Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][OH:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:18][C:5]1[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[N:7][C:2]([NH:19][C:20]2[CH:21]=[C:22]([CH2:23][OH:24])[CH:25]=[CH:26][CH:27]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CO)c1
Reactant: COc1cccc(CNc2nc(Cl)ncc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(CNc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Temperature: 105 °C
Yield: 97.6 %

Procedure:
Into the reaction flask was added 2,5-dichloro-N-(3-methoxybenzyl)pyrimidin-4-amine (0.82 g, 2.9 mmol), 1,4-dioxane (20 mL), 3-aminobenzyl alcohol (0.53 g, 4.3 mmol), and p-toluenesulfonic acid monohydrate (0.22 g, 1.2 mmol). The mixture was heated at 105° C. for 3 hours and then was heated at 70° C. overnight. The reaction was quenched with NaHCO3 (saturated). The organic solvent was removed under vacuum, followed by the addition of water and EtOAc. The aqueous layer was extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4 and concentrated under vacuum to give the desired product as a brown powder (1.05 g, 98%). LCMS for C19H20N4O2 (M+H)+: m/z=371.1, 373.0. 1H NMR (400 MHz, DMSO-d6): δ 9.54 (s, 1H), 8.28 (s, 1H), 8.03 (s, 1H), 7.54 (s, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.20 (t, J=8.3 Hz, 1H), 7.14 (t, J=7.9 Hz, 1H), 6.89 (m, 1H), 6.77 (ddd, J=8.3, 2.2, 1.4 Hz, 1H), 4.59 (d, J=6.2 Hz, 2H), 4.38 (s, 2H), 3.64 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][C:40]1=[O:45].C(OCC)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:42]3[CH2:43][CH2:44][NH:39][C:40](=[O:45])[CH2:41]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C1CNCCN1
Reactant: CCOc1ccccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOc1ccccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1
Reaction time: 0.25 h
Yield: 60.8 %

Procedure:
To a solution of (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (100 mg, 0.211 mmol, example 7) in methylene chloride (3 mL) cooled to 0° C. were added triethylamine (30 uL, 0.211 mmol) and 2-piperazinone (23 mg, 0.232 mmol), respectively. After 15 min, thin layer chromatography (silica gel, 20% ethyl acetate in hexanes) showed no starting material left. The reaction mixture was loaded into a flash silica gel column (12 g). Purification by flash column chromatography (eluting with 5% methanol and 0.1% triethylamine in ethyl acetate using Intelliflash 280 system) gave 4-[(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one as a white foam (69 mg). HR-MS (ES, m/z) calculated for C30H31N4O4Cl2 [(M+H)+] 581.1717, observed 581.1717
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([C@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)[CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:25]1[CH:30]=[CH:29][N:28]2[N:31]=[CH:32][CH:33]=[C:27]2[N:26]=1.C(O)(C)C>CCOCC>[F:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:25]2[CH:30]=[CH:29][N:28]3[N:31]=[CH:32][CH:33]=[C:27]3[N:26]=2)[CH:4]=1
Reactant: Clc1ccn2nccc2n1
Reactant: Oc1ccc(F)cc1[C@H]1CCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CC(C)O
Product: Oc1ccc(F)cc1[C@H]1CCCN1c1ccn2nccc2n1
Temperature: 120 °C
Yield: 88.5 %

Procedure:
A mixture of (R)-4-fluoro-2-(pyrrolidin-2-yl)phenol hydrochloride (Example 20, Step B, 1.50 g, 6.89 mmol), DIEA (2.67 g, 20.7 mmol), 5-chloropyrazolo[1,5-a]pyrimidine (1.11 g, 7.24 mmol) and isopropanol (1 mL) was heated at 120° C. overnight. The reaction was poured into ether (50 mL) and extracted with NaOH (1N aqueous, 3×25 mL). The combined aqueous extracts were brought to pH 4 with concentrated HCl and extracted with DCM. The combined DCM extracts were filtered through phase separator paper and concentrated to provide (R)-4-fluoro-2-(1-(pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenol (1.82 g, 89% yield) as beige solid. MS (apci) m/z=299.4 (M+H).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[CH:6]([NH:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7]>C1C=CC=CC=1>[CH:6]([N:9]([CH:1]=[CH:2][CH2:3][CH3:4])[CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7]
Reactant: CC(C)NC(C)C
Reactant: CCCC=O
Solvent: c1ccccc1
Product: CCC=CN(C(C)C)C(C)C
Yield: 64.6 %

