Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[N:13]([CH3:15])[CH3:14].Br[CH2:17][CH2:18][CH2:19][Cl:20].O>CN(C)C=O>[Cl:20][CH2:19][CH2:18][CH2:17][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[N:13]([CH3:14])[CH3:15]
Reactant: ClCCCBr
Reactant: CC(=O)c1ccc(O)c(N(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCCCl)c(N(C)C)c1
Temperature: 3 °C
Reaction time: 0.75 h
Yield: 179 %

Procedure:
To a suspension of sodium hydride (2.3 g, 48.5 mmol of 50% oil dispersion) with dimethylformamide (75 ml), and cooled to 3° C. in an ice-salt bath and under a stream of nitrogen was added, dropwise, 1-(4-hydroxy-3-dimethylamino-phenyl)ethanone (8.7 g, 48.5 mmol) dissolved in dimethylformamide (150 ml) so that the temperature did not go over 7° C. After the addition was over, the bath was removed and the reaction was stirred at ambient temperature for 45 minutes. The ice bath was reapplied and a solution of 1-bromo-3-chloropropane (8.4g, 53.4 mmol) in dimethylformamide (25 ml) was added dropwise. After the addition was complete, the reaction was stirred for 18 hours at ambient temperature under nitrogen. The reaction was chilled to 7° C. in an ice bath and water (200 ml) was carefully added. After stirring for 5 minutes, the aqueous mixture was extracted with ethyl acetate (5×200 ml). The ethyl acetate extract was washed with water (2×50 ml), dried with MgSO4, and concentrated to yield 22.2 g of a black oily liquid. The compound was purified by prep HPLC, and combination of appropriate fractions gave 5.0 g of brown oil.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:20][C:21]([NH2:23])=[O:22])=[C:8]([CH3:19])[N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:20][C:21]([NH2:23])=[O:22])=[C:8]([CH3:19])[N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(CC(N)=O)c(C)n(Cc3ccccc3)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1c(CC(N)=O)c2ccc(O)cc2n1Cc1ccccc1
Reaction time: 3 h
Yield: 44.7 %

Procedure:
To a solution of 1.53 g (5 mmol) of 6-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide was added 20 mL (20 mmol) of 1M BBr3 in methylene chloride and the mixture stirred for 3 hours. Water was added and the mixture extracted with EtOAc. The EtOAc solution was washed with a NaCl solution, dried (MgSO4), and concentrated at reduced pressure. The residue was chromatographed on silica and the product eluted with 5% MeOH/methylene chloride to give 658 mg (45% yield) of 6-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 174-179° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:24]([F:27])([F:26])[F:25])=[N:5][N:6]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C(C)=CC(C)=CC=1C.CS(C)=[O:39]>>[CH:2]([C:3]1[C:4]([C:24]([F:27])([F:26])[F:25])=[N:5][N:6]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:39]
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(CBr)c2-c2ccccc2)cc1
Reactant: CS(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C=O)c2-c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of the compound prepared in Step 1 (362 mg, 0.79 mmol) in dimethyl sulfoxide (7 mL) was added collidine (0.14 mL, 1.0 mmol). The solution was heated at 120° C. for 3 hours and then kept at overnight at room temperature. The reaction solution was partitioned between ethyl acetate and water and the organic solution was washed with water, dried and concentrated The residue was chromatographed (1:1 hexane:ethyl acetate) to give the desired product (205 mg, 66%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.[OH-].[Na+]>ClCCl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COC(=O)c1sccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(Br)cc1
Temperature: 45 °C
Yield: 70.8 %

