Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1)[CH:3]1[CH2:8][CH2:7][C:6]2([CH2:13][C:12](=[O:14])[C:11]3[CH:15]=[C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:18][C:10]=3[O:9]2)[CH2:5][CH2:4]1.C1C2C(=CC=CC=2)CCN1C1CCC2(CC(O)C3C=C(NS(C)(=O)=O)C=CC=3O2)CC1>>[CH3:1][N:2]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=1)[CH:3]1[CH2:8][CH2:7][C:6]2([CH2:13][CH:12]([OH:14])[C:11]3[CH:15]=[C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:18][C:10]=3[O:9]2)[CH2:5][CH2:4]1
Reactant: CN(Cc1ccc(C#N)cc1)C1CCC2(CC1)CC(=O)c1cc(NS(C)(=O)=O)ccc1O2
Agent: CS(=O)(=O)Nc1ccc2c(c1)C(O)CC1(CCC(N3CCc4ccccc4C3)CC1)O2
Product: CN(Cc1ccc(C#N)cc1)C1CCC2(CC1)CC(O)c1cc(NS(C)(=O)=O)ccc1O2

Procedure:
Prepared from the product of example 8 (N-[N'-Methyl-N'(p-cyanobenzyl)-4'-amino-3,4-dihydro-4-oxospiro[2H-1-benzopyran-2,1'-cyclohexan]-6-yl]methanesulfonamide) by a procedure identical to that already described for the preparation of the product of Example 2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].[NH2:13][C:14]1[C:23](Cl)=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>O1CCCC1>[NH2:13][C:14]1[C:23]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: Nc1nc2ccccc2nc1Cl
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2nc3ccccc3nc2N)cc1
Yield: 76 %

