Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:7]([C:10]1[CH:25]=[CH:24][C:13]2[C:14](=[O:23])[C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[CH:17]=[CH:18][C:12]=2[CH:11]=1)[CH:8]=[CH2:9].C1C=CC=CC=1.[CH2:32](O)[CH2:33][OH:34]>C(#N)C.C(N(CC)CC)C>[CH2:32]1[CH2:33][O:34][C:14]2([C:13]3[CH:24]=[CH:25][C:10]([CH2:7][CH:8]=[CH2:9])=[CH:11][C:12]=3[CH:18]=[CH:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]2=3)[O:23]1
Reactant: C=CCc1ccc2c(=O)c3ccccc3ccc2c1
Reactant: OCCO
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CCc1ccc2c(c1)C=Cc1ccccc1C21OCCO1

Procedure:
0.5 Gm. of phosphorus pentachloride is added to a solution of 0.5 gm. of 2-(2-propenyl)5H-dibenzo[a,d]cyclohepten-5-one in 20 ml. of benzene, and the mixture is stirred for one hour, and then added to a mixture of 1.0 ml. of ethylene glycol, 1.0 ml. of triethylamine and 20 ml. of acetonitrile. After 2 hours the mixture is washed with water, dried and evaporated to give a nearly quantitative yield of 5,5-ethylenedioxy-2-(2-propenyl)5H-dibenzo[a,d] cycloheptene.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([OH:7])[N:6]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].C(OCC)C>C(O)(=O)C>[C:13]([NH:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([OH:7])[N:6]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1sc(N)nc1O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(NC(C)=O)nc1O
Yield: 82.2 %

Procedure:
Ethyl 2-amino-4-hydroxy-1,3-thiazole-5-carboxylate (6.00 g, 31.9 mmol) was dissolved in 100 mL of acetic acid with stirring. Acetic anhydride (15.0 mL, 159 mmol) was added via syringe. The reaction was stirred for 16 hours and 100 mL of diethyl ether was added. The reaction was filtered and the pale yellow solid was washed with diethyl ether, dried, and collected to afford 6.04 g (82%) of ethyl 2-(acetylamino)-4-hydroxy-1,3-thiazole-5-carboxylate. 1H NMR (300 MHz, DMSO-d6) δ 12.32 (s, 1H), 11.32 (s, 1H), 4.16 (q, J=7.0 Hz, 2H), 2.16 (s, 3H), 1.23 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([O:28]CC)=[O:27])[CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[C@@H:10]([O:31][CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([OH:28])=[O:27])[CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[C@@H:10]([O:31][CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccc(-c2cccc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3OCc3ccc4ccccc4c3)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(-c3cccc(C(=O)O)c3)c2)[C@@H](OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A stirred mixture of (3R*,4R*)-4-(3-bromo-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester (300 mg, 0.6 mmol), 3-ethoxycarbonylphenyl boronic acid (136.8 mg, 0.71 mmol), dimethoxyethane (3 mL), H2O (1 mL), tetrakis-(triphenylphosphin)-palladium (46.5 mg, 0.04 mmol) and Na2CO3 (96 mg, 0.91 mmol) is heated at reflux under argon for 16 h. The mixture is cooled to RT, dimethoxyethane is removed in vacuo and the residue is diluted with aqueous 2N Na2CO3 solution containing a few mL of concentrated NH4OH. The aqueous layer is extracted three times with CH2Cl2. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. Flash chromatography of the dark residue (SiO2, hexane/ethyl acetate) affords (3R*,4R*)-4-(3′-ethoxycarbonyl-biphenyl-3-yl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester as a yellowish resin. The ester (138.7 mg, 0.245 mmol) is dissolved in MeOH (1 mL) and THF (1 mL), treated with aqueous NaOH (2 M, 0.5 mL, 1 mmol) and the mixture is stirred for 14 h at RT. The solvents are removed in vacuo, the residue is diluted with H2O and the pH adjusted to 5 by the addition of 1N HCl. The aqueous phase is extracted twice with ethyl acetate. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo to afford (3R*,4R*)-4-(3′-carboxy-biphenyl-3-yl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester as a white amorphous solid. A mixture of this acid (110.1 mg, 0.20 mmol) and HCl (5M in 2-propanol, 2 mL, 10 mmol) is stirred for 1 h at RT. The reaction mixture is evaporated in vacuo and the residue purified using preparative HPLC (H2O/CH3CN). The combined pure fractions are treated with solid K2CO3 and CH3CN is removed in vacuo. The aqueous layer is extracted twice with CH2Cl2. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. The residue is stirred with HCl (5M in 2-propanol, 1 mL, 5 mmol) for 2 h at RT. Evaporation of the solvent affords 3′-[(3R*,4R*)-3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-biphenyl-3-carboxylic acid hydrochloride as a white solid: MS 438.6 [M+H]+; retention time 5.23 min (HPLC, Nucleosil C18; 5→100% CH3CN in H2O within 8 min).
Reaction SMILES: [ClH:1].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)=[C:8](C)[CH:7]=1)(C)([CH3:4])[CH3:3].C(C1C=CC(CC#N)=C(C)C=1)(C)(C)C>>[ClH:1].[CH:2]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]2[NH:17][CH2:16][CH2:15][N:14]=2)=[CH:10][CH:11]=1)([CH3:4])[CH3:3]
Reactant: Cc1cc(C(C)(C)C)ccc1CC1=NCCN1
Agent: Cc1cc(C(C)(C)C)ccc1CC#N
Agent: Cl
Product: CC(C)c1ccc(CC2=NCCN2)cc1

