Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([SH:33])[CH:29]=[CH:30][C:31]=1[Cl:32]>CCCCO.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:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([S:33][C:28]4[CH:29]=[CH:30][C:31]([Cl:32])=[C:26]([Cl:25])[CH:27]=4)[CH:11]=3)[CH:6]=[CH:7][N:8]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Br)cc23)CC1
Reactant: Sc1ccc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Sc4ccc(Cl)c(Cl)c4)cc23)CC1
Temperature: 110 °C
Yield: 36.1 %

Procedure:
A mixture of 4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), 3,4-dichloro-thiophenol (165 uL, 1.3 mmol), NatBuO (0.44 g, 4.5 mmol), Pd(PPh3)4 (74 mg, 0.065 mmol) in n-BuOH (10 mL) was heated at 110° C., 3 h. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL×3), separated and dried (MgSO4), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiO2, n-pentane:ethyl acetate 9.5:0.5→8:2) to give 230 mg of the title compound as colorless oil (yield 36%). 1H NMR (CDCl3) δ 8.10-8.20 (m, 2H), 7.90 (bs, 1H), 7.65-7.75 (m, 2H), 7.10-7.55 (m, 3H), 3.50-3.65 (m, 4H), 3.20-3.30 (m, 4H), 1.50 (s, 9H).
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:33][C:32]([CH3:34])=[N:31][C:30]=2[C:35](O)=[O:36])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[S:33][C:32]([CH3:34])=[N:31][C:30]=2[C:35]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:36])=[CH:27][CH:28]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: Cc1nc(C(=O)O)c(-c2ccc(Cl)cc2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccc(Cl)cc2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(4-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: CC([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)(C)C(O)=O.C([O:34][C:35](=[O:47])[C:36]([CH3:46])([CH3:45])[CH2:37]SC1SC(N)=NC=1)C>>[CH3:37][C:36]([CH3:46])([CH2:45][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:15])=[N:10][CH:9]=1)[C:35]([OH:47])=[O:34]
Reactant: CCOC(=O)C(C)(C)CSc1cnc(N)s1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Product: CC(C)(CSc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl ester.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:12]1[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]1
Reactant: BrCc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccn2)CC1

Procedure:
Prepared from 2-(bromomethyl)pyridine and tert-butyl 1-piperazine-carboxylate using the procedure described in Step A of Intermediate 113. LC/MS: m/z (ES) 278.1 (MH)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:27]=[CH:26][C:7]2[N:8]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH2:9][CH2:10][CH2:11][CH:12]([NH:13][C:14]3[S:18][N:17]=[C:16]([CH3:19])[CH:15]=3)[C:6]=2[CH:5]=1.[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:33]Br>O1CCCC1.C(OCC)(=O)C>[F:28][C:29]([F:42])([F:43])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=1)[CH2:33][N:13]([C:14]1[S:18][N:17]=[C:16]([CH3:19])[CH:15]=1)[CH:12]1[CH2:11][CH2:10][CH2:9][N:8]([C:20]([O:22][CH:23]([CH3:24])[CH3:25])=[O:21])[C:7]2[CH:26]=[CH:27][C:4]([Br:3])=[CH:5][C:6]1=2
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: Cc1cc(NC2CCCN(C(=O)OC(C)C)c3ccc(Br)cc32)sn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C2CCCN(C(=O)OC(C)C)c3ccc(Br)cc32)sn1