Procedure:
6.25 ml (69.3 mmol) of butyraldehyde and 19.44 ml (139 mmol) of diisopropylamine were dissolved in 30 ml of benzene, and the mixture was heated under reflux, while removing the water produced, until the production of water stopped (about 15 hours). The solvent was then removed by distillation under reduced pressure, and the residue was distilled under atmospheric pressure. Those fractions of the distillate having a boiling point of from 140 to 160° C. were collected, to give 6.95 g of the title compound as a pale yellow oily substance (yield 65%).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH2:6][C:7]1([CH3:38])[CH2:12][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[CH:21]=3)=[CH:17][C:9]=2[O:8]1)C.O.[OH-].[Li+].O1CCCC1.O>CO>[N:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:36]=[CH:37][C:28]=1[CH2:27][O:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][O:18][C:16]1[CH:15]=[CH:14][C:10]2[C:11](=[O:13])[CH2:12][C:7]([CH2:6][CH2:5][C:4]([OH:39])=[O:3])([CH3:38])[O:8][C:9]=2[CH:17]=1
Reactant: CCOC(=O)CCC1(C)CC(=O)c2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc2O1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(CCC(=O)O)CC(=O)c2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc2O1
Yield: 34.5 %

Procedure:
2.6 g of ethyl-3-(7-(3-(quinolin-2-ylmethoxy)benzyloxy)-3,4-dihydro-2-methyl-4-oxo-2H-1-benzopyran-2-yl)propanoate and 1.02 g of lithium hydroxide hydrate are combined in 30 ml of methanol, 30 ml of tetrahydrofuran and 10 ml of water and stirred at room temperature for 3 hours. The solvent is removed by evaporation and the residue diluted with water and washed with ether. The pH of the aqueous portion is adjusted to 5 and the suspension extracted with ethyl acetate. The dried ethyl acetate solution is concentrated and the residue purified by chromatography on silica gel to give 0.85 g of 3-(7-(3-(quinolin-2-ylmethoxy)benzyloxy)-3,4-dihydro-2-methyl-4-oxo-2H-1-benzopyran-2-yl)propanoic acid; m.p. 152°-54° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:7][NH:8][CH:9]=1)=[O:4].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O>[O:15]=[C:13]1[C:7]2[NH:8][CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]=2[CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1c[nH]cc1CCCC(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c[nH]c2c1CCCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
4-[4-(methoxycarbonyl)-1H-pyrrol-3-yl]butanoic acid (500 mg, 2.36 mmol) was dissolved in TFA (3 mL). TFAA (0.329 mL, 2.36 mmol) was added and the reaction was stirred at room temperature for 1 h. Organic solvent was evaporated to dryness and the residue suspended in Et2O (15 mL) and filtrated to give 320 mg (yield: 64%) of the title compound as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O.[H][H]>CO.[Pd]>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[NH2:1])[C:6]#[N:7]
Reactant: [H][H]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc(N)c(N)c1
Yield: 90.1 %

