Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][C@@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[CH:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)([CH3:23])[CH3:22].[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[CH:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:10]2[CH2:11][CH2:12][C@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:14][C@@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][CH:7]=2)=[CH:26][CH:25]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1ccc(CBr)cc1
Reactant: COC(=O)[C@H]1CCN[C@@H](c2ccc(C(F)(F)F)cc2)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CCN(Cc2ccc(C(C)C)cc2)[C@@H](c2ccc(C(F)(F)F)cc2)C1
Temperature: 150 °C
Yield: 80.9 %

Procedure:
Methyl(cis)-2-[4-(trifluoromethyl)phenyl]piperidine-4-carboxylate (0.22 g), 4-isopropylbenzyl bromide (240 mg), NaI (15 mg), K2CO3 (287 mg) in DMF (2 ml) were placed in a microwave tube and the contents were heated in the microwave oven for 20 min at 150° C. The cooled mixture was dispersed between H2O and EtOAc and the organic extracts were washed with brine, dried (MgSO4) and evaporated. The crude oil was purified by chromatography on silica using 5-8% EtOAc in hexane to yield a colourless oil (260 mg, 81%) which crystallized on standing. 1H NMR (400 MHz, CDCl3) δ: 1.23 (6H, d, J 6.9), 1.71-1.81 (2H, m), 1.92 (1H, d, J 12.9), 1.97-2.04 (2H, m), 2.44-2.50 (1H, m), 2.82-2.90 (2H, m), 3.08-3.10 (1H, m), 3.25 (1H, dd, J 2.8, 11.3), 3.66 (4H, t, J 9.1), 7.14 (4H, q, J 6.3), 7.58 (4H, s); M/Z (ES+) 420 (MH+).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([CH3:23])[CH:17]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(N(CC)CC)C.[C:31]([Cl:42])(=[O:41])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].C(OC([O-])=O)([O-])=O.[Na+].[Na+]>C(Cl)Cl>[ClH:42].[C:31]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)=[CH:17][C:18]=1[CH3:23])(=[O:41])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Agent: Cl
Agent: O=C([O-])OC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)Nc1ccc(OC2CCNCC2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 114.7 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-4-(4-amino-3-methylphenyloxy)piperidine hydrochloride (0.7 g) in methylene chloride (10 ml) were added triethylamine (0.62 g) and decanoyl chloride (0.39 g) with ice-cooling and the mixture was stirred at room temperature for 1 hour. Aqueous saturated solution of sodium dicarbonate was added to the reaction mixture and the organic layer was separated. The aqueous layer was further extracted with methylene chloride (50 ml×2) and the combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the solidified residue was added trifluoroacetic acid (5 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, the resulting residue was dissolved in ethanol and conc. hydrochloric acid (0.20 ml) was added thereto. The resulting solution was concentrated under reduced pressure and the residue was washed with hexane to obtain 4-(4-decanoylamino-3-methylphenyloxy)piperidine hydrochloride (0.93 g) as white crystals, m.p. 177°-195° C.
Reaction SMILES: C(#N)C.CC1C=CC(C(C)C)=CC=1.[F:14][C:15]([F:25])([F:24])[C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(N(CC)CC)C.C(O)=O>[F:14][C:15]([F:24])([F:25])[CH:16]([OH:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: Cc1ccc(C(C)C)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC(O)C(F)(F)F
Temperature: 35 °C
Reaction time: 15 h

Procedure:
To 10 mL of acetonitrile were added 5 mL of a mixture of formic acid-triethylamine (5:2 in molar ratio), 7 mg of RuCl[(1R,2R)-p-TsNHCH(C6H5)CH(C6H5)NH2] (p-cymene), and 1.0 g of ethyl 4,4,4-trifluoro-3-oxobutanoate, and the whole was stirred at 35° C. for 15 hours, followed by concentration under reduced pressure using an evaporator. To the resulting concentrate were added 10 mL of water and 10 mL of ethyl acetate, and then a saturated sodium carbonate aqueous solution was added thereto under stirring until the pH became 7 or higher. The ethyl acetate layer separated from the aqueous layer was concentrated to obtain optically active ethyl 4,4,4-trifluoro-3-hydroxybutanoate. Upon the measurement under the above conditions, the optical purity and conversion were found to be 95.0% e.e. and 99.9%, respectively.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>C(Cl)Cl>[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:1])[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:4]=1)=[O:30]
Reactant: CN(c1cccnc1)c1cccc(N)c1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1cccnc1)c1cccc(NC(=O)c2cccc(Cl)c2)c1
Reaction time: 0.08 h
Yield: 71 %

