Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.B.C1COCC1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1CO
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-bromo-2-methylbenzoic acid (5 g, 22.8 mmol) is dissolved in dry THF (100 ml) and cooled to 0° C. A 1M solution of BH3.THF in THF (34 mL, 34 mmol) is slowly added. The resulting colorless suspension is then stirred overnight, allowing it to gradually reach room temperature. K2CO3 solid (1.1 g) and H2O (100 ml) are added to the colorless solution and the mixture is stirred for an additional 30 minutes. THF is then evaporated and the residue extracted with EtOAc (30 ml). The organic phase is washed with 1N HCl (3×50 ml), dried over Na2SO4 and evaporated. The residue gives the title compound which is used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH3:12][C:13](OC(C)=O)=[O:14]>C1COCC1>[C:13]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11])(=[O:14])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C=O)ccc1O
Solvent: C1CCOC1
Product: COc1cc(C=O)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 117 %

Procedure:
To a solution of of 4-hydroxy-3-methoxybenzaldehyde (10 g, 66 mmol) in 30 mL of THF was added Ac2O (8 g, 80 mmol) and TEA (20 g, 198 mmol). The reaction was stirred at room temperature overnight. The volatiles were evaporated to afford 15 g of product as an oil, which was used for next step without further purification.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([O:11]C)=O)[CH2:2]2.O.[NH2:14][NH2:15]>O.C(=O)([O-])[O-].[K+].[K+]>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([NH:14][NH2:15])=[O:11])[CH2:2]2
Reactant: COC(=O)C1CN2CCC1CC2
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NNC(=O)C1CN2CCC1CC2
Yield: 100 %

Procedure:
(±) Methyl 1-azabicyclo[2.2.2]octane-3-carboxylate* (0.36 g; 2.1 mmoles) and hydrazine hydrate (0.35 ml; 7.0 mmoles) were heated at 120° C. for 2 h. The reaction was diluted with water (10 ml), saturated with potassium carbonate and extracted into chloroform (3×15 ml). Combined organic extracts were dried (Na2SO4) and concentrated to give the title compound as a pale oil (0.36 g; 100%) which was used in the next stage without further purification. *
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[Br:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1.[F-].[Cs+].CNCCNC>O1CCOCC1.[Cu](I)I>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])=[CH:10][CH:9]=1
Reactant: Brc1ccc(I)cc1
Reactant: O=C1CCCN1
Agent: I[Cu]I
Agent: CNCCNC
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C1CCCN1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.7 %

Procedure:
The mixture of pyrrolidin-2-one (1.3 g, 15 mmol), 1-bromo-4-iodobenzene (2.8 g, 9.8 mmol), copper iodide (0.19 g, 0.98 mmol), cesium fluoride (3.7 g, 25 mmol) and N,N′-dimethylethylenediamine (186 mg, 0.196 mmol) in 1,4-dioxane (100 mL) was evacuated and back-filled with nitrogen three times. The reaction mixture was stirred at room temperature for 48 hours. The mixture was filtered and the filtrate was concentrated to give a white solid. The solid was purified by combi flash silica gel chromatography to give the title compound (1.1 g, 46% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.52 (d, 2H), 7.48 (d, 2H), 3.83 (t, 2H), 2.59 (t, 2H), 2.18 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](Cl)=[O:13])[C:10]3[N:15]=[CH:16][CH:17]=[CH:18][C:9]=3[NH:8][C:7](=[O:19])[C:6]=2[CH:20]=1.[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:33][CH2:34][NH2:35])[CH2:24][CH3:25])[CH3:22]>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]([NH:35][CH2:34][CH2:33][N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]3[CH2:26][N:23]([CH2:21][CH3:22])[CH2:24][CH3:25])=[O:13])[C:10]3[N:15]=[CH:16][CH:17]=[CH:18][C:9]=3[NH:8][C:7](=[O:19])[C:6]=2[CH:20]=1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccc(Cl)cc21
Reactant: CCN(CC)CC1CCCCN1CCN
Solvent: ClCCCl
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2ccc(Cl)cc2C(=O)Nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3.1 g (0.01 mol) of 8-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 2.6 g (0.0122 mol) of 2-[2-[(diethylamino)methy]-piperidin-1-yl]ethanamine and 310 ml of 1,2-dichloroethane was stirred for 21/2 hours at ambient temperature, then extracted exhaustively with dilute hydrochloric acid. The combined aqueous extracts were made alkaline with saturated aqueous potassium carbonate solution and extracted exhaustively with dichloromethane. The dichloromethane phases were combined, dried over sodium sulphate with the addition of 1 g of animal charcoal and evaporated down in vacuo. After being triturated with diisopropylether the oily residue became crystalline and was recrystallised from acetonitrile. 2.9 g (60% of theory) of colourless crystals were obtained, m.p. 138°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[CH:9]=[C:10]([C:17]([OH:19])=[O:18])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[O:7])=[CH:4][CH:3]=1.CCOCC.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1.Cl>O1CCCC1.C(OCC)(=O)C>[OH:7][C:6]([C:31]1[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=1)([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][CH:20]=1)[C:8]1[CH:9]=[C:10]([C:17]([OH:19])=[O:18])[C:11](=[CH:15][CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(C(=O)O)c(C(=O)O)c1
Reactant: Clc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(O)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1C(=O)O