Procedure:
Add sodium hydride to a stirring solution of isopropyl 7-bromo-5-(3-methylisothiazol-5-ylamino)-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate in anhydrous tetrahydrofuran at room temperature under nitrogen. After the appropriate stirring time, treat the mixture with 3,5-bis(trifluoromethyl)benzyl bromide and continue stirring for an appropriate time. Dilute the mixture with ethyl acetate, wash with water and brine and dry over sodium sulfate. Remove the solvents under reduced pressure and purify the residue by flash column chromatography on silica gel to provide the title compound.
Reaction SMILES: [CH:1]1[C:12]([OH:13])=[C:11]2[C:4]([C:5]([CH:7]=[CH:8][C:9]2=[O:10])=[O:6])=[C:3]([OH:14])[CH:2]=1.[OH-].[Na+].Cl.[C:18]([O:21][CH2:22][CH3:23])(=O)C>C(Cl)Cl.O.CCCCCC>[OH:14][C:3]1[CH:2]=[CH:1][C:12]([OH:13])=[C:11]2[C:4]=1[C:5](=[O:6])[C:7]1[CH:2]3[CH2:3][CH2:23][C:22]([O:21][CH3:18])([C:8]=1[C:9]2=[O:10])[CH:12]=[CH:1]3
Reactant: O=C1C=CC(=O)c2c(O)ccc(O)c21
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: ClCCl
Product: COC12C=CC(CC1)C1=C2C(=O)c2c(O)ccc(O)c2C1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
20.9 g (0.11 mol) of naphthazarin (8) and 28.4 g of 1-methoxy-1,3-chclohexadiene (19) (technical grade, 70%, 0.177 mol) were refluxed in 330 ml of methylene chloride (temperature oil bath 50° C.). The course of the reaction was followed by means of TLC (ethyl acetate:n-hexane, 2:5). After evaporation 330 ml of pentane was added to the residue and the solution was stirred for 5 minutes. The solution was cooled to 0° C. and filtrated. The filtrate was rinsed with 2×50 ml of petroleum ether. The yield of the yellow/brown product was 30.0 g (91%). The crystals were taken up in a solution of 22.0 g (0.55 mol) of caustic soda in 825 ml of water. During half an hour air was passed through the solution while the solution was stirred. The colour of the solution changed from green to blue. The course of the reaction was followed by means of TLC (ethyl acetate:n-hexane, 2:5). After the reaction 46.2 ml of concentrated HCl (37%) was added to the solution. The product precipitated as a red solid which was filtered off. This compound was dried on a film evaporator (2 mm Hg) and in a vacuum dessicator (over P2O5) during at least one night. The yield of the red compound (20) was 27.0 g (91%). The overall yield was 83%. Melting point 239°-241° C. 1H-NMR (90 MHz, CDCl3, TMS internal standard): δ=1.39-1.92 ppm (4H, m, CH2 --CH2), δ=3,69 ppm (3H, s, OMe), δ=4,53 ppm (1H, m, H4), δ=6.40 ppm (1H, dd, J=5.6 Hz and J=8 Hz), δ=6.64 ppm (1H, dd, J=8 Hz and J=1.5 Hz), δ=7.12 ppm (2H, s, ArH), δ=12.60 ppm (1H, s, ArOH), δ=13.06 ppm (1H, s, ArOH).
Reaction SMILES: NC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC#N)C=CC=1OC.[CH2:24]([O:26][C:27]1[CH:28]=[C:29](Br)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH3:25].[Mg].[CH3:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=[O:44])=[CH:41][C:40]=1[N+:47]([O-:49])=[O:48]>>[CH3:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]([C:29]2[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([O:26][CH2:24][CH3:25])[CH:28]=2)[OH:44])=[CH:41][C:40]=1[N+:47]([O-:49])=[O:48]
Reactant: CCOc1cc(Br)ccc1OC
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Agent: COc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1N
Agent: [Mg]
Product: CCOc1cc(C(O)c2ccc(OC)c([N+](=O)[O-])c2)ccc1OC
Yield: 42.4 %

Procedure:
(4-Methoxy-3-nitro-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol was prepared analogously to 3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile using 3-ethoxy-4-methoxy-bromobenzene (7.6 g, 33 mmol), magnesium turning (0.8 g, 33 mmol) and 4-methoxy-3-nitro-benzaldehyde (5.0 g, 27.6 mmol). The crude product was purified by flash chromatography (silica gel, CH2Cl2:EtOAc 9:1) to afford (4-methoxy-3-nitro-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol (3.9 g, 42%): 1H NMR (CDCl3) δ 7.88 (d, J=2 Hz, 1H), 7.53-7.49 (dd, J=3, 9 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 6.84 (s, 3H), 5.75 (d, J=3 Hz, 1H), 4.01 (m, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 2.30 (d, J=3 Hz, 1H), 1.44 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][NH:6][C:7]([CH:9]1[CH2:12][N:11]([C:13]2[S:14][CH2:15][C:16](=[O:18])[N:17]=2)[CH2:10]1)=[O:8].[Cl:20][C:21]1[CH:38]=[CH:37][C:24]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][C:31]([CH:35]=O)=[CH:32][CH:33]=3)[CH:28]=[N:27]2)=[C:23]([C:39]([F:42])([F:41])[F:40])[CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][NH:6][C:7]([CH:9]1[CH2:10][N:11]([C:13]2[S:14][C:15](=[CH:35][C:31]3[CH:30]=[C:29]4[C:34](=[CH:33][CH:32]=3)[N:26]([CH2:25][C:24]3[CH:37]=[CH:38][C:21]([Cl:20])=[CH:22][C:23]=3[C:39]([F:42])([F:40])[F:41])[N:27]=[CH:28]4)[C:16](=[O:18])[N:17]=2)[CH2:12]1)=[O:8]
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: COC(=O)CCNC(=O)C1CN(C2=NC(=O)CS2)C1
Product: COC(=O)CCNC(=O)C1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
3-[(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carbonyl)-amino]-propionic acid methyl ester was prepared from 3-{[1-(4-oxo-4,5-dihydro-thiazol-2-yl)-azetidine-3-carbonyl]-amino}-propionic acid methyl ester and 1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde following General Procedure D.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[C:7]=2[CH:21]=1)#[N:2].C(O)(=O)C.Cl.[H][H]>C(O)C.[Pd]>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[C:7]=2[CH:21]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)Oc2ccc(CN)cc2[C@@H](N2CCCC2=O)[C@@H]1O

