Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5]O.P(Br)(Br)[Br:12]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][Br:12]
Reactant: OCCc1ccccc1Br
Reactant: BrP(Br)Br
Product: BrCCc1ccccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 145.2 %

Procedure:
To 550.0 g of o-bromophenethyl alcohol, while stirring, is added, dropwise, 375.0 g of phosphorus tribromide. After stirring for three hours at room temperature, the reaction mixture is heated on a steam bath for three hours and then poured into 6 kg of crushed ice. The mixture is extracted with three 600 and two 200 ml portions of ether. The ether extracts are washed, dried, concentrated, and the residue is distilled to give 531.0 g of o-bromophenethyl bromide, bp. about 86°-88° (0.9mm), nD26 1.5922.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][NH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[N:24][CH:25]=1.CN(C)C=O>O>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][O:26][C:23]1[N:24]=[CH:25][C:20]([CH2:19][N:12]2[CH:13]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11]2)=[CH:21][CH:22]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Reactant: COC(=O)c1c[nH]cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)cc1-c1ccccc1
Reaction time: 15 h
Yield: 95.8 %

Procedure:
Sodium hydride (60%, oily, 310 mg) was added to a mixture of methyl 4-phenyl-3-pyrrolcarboxylate (1.20 g), 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (1.88 g), and N,N-dimethylformamide (50 ml) at room temperature, and the mixture was stirred for 15 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-4-phenyl-1H-pyrrol-3-carboxylate (2.74 g, yield: 96%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: O1C=CC(C2C=C(C3N4C=C(N[CH:22]5[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]5)C=CC4=NC=3)C=CN=2)=C1.[Cl:29][C:30]1[CH:35]=[C:34]([C:36]2[N:40]3[CH:41]=[C:42]([NH:45]C4CCC(O)CC4)[CH:43]=[CH:44][C:39]3=[N:38][CH:37]=2)[CH:33]=[CH:32][N:31]=1.[CH:53]1([OH:59])[CH2:58][CH2:57][CH2:56]CC1>>[Cl:29][C:30]1[CH:35]=[C:34]([C:36]2[N:40]3[CH:41]=[C:42]([NH:45][CH:23]4[CH2:22][CH2:27][CH2:26][CH:25]([OH:28])[CH2:24]4)[CH:43]=[CH:44][C:39]3=[N:38][CH:37]=2)[CH:33]=[C:32]([C:57]2[CH:58]=[CH:53][O:59][CH:56]=2)[N:31]=1
Reactant: OC1CCC(Nc2ccc3ncc(-c4ccnc(-c5ccoc5)c4)n3c2)CC1
Reactant: OC1CCCCC1
Reactant: OC1CCC(Nc2ccc3ncc(-c4ccnc(Cl)c4)n3c2)CC1
Product: OC1CCCC(Nc2ccc3ncc(-c4cc(Cl)nc(-c5ccoc5)c4)n3c2)C1

Procedure:
This compound is prepared analogously to 4-(3-(2-furan-3-yl-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol (Example 2.3) by replacing [4-[3-(2-chloro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino]-cyclohexanol (Example 2.1) with 1-(RS/RS)-3-(2,6-dichloro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol (Intermediate J); [M+H]+ 409
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[CH:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]#[N:28])[CH:25]=2)[NH:20][CH:19]=1)=O.[CH:29]([C:31]1[N:35]([CH3:36])[CH:34]=[C:33]([C:37]([O:39][CH3:40])=[O:38])[CH:32]=1)=O>>[C:27]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:16][N:2]1[C:29]([C:31]2[N:35]([CH3:36])[CH:34]=[C:33]([C:37]([O:39][CH3:40])=[O:38])[CH:32]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2=[O:15])=[N:1]1)#[N:28]
Reactant: N#Cc1ccc2[nH]cc(C=O)c2c1
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: COC(=O)c1cc(C=O)n(C)c1
Product: COC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(C#N)cc23)n(C)c1