Procedure:
According to Step 2 of Reference Example 7-1, by use of 4-methoxybenzyl alcohol (625 μL, 5.01 mmol), 60% sodium hydride (in oil) (200 mg, 5.01 mmol), tetrahydrofuran (6.0 mL) and 2-amino-3-chloroquinoxaline (300 mg, 1.67 mmol), the mixture was stirred and reacted at room temperature for 17 hours. Then, slurry purification was performed using diisopropyl ether, to give 2-amino-3-[(4-methoxyphenyl)methoxy]quinoxaline (Compound BB) (357 mg, yield: 76%).
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][NH:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]1[C:15]1([C:18]([OH:20])=O)[CH2:17][CH2:16]1.[NH2:21][C:22]1[CH:23]=[C:24]2[CH2:40][C:29]3([O:34][C:33]4[CH:35]=[CH:36][CH:37]=[N:38][C:32]=4[NH:31][C:30]3=[S:39])[CH2:28][C:25]2=[N:26][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[O:2]=[C:3]1[CH2:8][NH:7][CH:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][N:4]1[C:15]1([C:18]([NH:21][C:22]2[CH:23]=[C:24]3[CH2:40][C:29]4([O:34][C:33]5[CH:35]=[CH:36][CH:37]=[N:38][C:32]=5[NH:31][C:30]4=[S:39])[CH2:28][C:25]3=[N:26][CH:27]=2)=[O:20])[CH2:16][CH2:17]1
Reactant: Nc1cnc2c(c1)CC1(C2)Oc2cccnc2NC1=S
Reactant: O=C1CNC(c2ccccc2)CN1C1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C1CNC(c2ccccc2)CN1C1(C(=O)Nc2cnc3c(c2)CC2(C3)Oc3cccnc3NC2=S)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-(2-oxo-5-phenylpiperazin-1-yl)cyclopropanecarboxylic acid hydrochloride (57 mg, 0.22 mmol) [Wood et al. US 2007/0265225], 3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,2′-pyrido[3,2-b][1,4]oxazine]-3′(4′H)-thione (Intermediate 1, 57 mg, 0.20 mmol) and HATU (84 mg, 0.22 mmol) in DMF (2 mL) is treated with N-methylmorpholine (0.096 mL, 0.88 mmol). The mixture is stirred at rt for 18 h and is then purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and lyophilized to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19](=O)[CH3:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[Li].[H-]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCC(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Agent: [H-]
Agent: [Li]
Solvent: C1CCOC1
Product: CCN1CCC(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To a stirring suspension of 4-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-1-acetylpiperidine (0.11 mmol,41.4 mg) in THF (1.0 mL) was added lithium alumininum hydride (0.14 mmol, 0.14 mL of a 1M solution in THF) and the reaction stirred at room temperature for 2 h. The reaction was then quenched with water (0.1 mL), diluted with ethyl acetate (25 mL), the suspension filtered, the filtrates dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The residue was triturated with diethyl ether to give 25 mg of the title compound as a white powder.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][C:16](=[O:18])[CH3:17])([O:3]C)=[O:2].[C:19](OCC)(=[O:25])[C:20](OCC)=[O:21].[Na]>C(O)C>[C:1]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH:15]1[C:20](=[O:21])[C:19](=[O:25])[CH2:17][C:16]1=[O:18])([OH:3])=[O:2]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COC(=O)CCCc1ccccc1CCC(C)=O
Agent: [Na]
Solvent: CCO
Product: O=C(O)CCCc1ccccc1CC1C(=O)CC(=O)C1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
A solution of 96 g (0.44 mol) of 4-[2-(3-carbomethoxypropyl)phenyl]-2-butanone, 10, and 129 g (0.88 mol) of diethyl oxalate was added dropwise at room temperature to a solution made by dissolving 20.2 g (0.88 g-atm) sodium in 200 ml absolute ethanol. After the addition was complete, the reaction was stirred 1 hour at room temperature and 1 hour at 50° C. It was then concentrated, the residue taken up in H2O, and acidified with 70 ml concentrated HCl. The precipitated material was extracted into ether and washed twice with H2O. The acidic material was then extracted out of this ether phase with aqueous sodium carbonate solution. Upon acidification of the sodium carbonate solution a red oil separated. This oil was heated overnight in a solution of 200 ml concentrated HCl and 200 ml methanol. The reaction mixture was diluted with 300 ml H2O and extracted with ether. Evaporation of the ether gave 70 g of red oil. This was chromatographed on 400 g silicic acid and eluted with benzene:ethanol. Like fractions were combined and crystallized. Recrystallization from benzene gave 23 g of the trione acid 11, mp 123° C.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[NH:3][C:2]1=S.C(Cl)[Cl:12].S(Cl)(Cl)(=O)=O.[OH-].[Na+]>O>[Cl:12][C:2]1[S:1][C:9]2[C:4]([N:3]=1)=[N:5][CH:6]=[CH:7][N:8]=2
Reactant: ClCCl
Reactant: S=c1[nH]c2nccnc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Product: Clc1nc2nccnc2s1
Temperature: 40 °C
Yield: 53 %

Procedure:
A mixture of 3H-thiazolo[4,5-b]pyrazine-2-thione (4.36 g, 25.8 mmol) and DCM (60 mL) was sonicated (5 min). The suspension was treated with sulfuryl chloride (99.9 g, 740 mmol, 60 mL) and heated (40° C., 16 h). The reaction mixture was cooled (0° C.) and slowly treated with H2O (250 mL), followed by 4 N NaOH (550 mL). The aqueous mixture was extracted with EtOAc (2×1800 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the title compound as a solid (2.63 g, 53%). MS (ESI): mass calculated for C5H2ClN3S, 170.9; m/z found, 172.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 8.84 (d, J=2.5, 1H), 8.75 (d, J=2.5, 1H).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][N:6]([CH3:12])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11]>CO>[C:1]([CH2:2][CH2:3][NH:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]([CH3:12])[CH3:5])#[N:4]
Reactant: CN(C)CCCCN
Reactant: C=CC#N
Solvent: CO
Product: CN(C)CCCCNCCC#N
Temperature: 0 °C
Yield: 80 %