Procedure:
To a solution of 2.00 g of 4-(4-chlorobenzoyl) phthalic acid in 63 ml of tetrahydrofuran was dropwise added 50 ml of ether solution (0.59M) of 4-chlorophenylmagnesium bromide at room temperature in 20 minutes. The reaction mixture was refluxed under heating for 3 hours, cooled with ice, hydrolyzed with 10% hydrochloric acid and shaken with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was chromatographed on a column of silica gel, eluting with chloroform and methanol (2:1) to give crude 4-[hydroxybis(4-chlorophenyl)methyl]phthalic acid. This intermediate was provided for the following reaction without further purification.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3].[CH2:42]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1B(OC)OC)[CH2:43][CH:44]=[CH2:45].C([O-])([O-])=O.[K+].[K+]>CN(C=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>[CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:47]6[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=6[CH2:42][CH2:43][CH:44]=[CH2:45])[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCCc1ccccc1B(OC)OC
Reactant: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(Br)c5)nn34)c(Cl)c21
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: [K+]
Solvent: CN(C)C=O
Product: C=CCCc1ccccc1-c1cccc(-c2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(-c4ccc5c(c4Cl)N(CC=C)CCO5)n3n2)c1
Temperature: 90 °C
Yield: 59.6 %

Procedure:
To a 2-5 ml microwave tube was added (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.060 g, 0.094 mmol), dimethyl (2-(but-3-en-1-yl)phenyl)boronate (0.029 g, 0.141 mmol), and 2.0 M aqueous K2CO3 (0.094 ml, 0.188 mmol) in DMF (1 ml). The reaction was sparged with nitrogen for 10 minutes, treated with Pd(Ph3P)4 (10.83 mg, 9.38 pmol), then sparged for 15 min. The reaction tube was sealed and then heated (90° C., heating block) for 2.5 h. The reaction was cooled, then diluted with Et2O (20 mL) and washed with water, then brine (20 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to an orange oil (˜80 mg). The crude was purified by Biotage column chromatography, and product fractions were pooled and concentrated under reduced pressure, to afford (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(2′-(but-3-en-1-yl)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.039 g, 0.056 mmol, 60.2% yield). 