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 3-formyl-1H-indole-5-carbonitrile, followed by methyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylate. Mass: 514.05 (M+H).
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8](I)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].O>C(N(CC)CC)C.[Cu]I.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>[CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1CCc2cccc(I)c2C1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(C#C[Si](C)(C)C)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-di-n-propylamino-8-iodo-1,2,3,4-tetrahydronaphthalene (4.3 g, 12.1 mmol) in triethylamine (100 ml) was added copper(I) iodide (228 mg), bis(triphenylphosphine)palladium(II) chloride (841 mg) and trimethylsilylacetylene (1.7 ml). This mixture was stirred at room temperature overnight. The reaction was poured into water and extracted with ether. The extract was washed with brine, dried (Na2SO4), and concentrated to give 5 g of crude product. Purification by flash chromatography using 20:1 methylene chloride:methanol as solvent gave 4.33 g of 2-di-n-propylamino-8-(2-trimethylsilylethynyl)-1,2,3,4-tetrahydronaphthalene which was used in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([NH2:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33](=[O:34])[NH2:35])[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1
Reactant: NC(=O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1=C(CN2CCOCC2C(N)=O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.1 %

Procedure:
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (3.02 g, 6 mmol), morpholine-3-carboxamide (0.78 g, 6 mmol) and potassium carbonate (1.66 g, 12 mmol) in anhydrous ethanol (70 mL) was stirred at 25° C. for 12 hours under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=100/1) to give the title compound as a yellow solid (1.66 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)/[C:27]([O-])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].CS(Cl)(=O)=O.[NH2:57][C@@H:58]1[C:89](=[O:90])[N:60]2[C:61]([C:73]([O:75][CH:76]([C:83]3[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=3)[C:77]3[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=3)=[O:74])=[C:62]([CH2:65][S:66][C:67]3[CH2:71][O:70][C:69](=[O:72])[CH:68]=3)[CH2:63][S:64][C@H:59]12.N1C=CC=CC=1>CN(C)C=O>[O:72]=[C:69]1[CH:68]=[C:67]([S:66][CH2:65][C:62]2[CH2:63][S:64][C@@H:59]3[C@H:58]([NH:57][C:27](=[O:28])/[C:26](/[C:24]4[N:25]=[C:21]([NH:20][C:1]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[S:22][CH:23]=4)=[N:30]\[O:31][C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:89](=[O:90])[N:60]3[C:61]=2[C:73]([O:75][CH:76]([C:83]2[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=2)[C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[O:74])[CH2:71][O:70]1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSC3=CC(=O)OC3)CS[C@H]12
Reactant: O=C([O-])/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C1C=C(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)CO1
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
A stirred solution of sodium 2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetate (762 mg) in dimethylformamide (4 ml) was cooled to -55° C. to -60° C. and methanesulphonyl chloride (0.085 ml) was added. The mixture was stirred at the same temperature for 30 mins and then a solution of diphenylmethyl 7β-amino-3-(2,5-dihydro-2-oxofuran-4-ylthiomethyl)ceph-3-em-4-carboxylate (494 mg) in dimethylformamide (4 ml) was added followed by pyridine (0.08 ml). The mixture was then stirred at 0° C. for 90 mins and then partitioned between ethyl acetate and aqueous citric acid solution. The organic phase was washed successively with water, sodium bicarbonate solution, water, and brine. The solution was dried over magnesium sulphate and evaporated. The title compound (744 mg) was isolated by column chromatography of the residue using gradient elution (Kieselgel 2:1 going to 1:1 hexane:ethyl acetate). υmax (CHCl3) 3400, 1785, 1745 and 1685cm-1 . δH(CDCl3) 3.23 (1H, d, J 18.2Hz), 3.52 (1H, d, J 18.2Hz), 3.93 (1H, d, J 12.6Hz), 3.99 (1H, d, J 12.5Hz), 4.70 (2H, s), 5.08 (1H, d, J 5.0Hz),5.65 (1H, s), 6.11 (1H, dd, J 5.0 and 8.9Hz), 6.43 (1H, s), 6.75 (1H, s), 6.98 (1H, s), 7.15-7.5 (41H, m). [mass spectrum: +ve ion (thioglycerol) MH+ 1148].