Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2nc(COc3ccc4[nH]ccc4c3)ccc2c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 48.5 %

Procedure:
A mixture of 5-hydroxyindole (5.0 g), 2-chloromethylquinoline (7.0 g) and potassium carbonate (10.0 g) in N,N-dimethyl formamide (50 ml) was stirred at 80° C. for 4 hours. The cooled mixture was poured into water, and extracted with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, and concentrated in vacuo. The crude product was recrystallized from ethanol to yield the title product (5.0 g), m.p. 134°-137° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:9]=O.C(O)(=O)[CH2:20][C:21]([OH:23])=[O:22].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:20][C:21]([OH:23])=[O:22])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH3:18]
Reactant: O=C(O)CC(=O)O
Reactant: COCCOc1ccc(C=O)cc1OCCOC
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COCCOc1ccc(C=CC(=O)O)cc1OCCOC
Temperature: 110 °C
Yield: 93.2 %

Procedure:
To a solution of 3,4-Bis-(2-methoxy-ethoxy)-benzaldehyde (19 g, 72.4 mmol) in pyridine (60 ml), malonic acid (11.3 g, 108.6 mmol) was added, followed by piperidine (2 ml), the resulting mixture was heated at 110° C. for 6 hs under N2. After removal of most of pyridine, the residue was poured into water (200 ml) and acidified to PH=3 by aq.HCl. The precipitate was collected and dried to give product (20 g, 93.3%). LC-MS: m/e 295 (M−1)
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C=O)C>[N:25]1([C:7]2[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:22])([F:20])[F:21])[N:4]=[C:3]([C:2]([F:1])([F:24])[F:23])[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1Cl
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1N1CCCC1

Procedure:
This compound was prepared as described in Example 37: 6.0 g (0.016 mol) of product of Example 27, 2.6 ml (0.032 mol) of pyrrolidine in 30 ml of DMF were reacted affording a brown solid which was recrystallized in hot hexane giving 5.18 g (78.1%) of product as a tan solid; mp 68.5°-70° C.
Reaction SMILES: [Li]C(CC)C.[F:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:15][C:8]=12.C(Br)(Br)(Br)[Br:27].[Cl-].[NH4+]>C1COCC1>[Br:27][C:12]1[C:7]([F:6])=[C:8]2[CH:15]=[CH:14][N:13]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:23]([CH3:25])[CH3:24])[CH:17]([CH3:18])[CH3:19])[C:9]2=[N:10][CH:11]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)ccnc21
Reactant: BrC(Br)(Br)Br
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(Br)cnc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
s-BuLi (53.7 mL, 75.2 mmol, 1.4M in cyclohexane) was added to a solution of 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (10.0 g, 34.2 mmol, prepared as described in L′Heureux, et al. Org. Lett., 5(26), p. 5023 (2003)) in THF (250 mL) at −78° C., and the reaction was stirred at −78° C. for 30 minutes. A solution of CBr4 (28.3 g, 85.5 mmol) in THF (40 mL) was added next, and the reaction was stirred at this temperature for 1 hour. A saturated ammonium chloride solution (80 mL) was then added, and the reaction was extracted with hexane (200 mL), washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was then purified by column chromatography (hexane) to give 5-bromo-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (7.8 g, 61.4% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH2:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[N:6]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Reactant: C=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3ccccc3n2CCc2ccccc2)C1

