Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[S:8][C:7]([CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1.Cl[CH2:13][C:14]([OH:16])=[O:15]>CN(C)C=O>[CH3:3][C:4]1[S:8][C:7]([CH2:9][CH2:10][O:11][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1
Reactant: Cc1ccc(CCO)s1
Reactant: O=C(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCOCC(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.3 %

Procedure:
Sodium hydride (0.622 g) was suspended in dry dimethylformamide (5 ml) and treated dropwise with a solution of 2-(5-methyl-2-thienyl)ethanol (1.0 g) in dry dimethylformamide (5 ml). The mixture was stirred at room temperature under nitrogen for 2 hours then a solution of chloroacetic acid (0.664 g) in dry dimethylformamide (5 ml) added. The mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue quenched with water and extracted with ethyl acetate. The aqueous layer was adjusted to pH 2 using dilute hydrochloric acid and then extracted with ethyl acetate. This extract was washed with water, brine then dried (MgSO4). The solvent was removed in vacuo to give a brown oil (1.51 g) which was used without further purification.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]5[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH:26]=5)[CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH:26]=5)[CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1noc(N2CCC(Oc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1noc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
To a solution of tert-butyl 4-(2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (238 mg, 0.453 mmol) in CH2Cl2 (3.5 mL) was added TFA (0.5 mL, 6.7 mmol). The reaction mixture was stirred at rt for 4 h. The reaction mixture was diluted with CH2Cl2 (3 mL) and washed with aq. NaOH (1 N, 10 mL), then brine. The organic layer was dried (Na2SO4), filtered, and concentrated to afford 3-isopropyl-5-(4-(6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazol-2-yloxy)piperidin-1-yl)-1,2,4-oxadiazole (190 mg, 0.446 mmol, 99% yield) as a yellow foam. LCMS (m/z)=426 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>O1CCCC1.C(O)C.[H][H].[C].[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])c(C(=O)N(C)C)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C1CCN(c2ccc(N)c(C(=O)N(C)C)c2)CC1

Procedure:
1-(3-Dimethylcarbamoyl-4-nitrophenyl)-piperidine-4-carboxylic acid ethyl ester (1.578 g) was dissolved in tetrahydrofuran (5 mL) and ethanol (5 mL). After addition of 7.5% (w/w) palladium-carbon (0.316 g) to the solution, the mixture was stirred for 5 hours at normal pressure in hydrogen atmosphere. The reaction solution was filtered through a Celite pad and concentrated to give the title compound, which was used without isolation in the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[C:11]([CH3:22])[C:10]=2[CH3:23])=[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:4][N:3]=1.[Li+].[OH-]>O.O1CCCC1>[Cl:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[C:11]([CH3:22])[C:10]=2[CH3:23])=[C:5]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[S:4][N:3]=1
Reactant: CCOC(=O)CCc1ccc(OCc2c(Cl)nsc2-c2ccccc2)c(C)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CCC(=O)O)ccc(OCc2c(Cl)nsc2-c2ccccc2)c1C
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed ethyl 3-[4-[(3-chloro-5-phenyl-1,2-thiazol-4-yl)methoxy]-2,3-dimethylphenyl]propanoate (105 mg, 0.22 mmol, 1.00 equiv, 90%), a solution of LiOH (105 mg, 4.38 mmol, 19.95 equiv) in water (1 mL), tetrahydrofuran (1 mL). The resulting solution was stirred overnight at 20° C. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 5 with hydrogen chloride (2 mol/L). The solids were collected by filtration. The resulting mixture was concentrated under vacuum, washed with n-hexane. This resulted in 37 mg (41%) of 3-[4-[(3-chloro-5-phenyl-1,2-thiazol-4-yl)methoxy]-2,3-dimethylphenyl]propanoic acid as a white solid. 1H-NMR (300 MHz, CD3OD) δ 7.52-7.56 (m, 5H), 6.94 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 4.98 (s, 2H), 2.91 (t, J=8.4 Hz, 2H), 2.50 (t, J=7.5 Hz, 2H), 2.22 (s, 3H), 2.07 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H20ClNO3S, 402.0 (M+H). found 402.0.
Reaction SMILES: [Cl:1][C:2]1[C:8](I)=[CH:7][C:5]([NH2:6])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH:12]1(B(O)O)[CH2:14][CH2:13]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:7][C:5]([NH2:6])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)c(I)cc1N
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(Cl)c(C2CC2)cc1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 89.1 %

