Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=3[F:25])[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:16]=2[CH3:33])[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:34][N:35]1CCCC1=O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([Sn](C#N)(CCCC)CCCC)CCC>FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[Pd+2]>[F:25][C:23]1[CH:22]=[C:21]([F:26])[CH:20]=[C:19]2[C:24]=1[C:15]([NH:14][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH:5]=1)[C:34]#[N:35])=[C:16]([CH3:33])[C:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=[N:18]2
Reactant: CN1CCCC1=O
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(Cl)cc(N2CCOCC2)c1
Agent: [Pd+2]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: CCCC[Sn](C#N)(CCCC)CCCC
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(C#N)cc(N2CCOCC2)c1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-(3-chloro-5-morpholinophenyl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (0.059 g, 0.13 mmol) in 1-methylpyrrolidin-2-one (1.26 mL, 0.13 mmol) was added palladium bis(trifluoroacetate) (0.013 g, 0.038 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-triisopropyl-biphenyl (0.036 g, 0.076 mmol) followed by tri-n-butyltin cyanide (0.040 g, 0.13 mmol). The reaction was heated to 160° C. for 36 h. A further 0.3 eq of palladium bis(trifluoroacetate) and 0.6 eq of 2-(dicyclohexylphosphino)-2′,4′,6′,-triisopropyl-biphenyl were added. Heating continued at 160° C. for a further 3 h. After which, the reaction was cooled to 23° C. The crude product was filtered through a plug of alumina eluting with EtOAc. The organics were washed with water, dried over MgSO4 and filtered and evaporated in vacuo. The crude product was purified by column chromatography on alumina (0 to 50% EtOAc/hexane)) to give the desired product 3-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinobenzonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (1H, ddd, J=4.9, 1.8, 1.0 Hz), 8.62 (1H, s), 8.02 (1H, td, J=7.6, 1.8 Hz), 7.91 (1H, dt, J=7.8, 1.1 Hz), 7.65-7.70 (1H, m), 7.45-7.54 (2H, m), 6.81 (1H, dd, J=2.1, 1.3 Hz), 6.56 (1H, t, J=2.1 Hz), 6.34 (1H, d, J=1.2 Hz), 3.69 (4H, m), 3.09 (4H, m), 2.19 (3H, s). Mass Spectrum (ESI) m/e=458.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1([CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:18].[O-]S([O-])(=O)=O.[Ca+2].[CH3:25]I>>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1([CH2:8][CH2:9][CH:10]([O:13][CH3:25])[CH2:11][CH2:12]1)[CH2:6][C:5]2=[O:18]
Reactant: O=C1CC2(CCC(O)CC2)Oc2ccc(Br)cc21
Reactant: CI
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Product: COC1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Temperature: 25 °C
Yield: 100 %

Procedure:
In a 20 mL vial was placed 6-bromo-4′-hydroxyspiro[chroman-2,1′-cyclohexan]-4-one (46 mg, 0.148 mmol) and it was azeotroped with acetonitrile (3 mL) The solid was dissolved in acetonitrile (1 mL) To this heterogenous solution was added Ag2O (103 mg, 0.444 mmol) followed by freshly grounded Drierite (160 mg). Then MeI (185 μL, 2.97 mmol) was added, the vial was capped and the reaction was allowed to stir at room temperature. After 2 days stirring the alcohol was totally consumed. The reaction mixture was filtered through a plug of Celite and the cake was rinsed with ethyl acetate three times (2 mL/each). The filtrate was concentrated yielding crude 6-bromo-4′-methoxyspiro[chroman-2,1′-cyclohexan]-4-one (48 mg, 0.148 mmol, 100% yield) which by 1H NMR looked >90% pure.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([CH:12]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH2:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:9][C:6]2=[N:7][CH:8]=1.[C-:29]#[N:30].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:14]1([CH2:13][CH:12]([C:10]2[NH:9][C:6]3=[N:7][CH:8]=[C:3]([CH2:2][C:29]#[N:30])[CH:4]=[C:5]3[CH:11]=2)[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CCl)cnc3[nH]2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CC#N)cnc3[nH]2)cc1
Yield: 17.9 %