Procedure:
The title compound was prepared according to General Method 2. 2,3,4,5-Tetrahydro-2-methyl-5-phenethyl-1H-pyrido[4,3-b]indole was prepared from 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (200 mg, 1.07), styrene (1.23 mL mmol, 10.65) and NaH (250 mg, 6.25 mmol) in DMF (6 ml) at 200° C. for 16 h to obtain 15 mg of 2,3,4,5-tetrahydro-2-methyl-5-phenethyl-1H-pyrido[4,3-b]indole after purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[NH:21][C:22](=[O:30])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[Cl:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:22]([NH:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)ccc1C1=CCNCC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To the solution of 4-[4-chloro-2-(3-chloro-benzoylamino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.504 g, 1.13 mmol) in dichloromethane (10 mL) is added trifluoroacetic acid (1 mL) in a dropwise fashion. The resulting reaction is allowed to stir at room temperature for 2 h. 2N NaOH aqueous solution is added to adjust the pH>12. The mixture is then extracted with dichloromethane 3×. The organic layers are combined, washed with brine 1×, dried (Na2SO4) and concentrated under vacuum to give 0.391 g of 3-chloro-N-[5-chloro-2-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide in 99% yield.
Reaction SMILES: O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[C:16]([C:20]1[CH:25]=[CH:24][C:23](/[C:26](/[C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([O:53]CC3C=CC(OC)=CC=3)[N:46]=2)=[CH:27]\[C@@H:28]2[N:32]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=3[O:42][CH3:43])[C:31](=[O:44])[CH2:30][CH2:29]2)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>C(Cl)(Cl)Cl>[C:16]([C:20]1[CH:21]=[CH:22][C:23](/[C:26](/[C:45]2[NH:46][C:47](=[O:53])[C:48]([O:51][CH3:52])=[CH:49][CH:50]=2)=[CH:27]\[C@H:28]2[CH2:29][CH2:30][C:31](=[O:44])[N:32]2[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH3:43])=[CH:24][CH:25]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1ccc(COc2nc(/C(=C/[C@H]3CCC(=O)N3Cc3ccc(OC)cc3OC)c3ccc(C(C)(C)C)cc3)ccc2OC)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(OC)c(=O)[nH]2)c(OC)c1
Temperature: 65 °C
Reaction time: 21 h
Yield: 39.7 %

Procedure:
Water (0.2 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (72 mg) were added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-{5-methoxy-6-[(4-methoxybenzyl)oxy]-pyridin-2-yl}ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (202 mg) in chloroform (4 mL), and the mixture was stirred at 65° C. for 21 hours. Chloroform was added. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=1:0→95:5 9:1) to give 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-3-methoxypyridin-2(1H)-one (65 mg).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40](=[O:47])[N:41]([CH:43]2[CH2:46][O:45][CH2:44]2)[CH:42]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[CH:38]=[CH:39][C:40](=[O:47])[N:41]([CH:43]4[CH2:46][O:45][CH2:44]4)[CH:42]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: O=c1ccc(Br)cn1C1COC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C3COC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 5-bromo-1-oxetan-3-yl-1H-pyridin-2-one following a procedure analogous to that described in Example 35. LC (method 4): tR=0.97 min; Mass spectrum (ESI+): m/z=503 [M+H]+; 1H NMR (CDCl3) δ 1.05 (s, 3H), 1.12 (s, 3H), 1.48 (d, 3H), 2.10-2.22 (m, 5H), 2.34 (m, 1H), 2.83 (m, 1H), 4.72 (m, 2H), 5.10 (m, 2H), 5.63 (m, 1H), 5.83 (m, 1H), 6.57 (d, 1H), 6.97 (d, 2H), 7.12 (d, 2H), 7.20-7.32 (m, 5H), 7.49 (d, 1H), 7.65 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:15])[CH2:9][N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)(C)(C)C.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[CH3:15][C@@H:8]([NH2:7])[CH2:9][N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: C[C@H](Cn1cccn1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)Cn1cccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
((R)-1-Methyl-2-pyrazol-1-yl-ethyl)-carbamic acid tert-butyl ester (49 mg, 0.22 mmol) was dissolved in dichloromethane (2.4 ml) and cooled in an ice bath. Trifluoroacetic acid (1.2 ml) was slowly added and the reaction was stirred at room temperature for 2 h then evaporated and dried under high vacuum to afford (R)-1-methyl-2-pyrazol-1-yl-ethylamine trifluoroacetate which was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@H:9]([N:13]1[CH:17]=[C:16]([CH2:18][C@@H:19]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:20]([NH2:22])=[O:21])[N:15]=[N:14]1)[CH2:8][CH2:7][CH2:6]2)=O.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[CH3:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([NH:23][C@H:19]([CH2:18][C:16]2[N:15]=[N:14][N:13]([C@H:9]3[C:10]4[C:5](=[CH:4][C:3]([CH2:1][N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[CH:12][CH:11]=4)[CH2:6][CH2:7][CH2:8]3)[CH:17]=2)[C:20]([NH2:22])=[O:21])(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCCc4cc(C=O)ccc43)nn2)C(N)=O)cc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCCc4cc(CN5CCCCC5)ccc43)nn2)C(N)=O)cc1
Temperature: 60 °C

