Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13][CH2:12][CH:11]1[CH:22]=[O:23].[OH-].[Na+]>CO>[CH:22]([CH:11]1[CH2:12][CH2:13][CH:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:24])=[O:2])=[O:23]
Reactant: COC(=O)CCCCCCC1C(C=O)CCC1OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=CC1CCC(OC2CCCCO2)C1CCCCCCC(=O)O
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a solution of 2-formyl-5-(tetrahydropyran-2-yloxy)-cyclopentaneheptanoic acid methyl ester (23.64 g), described by J. Bagli and T. Bogri, Tetrahedron Letters, 3815 (1972), see also U.S. Pat. No. 3,773,795 issued November 20, 1973, in methanol (20 ml) is added 10% NaOH (33.5 ml). The reaction mixture is stirred under a nitrogen atmosphere at 40° C (bath temperature) for 18 hr. The mixture is cooled and the methanol is evaporated from the mixture. The residue is taken up in ether and the resulting mixture is washed with a small amount of water. The aqueous layer is acidified with acetic acid and extracted with ether. The ether extract is washed with water, dried and concentrated to yield the title compound, νmaxfilm 2700, 1712, 1125 and 1025 cm-1.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:11][C:12]1[C:13]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:21][CH:20]=2)=[N:14][CH:15]=[C:16]([OH:18])[CH:17]=1>N1C=CC=CC=1>[C:1]([O:18][C:16]1[CH:17]=[C:12]([Cl:11])[C:13]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:23][CH:24]=2)=[N:14][CH:15]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)Cl
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cc2Cl)cc1
Solvent: c1ccncc1
Product: CCCCCCCCOc1ccc(-c2ncc(OC(=O)CCCCCCC)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
1.2 ml (7.1 mmol) of octanoyl chloride are added dropwise at 0° C. to 1.57 g (4.7 mmol) of 3-chloro-5-hydroxy-2-(4-octyloxyphenyl)pyridine in 20 ml of pyridine, and the mixture is stirred at 0° C. for 3 hours. The mixture is subsequently poured into ice water and filtered, and the residue is purified by chromatography (silica gel/ hexane:ethyl acetate 9:1) and by recrystallization from acetonitrile, giving 1.34 g of 3-chloro-2-(4-octyloxyphenyl)pyridin-5-yl octanoate. ##STR20##
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([C:14](OCC)=[O:15])[CH2:7][CH2:8][C:9](OCC)=[O:10])C.[BH4-].[Na+].CO.Cl>C(O)(C)(C)C>[OH:15][CH2:14][CH:6]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CCC(CC(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)(C)O
Product: OCCCC(CO)CCO

Procedure:
To a solution of 3-ethoxycarbonylhexanedioic acid diethyl ester (10 g, 0.036 mol) in tert-butanol (100 mL) was added sodiumborohydride (6 g). The mixture was heated to reflux. Methanol (10 mL) was added in 3 aliquots over 30 minutes. The solution was heated at reflux for a further 30 minutes and allowed to cool. The solution was neutralised with 5 M hydrochloric acid with care. The solution was filtered and extracted with ethanol (2×50 mL). The solutions were combined and the solvent was removed at reduced pressure. The residue was extracted with ethanol (60 mL), filtered and concentrated at reduced pressure to yield the desired product as a clear, colourless liquid. This was analysed by NMR in D2O and found to be 3-hydroxymethylhexane-1,6-diol in a yield of 4.5 g (85%).
Reaction SMILES: C([O:8][C:9]1[C:17]([O:18][CH2:19]C)=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)C1C=CC=CC=1.C(OC1C(OC)=CC=C2C=1C=CN2)C1C=CC=CC=1>>[OH:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2
Reactant: CCOc1ccc2[nH]ccc2c1OCc1ccccc1
Agent: COc1ccc2[nH]ccc2c1OCc1ccccc1
Product: COc1ccc2[nH]ccc2c1O
Yield: 90 %