Procedure:
A mixture of 5-chloromethyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (798 mg, 1.92 mmol) and sodium cyanide (500 mg, 10.87 mmol) in N,N-dimethylformamide (3 mL) was subjected to microwave irradiation for 0.5 h at 100° C. The mixture was diluted with ethyl acetate (250 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 5% methanol/dichloromethane) afforded {2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acetonitrile (140 mg, 18%) as a light yellow solid: LC/MS m/e calcd for C23H25N3O2S [M+H]+ 408.54, observed 408.0; 1H NMR (400 MHz, CDCl3) δ ppm 1.21 (m, 2H), 1.48 (m, 2H), 1.57-1.90 (m, 5H, H), 2.18 (m, 1H), 2.26 (m, 1H), 3.06 (s, 3H), 3.99 (s, 2H), 4.43 (m, 1H), 6.59 (s, 1H), 7.56 (d, J=8.2 Hz, 2H), 7.90 (d, J=8.2 Hz, 2H), 8.24 (s, 1H), 8.32 (s, 1H), 12.48 (br, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C(N(C(C)C)CC)(C)C.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(Cl)(Cl)Cl>CCCCO.CO>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[N:10]=1
Reactant: NCc1ccncc1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Fc1nc(NCc2ccncc2)c2nc[nH]c2n1
Reaction time: 1 h

Procedure:
To a stirred solution of 6-chloro-2-fluoropurine (1 g, 5.8 mmol) in n-BuOH (50 mL) under an argon atmosphere at 0° C., was added diisopropylethylamine (3 ml, 17.4 mmol) followed by 4-(aminomethyl)pyridine (0.9 ml, 1.5 eq, 8.7 mmol). The reaction mixture was stirred at this temperature for 1 h and then allowed to return to room temperature and stirred for 4 h, when TLC(CHCl3:MeOH; 90:10) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue was purified by gradient flash column chromatography on silica gel, eluted with CHCl3:MeOH (100:0→90:10), to afford the product as a white solid; Yield: 0.85 g (60%). mp 200-202° C. 1H-NMR (d6-DMSO, 250 MHz): δ 4.67 (2 H, d, J 5, —HNCH2-Pyr), 7.34-7.28 (2 H, m, Pyr-H), 8.48-8.42 (2 H, m, Pyr-H), 8.54 (1 H, s, —N═CH—NH—), 8.84 (1 H, s, br, —HNCH2-Pyr), 13.13 (1 H, s, b, —N═CH—NH—); m/z 245 ([M+H]+
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:8][S:9](O)(=[O:11])=[O:10]>>[CH:6]1[C:1]([OH:7])=[CH:2][CH:3]=[C:4]([S:9]([OH:11])(=[O:10])=[O:8])[CH:5]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(O)O
Product: O=S(=O)(O)c1ccc(O)cc1

Procedure:
In this embodiment, PholTMS was grafted onto silica gel to form phenol-functionalized silica gel, which is denoted by Phol-SiO2. Then, phenol-functionalized silica gel was sulfonated by concentrated H2SO4 to form phenolsulfonic acid-functionalized silica gel, which is denoted by PholSO3H—SiO2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=[N:19][C:18]1[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1cc(C=O)cc(OC)c1O
Solvent: CO
Product: COc1cc(C=Nc2ccc(F)cc2)cc(OC)c1O