Procedure:
To a solution of methyl 3-aminothiophene-2-carboxylate (2.98 g; 11.7 mmol) in anhydrous dichloromethane (32 mL) were added pyridine (1.54 mL; 19.0 mmol) and 4-bromobenzenesulfonyl chloride (1.49 g; 9.5 mmol) in one portion. The reaction mixture was heated at 45° C. for 71 hours, allowed to cool to room temperature, and then diluted with dichloromethane (100 mL). The resulting mixture was successively washed with aqueous hydrochloric acid (50 mL; 2N) and aqueous saturated sodium chloride (50 mL), dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to yield an off-white solid. The crude product was dissolved in dichloromethane (100 mL) and treated with aqueous sodium hydroxide (60 mL; 2N) resulting in a white precipitation. The white solid was isolated by filtration and washed with dichloromethane (50 mL). The white solid was then acidified with aqueous hydrochloric acid (60 mL; 6N) and extracted with dichloromethane (2×100 mL). The organic extracts were combined, washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title compound as a pale yellow solid (2.53 g).
Reaction SMILES: [NH2:1][CH:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]1[SH:12].[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[NH2:1][CH:2]1[N:7]=[C:6]([N:23]2[CH2:22][CH2:21][N:20]([C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)[CH2:25][CH2:24]2)[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]1[SH:12]
Reactant: CC1=C(C#N)C(Br)=NC(N)N1S
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C#N)C(N2CCN(c3ccc(F)cc3)CC2)=NC(N)N1S

Procedure:
In analogy to the procedure described in example 20b, 2-amino-4-bromo-6-methyl-sulfanyl-pyrimidine-5-carbonitrile (see example 69) was treated with 1-(4-fluorophenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at room temperature during 36 hours to yield 2-amino-4-[4-(4-fluoro-phenyl)-piperazin-1-yl]-6-methyl-sulfanyl-pyrimidine-5-carbonitrile as a yellow powder; MS: [M+H]+=345.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13]([OH:15])=O)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C@@H:64]1[C:67](=[O:68])[NH:66][C@@H:65]1[CH2:69][N:70]1[N:74]=[N:73][C:72]([CH2:75][NH:76][C:77](=[O:83])[O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[N:71]1>C(Cl)Cl.CN(C=O)C>[C:79]([O:78][C:77]([NH:76][CH2:75][C:72]1[N:73]=[N:74][N:70]([CH2:69][C@@H:65]2[C@H:64]([NH:63][C:13](=[O:15])/[C:12](=[N:11]\[O:10][C:7]([CH3:8])([CH3:9])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:29])/[C:16]3[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[S:19][CH:20]=3)[C:67](=[O:68])[NH:66]2)[N:71]=1)=[O:83])([CH3:82])([CH3:80])[CH3:81]
Reactant: CC(C)(C)OC(=O)NCc1nnn(C[C@H]2NC(=O)[C@H]2N)n1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1nnn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a solution of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (938 mg, 2.18 mmol) in DCM:DMF (5:1, 8.5 mL) at 0° C. was added DIPEA (953 μL, 5.46 mmol) followed by HATU (830 mg, 2.18 mmol). To the resulting solution was added a solution of tert-butyl ((2-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-2H-tetrazol-5-yl)methyl)carbamate (541 mg, 1.82 mmol) in DCM:DMF (5:1, 8.5 mL). The solution was stirred at rt for 1 h then concentrated in vacuo, dissolved in EtOAc and washed with brine. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine (3×), dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM, 30-50%), affording the title compound (897 mg, 70%) as a purple solid. LCMS: Rt=1.01 min, m/z=709.3 (M+1) Method 2m_acidic.
Reaction SMILES: N[C:2]1[N:6]([CH2:7][C:8]([OH:11])([CH3:10])[CH3:9])[C:5]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:4][C:3]=1[C:16]#[N:17].C(I)[I:19].C(ON=O)CC(C)C>C(Cl)(Cl)Cl>[CH2:12]([C:5]1[N:6]([CH2:7][C:8]([OH:11])([CH3:10])[CH3:9])[C:2]([I:19])=[C:3]([C:16]#[N:17])[N:4]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1nc(C#N)c(N)n1CC(C)(C)O
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: CCCCc1nc(C#N)c(I)n1CC(C)(C)O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of 5-amino-2-butyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazole-4-carbonitrile S4 (600 mg, 2.54 mmol, 1.0 equiv) and CH2I2 (2.0 mL) in CHCl3 (25 mL) at 80° C. was added a solution of isoamylnitrite (1.36 mL, 10.2 mmol, 4.0 equiv) in CHCl3 (5 mL) over 20 min. The reaction was stirred for additional 30 min at 80° C. then cooled to 25° C. The reaction was concentrated in vacuo and purification by silica gel column chromatography (1/9 EtOAc/hexanes-7/3 EtOAc/hexanes, gradient) afforded the title compound (687 mg, 78%) as a yellow solid: 1H NMR (CDCl3, 600 Hz) δ 0.88 (t, J=6.0 Hz, 3H), 1.29 (s, 6H), 1.33 (hex, J=7.8 Hz, 2H), 1.66 (pent, J=7.8 Hz, 2H), 2.88 (t, J=7.8 Hz, 2H), 3.95 (s, 2H); 13C NMR (CDCl3, 150 Hz) δ 13.7, 22.2, 28.3, 28.4, 29.6, 56.6, 71.6, 83.6, 115.1, 120.6, 155.4; MS (APCI+): calcd C12H19IN3O [M+H]+348.2. found 348.2.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:17]=[CH:16][C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=2[CH:8]=1)=[O:6])[C:2]#[CH:3].[C:18]([OH:21])(=[O:20])C>C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[C:7]([O:21][C:18]([N:13]1[CH2:12][CH2:11][C:10]2[CH:16]=[CH:17][C:7]([C:5]3[O:6][C:2]([CH3:3])=[CH:1][N:4]=3)=[CH:8][C:9]=2[CH2:15][CH2:14]1)=[O:20])([CH3:17])([CH3:8])[CH3:5]
Reactant: C#CCNC(=O)c1ccc2c(c1)CCNCC2
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [Hg+2]
Product: Cc1cnc(-c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)o1