1H NMR (500 MHz, CDCl3) δ: 7.85 (d, J=7.8 Hz, 1H), 7.78-7.82 (m, 1H), 7.42 (t, J=7.7 Hz, 1H), 7.30-7.35 (m, 2H), 7.25 (t, J=3.4 Hz, 2H), 6.93-7.01 (m, 2H), 6.89 (s, 1H), 5.97-6.10 (m, 1H), 5.69 (ddt, J=16.9, 10.3, 6.7 Hz, 1H), 5.32 (m, J=17.2, 1.4 Hz, 1H), 5.23 (m, J=10.3, 1.3 Hz, 1H), 4.81-4.94 (m, 2H), 4.25 (t, J=4.4 Hz, 2H), 3.66-3.75 (m, 1H), 3.65 (s, 3H), 3.55-3.62 (m, 1H), 3.19 (q, J=3.9 Hz, 2H), 2.84 (s, 3H), 2.64-2.71 (m, 2H), 2.18-2.28 (m, 2H), 1.25-1.33 (m, 1H), 1.17 (s, 9H). LCMS (M+H)=691.5.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:21]=[CH:20][C:15]2[S:16][CH:17]([CH3:19])[CH2:18][C:14]=2[CH:13]=1)=O)C1C=CC=CC=1.CO.CC(C)([O-])C.[Li+].[C:30]([O:33][C@H:34]([CH2:40]Cl)[CH2:35][NH:36][C:37](=[O:39])[CH3:38])(=[O:32])C.[Cl-].[NH4+]>CN(C)C=O.CS(C)=O>[CH3:19][CH:17]1[CH2:18][C:14]2[CH:13]=[C:12]([N:11]3[CH2:40][C@@H:34]([CH2:35][NH:36][C:37](=[O:39])[CH3:38])[O:33][C:30]3=[O:32])[CH:21]=[CH:20][C:15]=2[S:16]1
Reactant: CC(=O)NC[C@@H](CCl)OC(C)=O
Reactant: CC1Cc2cc(NC(=O)OCc3ccccc3)ccc2S1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC(=O)NC[C@@H]1CN(c2ccc3c(c2)CC(C)S3)C(=O)O1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
To a 15° C. suspension of 5-{[(benzyloxy)carbonyl]amino}-2-methyl-2,3-dihydrobenzo[b]thiophene (1.5 g, 5 mmol) in dimethylformamide (3 mL) is added methanol (406 μL, 10 mmol) and then 1M lithium-t-butoxide in hexanes (15 mL, 15 mmol) dropwise over 2 h. The mixture is cooled to 5° C. and (1S)-2-(acetylamino)-1-(chloromethyl)ethyl acetate (1.94 g, 10 mmol) is added in one portion. Stirring is continued overnight at room temperature when saturated aqueous ammonium chloride (50 mL) is added and then extracted with dichloromethane, dried, and flash chromatographed on silica gel eluting with 5% methanol in dichloromethane to give 1.20 (78%) of a mixture of the title compounds. The title compounds are resolved on a Chiralpak AD column eluting with ethanol to give the 2-(−)-isomer ([α]25D=−102 (c 0.49, DMSO). Anal. Calcd for C15H18N2O3S: C, 58.80; H, 5.92; N, 9.14. Found: C, 59.03; H, 6.03; N, 8.99) and the 2-(+)-isomer ([α]25D=55 (c 0.58, DMSO). Anal. Calcd for C15H18N2O3S: C, 58.80; H, 5.92; N, 9.14. Found: C, 59.12; H, 6.09; N, 8.78.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]([CH3:31])(OC(OC2C=CC=CC=2)=S)[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]([CH3:31])=[CH:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(C)(Cc2ccccc2)OC(=S)Oc2ccccc2)COC1(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: CC(=Cc1ccccc1)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 59.2 %