Procedure:
trans-6-Cyano-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol (5 g, prepared as described in J. Med. Chem. 29, 2194 (1986)), in ethanol (375 ml) and glacial acetic acid (75 ml) containing concentrated HCl (5 ml) was shaken in the presence of 10% Pd/C (1 g) in an atmosphere of hydrogen for 4 h. The catalyst was filtered off and the solution neutralised with 10% aqueous NaOH solution, and the solution evaporated to dryness. Acid-base extraction, and drying of a dichloromethane solution of the residue, furnished, after recrystallisation from ethyl acetate-pentane, 2.03 g of the required aminomethyl compound of example 4 of mp 191°-193° C. as the hemihydrate.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[CH:6][C:5]=1[NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:3].[H][H]>CO.[Pd]>[NH2:1][C:2]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:3]
Reactant: NC(=O)c1ccc(C(=O)OCc2ccccc2)cc1NC1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1ccc(C(=O)O)cc1NC1CCCCC1
Yield: 74.2 %

Procedure:
To a solution of benzyl 4-(aminocarbonyl)-3-(cyclohexylamino)benzoate (45 mg, 0.128 mmol) in methanol (2 mL) was added palladium on carbon (10W %, Degussa type, 45 mg). The mixture was vigorously stirred under 1 atm of hydrogen for 50 minutes. The catalyst was removed by filtration through celite, and the filtrate was concentrated to provide 4-(aminocarbonyl)-3-(cyclohexylamino)benzoic acid (25 mg, 0.095 mmol, 74% yield) as a yellow powder. 1H NMR (400 MHz, CD3OD): 7.59 (d, 1H), 7.35 (s, 1H), 7.14 (dd, 1H), 3.47-3.39 (m, 1H), 2.05-1.98 (m, 2H), 1.81-1.73 (m, 2H), 1.68-1.60 (m, 1H), 1.52-1.41 (m, 2H), 1.38-1.25 (m, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11](=[O:19])[CH2:12][N:13]([OH:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][C:4]=1[Cl:20]>>[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([CH:11]([OH:19])[CH2:12][N:13]([OH:18])[C:14]([CH3:17])([CH3:15])[CH3:16])=[CH:5][C:4]=1[Cl:20]
Reactant: CC(C)(C)N(O)CC(=O)c1cc(Cl)c(N)c(C#N)c1
Agent: Cl
Product: CC(C)(C)N(O)CC(O)c1cc(Cl)c(N)c(C#N)c1

Procedure:
m.p. of the hydrochloride: 228°-230° C. (decomp.), was prepared from 4'-amino-3'-chloro-5'-cyano-2-(hydroxy-tert.butylamino)-acetophenone analogous to Example 48.
Reaction SMILES: CCN(CC)CC.[CH2:8]([N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[N:12]1)[C:9]#[CH:10].[Cl:23][C:24]1[CH:29]=[C:28]([NH2:30])[C:27](I)=[CH:26][N:25]=1.CO>CC#N.C(Cl)Cl>[NH2:30][C:28]1[CH:29]=[C:24]([Cl:23])[N:25]=[CH:26][C:27]=1[C:10]#[C:9][CH2:8][N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[N:12]1
Reactant: Nc1cc(Cl)ncc1I
Reactant: C#CCn1nc(-c2cccs2)ccc1=O
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: Nc1cc(Cl)ncc1C#CCn1nc(-c2cccs2)ccc1=O
Temperature: 80 °C
Yield: 33.7 %