Procedure:
A mixture of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-carboxylic acid prop-2-ynyl amide (3.8 g) and mercury (II) acetate (350 mg) in glacial acetic acid was heated under reflux for 1.5 h. After cooling, the solvent was removed in vacuo and the residue partitioned between EtOAc (200 ml) and saturated NaHCO3 solution (100 ml). The aqueous layer was re-extracted with EtOAc and the combined organic layers dried and evaporated in vacuo. The residue was purified using silica gel chromatography (gradient elution, hexane/EtOAc) to give the title compound (2.35 g) as a colourless oil.
Reaction SMILES: O.[OH-].[Li+].[O:4]([CH:11]1[CH2:20][CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([C:21]([O:23]C)=[O:22])[CH:14]=[CH:13][C:12]1=2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O1CCCC1.CO>O>[O:4]([CH:11]1[CH2:20][CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([C:21]([OH:23])=[O:22])[CH:14]=[CH:13][C:12]1=2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc2c(c1)CCCC2Oc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)CCCC2Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
Lithium hydroxide hydrate (0.04 g, 1.0 mmol) was added to a solution of methyl 5-phenoxy-5,6,7,8-tetrahydronaphthalene-2-carboxylate (0.04 g, 0.14 mmol) in a mixed solution of tetrahydrofuran (6.0 mL), methanol (2 mL) and water (2 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was removed in vacuo. Hydrochloric acid aqueous (3 mol/L) was added to make pH 3-5, and the mixture was extracted with dichloromethane. The combined organic phase was washed with water (20 mL×3), dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated to dryness to give pure product 5-phenoxy-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid as a white solid (0.032 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]2[NH:6][C:7](=S)[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1.O.[NH2:32][NH2:33]>C(O)CCC.CO>[Cl:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]2[N:6]=[C:7]([NH:32][NH2:33])[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1nc2cnccc2n1-c1ccc(C2=Nc3cc(Cl)c(Cl)cc3NC(=S)C2)cc1
Reactant: NN
Solvent: O
Solvent: CO
Solvent: CCCCO
Product: Cc1nc2cnccc2n1-c1ccc(C2=Nc3cc(Cl)c(Cl)cc3N=C(NN)C2)cc1
Temperature: 100 °C

Procedure:
A mixture of 7,8-dichloro-2,3-dihydro-4-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-1H-[1,5]benzodiazepin-2-thione (452 mg, 1.0 mmol), hydrazine hydrate (100 mg, 2 mmol) and red mercuric oxide (217 mg, 1.0 mmol) in n-butanol was heated at 100° C. for 30 minutes. The mixture was diluted with methanol (300 ml), filtered through Arbocel filter aid and the filtrate was concentrated under reduced pressure. The crude product was used directly for Example 32.
Reaction SMILES: O.NN.[CH3:4][CH:5]1[C:9]2[C:10]([O:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=3)=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6]1>C(O)C.[Pd]>[CH3:4][CH:5]1[C:9]2[C:10]([O:14][C:15]3[N:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=3)=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6]1
Reactant: CC1OCc2cccc(Oc3ccc([N+](=O)[O-])cn3)c21
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC1OCc2cccc(Oc3ccc(N)cn3)c21
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 93.9 %