Procedure:
A solution of acrylonitrile (1.17 g, 22.07 mmol) in methanol (1.0 ml) was added dropwise to a solution of N,N-dimethyl-1,4-diaminobutane 322 (2.1 g, 18.42 mmol) in methanol (1.0 ml) at 0° C., and the mixture was stirred at 0° C. for sixteen hours. Evaporation of the solvent in vacuo afforded almost pure N-(2-cyanoethyl)-N',N'-dimethyl-1,4-diaminobutane 323 as a colorless oil (2.5 g, 80% yield based on 322). 1H NMR (400 MHz, CDCl3) δ: 1.45 (4H, m, --CH2 --CH2 --CH2 --CH2 --), 2.15 (6H, s, --N(CH3)2), 2.22 (2H, t, --CH2N), 2.47 (2H, t, --CH2CH2CN), 2.60 (2H, t, --CH2CH2NH--), 2.88 (2H, t, --CH2CH2NH--), 3.37 (1H, s, --NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH2:15][OH:16])=[CH:13][N:12]=[C:11]([NH:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:10]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH:15]=[O:16])=[CH:13][N:12]=[C:11]([NH:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:10]=1
Reactant: CC(C)(C)OC(=O)NCCNc1ncc(CO)c(-c2ccc(Cl)cc2Cl)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNc1ncc(C=O)c(-c2ccc(Cl)cc2Cl)n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Using the method of Swern, et al., 100 mg of N-(2-{[4-(2,4-dichlorophenyl)-5-(hydroxymethyl)pyrimidin-2-yl]amino}ethyl)(tert-butoxy)carboxamide was dissolved in 1 mL of anhydrous methylene chloride and added to a solution of oxalyl chloride (30.7 μL, 0.363 mmol) and DMSO (51.6 μL, 0.726 mmol) which had been stirring at −78° C. for 15 min. The resulting solution was stirred for an additional 30 min, at which time 202 μL (1.45 mmol) of triethyl amine was added. The resulting suspension was allowed to warm to room temperature after 15 min and 1 mL of water was added and the layers separated. The aqueous layer was extracted with methylene chloride and the combined organic layers dried (sodium sulfate) and concentrated to afford N-(2-{[4-(2,4-dichlorophenyl)-5-formylpyrimidin-2-yl]amino}ethyl)(tert-butoxy)carboxamide as a light yellow foam. This product proved to be air sensitive and was used without further manipulation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)[S:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1.C(O)(C(F)(F)F)=O.CCOCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[S:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1
Reactant: CC(C)c1nnc2ccc(-c3sc(C4CCN(C(=O)OC(C)(C)C)CC4)nc3-c3ccc(F)cc3F)nn12
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nnc2ccc(-c3sc(C4CCNCC4)nc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 19 h
Yield: 76.1 %

Procedure:
A 100 mL flask was charged with tert-butyl 4-(4-(2,4-difluorophenyl)-5-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiazol-2-yl)piperidine-1-carboxylate (1.05 g, 1.94 mmol, prepared using General Procedure O from Preparation #A.2 and tert-butyl 4-(aminocarbothioyl) tetrahydropyridine-1-(2H)-carboxylate) in DCM (10 mL) to give a yellow solution. To the solution was added TFA (1.50 mL, 19.4 mmol) and the mixture was stirred at ambient temperature. After about 19 h, the reaction was concentrated under reduced pressure to give a yellow oil which was redissolved in DCM and washed sequentially with 10% aqueous NaOH, water, and brine. The organic solution was dried over MgSO4, filtered, and concentrated to dryness under reduced pressure to give a yellow oil. Upon addition of Et2O, a cloudy solution was formed. Concentration of this solution yielded the title compound as a yellow powder (0.65 g, 76%): LC/MS (Table 1, Method a) Rt=1.54 min; MS m/z: 441.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH:6]=[CH:5][CH2:4]1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>N1C=CC=CC=1>[CH:3]1([CH2:2][O:1][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH:6]=[CH:5][CH2:4]1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCC1CC=CC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(OCC1CC=CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 91 %

