Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]3[CH2:19][CH2:20][N:21](C(OCC(Cl)(Cl)Cl)=O)[CH2:22][C:5]=3[C:4]=2[CH:3]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C.[Zn]>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]3[CH2:19][CH2:20][NH:21][CH2:22][C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)c1c(n2CCc2ccccc2)CCN(C(=O)OCC(Cl)(Cl)Cl)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccc2)CCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
A mixture of 2,2,2-trichloroethyl 3,4-dihydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (100 mg, 0.2 mmol) and Zn dust (120 mg, 1.9 mmol) in acetic acid (1.2 ml) was stirred at 25° C. for 2 h. The reaction mixture was basified with saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated to obtain 30 mg of 2,3,4,5-tetrahydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indole after purification on silica gel (230-400 mesh) chromatography eluting with methanol-dichloromethane gradient.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[N+:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:17])[CH2:15]Cl)([O-:6])=[O:5]>C(O)C>[N+:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:17])[CH2:15][N:2]([CH3:3])[CH3:1])([O-:6])=[O:5]
Reactant: O=C(CCl)Nc1ccccc1[N+](=O)[O-]
Reactant: CNC
Solvent: CCO
Product: CN(C)CC(=O)Nc1ccccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A solution of dimethylamine in ethanol (40 ml. of a 33% w/w solution) was added to a suspension of N-(2-nitrophenyl)-2-chloroacetamide (14.9 g) [prepared by the method described by G. Tennant, J.C.S., (1963), 2428] in ethanol (70 ml) and the mixture was heated to reflux, with stirring, for 2hours. After cooling, the ethanol and excess dimethylamine were evaporated off under reduced pressure and the solid residue was treated with an aqueous potassium hydroxide solution (100 ml., 40% w/v). The resulting suspension was extracted with diethyl ether (3 × 100 ml) and the combined extracts dried over magnesium sulphate and evaporated to give N-(2-nitrophenyl)-2-dimethylaminoacetamide (13.8 g), m.p. 44°-47° C., sufficiently pure to be used in the next stage of the synthesis, the preparation of N-(2-aminophenyl)-2-dimethylaminoacetamide.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[CH:3]=1.C(B(CC)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)C.CN(C=O)C>O>[I:8][C:4]1[CH:3]=[C:2]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CCB(CC)c1cccnc1
Reactant: Ic1cccc(I)c1
Solvent: O
Solvent: CN(C)C=O
Product: Ic1cccc(-c2cccnc2)c1

Procedure:
A solution of 1,3-diiodobenzene (1.10 g, 3.3 mmol), 3-(diethylboryl)pyridine (0.48 g, 3.3 mmol), tetrakis(triphenlyphosphine)palladium(0) (0.010 g, 0.0086 mmol) potassium carbonate (0.922 g, 6.64 mmol), in mixed solvent of 3 mL DMF and 1 mL water, was heated at 150° C. for 5 minutes under microwave irradiation. The reaction mixture was quenched with H2O (30 mL), then extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude purified by liquid chromatography on silica gel using an ISCO single channel system (Hexane/EtOAc=9/1 to 1/9) to afford 3-(3-iodophenyl)pyridine as a yellow oil.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[NH2:18][C:19]1[CH:27]=[CH:26][C:25]2[N:24]([CH2:28][CH2:29][OH:30])[C:23]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:22][C:21]=2[C:20]=1[C:35]#[N:36].C(N(CC)CC)C>ClCCl>[C:31]([C:23]1[N:24]([CH2:28][CH2:29][OH:30])[C:25]2[C:21]([CH:22]=1)=[C:20]([C:35]#[N:36])[C:19]([NH:18][C:14]([C:11]1([C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:17])([F:1])[O:3][C:4]=4[CH:10]=3)[CH2:13][CH2:12]1)=[O:15])=[CH:27][CH:26]=2)([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: CC(C)(C)c1cc2c(C#N)c(N)ccc2n1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2c(C#N)c(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (196 mg, 0.75 mmol) was added to a solution of 5-amino-2-tert-butyl-1-(2-hydroxyethyl)-1H -indole-4-carbonitrile (150 mg, 0.58 mmol) and triethylamine (242 μL, 1.74 mmol) in dichloromethane (2 mL). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and extracted with 1N HCl solution (×2), saturated NaHCO3 solution (×2), brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in DMSO and purified by reverse-phase HPLC to yield the product, N-(2-tert-butyl-4-cyano -1-(2-hydroxyethyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 481.2, found 482.5 (M+1)+. Retention time 1.99 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.33 (d, J=1.6 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 6.28 (s, 1H), 5.05 (t, J=5.6 Hz, 1H), 4.42 (t, J=6.8 Hz, 2H), 3.70-3.65 (m, 2H), 1.51-1.48 (m, 2H), 1.44 (s, 9H), 1.19-1.16 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[Cl:12][C:13]1[CH:14]=[C:15]([NH:23][C:24](OC2C=CC=CC=2)=[O:25])[C:16](=[CH:21][CH:22]=1)[C:17](OC)=[O:18]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:17](=[O:18])[C:16]2[C:15](=[CH:14][C:13]([Cl:12])=[CH:22][CH:21]=2)[NH:23][C:24]1=[O:25])(=[O:9])=[O:10]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: Nc1ccccc1S(=O)(=O)n1c(=O)[nH]c2cc(Cl)ccc2c1=O
Yield: 58 %

