Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[O:7].CCN(C(C)C)C(C)C.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])=O>CN1C(=O)CCC1.Cl>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[C:20]1[N:8]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[O:7][CH:19]=1
Reactant: NC(=O)c1ccco1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(-c2coc(-c3ccco3)n2)c(Cl)c1
Temperature: 130 °C
Yield: 55 %

Procedure:
To the solution of furan-2-carboxamide (56 mg, 0.5 mmol. 1 eq) and DIEA (0.13 mL, 0.75 mmo, 1.5 eq) in NMP (1 mL) was added 2-bromo-1-(2,4-dichlorophenyl)ethanone (0.6 mmol, 1.2 eq). Reaction mixture was heated at 130° C. for 15 h. The mixture was cooled down, diluted with 1 M HCl (30 mL) and extracted with EtOAc (40 mL). The organic layer was washed with 1 M HCl (30 mL), 5% solution of NaHCO3 (30 mL), brine (2×40 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting residue was purified by HPLC purification to provide desired 4-(2,4-Dichloro-phenyl)-2-furan-2-yl-oxazole in a yield of 55% and HPLC 99.9% purity. LC-MS [M+H]-280.4 (C13H7Cl2NO2+H, requires 281.11). 1H NMR (DMSO-d6) δ 8.84 (s, 1H), 8.13 (d, 1H, J=8.5), 8.01 (s, 1H), 7.78 (s, 1H), 7.58 (d, 1H, J=8.5), 7.29 (d, 1H, J=3.5), 6.77 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[CH2:14]([O:16][P:17]([C:22](=[N:28][OH:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:21])[O:18][CH2:19][CH3:20])[CH3:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:19]([O:18][P:17]([C:22](=[N:28][O:29][C:8](=[O:9])[CH:7]([O:6][C:5]1[CH:12]=[CH:13][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:11])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:21])[O:16][CH2:14][CH3:15])[CH3:20]
Reactant: CCCCCC(=NO)P(=O)(OCC)OCC
Reactant: CC(Oc1ccc(Cl)cc1)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCC(=NOC(=O)C(C)Oc1ccc(Cl)cc1)P(=O)(OCC)OCC
Temperature: 55 °C
Reaction time: 9 h
Yield: 79.5 %