Procedure:
A mixture of (R)-3-(1-((R)-6-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylbenzenesulfonamido)propanamide (0.21 g, 0.45 mmol) and piperidine (0.20 g, 2.2 mmol) in 5 mL 1,2-dichloroethane was heated to 60° C. for 30 min. The reaction mixture was cooled and treated with NaBH(OAc)3 and a drop of HOAc. The resulting mixture was heated to 80° C. for 16 h. The reaction mixture was cooled, quenched with H2O, and extracted with CHCl3 (3×). The combined extracts were dried over MgSO4, concentrated and purified by SiO2 (5% MeOH/CH2Cl2) to give a white solid. MS (m/z): 537.4 (m+H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][CH:4]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCc1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
To a solution of methyl 4-bromomethylbenzoate (5.73 g, 25 mmol) in dry CH2Cl2 (150 mL) cooled to −78° C. with stirring under nitrogen was added dropwise a solution of DIBAL-H (82.5 mL, 1.0 M solution in THF). Stirring was continued for 1.5 h at −78° C., and the reaction mixture was then allowed to warm to 0° C. and quenched with H2O. The organic layer was separated and the aqueous was extracted with CH2Cl2 (2×100 mL). The combined organic extracts were dried (MgSO4) and evaporated to give the desired alcohol (5.0 g, 100%) as a white solid: 1H NMR (CDCl3) δ1.84 (br, 1H), 4.49 (s, 2H), 4.67 (s, 2H), 7.33 (d, 2H, J=8.2 Hz), 7.38 (d, 2H, J=8.2 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([Si](C(C)C)(C(C)C)C(C)C)[CH:18]=[CH:17]3)=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:33][O:34][C:35](=[O:38])[C:36]#[CH:37].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH3:33][O:34][C:35](=[O:38])[CH:36]=[CH:37][N:19]1[C:20]2[C:16](=[CH:15][C:14]([CH2:13][CH2:12][C:11]3[C:2]([CH3:1])=[N:3][C:4]4[C:9]([CH:10]=3)=[CH:8][CH:7]=[CH:6][N:5]=4)=[CH:22][CH:21]=2)[CH:17]=[CH:18]1
Reactant: Cc1nc2ncccc2cc1CCc1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: C#CC(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COC(=O)C=Cn1ccc2cc(CCc3cc4cccnc4nc3C)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A mixture of 2-methyl-3-[2-(1-triisopropylsilanyl-1H-indol-5-yl)-ethyl]-[1,8]naphthyridine (0.25 g, 0.74 mmol), propynoic acid methyl ester (0.07 g, 0.84 mmol), and tetrabutylammonium fluoride [1.0 M] (2.23 mL, 2.23 mmol) was stirred at room temperature overnight. The solvent was removed under reduced pressure to give a crude mixture which was purified via column chromatography with silica gel, eluting with methylene chloride/methanol (95/5) to give the title compound (66% yield) as an E/Z isomeric mixture. 1H NMR (CDCl3) δ 9.00 (m, 1H), 8.23 (s, 1H), 8.08 (m, 1H), 7.80 (m, 1H), 7.50 (d, 1H). Mass Spectrum (LCMS, ESI) calculated for C22H22N3O2 372.2 (M+H); found 372.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:12])[C:10]=1[Br:11])=[O:5])C.[Li+].[OH-]>CO.O>[Br:11][C:10]1[N:9]([CH3:12])[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(C)c1Br
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1ncc(C(=O)O)c1Br