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8](OCC)=O)=[N:4][NH:5][C:6]=1C.[CH2:13]([N:17](CCCC)[C:18]1[CH:22]=[C:21]([CH3:23])NN=1)[CH2:14][CH2:15][CH3:16]>>[CH2:13]([N:17]([CH2:18][CH2:22][CH2:21][CH3:23])[C:6]1[C:2]([Cl:1])=[C:3]([CH3:8])[NH:4][N:5]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCOC(=O)c1n[nH]c(C)c1Cl
Reactant: CCCCN(CCCC)c1cc(C)[nH]n1
Product: CCCCN(CCCC)c1n[nH]c(C)c1Cl
Yield: 61 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1A, N,N-dibutyl-5-methyl-1H-pyrazol-3-amine (419 mg, 2.00 mmol) was converted to the title compound (297 mg, 61%). 1H NMR (CDCl3) δ 3.26-3.17 (m, 4H), 2.19 (s, 3H), 1.57-1.44 (m, 4H), 1.32 (qd, J=15.0, 7.3 Hz, 4H), 0.91 (t, J=7.4 Hz, 6H); MS(ESI+) m/z 243.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:36][CH2:35][C:11]3[NH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH:21][CH:22]5[CH2:27][CH2:26][N:25]([C:28]([O:30]C(C)(C)C)=O)[CH2:24][CH2:23]5)=[O:20])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:4][CH:3]=1.[F:37][C:38]1[CH:46]=[CH:45][C:41](C(Cl)=O)=[CH:40][CH:39]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>Cl.O1CCOCC1>[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:28]([N:25]2[CH2:26][CH2:27][CH:22]([NH:21][C:19]([C:16]3[CH:15]=[CH:14][C:13]4[NH:12][C:11]5[CH2:35][CH2:36][N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[CH2:9][C:10]=5[C:18]=4[CH:17]=3)=[O:20])[CH2:23][CH2:24]2)=[O:30])=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3[nH]c4c(c3c2)CN(c2ccc(F)cc2)CC4)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(C(=O)c2ccc(F)cc2)CC1)c1ccc2[nH]c3c(c2c1)CN(c1ccc(F)cc1)CC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of tert-butyl 4-(2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate (Compound 38, 50 mg, 100 μmol) in 4 N HCl/dioxane (3.0 mL) was allowed to stir at room temperature for 2 h. The reaction mixture was then concentrated, MeOH (5.0 mL) was added and the volatiles were evaporated (2×). The resulting residue was dissolved in DMF (2.0 mL) and 4-fluorobenzoyl chloride (15 μL, 20 mg, 130 μmol) and triethylamine (0.5 mL, 0.36 g, 3.6 mmol) were added. The resulting reaction mixture was allowed to stir at room temperature overnight, poured into saturated sodium bicarbonate solution (20 mL) to give a yellow solid which was triturated with ethyl ether and then purified by reverse phase HPLC to provide N-(1-(4-fluorobenzoyl)piperidin-4-yl)-2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide (Compound 39) (46%). 1H NMR (DMSO-d6, 300 MHZ) 11.13 (s, 1H), 8.09 (d, J=7.7 Hz, 1H), 8.03 (s, 1H), 7.58 (dd, J=8.4, 1.5 Hz, 1H), 7.45 (dd, J=8.5, 5.5 Hz, 2H), 7.28 (t, J=8.8 Hz, 3H), 7.10 (m, 4H), 4.43 (s, 3H), 4.18-4.03 (m, 2H), 3.70-3.54 (m, 3H), 3.16 (br s, 1H), 2.92 (br s, 2H), 1.87 (br s, 2H), 1.54 (br s, 2H) ppm; MS (ES) 515 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].[OH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C)C=O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][C:15]1[N:14]=[CH:13][N:12]=[C:11]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:16]=1)#[N:5]
Reactant: Clc1cc(Cl)ncn1
Reactant: COC(=O)Cc1ccccc1O
Reactant: N#Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Reaction time: 3 h