Procedure:
Compound 17 (25 mg, 0.13 mmol, 1.0 eq) was dissolved in CH2Cl2 (1 mL) and DIEA (24 μL, 0.14 mmol, 1.1 eq) was added and the reaction stirred for 5 min. 3-Chlorobenzoyl chloride (16.1 μL, 0.125 mmol, 1.00 eq) was added and the reaction was stirred until determination of completion by LCMS. The reaction was diluted with CH2Cl2, washed with water (1×), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 30 mg (71%) of the title compound as a light-yellow solid: 1H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 8.36-8.15 (m, 2H), 7.98 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.76-7.72 (m, 1H), 7.71-7.60 (m, 4H), 7.56 (t, J=7.9 Hz, 1H), 7.44 (t, J=8.1 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 3.36 (s, 3H); ES-MS [M+1]+: 338.2.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[N:3]1.C([Mg]Cl)(C)C.CON(C)[C:15](=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][CH3:24])[CH:17]=1.Cl>C1COCC1>[CH3:24][O:23][CH2:22][C:18]1[CH:17]=[C:16]([C:15]([C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)=[O:25])[CH:21]=[CH:20][CH:19]=1
Reactant: Cn1cnnn1
Reactant: COCc1cccc(C(=O)N(C)OC)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: COCc1cccc(C(=O)c2nnnn2C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
To a stirred solution of 1-methyl-1H-tetrazole (9.35 g, 111 mmol) in anhydrous THF (360 mL), cooled to 0° C. with a brine/ice bath, was added dropwise a solution of isopropylmagnesium chloride (2 M in THF, 55.6 mL, 111 mmol). After the addition was over, the resulting cloudy suspension was stirred for 15 min at 0° C. A solution of N-methoxy-3-(methoxymethyl)-N-methylbenzamide (19.4 g, 92.6 mmol) in THF (60 mL) was then added dropwise while keeping the internal temperature below 5° C. The reaction mixture was then allowed to warm up and stirred at room temperature for 24 h. The reaction mixture was poured into a mixture of ice-cold water (150 mL) and aq. HCl (1 M, 150 mL), the layers were separated, the water phase was extracted with ethyl acetate (2×150 mL) and the combined organic layers were dried (MgSO4). Purification on silica gel afforded [3-(methoxymethyl)phenyl](1-methyl-1H-tetrazol-5-yl)methanone as an oil [7.17 g, yield 33%; HPLC/MS m/z=233 (M+H); log P(HCOOH)=2.01].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:29])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([CH:27]=[O:28])[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:30]([F:33])([F:32])[F:31])=[N:10]2)=[CH:5][CH:4]=1.[Zn](C)[CH3:35]>CCOCC.Cl[Ti](Cl)(Cl)Cl>[OH:28][CH:27]([C:24]1([C:21]2[CH:22]=[CH:23][C:18]([N:15]3[CH2:16][CH2:17][C:12]4[C:11]([C:30]([F:33])([F:31])[F:32])=[N:10][N:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[C:13]=4[C:14]3=[O:29])=[CH:19][CH:20]=2)[CH2:25][CH2:26]1)[CH3:35]
Reactant: C[Zn]C
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C=O)CC4)cc2)CC3)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C(C)O)CC4)cc2)CC3)cc1
Reaction time: 1 h
Yield: 64.5 %

