Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[O:30][C:29]([CH3:35])([CH3:34])[C:25]1([CH2:28][O:27][CH2:26]1)[C@@:5]12[CH2:9][O:8][C:7]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])C(OC(C)(C)C)=O)=[N:6]1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C[Si]([N-:58][Si](C)(C)C)(C)C.[Li+].Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C(Cl)(Cl)Cl>[NH2:58][C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[O:30][C:29]([CH3:34])([CH3:35])[C:25]1([CH2:28][O:27][CH2:26]1)[C@@:5]12[CH2:9][O:8][C:7]([NH:10][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:6]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(CO1)c1cc(Br)ccc1OC(C)(C)C21COC1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(N)ccc1OC(C)(C)C21COC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
To a mixture of di-tert-butyl [(4S)-6′-bromo-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]imidodicarbonate (3.40 g, 6.14 mmol), bis(dibenzylideneacetone)palladium(0) (353 mg, 0.614 mmol), and tri-tert-butylphosphonium tetrafluoroborate (179 mg, 0.617 mmol) was added lithium bis(trimethylsilyl)amide (1M solution in toluene, 31 mL, 31 mmol) at ambient temperature under argon atmosphere. After stirring for 1.5 hours at 60° C., the mixture was cooled in an ice-water bath and 1M aqueous HCl (31 mL) was added. After stirring for 10 minutes at ambient temperature, to the mixture was added CHCl3, and the mixture was filtered through a pad of celite. The filtrate was separated and the aqueous layer was extracted with CHCl3. The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated at reduced pressure. To the residue were added MeOH (34 mL) and silica gel (neutral; 17 g) at ambient temperature. After stirring for 1 hour at 40° C., the mixture was concentrated at reduced pressure. The residue was purified with column chromatography on silica gel (hexane-EtOAc, a linear gradient of EtOAc from 10 to 100%) to afford tert-butyl [(4S)-6′-amino-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]carbamate (2.38 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH2:12][CH2:13][CH3:14])=[CH:5][C:6]=1[C:7]([O:9]C)=O.Cl[C:16]1[N:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1>>[CH2:11]([C:4]1[S:3][C:2]2[N:1]=[C:16]3[CH:17]=[CH:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][N:21]3[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH2:12][CH2:13][CH3:14]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCCCc1cc(C(=O)OC)c(N)s1
Product: CCCCc1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1