Procedure:
2-[(4-t-Butyl-2-methylphenyl)methyl]-4,5-dihydro-1H-imidazole hydrochloride, from 4-t-butyl-2-methylphenylacetonitrile (Example 4e); white solid, mp 255° C., Anal. C15H22N2.HCl.0.25H2O: C, H, N.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[C:20]1(=[O:26])[NH:24][C:23](=[O:25])[CH2:22][CH2:21]1>>[O:25]=[C:23]1[CH2:22][CH2:21][C:20](=[O:26])[N:24]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(CN2C(=O)CCC2=O)cc1)c1ccccc1
Yield: 57 %

Procedure:
The title compound was prepared in 57% yield as beige crystals using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and succinimide. 1H NMR (400 MHz; CDCl3): δ 2.68 (s, 4H), 3.41 (br s, 3H), 4.60 (s, 2H), 7.04 (br d, 2H), 7.23–7.41 (m, 7H); HPLC-MS: m/z=339.1 (M+1); Rt=3.40 min.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[N:7][C:6]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:5]=2[CH:4]=1)[NH2:2].[C:15](/[N:17]=[C:18](\OC1C=CC=CC=1)/[NH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[CH:22][CH:21]=1)#[N:16]>C(O)(C)C>[CH:32]1([N:29]2[CH2:30][CH2:31][N:26]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:18]4[N:17]=[C:15]([NH2:16])[N:1]([C:3]5[N:8]=[N:7][C:6]6[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:5]=6[CH:4]=5)[N:2]=4)=[CH:25][CH:24]=3)[CH2:27][CH2:28]2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: N#C/N=C(/Nc1ccc(N2CCN(C3CCCCC3)CC2)cc1)Oc1ccccc1
Reactant: NNc1cc2c(nn1)CCCCCC2
Solvent: CC(C)O
Product: Nc1nc(Nc2ccc(N3CCN(C4CCCCC4)CC3)cc2)nn1-c1cc2c(nn1)CCCCCC2