Procedure:
A solution of crude (R)-2,2-dimethyl-4-(1-methyl-1-phenoxythiocarbonyloxy-2-phenyl-ethyl)-oxazolidine-3-carboxylic acid tert-butyl ester (700 mg) in toluene (5 ml) was treated under an argon atmosphere with 2,2′ azobis(2-methylproponitrile) (122 mg) and tri-N-butyltin hydride (0.79 ml). The reaction mixture was refluxed for 30 min, then cooled to r.t. and then directly purified by column chromatography (silica gel, gradient: cyclohexane ->cyclohexane/EtOAc 10:1) to give (S)-2,2-dimethyl-4-(1-methyl-2-phenyl-vinyl)-oxazo-lidine-3-carboxylic acid tert-butyl ester (279 mg, 59%) as light yellow waxy solid. MS (ISP): 318.3 ([M+H]+))
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[CH2:19]([O:21][C:22]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])[CH3:20].O>CN1C(=O)CCC1>[CH2:19]([O:21][C:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20]
Reactant: Cc1nc(N)nc(Cl)c1C#Cc1ccc(N)nc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCN(c2nc(N)nc(C)c2C#Cc2ccc(N)nc2)CC1
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
The title compound is synthesized according to general procedure GP7 starting from 2.0 g (7.7 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidin-2-ylamine and 1.33 g (8.47 mmol) piperidine-4-carboxylic acid ethyl ester using 1.18 mL (8.5 mmol) triethylamine in 12 mL NMP. Work up is performed by addition of 50 mL water to the reaction mixture and stirring for 30 min. The solid material is filtered off, washed with water (50 mL three times) yielding 1.58 g (4.15 mmol) of the desired product with sufficient purity.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8]O)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][N:36]1[C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]2[C:32]1=[O:42])([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Nitrophenethyl alcohol (15 g) was dissolved in tetrahydrofuran (225 ml). After adding triphenylphosphine (26 g) and phthalimide (13.9 g) thereto, the mixture was ice-cooled and diethylazodicarboxylate (15.5 ml) was added dropwise thereinto. After stirring at room temperature for one hour, the resulting crystals were collected by filtration, washed with diethyl ether and dried, to give N-(3-nitrophenethyl)phthalimide as colorless crystals.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]([CH3:16])=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][C:7]=1[CH3:17])[CH2:2][CH2:3][CH3:4].CO>[OH-].[K+]>[CH2:1]([O:5][C:6]1[C:7]([CH3:17])=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][C:15]=1[CH3:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(C)cc(C(=O)OC)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1c(C)cc(C(=O)O)cc1C
Temperature: 25 °C
Yield: 46 %

Procedure:
A solution of methyl 4-butoxy-3,5-dimethylbenzoate represented by Formula 147 (2.1 g, 8.89 mmol) dissolved in potassium hydroxide (KOH, 44%, 5 mL) and methanol (40 mL) was agitated at 65° C. for 2 hours and cooled to room temperature, and the solvent was removed under reduced pressure. After dissolving the concentrate mixture in water then washing the mixture with ethylether (×3), 5N HCl aqueous solution was added to the obtained solution to reach pH 1. A precipitate generated during this process was obtained through filtration. After washing the obtained precipitate with water several times and drying the same, the dried precipitate was subjected to recrystallization in an ethyl acetate/hexane solvent. As a result, benzoic acid represented by Formula 145 was obtained as a desired product (907 mg, 46%). Analysis data of the product is provided as follows:
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][CH:17]=1>C(OCC)C>[N:16]1([C:2]2[O:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CCOC(=O)c1oc(Cl)nc1C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)c1oc(-n2cnc3ccccc32)nc1C(F)(F)F
Temperature: 25 °C
Yield: 41 %

Procedure:
A reaction vessel was charged with 5 g (21 mmol) ethyl 2-chloro-4-trifluoromethyl-5-oxazolecarboxylate and 4.96 g (42 mmol) benzimidazole. This mixture without solvent was heated at a temperature of about 100°-110° C. for 30 hours. The mixture was cooled to room temperature. This mixture was slurried in ethyl ether, washed with 5% hydrochloric acid, and then washed with large amounts of water, at which time a white precipitate began to form. A yellow filtrate was separated from 2.1 g of the precipitate (m.p. 133°-135° C.). The filtrate was concentrated under reduced pressure to provide 2.80 g of an off-white solid material (m.p. 132°-134° C.). This solid material and the white precipitate were combined and recrystallized from ethanol-water solution to give 4.03 g of an off-white solid product (m.p. 132°-134° C.) identified in Table I.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[CH2:12][CH2:13][NH:14][CH2:15][C:4]1=2.[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](O)=[O:21].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(Cl)CCl>CN(C=O)C.O>[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([N:14]1[CH2:13][CH2:12][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH3:2])[C:4]=2[CH2:15]1)=[O:21]
Reactant: Cn1c2c(c3ccccc31)CCNC2
Reactant: Nc1cccc(C(=O)O)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c2c(c3ccccc31)CCN(C(=O)c1cccc(N)c1)C2
Reaction time: 0.17 h
Yield: 92.7 %