Procedure:
A mixture of 4-chloro-5-iodo-2-methoxyaniline (5.0 g, 17.6 mmol), cyclopropylboronic acid (1.8 g, 21.1 mmol), Pd(OAc)2 (314 mg, 1.4 mmol), tricyclohexylphosphine (500 mg, 17.6 mmol), K3PO4.3H2O (16.4 g, 61.6 mmol) in toluene (62.5 mL) and H2O (3 mL) was stirred at 80° C. under argon for 16 h. The mixture was allowed to cool to RT, and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=10:1) to afford the desired product (3.1 g, 88.5% yield). ESI-MS m/z: 198.2[M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[C:8]1([CH2:14][CH2:15][OH:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:16][CH2:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCc1ccccc1
Reactant: BrCCCCCBr
Product: BrCCCCCOCCc1ccccc1

Procedure:
(3.8 g), T.l.c. [K] Rf 0.46 from 1,5-dibromopentane (11.3 g) and benzeneethanol (2 g).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[O:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:34][CH2:33]1>C(Cl)Cl>[OH:19][C:20]1[C:21](=[O:22])[C:13]2[CH:8]3[C:7]([CH3:31])([CH:11]([OH:12])[CH2:10][CH2:9]3)[CH2:6][CH:5]([O:4][C:2](=[O:3])[CH3:1])[C:14]=2[C:15]2([CH3:30])[C:16]=1[C:17](=[CH:18][N:43]1[CH2:42][CH2:41][N:40]([CH2:39][CH2:38][N:35]3[CH2:34][CH2:33][O:32][CH2:37][CH2:36]3)[CH2:45][CH2:44]1)[C:23](=[O:24])[O:25][CH:26]2[CH2:27][O:28][CH3:29]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: C1CN(CCN2CCOCC2)CCN1
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN2CCN(CCN3CCOCC3)CC2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 1-(2-morpholinoethyl)piperazine (93 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 631 (M+H).
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.OC1[C:12](C)=[C:11]([O:14]C)[S:10]C=1C(OC)=O.S(=O)(=O)(O)O.C(O)(=S)C>C(O)(=O)C>[C:11]([S:10][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1)(=[O:14])[CH3:12]
Reactant: COC(=O)c1sc(OC)c(C)c1O
Reactant: Clc1cccs1
Agent: CC(O)=S
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)Sc1cccs1
Reaction time: 8 h
Yield: 75 %

Procedure:
The chlorothiophene of (e) above (0.016 mol) in 10 ml of acetic acid was added to a solution of 0.9 ml of concentrated sulphuric acid in 10 ml of acetic acid. Whilst stirring, thioacetic acid (0.016 mol) was added and the mixture stood at room temperature for eight hours. Filtration of the precipitate afforded 75% of acetylthiothiophene which was recrystallised from hexane, m.p. 112°-114° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([OH:18])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>CN(C)C(=O)C>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([O:7][C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([O:18][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(Oc2ccc([N+](=O)[O-])cc2)c1
Reaction time: 8 h
Yield: 68 %