Procedure:
1-{4-[1-(4-Methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-phenyl}-cyclopropanecarbaldehyde (93 mg, 0.21 mmol) was stirred in Et2O (2 mL) at −78° C. ZnMe2 (2M in toluene, 0.16 mL, 1.5 eq) was added followed by the addition of TiCl4 (1 M in CH2Cl2, 0.3 mL). The resulting mixture was stirred for 1 h. The reaction was quenched by addition of NH4Cl, extracted with EtOAc, washed with H2O and brine, dried over MgSO4, filter, and concentrated. The residue was purified by silica gel column to yield the pure desired product (62 mg, yield: 64.5%). LC/MS (ESI+) 472.6 (M+H)+, tR=2.44 min (35–95% CH3CN/H2O in a 6-min run).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:32]2([CH3:33])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:34])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:27])[C@H:18]([O:25][CH3:26])[CH2:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:35][C:36](=[O:38])[CH3:37])[CH2:6]1)(=[O:3])[CH3:2].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C@@H:5]1[C@@:32]2([CH3:33])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:34])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:27])[C@H:18]([O:25][CH3:26])[CH2:19][CH2:20][C:21]([OH:24])([CH3:22])[CH3:23])[CH2:8][C@@H:7]([O:35][C:36](=[O:38])[CH3:37])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CO[C@H](CCC(C)(C)O)[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CO[C@H](CCC(C)(C)O)[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
25.6 mg of (22R)-1α,3β-diacetoxy-25-hydroxy-22-methoxy-cholest-5-en (Vb1) was dissolved in 2 ml of carbon tetrachloride, the mixuture was refluxed under heating under an argon gas stream atmosphere, and 12 mg of N-bromosuccinimide was added to the mixture. After refluxing for 25 minutes, the mixture was cooled with ice-water, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was dissolved in 5 ml of tetrahydrofuran, and after adding thereto catalytic amount of tetra-n-butyl ammonium bromide, the mixture was stirred for 1 hour under an argon gas stream atmosphere. To the reaction mixture was added 0.17 ml of tetra-n-butyl ammonium fluoride (1M solution), and the mixture was stirred for 30 minutes at room temperature. The mixture was diluted with ethyl acetate, washed with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and water, successively, and dried over sodium sulfate. The residue was dissolved in 10 ml of acetone, and after adding thereto about 5 mg of p-toluenesulfonic acid, the mixture was stirred overnight at room temperature under an argon gas stream atmosphere, under dark condition. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was distilled away, and the residue was purified by using a column (Merck Company. Lichroprep RP-8, size A, solution; 15% watermethanol) to give 4.33 mg of (22R)-1α,3β-diacetoxy- 22-methoxy-cholest-5,7-dien-25-ol (VIb1).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].F[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1>>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:3][CH2:2][CH2:1][NH2:4]
Reactant: NCCN
Reactant: Fc1ccccn1
Product: NCCNc1ccccn1

Procedure:
Ethylenediamine (6 g, 0.1 mol) and 2-fluoropyridine (10 g, 0.1 mol) were heated neat at 120° C. overnight. The reaction was cooled and the residue was used in next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:13])([CH3:12])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:21]N>O>[NH:1]([C:2]1[C:11]([CH3:13])([CH3:12])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:21]
Reactant: CC1(C)C(N)=Nc2ccccc2C1(O)c1ccccc1
Reactant: NN
Solvent: O
Product: CC1(C)C(NN)=Nc2ccccc2C1(O)c1ccccc1
Yield: 86.3 %

Procedure:
2-Amino-3,4-dihydro-3,3-dimethyl-4-phenylquinolin-4-ol (10.0 g., 0.0375 mole) was added to anhydrous hydrazine (34g., 1.06 mole) and the solution refluxed for 51/2 hours, cooled, poured on to water, extracted with chloroform, dried and evaporated. Trituration with toluene yielded the title compound as a white solid (9.11g., m.p. 195° - 196° C) [Found: C, 72.5; H, 7.0; N, 14.8% C17H19N3O requires C, 72.6; H, 6.8; N, 14.9%]
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C.C(=O)(O)[O-]>C1COCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCCBr
Reactant: c1ccc(COc2ccc(CN3CCCNCC3)cc2)cc1
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCCN1CCCN(Cc2ccc(OCc3ccccc3)cc2)CC1
Yield: 79.7 %