Procedure:
To a solution of 5-bromo-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (6.9 g, 29.6 mmol) in CH3OH (25 mL) and water (25 mL) was added LiOH (0.78 g, 32.6 mmol). The reaction mixture was stirred at reflux for 4 h, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was diluted with water and the solution was acidified to pH 2 with concentrated HCl (˜3 mL). The resulting mixture was then extracted with ethyl acetate. The combined organic extracts were concentrated in vacuo to give 5-bromo-1-methyl-1H-pyrazole-4-carboxylic acid, which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[C:13]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:12]1.C([O-])(=O)C.[K+].O>CN(C)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>[CH:24]1([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:19]=3[N:11]3[CH2:10][CH2:9][CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[C:12]=23)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)cn(CCCc3ccccc3Br)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCCc1ccccc1-3
Temperature: 160 °C
Reaction time: 5 h
Yield: 26.8 %

Procedure:
To a solution of methyl 1-[3-(2-bromophenyl)propyl]-3-cyclohexyl-1H-indole-6-carboxylate (250 mg, 0.550 mmol) in N,N-dimethylacetamide (7.5 ml) were added potassium acetate (59 mg, 0.605 mmol) and tetrakis(triphenylphosphine)palladium (32 mg, 0.0275 mmol), and the mixture was stirred at 160° C. for 5 hr. The reaction mixture was allowed to cool to room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=8:1-4:1) to give methyl 13-cyclohexyl-6,7-dihydro-5H-benzo[3,4]azepino[1,2-a]indole-10-carboxylate (55 mg, yield 27%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:22])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:22])[NH:11][C:12]([C:15]1[CH:16]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:19][CH:20]=1)([CH3:14])[CH3:13])[CH2:2]2
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cccc(-c2ccccc2)c1
Yield: 63.8 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromophenyl)propan-2-yl]carbamate (600 mg, 1.63 mmol), phenylboronic acid (398 mg, 3.27 mmol) and palladium (II) acetate gave the title compound as a white solid (379 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.56 (d, J=7.4 Hz, 2H), 7.50-7.38 (m, 4H), 7.34 (m, 2H), 5.16 (s, 1H), 4.63 (s, 1H), 3.39-2.09 (m, 6H), 1.72 (s, 6H), 2.02-0.73 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3) δ 154.8, 147.8, 141.6, 129.0, 129.0, 128.6, 127.5, 125.8, 125.0, 124.0, 71.6, 71.3, 55.9, 55.5, 47.6, 46.8, 31.5, 30.2, 30.0, 29.5, 25.6, 24.8, 19.8 ppm. Purity: 99% UPLCMS (210 nm); retention time 0.84 min; (M+1) 365.0. Anal. Calcd. for C23H28N2O20.0.29 (CHCl3): C, 70.02; H, 7.14; N, 7.01. Found: C, 70.02; H, 7.37; N, 6.84.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.C([Li])CCC.[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16]1>C1COCC1.CCCCCC>[OH:24][C:21]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)[CH2:22][CH2:23][C:18]2([O:17][CH2:16][CH2:15][O:25]2)[CH2:19][CH2:20]1
Reactant: N#Cc1ccc(Br)nc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1ccc(C2(O)CCC3(CC2)OCCO3)nc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
A solution of 6-bromonicotinonitrile (2 g, 0.011 mol) in 50 mL of dry THF and 15 mL of dry hexane under argon was cooled to −100° C. in a liquid nitrogen-Et2O bath. n-Butyllithium (7.5 mL, 0.011 mol, 1.6 M solution in hexane) was added rapidly dropwise so that the internal temperature did not exceed −95° C. The orange solution was stirred for an additional 10 min at −100° C. to −95° C. and then treated dropwise over 10 min with a solution of 1,4-cyclohexanedione monoethylene ketal (1.8 g, 0.011 mol) in 55 mL of dry THF, again carefully maintaining the temperature below −95° C. The reaction mixture was stirred for 10 min at −100° C. to −95° C., allowed to warm to 20° C. and poured into ice water (400 mL). The organic layer was separated, and the aqueous layer was extracted twice with Et2O (200 mL). The combined organic extracts were dried over MgSO4 and evaporated to give 2.8 g of white crystalline solid. Trituration with Et2O afforted 1.9 g (67% yield) of white crystals: MS: 261 (M+1)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([NH:11][C:12]#[C:13][Si](C)(C)C)[CH:10]=1>CCO>[F:3][C:4]([F:19])([F:18])[C:5]1[CH:10]=[C:9]2[C:8]([CH:13]=[CH:12][NH:11]2)=[CH:7][CH:6]=1
Reactant: C[Si](C)(C)C#CNc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: FC(F)(F)c1ccc2cc[nH]c2c1
Reaction time: 2 h