Procedure:
This compound is obtained according to the operating method described in Example 1d, in which the 4-benzyloxy-5-ethoxyindole is replaced with 4-benzyloxy-5-methoxyindole. A white powder (yield=90%, m.p.=146° C., decomposition) is obtained.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]([O:12]C)=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:14](#[N:16])[CH3:15]>C1COCC1>[O:12]=[C:10]([CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:15][C:14]#[N:16]
Reactant: CC#N
Reactant: COC(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)Cc1ccccc1
Temperature: 25 °C
Yield: 26.1 %

Procedure:
To a suspension of 60% sodium hydride in mineral oil (1.00 g, 25.0 mmol) in THF (40 mL) at reflux is added a solution of methyl phenylacetate (2.50 g, 16.6 mmol) and anhydrous acetonitrile (1.74 mL, 33.3 mmol) in THF (40 mL), dropwise. The mixture is stirred at reflux for 6 h, then cooled to room temperature and stirred an additional 16 h. The reaction is quenched with H2O and is stirred for 10 min, after which the mixture is diluted with ethyl acetate and saturated aqueous NaHCO3 solution. The layers are separated and the aqueous layer is extracted with ethyl acetate. The organic layers are washed with brine and dried (Na2SO4). The solvent is removed in vacuo and the crude material is purified via flash column chromatography using a gradient elution of 0-40% ethyl acetate/heptane to afford the title compound as a yellow oil (690 mg, 26%). LCMS: 160.20 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([C:14](=O)[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11]([CH3:13])[N:12]=2)[CH:5]=[N:6][CH:7]=1.[CH3:24][NH:25][NH2:26]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([C:14]3[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:25]([CH3:24])[N:26]=3)=[C:11]([CH3:13])[N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CNN
Reactant: CCOC(=O)C(=O)CC(=O)c1sc(-c2cncc(F)c2)nc1C
Solvent: CCO
Product: CCOC(=O)c1cc(-c2sc(-c3cncc(F)c3)nc2C)nn1C
Yield: 17.5 %

Procedure:
Ethyl 4-[2-(5-fluoropyridin-3-yl)-4-methyl-1,3-thiazol-5-yl]-2,4-dioxobutanoate (6.9 g, 20.5 mmol) and methylhydrazine (0.65 g, 20.5 mmol) were heated in ethanol (250 ml) under reflux for 2 h. The product formed was filtered off with suction and the solvent of the filtrate was removed under reduced pressure. The residue was chromatographed on silica gel (cyclohexane/ethyl acetate eluent). This gave a total of 1.24 g (17% of theory) of ethyl 3-[2-(5-fluoropyridin-3-yl)-4-methyl-1,3-thiazol-5-yl]-1-methyl-1H-pyrazole-5-carboxylate. As a by-product, 4.8 g (67% of theory) of ethyl 5-[2-(5-fluoropyridin-3-yl)-4-methyl-1,3-thiazol-5-yl]-1-methyl-1H-pyrazole-3-carboxylate were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)[OH:13])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][C:33]([Cl:39])=[CH:34][CH:35]=2)[N:30]=1>CC(C)=O>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][C:33]([Cl:39])=[CH:34][CH:35]=3)[N:30]=2)[CH:15]=1)[OH:13])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccccc1CCC(O)c1cccc(O)c1
Reactant: Clc1ccc2ccc(CBr)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccccc1CCC(O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Yield: 93.8 %

Procedure:
A mixture of the phenol of Step 4 (3.322 g, 12.3 mmol), K2CO3 (4.08 g, 29.5 mmol) and 2-(bromomethyl)-7-chloroquinoline (3.771 g, 14.7 mmol) in 60 mL of acetone was heated to reflux for 8 h. CD2Cl2 (100 mL) was added and the mixture was filtered through silica with EtOAc. Flash chromatography of the residue on silica using EtOAc:toluene 15:85 and 20:80 afforded 5.145 g (94%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:8]([C:5]1[N:6]=[CH:7][C:2]([C:19]2[CH:24]=[N:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(Br)cn1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
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: Cc1ccccc1
Product: CC(=O)c1ccc(-c2ccc(C#N)nc2)cn1
Temperature: 77.5 °C
Reaction time: 6 h
Yield: 80.6 %