Procedure:
To a stirred, cooled (0° C.) solution of 4-hydroxymethylcyclopentene (J.-P. Depres and A. E. Green, J. Org. Chem. 1984, 49, 928-931, and references therein) (37.0 g, 276 mmol) in pyridine (450 mL) was added benzoylchloride (32.1 mL, 276 mmol) over 30 minutes. The resulting mixture was stirred at room temperature for 1.25 hours. Water (50 mL) was added and the volatiles removed in vacuo. The residual oil was dissolved in chloroform and the solution extracted with water and then dried over sodium sulfate. Evaporation of solvent gave (3-cyclopenten-1-yl)methylbenzoate as a yellow oil (53.94 g, 91%), sufficiently pure for use; 1H-NMR (DMSO-d6) δ: 7.98, 7.67, 7.56 (m, 5, C6H5), 5.72 (s, 2, CH=CH), 4.19 (m, 2, OCH2), 2.71 (m, 1, CH), 2.56-2.77 (m, overlapping solvent, 2CH), 2.21-2.14 (m, 2,2CH).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12]CC1C=CC=CC=1)(=[O:4])=[O:3].B(F)(F)F.CCOCC.CSC>C(Cl)Cl>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Oc1ccccc1OCc1ccccc1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Solvent: CCOCC
Product: CS(=O)(=O)Oc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
2-(Benzyloxy)phenyl methanesulfonate (4.00 g, 14.37 mmol) was dissolved in dry DCM (50 mL) under nitrogen atmosphere. Boron trifluoride diethyl etherate (8.16 g, 57.49 mmol) was added followed by dimethyl sulfide (3.57 g, 57.49 mmol) and the reaction mixture was stirred at rt overnight. The reaction mixture was poured onto ice and the aqueous layer was extracted with DCM. The organic layers were combined, washed with water, dried (Na2SO4), filtered and evaporated to give the title compound (2.49 g, 92%). 1H NMR (500 MHz, CDCl3): δ 3.26 (s, 3H), 6.16 (s, 1H), 6.96 (dt, 1H), 7.09 (dd, 1M), 7.22-7.28 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 37.74, 119.01, 121.65, 123.71, 129.09, 136.99, 148.43; Mass Spectrum: M−H+ 187.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([N:23]=[C:24]=[S:25])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:10][C:9]=2[S:19]([OH:22])(=[O:21])=[O:20])([OH:4])(=[O:3])=[O:2].[Na:26].C[N:28](C)CC=C>O>[S:1]([C:5]1[CH:6]=[C:7]([NH:23][C:24]([NH2:28])=[S:25])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15]([OH:18])(=[O:16])=[O:17])=[CH:10][C:9]=2[S:19]([OH:22])(=[O:21])=[O:20])([OH:4])(=[O:3])=[O:2].[Na:26]
Reactant: C=CCN(C)C
Reactant: O=S(=O)(O)c1cc(N=C=S)c2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2c1
Agent: [Na]
Solvent: O
Product: NC(=S)Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12