Procedure:
In a 50 ml round-bottomed flask 2-[(3-methyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-5-nitropyridine (Intermediate 99, 38.3 mg) was dissolved in ethanol (10 ml) to give a pale yellow solution. Pd/C (14.22 mg, 0.013 mmol) and hydrazine hydrate (0.026 ml, 0.267 mmol) were added. The reaction mixture was stirred at 90° C. After 45 minutes, the reaction mixture was filtered and the organic phase was evaporated under vacuum to afford the title compound (32 mg).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8]([O:11]C)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl.N1C=CC=CC=1>O>[F:1][C:2]1[C:9]([F:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(F)c1F
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=Cc1ccc(O)c(F)c1F
Temperature: 170 °C
Yield: 6759.9 %

Procedure:
Combine 2,3-difluoro-4-methoxy-benzaldehyde (2.76 g, 16.0 mmol) and pyridine hydrochloride (18.5 g, 160 mmol) in a round bottom flask equipped with nitrogen inlet. Heat the mixture at 170° C. two hours, cool to near ambient temperature and dilute with water. Extract aqueous with EtOAc (2×), wash extract with 0.1 N aq. HCl (2×), water (2×) and brine, dry (MgSO4) and concentrate. Purify on silica gel (20% EtOAc/Hexane) to give 2,3-difluoro-4-hydroxy-benzaldehyde (171 g) as a yellow solid. 1HNMR (CDCl3): 10.18 (s, 1H), 7.59 (t, 1H), 6.90 (t, 1H), 6.14 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[Br:12][CH2:13][CH2:14][CH2:15]Br>C(#N)C>[Br:12][CH2:13][CH2:14][CH2:15][O:11][C:3]1[CH:4]=[CH:5][C:6]([C:8](=[O:9])[CH3:10])=[CH:7][C:2]=1[CH3:1]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: BrCCCBr
Solvent: CC#N
Product: CC(=O)c1ccc(OCCCBr)c(C)c1

Procedure:
A mixture of 4-hydroxy-3-methylacetophenone (14.5 g, 96 mmol), K2 CO3 (17.5 g, 144 mmol), and 1,3-dibromopropane (30 g, 144 mmol) in acetonitrile (400 ml) was heated at reflux for 6 hours. At the end of the reaction, the solvent was removed on a rotary evaporator, and the crude solid was extracted into dichloromethane (750 ml). The insoluble inorganics were filtered off. The dichloromethane solution was concentrated again to a crude oil (34.5 g). Purification was effected by flash chromatography over a silica gel column (SiO2, 150 g; eluted with 7:3 hexane:dichloromethane, 2 l; and dichloromethane 2 l). The material thus purified weighed 14.6 g (56%) and was recrystallized from ethanol. Recrystallization again from ethanol gave analytically pure 1-[4-(3-bromopropoxy)-3-methylphenyl]ethanone, m.p.=59°-61° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12]#[N:13])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C(N)(=[S:16])C.Cl>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12](=[S:16])[NH2:13])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: CC(N)=S
Reactant: Cc1cnc2c(c1)CCCC2C#N
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Yield: 63.8 %