Procedure:
A mixture of potassium carbonate (98.72 g, 0.714 mol) and 550 ml of N,N-dimethylacetamide (DMAC) is added to a 1L, three-necked round-bottom flask equipped with an overhead stirrer, condenser and a nitrogen inlet tube. Nitrogen is bubbled through the solution for 1 hour, following which methyl 3,5-dihydroxybenzoate (60.00 g, 0.357 mol) and 1-fluoro-4-nitrobenzene (100.79 g, 0.714 mol) are added. The slurry solution is stirred and heated to 80°-90° C. under nitrogen for 10 hours, and the mixture is then filtered while hot to remove inorganic salts. The filtrate is kept in a freezer overnight and the yellow crystals are collected by filtration, washed with water and dried. The product is recrystallized from ethyl acetate to yield 68 percent of yellow crystals: mp 180.5°-182.0° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[OH-].[Na+].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(OCc2ccccc2)c2[nH]cnc2n1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To a 500 mL 3 neck round bottom flask equipped with a magnetic stirrer, temperature probe and nitrogen inlet was added 2-amino-6-chloropurine (20 g), sodium hyroxide (28 g) and benzyl alcohol (200 mL). The mixture was stirred for 20 minutes and then heated at 100° C. for 2-3 hours. The reaction mixture was then cooled to room temperature and partitioned between methyl t-butyl ether (300 mL) and water (300 mL). The aqueous layer was separated and the pH was adjusted to 7-8 with 6 M HCl. The resulting solid was filtered, washed with water (50 mL) and dried under vacuum at 50° C. for 20 hours to provide the desired product as a pale yellow solid (24.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:16][O:17][C:18](=[O:25])[CH2:19][CH2:20][C:21](=[O:24])[CH2:22]Br.O>CN(C)C=O>[CH3:16][O:17][C:18](=[O:25])[CH2:19][CH2:20][C:21](=[O:24])[CH2:22][N:10]1[C:11]([CH3:13])=[CH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1
Reactant: COC(=O)CCC(=O)CBr
Reactant: Cc1cc(-c2ccc(Cl)cc2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCC(=O)Cn1nc(-c2ccc(Cl)cc2)cc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
3-(4-Chloro-phenyl)-5-methyl-1H-pyrazole (1.84 g, 9.6 mmol) was dissolved in dimethylformamide (20 ml) followed by the addition of sodium hydride (60% dispersion in oil, 384 mg, 9.6 mmol). The reaction was stirred at room temperature for 15 min, followed by the addition of 5-bromo-4-oxo-pentanoic acid methyl ester (2 g, 9.6 mmol). The reaction was stirred at room temperature for a further 30 min, before the addition of water (200 ml). The solution was then extracted with ethyl acetate (2×150 ml). The organics were dried over magnesium sulfate and concentrated in vacuo. The crude product was then purified by column chromatography (120g column, DCM to 90% DCM/EtOAc over 50 mins) to give 5-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl]-4-oxo-pentanoic acid methyl ester (1.84 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[CH3:22][Si:23]([CH3:33])([CH3:32])[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:29][C:28]2[CH:27]=[CH:26][C:25]([O:24][Si:23]([CH3:33])([CH3:32])[CH3:22])=[CH:31][CH:30]=2)[CH3:20])[N:14]=1)[CH3:12]
Reactant: C[Si](C)(C)Oc1ccc(N)cc1
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccc(O[Si](C)(C)C)cc1)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1

Procedure:
Monoimine (1, 1.4 g, 5 mmol) and 4-trimethylsiloxy-aniline (8, 906 mg, 5 mmol) were dissolved in 50 ml of toluene. To this solution 4 Å molecular sieves were added. After standing at room temperature for 4 days with addition of more molecular sieves the reaction mixture was filtered and the solvent was removed in vacuo. The product was washed with a small amount of methanol. Yield 1.4 g (63%) of mixed diimine (9). 1H NMR (CDCl3) δ 8.42 (dd, 1H), 8.33 (dd, 1H), 7.86 (t, 1H), 6.88 (s, 2H), 6.86 (d, 2H), 6.74 (d, 2H), 2.42 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 2.00 (s, 6H), 0.27 (s, 9H).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10](O)=[O:11])=[CH:8][N:7]=[C:6]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]5[O:23][C:24]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:25][N:26]=5)[CH:20]=4)[N:15]([S:31]([C:34]4[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[CH:14]=3)[N:5]=2)[CH2:3][CH2:2]1.C1C[N:44]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O1CCOCC1.N>CN(C=O)C>[CH:1]1([C:4]2[C:9]([C:10]([NH2:44])=[O:11])=[CH:8][N:7]=[C:6]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]5[O:23][C:24]([NH:27][CH:28]([CH3:29])[CH3:30])=[N:25][N:26]=5)[CH:20]=4)[N:15]([S:31]([C:34]4[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[CH:14]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(C(=O)O)c(C4CC4)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(C(N)=O)c(C4CC4)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 243.8 %

Procedure:
4-Cyclopropyl-2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)pyrimidine-5-carboxylic acid (107 mg, 0.192 mmol) was treated with PyBOP (169 mg, 0.326 mmol) and 1,4-dioxane (5 mL) and DMF (1.0 mL) and stirred at RT for 10 min. The reaction was then cooled in an ice bath and treated with NH3, 0.5 M solution in 1,4-dioxane (1.9 mL, 0.96 mmol) and stirred at 0° C. for 1.5 h. The reaction was quenched with water, extracted with EtOAc (25 mL), washed with brine (2×25 mL), dried over MgSO4, filtered and concentrated affording 261 mg of the crude amide. MS (ESI, pos. ion) m/z: 558.2 (M+H)+. The crude material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[NH:9][C:8]([CH2:10][CH2:11][CH3:12])=[N:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[CH:40]=[CH:39][C:26]2/[C:27](=[CH:36]/[C:37]#[N:38])/[C:28]3[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=3[CH2:30][CH2:31][C:25]=2[CH:24]=1.C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH3:12])[N:7]([CH2:22][C:23]3[CH:40]=[CH:39][C:26]4/[C:27](=[CH:36]/[C:37]#[N:38])/[C:28]5[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=5[CH2:30][CH2:31][C:25]=4[CH:24]=3)[C:6]=2[CH:13]=1
Reactant: CCCc1nc2cc(Br)cc(C)c2[nH]1
Reactant: N#C/C=C1\c2ccccc2CCc2cc(CBr)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc2c(C)cc(Br)cc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 104.1 %

