Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[NH:31]1[CH:35]=[CH:34][CH:33]=[N:32]1.C(=O)([O-])[O-].[K+].[K+].CN(C)[C@@H]1CCCC[C@H]1N.CN[C@@H]1CCCC[C@H]1NC>CS(C)=O.C(OCC)(=O)C.O.[Cu]I>[OH:29][C@@H:24]1[C@@H:23]([N:13]2[C:12](=[O:30])[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[C:9]([CH2:8][C:5]4[CH:6]=[N:7][C:2]([N:31]5[CH:35]=[CH:34][CH:33]=[N:32]5)=[CH:3][CH:4]=4)[CH:10]=3)[N:15]=[CH:14]2)[CH2:28][CH2:27][O:26][CH2:25]1
Reactant: c1cn[nH]c1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=c1c2cc(Cc3ccc(-n4cccn4)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Temperature: 120 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (Example 1, 0.080 g, 0.19 mmol) and pyrazole (0.052 g, 0.15 mmol) in 2 mL of DMSO under an atmosphere of nitrogen was added potassium carbonate (0.57 mL, 1 N aqueous, 0.57 mmol), trans-N,N-dimethylcyclohexane-1,2-diamine (21.6 mg, 0.152 mmol), and copper(I) iodide (0.014 g, 0.076 mmol). The mixture was heated at 120° C. for 20 h, cooled to rt, and additional trans-N,N′-dimethylcyclohexane-1,2-diamine (21.6 mg, 0.152 mmol) and copper(I) iodide (0.014 g, 0.076 mmol) were added. The reaction was heated at 150° C. for 24 h, cooled to rt, and diluted with ethyl acetate and water. The aqueous layer was extracted 3× with ethyl acetate, and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 453.51 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 8.93 (d, J=7.3 Hz, 1H), 8.46 (s, 1H), 8.30 (s, 1H), 8.26 (s, 1H), 7.90 (s, 1H), 7.86 (d, J=9.2 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.66-7.57 (m, 2H), 7.50 (d, J=8.5 Hz, 1H), 6.39 (s, 1H), 6.30 (s, 1H), 4.86-4.84 (m, 1H), 4.36 (s, 2H), 4.23-4.13 (m, 2H), 4.12-4.04 (m, 1H), 3.56-3.50 (m, 1H), 3.34-3.32 (m, 1H), 2.24-2.19 (m, 1H), 2.00-1.97 (m, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]CC4C=CC=CC=4)=[C:18]([O:30]CC4C=CC=CC=4)[CH:17]=3)[CH2:10][N:9]([CH3:38])[C:8](=[O:39])[C:7]=2[CH:40]=1.[H][H]>[Pd].CO>[ClH:2].[OH:30][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[OH:22])[CH2:15][CH2:14][NH:13][C:11]1[CH2:10][N:9]([CH3:38])[C:8](=[O:39])[C:7]2[CH:40]=[CH:3][CH:4]=[CH:5][C:6]=2[N:12]=1
Reactant: [H][H]
Reactant: CN1CC(NCCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)=Nc2ccc(Cl)cc2C1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN1CC(NCCc2ccc(O)c(O)c2)=Nc2ccccc2C1=O

Procedure:
A mixture of 11.34 g (0.0197 m) of 7-chloro-2-(3,4-dibenzyloxyphenethylamino)-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-5-one hydrochloride and 10% palladium on charcoal catalyst in 250 ml of absolute methanol is hydrogenated until no more hydrogen is absorbed. The catalyst is removed by filtration and the filtrate is concentrated to dryness in vacuo to give crude 3,4-dihydro-2-(3,4-dihydroxyphenethylamino)-4-methyl-5H-1,4-benzodiazepine-5-one hydrochloride hemi methanolate. Several recrystallizations from ethanol/ether give the pure product, m.p. 179° - 180° C. dec.
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH:10]([CH2:13][C:14]([OH:16])=[O:15])[C:9](=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:20])=[N-]>CCOCC>[C:1]1([C:7]2[CH2:12][CH2:11][CH:10]([CH2:13][C:14]([O:16][CH3:20])=[O:15])[C:9](=[O:17])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)CC1CCC(c2ccccc2)=CC1=O
Solvent: CCOCC
Product: COC(=O)CC1CCC(c2ccccc2)=CC1=O

