Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=3)=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>Br.C(O)(=O)C>[Cl:35][C:30]1[CH:29]=[C:28]([C:19]2[NH:18][C:17]([CH:14]3[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]3)=[N:21][C:20]=2[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)[CH:33]=[CH:32][C:31]=1[Cl:34]
Reactant: O=C(OCc1ccccc1)N1CCC(c2nc(-c3ccncc3)c(-c3ccc(Cl)c(Cl)c3)[nH]2)CC1
Agent: Br
Solvent: CC(=O)O
Product: Clc1ccc(-c2[nH]c(C3CCNCC3)nc2-c2ccncc2)cc1Cl
Temperature: 80 °C
Yield: 78.6 %

Procedure:
4-[5-(3,4-Dichlorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]piperidine-1-carboxylic acid benzyl ester (3.8 g, 7.5 mmol) dissolved in hydrogen bromide (30 wt. %) in acetic acid (20 mL) was heated to 80° C. for one hour, after which time the reaction mixture was allowed to cool to ambient temperature and concentrated at reduced pressure. The residue was then dissolved in hydrochloric acid (100 mL of 1N) and extracted with ethyl acetate (100 mL). The aqueous layer was then basified with sodium hydroxide (35 mL of 3N) and buffered with saturated aqueous sodium hydrogen carbonate (300 mL). The aqueous layer was extracted with chloroform (5×200 mL) and the organic layers combined, dried over anhydrous sodium sulfate, filtered and concentrated at reduced pressure. The resulting foam was crystallized from ethyl acetate/hexane to give the free amine (2.2 g).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:94]=[CH:95][CH:96]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([CH:71]5[CH2:76][CH2:75][N:74]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[CH2:73][CH2:72]5)=[N:69][CH:70]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:94]=[CH:95][CH:96]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([CH:71]5[CH2:76][CH2:75][N:74]([C:77]([O:79][C:80]([CH3:82])([CH3:83])[CH3:81])=[O:78])[CH2:73][CH2:72]5)=[N:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Yield: 97.6 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperidine-1-carboxylate (step ii of example 102A) (126 mg, 0.178 mmol) was hydrolyzed by lithium hydroxide (75 mg, 1.78 mmol) in THF/methanol/water (20/10/5 ml) to yield 96 mg (98% yield) of the titled compound. MS: m/z=553.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]([CH3:18])[C:13]([O:15]CC)=[O:14])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].Cl>C(O)C>[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]([CH3:18])[C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(C)c1cccc(OCc2c(C)cccc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1COc1cccc(C(C)C(=O)O)c1
Reaction time: 3 h

Procedure:
To a stirred solution of Ethyl 2-(3-(2,6-dimethylbenzyloxy)phenyl)propanoate (Step C, 3 g, 9.6 mmol) in absolute ethanol (60 ml) was added 1N NaOH (20 ml) at room temperature. The reaction mixture was stirred for 3 hours, acidified to pH 3.5-4.0 by adding 1N HCl and concentrated. The residue was taken into chloroform and washed with 0.1N HCl, brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to give the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([O:32][CH3:33])=[O:31])[CH:18]=[C:17]3[C:34]([O:36][CH3:37])=[O:35])[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>O1CCCC1.CO>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([O:32][CH3:33])=[O:31])[CH:18]=[C:17]3[C:34]([O:36][CH3:37])=[O:35])[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nc(-c3ccccc3C(=O)OC)cc(C(=O)OC)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nc(-c3ccccc3C(=O)OC)cc(C(=O)OC)c2c1
Yield: 76.9 %