Procedure:
8.8 g (0.04 mole) of 2-(4-chlorophenoxy)-propionyl chloride, dissolved in 20 ml of toluene, were added dropwise to a solution of 10.0 g (0.04 mole) of 1-hydroximinohexanephosphonic acid diethyl ester and 5.0 g (0.05 mole) of triethylamine in 80 ml of toluene. The mixture was subsequently stirred at 55° C. for 9 hours and cooled, the triethylamine hydrochloride which had precipitated was filtered off with suction and the organic phase was washed with water. After drying with Na2SO4, evaporating off the toluene on a rotary evaporator and removing, under a high vacuum, the solvent which still adhered, 13.8 g (77.8%) of 1-[2-(4-chlorophenoxy)-propionyloximino]-hexanephosphonic acid diethyl ester of nD22 =1.4919 were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][S:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH2:24][C:25]#[CH:26])[CH:20]=[CH:19][C:17]=3[N:18]=2)(=[O:13])=[O:12])=[CH:5][CH:4]=1.[N:41]([C@@H:44]([CH2:71][C:72]1[CH:77]=[CH:76][C:75]([O:78][CH2:79][CH2:80][O:81][S:82]([C:85]2[CH:91]=[CH:90][C:88]([CH3:89])=[CH:87][CH:86]=2)(=[O:84])=[O:83])=[CH:74][CH:73]=1)[C:45]([N:47]([C@@H:55]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([C:67]([F:70])([F:69])[F:68])=[CH:63][CH:62]=1)[C:56]([O:58][CH3:59])=[O:57])[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:46])=[N+:42]=[N-:43].C(N(C(C)C)CC)(C)C>C1COCC1.[Cu]I>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][S:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[N:43]=[N:42][N:41]([C@@H:44]([CH2:71][C:72]5[CH:73]=[CH:74][C:75]([O:78][CH2:79][CH2:80][O:81][S:82]([C:85]6[CH:91]=[CH:90][C:88]([CH3:89])=[CH:87][CH:86]=6)(=[O:84])=[O:83])=[CH:76][CH:77]=5)[C:45]([N:47]([C@@H:55]([CH2:60][C:61]5[CH:62]=[CH:63][C:64]([C:67]([F:70])([F:69])[F:68])=[CH:65][CH:66]=5)[C:56]([O:58][CH3:59])=[O:57])[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:46])[CH:26]=4)[CH:20]=[CH:19][C:17]=3[N:18]=2)(=[O:13])=[O:12])=[CH:38][CH:37]=1
Reactant: C#CCOc1ccc2nc(S(=O)(=O)NC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)sc2c1
Reactant: COC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(C(=O)OC(C)(C)C)C(=O)[C@H](Cc1ccc(OCCOS(=O)(=O)c2ccc(C)cc2)cc1)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(C(=O)OC(C)(C)C)C(=O)[C@H](Cc1ccc(OCCOS(=O)(=O)c2ccc(C)cc2)cc1)n1cc(COc2ccc3nc(S(=O)(=O)NC(c4ccccc4)(c4ccc(OC)cc4)c4ccc(OC)cc4)sc3c2)nn1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a stirring solution of N-(bis(4-methoxyphenyl)(phenyl)methyl)-6-(prop-2-ynyloxy)benzo[d]thiazole-2-sulfonamide (83 mg, 0.145 mmol) and the Boc-protected amide 151 (107 mg, 0.145 mmol) in THF (0.7 mL) was added copper(I) iodide (3 mg, 0.0145 mmol) then diisopropylethylamine (28 μL, 0.16 mmol). The mixture was allowed to stir for 2 h at 23° C. then concentrated in vacuo and the crude residue purified by flash chromatgraphy on silica gel using hexanes/ethyl actetate on a Biotage purification system yielding the desired product as a yellow, crystalline solid (145 mg, 82%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=1>C(O)C>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:13][C:14]3[CH:19]=[C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=4)[CH:17]=[CH:16][C:15]=3[S:31][C:32]3[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCc3cccc([N+](=O)[O-])c3)cc2N)cc1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3cccc([N+](=O)[O-])c3)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product from Example 155a (34 mg, 0.085 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (13 mg, 29%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.35 Hz, 3H) 1.72-1.92 (m, 2 H) 2.02 (s, 3 H) 2.99 (t, J=7.54 Hz, 2 H) 5.32 (s, 2 H) 6.30 (d, J=6.99 Hz, 1 H) 7.15 (d, J=8.46 Hz, 2 H) 7.19-7.25 (m, 1 H) 7.27 (d, J=2.57 Hz, 1 H) 7.38 (d, J=8.82 Hz, 1 H) 7.43 (d, J=8.46 Hz, 2 H) 7.72 (t, J=7.91 Hz, 1 H) 7.81 (d, J=8.82 Hz, 1 H) 7.91 (d, J=7.72 Hz, 1 H) 8.22 (d, J=8.82 Hz, 1 H) 8.32 (s, 1 H) 8.37 (d, J=7.35 Hz, 1 H) 8.97 (d, J=8.82 Hz, 1 H) 9.98 (s, 1 H) 11.01 (s, 1 H) 14.37 (s, 1 H); MS (ESI+) m/z 580(M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Br:23])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]C)=[C:7]([CH:13]([CH3:15])[CH3:14])[CH:6]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Br:23])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:13]([CH3:15])[CH3:14])[CH:6]=1
Reactant: COc1ccc(Oc2c(Br)cc([N+](=O)[O-])cc2Br)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Br)cc([N+](=O)[O-])cc2Br)ccc1O
Temperature: 8.699999809265137 °C
Yield: 109.3 %