Procedure:
2.7 g (15.7 mmol) of 2-aminobenzenesulfonamide and 4.8 g (15.7 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as Preparation Example 1 to obtain 3.2 g (yield 58%: 3 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 6.46 (2H, s), 6.65 (1H, t), 6.81 (1H, d), 7.12 (1H, s), 7.23 (1H, d), 7.34 (1H, t), 7.76 (1H, d), 7.86 (1H, d).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].I[CH2:12][CH3:13]>CN(C=O)C>[CH2:12]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)[CH3:13]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen inlet and charged with 4-nitropyrazole (3.00 g, 26.5 mmol) and DMF (50 mL). The mixture was cooled to 0° C. using an ice bath. Sodium hydride (60% dispersion in mineral oil, 1.17 g, 29.2 mmol) was added portionwise. After the addition was complete, the mixture was stirred at 0° C. for 30 min. After that time, iodoethane (6.21 g, 39.8 mmol) was added over 15 min. After the addition was complete, the mixture was stirred at 0° C. for 30 min and then at room temperature for 3 h. After this time, the mixture was concentrated in vacuo. The residue was diluted with water (200 mL). The resulting precipitate was filtered, and the filter cake was dried in the oven to afford a 51% (1.90 g) of 111a as an off-white solid. The aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 50% hexanes/ethyl acetate) to afford another 49% yield (1.84 g, in total quantitative yield (3.74 g)) of 111a as an off-white solid: mp 54-55° C.; 1H NMR (300 MHz, CDCl3) δ 8.14 (s, 1H), 8.07 (s, 1H), 4.22 (q, 2H, J=7.2 Hz), 3.41 (s, 3H), 1.56 (s, 3H, J=7.2 Hz); MS (ESI+) m/z 142.0 (M+H).
Reaction SMILES: [H-].[Na+].C(O[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.BrC[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C)C=O>[CH2:29]([O:28][C:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:11][NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:27])[CH3:30]
Reactant: CCOC(=O)CCCCCBr
Reactant: O=C(Nc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCNc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
Under ice-cooling, 1.87 g of 62% sodium hydride was added to 100 ml of a dimethylformamide (DMF) solution containing 10.00 g of N-benzyloxycarbonylaniline, and the mixture was stirred at room temperature for one hour. Under ice-cooling, to the above mixture was added dropwise 50 ml of a DMF solution containing 10.31 g of ethyl 6-bromohexanoate, and the resulting mixture was stirred at room temperature overnight. DMF was removed under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed under reduced pressure. The residue was dissolved in 160 ml of methanol and 2 g of 10% palladium-carbon (Pd-C) was added to the solution. The mixture was subjected to catalytic reduction at normal temperature under normal pressure for 2 hours. After removing the catalyst by filtration, the filtrate was condensed and the residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=4:1) to give 8.13 g of N-ethoxycarbonylpentyl-N-phenylamine (yield; 79%, melting point: 34°-37° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][C:17]=3[CH2:30][NH2:31])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.Cl.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][C:17]=3[CH2:30][NH:31][C:37](=[O:44])[C:38]3[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=3)=[CH:32][CH:33]=2)=[O:10])=[CH:34][CH:35]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(CN)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(CNC(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
A mixture of tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-(aminomethyl)phenyl)acetate (0.015 g, 0.030 mmol), nicotinoyl chloride hydrochloride (0.007 g, 0.039 mmol), and triethylamine (0.013 ml, 0.091 mmol) in dichloromethane (1 ml) was stirred at ambient temperature for 1 hour. The reaction was loaded onto a silica gel sample and the product was eluted using a gradient system of 0.5% methanol/dichloromethane to 5% methanol/dichloromethane to provide tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-(nicotinamidomethyl)phenyl)acetate (0.005 g, 275%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[S:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[O:22][CH:23]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:18][C:19]3[N:20]=[C:21]([C:24]4[S:25][C:26]([CH3:29])=[CH:27][CH:28]=4)[O:22][CH:23]=3)=[CH:3][CH:4]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Cc1ccc(-c2nc(CCl)co2)s1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Product: Cc1ccc(-c2nc(COc3ccc(CCCCn4ccnc4)cc3)co2)s1
Yield: 65 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with 4-chloromethyl-2-(5-methyl-2-thienyl)oxazole to give 4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(5-methyl-2-thienyl)oxazole. The yield was 65%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 82-83° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:9][CH:10]=[N:11]2)=[CH:6][C:5]=1[N+:20]([O-:22])=[O:21])[CH3:2].[N-:23]=[C:24]=[S:25]>>[CH2:8]([NH:23][C:24]([N:17]1[CH2:18][CH2:19][N:14]([C:8]2[C:7]3[C:12](=[CH:13][C:4]([NH:3][CH2:1][CH3:2])=[C:5]([N+:20]([O-:22])=[O:21])[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH2:15][CH2:16]1)=[S:25])[C:7]1[CH:12]=[CH:13][CH:4]=[CH:5][CH:6]=1
Reactant: [N-]=C=S
Reactant: CCNc1cc2ncnc(N3CCNCC3)c2cc1[N+](=O)[O-]
Product: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1[N+](=O)[O-]
Yield: 77 %