Procedure:
A mixture of 2-amino-5-butyl-3-thiophenecarboxylic acid, methyl ester, 21.33 g (0.1 mol) and 6-chloro-3-pyridinecarboxylic acid (Aldrich Chemical Company), 15.76 g (0.1 mol) is heated in a wax bath at 178°-180° C. for one hundred ninety minutes. The mixture is cooled, extracted with hot chloroform and the residue is dissolved in 300 ml of hot glacial acetic acid filtered and 600 ml of hot water added and the mixture stirred on a steam bath for forty minutes and filtered to give 1.23 g of 2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid; mp 250°-252° C. after recrystallization from pyridine.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35](=[O:38])(=[O:37])[NH2:36])=[CH:25][CH:24]=2)[C:7](=[O:21])[N:8]([C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35](=[O:38])(=[O:37])[NH:36][C:42](=[O:43])[C:41]3[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=3[Cl:39])=[CH:25][CH:24]=2)[C:7](=[O:21])[N:8]([C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:20])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared from 5-n-butyl-2-[5-(carbomethoxy)-2-chlorophenyl]-2,4-dihydro- 4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step C) and 2-chlorobenzoic acid (2 equivalents), CDI (2 equiv), and DBU (2 equiv) according to the procedure of Example 51 to give an 88% yield of the desired material as a white solid after flash chromatography, mp 98°-101° C., homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 693 (M+1)+.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1>CO.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>[CH3:21][O:20][C:18]([C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2coc3c(Br)cccc23)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Product: COC(=O)c1cccc2c(CN3CCN(C(=O)OC(C)(C)C)CC3)coc12
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 4-[(7-bromo-1-benzofuran-3-yl)methyl]piperazine-1-carboxylate (100 mg, 0.253 mmol), Pd(PPh3)2Cl2 (10 mg, 0.0142 mmol) and TEA (2 mL) in 20 mL of MeOH was heated at 100° C. under CO (3 MPa) overnight. After cooling, the mixture was filtered. The filtrate was then partitioned between EtOAc and water. The combined organics were washed with water (150 mL) and brine (150 mL), dried over Na2SO4 and concentrated to give tert-butyl 4-{[7-(methoxycarbonyl)-1-benzofuran-3-yl]methyl}piperazine-1-carboxylate. 1H-NMR (400 MHz, CDCL3) δ ppm 7.88-7.91 (m, 2H), 7.59 (s, 1H), 7.24 (t, J=7.6 Hz, 1H), 3.94 (s, 3H), 3.59 (s, 2H), 3.30-3.50 (m, 4H), 2.30-2.40 (m, 4H), 1.39 (s, 9H); MS m/z 375 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH3:44])[CH2:3][C:4]([NH:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][C:15]([NH:17][C@H:18]([B:31]2[O:39]C3C(C)(C4CC(C3)C4(C)C)[O:32]2)[CH2:19][C:20]2[C:21](OC)=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23]([OH:25])=[O:24])=[O:16])[CH2:10][CH2:9]1)=[O:5].B(Cl)(Cl)Cl>>[CH3:1][N:2]([CH3:44])[CH2:3][C:4]([NH:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][C:15]([NH:17][C@H:18]2[CH2:19][C:20]3[CH:28]=[CH:27][CH:26]=[C:22]([C:23]([OH:25])=[O:24])[C:21]=3[O:32][B:31]2[OH:39])=[O:16])[CH2:10][CH2:9]1)=[O:5]
Reactant: COc1c(C[C@H](NC(=O)C[C@H]2CC[C@H](CNC(=O)CN(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Agent: ClB(Cl)Cl
Product: CN(C)CC(=O)NC[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1

Procedure:
Prepared from 3-((2R)-2-(2-(trans-4-((2-(dimethylamino)acetamido)methyl)cyclohexyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoic acid and BCl3 following the procedure described in Step 2 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 446 (MH)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][PH:6]([C:8]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[CH3:9])=[O:7])[CH3:4].Br[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.O>O1CCCC1>[CH2:3]([O:5][P:6]([C:8]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[CH3:9])([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:7])[CH3:4]
Reactant: BrCC1CCCCC1
Reactant: CCO[PH](=O)C(C)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C)(OCC)P(=O)(CC1CCCCC1)OCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
21 g of 99% sodium hydride are suspended at room temperature under argon in 1000 ml of anhydrous tetrahydrofuran, and a solution of 172.2 g of 1,1-diethoxyethylphosphinic acid ethyl ester is added dropwise over a period of 2.5 hours, the temperature being maintained at from 20° to 25°. The reaction is exothermic and involves the evolution of gas. The batch is then stirred for 1.5 hours at room temperature, 142.2 g of bromomethylcyclohexane are added and heating under reflux is effected for 24 hours. The suspension is cooled to 4° and 250 rnl of water are carefully added. Two phases are formed. The tetrahydrofuran phase is separated off and the aqueous phase is extracted twice with 250 ml of dichloromethane each time. Concentration by evaporation yields a brown oil which, after distillation under reduced pressure, gives 1,1-diethoxyethyl(cyclohexylmethyl)phosphinic acid ethyl ester having a boiling point of 95° (1.8×10-4 mbar).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:24][C:25]1[C:26]([C:33]([NH:35][C:36](SC)=[NH:37])=[O:34])=[N:27][C:28]([Cl:32])=[C:29]([NH2:31])[N:30]=1.C(N(C(C)C)CC)(C)C>CCO>[NH2:24][C:25]1[C:26]([C:33]([NH:35][C:36](=[NH:37])[NH:23][CH2:22][CH2:21][CH2:20][CH2:19][C:14]2[CH:13]=[CH:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:10]=3)[CH:15]=2)=[O:34])=[N:27][C:28]([Cl:32])=[C:29]([NH2:31])[N:30]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(CCCCN)ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(CCCCNC(=N)NC(=O)c3nc(Cl)c(N)nc3N)ccc2c1
Temperature: 70 °C
Yield: 50.6 %