Procedure:
A mixture of Et3N (200 μl, 1435 μmol), Cu(I) (10 mg, 53 μmol), PdCl2(PhP3)2 (20 mg, 28 μmol), 2-(prop-2-ynyl)-6-(thiophen-2-yl)pyridazin-3(2H)-one (90 mg, 416 μmol), and 2-chloro-5-iodopyridin-4-amine (138 mg, 542 μmol) in MeCN (1.5 mL) was heated to 80° C. under nitrogen for 1 h. The mixture was cooled to room temperature, and was loaded to a silica column. Chromatography with 0.5-5% MeOH in CH2Cl2 afforded a pink solid which was triturated with EtOAc-hexane (1:2, 10 mL) to give a pink solid as the pure product (48 mg). MS (ESI pos. ion) calc'd for C16H11ClN4OS: 342.0; found 343.1 (MH+). 1H NMR (400 MHz, Chloroform-d) δ ppm 5.18 (s, 2 H) 5.75 (br. s., 2 H) 6.64 (s, 1 H) 7.03 (d, J=9.78 Hz, 1 H) 7.11 (dd, J=5.09, 3.72 Hz, 1 H) 7.37-7.48 (m, 2 H) 7.73 (d, J=9.78 Hz, 1 H) 8.03 (s, 1 H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([Mg]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]1([CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]2[CH2:23][C:22](=[O:24])[CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:22]2([OH:24])[CH2:23][N:20]([CH:19]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:21]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4-tert-butylphenyhnagnesium bromide (11.5 mL, 2.0M (Et2O)) in toluene (50 mL) at −78° C. under argon, was added, dropwise, a solution of 1-diphenylmethyl-3-azetidinone (3) (5.0 g) in toluene (100 mL) over 30 minutes. The mixture was stirred for 4 hours at −78° C. then warmed to room temperature and partitioned between aqueous ammonium chloride solution (50 mL) and diethyl ether (3×50 mL). The combined organic fractions were washed (water, brine), dried (Na2SO4) and concentrated in vacuo. Recrystallisation from cyclohexane gave 3-(4-tert-butylphenyl)-1-diphenylmethyl-3-azetidinol (9) (6.23 g), m.p. 168-169° C. (cyclohexane). Found: C. 83.68; H, 7.97; N, 3.72. C26H29NO requires C, 84.06; H, 7.87; N, 3.77%.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1Cc2ccccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 3-neck 500 mL round-bottomed flask fitted with a condenser and an addition funnel was charged with 2.62 g (0.11 mol) of Mg turnings and 20 mL of anhydrous Et2O. Slow addition of a solution of 25.10 g (0.09 mol) of 3,5-bis(trifluoromethyl) bromobenzene in Et2O (100 mL), followed by refluxing for 30 min, gave a brown-grey solution of the aryl Grignard reagent. The solution was cooled to room temperature, filtered over a plug of Celite and evacuated to yield a brown oil. Toluene (40 mL) was added and the suspension cooled to 0° C. whereupon a solution of 2-indanone (9.22 g, 0.07 mol) in toluene (60 mL) was added dropwise to give a tan-brown slurry. This mixture was warmed to room temperature and stirred for an additional 3 hours. After cooling to a 0° C. it was quenched with 150 mL of water. Hexane (200 mL) was added and the reaction mixture neutralized with 5M HCl. The organic layer was separated, and the aqueous layer was extracted with two 50-mL portions of hexane. The combined organic layers were washed with two 50-mL portions of brine and dried over anhydrous magnesium sulfate. After filtration over Celite, the solvent was removed under vacuo yielding 21.5 g (89% based on 2-indanone) of 2-(bis-3,5-(trifluoromethyl)phenyl)indanol as an off-white solid. 1H NMR (DCDl3, 23° C., 400 Mhz): d 8.05 (s, 2H), 7.80 (s, 1H), 7.5-7.0 (M, 4H), 3.41 (m, 4H), 2.21 (s, 1H, OH). Under argon, this alcohol (21.5 g, 0.06 mol) and p-toluene-sulfonic acid monohydrate (800 mg) were dissolved in toluene (250 mL) and the solution was heated to reflux for 6 hours to afford 14.4 g, (70%) of 2-(bis-3,5-(trifluoromethyl)-phenyl) indene upon recrystallization from diethyl ether/hexane at -18° C. 1H NMR (CDCl3, 23° C., 400 Mhz): d 8.01 (s, 2H), Arf), 7.75 (s, 1H, Arf), 7.52 (d, J=7 Hz, 1H), 7.47 (d, J=7 Hz, 1H), 7.43 (s, 1H), 7.33 (dd, 2J=7 Hz, 1H), 7.27 (dd, 2J- 7 Hz, 1H), 2.83 (s, 2H). 13C NMR (CDCl3, 23° C., 100 Mhz): d 144.3 (s), 143.1 (s), 138.0 (s), 132.1 (q 2JC-F =33 Hz), 130.1 (d, JC-H =167 Hz), 127.0 (dd), JC-H =160 Hz, 2JC-H =7 Hz), 126.0 (dd, JC-H =159 Hz, 2JC-H =7 Hz)m 125.2 (brd, JC-H =162 Hz), 123.9 (dd, JC-H =156 Hz, 2JC-H =9 Hz), 123.4 (q, JC-F =273 Hz, CF3), 121.8 (dd, JC-H =160 Hz, 2JC-H =8 Hz), 120.6 (brd, JC-H =167 Hz), 38.9 (td, JC-H =127 Hz, 2JC-H =7 Hz, CH2). C,H analysis: Anal. Found (Calcd): C, 62.45 (62.20); H 3.01 (3.07).
Reaction SMILES: [CH3:1][Si:2]([CH3:48])([CH3:47])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31]C(CC(OCC)=O)[CH2:29][CH2:28]2)[CH:9]=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC(I)=C2N=C(C2CC[N:69]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])CC2)C=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC(I)=C2N=C(C2CCC(CC(OCC)=O)CC2)C=1>>[CH3:46][Si:43]([CH3:45])([CH3:44])[CH2:42][CH2:41][O:40][CH2:39][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:47])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][N:69]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[CH2:29][CH2:28]2)[CH:9]=1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Agent: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1