Procedure:
A 12 L three-necked round bottom flask equipped with a mechanical stirrer, an addition funnel, and a temperature probe was charged with 4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole (752.1 g, 1.69 moles), which was dissolved by stirring in dichloromethane (2 L) at room temperature. The mixture was cooled to 8.7° C. in an ice-water bath. A solution of boron tribromide (2.050 L, 1M in CH2Cl2, 2.05 moles) was added over 30 min. An increase of approximately 10° C. in the temperature of the reaction mixture was observed. The ice-water bath was removed and the reaction mixture was allowed to stir at room temperature until the reaction was complete, as assayed by HPLC. The reaction mixture was cooled once more in an ice-water bath, then quenched by slow addition of methanol (850 mL), during which the temperature of the reaction mixture was maintained below 18° C. Saturated aqueous sodium bicarbonate solution was added until the pH of the reaction mixture was 6 or 7. The aqueous phase was separated and washed with aliquots of ethyl acetate (2×1 L). The organic layers were combined and the solvent removed under a vacuum at room temperature to yield crude 4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylphenol (796 g, 110%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH3:12][O:13][C:14](=[O:31])[C:15]1[C:16](=[C:21]([NH:25]CCCCC)[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]>>[CH3:12][O:13][C:14](=[O:31])[C:15]1[C:16](=[C:21]([NH:25][CH2:10][C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Reactant: O=Cc1cc2ccccc2o1
Product: COC(=O)c1cccc(NCc2cc3ccccc3o2)c1C(=O)OC
Yield: 83 %

Procedure:
Benzofuran-2-carbaldehyde (1.17 ml, 8 mmol) was treated in the same manner as described above for the synthesis of 3-pentylamino-phthalic acid dimethyl ester. The residue (oil) was purified by chromatography (SiO2, 50% methylene chloride/hexane) to give 1.12 g (83%) of product as a yellow oil: 1H NMR (CDCl3) δ 7.50–7.43 (m, 2H), 7.33–7.16 (m, 3H), 6.88–6.84 (m, 2H), 6.58 (s, 1H), 4.54 (d, J=6.1 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: CO[C:3](=[O:25])[CH:4]=[CH:5][C:6]1[C:14]2[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[N:11][C:10]=2[CH:9]=[C:8]([C:21]([F:24])([F:23])[F:22])[CH:7]=1.C[N:27]1[CH2:32][CH2:31]N(C(=O)C=CC2N(C3C=CC=CC=3)C3C=CC(C(F)(F)F)=CC=3N=2)[CH2:29][CH2:28]1>>[CH2:28]([N:27]([CH2:32][CH3:31])[C:3](=[O:25])[CH:4]=[CH:5][C:6]1[C:14]2[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[N:11][C:10]=2[CH:9]=[C:8]([C:21]([F:24])([F:23])[F:22])[CH:7]=1)[CH3:29]
Reactant: CN1CCN(C(=O)C=Cc2nc3cc(C(F)(F)F)ccc3n2-c2ccccc2)CC1
Reactant: COC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Product: CCN(CC)C(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Yield: 53 %