Procedure:
To a solution of amine 77 (337 mg, 1.02 mmole) and methyl 3,5-diamino-6-chloropyrazine-2-carbonylcarbamimidothioate (10, 596 mg, 1.53 mmole) in EtOH (20 mL) was added diisopropylethylamine (1.06 mL, 6.13 mmole) at room temperature. The reaction mixture was heated at 70° C. in a sealed tube for 6 h, then cooled to room temperature, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 80:18:2 CHCl3/CH3OH/NH4OH) to afford carboxamide 78 (280 mg, 50%) as a light yellow solid: 1H NMR (300 MHz, CD3OD) δ 7.67 (d, J=9.2 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.57 (br s, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.14 (br s, 1H), 7.03 (dd, J=9.2, 1.7 Hz, 1H), 3.30 (m, 2H), 2.81 (t, J=7.0 Hz, 2H), 1.95-1.62 (m, 4H), 1.03 (s, 9H), 0.24 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[C:13]3[C:18]([N:19]=[C:20]([CH3:21])[C:11]2=[C:10]([CH3:23])[N:9]=1)=[CH:17][C:16]([OH:22])=[CH:15][CH:14]=3.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[N+:35]([C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41]Br)([O-:37])=[O:36]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[C:13]3[C:18]([N:19]=[C:20]([CH3:21])[C:11]2=[C:10]([CH3:23])[N:9]=1)=[CH:17][C:16]([O:22][CH2:41][C:40]1[CH:43]=[CH:44][CH:45]=[C:38]([N+:35]([O-:37])=[O:36])[CH:39]=1)=[CH:15][CH:14]=3
Reactant: Cc1nc(-c2ccccc2Cl)n2c1c(C)nc1cc(O)ccc12
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccccc2Cl)n2c1c(C)nc1cc(OCc3cccc([N+](=O)[O-])c3)ccc12
Temperature: 120 °C
Reaction time: 3 h

Procedure:
1.5 g 1-(2-Chloro-phenyl)-3,4-dimethyl-7-hydroxy-imidazo(1,5-a)quinoxaline, 3.36 g Caesium carbonate, 80 mL N,N-dimethylformamide, and 9 mL water were stirred for 10 min followed by addition of 1.3 g 3-nitro-benzylbromide. After 3 h stirring at 120° C. the reaction mixture was given into 250 mL water, filtered off, washed with water, dried under reduced pressure.
Reaction SMILES: [CH2:1]([N:3]1[CH2:12][CH2:11][C@@:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[C@@H:5]([CH2:6][CH2:7][C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(O)[CH2:9]2)[CH2:4]1)[CH3:2]>Cl>[CH2:1]([N:3]1[CH2:12][CH2:11][C@@:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[C@@H:5]([CH2:6][CH:7]=[C:8]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:9]2)[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@]2(c3cccc(OC)c3)CC(O)(c3ccccc3)CC[C@H]2C1
Agent: Cl
Product: CCN1CC[C@]2(c3cccc(OC)c3)CC(c3ccccc3)=CC[C@H]2C1
Yield: 102.6 %