Procedure:
After 4-amino-3-nitrobenzonitrile (3.26 g, 20 mmol) was treated with hydrogen in MeOH (300 mL) in the presence of 5% palladium on active carbon (1 g) at room temperature for 16 hours, the reaction mixture was filtered and the filtrate was concentrated to give 3,4-diaminobenzonitrile (2.4 g, 90% yield). A solution of 3,4-diaminobenzonitrile (2 g, 15 mmol) in THF (100 mL) was treated with carbonyldiimidazole (CDI, 3.2 g, 19 mmol) at room temperature for 18 hours. The mixture was diluted with EtOAc (150 mL), washed with 1N HCl (30 mL) and brine, and dried over MgSO4. Filtration and concentration gave 5-cyanobenzimidazolinone (1.9 g, 80%). 1H NMR (CD3OD) δ 7.40 (dd, J=8.1 Hz, J=1.5 Hz, 1H), 7.34 (d, J=1.5 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H); MS: 160.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:16])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:20][O:21][CH3:22].O>CN(C=O)C>[Br:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([O:16][CH2:20][O:21][CH3:22])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)c2c1Sc1ccccc1S2
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)c2c1Sc1ccccc1S2
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of 4-Bromo-thianthren-1-ol (1.0 g, 3.21 mmol) in DMF (12 ml) was added NaH (60% dispersed in mineral oil, 0.23 g, 9.63 mmol) portionwise over 30 minutes and stirred for a further 30 minutes at this temperature. Chloromethylmethylether (0.26 g, 3.241 mmol) was then added and the reaction allowed to stir at room temperature for 2 hours. Water was added to the mixture which was then extracted using EtOAc (3×50 ml). The combined organic extracts were then dried (MgSO4), filtered and concentrated in vacuo to give a mild amber liquid. The crude residue was purified by flash chromatography (SiO2) (10:1, Hexanes/EtOAc) to give the title compound as a mild amber oil that crystallised upon standing (1.11 g, 97%). m/z (LC-MS, ESP):, RT=5.55 min, (M++1)=355.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[C:20]([O:23][CH2:24][C:25](Cl)=[O:26])(=[O:22])[CH3:21].O>C1COCC1>[C:20]([O:23][CH2:24][C:25]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:12])=[O:26])(=[O:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CC(=O)OCC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)NCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of tert-butyl N-(3-aminopropyl)carbamate (1.00 g, 5.74 mmol) in THF (10 mL) were added triethylamine (1.6 mL, 11.5 mmol) and acetoxyacetyl chloride (0.678 mL, 6.31 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water (30 mL), and the mixture was extracted with ethyl acetate (20 mL×3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=4:1→1:4) to give the title compound (1.35 g, 86%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[N:13]1[CH:18]=[C:17](B(O)O)[CH:16]=[N:15][CH:14]=1.[CH3:22][C:23]1[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][N:24]=1>>[CH3:22][C:23]1[CH:28]=[C:27]([NH:29][C:2]2[C:7]3[N:8]=[C:9]([CH3:11])[S:10][C:6]=3[C:5]([C:17]3[CH:18]=[N:13][CH:14]=[N:15][CH:16]=3)=[CH:4][N:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: Cc1cc(N)ccn1
Reactant: OB(O)c1cncnc1
Reactant: Cc1nc2c(Cl)ncc(I)c2s1
Product: Cc1cc(Nc2ncc(-c3cncnc3)c3sc(C)nc23)ccn1

Procedure:
The title compound, MS: m/e=335.2 (M+H+), was prepared in accordance with the general method of example 2, step 1 and step 2 from 4-chloro-7-iodo-2-methyl-thiazolo[4,5-c]pyridine (Example B), 5-pyrimidineboronic acid and 2-methyl-4-aminopyridine.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:3]=1.[CH2:20]([CH2:22][NH2:23])[OH:21]>>[ClH:1].[CH3:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:23][CH2:22][CH2:20][OH:21])=[CH:3][C:4]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1ccc(-c2cc(Cl)c3ccc(C)cc3n2)cc1
Reactant: NCCO
Product: Cc1ccc(-c2cc(NCCO)c3ccc(C)cc3n2)cc1
Product: Cl

Procedure:
The title compound, m.p. 260-263° C. and MS: m/e=293.3 (M+H+), was prepared from 4-chloro-7-methyl-2-p-tolyl-quinoline and ethanolamine.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH:6]([CH3:12])[CH2:7][C:8]([CH3:11])=[CH:9][CH3:10])[CH:3]=O.NC1C=CC=CC=1.S([O-])([O-])(=O)=[O:21].[Na+].[Na+].[OH-].[K+]>CCOCC>[CH3:12][CH:6]1[CH2:5][C:2]([CH3:3])([CH3:1])[C:9]([CH:10]=[O:21])=[C:8]([CH3:11])[CH2:7]1
Reactant: CC=C(C)CC(C)C=C(C)C=O
Reactant: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Nc1ccccc1
Product: CC1=C(C=O)C(C)(C)CC(C)C1
Reaction time: 1 h

