutes. Phenylboronic acid (1.5 eq) was then added and the tube was purged with argon under stirring for 15 minutes. Finally, palladium(0)tetrakis triphenylphosphine (0.03 eq) was added under argon and the flask was affixed to a reflux condenser and heated to 80° C. for 5 hours. The completion of the reaction was monitored on TLC using ethyl acetate:hexanes (5:5) as a mobile phase. After completion of the reaction, reaction mixture was diluted with ethyl acetate (100 ml) and then washed with water (5*100 ml). The ethyl acetate layer was dried over anhydrous sodium sulphate and then solvent was distilled out and the crude was subjected to purification by silica gel column chromatography to provide 9.0 g of 2-hydroxy-6-phenyl-N-(pyridin-3-yl)quinoline-4-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11](=[O:27])[CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N+:23]([O-])=O)[CH:19]=2)[C:14]1=[O:26].O.O.[Sn](Cl)Cl>C1COCC1>[NH2:23][C:18]1[CH:17]=[CH:16][CH:15]=[C:20]2[C:19]=1[C:14](=[O:26])[N:13]([CH2:12][C:11]([O:10][C@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:36])[F:37])=[C:30]([O:38][CH2:39][CH:40]3[CH2:41][CH2:42]3)[CH:29]=1)[CH2:8][C:7]1[C:6]([Cl:43])=[CH:5][N+:4]([O-:44])=[CH:3][C:2]=1[Cl:1])=[O:27])[C:21]2=[O:22]
Reactant: O=C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc2c1C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.3 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-nitro-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (80 mg, 0.123 mmol) was dissolved in THF (10 ml), and added with tin(II) chloride dihydrate (80 mg, 0.355 mmol). The reaction was stirred at RT for 3 days. The reaction was quenched by addition of K2CO3/H2O. The solid precipitated was filtered and the solution extracted with EtOAc (50 ml). The organic phase was washed with K2CO3/H2O conc. (×3), dried over Na2SO4 and the solvent removed under reduced pressure to yield the title compound (50.0 mg, 66% yield).). 1H NMR (400 MHz, acetone) ppm 8.20 (s, 2H), 7.50 (d, J=7.50 Hz, 1H), 7.14-7.24 (m, 2H), 7.01-7.13 (m, 3H), 6.92 (t, J=75.00 Hz, 1H), 6.17 (dd, J=9.48, 5.07 Hz, 3H), 4.37 (d, J=7.50 Hz, 2H), 4.00 (dd, J=7.06, 3.09 Hz, 2H), 3.53 (m, 1H), 3.34 (d, J=4.41 Hz, 1H), 1.30 (br. s., 2H), 0.56-0.68 (m, 2H), 0.41 (d, J=4.41 Hz, 2H); MS/ESI+ 608.39 [MH]+
Reaction SMILES: [CH2:1]([C:3](=[CH:6][CH2:7][CH2:8][CH3:9])[CH:4]=O)[CH3:2].[CH2:10]=[O:11].CO.[OH-:14].[Na+]>COCCOCCOC>[CH2:8]([C:7]1[CH:10]([OH:14])[O:11][CH2:4][CH:3]([CH2:1][CH3:2])[CH:6]=1)[CH3:9]
Reactant: [OH-]
Reactant: C=O
Reactant: CCCC=C(C=O)CC
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CO
Product: CCC1=CC(CC)COC1O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a mixture of 776 g of 2-ethyl-2-hexenal (purity: 97.6%, 6.0 mol), 324 g (4.0 mol) of 37% formalin, and 550 g of methanol heated to 50° C. was added dropwise with stirring 64 g (0.4 mol) of a 25% aqueous solution of sodium hydroxide over one hour. After the dropping was completed, the mixture was further stirred at 50° C. for 3 hours. The reaction mixture was analyzed by gas chromatography (the internal standard method with diethylene glycol dimethyl ether as an internal standard), and the yields of 3,5-diethyl-5,6-dihydro-2H-2-pyranol based on the used formaldehyde and the consumed 2-ethyl-2-hexenal were found to be 26% and 30%, respectively.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.[F:12][C:13](I)([F:15])[F:14].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([C:13]([F:15])([F:14])[F:12])=[N:8]2)=[C:4]([NH2:11])[N:3]=1
Reactant: FC(F)(F)I
Reactant: Nc1nc(N)c2[nH]cnc2n1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: CS(C)=O
Product: Nc1nc(N)c2[nH]c(C(F)(F)F)nc2n1
Temperature: 25 °C
Yield: 40 %

Procedure:
0.12 g (0.8 mmol) of 2,6-diaminopurine was weighed and placed in a two-neck flask and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 3.0 ml of dimethyl sulfoxide, 0.8 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.25 ml of a 1.0 mol/l aqueous solution of iron(II) sulfate and 0.15 ml of a 30% hydrogen peroxide aqueous solution, and the mixture was stirred for 20 minutes. During the stirring, the temperature of the reaction system rose up in the range of from 40° C. to 50° C. Thereafter, the resulting solution was cooled to room temperature. Formation of 2,6-diamino-8-trifluoromethylpurine (19F-NMR yield: 40%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. Water was added to the resulting solution, sodium hydrogen carbonate was added thereto to neutralize, and the desired product was extracted with ethyl acetate. The extract was passed through column chromatography and concentrated under reduced pressure to obtain 2,6-diamino-8-trifluoromethylpurine as a white solid (0.043 g, yield: 20%).