Procedure:
Carefully add NaH (10.83 g, 60% in oil, 270.8 mmol, 4 eq.) to EtOH (200 mL). When cool, add a solution of 5-trifluoromethyl-2-trimethylsilanylethynylphenylamine (22.3 g, 67.7 mmol) in EtOH (400 mL) with vigorous stirring. After 2 hours, heat to reflux. After 4 hours, evaporate in vacuo to remove the EtOH and dilute the residue obtained with water and extract with Et2O. Combine the organic layers and wash with brine, dry over MgSO4, filter, and evaporate to give a dark oil. Absorbed the oil onto silica gel and load onto short column of silica gel. Elute with 20% EtOAc in hexanes. Pool fractions containing the product and remove the solvent leaving a dark brown oil. Further purification of the oil by HPLC (silica column) using a gradient 1% Et2O in hexanes to 15% Et2O in hexanes. Pool fractions containing the product and remove the solvent to give the title compound as an orange solid: 1H NMR (300 MHz, d6-DMSO-d6): 6.58 (m, 1H), 7.28 (m, 1H), 7.61 (t, 1H), 7.74 (m, 2H), 11.51 (bs, 1H); MS(EI+): m/z 185 (M+).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.C[N:18](C=O)C>COCCOC.[Cu]Cl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([NH2:18])[CH:9]=1
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: Cl[Cu]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: Nc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To a solution of potassium tert-butoxide (21.92 g, 195 mmol) and copper (I) chloride (2.36 g, 23.8 mmol) in ethyleneglycol dimethylether (170 mL), stirred at 0° C. under nitrogen, a solution of 1-bromo-4-nitrobenzene (141, 8.69 g, 43.0 mmol) in DMF (45 mL) was added drop wise over 50 min. After complete addition the cooling bath was removed and the mixture was allowed to stir at room temperature for 4 h, diluted with DCM, washed with aqueous NH4Cl, dried over MgSO4, filtered and concentrated to give compound 142 (7.85 g, 84% yield).
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21](O)=[O:22])[C:2]1=[O:3].S(Cl)[Cl:29]>C(Cl)Cl>[O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([Cl:29])=[O:22])[C:2]1=[O:3]
Reactant: O=C(O)c1ccccc1CCCCCCOc1cc2ccccc2oc1=O
Reactant: ClSCl
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1CCCCCCOc1cc2ccccc2oc1=O
Temperature: 35 °C
Reaction time: 5 h

Procedure:
After about 5 g of coumarin-oxyhexylbenzoic acid (compound 3) (about 13.075 mol, about 1 eq) was added to about 100 ml of methylene chloride under nitrogen atmosphere, about 1.71 g of thiochloride (about 14.383 mol, about 1.1 eq) was added thereto and the mixture was stirred at about 35° C. for about 5 hours. Then, the reaction mixture was subjected to evaporation to remove the solvent and recrystalized with ethylacetate/hexane, to obtain coumarin-oxyhexylbenzoyl chloride (compound 4).