Procedure:
To a stirred solution of 1-(5-bromopyridin-2-yl)ethanone (0.2 g, 1 mmol) in toluene (10 mL) and ethanol (5 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (0.46 g, 2 mmol) and Pd(PPh3)4 (0.057 g, 0.05 mmol). The reaction mixture was purged with argon for 5 min, 2M Na2CO3 solution (3.5 mL, 0.74 g, 7 mmol) was added, and the reaction mixture was stirred at 75-80° C. for 6 h. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution (2×100 mL), and extracted into ethyl acetate (2×100 mL). The organic layer was washed with brine and ice-cold water (2×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (100-200μ silica gel, using 15-16% ethyl acetate in hexane) to obtain 6′-acetyl-[3,3′-bipyridine]-6-carbonitrile as white solid (0.18 g, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.24 (dd, 1H), 9.20 (dd, 1H), 8.54 (dd, 1H), 8.46 (dd, 1H), 8.23 (dd, 1H), 8.09 (dd, 1H), 2.68 (s, 3H); LC-MS m/z calculated for [M+H]+ 224.07. found 224.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[C:4]([Cl:11])[C:3]=1[OH:12].C(N(CC)CC)C.[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:33]([Si:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[O:10][CH2:9][CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([OH:12])=[C:4]([Cl:11])[CH:5]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: OCCc1cc(Cl)c(O)c(Cl)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCc1cc(Cl)c(O)c(Cl)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
A solution of 2,6-dichloro-4-(2-hydroxy-ethyl)-phenol (16) (2.0 g, 9.66 mmol) in methylene chloride (20 mL) at 25° C. was treated with triethylamine (1.35 mL, 9.66 mmol) and tert-butyl diphenylsilylchloride (2.48 mL, 9.66 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was diluted with methylene chloride. The organics were washed with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95:5 petroleum ether/ethyl acetate) afforded 4-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-2,6-dichloro-phenol (70) (2.60 g, 60%) as a pale yellow oil; HRMS m/e calcd for C24H26Cl2O2Si (M+Na)+ 467.0971, found 467.0977. Exact Mass=444.1079; Molecular Weight=445.47.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O:45]1[CH2:50][CH2:49][CH:48](O)[CH2:47][CH2:46]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH:48]4[CH2:49][CH2:50][O:45][CH2:46][CH2:47]4)=[CH:23][CH:24]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1
Reactant: OC1CCOCC1
Reactant: N#Cc1c(-c2ccc(O)cc2)nn2c1NCCC2c1ccccc1N
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1c(-c2ccc(OC3CCOCC3)cc2)nn2c1NCCC2c1ccccc1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 12 %

Procedure:
To a solution of 7-(2-aminophenyl)-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carbonitrile (33 mg, 0.1 mmol) in THF (5 mL) was added PPh3 (78.6 mg, 0.25 mmol) and tetrahydro-2H-pyran-4-ol (10 mg, 0.1 mmol). Then, DIAD (51 mg, 0.25 mmol) was added dropwise to the mixture at 0° C. and stirred at 0° C. for 10 min under N2. The mixture was allowed to warm to it and stirred at RT for 16 hr. The mixture was concentrated in vacuum and partitioned between DCM (20 mL) and brine (20 mL). Organic layer was separated from aqueous layers, dried over sodium sulfate and purified by Pre-TLC (DCM/CH3OH=10/1) to afford 5 mg (12%) of 7-(2-aminophenyl)-2-(4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J=8.4 Hz, 2H), 7.66-7.58 (m, 2H), 7.58-7.52 (m, 1H), 7.03 (d, J=8.4 Hz, 2H), 6.97 (t, J=7.6 Hz, 1H), 6.69 (d, J=8.0 Hz, 1H), 6.49 (t, J=7.6 Hz, 1H), 6.23 (d, J=8.0 Hz, 1H), 5.63 (s, 1H), 5.21 (s, 2H), 4.66-4.56 (m, 1H), 3.90-3.79 (m, 2H), 3.54-3.43 (m, 2H), 3.25-3.18 (m, 1H), 2.97-2.86 (m, 1H), 2.21-2.07 (m, 2H), 2.02-1.92 (m, 2H), 1.65-1.50 (m, 2H). MS (ESI) m/e [M+1]+ 415.9.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[CH:29]=O>>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[CH2:29][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cc2ccccc2o1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cc5ccccc5o4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1-benzofuran-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1-benzofuran-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: COC1C=CC(C[N:10]2[C:15](=[O:16])[CH:14]=[C:13]3[CH2:17][CH2:18][CH2:19][O:20][C:12]3=[N:11]2)=CC=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[N:11]1[NH:10][C:15](=[O:16])[CH:14]=[C:13]2[CH2:17][CH2:18][CH2:19][O:20][C:12]=12
Reactant: COc1ccc(Cn2nc3c(cc2=O)CCCO3)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc2c(n[nH]1)OCCC2
Temperature: 70 °C
Yield: 88.5 %

