Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[CH2:11]O.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:14][CH2:11][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[I:1])[CH2:8][CH2:7][CH2:6]2
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc2c(cc1I)CCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cc2c(cc1I)CCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.6 %

Procedure:
To a solution of (6-iodo-2,3-dihydro-1H-inden-5-yl)methanol (36 mg, 0.131 mmol) and carbon tetrabromide (52 mg, 0.158 mmol) in dichloromethane (1 mL) at 0° C. under N2, was added triphenylphosphine (41 mg, 0.158 mmol). The resulting solution was allowed to warm to room temperature and was stirred for 4 h. Another portion of carbon tetrabromide (52 mg, 0.158 mmol) and triphenylphosphine (41 mg, 0.158 mmol) was added to the mixture at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (Si, 1% EtOAc in hexanes) to afford 5-(bromomethyl)-6-iodoindane (44.4 mg, 100%). 1H NMR (500 MHz, CDCl3) δ 7.72 (s, 1H), 7.36 (s, 1H), 4.62 (s, 2H), 2.89 (m, 4H), 2.11-2.07 (m, 2H).
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:12]([NH:15][CH3:16])[C:13]#[N:14]>C1(C)C=CC=CC=1.O.[OH-].[Na+]>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:12]([N:15]([CH3:16])[C:3](=[O:4])[CH:2]([Cl:6])[Cl:1])[C:13]#[N:14]
Reactant: CNC(C#N)c1ccc(OC)c(OC)c1
Reactant: O=C(Cl)C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(C#N)N(C)C(=O)C(Cl)Cl)cc1OC

Procedure:
A solution of 14.7 g of dichloroacetylchloride in 10 ml of toluene are added dropwise, while stirring at a temperature of -10° to 15° C. to another solution of 20.6 g of N-(3,4-dimethoxy-α-cyanobenzyl-N-methylamine (prepared according to J. Prakt. Chem. 285 (1961) p. 258) in 80 ml of toluene and 20 ml of water, in which was dissolved 4 g of solid NaOH. A solid reaction product precipitates, which is filtered and washed with water until the aqueous filtrate is neutral. The solid acid amide is dried under vacuum to yield 27.7 g of raw product melting at 102°. After treating it with charcoal and recrystallisation from ethanol one obtains 125 g of crystalline title product, melting at 111°-112°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:29][C:30]([O:32]C)=[O:31])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:34][CH3:35])[CH:3]=1.C(OCC)(=O)C>CO.O1CCCC1.[OH-].[Na+]>[C:30]([CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][CH2:21][C:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[O:34][CH3:35])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:20])=[CH:12][C:13]([CH3:18])([CH3:19])[NH:14]2)([OH:32])=[O:31]
Reactant: COC(=O)Cc1ccccc1OCc1c(-c2ccc(F)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(F)ccc1-c1ccc2c(c1COc1ccccc1CC(=O)O)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
6-(4-Fluoro-2-methoxyphenyl)-5-(2-methoxycarbonylmethylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 14-1, 84.0 mg, 0.18 mmol) was dissolved in methanol (2 mL)—tetrahydrofuran mL) and 1N aqueous NaOH solution (0.56 mL) was added thereto and the mixture was stirred at room temperature overnight. After ethyl acetate (100 mL) was added to the reaction mixture, the whole was washed with 0.01N aqueous HCl solution (100 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (74.1 mg) as a colorless solid. (Yield 89%)
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]([C:18]1[C:19]([OH:26])=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[C:19]([OH:26])=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1cccc(C=O)c1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: CC(C)(C)c1cccc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1O