Procedure:
Under the dried nitrogen atmosphere, to a reaction flask were added 540 mL of dried N,N-dimethylformamide, 26.2 g of 2-hydroxybenzonitrile, 29.8 g of 4,6-dichloropyrimidine and 27.6 g of anhydrous potassium carbonate, and this mixture is heated under stirring to 100. degree. C. to be followed by reacting for 3 hrs. Then, 34.9 g of methyl 2-hydroxyphenylacetate and 13.8 g of anhydrous potassium carbonate were added and the temperature was increased to 120. degree. C. The reaction went on under stirring for 5 hrs. Afterwards, N,N-dimethylformamide was recovered by concentrating the reaction mixture under reduced pressure, 150 mL of toluene and 100 mL of water were added to the residue to dissolve the solid under stirring. The solution was left to stand still for separation of an organic phase and an aqueous phase. The organic phase was concentrated to obtain .a solid crude product of methyl 2-(2-(6-(2-cyanophenoxy)pyrimidine-4-oxy)phenyl)acetate. After purification, 54 g of amber solid was obtained from the crude product with a yield of 75%.
Reaction SMILES: [CH3:1][Li].[F:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]([OH:16])=O.[OH-].[Na+]>C1COCC1>[F:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14](=[O:16])[CH3:1]
Reactant: [Li]C
Reactant: O=C(O)c1cccc2c(F)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)c1cccc2c(F)cccc12
Temperature: 25 °C

Procedure:
Methyl lithium (1.4M solution in ether; 6.6 ml) was added dropwise to a stirred solution of 5-fluoro-1-naphthalene carboxylic acid (870 mg) in dry THF (15 ml) at -78° under nitrogen. The reaction mixture was allowed to warm to room temperature over 2 h and was treated with 2N sodium hydroxide (60 ml). The mixture was extracted with ether (2×30 ml), and the combined, dried organic extracts were evaporated to give the title compound (865 mg) as an oil, t.l.c. (System B, 1:6) Rf 0.3.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12.[CH3:11][O-:12].[Na+]>O1CCOCC1.O>[CH3:11][O:12][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12
Reactant: Clc1nccc2ccoc12
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1nccc2ccoc12
Yield: 89.9 %

Procedure:
A solution of 7-chlorofuro[2,3-c]pyridine (1.1 g) was stirred at room temperature under dry nitrogen in 1,4-dioxane (40 ml). Sodium methoxide (1.2 g) was added and the resulting mixture heated at reflux overnight. The mixture was diluted with water (100 ml) then extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine (50 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo to give the title compound (0.96 g) as a brown oil.
Reaction SMILES: C(OC(=O)[CH:7]([C:19]#[N:20])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([O:17][CH3:18])[CH:9]=1)(C)(C)C.C(Cl)Cl.FC(F)(F)C(O)=O>>[CH3:18][O:17][C:10]1[CH:9]=[C:8]([CH2:7][C:19]#[N:20])[CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15]
Reactant: COc1cc(C(C#N)C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(CC#N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
Into a 1-neck round-bottom flask, Cyano-(3-methoxy-4-nitro-phenyl)-acetic acid tert-butyl ester (12.80 g, 43.79 mmol), Methylene chloride (50 g, 600 mmol), and Trifluoroacetic Acid (20 mL, 200 mmol) were added and stirred at room temperature overnight. The solvent was removed under vacuum. The residual TFA was co-evaporated with DCM three times to give brown oil. The reaction was partitioned with saturated NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc as eluant. The collected fractions afforded as a light brown solid. The solid was triturated with Et2O to give (3-Methoxy-4-nitro-phenyl)-acetonitrile as a light yellow solid (5.20 g, 61%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[C:21]([NH:25][C:26](=[O:27])[O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:15]=[O:16])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=Cc1ccc(OCCc2ccc(O)cc2)cc1
Reactant: CC(C)(C)N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)Oc1ccc(CCOc2ccc(C=O)cc2)cc1
Temperature: 0 °C
Yield: 83.7 %