Procedure:
To a stirred solution of 9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]-indole mono hydrochloride (0.35 g, 1.59 mmole) in dry DMF (20 mL) at RT was added 3-aminobenzoic acid (0.24 g, 1.75 mmole), 1-hydroxybenzotriazole hydrate (0.24 g, 1.75 mmole) and diisopropylethylamine (0.45 g, 3.50 mmole). After 10 min, EDC (0.33 g, 1.75 mmole) was added and the reaction was allowed to stir for 12 hr. The reaction contents were poured into H2O (100 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure gave a yellow oil. Purification on silica (CHC13/CH3OH, 95:5) afforded the title compound (0.45 g, 92%) as a white solid: MS (ES) m/e 306 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4](/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])[N:3]=[CH:2]1.Cl[C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[C:13]1([C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:1]2[CH:5]=[C:4](/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])[N:3]=[CH:2]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)/C=C/c1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=C(O)/C=C/c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
(E)-3-(imidazol-4-yl)acrylic acid was reacted with chlorotriphenylmethane in N,N-dimethylformamide to obtain (E)-3-(N-triphenylmethylimidazol-4-yl)acrylic acid.
Reaction SMILES: Br[CH2:2][C:3]([CH3:18])([CH3:17])[CH2:4][O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9]1)=[O:7].[C:19]([OH:24])(=[O:23])[C:20]([CH3:22])=[CH2:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:17][C:3]([CH3:18])([CH2:2][O:24][C:19](=[O:23])[C:20]([CH3:22])=[CH2:21])[CH2:4][O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9]1)=[O:7]
Reactant: C=C(C)C(=O)O
Reactant: CCCC1CCC(C(=O)OCC(C)(C)CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=C(C)C(=O)OCC(C)(C)COC(=O)C1CCC(CCC)CC1

Procedure:
4-Propyl-cyclohexanecarboxylic acid 3-bromo-2,2-dimethyl-propyl ester (4.3 g, 13.3 mmol), methacrylic acid (3.4 g, 39.9 mmol) and potassium carbonate (6.9 g, 50.0 mmol) are stirred at 100° C. in dimethyl sulphoxide (100 ml) for 3d. A solid precipitate is removed by filtration and washed with diethyl ether. The filtrate is washed with water, removed, dried and evaporated to dryness. Purification is achieved by flash column chromatography using petrol as eluant to give 22 as a liquid.
Reaction SMILES: ClC1C=C(C2C=C(C([N:22]3[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=O)OC=2C2C=CC(F)=CC=2)C=CC=1.[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[O:41][C:40]([C:42](O)=[O:43])=[CH:39][C:38]=2[C:45]2[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([Cl:52])[CH:46]=2)[CH:33]=[CH:34][C:35]=1[F:36].N1CCNCC1=O>>[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[O:41][C:40]([C:42]([N:22]3[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=[O:43])=[CH:39][C:38]=2[C:45]2[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([Cl:52])[CH:46]=2)[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)c(-c2ccc(F)c(Cl)c2)o1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(-c3ccc(F)cc3)o2)CCN1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)c(-c3ccc(F)c(Cl)c3)o2)CCN1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 6 starting with the compound from Example 21A. Instead of 1.5 equivalents of piperazin-2-one, 1.1 equivalents are used. 33.0 mg (53% of theory) of the title compound are obtained.