Procedure:
The reaction was conducted as described in Example 2, using 0.79 g (2.16 mmol) of (±)-trans-1,2,3,4,4a,5,6,7,8,8a-decahydro-2-ethyl-4a-(3-methoxyphenyl)-6-phenyl-6-isoquinolinol and 30 ml of 37% HCl, yielding 0.77 g of the title compound. C24H29NO
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13]C)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1.[OH-].[K+]>O>[OH:13][C:12]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cc(O)c(OC)cc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A mixture of 500 g methyl 4,5-dimethoxy-2-nitro-benzoate and 625 g potassium hydroxide in 2300 ml of water is heated to 95° C. for 18.5 h. After cooling, the mixture is filtered clear and the filtrate is diluted with 3 l water. The solution is combined with 950 ml acetic acid and after 1 h the precipitate is filtered off. The precipitate is suspended in 3250 ml ethyl acetate and then 100 ml of water and 200 ml 12N hydrochloric acid are added. After 1.5 h the phases are separated and the aqueous phase is extracted with 700 ml ethyl acetate. The combined organic phases are dried on magnesium sulphate and after filtration they are evaporated down. The mixture is evaporated again with 200 ml methylcyclohexane. The residue is refluxed together with 1600 ml of methanol and 100 ml conc. sulphuric acid for 16.5 h. The mixture is evaporated down until crystallisation begins. 1000 ml of water are added and the mixture is stirred until a homogeneous suspension is obtained. The precipitate is filtered off, washed with 500 ml of water and suspended in 1000 ml of water. After 1.5 h stirring the precipitate is filtered off and washed with 500 ml of water. After the filter cake is dried, 364 g product are obtained.
Reaction SMILES: [CH2:1]1C[C@H]2N(C[C@H]3[C@@H]4CCCCN4C[C@@H]2C3)CC1.C([Li])(CC)C.[CH:23]([N:26]([CH:39]([CH3:41])[CH3:40])[C:27](=[O:38])[O:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])([CH3:25])[CH3:24].CI.Cl>C(OCC)C.C1CCCCC1.O>[CH:39]([N:26]([CH:23]([CH3:24])[CH3:25])[C:27](=[O:38])[O:28][CH:29]([CH3:1])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])([CH3:41])[CH3:40]
Reactant: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Reactant: CC(C)N(C(=O)OCCc1ccccc1F)C(C)C
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CI
Solvent: CCOCC
Solvent: O
Product: CC(Cc1ccccc1F)OC(=O)N(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.3 %

Procedure:
Under a nitrogen atmosphere, a solution of 14.1 g (60.2 mmol) of (−)-Sparteine in 75 ml of diethyl ether was cooled to −78° C. and a 1.0M solution of 60.2 ml (60.2 mmol) of s-butyllithium in cyclohexane was added dropwise. The reaction mixture was stirred for 15 min and then added to a solution of 10 g (40.1 mmol) of 2-(2-fluorophenyl)ethyl diisopropylcarbamate in diethyl ether at −78° C. After stirring for 4 hr, methyl iodide was added, followed by stirring for 2 hr. Water was added and the resulting mixture was warmed to room temperature. The mixture was treated with 1 N—HCl, extracted 3 times with ethyl acetate, washed with water and brine and then dried over sodium sulfate. After the solvent was distilled off, purification of the residue by silica gel column chromatography gave 5.11 g of the title compound. (Yield: 45%).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[C:2]1([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:14]2[CH2:19][CH2:18][N:17]([CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])[CH2:16][CH2:15]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: OCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
71.7 g (284 mmol) benzhydrylpiperazine, 45 g (361 mmol) 2-(2-chloroethoxy)-ethanol, 43.2 g (312 mmol) potassium carbonate and 9.4 g (57 mmol) potassium iodide are stirred in 400 ml absolute DMF for 8 hours at 75° C. After cooling, the solution is concentrated under vacuum. The residue is distributed between acetic acid ethyl ester and water. The aqueous phase is extracted twice with acetic acid ethyl ester and the combined organic phases are washed three times with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (90/10): Yield 104 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.I[C:20]1[C:28]2[C:23](=[N:24][CH:25]=[N:26][C:27]=2[NH2:29])[N:22]([CH:30]([CH3:32])[CH3:31])[N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[Br:1][C:2]1[CH:3]=[C:4]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[N:26][C:27]=3[NH2:29])[N:22]([CH:30]([CH3:32])[CH3:31])[N:21]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COc1cc(Br)cc(-c2nn(C(C)C)c3ncnc(N)c23)c1
Temperature: 80 °C
Yield: 35.8 %