Procedure:
0.5 g (2.1 mmole) 4-[2-(4-hydroxyphenyl)ethoxy]benzaldehyde was dissolved in tetrahydrofuran, cooled to 0° C. and 0.092 g (2.1 mmole) sodium hydride in tetrahydrofuiran was added. The reaction mixture was stirred until gas development ceased, then 0.4 g (4 mmole) tert-butyl isocyanate in tetrahydrofuran was added and the temperature was allowed to rise to room temperature. The reaction was followed by TLC. More 0.4 g (4 mmole) tert-butyl isocyanate was added. After 3 days the reaction was quenched with ice and sodium hydroxide (aq), extracted with dichloromethane, dried and evaporated. Purification by chromatography on silica gel using ethyl acetate:petroleum ether (1:2) as eluent gave 0.6 g (yield 84%) of 4-[2-(4-formylphenoxy)ethyl]phenyl N-(tert-butyl)carbamate.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](B(O)O)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([CH3:37])([CH3:36])[CH3:35])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.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>[C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:11]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: O=S(=O)(c1ccccc1)n1cc(B(O)O)c2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1ccccc1-c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Temperature: 150 °C
Yield: 90.1 %

Procedure:
1-(Phenylsulfonyl)-1H-indol-3-ylboronic acid (150.9 mg, 0.501 mmol), 2-tert-butylphenyl trifluoromethanesulfonate (255 mg, 0.902 mmol) and tetrakis(triphenylphosphine)palladium (0) (58 mg, 0.050 mmol) are combined in a septa capped microwave vial and placed under an argon atmosphere. Degassed solutions of 2 M sodium carbonate (0.75 mL, 1.50 mmol) and of dioxane (2.5 mL) were introduced and the vial heated to 150° C. for 15 minutes in a microwave reactor. The cooled reaction mixture was diluted with water and ethyl acetate, the phases separated and the aqueous extracted twice more with ethyl acetate. The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate and hexanes to give 3-(2-tert-butylphenyl)-1-(phenylsulfonyl)-1H-indole (175.8 mg, 92%) as a colorless gummy solid.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=O.O.[OH-].[NH4+:29]>CO>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:5]([C:3]([NH2:29])=[O:2])[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: COC(=O)C1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2C(C(N)=O)CCC2c2ccc(F)cc2)cc1

Procedure:
A solution of (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (1.3 g, 3.44 mmol) in MeOH (75 ml) and ammonium hydroxide solution (50 ml, 25%) was stirred at room temperature for 72 h. The volume of the solution was reduced to 50 ml and water (150 ml) was added. The title compound precipitated as a white solid (0.95 g, yield 76%), m.p. 137° C. and MS: m/e=363.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][C:12](=O)[NH:13][N:14]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:24])=O>C1C=CC=CC=1>[Cl:24][C:12]1[N:13]=[N:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2n[nH]c(=O)cc2-c2ccccc2)cc1
Solvent: c1ccccc1
Product: COc1ccc(-c2nnc(Cl)cc2-c2ccccc2)cc1

Procedure:
6-(4-Methoxyphenyl)-5-phenyl-2H-pyridazin-3-one [WO 9925697] (2.76 g, 9.60 mmol) and phosphorus oxychloride (2.8 mP) were stirred at 90° C. for 5 hours in benzene. The reaction mixture was processed in a similar manner as in Example 22, whereby the title compound was obtained as a pale yellow-brown oil (1.83 g, 64.3%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1)/[CH:6]=[CH:7]/[C:8](O)=[O:9].S(Cl)([Cl:18])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1)/[CH:6]=[CH:7]/[C:8]([Cl:18])=[O:9]
Reactant: COc1cc(/C=C/C(=O)O)cc(OC)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(/C=C/C(=O)Cl)cc(OC)c1

Procedure:
A mixture of trans-3,5-dimethoxycinnamic acid (15.30 g, 73.48 mmol) and thionyl chloride (13.11 g, 0.11 mol) were placed in a 250 mL single-necked round-bottomed flask fitted with a magnetic stirring bar and reflux condenser. Dry methylene chloride (80.0 mL) was added to the above mixture. The resulting solution was heated to reflux for 3 hours. Then, the solvent was removed under reduced pressure. The residue was dried under vacuum overnight to give a pale-yellow solid, trans-3,5-dimethoxycinnamic acid chloride.