Procedure:
This was prepared from 3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methyl ester in a similar manner to 1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzoimidazol-yl)prop-2-en-1-one. The oily residue was purified by flash chromatography over silica gel (eluted with dichloromethane/methanol 0.5-2.5% gradient) to afford the title compound as a white solid (300 mg, 53%), m/z 388.0 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:24])=O>C(Cl)(Cl)Cl>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][Cl:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(Oc2ccccc2)c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: ClCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 200 g. of m-phenoxy-benzyl alcohol in 1 liter of dry chloroform 2 ml. of pyridine are added and a solution of 142.8 g. thionyl-chloride in 150 ml. of chloroform is added dropwise under cooling with ice water. When the addition is completed the cooling is terminated and the solution is allowed to warm up to room temperature under stirring and the temperature is maintained under stirring until the vigorous gas evolution ceases. The mixture is then boiling under stirring until the gas evolution ceases completely. The solution is then poured into 2 liters of cold water, the chloroform layer is separated and the aqueous layer is shaken out in 400 ml. of chloroform. The combined chloroform solutions are washed once with water and dried above sodium sulphate. The drying agent is filtered off and chloroform is distilled off; thus 210 g. (96%) of m-phenoxy-benzyl chloride are obtained, which can be distilled at 128° to 130° C. at a pressure of 0.3 mmHg. Substantially no forerun and residue are obtained.
Reaction SMILES: ClC(OCC(C)C)=O.[CH3:9][N:10]([CH3:17])[CH2:11][C:12]#[C:13][C:14](O)=[O:15].CN1CCOCC1.[NH2:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]=[CH:31][C:30]([C:36]#[N:37])=[C:29]2[NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Br:45])[CH:40]=1>N1C=CC=CC=1>[Br:45][C:41]1[CH:40]=[C:39]([NH:38][C:29]2[C:28]3[C:33](=[CH:34][CH:35]=[C:26]([NH:25][C:14](=[O:15])[C:13]#[C:12][CH2:11][N:10]([CH3:17])[CH3:9])[CH:27]=3)[N:32]=[CH:31][C:30]=2[C:36]#[N:37])[CH:44]=[CH:43][CH:42]=1
Reactant: CN(C)CC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: CN(C)CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16.9 %

Procedure:
Isobutyl chloroformate (0.342 g, 2.5 mmol) was dropwise added into an ice cold solution of 4-dimethylamino-2-butynoic acid (0.9 g, 3.8 mmol) and N-methyl-morpholine (0.384 g, 3.8mmol) in 50 mL of tetrahydrofaan under N2. After stirring for 30 min, a solution of 0.644 g (1.9 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 10 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2.5 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 15% methanol in ethyl acetate. The product was collected, and dried in vacuo to give 0.144 g (21%) of yellow solid; mass spectrum (electrospray, m/e,): 447.9, 450.2 (M+H+); mp 180° C. (dec.).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:20]=[O:21].O>O1CCCC1>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH:20]=[O:21])=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)c2ccccc12
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(Br)c2ccccc12
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
To a solution of 1,4-dibromonaphthalene (1.00 g, 3.50 mmol) in tetrahydrofuran (15 mL) were added n-butyllithium (1.6 mol/L; 3.1 mL) and dimethylformamide (0.54 mL, 7.0 mmol) sequentially at −78° C. under nitrogen atmosphere, and the mixture was stirred for 15 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was combined, washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (8:1 hexane/ethyl acetate) to afford 4-bromo-1-naphthalenecarboxaldehyde (458 mg, 56%).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>CC#N>[Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc2c(Br)cccn2n1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1cc2c(Br)cccn2n1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-bromo-pyrazolo[1,5-a]pyridin-2-ylamine (Intermediate 3) (259 mg, 1.22 mmol) was dissolved in dry CH3CN (10 mL) at 5° C. and Et3N (425 μL, 3.05 mmol) was added followed by the cyclopropane carbonyl chloride (278 μL, 3.05 mmol). The reaction mixture was then allowed to warm to room temperature. The solvent was removed in vacuo the residue was treated with 7 M methanolic ammonia solution (5 mL) and stirred at room temp for 1 h to hydrolyse any bis-acylated product. The solvent was removed in vacuo and the residue was re-dissolved in DCM and washed with water and brine. The organics were passed through a hydrophobic frit and concentrated in vacuo. Purification by flash column chromatography (2:1 petroleum ether 40-60:EtOAc) yielded cyclopropanecarboxylic acid (4-bromo-pyrazolo[1,5-a]pyridin-2-yl)-amide (Intermediate 4).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[O:5]1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1>C1COCC1>[Si:18]([O:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[O:5]1)([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: O=C1OC(CCO)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC1OC(=O)c2ccccc21
Reaction time: 8 h