Procedure:
6-[4-(3-tert-Butyl-2-hydroxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-tert-butyl-2-hydroxybenzaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 2.58-2.63 (m, 4H), 3.48-3.60 (m, 4H), 3.73 (s, 2H), 5.40 (s, 1H), 6.72-6.76 (m, 1H), 6.84-6.86 (m, 1H), 7.20-7.22 (m, 1H), 7.85 (s,1H), 10.80 (br s, 1H), 12.65 (br s, 1H). Mass spectrum (ES) MH+=343.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]([C:15]([F:18])([F:17])[F:16])[O:12]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[Cl:24]Cl>C(O)(=O)C.[Zn]>[Cl:24][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:1][CH2:2][CH3:3])[O:12][CH:11]([C:15]([F:18])([F:16])[F:17])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:9]2
Reactant: ClCl
Reactant: CCCOc1ccc2c(c1)OC(C(F)(F)F)C(C(=O)OCC)=C2
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCOc1cc2c(cc1Cl)C=C(C(=O)OCC)C(C(F)(F)F)O2
Reaction time: 3 h
Yield: 69 %

Procedure:
The ester from Step 1 (0.4 g, 1.2 mmole) in acetic acid (10 mL) was treated with Cl2 (gas) in HOAc solution (Pre-prepared 0.5 M) (7.3 ml, 3.6 mmole). The mixture was stirred for 3 hours. After Cl2 (gas) was blown away, Zn powder (3 eq) was added to the mixture and stirred for 30 min. The Zn salts were removed by filtration and the filtrate was evaporated to dryness. The residue was purified by flash chromatography with 10% ethyl acetate in hexane to give clear oil (0.33 g, 69%). This ester was of suitable purity to use without further purification.
Reaction SMILES: C[O-].[Na+].[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][SH:11])=[CH:6][CH:5]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:15]>C(O)C>[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:15])=[CH:6][CH:5]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: SCc1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(=O)CSCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.8 %

Procedure:
Under a nitrogen atmosphere sodium methoxide (0.62 g., 11.4 mmoles) was dissolved in approximately 15 ml. of absolute ethanol and cooled in an ice bath. 4-Picolyl mercaptan (1.43 g., 11.4 mmoles) in approximately 3 ml. of absolute ethanol was added over approximately 5 minutes. After stirring for an additional 10 minutes, a slurry of alpha-bromo-p-methoxyacetophenone (2.62 g., 11.4 mmoles) in approximately 5 ml. of absolute ethanol was added over 10 minutes. The mixture was allowed to warm to room temperature and stirred for approximately 16 hours. The reaction mixture was concentrated to an oil containing solids, triturated with chloroform, salts removed by filtration and reconcentration to an oil (3.6 g.). The oil was chromatographed on 120 g. of silica gel with chloroform as eluant. Product containing fractions were combined and stripped to an oil which crystallized on trituration with cold ether. Filtration gave alpha(4-picolylthio)-p-methoxyacetophenone [2.27 g.; m.p. 64-65° C.; ir (KBr): 3-3.5, 5.95, 6.25, 7.95, 8.55, 12.0 and 12.2,μ mass spectra: m/e calcd: 273, found: 273, 150, 135, 124, 107, 92; pnmr/CDCl3 /TMS/delta: 6.35 (s, 2H), 6.3 (s, 2H), 6.1 (s, 3H), 3.1 (d, 2H), 2.7 (d, 2H), 2.0 (d, 2H), 1.4 (d, 2H)].
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.S(Cl)(Cl)=O>O>[CH3:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: Cc1cnc2ccccc2c1
Reactant: O=S(=O)(O)Cl
Solvent: O
Solvent: O=S(Cl)Cl
Product: Cc1cnc2c(S(=O)(=O)Cl)cccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
The title compound was prepared according to the procedure of U.S. Pat. No. 5,332,822. To 9 mL (135 mmol) of chlorosulfonic acid at 0° C. was added slowly 3-methylquinoline (5.2 g, 36 mmol). The bath was removed and stirring was continued at 100° C. overnight. The reaction mixture was cooled to ambient temperature and then treated with 3.3 mL (45 mmol) of thionyl chloride. The reaction mixture was heated at 70° C. for 1 h, cooled to 0° C. and carefully quenched with ice (very vigorous reaction). The reaction mixture was diluted with 100 mL of water and extracted into dichloromethane (100 mL). The organic phase was washed with water, dried (MgSO4) and concentrated. The residue was triturated with dichloromethane/diethyl ether to provide 1.58 g (18%) of the title compound as a tan solid. 1H-NMR (300 MHz, DMSO-d6) δ9.17-9.29 (m, 2H), 8.32-8.38 (m, 2H), 7.96 (dd, 1H, J=7 Hz), and 2.51 (t, 3H, J=2 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:33])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][N:38]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(COC)OC>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:33])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:40]3[CH:39]=[N:38][C:37]([O:36][CH3:35])=[CH:42][CH:41]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(I)cc2)c1
Agent: Cl[Pd]Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)Nc4ccccc4NC(=O)OC(C)(C)C)c3)cc2)cn1
Yield: 87 %