Procedure:
A mixture of the two isomeric aldehydes obtained according to paragraph (d) (36.5 g.), aniline (21.4 g.) and anhydrous sodium sulphate (20 g.) in 55 ml. of ether was left at 20° under stirring during one night. After having filtered washed and concentrated to the initial volume the solution was poured with vigorous stirring into 221 ml. of conc. H2SO4 and 22.1 g. of ice. The temperature was kept between -20 and -25° during 1 h., and the mixture was then added to 300 g. of ice and immediately distilled by means of steam distillation. The distillate was saturated with NaCl, extracted with ether and treated as usual. 36 g. of a mixture of crude α- and β-cyclocitral were thus obtained. The subsequent isomerisation was carried out at -10° in 120 ml. of a 8.5% Chanolic KOH solution (80% ethanol). The mixture was allowed to react during 3 h. in an atmosphere of argon, diluted then with pet.-ether (30°-50°), poured into 400 ml. of a NaCl saturated aqueous solution and finally extracted with pet.-ether. By distillation 4-methyl-β-cyclocitral was obtained:
Reaction SMILES: O=C1[CH:6]([C:7](=[O:17])[C:8]([F:16])([F:15])[CH2:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5][CH2:4][O:3]1>Cl.C(O)(=O)C>[OH:3][CH2:4][CH2:5][CH2:6][C:7](=[O:17])[C:8]([F:16])([F:15])[CH2:9][CH2:10][C:11]([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)CCC(F)(F)C(=O)C1CCOC1=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C)CCC(F)(F)C(=O)CCCO
Temperature: 110 °C

Procedure:
A 10 mL one neck round bottom flask, fitted with argon inlet, magnetic stirrer, and reflux condenser was charged with 1.0 mL glacial acetic acid, 4 drops of concentrated HCl and 200 mg(0.81 mM) of 2,3,4,5-tetrahydro-2-oxo-3-(5,5-di-methyl-2,2-difluoro-1-oxohexyl) furan. The reaction mixture was heated at 110° C. overnight under a blanket of argon. The reaction was extracted with ethyl ether, and the ether was cross washed with water, dried (anhydrous MgSO4), and solvent removed under reduced pressure. The residue was chromatographed on a 10×60 mm silica gel column using a 9:1 hexane:ethyl acetate mixture to give a clear oil. nmr(CDCl3 α-0.95(s,9H), 1.45(t,2H), 2.00(m,6H), 3.12(bs,1H), 4.15(m,1H)
Reaction SMILES: Cl[C:2]([F:7])([F:6])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([OH:24])=[C:20]([CH:23]=1)[C:21]#[N:22]>CN(C=O)C.O>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:24][CH:2]([F:6])[F:7])=[C:20]([CH:23]=1)[C:21]#[N:22]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: N#Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)ccc1OC(F)F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
Sodium chloro(difluoro)acetate (9.62 g, 63.1 mmol) and cesium carbonate (12.3 g, 37.9 mmol) were added to a mixed solution of 5-bromo-2-hydroxybenzonitrile (5.00 g, 25.2 mmol) in DMF (50 mL) and water (5 mL), and the mixture was stirred at 100° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=100/0-98/2] to obtain the title compound (3.83 g, yield: 61%).
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=[O:10])[CH2:4][C:5](OCC)=O.[H][H].ClC[C:18]1[CH:22]=[C:21]([CH3:23])[O:20][N:19]=1>O1CCCC1>[CH3:23][C:21]1[O:20][N:19]=[C:18]([CH2:5][CH2:4][C:3]([OH:11])=[O:10])[CH:22]=1
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cc(CCl)no1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(CCC(=O)O)no1
Reaction time: 72 h
Yield: 59.2 %

Procedure:
To a stirred suspension of 78.5 g of sodium hydride in 1 liter of tetrahydrofuran under nitrogen was added in portions 261 g of diethyl malonate. When evolution of hydrogen had ceased, 108 g of 3-chloromethyl-5-methylisoxazole was added and the reaction mixture was heated at reflux for four hours. A portion of the tetrahydrofuran (800 ml) was distilled off and 1 liter of 5% sodium hydroxide solution was added to the remaining mixture which was then heated at reflux for three hours and allowed to stand at room temperature for three days. The reaction mixture was filtered and the filtrate extracted with hexane. The aqueous layer was acidified with concentrated hydrochloric acid and extracted repeatedly with ethyl acetate. The ethyl acetate was removed in vacuo, 100 ml of pyridine added to the residue, and the mixture heated at reflux for three hours until evolution of carbon dioxide ceased. The mixture was concentrated in vacuo and the residue acidified with 6N hydrochloric acid and cooled. The solid which separated was collected and dissolved in methylene dichloride. The layers were separated and the methylene dichloride layer concentrated in vacuo. The residual solid was slurried with isopropyl acetatehexane to give 75.4 g of 5-methyl-3-isoxazolepropanoic acid, m.p. 82°-84° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:17][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=1
Reactant: NCc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1NCc1cccc(F)c1
Temperature: 80 °C