Procedure:
65.5 mg (0.126 mmol) of methyl 6-[(2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl]-2-(2-methoxycarbonyl-phenyl)-4-quinolinecarboxylate obtained in Example 7 was dissolved in a mixed solvent of 2 ml of tetrahydrofuran and 2 ml of methanol and the mixture was stirred. After adding 5.24 mg (0.139 mmol) of sodium borohydride, the reaction mixture was allowed to react at room temperature for one hour. Then, the reaction mixture was concentrated under reduced pressure and dichloromethane was added to the residue followed by washing with a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 50.6 mg of methyl 6-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]-2-(2-methoxycarbonyl-phenyl)-4-quinolinecarboxylate. NMR (270 MHz, CDCl3):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:10]([O:12][C:13]([C:15]1([CH2:29]I)[CH2:19][CH2:18][N:17]([C:20](=[O:28])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:16]1)=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1([CH2:29][O:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:19][CH2:18][N:17]([C:20](=[O:28])[C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH2:16]1)=[O:14])[CH3:11]
Reactant: Oc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(F)cc2)C1
Product: CCOC(=O)C1(COc2ccc(F)c(Cl)c2)CCN(C(=O)c2ccc(F)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 3-chloro-4-fluoro-phenol and 1-(4-fluoro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 12) to afford the racemate as a white solid (153 mg, 69%) ES m/z 424 [MH]+
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:9](=[O:10])[CH:8]=[CH:7][N:6]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]1=[O:16].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26]C(=O)OC(C)(C)C)=[CH:22][C:21]=1[S:34]([NH2:37])(=[O:36])=[O:35]>O1CCOCC1>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]2[NH:19][C:3]([C:4]3[C:5](=[O:16])[N:6]([CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])[CH:7]=[CH:8][C:9]=3[OH:10])=[N:37][S:34](=[O:36])(=[O:35])[C:21]=2[CH:22]=1
Reactant: CSC(SC)=C1C(=O)C=CN(CCC(C)C)C1=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Solvent: C1COCCO1
Product: CC(C)CCn1ccc(O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product of Example 457C (2.08 g, 7.29 mmol) was treated with the product of Example 414A (2.00 g, 6.96 mmol) in dioxane (20 mL) at 115° C. for 30 minutes, cooled to 25° C. and concentrated under reduced pressure. A solution of the residue in 4M hydrochloric acid in dioxane (20 mL) was stirred at 25° C. for 18 hours and concentrated under reduced pressure. The residue was triturated with dichloromethane and filtered to give the title compound. The filtrate containing the protected intermediate was concentrated and purified by chromatography on silica gel eluting with 1% methanol in dichloromethane. The protected product was re-subjected to the above deprotection conditions to provide the title compound as its hydrochloride salt (2.02 g, 96%). 1H NMR (300 MHz, DMSO-d6) δ 0.92 (s, 3 H) 0.94 (s, 3 H) 1.58 (m, 3 H) 3.99 (m, 2 H) 6.31 (d, J=7.35 Hz, 1 H) 6.96 (m, 2 H) 7.34 (d, J=8.46 Hz, 1 H) 8.04 (d, J=7.35 Hz, 1 H) 14.04 (s, 1 H) 14.19 (s, 1 H). MS (ESI−) m/z 375 (M−H)−.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][NH:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:7][N:8]1[C:9]2[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:11][C:2](=[O:3])[C:1]1=[O:5]
Reactant: CNc1ccccc1N
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1c(=O)c(=O)[nH]c2ccccc21

Procedure:
A mixture of 12 g of 98% oxalylchloride in 19.5 ml of triethylamine and 50 ml of toluene was added dropwise to a stirred solution of 8.5 g of o-N-methylamino aniline in 80 ml of toluene. The resulting mixture was heated at reflux for one hour. The precipitate was washed with ether. The residue was stirred with water and filtered to give 1,2,3,4-tetrahydro-1-methyl-2,3-dioxo-quinoxaline.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=O.Cl.[NH2:14][OH:15]>N1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6]/[C:7]/2=[N:14]\[OH:15]
Reactant: NO
Reactant: O=C1CCCc2c(Br)cccc21
Agent: Cl
Solvent: c1ccncc1
Product: O/N=C1\CCCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 132.3 %