Procedure:
3-(2-hydroxyethyl)-3H-isobenzofuran-1-one (1.03 g, 5.781 mmol) dissolved in THF (10 mL) under N2 and TBDMSCl (958.4 mg, 6.359 mmol) then imidazole (472.3 mg, 6.937 mmol) added at RT. Reaction mixture stirred overnight then concentrated. Residue partitioned between EtOAc and water. Aqueous phase extracted with EtOAc and combined organics dried and concentrated. Residue purified by chromatography (silica, 0-100% EtOAc-petrol gradient elution). Title compound obtained as a colourless oil (1.47 g, 87%), 1H NMR (400 MHz, DMSO) 0.00 (3H, s), 0.01 (3H, s), 0.83 (9H, s), 1.76-1.85 (1H, m), 2.23-2.31 (1H, s), 3.71-3.80 (2H, m), 5.66 (1H, dd), 7.57 (1H, t), 7.68 (1H, d), 7.75 (1H, dt), 7.81 (1H, d); MS (ES+) 293.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1Cl.C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1ccncc1Br
Reactant: Oc1cc(F)ccc1Cl
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: Fc1ccc(Cl)c(Oc2ccncc2Br)c1
Yield: 84 %

Procedure:
A mixture of 2-chloro-5-fluorophenol (1.50 g, 10.24 mmol), 3-bromo-4-chloropyridine (1.50 g, 7.79 mmol) and DBU (1.50 g, 9.85 mmol) were heated at 130° C. in NMP (10 mL) for 15 hours. The reaction mixture was cooled and partitioned between water (100 mL) and MTBE (100 mL). The organic layer was separated, washed with dilute aq NaOH and brine, dried (MgSO4) and concentrated in vacuo to provide 3-bromo-4-(2-chloro-5-fluorophenoxy)pyridine (1.98 g, 84% yield) as brownish oil suitable for use in the next reaction. MS (ESI) m/z: 303.9 (M+H+).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][OH:12].[CH3:13]OS(C)(=O)=O.C(=O)([O-])[O-].[Ca+2].O>CCOCC>[CH3:13][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][OH:12]
Reactant: COS(C)(=O)=O
Reactant: OCC1CCc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCOCC
Solvent: O
Product: CN1c2ccccc2CCC1CO
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In 120 ml of ethanol, 6 g of methyl quinaldinate was reduced by hydrogen in the presence of 400 mg of platinum oxide to give 6.8 g of methyl 1,2,3,4-tetrahydroquinaldinate as an oil. 3.0 g of the resulting methylester was further reduced in a dry ether by 1 g of lithium aluminum hydride to give 2.6 g of 1,2,3,4-tetrahydro-2-quinolinemethanol. A mixture of 1.6 g of the resulting alcohol, 0.93 ml of dimethylsulfonic acid, 2.16 g of calcium carbonate and 8 ml of water was stirred at room temperature for 6 hours. To the reaction mixture was added ether and insolubles were removed by filtration. The organic portion was separated, washed with water and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the organic portion was purified by silica gel column chromatography (eluent: chloroform) to give 1.4 g of 1-methyl-1,2,3,4-tetrahydro-2-quinolinemethanol as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11]([Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH:10]=2)=[C:6]([F:34])[CH:5]=[CH:4][C:3]=1[OH:35].[H-].[Na+].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41].O>O1CCCC1>[CH3:43][O:42][C:40](=[O:41])[CH2:39][O:35][C:3]1[CH:4]=[CH:5][C:6]([F:34])=[C:7]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11]([Si:24]([CH:28]([CH3:29])[CH3:30])([CH:31]([CH3:33])[CH3:32])[CH:25]([CH3:26])[CH3:27])[CH:10]=2)[C:2]=1[F:1]
Reactant: COC(=O)CBr
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2c(F)ccc(O)c2F)c2cc(-c3cccnc3)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COc1ccc(F)c(Cc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncc(-c4cccnc4)cc23)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 2,4-Difluoro-3-(5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenol (549, 427.0 mg, 0.87 mmol) in tetrahydrofuran (20.0 mL) was added sodium hydride (60% in mineral oil, 42.0 mg, 1.1 mmol). 30 minutes later, methyl bromoacetate (146 mg, 0.95 mmol) was added to the reaction. The reaction was stirred at room temperature for 4 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude compound that was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.[CH2:14]([O:16][CH:17]([O:22][CH2:23][CH3:24])[CH2:18][N:19]=[C:20]=[S:21])[CH3:15]>C(O)C>[CH2:23]([O:22][CH:17]([O:16][CH2:14][CH3:15])[CH2:18][NH:19][C:20]([NH:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2)=[S:21])[CH3:24]
Reactant: Cc1ccc2c(N)c(F)ccc2n1
Reactant: CCOC(CN=C=S)OCC
Solvent: CCO
Product: CCOC(CNC(=S)Nc1c(F)ccc2nc(C)ccc12)OCC