Procedure:
To mixture of 0.3 g (2-{(E)-3-[1-(4-Iodo-benzenesulfonyl)-1H-pyrrol-3-yl]-allanoylamino}-phenyl)-carbamic acid tert-butyl ester, 0.116 g 2-methoxy-5-pyridineboronic acid and 11 ml dimethoxyethane are added under an inert gas atmosphere 0.9 ml of an aqueous solution of 2N sodium sulfate and 70 mg of bis-(triphenylphosphine)palladium-(II)chloride. The mixture is refluxed for 24 h and after filtration and evaporation the residue is extracted between ethyl acetate and a 5% aqueous solution of sodium bicarbonate. The organic phase is dried and evaporated and th4e crude product is purified by silica gel flash chromatography. 87% of a colorless solid are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10][CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8]2)[N:4]=[C:3]1SC.[NH4+:25].[I-]>N.CCO>[NH2:25][C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10][CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8]2)[N:4]=1
Reactant: [NH4+]
Reactant: CSC1=NC2(CC(c3ccccc3)Oc3ccccc32)C(=O)N1C
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccccc32)N=C1N
Yield: 11 %

Procedure:
A solution of 1′-methyl-2′-(methylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (50 mg, 0.148 mmol) and NH4I (42.9 mg, 0.296 mmol) in NH3/EtOH (4 mL, 1.5 N) is heated at 110° C. in a tube under microwave reactor for 2-2.5 h. After cooling, the mixture is concentrated in vacuo to give a residue, which is purified by preparative TLC to afford 2′-amino-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (5 mg, 10%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[C:17]([CH:18]=O)[C:16]=1[OH:24]>>[F:14][C:15]1[C:16]([OH:24])=[C:17]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cc(F)cc(F)c1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cc(F)cc(F)c3O)CC2)nc[nH]1

Procedure:
6-[4-(3,5-Difluoro-2-hydroxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3,5-difluorosalicylaldehyde (available from Aldrich). 1H NMR (400 MHz, DMSO-d6) δ 3.48-3.53 (m, 4H), 3.67 (s, 2H), 5.27 (s, 1H), 6.89-6.91 (m, 1H), 7.09-7.13 (m, 1H), 7.89 (s, 1H), 11.64 (br s, 1H). Mass spectrum (ES) MH+=323.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15]B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH3:14].O[C:20]1[CH:21]=[CH:22][C:23]2[S:29](=[O:31])(=[O:30])[CH2:28][CH2:27][C:26]([C:32]([O:34][CH3:35])=[O:33])=[CH:25][C:24]=2[CH:36]=1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH3:14])[O:15][C:20]1[CH:21]=[CH:22][C:23]2[S:29](=[O:31])(=[O:30])[CH2:28][CH2:27][C:26]([C:32]([O:34][CH3:35])=[O:33])=[CH:25][C:24]=2[CH:36]=1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCCOCCOc1ccc(OB(O)O)cc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1C
Reaction time: 24 h
Yield: 69.2 %