Procedure:
3-Methyl-8-cyano-5,6,7,8-tetrahydroquinoline (1.7 g., 0.01 m.) and thioacetamide (1.5 g., 0.02 m.) were dissolved in dimethylformamide (50 ml.), the solution saturated with dry hydrogen chloride gas and then heated on a steam bath for 4 hours. The cooled reaction mixture was poured onto water (200 ml.), washed with ethyl acetate (2 × 200 ml.) and the extracts discarded. The aqueous solution was adjusted to pH 10.0 with 46% sodium hydroxide and extracted into methylene chloride (2 × 200 ml.). The combined extracts were dried (sodium sulphate), evaporated in vacuo and the residual oil triturated with isopropanol and filtered. Recrystallisation from benzene gave the title compound as pale yellow needles (1.3 g., 63%) m.p. 149°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Sn](C)(C)C)[CH:5]=[C:4]([CH3:12])[N:3]=1.Br[C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[C:19]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20][N:21]2[CH:24]2[CH2:26][CH2:25]2)=[CH:16][C:15]=1[F:33].CN(C)P(N(C)C)(N(C)C)=O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:24]1([N:21]2[C:22]3[C:17](=[CH:16][C:15]([F:33])=[C:14]([C:6]4[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:12])[CH:5]=4)[CH:23]=3)[C:18](=[O:32])[C:19]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20]2)[CH2:25][CH2:26]1
Reactant: Cc1cc([Sn](C)(C)C)cc(C)n1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(Br)c(F)cc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1cn(C2CC2)c2cc(-c3cc(C)nc(C)c3)c(F)cc2c1=O

Procedure:
2,6-Dimethyl-4-(trimethylstannyl)pyridine (part g (10.1 g) and 1.52 g dichlorobis(triphenylphosphine)-palladium was added to a stirred solution of 12.13 g ethyl 7-bromo-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (part f) and 10 ml hexamethylphosphoramide (HMPA) in 240 ml dioxane under nitrogen. The reaction mixture was heated under reflux for 24 hours, then cooled and partitioned between water and methylene dichloride. The organic extract was washed with sodium chloride solution, dried (magnesium sulfate) and concentrated to give 12.0 g ethyl 1-cyclopropyl-7-(2,6-dimethyl-4-pyridinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, m.p. 198°-200° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:56]=[C:57]([NH2:64])[C:58]4[CH:59]=[N:60][NH:61][C:62]=4[CH:63]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1>CN(C=O)C>[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:63]=[C:62]4[C:58]([CH:59]=[N:60][NH:61]4)=[C:57]([NH:64][C:6](=[O:8])[C:5]4[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=4[O:11][CH3:12])[CH:56]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1
Reactant: COc1cc(C)ccc1C(=O)O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)ccc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 2 h
Yield: 16.3 %

Procedure:
To a solution of 4-methyl-2-(methyloxy)benzoic acid (67 mg, 0.40 mmol) in DMF (1 ml) were added HATU (248 mg, 0.40 mmol) and DIPEA (0.211 mL, 1.21 mmol). The mixture was stirred for 30 mins under nitrogen before addition of 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg, 0.201 mmol). The reaction was stirred for 2 h then it was loaded onto PS-aminopropyl cartridge (5 g) and left for 3 h. The cartridge was washed with 10% MeOH in DCM. Appropriate fractions were combined and the solvent was evaporated. The residue was dissolved in MeOH: DMSO (1 ml; 1:1, v/v) and purified by Mass Directed Automated Preparative HPLC using method B. Solvent was evaporated under a stream of nitrogen to give title compound (13 mg).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([O:12][C@@H:13]1[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[C@@H:30]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C@H:22]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C@H:14]1[O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6][NH:7]2)#[CH:2].I[C:49]1[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([CH3:56])[CH:50]=1>C(N(CC)CC)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[OH:55][C:52]1[CH:53]=[CH:54][C:49]([C:2]#[C:1][C:3]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:4]=2[C:5]([O:12][C@@H:13]2[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[C@@H:30]([O:31][C:32](=[O:37])[C:33]([CH3:34])([CH3:35])[CH3:36])[C@H:22]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C@H:14]2[O:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:19])[CH3:20])=[N:6][NH:7]3)=[CH:50][C:51]=1[CH3:56]
Reactant: Cc1cc(I)ccc1O
Reactant: C#Cc1cccc2[nH]nc(O[C@@H]3O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]3OC(=O)C(C)(C)C)c12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(C#Cc2cccc3[nH]nc(O[C@@H]4O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]4OC(=O)C(C)(C)C)c23)ccc1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of 4-ethynyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (66 mg) in triethylamine (1 mL) were added 4-iodo-2-methylphenol (25 mg), tetrakis(triphenylphosphine)palladium (0) (12 mg) and copper (I) iodide (4 mg), and the mixture was stirred at 80° C. under an argon atmosphere overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethylacetate=3/1-2/1-1/1) to give the title compound (47 mg).