Procedure:
A solution of 4-phenyl-2-oxo-3-cyclohexene-1-acetic acid (Tet. Lett. 1968, 4739) (10.0 g, 43.4 mmol) in Et2O (150 ml) was treated with ethereal diazomethane at 0° C. until TLC indicated the reaction to be complete. The solvent was evaporated to yield methyl 4-phenyl-2-oxo-3-cyclohexene-1-acetate (10.6 g, quant.): Rf 0.33 (20% EtOAc in hexane);
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:12]([CH3:15])[CH:13]=[N:14][C:10]=2[C:9]2[O:8][C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:6]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4([NH:32]C(=O)O)[CH2:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:5](=[O:36])[C:4]=2[CH:3]=1.C(OC(=O)NC1(C2C=CC(C3C(=O)C4C=C(Cl)C5N=CN(C)C=5C=4OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO.O.Cl>[ClH:1].[NH2:32][C:28]1([C:25]2[CH:24]=[CH:23][C:22]([C:6]3[C:5](=[O:36])[C:4]4[CH:3]=[C:2]([Cl:1])[C:11]5[N:12]([CH3:15])[CH:13]=[N:14][C:10]=5[C:9]=4[O:8][C:7]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:27][CH:26]=2)[CH2:29][CH2:30][CH2:31]1
Reactant: Cn1cnc2c3oc(-c4ccccc4)c(-c4ccc(C5(NC(=O)O)CCC5)cc4)c(=O)c3cc(Cl)c21
Agent: Cl
Agent: Cn1cnc2c(Cl)cc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cnc2c3oc(-c4ccccc4)c(-c4ccc(C5(N)CCC5)cc4)c(=O)c3cc(Cl)c21
Reaction time: 1 h

Procedure:
To a stirred solution of {1-[4-(4-chloro-3-methyl-6-oxo-8-phenyl-3,6-dihydro-chromeno[7,8-d]imidazol-7-yl)-phenyl]-cyclobutyl}-carbamic acid tea-butyl ester and {1-[4-(4-chloro-1-methyl-6-oxo-8-phenyl-1,6-dihydro-chromeno[7,8-d]imidazol-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (43 mg, 0.08 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at RT. After 1 h, the reaction mixture was concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 20% MeOH in DCM) to yield a white solid. This crude residue was dissolved in a mixture of MeOH (0.5 mL), water (1.5 mL) and 1 M HCl (0.1 mL) and chromatographed on a 10 g C18 cartridge {30 to 60% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound as a white solid (4.0 mg). LCMS (Method E): RT=3.27 min, [M÷H]+=456/458. 1H NMR (300 MHz, CD3OD): δ 8.40 (s, 1H), 7.99 (s, 1H), 7.60-7.49 (m, 4H), 7.47-7.30 (m, 5H), 4.29 (s, 3H), 2.86-2.58 (m, 4H), 2.36-2.22 (m, 1H), 2.06-1.92 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([CH2:11][O:12][CH2:13][CH3:14])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:18].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>CO.C1COCC1>[Br:18][CH2:16][C:15]([C:7]1[CH:8]=[C:9]([CH2:11][O:12][CH2:13][CH3:14])[CH:10]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:6]=1)=[O:17]
Reactant: CCOCc1cc(C(C)=O)cc(C(C)(C)C)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: CCOCc1cc(C(=O)CBr)cc(C(C)(C)C)c1
Yield: 132.8 %