Procedure:
In a manner similar as described above in Paragraph A, a solution of hexahydro-1-[[4-(phenylmethoxy)phenyl]methyl]-1H-1,4-diazepine (150 mg, 0.506 mmol) and methyl 4-bromobutanoate (0.29 mL, 2.0 mmol) in THF (6 mL) was treated with triethylamine (0.28 mL, 2 mmol) and the reaction was heated at reflux for 4 hours. The reaction was allowed to cool and treated with an aqueous bicarbonate solution. The combined ethyl acetate extracts were washed with water, dried and concentrated to give 0.16 g of methyl hexahydro-4-[[4-(phenylmethoxy)phenyl]methyl]-1H-1,4-diazepine-1-butanoate.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[CH2:7]([OH:14])[C@@H:8]([C@@H:10](CO)[OH:11])[OH:9]>S(=O)(=O)(O)O>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:14])[OH:6])[OH:4]
Reactant: OCC(O)CO
Reactant: OC[C@@H](O)[C@@H](O)CO
Agent: O=S(=O)(O)O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Separately, the polyol-type ganoderan was kept at 90°-100° C. for 1-2 hours in 0.05-0.1M sulfuric acid to obtain, as well as glycerol and erythritol, an insoluble substance. Hydrolysis of the insoluble substance gave D-glucose as sole product, while hydrolysis of a methylated polyol-type ganoderan gave a substantial amount of 2,4,6-tri-O-methyl-D-glucose. By exposure to the action of exo-beta-1,3 glucanase, only D-glucose was obtained. These facts confirm that the backbone of ganoderan consists of beta-1,3-linked D-glucopyranose residues.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:15].[F:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:22][NH:23]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[F:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([CH:26]3[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][N:4]4[C:13](=[O:14])[C:12]5[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=5)[NH:6][C:5]4=[O:15])[CH2:28][CH2:27]3)=[CH:22][NH:23]2)=[CH:19][CH:18]=1
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCl
Reactant: Fc1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2ccccc2c(=O)n1CCN1CCC(c2c[nH]c3cc(F)ccc23)CC1

Procedure:
A mixture of 7.5 parts of 3-(2-chloroethyl)-2,4(1H,3H)-quinazolinedione, 6.8 parts of 6-fluoro-3-(4-piperidinyl)-1H-indole, 10 parts of sodium carbonate, 0.1 parts of potassium iodide and 240 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. Water is added and the layers are separated. The aqueous phase is set aside. The organic phase is dried, filtered and evaporated. The solid residue is boiled in 2-propanol. The product is filtered off and dried, yielding a first fraction of 4 parts of 3-[2-[4-(6-fluoro-1H-indol-3-yl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](I)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn]([C:40]#[N:41])(CCCC)CCCC)CCC>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:40]#[N:41])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Reactant: Ic1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Agent: Cl[Pd]Cl
Agent: [Pd]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N#Cc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Yield: 73.8 %

Procedure:
(4-Benzyloxy-phenyl)-(6-iodoquinazolin-4-yl)-amine (1.2 g) in dioxane (10 ml) under N2 was treated with tributyltin cyanide (0.79 g) and catalytic quantities of 1,4-bis-(diphenylphosphino)-butane palladium (II) chloride and tetrakis (triphenylphosphine) palladium at reflux for 23 hours. The mixture was absorbed onto silica and chromatographed to give the title compound (0.65 g); δH [2H6]DMSO 10.01(1H,s), 9.14(1H,s), 8.63(1H,s), 8.15(1H,d), 7.87(1H,d), 7.73(2H,d), 7.45(5H,m), 7.10(2H,d), 5.13(2H,s); m/z (M+1)+353.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH2:24][CH:25]([CH3:27])[CH3:26])[NH:14][C:13](=[O:28])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[C:38](O)(=[O:41])[CH2:39][CH3:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[CH3:27][CH:25]([CH3:26])[CH2:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[NH:14][C:13](=[O:28])[N:12]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][C:38](=[O:41])[CH2:39][CH3:40])[CH:16]=1
Reactant: CCC(=O)O
Reactant: CC(C)COc1ccccc1-c1cc(-c2ccc3[nH]nc(N)c3c2)nc(=O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)Nc1n[nH]c2ccc(-c3cc(-c4ccccc4OCC(C)C)[nH]c(=O)n3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.3 %