Procedure:
To a solution of 5-bromo-3,4-dihydronaphthalen-1(2H)-one (1.0 g, 4.44 mmol) in pyridine (15 mL) was added hydroxylamine hydrochloride (0.617 g, 8.89 mmol). The reaction mixture was stirred at room temperature for 1 h and then concentrated. The resulting residue was treated with water (60 mL) and extracted with ethyl acetate (60 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound (1.41 g, 99% yield) as white solid. LCMS, [M+Na]+=240.0.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(O)c1ccc2c(c1)CCCN2
Temperature: 25 °C

Procedure:
Quinoline-6-carboxylic acid (1.0 eq, 14.01 mmol) and ammonium formate (22 g, 350.1 mmol) were dissolved in MeOH (100 mL) and 10% Pd/C (4.04 g) was added. The solution was heated at reflux for 2.5 h then cooled to room temperature and filtered through celite. The solvent was removed to provide 1,2,3,4-tetrahydroquinoline-6-carboxylic acid in quantitative yield. 1H NMR (200 MHz, DMSO) δ1.78 (m, 2H), 2.65 ((m, 2H), 3.2 (m, 2H), 6.4 (m, 2H), 7.45 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH2:12][N:11]2[N:7]([C:8](=[O:32])[CH:9]([NH:13][C:14](=[O:31])/[C:15](/[C:19]3[N:20]=[C:21]([NH:24]C(OCC=C)=O)[S:22][CH:23]=3)=[N:16]\[O:17][CH3:18])[CH2:10]2)[C:6]=1[C:33]([O:35]CC=C)=[O:34])(=[O:4])[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([SnH](CCCC)CCCC)CCC.Cl>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C)=O.C(OCC)C>[C:1]([C:5]1[CH2:12][N:11]2[N:7]([C:8](=[O:32])[CH:9]([NH:13][C:14](=[O:31])/[C:15](/[C:19]3[N:20]=[C:21]([NH2:24])[S:22][CH:23]=3)=[N:16]\[O:17][CH3:18])[CH2:10]2)[C:6]=1[C:33]([OH:35])=[O:34])(=[O:4])[CH2:2][CH3:3]
Reactant: C=CCOC(=O)Nc1nc(/C(=N/OC)C(=O)NC2CN3CC(C(=O)CC)=C(C(=O)OCC=C)N3C2=O)cs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: CC#N
Product: CCC(=O)C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)CN2C1
Temperature: 0 °C
Yield: 20.8 %

Procedure:
Under a nitrogen atmosphere, allyl 3-(propionyl)-7-(R,S)-[2-(2-(allyloxycarbonylamino)thiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-8-oxo-1,5-diazabicyclo[3.3.0]octa-2-ene-2-carboxylate (270 mg, 0.49 mmol) was suspended in a mixture of acetonitrile (10 ml)/diethyl ether (5 ml). Palladium(II) acetate (5.5 mg, 0.0245 mmol) and triphenylphosphine (51.4 mg, 0.196 mmol) were added to the suspension then acetone (45 ml) was added to effect solution and the resultant solution was stirred for 30 minutes at room temperature then cooled to 0° C. Tri(n-butyl)tin hydride (291.05 mg, 0.27 ml, 1 mmol) was added and the resultant solution was stirred at room temperature for 3 hours. Concentrated hydrochloric acid (12M, 0.08 ml, 1 mmol) was added and the solution was concentrated in vacuo. The concentrate was dissolved in methylene chloride, precipitation was effected by the addition of diethyl ether and the precipitate was collected by filtration. The precipitate was chromatographed by medium pressure liquid chromatography on a C18 column eluted with 10% acetonitrile/1% acetic acid in water. The product-containing fractions were lyophilized to give 43 mg (21%) of 3-(propionyl)-7-(R,S)-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-8-oxo-1,5-diazabicyclo[3.3.0]octa-2-ene-2-carboxylic acid: n.m.r. (300 MHz, DMSO-d6): δ 0.92 (t, 3, J=6), 2.97 (dd, 1, J=6, 12), 2.46-2.48 (m, 2), 3.83 (s, 3), 3.00-4.20 (m, 3), 4.92-5.06 (m, 1), 7.03 (s, 1), 7.24 (br. s, 2), 9.15 (d, 1, J=9); i.r. (KBr) 3310 (br), 1716, 1636, 1534, 1414, 1380, 1257, 1050 cm- 1 ; u.v. (EtOH) λmax =233 (ε=15992), 300 (ε=6987), 350 (ε=9801); m.p.>260° C.; f.a.b.m.s. (m/e) M+ +1=423.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[CH:5]=[CH:4][N:3]=1.Br[CH2:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[F:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[CH2:11][O:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][C:6]=1[F:9]
Reactant: Nc1nccc(F)c1O
Reactant: Fc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nccc(F)c1OCc1c(F)cccc1F
Temperature: 50 °C