Procedure:
1-(3-tert-Butyl-5-ethoxymethylphenyl)ethanone (O2.008; 550 mg) was dissolved in methanol/THF (10 ml/10 ml), admixed with phenyltrimethylammonium tribromide (882 mg) while stirring and stirred at RT for 2 h. Subsequently, the reaction mixture was poured onto DCM (200 ml) and washed thoroughly once with 5% sodium thiosulfate solution and once with water. Then the DCM phase was dried and concentrated. The residue was purified using silica gel (40 g cartridge, n-heptane/EA gradient of 0-50% in 30 min). 566 mg of the title compound were obtained. LC-MS rt: 1.83 min [M+H]+: 313.2 (met. a)
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10](C(O)=O)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1.[CH3:20][O:21]C1C=CC(NN)=CC=1>>[C:16]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:21][CH3:20])=[CH:14][CH:15]=2)[N:5]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(C(=O)O)cc2)n1
Product: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1

Procedure:
The title compound was prepared in the same manner as described for 4-(5-amino-3-tert-butyl-pyrazol-1-yl)benzoic acid, replacing 4-hydrazinobenzoic acid with 4-methoxyphenylhydrazine. 1H-NMR (DMSO-d6) δ 7.40 (d, J=5.1 Hz, 2H), 6.98 (d, J=4.8 Hz, 2H), 5.32 (s, 1H), 5.05 (s, 2H), 3.77 (s, 3H), 1.20 (s, 9H); MS LC-MS [M+H]+=246, RT=1.76 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33].O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:1][C:2]1[CH:7]=[C:6]([C:29]2[CH:38]=[CH:37][CH:36]=[C:31]([C:32]([O:34][CH3:35])=[O:33])[CH:30]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][N:19]=2)[CH:3]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)c1
Temperature: 160 °C

Procedure:
A suspension of N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (1.00 g, 2.64 mmol), methyl 3-bromobenzoate (0.581 g, 2.70 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.054 g, 0.066 mmol), 1,4-dioxane (10 mL), and aqueous sodium carbonate (2 M, 2.64 mL, 5.27 mmol) was placed under an argon atmosphere by performing 6 vacuum/argon cycles. The reaction mixture was then heated to 160° C. for 10 minutes in a microwave reactor. The resulting suspension was diluted with ethyl acetate (75 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The layers were separated, and the organic layer was washed with water (10 mL) and then brine (25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/hexanes) to afford methyl 3′-methyl-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-carboxylate. MS ESI calc'd. for C20H17F3N3O2 [M+H]+ 388, found 388.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:12][C@@H:11]1[OH:37].[Br:39]N1C(=O)CCC1=O>C(Cl)Cl.CN(C)C=O>[CH3:1][O:2][C:3](=[O:38])[CH2:4][CH2:5][CH2:6][CH:7]([Br:39])[CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OC)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Under an atmosphere of nitrogen, a solution of 3.4 g of (5Z,13E)-(9α,11α,15S)-9-hydroxy-11,15-bis(tetrahydropyran-2-yloxy)prosta-5,13-dienoic acid methyl ester in a mixture of 30 ml of methylene chloride and 6 ml of N,N-dimethylformamide was added dropwise to a suspension of 1.35 g of N-bromosuccinimide in 50 ml of methylene chloride at -20° to -10° C. and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was then poured into ice-water and extracted with diethyl ether. The extract was washed with water and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (4:1) as eluent to give 3.43 g of the title compound having the following physical characteristics:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][NH:30][CH2:31]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][N:30]([C:16]1[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=1[F:21])[CH2:31]2
Reactant: Clc1cccc2c1CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(N3Cc4cccc(Cl)c4C3)c(F)cc2c1=O
Yield: 24.5 %

Procedure:
178 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 89 mg of 4-chloroisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 60 mg of the target compound.
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[Cl:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:1]2[C:12](=[O:13])[C:11]3[N:9]([CH3:10])[CH:8]=[N:7][C:6]=3[N:4]([CH3:5])[C:2]2=[O:3])=[CH:17][CH:16]=1
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: Clc1ccc(OCCCCCCBr)cc1
Product: Cn1cnc2c1c(=O)n(CCCCCCOc1ccc(Cl)cc1)c(=O)n2C
Yield: 61 %