Procedure:
3,5-Dimethoxy-4-hydroxybenzaldehyde (1 g, 5.46 mmol) was dissolved in methanol (30 ml) and to this solution was added 4-fluoroaniline (600 mg, 5.46 mmol, 0.51 ml). The resultant reaction solution was stirred for forty-eight (48) hours at room temperature under nitrogen. The reaction solution was then cooled in the freezer and the resultant precipitate was isolated by filtration and washed with cold methanol and ether. The isolated light yellow powder was the title product: 1H NMR (300 MHz, CDCl3); δ 8.31 (S, 1H) , 7.20-7.04 (m, 4H), 5.85 (S, 1H), 3.98 (S, 6H).
Reaction SMILES: COC(=O)[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.NC1[NH:77][N:76]=[N:75][N:74]=1>CN(C)C=O>[Cl:36][C:8]1[CH:9]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])[C:11]([Cl:13])=[CH:12][C:7]=1[C:6]([NH:5][C:4]1[NH:77][N:76]=[N:75][N:74]=1)=[O:37]
Reactant: Nc1nnn[nH]1
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[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: O=C(Nc1nnn[nH]1)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 22 %

Procedure:
To a solution of 0.20 g (0.41 mmol) 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) in 2 mL N,N-dimethylformamide were added 0.165 g (0.43 mmol) O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 0.21 mL (1.24 mmol) N,N-diisopropylethylamine. To the yellow solution 0.037 g (0.43 mmol) 5-amino-1H-tetrazole (commercially available, CAS RN 4418-61-5) was added and the solution was stirred at room temperature for 3.25 hours. Then the solution was heated to 60° C. and stirred at this temperature for 88 hours. After filtration over a syringe micro filter, the reaction mixture was purified by preparative HPLC (Phenomenex Gemini column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give the desired compound as a light brown solid (0.051 g, 22%). MS (ESI): m/z=551.11 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[C:30]([C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][C:41]=1[O:55][CH3:56])=[O:38])[N:31]2[CH3:36].C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[C:30]([C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:2]3[N:3]=[C:4]([C@H:12]4[CH2:17][CH2:16][C@H:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[N:5]4[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=34)=[CH:42][C:41]=1[O:55][CH3:56])=[O:38])[N:31]2[CH3:36]
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(-c2nc([C@H]3CC[C@H](N4CCN(C)CC4)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Temperature: 100 °C

Procedure:
To a stirred suspension of 1-bromo-8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (1.04 g) and 4-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (2.227 mmol, 0.972 g) in dioxane (18 mL) and 2 M aqueous potassium carbonate (10.6 mmol, 5.3 mL) under a nitrogen atmosphere was added 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride, complex with dichloromethane (0.212 mmol, 0.171 g) and the reaction mixture was heated by a preheated oil bath at 100° C. After two hours the reaction mixture was cooled to room temperature, water added and extracted with dichloromethane/methanol 9/1. The organic layer was separated and the water layer was extracted again with dichloromethane/methanol 9/1. The combined organic layers were washed with brine and dried (sodium sulfate) and evaporated to dryness to afford crude sample which was purified using column chromatography (silica gel; dichloromethane/methanol gradient (0 to 15% methanol)). Trituration with ethanol afforded 4-methoxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (0.44 g).
Reaction SMILES: ClC1C=CC(C2C([C:12]3C=C[C:19]4[C:14](=[CH:15][CH:16]=[C:17](C(O)=O)[CH:18]=4)[N:13]=3)=CC(OC)=CC=2)=CC=1.C[N:30](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>[N:30]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:13][CH:12]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(C(=O)O)ccc3n2)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 525c (0.38 g, 0.97 mmol) was reacted with HBTU (0.444 g, 1.2 mmol) in anhydrous DMF (5 mL) in the presence of DIEA (0.41 mL, 2.35 mmol) for 30 min. The mixture was then transferred to a suspension of amine-resin in DMF (5 mL). The reaction mixture was shaken at room temperature overnight. The solution was drained and the resin was washed with DMF (5 mL×5), MeOH (5 mL×5), and CH2Cl2 (5 mL×5). The resin was dried under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH2:22])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:16]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2ncsc2n1
Reactant: COc1ccc(N)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
A mixture of 5,7-dichlorothiazolo[5,4-d]pyrimidine (0.925 g, 4.49 mmol), 3,4-dimethoxybenzenamine (0.89 g, 5.8 mmol) and DIEA (0.86 g, 6.66 mmol) in 12 mL of DMSO was stirred at room temperature for 24 hours. Then the reaction mixture was poured into 50 mL of water, the solid was filtered and washed with water (50 mL) to give a crude product as a solid. It was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with ethyl acetate) to give 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (1.2 g, 82.8%) as a grey solid. LC-MS: 322.9 [M+H]+, tR=1.51 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH2:14][CH2:15][CH2:16][CH2:17]O)[C:12]3[C:19]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][CH:21]=[C:22]([Cl:23])[C:11]=3[N:10]=2)=[C:4]([CH3:29])[CH:3]=1.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(N(CC)CC)C.C(=O)([O-])O.[Na+].CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3=[N:10][C:11]4[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:12]=4[N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]2)=[C:4]([CH3:29])[CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(Br)cc3C)n(CCCCO)c12
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(Br)cc1C
Temperature: 0 °C
Reaction time: 14 h