Reaction SMILES: [NH2:1][CH:2]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]12[CH2:10][CH2:9][CH2:8][N:7]1[CH2:6][CH2:5][CH2:4]2.[O:15]=[C:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH2:21][C:22](OCC)=[O:23]>>[O:15]=[C:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH2:21][C:22]([NH:1][CH:2]([C:3]12[CH2:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH2:10]2)[Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:23]
Reactant: CCOC(=O)CN1CCCC1=O
Reactant: C[Si](C)(C)C(N)C12CCCN1CCC2
Product: C[Si](C)(C)C(NC(=O)CN1CCCC1=O)C12CCCN1CCC2
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 150 mg (0.706 mmol) of 7a-[(amino)(trimethylsilyl)methyl]pyrrolizidine and 133 mg (0.777 mmol) of ethyl 2-oxo-1-pyrrolidineacetate was stirred at 80° C. for 5 hours. After cooled, the reaction mixture was chromatographed on alumina column to afford 95.3 mg
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]([O:9]CC)=[O:8])=[CH:5][N:6]=1.C[O-:13].[Na+]>CC#N.CO>[O:13]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[O:3]1
Reactant: CCOC(=O)c1cnc(Cl)o1
Reactant: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: O=C(O)c1c[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-chlorooxazole-5-carboxylate (1.816 g, 10.34 mmol) was solubilised in MeCN (20 ml) and MeOH (20 ml). Sodium methoxide (9 ml, 25% solution in MeOH, 41.4 mmol) was added and the reaction mixture was heated at reflux overnight. The solvent was removed under reduced pressure and the crude product was dissolved in MeOH (20 ml) and 2M NaOH(aq) (20 ml) and stirred at RT overnight. The resulting mixture was acidified with 1M HCl and evaporated under reduced pressure. The residue was triturated with a minimal volume of 5M HCl and filtered. The solid was slurried with ice chips (approx. 10 ml), filtered, washed with water and dried under high vacuum to afford the title compound;
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:3]=1.[H][H]>C(Cl)Cl.CO.C(N(CC)CC)C.[Pd]>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[CH:10]=[C:6]3[N:5]=[C:4]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:3]=[CH:2][N:7]3[N:8]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cc(Cl)n2nc(-c3ccc(OC)cc3)cc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1ccn2nc(-c3ccc(OC)cc3)cc2n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 70.6 %

Procedure:
To a solution of ethyl 7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (767 mg; 2.31 mmol) in methylene chloride (10 mL), methanol (10 mL) and triethylamine (2 mL) was added 10% Pd on carbon (77 mg) and the mixture was cooled to 0° C. The reaction flask was put under vacuum and then hydrogen was introduced using a balloon. A second cycle of vacuum and hydrogen purge was performed and the mixture was stirred at 0° C. for 1.5 h. The mixture was flushed with two cycles of vacuum and nitrogen, diluted with methylene chloride and then filtered through a 0.45 micron filter to remove the catalyst. Concentration afforded the crude product which was triturated in methanol (25 mL) and filtered to afford 485 mg (71%) of the title compound. LCMS m/z 298.1 (M+H)+, ret. time=2.53 min.