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitrobenzene (500 mg, 2.273 mmol) and 3-fluorobenzylamine (370 mg, 2.95 mmol) in N,N-dimethylformamide (7 mL) was treated with potassium carbonate (1.00 g, 7.24 mmol) and heated at 80° C. for 1 hour. The mixture was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude title compound which was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8](C)(C1C=CC(C(C)(C)O)=CC=1)O.C(OC=C)(=O)C.[OH:27][C:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]([CH3:42])([O:39][CH:40]=[CH2:41])[CH3:38])=[CH:33][CH:32]=1)([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[CH3:38][C:37]([C:34]1[CH:35]=[CH:36][C:31]([C:28]([O:27][CH:7]=[CH2:8])([CH3:30])[CH3:29])=[CH:32][CH:33]=1)([O:39][CH:40]=[CH2:41])[CH3:42]
Reactant: C=COC(C)(C)c1ccc(C(C)(C)O)cc1
Reactant: CC(C)(O)c1ccc(C(C)(C)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C=COC(C)=O
Product: C=COC(C)(C)c1ccc(C(C)(C)OC=C)cc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (67 mg, 0.1 mmol) and sodium carbonate (640 mg, 6 mmol) in toluene (5 ml) were added α,α,α′,α′-tetramethyl-1,4-benzenedimethanol (5 mmol) and vinyl acetate (2.15 g, 25 mmol), followed by stirring at 100° C. in an atmosphere of argon gas for 6 hours. The reaction mixture was analyzed by gas chromatography to find that 1-(1-hydroxy-1-methylethyl)-4-(1-methyl-1-vinyloxyethyl)benzene and 1,4-bis(1-methyl-1-vinyloxyethyl)benzene were formed in yields of 11% and 62%, respectively, with a conversion from α,α,α′,α′-tetramethyl-1,4-benzenedimethanol of 95%.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][CH:22]=[CH:23][CH:24]=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1C=CC=CC=1>[Br-:20].[CH2:29]([O:28][C:26]([CH:25]=[CH:24][CH:23]=[CH:22][CH2:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:27])[CH3:30]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)C=CC=CCBr
Solvent: c1ccccc1
Product: CCOC(=O)C=CC=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Reaction time: 18 h
Yield: 64.1 %

Procedure:
To a stirred solution of triphenylphosphine (34 g.) in dry benzene (300 ml.) was added ethyl 6-bromohexa-2,4-dienoate (30 g.). After 18 hours, the benzene was decanted from the precipitated paste which solidified on adding diethyl ether and was ground up and filtered to give 5-ethoxycarbonylpenta-2,4-dienyltriphenylphosphonium bromide (40 g.), m.p. 139°-144° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1)=[O:18].[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1)=[O:18])(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2cncnc2)c(N)c2ccc(Cl)cc21
Product: CCOC(=O)n1c(C(=O)c2cncnc2)c(NC(C)=O)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) employing 3-amino-6-chloro-1-ethoxycarbonyl-2-(5-pyrimidinylcarbonyl)indole (step 2) and acetyl chloride.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[CH2:29]([NH2:31])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:29]([NH:31][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:14])[CH3:30]
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2CC

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ethylamide (70.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (150.0 mg), ethylamine (2.0 M solution in THF, 1.0 mL), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 435; and 1H NMR (DMSO-d6, 400 MHz): δ 8.45-8.39 (1H, m), 8.29-8.25 (1H, m), 8.12-8.08 (1H, m), 7.82-7.67 (3H, m), 7.57-7.50 (1H, m), 4.26-4.22 (2H, m), 3.31-3.29 (2H, m), 1.35-1.32 (3H, t), 1.17-1.13 (3H, t), —NH proton signal was not observed.