Procedure:
tert-Butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate, but with tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate substituted for ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([OH:9])=[O:8])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23](O)[CH2:22]2.O.N1(O)C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([O:9][C@@H:23]2[CH:24]3[CH2:27][CH2:28][N:21]([CH2:26][CH2:25]3)[CH2:22]2)=[O:8])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1ccccc1)c1csc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 44.1 %

Procedure:
2-(Benzo[b]thiophen-3-yl)-2-(phenylamino)acetic acid (I18) (295 mg, 1.04 mmol), (R)-quinuclidin-3-ol (159 mg, 1.25 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (191 mg, 1.25 mmol), and DCC (258 mg, 1.25 mmol) were dissolved in dry THF and stirred at room temperature for 15 hours. The solvent was evaporated, and the crude product was dissolved in EtOAc and washed with NaHCO3, water and brine. The organic phase was dried with Na2SO4, filtered and evaporated under vacuum. The crude product was purified by flash chromatography (DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetate (180 mg, 44% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[CH:10][C:11]([OH:16])=[C:12]([CH:15]=1)[CH:13]=O.C(OC(=O)[CH:21]=[C:22]([CH3:24])[CH3:23])C>CN(C)C=O>[CH3:21][C:22]1([CH3:24])[CH:23]=[CH:13][C:12]2[C:11](=[CH:10][CH:9]=[C:8]([F:7])[CH:15]=2)[O:16]1
Reactant: CCOC(=O)C=C(C)C
Reactant: O=Cc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C=Cc2cc(F)ccc2O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
83.1 g (0.2 mol) of potassium carbonate are added, while stirring, to a solution of 28.0 g (0.2 mol) of 5-fluoro-2-hydroxy-benzaldehyde [prepared according to Y. Suzuki and H. Takahashi, Chem. Pharm. Bull. 31, 1751 (1983)] in 500 ml of N,N-dimethylformamide. 36.3 g (0.2 mol) of 3,3-dimethylacrylic acid ethyl ester are added to the resulting viscous suspension. The reaction mixture is then stirred for 16 hours at 150° and, after cooling to room temperature, concentrated by evaporation in vacuo. Water is added to the resulting solid residue and the aqueous mixture is extracted with diethyl ether. The combined ethereal phases are washed in succession with water, 2N hydrochloric acid, 2N sodium hydroxide solution and again with water, dried over sodium sulfate and concentrated by evaporation in vacuo. The resulting oily residue is chromatographed on 1000 g of silica gel (0.040-0.063 mm) with toluene as eluant, yielding 19.5 g (55% of the theoretical yield) of 2,2-dimethyl-6-fluoro-2H-chromene in the form of a light-yellow oil.