Procedure:
To 17.85 g (0.1013 mole) of 5-amino-6-fluoro-2-methylquinoline was added 19.5 g (0.1114 mole) of 2,2-diethoxyethylisothiocyanate and the mixture was heated at 80°-90° C. for 1.5 hours. The residue was slurried in ethanol, separated by filtration, washed with ethanol and then recrystallized from ethanol to provide N-(2,2-diethoxyethyl)-N'-(6-fluoro-2-methylquinolin-5-yl)thiourea, m.p. 189°-191° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:25]([CH3:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])=[CH:5][C:4]=1[C:27]([F:30])([F:29])[F:28].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH3:26][CH:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]1[S:9]([C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[C:4]([C:27]([F:29])([F:28])[F:30])[CH:5]=1)(=[O:10])=[O:11]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc1C(F)(F)F
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)c(C(F)(F)F)c1
Yield: 9 %

Procedure:
The title compound was prepared from 5-{[4-methoxy-3-(trifluoromethyl)phenyl]sulfonyl}-6-methyl-5,6-dihydrophenanthridine (0.5 g, 1.15 mmol), cyclohexene (0.29 mL, 2.88 mmol), and 1.0 M boron tribromide in dichloromethane (6.92 mL, 6.92 mmol) according to the procedure and in the same manner as described in Example 1, step b. The crude product was purified by flash column chromatography on silica gel, eluting with dichloromethane to yield 4-[(6-methylphenanthridin-5(6H)-yl)sulfonyl]-2-(trifluoromethyl)phenol (0.044 g, 0.104 mmol, 9%) as an off-white solid, m.p. 213-215° C.;
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([F:7])([F:6])[F:5].[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]([NH2:18])=[S:17])[CH2:12][CH2:11]1>C(O)C>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[S:17][CH:2]=[C:3]([C:4]([F:7])([F:6])[F:5])[N:18]=2)[CH2:12][CH2:11]1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CN1CCN(C(N)=S)CC1
Solvent: CCO
Product: CN1CCN(c2nc(C(F)(F)F)cs2)CC1

Procedure:
To a solution of 33.9 g 1-bromo-3,3,3-trifluoro-2-propanone in 300 ml of absolute ethanol are added 28.6 g 4-methyl-1-piperazinylthiocarboxamide. The mixture is refluxed for 4 hours, evaporated to dryness and the residue partitioned between ethyl ether and aqueous NaOH. The ether phase is washed, dried and evaporated, whereby the title compound is obtained, m.p. 62° (ethyl acetate/hexane).