Procedure:
2-{[4-(Methyloxy)phenyl]methyl}-6,7-dihydro-2H-pyrano[2,3-c]pyridazin-3(5H)-one (2.75 g, 10.1 mmol) was treated with anisole (10 ml) and TFA (100 ml) and heated at 70° C. for 24 hours. The solution was cooled and evaporated and the residue taken up in 2.5% methanol/dichloromethane. This was applied to a column of silica, and then elution with this solvent mixture followed by 5% methanol/dichloromethane gave the product as an off white solid (1.36 g, 88%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.C(=O)([O-])[O-].[K+].[K+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[CH:6]2[CH2:10][CH2:9][CH2:8][N:7]2[C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: C1CNC(C2CCCN2)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCC2C2CCCN2c2ccc([N+](=O)[O-])cc2)cc1
Yield: 37.5 %

Procedure:
2.6 g (˜15 mmol) of [2,2′]bipyrrolidinyl (1) obtained above were refluxed in the presence of 5 g (35.7 mmol) of potassium carbonate and 5 g (35.7 mmol) of para-fluoronitrobenzene in 25 ml of water overnight. The agglomerate formed was filtered off and then rinsed with acetone and isopropanol to give 2.15 g of a mixture of two isomers (55/45) (44%). After purification by chromatography on silica gel, a majority isomer was isolated (1.2 g), the analyses for which were:
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:12])=[CH:7][CH:6]=1)(=O)C.C(N)C1C=CC=CC=1>C(O)C.C(Cl)(Cl)Cl>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([O:13][CH:14]([CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:12])=[CH:9][CH:10]=1
Reactant: CCCCCCC(CC)OC(=O)c1ccc(OC(C)=O)cc1
Solvent: CCO
Solvent: NCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCC(CC)OC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
The crude final product (2) (1.9 g) was dissolved in 50 ml of ethanol, and 4 g of benzylamine was added dropwise. The mixture was stirred at room temperature for 4 hours, then diluted with 500 ml of chloroform, washed with dilute hydrochloric acid and water in this sequence, and dried over magnesium sulfate. After the solvent was evaporated, the solid was purified by silica gel column chromatography to obtain 1.1 g of a final product (3).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=O.N1CCCCC1>C(O)(=O)C>[O:10]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[CH:11][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: O=C1CCc2ccccc21
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C=C2Cc3ccccc3C2=O)cc1

Procedure:
A mixture of indan-1-one (3.3 g), methyl 4-formylbenzoate (5.0 g), piperidine (0.6 ml) and glacial acetic acid (0.5 ml) was heated on a steam bath for 3 hours. The solid mass obtained was boiled up in industrial methylated spirits (200 ml) and then hot filtered. The solid residue obtained was washed with industrial methylated spirits and dried to give methyl 4-(1-oxoindan-2-ylidenemethyl)benzoate, m.p. 194-198° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[CH3:19][Si:20]([CH3:42])([CH3:41])[CH2:21][CH2:22][O:23][C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=1)=[O:25].C([O-])(O)=O.[Na+].ClCCl>CCOC(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].CCO.C1(C)C=CC=CC=1>[CH3:19][Si:20]([CH3:42])([CH3:41])[CH2:21][CH2:22][O:23][C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[C:32]([C:33]1[CH:34]=[CH:35][C:36]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[O:10][C:11]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=4[N:13]=3)=[CH:4][CH:3]=2)=[CH:37][CH:38]=1)=[O:40])=[O:25]
Reactant: C[Si](C)(C)CCOC(=O)[C@@H]1CCCC[C@H]1C(=O)c1ccc(Br)cc1
Reactant: Cc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc2oc(Nc3ccc(-c4ccc(C(=O)[C@@H]5CCCC[C@H]5C(=O)OCC[Si](C)(C)C)cc4)cc3)nc2c1
Temperature: 90 °C
Yield: 50.2 %