Procedure:
55 mg (0.43 mmol) of 2-amino-4-fluoropyridin-3-ol Example 109A, 98 mg (0.47 mmol) of 2-(bromomethyl)-1,3-difluorobenzene and 308 mg (0.95 mmol) of caesium carbonate were initially charged in 1 ml of dry DMF and heated in an oil bath warmed to 50° C. for 15 min. The mixture was then filtered off and purified by preparative HPLC (Method 9). This gave 70 mg of the title compound (64% of theory).
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[OH:11].[CH3:12][C:13]1[N:14]=[C:15]2[C:20]([O:21][CH2:22][CH2:23][CH:24]([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:19][C:18]([CH3:33])=[CH:17][N:16]2[C:34]=1[C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:11][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]1[NH:1][C:35]([C:34]1[N:16]2[CH:17]=[C:18]([CH3:33])[CH:19]=[C:20]([O:21][CH2:22][CH2:23][CH:24]([C:25]([F:28])([F:27])[F:26])[C:29]([F:30])([F:31])[F:32])[C:15]2=[N:14][C:13]=1[CH3:12])=[O:36]
Reactant: Cc1cc(OCCC(C(F)(F)F)C(F)(F)F)c2nc(C)c(C(=O)O)n2c1
Reactant: NC1c2ccccc2CC1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(OCCC(C(F)(F)F)C(F)(F)F)c2nc(C)c(C(=O)NC3c4ccccc4CC3O)n2c1
Reaction time: 8 h

Procedure:
12 mg (0.08 mmol) of 1-aminoindan-2-ol were initially charged, 31 mg (0.08 mmol) of 2,6-dimethyl-8-[4,4,4-trifluoro-3-(trifluoromethyl)butoxy]imidazo[1,2-a]pyridine-3-carboxylic acid Example 91A, dissolved in 0.3 ml of DMF, 40 mg (0.104 mmol) of HATU, dissolved in 0.3 ml of DMF, and then 16 mg (0.16 mmol) of 4-methylmorpholine were added and the mixture was shaked at RT overnight. The target compound was isolated by preparative HPLC (Method 11). This gave 15 mg (36% of theory).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[N:3]=1.CC1(C)C(C)(C)OB([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+].[Cl-]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.O1CCOCC1>[Cl:17][C:13]1[CH:12]=[C:11]([C:4]2[N:3]=[C:2]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=3)[CH:7]=[C:6]([CH:8]3[CH2:10][CH2:9]3)[N:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Clc1cccc(-c2nc(Cl)cc(C3CC3)n2)c1
Reactant: COC(=O)Cc1ccc(CB2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(Cc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)cc1
Temperature: 25 °C
Yield: 52.6 %