Procedure:
To a solution of commercially available 4-(3-amino-1H-indazol-5-yl)-6-(2-isobutoxyphenyl)pyrimidin-2(1H)-one (60 mg, 0.15 mmol) in dimethylacetamide (4 mL) and diisopropylethylamine (130 pt, 0.76 mmol, 5 eq) was added propionic acid (56 μL, 0.76 mmol, 5 eq) followed by HATU (290 mg, 0.76 mmol, 5 eq). The reaction mixture was stirred at room temperature for 16 h. Formation of product was confirmed by LC/MS and the product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to yield 17 mg (26%) of the title compound: 1H-NMR (400 MHz, d6-DMSO): δ 11.85 (s, 1H), 8.79 (s, 1H), 8.28-8.35 (m, 1H), 7.64 (s, 1H), 7.49-7.58 (m, 1H), 7.20 (d, 1H), 7.08-7.13 (m, 1H), 6.63 (s, 2H), 4.07-4.14 (m, 1H), 3.83-3.91 (m, 2H), 3.15-3.19 (m, 1H), 2.93-3.03 (m, 2H), 1.95-2.08 (m, 1H), 1.14-1.21 (m, 3H), 0.90-0.96 (m, 6H). MS (EI) for C24H25N5O3: 431 (MH+).
Reaction SMILES: CS([Cl:5])(=O)=O.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH:20](O)[C:21]2[O:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[N:29]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>N1C=CC=CC=1>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH:20]([Cl:5])[C:21]2[O:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[N:29]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CC(O)c2nc3cnccc3o2)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(CC(Cl)c2nc3cnccc3o2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
MsCl (29 μL, 0.38 mmol) was added to a stirred solution of 4-(2-hydroxy-2-oxazolo[4,5-c]pyridin-2-yl-ethyl)piperidine-1-carboxylic acid tert-butyl ester (Preparation 7, 110 mg, 0.32 mmol) in anhydrous pyridine (5 mL) at 0° C. After 1 h, more MsCl (29 μL, 0.38 mmol) was added, then the mixture was stirred at 0° C. for an additional 1 h, before being heated under reflux for 1 h. The reaction was concentrated under reduced pressure, then the residue was purified by flash chromatography (EtOAc-IH, 7:3) to furnish the title compound: RT=3.57 min; m/z (ES+)=310.0 [M+2H-t-Bu]+.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:18][C:19]([F:44])([F:43])[CH2:20][NH:21][C:22]([C:24]1([CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[S:31][C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]>>[F:44][C:19]([F:18])([F:43])[CH2:20][NH:21][C:22]([C:24]1([CH2:38][CH2:39][CH2:40][CH2:41][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[S:31][C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:23]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Sc2ccccc21
Product: CCOC(=O)c1ccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4Sc4ccccc43)CC2)cc1

Procedure:
Step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 80 and the compound prepared in step (d) of Example 133 were used as the starting compounds. Thus, ethyl 4-[4-[4-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-thioxanthen-9-yl]butyl]piperazin-1-yl]benzoate was obtained.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[C:5](=[O:13])[N:4]([CH3:14])[CH:3]=1.[CH:15]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][C:21]=2B2OC(C)(C)C(C)(C)O2)[CH2:17][CH2:16]1.CC(=O)OCC>CCCCCC>[CH:15]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][C:21]=2[C:2]2[C:7]3[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=3[C:5](=[O:13])[N:4]([CH3:14])[CH:3]=2)[CH2:16][CH2:17]1
Reactant: Cn1cc(Br)c2c(c1=O)NC(=O)CO2
Reactant: CCS(=O)(=O)c1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cn(C)c(=O)c3c2OCC(=O)N3)c1

Procedure:
The title compound of step 2 was reacted with 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in a manner similar to Example 224, step 5. Silica gel chromatography (40-100% EA in hexane over 8 min) gave the title compound. 1H NMR: (DMSO-d6, 400 MHz) δ ppm 0.27-0.33 (m, 2H) 0.51-0.57 (m, 2H) 1.11 (t, J=7.33 Hz, 3H) 1.14-1.22 (m, 1H, partially obscured) 3.22-3.28 (m, 2H) 3.51 (s, 3H) 3.96 (d, J=7.07 Hz, 2H) 4.54 (s, 2H) 7.27 (d, J=8.84 Hz, 1H) 7.52 (s, 1H) 7.67 (d, J=2.02 Hz, 1H) 7.79-7.92 (m, 1H) 10.10 (s, 1H) LCMS: 419 (M+H)+