Procedure:
A solution of 2-(3-bromo-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (137 mg, 0.43 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (65 mg, 0.216 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA85 (28 mg, 36% yield). ESI-MS (M+H)+ m/z calcd 362.1, found 362.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:18]1[CH:19]=[CH:20][C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:22])=[CH:16][CH:17]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccccc2Cl)cc1
Yield: 83.3 %

Procedure:
2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 2-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.060 g (82%) of 2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27]Cl)=[CH:21][CH:20]=1>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][O:18][CH2:27][C:26]#[C:25][C:22]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: ClCC#Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCOCC#Cc2ccccc2)CC1
Temperature: 0 °C
Yield: 15.6 %

Procedure:
Sodium hydride (0.912 g, 23 mmol, 60% oil disp.) which had been rinsed with hexanes (3×10 mL), and dry N,N-dimethylformamide (50 mL) were cooled to 0° C. with stirring under a nitrogen atmosphere. A solution of 1-t-butyloxycarbonyl-4-hydroxyethylpiperidine (4.3 g, 19 mmol) in dry DMF (15 mL) was added, and the mixture stirred for 1 hour. 3-Phenylpropargyl chloride (2.8 g, 19 mmol) was added, and the mixture was heated to reflux for 24 hours. After cooling, the solvent was removed by distillation under reduced pressure. The residue was dissolved in ethyl acetate and extracted with water (3×100 mL), brine (100 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with 5% ethyl acetate in hexanes, and concentrated under reduced pressure to yield 1-t-butyloxycarbonyl-4-[(3-phenyl-2-propynyloxy)ethyl]piperidine (1.02 g, 16%) as a dark oil. 1H NMR (300 MHz, CDCl3 /TMS, δ): 7.5(m,2H), 7.3(m,3H), 4.4(s,2H), 4.1(m,2H), 3.6(t,2H), 2.7(br t,2H), 1.8-1.1(m,16H). MSCI: 344 (MH+, base).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH:16]=2)=[CH:6][CH:5]=1.[H][H]>[Pd].CO>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(C2=CCNCCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(C2CCCNCC2)cc1
Yield: 80 %

Procedure:
A mixture of 5-(4-methoxyphenyl)-2,3,4,7-tetrahydro-1H-azepine hydrochloride (0.35 g, 1.5 mmol) and 10% palladium on carbon (0.2 g) in methanol (10 mL) was stirred overnight under balloon pressure of hydrogen. The reaction mixture was filtered through Celite and concentrated to yield 4-(4-methoxyphenyl)azepane (0.26 g, 1.2 mmol, 79%). LCMS: R.T. 0.60 min. LCMS (ES-API), m/z 206.0 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[C:3]=1[CH:15](SC1C=CC=CC=1)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Ni].C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[C:3]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=c1oc(-c2ccccc2)cc(O)c1C(CCc1ccccc1)Sc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: O=c1oc(-c2ccccc2)cc(O)c1CCCc1ccccc1

Procedure:
The title compound was prepared by Method F using Raney-Nickel (Grace 3100), ethanol (15 mL), 4-hydroxy-6-phenyl-3-[3-phenyl-1-(phenylthio)propyl]-2H-pyran-2-one (0.150 g, 0.362 mmol). m.p. 195°-196° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.73 (m, 2 H), 2.40 (t, 2 H), 2.60 (t, 2 H), 6.68 (s, 1 H), 7.23 (m, 5 H), 7.52 (m, 3 H), 7.74 (m, 2 H).