Procedure:
[step 1] Under a nitrogen atmosphere, 6-bromo-4-methyl-2-propylbenzimidazole (WO2004082621; 300 mg, 1.19 mmol) was dissolved in DMF (3 mL), and the mixture was cooled to 0° C. Potassium carbonate (829 mg, 6.00 mmol) was added, and the mixture was stirred at room temperature for 20 min. To this mixture was added (E)-2-(2-bromomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetonitrile (421 mg, 1.30 mmol) obtained in Reference Example B1, and the mixture was stirred at room temperature for 4 hr. Ethyl acetate was added to the mixture, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/3) to give (E)-[2-(6-bromo-4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (615 mg, 95%).
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][NH:8][C:9]([C:11]1[C:25](=[O:26])[C:24]2[C:19](=[C:20]([Cl:27])[CH:21]=[CH:22][CH:23]=2)[C:13]2([CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:12]=1[OH:28])=[O:10])(C)(C)C>C(O)(C(F)(F)F)=O.O>[Cl:27][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:19]=1[C:13]1([CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:12]([OH:28])=[C:11]([C:9]([NH:8][CH2:7][C:6]([OH:29])=[O:5])=[O:10])[C:25]2=[O:26]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C2(CCOCC2)c2c(Cl)cccc2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)CNC(=O)C1=C(O)C2(CCOCC2)c2c(Cl)cccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A mixture of t-butyl-N-((8-chloro-2-hydroxy-4-oxo-2′,3′,5′,6′-tetrahydro-4H-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (0.13 g, 0.31 mmol) in 1.5 mL TFA was stirred at room temperature for 30 minutes. The mixture was diluted with 20 mL water, and a white solid precipitate formed. The solid was collected by filtration and washed with 20 mL water. The solid was dried under high vacuum to give 0.11 g off-white solid. MS m/e: (M+H)+ 366.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:16][C:17]([F:28])([F:27])[N:18]1[CH:23]=[C:22]([CH:24]=[CH2:25])[CH:21]=[CH:20][C:19]1=[O:26].[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:22]3[CH:21]=[CH:20][C:19](=[O:26])[N:18]([C:17]([F:28])([F:16])[F:27])[CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1ccc(=O)n(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2ccc(=O)n(C(F)(F)F)c2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 1-(trifluoromethyl)-5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:8]=2[CH:26]=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].S([CH2:44][N+:45]#[C-:46])(C1C=CC(C)=CC=1)(=O)=O>CO.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:23]([CH3:24])[CH3:25])=[O:22])[C:8]=2[C:26]2[O:27][CH:46]=[N:45][CH:44]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(C=O)n(CC(=O)N(C)C)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cnco3)n(CC(=O)N(C)C)c2c1

Procedure:
To a solution of methyl 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-formyl-1H-indole-6-carboxylate (from Step 4) in MeOH (0.05 M) was added K2CO3 (1.05 eq.) and tosylmethyl isocyanide (1.05 eq.). The resulting solution was refluxed under nitrogen for 1.5 h. The mixture was diluted with EtOAc and the organic phase was extracted with HCl (1N) and brine. The organic phase was then dried over Na2SO4 and evaporated in vacuo to give the clean product (quantitative).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(O)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1cccnc1Cl
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1ncccc1C#N
Temperature: 85 °C
Yield: 65.6 %

Procedure:
To a 250-mL, round-bottomed flask containing a large magnetic stir bar were added 2-chloro-3-cyanopyridine (1.39 g, 10.0 mmol), 2-methoxyphenylboronic acid (1.82 g, 12.0 mmol), and dichlorobis(triphenylphosphine)palladium(II) (351 mg, 0.50 mmol). Isopropyl alcohol (50 mL) and 2M sodium carbonate solution (50 mL) were added. The flask was stoppered and immersed in an oil bath heated to 80-90° C. The biphasic mixture was stirred vigorously and heated for 8 hours. After cooling to room temperature, ethyl acetate (50 mL) was added and the black mixture was transferred to a separatory funnel. The aqueous layer was removed and subsequently extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to give a brown oil. The product was crystallized from ethyl acetate/hexanes to give 1.38 g (66%) of the title compound as a tan powder.