Procedure:
To 3-methyl-4-propoxyethoxyphenylboric acid (710 mg), methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg) and cupric acetate (270 mg) suspended in dichloromethane (15 ml) was added triethylamine (1.04 ml). The resulting mixture was stirred for one day with a calcium chloride tube attached to the reaction vessel, was then mixed with celite and was filtered to remove an insoluble material. The filtrate was concentrated and the residue was subjected to purification using silica gel column chromatography to obtain methyl 7-[3-methyl-4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (475 mg) as a brown oily substance.
Reaction SMILES: C(C1(C(OC)=O)CCCC1=O)C=C.N.[CH3:15][O:16][C:17]([CH:19]([CH2:26][CH:27]=[CH2:28])[CH2:20][CH2:21][CH2:22][C:23]([NH2:25])=O)=[O:18].COC(C(CC=C)CCCC(OC)=O)=O.S(Cl)(Cl)=O>CO>[CH3:15][O:16][C:17]([CH:19]([CH2:26][CH:27]=[CH2:28])[CH2:20][CH2:21][CH2:22][C:23]#[N:25])=[O:18]
Reactant: C=CCC(CCCC(N)=O)C(=O)OC
Agent: C=CCC(CCCC(=O)OC)C(=O)OC
Agent: C=CCC1(C(=O)OC)CCCC1=O
Agent: N
Solvent: CO
Solvent: O=S(Cl)Cl
Product: C=CCC(CCCC#N)C(=O)OC

Procedure:
Methyl 1-allyl-2-oxocyclopentane-1-carboxylate (1.1 kg) is added to 1100 ml of methanol previously saturated with ammonia gas at ice bath temperature. The reaction mixture is stirred first at ice bath temperature and then at room temperature overnight with constant introduction of ammonia. The reaction mixture is evaporated to dryness to yield starting material and a mixture of 5-methoxycarbonyl-oct-7-enoic acid amide and methyl 5-methoxycarbonyl-oct-7-enoate. The residue is distilled under reduced pressure to yield a mixture of the diester and ester amide. A portion (25 g) is added dropwise over 40 min to 23.6 g of thionyl chloride and the mixture is heated at 80° for 30 min. The reaction mixture is evaporated to dryness under water vacuum and then distilled under high vacuum to yield 5-methoxycarbonyl-oct-7-enenitrile.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:30])[NH:5][C:6](=[O:29])[N:7]([CH:28]=1)[C@@H:8]1[O:27][C@H:12]([CH2:13][NH:14][C:15](=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].[H][H]>C(O)C.[Pd]>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][C:15]([NH:14][CH2:13][C@H:12]1[O:27][C@@H:8]([N:7]2[CH:28]=[C:3]([CH2:1][CH3:2])[C:4](=[O:30])[NH:5][C:6]2=[O:29])[CH2:9][C@@H:10]1[OH:11])=[O:26]
Reactant: [H][H]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3ccccc3[N+](=O)[O-])O2)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3ccccc3N)O2)c(=O)[nH]c1=O
Yield: 53.9 %

Procedure:
A solution of 0.2 g of 2',5'-dideoxy-5-ethyl-5'-[2-(2nitrophenyl)acetamido]uridine in 100 ml of ethanol was hydrogenated over 0.1 g of 10% palladium-on-carbon catalyst at room temperature and under atmospheric pressure until the uptake of hydrogen was complete. The mixture was filtered and the filtrate was evaporated to yield an oil which crystallized from ethanol to give 0.1 g of 5'-[2-(2-aminophenyl)acetamido]2',5'-dideoxy-5-ethyluridine in the form of a white solid of melting point 195°-196° C.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=12.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[CH:2]1[N:1]=[CH:5][N:4]2[CH:9]=[C:8]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)[CH:7]=[CH:6][C:3]=12
Reactant: O=C(O)c1ccc2nccn2c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4cncn4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using imidazo[1,2-a]pyridine-6-carboxylic acid (Maybridge) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.67 (ddd, J=8.1, 4.8, 1.0 Hz, 1 H), 7.76 (d, J=1.4 Hz, 1 H), 7.78-7.92 (m, 2 H), 8.21 (s, 1 H), 8.46 (dt, J=8.2, 1.8 Hz, 1 H), 8.83 (dd, J=4.7, 1.7 Hz, 1 H), 9.27 (dd, J=2.2, 0.8 Hz, 1 H), 9.69 (dd, J=1.7, 1.0 Hz, 1 H) ppm; MS (DCI/NH3) m/z 264 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(C2(CO)CCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C2(CO)CCC2)cc1