Procedure:
Substantially the same procedure as in Example 60 was repeated, except that 7-ethylamino-6-nitro-4-(1-piperazinyl)quinazoline obtained in Reference Example 5 (1) was used in place of 6,7-dimethoxy-4-(1-piperazinyl)quinazoline, and the corresponding isothiocyanate was used in place of 4-phenoxyphenyl isocyanate, to give the desired compound.
Reaction SMILES: C1(C2C=CC3=NN(C4C=C(C(CC(C)(C)C)(C)C)C=C(C5C=CC=CC=5)C=4O)N=C3C=2)C=CC=CC=1.[OH-].[Na+].[OH:39][C:40]1[C:45]([C:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([CH3:48])[CH3:47])=[CH:44][C:43]([C:55]([CH2:58][C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:57])[CH3:56])=[CH:42][C:41]=1[N:63]=[N:64][C:65]1[CH:70]=[CH:69][C:68]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)=[CH:67][C:66]=1[N+:77]([O-])=O>O>[C:71]1([C:68]2[CH:69]=[CH:70][C:65]3=[N:64][N:63]([C:41]4[CH:42]=[C:43]([C:55]([CH2:58][C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:57])[CH3:56])[CH:44]=[C:45]([C:46]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)([CH3:48])[CH3:47])[C:40]=4[OH:39])[N:77]=[C:66]3[CH:67]=2)[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1
Reactant: CC(C)(C)CC(C)(C)c1cc(N=Nc2ccc(-c3ccccc3)cc2[N+](=O)[O-])c(O)c(C(C)(C)c2ccccc2)c1
Agent: CC(C)(C)CC(C)(C)c1cc(-c2ccccc2)c(O)c(-n2nc3ccc(-c4ccccc4)cc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(-c4ccccc4)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1