Procedure:
To a solution of 4-[2-[(4-bromo-2-methylphenyl)amino]-4-chloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butan-1-ol (Reference Example 61; 1.10 g, 2.30 mmol) in tetrahydrofuran (20 mL) and triethylamine (1.6 mL) was added methanesulfonyl chloride (0.72 mL, 9.24 mmol) at 0° C. The mixture was stirred at 0° C. for 14 hr, and diluted with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. A mixture of the resulting mesylate, potassium carbonate (150 mg, 1.09 mmol) in N,N-dimethylformamide (15 mL) was stirred at 70° C. for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30 % ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was purified by preparative HPLC to give a mixture contained the title compound as the trifluoroacetic acid salt. The trifluoroacetic acid salt was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a colorless amorphous (680 mg, 1.48 mmol, 64% in 2 steps).
Reaction SMILES: [CH:1]1[C:6]([CH:7](O)[CH2:8][NH2:9])=[CH:5][C:4]([OH:11])=[C:3]([OH:12])[CH:2]=1.[Na+].[Cl-].[Cl-].[K+].[Mg+2].[Cl-].[Cl-].[Cl-].[Cl-].[Ca+2].O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.C([O-])(O)=O.[Na+].O=C1O[C@H]([C@H](CO)O)C(O)=C1O.C(N(CC(O)=O)CC(O)=O)CN(CC([O-])=O)CC([O-])=O.[Na+].[Na+].O=O>>[NH2:9][CH2:8][CH2:7][C:6]1[CH2:5][CH:4]([C:3](=[CH:2][CH:1]=1)[OH:12])[OH:11]
Reactant: NCC(O)c1ccc(O)c(O)c1
Agent: O=C([O-])CN(CCN(CC(=O)O)CC(=O)O)CC(=O)[O-]
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: NCCC1=CC=C(O)C(O)C1
Temperature: 34 °C
Reaction time: 0.5 h