Procedure:
A 20-mL sealed tube, with stirrer bar, was charged with 4-chloro-2-(3-chlorophenyl)-6-cyclopropylpyrimidine (0.365 g, 1.38 mol), methyl 2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate (0.400 g, 1.38 mmol), Pd(dppf)Cl2 (0.113 g, 0.14 mmol), and powdered Na2CO3 (0.438 g, 4.14 mmol). Dioxane (6 mL) and water (3 mL) were added. The resulting mixture was stirred under Ar at 90° C. for 1.5 h until the starting chloride was consumed. After cooling to room temperature, the reaction mixture was filtered through celite washing with ethyl acetate until the filtrate was colorless. The aqueous layer was separated and the organic layer was washed with saturated sodium chloride (2×5 mL) then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexane/ethyl acetate (95:5 to 1:2) as eluent to afford the title compound (0.285 g, 52%) as a colorless oil. MW=392.88. 1H NMR (DMSO-d6, 500 MHz) δ 8.30-8.27 (m, 2H), 7.59-7.51 (m, 2H), 7.31 (d, J=8.0 Hz, 2H), 7.28 (s, 1H), 7.21 (d, J=8.0 Hz, 2H), 4.07 (s, 2H), 3.64 (s, 2H), 3.59 (s, 3H), 2.16-2.09 (m, 1H), 1.16-1.05 (m, 4H); ESI MS m/z 393 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[C:11]=3[CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[CH3:19]O>S(=O)(=O)(O)O>[CH3:19][O:15][C:14]([C:12]1[C:11]2[CH:17]=[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]=2[CH:13]=1)=[O:16]
Reactant: O=C(O)C1=Cc2ccc(C3CCCCC3)cc21
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C1=Cc2ccc(C3CCCCC3)cc21

Procedure:
A solution of 15 g of 5-cyclohexyl-1-benzocyclobutenecarboxylic acid in 150 ml of absolute methanol and 1.5 ml of concentrated sulphuric acid is boiled for 14 hours under reflux whilst excluding water. The reaction mixture is evaporated in vacuo at 30°C to a volume of approx. 30 ml and the evaporation residue is partitioned between three times 200 ml of ether and twice 200 ml of ice water. The combined organic phases are successively washed with saturated sodium bicarbonate solution and water, dried over sodium sulphate and evaporated in vacuo. Distillation of the evaporation residue in a high vacuum yields 5-cyclohexyl-1-benzocyclobutenecarboxylic acid methyl ester in the fraction boiling at approx. 150°C/0.07 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.CC(C)([O-])C.[K+].C1C=CC(C2C=CN=C3C=2C=CC2C3=NC=CC=2C2C=CC=CC=2)=CC=1.Cl>C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni].C(O)(C)(C)C>[CH:12]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: OB(O)c1cccc(F)c1
Reactant: BrC1CCCC1
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Agent: CC(C)(C)[O-]
Solvent: CC(C)(C)O
Solvent: C1=CCCC=CCC1
Product: Fc1cccc(C2CCCC2)c1
Temperature: 25 °C
Reaction time: 0 h
Yield: 45.1 %