Procedure:
A mixture of [(4-nitrophenyl)cyclobutyl]methane-1-ol (500 mg) was mixed with Pd—C (10%, 80 mg) in EtOH (100 ml) and hydrogenated under H2 atmosphere for 1 hour. The reaction was filtered through Celite and evaporated to give [(4-aminophenyl)cyclobutyl]methane-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13](OCCCC(OCC)=O)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:30])[CH:3]=1.O.CO.Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:30])[CH:3]=1
Reactant: CCOC(=O)CCCOc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2ncnc(Nc3ccc(Cl)cc3F)c2c1
Temperature: 40 °C
Yield: 111.9 %

Procedure:
A mixture of 4-(4chloro-2-fluoroanilino)-7-(3-ethoxycarbonylpropoxy)-6-methoxyquinazoline (220 mg, 0.5 mmol) in aqueous sodium hydroxide solution (4 ml of a 2M solution, 8 mmol), water (2 ml) and methanol (0.5 ml) was stirred and heated at 40° C. for 3 hours. The mixture was allowed to cool and was then acidified with 2M hydrochloric acid. The resulting white precipitate was collected by filtration and washed with acetone and water to give 7-3-carboxypropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (170 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=O)=[N:21]1>CO.N1CCCCC1>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](/[CH:29]=[C:8]2\[O:9][C:5]3[C:4]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]4)=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:21]1
Reactant: CN1CCN(Cc2cc(Cl)cc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CN1CCN(Cc2cc(Cl)cc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 23.9 %

Procedure:
A solution of 5-chloro-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.12 g, 0.43 mmol) in methanol (5.0 mL) was added with 1H-indazole-3-carboxaldehyde (0.063 g, 0.43 mmol). Then, the mixture was added with 7 drops of piperidine, and then the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (eluted with chloroform/methanol (99:1→90:10)) to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-5-chloro-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.042 g, 24%).
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([N+:30]([O-])=O)[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]3[CH2:25][CH2:24][CH2:23]3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1>O1CCCC1.CO.[C].[Pd]>[NH2:30][C:28]1[CH:27]=[CH:26][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]4[CH2:25][CH2:24][CH2:23]4)[CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:29]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)N1CCN(CCN2CCC2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCN(CCN4CCC4)CC3)c2)c(F)c1
Reaction time: 22 h
Yield: 66.8 %

Procedure:
4-[2-(Azetidin-1-yl)ethyl]piperazine-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]amide (114 mg) was dissolved in tetrahydrofuran (3 ml) and methanol (3 ml). 10% Palladium carbon (55 mg) was added, followed by stirring under a hydrogen atmosphere for 22 hrs. The reaction mixture was filtered to remove the catalyst, and the catalyst was washed with methanol. The filtrate was concentrated under reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated to give a crude product of the titled compound (71 mg) as a pale yellow oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].C(N(CC)CC)C.[N:25]1[C:34]2[C:29](=[CH:30][C:31]([S:35](Cl)(=[O:37])=[O:36])=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>CC#N.CCOC(C)=O>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:35]([C:31]2[CH:30]=[C:29]3[C:34](=[CH:33][CH:32]=2)[N:25]=[CH:26][CH:27]=[CH:28]3)(=[O:36])=[O:37])[C:4]1=[O:17])#[N:13]
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: O=S(=O)(Cl)c1ccc2ncccc2c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc4ncccc4c3)C2=O)c1
Reaction time: 1.5 h
Yield: 36.4 %

Procedure:
3-(3-(S)-Amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride (0.32 g, 1.26 mmol) is suspended in 15 mL of CH3CN. To the solution is added triethylamine (0.384 g, 3.78 mmol) followed by quinoline-6-sulfonyl chloride (0.25 g, 0.99 mmol). After stirring for 1.5 hours, the solution is diluted with EtOAc and washed with 0.1 N aqueous HCl, water and saturated NaCl solution. The organic layer is dried over Na2SO4, filtered and concentrated. The crude residue is purified by column chromatography (4% MeOH/CH2Cl2) to afford the title compound (0.146 g, 0.36 mmol) and as a solid.