Procedure:
The procedure of Example 1 (E) is followed using sodium hydroxide (4 g, 0.1 mol), 5 mL of water, 2-hydroxy-2′nitro-3-α-cumyl-4′-phenyl-5-tert-octylazobenzene (4 g, 0.0072 mol) and fomamidine sulfinic acid (6.5 g, 0.06 mol) to give the title compound as a pale yellow crystalline solid melting at 137-139° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:38]=[CH:39][CH:40]=1)[CH2:7][C:8]1[C:9](=[O:37])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][C:34](=[O:36])[O:33][N:32]=3)=[CH:21][CH:20]=2)[C:11]([CH2:15][CH2:16][CH3:17])=[N:12][C:13]=1[CH3:14])(=[O:3])[CH3:2].[BH4-].[Na+]>O1CCCC1CO.C(OCC)(=O)C>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]([CH:38]=[CH:39][CH:40]=1)[CH2:7][C:8]1[C:9](=[O:37])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][C:34](=[O:36])[O:33][N:32]=3)=[CH:21][CH:20]=2)[C:11]([CH2:15][CH2:16][CH3:17])=[N:12][C:13]=1[CH3:14])[CH3:2]
Reactant: CCCc1nc(C)c(Cc2cccc(C(C)=O)c2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: OCC1CCCO1
Product: CCCc1nc(C)c(Cc2cccc(C(C)O)c2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a solution of 5-(3-acetylbenzyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one (0.20 g) in tetrahydrofuran-methanol (1:1, 4 mL) was added sodium borohydride (0.014 g), and the mixture was stirred for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.14 g, 69%) as a colorless solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:19]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[NH:21]1[CH2:24][CH2:23][C:22]1=[O:25]>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:19][N:21]3[CH2:24][CH2:23][C:22]3=[O:25])=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[N:11]=2)[CH:8]=1
Reactant: O=C1CCN1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12
Agent: Cl
Product: O=C1CCN1Cc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and azetidin-2-one. m/e+ 346 for C17H14Cl2N3O4 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.59 (d, J=9.5 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.25 (m, 1H), 4.79 (s, 2H), 3.18 (t, J=4.0 Hz, 2H), 3.00 (t, J=4.0 Hz, 2H) ppm; 13C-NMR (100 MHz, CDCl3, δ) 168.269, 145.293, 143.807, 134.791, 132.129, 129.877, 129.324, 127.269, 122.325, 121.771, 118.185, 115.333, 39.400, 37.512, 35.449 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]2=[O:22])=[CH:6][C:3]=1[CH2:4][OH:5].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:18])([F:20])[F:19])[N:12]([CH3:21])[C:11]2=[O:22])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(CO)c2)c1=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=O)c2)c1=O
Reaction time: 3 h

Procedure:
A solution of 20.08 g of 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl] benzyl alcohol in 250 ml dichloromethane is added dropwise in the course of 30 minutes with stirring at room temperature to a suspension of 19.38 g of pyridinium chlorochromate in 250 ml of dichloromethane, and stirring of the reaction mixture is continued for 3 hours at 25°-28° C. The clear solution is decanted, the brown residue is washed with 100 ml of dichloromethane, and the dichloromethane solution is filtered through 150 g of silica gel. The filtrate is concentrated, and the residue is recrystallised from n-hexane/ethyl acetate; m.p.: 168°-169° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>C(OC(O)C)C>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:2]2[N:7]=[C:6]([S:8][C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:18][CH:19]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1ccc(Sc2ccnc(Cl)n2)cc1
Agent: CCOC(C)O
Product: Cc1ccc(Sc2ccnc(Nc3ccc(O)cc3)n2)cc1
Yield: 46.2 %

Procedure:
A mixture of 2-chloro-4-(4-methylphenylsulphanyl)pyrimidine (100 mg, 0.42 mmol) and 4-aminophenol (55 mg, 0.5 mmol) was heated at reflux in ethoxyethanol (2 ml) for 1.5 h. The reaction was concentrated under reduced pressure and subjected to column chromatography [silica, 20% ethyl acetate--CH2Cl2 ] to give the title compound (60 mg) as a buff solid m.p. 179-180°. δH (CDCl3) 8.01 (1H, d, J 5.4 Hz), 7.50-7.45 (2H, m), 7.31-7.27 (4H, m), 6.93 (1H, br s), 6.71-6.66 (2H, m), 6.25 (1H, d, J 5.4 Hz), 4.70 (1H, br s) and 2.44 (3H, s).
Reaction SMILES: [CH2:1]([N:4]1[CH:9]=[C:8]([O:10]CC2C=CC=CC=2)[C:7](=[O:18])[CH:6]=[C:5]1[CH:19]([F:21])[F:20])[CH:2]=[CH2:3].B(Br)(Br)Br>ClCCl>[CH2:1]([N:4]1[CH:9]=[C:8]([OH:10])[C:7](=[O:18])[CH:6]=[C:5]1[CH:19]([F:21])[F:20])[CH:2]=[CH2:3]
Reactant: C=CCn1cc(OCc2ccccc2)c(=O)cc1C(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=CCn1cc(O)c(=O)cc1C(F)F
Reaction time: 0.33 h
Yield: 131.7 %