Procedure:
Theobromine and 6-(4-chlorophenoxy)hexyl bromide were reacted and treated in substantially the same manner as described in Example 9(a) to give 6-(4-chlorophenoxy)hexyltheobromine (61%).
Reaction SMILES: [NH2-].[Na+].[C:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].C[O:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CCOCC>[C:19]1([C:18](=[O:17])[CH2:4][C:3]([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)=[O:5])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1cccc2ccccc12
Reactant: COC(=O)c1ccccc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CC(=O)c1cccc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
9.5 gr of 50% slurry of sodium amide was suspended in 100 ml of anhydrous ether in a 250 ml round bottom flask that was equipped with a magnetic stir bar and a condenser. To this suspension was added 10.2 gr of solid acetonaphthone and continued stirring for 5 min at room temperature. After 5 minutes, 8.16 gr of methylbenzoate was added in one lot as a neat liquid. At this point, the reaction flask was transferred to an oil bath and the bath temperature was raised so that the contents reflux gently in ether for 3 hours. The contents were then poured onto 300 gr of solid ice and the pH was adjusted to 7.0 with conc. HCl while stirring. The ether layer was separated and the aqueous layer was extracted with 150 ml aliquots of ether twice. Combined ether layers were dried over a bed of anhydrous sodium sulfate and concentrated on rotavapor to about 100 ml and let it sit at RT. The recrystallized solid was filtered, washed with ether and dried to obtain 10.6 gr of solid diketone.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>CCO>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: C1COCCN1
Agent: C=O
Solvent: CCO
Product: CC(=O)Nc1ccc(N2CCOCC2)c(O)c1
Yield: 13 %

Procedure:
N-(3-hydroxyphenyl)acetamide (0.50 g, 3.31 mmol), formaldehyde 37% (678 μL, 2.7 eq), and morpholine (290 μL, 1 eq) were dissolved in 10 mL of EtOH. The reaction mixture was refluxed overnight, evaporated and purified by flash chromatography (DCM/MeOH/NH4OH 9.6:0.4:0.1) to yield expected compound as a pale yellow oil (107 mg, 13% yield). LC-MS: m/z (ESI) 251.3 [M+H]+; 1H NMR (300 MHz, MeOH-d4) δ7.09; (d, J=1.3 Hz, 1H), 6.8-6.9; (m, 2H), 3.6-3.7; (m, 4H), 3.58; (s, 2H), 2.4-2.5; (m, 4H), 2.0; (s, 3H)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[N:6]=1.[C:27](Cl)([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:28]>O1CCCC1.N1C=CC=CC=1>[CH:14]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:28])[S:3][CH:4]=2)[CH2:9][CH2:10]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Yield: 30.5 %