Procedure:
Solid sodium 3,6,8-trisulfonaphthylisothiocyanate (250 mg; 0.5 mmol) was added to a solution of PAMAM 4.0 (51 mg; 0.01 mmol) and N,N-dimethyl-N-allylamine buffer (pH 9.5; 1 ml) in water (2 ml) and the mixture heated under nitrogen at 53° for two hours and then cooled. The mixture was concentrated under reduced pressure to give an orange solid. The residual solid was dissolved in water (2 ml) and passed through a short column of Amberlite IR-120(Na). The filtrate was then concentrated and the residue purified by gel filtration (Sephadex LH20; water). The pure fractions were combined and freeze dried to give the sodium 3,6,8-trisulfonaphthylthiourea terminated PAMAM 4.0 dendrimer as an off-white solid (102 mg). 1H nmr (D2O): δ2.65; 3.02; 3.30; 3.66; 8.05; 8.42; 8.59; 8.67. 13C nmr (D2O): δ33.2; 38.7; 43.2; 43.7; 47.8; 54.0; 54.3; 56.7; 131.0; 131.3; 131.9; 135.9; 138.0; 139.6; 143.8; 144.1; 145.6; 176.2; 176.5; 186.0.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][N:22]1[CH2:27][CH2:26][NH:25][C:24](=[O:28])[C:23]1([CH3:30])[CH3:29])C1C=CC=CC=1>CO>[CH3:29][C:23]1([CH3:30])[N:22]([CH2:21][C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)[CH2:27][CH2:26][NH:25][C:24]1=[O:28]
Reactant: CC1(C)C(=O)NCCN1C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: CO
Product: CC1(C)C(=O)NCCN1C[C@H]1CNCCN1
Yield: 97 %

Procedure:
4-(((2R)-1,4-dibenzyl-2-piperazinyl)methyl)-3,3-dimethyl-2-piperazinone (0.500 g, 1.23 mmol) was dissolved in MeOH (25 mL). This solution was passed through an H-Cube™ flow hydrogenator (ThalesNano Technology, Budapest, Hungary) via the solvent inlet using a 10% Pd/C CatCart™ (30 mm cartridge length, source ThalesNano, pre-washed and hydrogenated at full H2 mode for 10 min at 1 mL/min) at 1 mL/min flow rate in full H2 mode at 60° C. The solution collected was concentrated in vacuo to give 3,3-dimethyl-4-((2R)-2-piperazinylmethyl)-2-piperazinone (0.27 g) as a colorless solid.
Reaction SMILES: [OH-].[K+].Br[CH:4]([CH3:22])[C:5]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=1)=[O:6].Cl.O.[CH2:25]([OH:27])[CH3:26]>CN1CCCC1=O>[C:18]([C:9]1[CH:8]=[C:7]([C:5](=[O:6])[CH:4]([O:27][CH2:25][CH3:26])[CH3:22])[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[OH:17])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(Br)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(C)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 1 h
Yield: 45 %

Procedure:
6.6 g (117 mmol) of potassium hydroxide are dissolved in 130 ml of ethanol and stirred for one hour. Then 10.0 g (29.3 mmol) of 2-bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-propan-1-one dissolved in 20 ml of n-methylpyrrolidone is added at room temperature while stirring. After stirring for 20 hours the reaction mixture is cooled with an ice bath and 5 ml of concentrated hydrochloric acid and 150 ml of water is added. Then ethanol is evaporated, 200 ml of ethylacetate added and the water phase split off. The organic phase is washed with 100 ml of brine, dried over sodium sulfate and evaporated. The residue is purified by column chromatography and crystallisation of the pure fractions from hexane to give 4.1 g (45%) of compound 115; m.p. 64° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:6]=2[N:7]=1.[C:17](Cl)(=[O:19])[CH3:18].ClC1N=CC2C(C(=O)C)=CN(C3CCCC3)C=2N=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:17](=[O:19])[CH3:18])=[C:9]([CH3:11])[N:8]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16]3)[C:6]=2[N:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc2cnc(Cl)nc2n1C1CCCC1
Agent: CC(=O)c1cn(C2CCCC2)c2nc(Cl)ncc12
Product: CC(=O)c1c(C)n(C2CCCC2)c2nc(Cl)ncc12

Procedure:
1-(2-Chloro-7-cyclopentyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethanone is prepared from 2-Chloro-7-cyclopentyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidine and acetyl chloride using a method similar to that for the preparation of 1-(2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethanone given in Example 325.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][O:12][CH3:13]>>[CH3:13][O:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: COCCCCl
Reactant: O=C1CCNCC1
Product: COCCCN1CCC(=O)CC1