Procedure:
N-(4-Bromophenyl)-5-methyl-1,3-benzoxazol-2-amine (76.70 mg, 0.25 mmol) and trans-2-(trimethylsilyl)ethyl-2-(4-bromobenzoyl)cyclohexanecarboxylate (105.45 mg, 0.23 mmol) were combined in a clean dry flask under argon. Toluene (25 mL), EtOH (8 mL), and saturated aqueous NaHCO3 (5 mL) were added, and the resulting solution was degassed by bubbling with argon for 30 minutes. Then, [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II), 1:1 complex with dichloromethane (18.78 mg, 0.02 mmol) was added, and the resulting mixture was heated at 90° C. for 16 h. The reaction mixture was then diluted with EtOAc and passed through a Celite® pad, and the solvent was removed by rotary evaporation. Silica gel chromatography (Biotage cartridge), eluting with 25% EtOAc in hexane gave trans-2-(trimethylsilyl)ethyl-2-({4′-[(5-methyl-1,3-benzoxazol-2-yl)amino]biphenyl-4-yl}carbonyl)cyclohexanecarboxylate (64 mg, 50%). 1H NMR (400 MHz, CD2Cl2) δ−0.013 (s, 9H), 0.88 (m, 2H), 1.41 (m, 3H), 1.71˜2.15 (m, 5H), 2.44 (s, 3H), 2.73 (m, 1H), 3.88 (m, 1H), 4.08 (m, 2H), 7.08 (d, 1H), 7.21 (s, 1H), 7.33 (d, 1H), 7.67 (m, 2H), 7.69 (m, 2H), 7.73 (m, 2H), 7.89 (m, 1H), 7.91 (m, 1H).
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH2:9]1[CH2:13]O[CH2:11][CH2:10]1>>[OH:7][C:4]1([C:11]#[C:10][C:9]2[CH:13]=[CH:3][CH:2]=[CH:1][CH:6]=2)[CH:5]=[CH:6][C:1](=[O:8])[CH:2]=[CH:3]1
Reactant: O=C1C=CC(=O)C=C1
Reactant: C1CCOC1
Product: O=C1C=CC(O)(C#Cc2ccccc2)C=C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 31 %

Procedure:
Benzoquinone (6.3 g, 0.006 mole) was dissolved in 25 mL of dry THF and placed under nitrogen. The reaction was cooled to -78° C. and the solution prepared above was added slowly. The reaction was stirred at -78° C. for 1.5 hr and quenched with ammonium chloride solution. The mixture was extracted with ether, the ether phase washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.91 g of a brown oil which crystallized while under vacuum. The crystals were further purified by flash column chromatography on silica using 1:4 EtOAc/hexane. The compound-bearing fractions were combined and concentrated in vacuo to yield 31% of the title 1,2-1,4 adduct.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[N:7]=[C:8]([NH:10][C@H:11]3[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]3)[S:9][C:5]=2[CH:4]=1.Cl.O1CCOCC1>CO.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[N:7]=[C:8]([NH:10][C@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)sc2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2nc(N[C@H]3CCCNC3)sc2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of (S)-tert-butyl 3-(6-methoxybenzo[d]thiazol-2-ylamino)piperidine-1-carboxylate (3.35 g, 9.22 mmol) in methanol/dioxane (3 ml/3 ml) was added slowly 4M HCl in dioxane (60 ml, 240 mmol) [Caution: gas development!]. The reaction mixture was stirred 2.5 hours at ambient temperature and concentrated in vacuo in order to remove methanol and half of dioaxane. The residue was suspended in diethylether (50 ml). The solids were filtered off, washed with diethylether (50 ml) and dried in vacuo to give (S)-6-methoxy-N-(piperidin-3-yl)benzo[d]thiazol-2-amine as its hydrochloride salt as white solid. Yield: 4.29 g. ES/MS m/z 264.1 (MH+), Rt=1.62 min.