Procedure:
An alternative debenzylation procedure was used for the allyl derivative in order to avoid reduction of the allyl double bond. Thus, a clear yellow/brown solution of 1-allyl-5-benzyloxy-2-difluoromethyl-1H-pyridin-4-one (2.91 g, 10 mmol) in dichloromethane (30 mL) was cooled in an ice-salt bath under a positive nitrogen atmosphere. Then, a pre-mixed 1.0 M boron tribromide solution (10 mL) and dichloromethane (10 mL) was added dropwise. After 20 min, the reaction mixture was quenched with 25 mL of methanol. The solution was concentrated to dryness. The obtained solid was suspended in ether. The solid was collected by filtration to afford the title product (2.65 g, 94% yield) as the hydrobromide salt. HPLC purity (peak area percent) is 99.4% at x=267 nm using HPLC Method 1 as described above. 1H NMR (400 MHz, DMSO-D6+D2O) δ (ppm): 8.10 (s, 1H), 7.29 (t, J=53.0 Hz, 1H, CF2H), 6.26 (s, 1H), 5.07-6.00 (m, 1H), 5.36 (d, J=10.3 Hz, 1H), 5.20 (d, J=17.1 Hz, 1H), 4.95 (d, J=5.1 Hz, 2H).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:19]([NH2:21])=[O:20])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>C(O)C>[OH:20][C:19]1[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:21]=1
Reactant: NC(=O)c1[nH]c2ccccc2c1NC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(-c2ccccc2)nc2c1[nH]c1ccccc12

Procedure:
A mixture of 3-Benzamidoindole-2-carboxamide (276 mg), sodium hydride (5 mg) and ethanol (5 mL) was refluxed for 2 h. The reaction mixture was quenched with saturated ammonium carbonate and the product was extracted with methylene chloride. After drying over magnesium sulfate, the solvent was removed in vacuo and the residue was triturated with ether to afford 4-Hydroxy-2-phenyl-5H-indolo[3,2-d]pyrimidine (Compound 2) as a white solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:19].CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:31]=[CH:32][CH:33]=2)O1>>[OH:19][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[CH:7]=2)[C:2]=1[C:28]1[CH:29]=[C:30]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:31]=[CH:32][CH:33]=1
Reactant: Oc1cccc(-c2ccc3c(Br)c(O)ccc3c2)c1
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Product: CS(=O)(=O)Nc1cccc(-c2c(O)ccc3cc(-c4cccc(O)c4)ccc23)c1
Reaction time: 2 h
Yield: 64 %

Procedure:
The compound is prepared by the reaction of 1-bromo-6-(3-hydroxyphenyl)-naphthalene-2-ol (100 mg, 0.32 mmol, 1 eq) with N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (94.3 mg, 0.32 mmol, 1 eq) according to method A in 2 h. Purification by column chromatography with hexane/ethyl acetate 3/2 yields the desired compound in a yield of 64%, 83 mg.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[CH3:27][O:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][C:35]([CH:39]=O)=[N:36]2)=[CH:31][C:30]=1[CH3:41]>C(O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10]/[N:11]=[CH:39]/[C:35]2[CH:34]=[CH:33][C:32]3[C:37](=[CH:38][C:29]([O:28][CH3:27])=[C:30]([CH3:41])[CH:31]=3)[N:36]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: COc1cc2nc(C=O)ccc2cc1C
Solvent: CCO
Product: COc1cc2nc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)ccc2cc1C

Procedure:
tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (187 mg, 0.497 mmol) and 7-methoxy-6-methylquinoline-2-carbaldehyde (100 mg, 0.497 mmol) in ethanol (5 mL) were stirred at ambient temperature for 24 hours. After concentration, the residue was used in the next step without purification.