Procedure:
3-fluorophenylboronic acid (0.5 g; 3.6 mmol), bromocyclopentane (0.41 g; 2.7 mmol), potassium tert-butoxide (0.49 g; 4.3 mmol), bathophenanthroline (72 mg; 0.22 mmol), bis(1,5-cyclooctadiene)nickel(0) (30 mg; 0.11 mmol) and t-butanol (9 mL) were added sequentially to a 10-20 mL microwave reactor tube containing a stir bar. The vessel was capped, placed under nitrogen, and then subjected to the following microwave conditions: Temperature=160° C.; Time=5 minutes; Power=250 W; Cooling turned on; Absorption=High; prestir=5 s; FHT turned off. The crude reaction mixture was allowed to cool to room temperature and then acidified by the addition of aqueous hydrochloric acid (15 mL; 1N) and extracted with ethyl acetate (3×20 mL). The combined organic phases were successively washed with aqueous saturated sodium bicarbonate, aqueous saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes to give the title product as a light red solid (0.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:12]([C:13](=[O:19])[C:14]2[S:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:5]2[CH2:6][CH:7](C=O)[O:8][C:4]=2[C:3]=1[Cl:20].CO[CH:23]([O:26][CH3:27])[O:24][CH3:25].C(=O)([O-])O.[Na+]>[Cl-].[Cs+]>[CH3:27][O:26][CH:23]([O:24][CH3:25])[CH:7]1[CH2:6][C:5]2[CH:11]=[C:12]([C:13](=[O:19])[C:14]3[S:18][CH:17]=[CH:16][CH:15]=3)[C:2]([Cl:1])=[C:3]([Cl:20])[C:4]=2[O:8]1
Reactant: O=CC1Cc2cc(C(=O)c3cccs3)c(Cl)c(Cl)c2O1
Reactant: COC(OC)OC
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Cs+]
Product: COC(OC)C1Cc2cc(C(=O)c3cccs3)c(Cl)c(Cl)c2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6,7-Dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxaldehyde (3.2 g., 0.01 mole) is dissolved in methanolic cesium chloride (25 ml., 0.4 M). Trimethylorthoformate (2.12 g., 0.02 mole) is added and the solution is stirred (magnetically) at room temperature for 30 minutes and then poured into aqueous sodium hydrogen carbonate (50 ml.). The mixture is extracted with ether (2×50 ml.). The ether extracts are combined, washed with brine (2×15 ml.), dried over MgSO4 and distilled at reduced pressure to give the 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxaldehyde dimethylacetal.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:15](Cl)(=[O:17])[CH3:16].[Al+3].[Cl-].[Cl-].[Cl-].O>ClCCCl.CCOCC.CCOC(C)=O>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[C:15](=[O:17])[CH3:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1cccc2c1CCN2C(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Solvent: CCOCC
Product: COc1ccc(C(C)=O)c2c1CCN2C(C)=O
Temperature: 50 °C
Yield: 45.3 %

Procedure:
To a solution of 1-acetyl-4-methoxyindoline (4.02 g, 21 mmol) in dry 1,2-dichloroethane (30 ml) cooled in ice was added acetyl chloride (2.1 ml, 30 mmol). Powdered anhydrous AlCl3 (8.4 g, 63 mmol) was added portionwise with stirring. The mixture was stirred at rt overnight, then warmed to 50° C. for 2 h. The red/brown slurry was poured into acidified cold water (200 ml) and extracted with CH2Cl2. The combined organic phases were washed with 0.5 M aq. NaOH and brine, dried and evaporated to give a brown oil. Flash chromatography (EtOAc) followed by trituration with Et2O afforded 22 as pale yellow needles (2.22 g, 54%), mp 88-89° C., (Found: C, 66.89; H, 6.50; N, 5.95. C13H15NO3 requires C, 66.94; H, 6.48; N, 6.00%); δH (90 MHz) 7.33 (1 H, d, J 8.3, H-5), 6.61 (1 H, d, H-6), 4.17 (2 H, t, J 8.1, H-2), 3.85 (3 H, s, OMe), 3.05 (2 H, t, 3-H), 2.44 (3 H, s, 7-Ac) and 2.21 (3 H, s, N-Ac).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8](O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.C(O)(C)(C)C>CO>[C:4]([OH:6])(=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:1]
Reactant: O=C(O)c1cc(O)ccc1O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(C)(C)O
Product: O=C(O)c1ccccc1O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
100 g of 2,5-dihydroxybenzoic acid and 1,441 g of 80% sulfuric acid were heated to 50° C. and mixed. To the liquid dispersion obtained, 144 g of tert-butyl alcohol was added, and the mixture was stirred at 50° C. for 30 minutes. Thereafter, the operation that 144 g of tert-butyl alcohol was added to the liquid dispersion and the mixture was stirred for 30 minutes was carried out three times. The reaction solution obtained was cooled to room temperature, and then dropwise added to 1 kg of ice water, where the precipitate formed was filtered, which was then washed with water and further washed with hexane. The precipitate formed was dissolved in 200 mL of methanol, and the solution obtained was re-precipitated in 3.6 L of water. After filtration, the product was dried at 80° C. to obtain 74.9 g of a salicylic acid intermediate represented by the following formula (3).