Procedure:
Alkaloid effects on [3H]overflow from rat striatal slices preloaded with [3H]DA and hippocampal slices preloaded with [3H]NE were determined using modifications of a previously published method (Dwoskin and Zahniser, 1986). Briefly, coronal striatal or hippocampal slices (500 μm, 6-8 mg) were incubated in Krebs' buffer (118 mM NaCl, 4.7 mM KCl, 1.2 mM MgCl2, 1.0 mM NaH2PO4, 1.3 mM CaCl2, 11.1 mM α-D-glucose, 25 mM NaHCO3, 0.11 mM L-ascorbic acid and 4.0 mM disodium ethylenediaminetetraacetate; pH 7.4, and saturated with 95% O2/5% CO2) in a metabolic shaker at 34° C. for 30 min. Striatal or hippocampal slices were incubated in fresh buffer (6-8 slices/3 mL) containing 0.1 μM [3H]DA (3,4-[7-3H]-dihydroxyphenylethylamine; specific activity 28 Ci/mMol) or 0.1 μM [3H]NE (levo-[7-3H]-norepinephrine; specific activity 14.4 Ci/mMol), respectively, for an additional 30 min. After rinsing, each slice was transferred to a glass superfusion chamber maintained at 34° C. and was superfused at 1 mL/min with oxygenated Krebs' buffer containing pargyline (10 μM) and nomifensine (10 μL) or pargyline and desipramine (10 μL) in experiments assessing [3H]DA and [3H]NE overflow, respectively. After 60 min of superfusion, three 5-min samples (5 mL) were collected to determine basal [3H]outflow. After collection of the third basal sample, slices from an individual rat were superfused in the absence or presence of a single concentration of analog, which remained in the buffer until the end of the experiment. Each slice was exposed to only one concentration of analog. After 30 min, S(−)-nicotine (10 μM) was added to the buffer containing analog, and superfusion continued for an additional 60 min. These experiments utilized a repeated measures design, such that the analog concentration-effect was determined in both the absence and presence of S(−)-nicotine using striatal or hippocampal slices from a single rat. Additionally, one striatal or hippocampal slice was superfused in the absence of analog and constituted the control condition. At the end of the experiment, each slice was solubilized with TS-2. The pH and volume of the solubilized tissue samples were adjusted to those of the superfusate samples. Radioactivity in the superfusate and tissue samples was determined by liquid scintillation spectroscopy (Packard model B1600 TR Scintillation Counter, Downer's Grove, Ill.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH:19]([C:20]([O:22][CH3:23])=[O:21])[C:18](=[O:24])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[BH4-].[Na+].O>O1CCCC1.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH:19]([C:20]([O:22][CH3:23])=[O:21])[CH:18]([OH:24])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)C1C(=O)c2ccccc2OC1c1ccc2c(c1)OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)C1C(O)c2ccccc2OC1c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A solution of methyl 2-(benzo[d][1,3]dioxol-5-yl)-4-oxochroman-3-carboxylate (58 mg, 178 μmol) in tetrahydrofuran (1.0 mL) was diluted with methanol (2.0 mL) and stirred on an ice/acetone bath. Sodium borohydride (7 mg, 178 μmol) was added and the resulting mixture was stirred for 40 min. After this time, water (about 10 mL) was added and the mixture was stirred while warming to rt. The resulting white solid was collected by filtration, washed with water and dried under vacuum to provide racemic methyl 2-(benzo[d][1,3]dioxol-5-yl)-4-hydroxychroman-3-carboxylate (51 mg, 87%). 1H NMR (400 MHz, CDCl3) δ ppm 2.69 (s, 1 H) 3.47 (dd, J=6.6, 2.5 Hz, 1 H) 3.51 (s, 3 H) 5.25 (d, J=5.6 Hz, 1 H) 5.31 (d, J=2.5 Hz, 1 H) 5.99 (s, 2 H) 6.82 (d, J=8.1 Hz, 1 H) 6.89 (d, J=8.1 Hz, 1 H) 6.92 (m, 2 H) 7.03 (t, J=7.4 Hz, 1 H) 7.23 (td, J=7.1, 1.0 Hz, 1 H) 7.57 (d, J=7.6 Hz, 1 H). Mass spectrum m/z 351.20 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16](I)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[C:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=1.[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49](B2OC(C)(C)C(C)(C)O2)[C:48]([CH3:61])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:49]4[C:48]([CH3:61])=[N:47][N:46]([CH2:45][C:44]5[CH:62]=[CH:63][CH:64]=[C:42]([F:41])[CH:43]=5)[C:50]=4[CH3:51])=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[C:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Yield: 74.9 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(2-fluoro-4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (intermediate 66Q) (300 mg, 0.445 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (177 mg, 0.534 mmol) using Pd(dppf)Cl2 (16 mg, 0.022 mol) and sodium carbonate (141 mg, 1.335 mmol) in toluene/ethanol/water (5/8/1 mL) to afford 250 mg (74.8% yield) of the titled compound. MS: m/z=750.4 (M+1).