Procedure:
1-(3-Methoxypropyl)4piperidone is prepared from 4-piperidone and 1-chloro-3-methoxypropane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].Cl[C:10]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:27]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)([C:29]3[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=3)[OH:28])[CH:16]=2)[N:11]=1.CN(C=O)C>C(NCC)C.C(OCC)C.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.[Cu]I>[Cl:26][C:22]1[CH:21]=[C:20]([C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:27]([C:35]4[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=4)([C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[OH:28])[CH:16]=3)[N:11]=[C:10]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:19]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: C#Cc1ccccc1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)cc(-c3cccc(Cl)c3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(C#Cc3ccccc3)cc(-c3cccc(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
A mixture of ethynyl-benzene (0.0021 mol), Pd(PPh3)2Cl2(0.0002 mol) and copper (I) iodide (0.0002 mol) was added at room temperature to a mixture of (±)-2-chloro-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol (0.0014 mol), described in International Patent Specification WO 00/39082, in N-ethyl-ethanamine (7ml) and DMF (7 ml) under N2 flow. The mixture was stirred at room temperature overnight, then at room temperature for 3 days, poured out into ice water and extracted with EtOAc. The organic layer was separated, washed three times with water, dried (MgSO4), filtered and the solvent was evaporated. The residue (1.2 g) was purified by column chromatography over silica gel (eluent: CH2Cl2 100 to CH2Cl2/CH3OH 98/2 98/2; 35–70 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.5 g of a fraction which was taken up in diethyl ether. The precipitate was filtered off and dried. The residue (0.28 g) was purified by column chromatography over kromasil (eluent: CH3CN/CH3COONH4 1% 75/25; 10 μm). The pure fractions were collected and the solvent was evaporated, yielding: 0.279 g of a product which was dried at 90° C. in a vacuum for 4 hours, yielding 0.14 g (18%) of 4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-2-(phenylethynyl)-6-quinolinemethanol, mp. 154° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]([B:15]2[O:19]C(C)(C)C(C)(C)[O:16]2)[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][C:7]([CH3:10])([OH:9])[CH3:8].O.I([O-])(=O)(=O)=O.[Na+].C([O-])(=O)C.[NH4+]>CC(C)=O>[OH:9][C:7]([CH3:10])([CH3:8])[CH2:6][O:5][C:4]1[CH:11]=[CH:12][C:13]([B:15]([OH:16])[OH:19])=[CH:14][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCC(C)(C)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(B(O)O)ccc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
To a solution of 1-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-methylpropan-2-ol Part B (0.880 g, 2.73 mmol) in acetone (20 mL) and water (20 mL) was added sodium periodate (2.3 g, 10.92 mmol) and ammonium acetate (0.84 g, 10.92 mmol). The mixture stirred at RT overnight. Filtered the white solids, washed the filter cake with acetone and removed the acetone. The product was then extracted with EtOAc, and brine, and, dried (MgSO4), concentrated to afford the crude product. Residue was purified using ISCO flash chromatography (silica gel/methylene chloride-methanol 100:0 to 85:15 gradient) to afford the desired product 4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acid 9C (0.443 g, 1.845 mmol, 67.6% yield) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[N:11][C:10]([C:21]([OH:23])=O)=[N:9]1.C(Cl)(=O)C([Cl:27])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[N:11][C:10]([C:21]([Cl:27])=[O:23])=[N:9]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccccc2Cl)n1
Solvent: ClCCl
Product: O=C(Cl)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccccc2Cl)n1

Procedure:
Part B: To a stirred solution of 1-(chlorophenyl)-5-(2,4-dichlorophenyl)-1H-1,2,4-triazole-3-carboxylic acid (0.37 g, 1.00 mmol) in dichloromethane (10 mL) is added oxalyl chloride (0.254 g, 2.00 mmol). The resulting mixture is concentrated in vacuo to give crude 1-(chlorophenyl)-5-(2,4-dichlorophenyl)-1H-1,2,4-triazole-3-carbonyl chloride.