Procedure:
To a solution of 2-amino-4-(4-benzhydrylpiperazin-1-ylmethyl)thiazole (1.8 g) in tetrahydrofuran (5 ml) and pyridine (10 ml) was added dropwise ethoxalyl chloride (1.1 g) under ice-cooling with stirring, and the stirring was continued at the same temperature for an hour. After concentration of the reaction mixture, the residue was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and then evaporated to dryness to give a residue, which was chromatographed on silica gel using ethyl acetate as an eluent. The eluates containing the desired compound were collected and evaporated, followed by recrystallization from a mixture of ethyl acetate and n-hexane to obtain pale yellow crystals (0.7 g) of 4-(4-benzhydrylpiperazin-1-ylmethyl)-2-ethoxalylaminothiazole, mp 125°-128° C.
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]1[C@@:39]2([CH3:40])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:41])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:34])[CH2:21][C:22]#[C:23][C:24]([O:27]C2CCCCO2)([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:42]C2CCCCO2)[CH2:9]1.C(=O)([O-])O.[Na+].[H][H]>C(O)C.[Ni]>[OH:7][C@@H:8]1[C@@:39]2([CH3:40])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:41])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:34])[CH2:21][CH2:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[CH2:11][C@@H:10]([OH:42])[CH2:9]1
Reactant: C[C@H](CC#CC(C)(C)OC1CCCCO1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Reactant: [H][H]
Agent: [Ni]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
A solution of 0.2 g (0.3 mmol) of 1α,3β,25-tris[(tetrahydro-2H-pyran-2-yl)oxyl]-cholest-5-en-23-yne in 10 ml of ethanol was treated with 0.05 g of sodium hydrogen carbonate and 0.4 ml of concentrated ethanolic Raney-nickel suspension, and the mixture was shaken in a hydrogen atmosphere at normal pressure for 24 hours. The catalyst was filtered off, and the filtrate was evaporated. The residue, containing 1α,3β,25-tris[(tetrahydro-2H-pyran-2-yl)oxy]-cholest-5-ene, was dissolved in 5 ml of methanol. 10 mg of p-toluenesulphonic acid monohydrate were added. The solution was left at room temperature for 3 hours. While stirring there were added dropwise 5 ml of water, the suspension was suction filtered, and the residue was dried. There was obtained 0.11 g (89%) of 1α,3β,25-trihydroxy-cholest-5-ene which melts at 174°-176° C. after recrystallization from acetone.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][N:16]=1.[NH2:21][C:22]1[CH:23]=[C:24]2[CH2:39][C:29]3([C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:38])[CH2:28][C:25]2=[N:26][CH:27]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([NH:21][C:22]2[CH:23]=[C:24]3[CH2:39][C:29]4([C:37]5[C:32](=[N:33][CH:34]=[CH:35][CH:36]=5)[NH:31][C:30]4=[O:38])[CH2:28][C:25]3=[N:26][CH:27]=2)=[O:10])[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][N:16]=1
Reactant: Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: O=C(O)Cn1c(=O)n(-c2ccncn2)c2ccccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1c(=O)n(-c2ccncn2)c2ccccc21)Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (2-oxo-3-pyrimidin-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid (62 mg, 0.23 mmol, described in Intermediate 8), (±)-3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 4), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is 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 made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:8](Br)=[N:9][C:10]([Br:13])=[N:11][CH:12]=1)(=[O:3])[CH3:2].[CH:15]1([C:18]2[NH:22][N:21]=[C:20]([NH2:23])[CH:19]=2)[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CC(O)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:8]([NH:23][C:20]2[CH:19]=[C:18]([CH:15]3[CH2:17][CH2:16]3)[NH:22][N:21]=2)=[N:9][C:10]([Br:13])=[N:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: CC(=O)OCCc1cnc(Br)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(=O)OCCc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 53.2 %

Procedure:
A mixture of 2-(2,4-dibromopyrimidin-5-yl)ethyl acetate (650 mg, 2.0 mmol, 1.0 eq), 5-cyclopropyl-1H-pyrazol-3-amine (296 mg, 2.4 mmol, 1.2 eq) and DIPEA (387 mg, 3.0 mmol, 1.5 eq) in propan-2-ol (10 mL) was stirred at 60° C. for 16 h. The mixture was extracted with EtOAc. The combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated to give a residue, which was purified by silica gel column chromatography (PE/EtOAc=1:2) to give 2-(2-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-5-yl)ethyl acetate (390 mg, 53%) as a white solid. LC-MS (m/z)=366 [M+H]+
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[CH3:7][S:8](Cl)(=[O:10])=[O:9].O>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:2]([CH:3]([O:6][S:8]([CH3:7])(=[O:10])=[O:9])[CH2:4][CH3:5])[CH3:1]
Reactant: CCC(O)CC
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCC(CC)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a colorless solution of 88.15 g 3-pentanol (1.0 mol) in 150 ml pyridine were added under stirring at 0° C. 126.0 g methanesulfonyl chloride (1.1 mol) over 1 h. After warming up (15 min.) and stirring at room temperature for 1 h, 50 ml deionized water were added all at once and stirring at room temperature was continued for 1 h. The reaction mixture was diluted with 500 ml ethyl acetate and washed with 800 ml 1N HCl and 250 ml 10% brine. Both aqueous layers were extracted sequentially with 250 ml ethyl acetate. After drying the combined organic layers over ca. 20 g Na2SO4, the solvent was removed on the rotary evaporator (50° C./≧1 mbar) affording 154.4 g (92.9%) yellow, oily title product, which could be used in the next step without purification.