Procedure:
3-Hydrazinyl-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine (101 mg, 0.53 mmol) and (Z)-phenyl N′-cyano-N-(4-(4-cyclohexylpiperazin-1-yl)phenyl)carbamimidate (212 mg, 0.53 mmol) were suspended in isopropanol (3 mL) and subjected to microwave irradiation (150° C., 20 min). A portion of the crude product was purified by C-18 reversed phase hplc to give N3-(4-(4-cyclohexylpiperazin-1-yl)phenyl)-1-(5,6,7,8,9,10-hexahydrocycloocta[c]pyridazin-3-yl)-1H-1,2,4-triazole-3,5-diamine, compound #16, 17 mg. 1H NMR (CDCl3, 300 MHz) 8.41 (s, 1H), 7.55 (d, 2H), 6.92 (d, 2H), 3.38 (m, 3H), 3.15 (m, 6H), 2.96 (m, 1H), 2.80 (m, 2H), 2.11 (m, 2H), 1.67-1.90 (m, 7H), 1.05-1.45 (m, 10H) ppm; MS (ES) 502.28 (M+H).
Reaction SMILES: [FH:1].N[C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.N([O-])=O.[Na+]>CN(C)C=O>[Cl:10][C:4]1[C:3]([F:1])=[CH:8][C:7]([Cl:9])=[CH:6][N:5]=1
Reactant: Nc1cc(Cl)cnc1Cl
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(Cl)cnc1Cl
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A 500 ml polytetrafluoroethylene reactor equipped with stirrer, thermometer and reflux condenser is charged with 120 g of hydrogen fluoride. A solution of 40.7 g (0.25 mol) of 3-amino-2,5-dichloropyridine in 100 ml of dimethylformamide is added dropwise at a temperature in the range from 0° C. to +10° C. Then 20.7 g (0.3 mol) of sodium nitrite are introduced into this solution at 55° C. The resultant nitrogen is removed from the reactor through the reflux condenser. Gas evolution ceases after 2 hours at +50° C. 150 ml of methylene chloride are added to the reaction mixture wich is then poured into ice water. The two-phase mixture is neutralized with concentrated ammonia solution. The organic phase is separated and the aqueous phase is extracted several times with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated by evaporation. The crude product is purified by distillation, affording 37.9 g (91.4% of theory) of 2,5-dichloro-3-fluoropyridine.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:21][C:22]2[C:27]([Cl:28])=[CH:26][N:25]=[CH:24][C:23]=2[Cl:29])=[N:11][N:10]=1>CN(C=O)C>[Cl:29][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:28])[C:22]=1[CH2:21][C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:9]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[N:10][N:11]=1
Reactant: c1c[nH]cn1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(-n3ccnc3)c2c1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 41.3 %

Procedure:
A solution of imidazole (0.814 g, 11.21 mmoles) in dry DMF (30 ml) was stirred under N2 at room temperature and added with NaH (8.46 mmoles). After 30 minutes 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (2 g, 5.64 mmoles), prepared as described in example 45, in dry DMF (30 ml) was added. The mixture was heated at 80° C. 5 for 3.5 hours, cooled, poured into water/ice and extracted three times with CH2Cl2. The organic phase was washed with water, anhydrified and concentrated to give a solid which was flash chromatographed (eluent: ethyl acetate) yielding 0.9 g of the title compound (yield: 50%). m.p.>250° C.
Reaction SMILES: C(O)(=O)C.[OH:5][CH2:6][C@@:7]12[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C:19](=[O:25])[CH2:18][CH2:17]4)[CH2:14][CH2:13][C@H:12]1[CH2:11][C@@H:10]([O:26][Si:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:9][CH2:8]2.C([O:49][C@H:50]1[CH2:67][C@@H:66]([CH3:68])[C@@:65]2([CH2:69][O:70][CH3:71])[C@@H:52]([CH2:53][CH2:54][C@@H:55]3[C@@H:64]2[CH2:63][CH2:62][C@@:60]2([CH3:61])[C@H:56]3[CH2:57][CH2:58][C@@H:59]2[O:72]C(=O)C)[CH2:51]1)(=O)C>>[OH:5][CH2:6][C@@:7]12[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C:19](=[O:25])[CH2:18][CH2:17]4)[CH2:14][CH2:13][C@H:12]1[CH2:11][C@@H:10]([O:26][Si:27]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:9][CH2:8]2.[CH3:71][O:70][CH2:69][C@@:65]12[C@@H:64]3[C@H:55]([C@H:56]4[C@@:60]([CH2:62][CH2:63]3)([CH3:61])[C@@H:59]([OH:72])[CH2:58][CH2:57]4)[CH2:54][CH2:53][C@H:52]1[CH2:51][C@@H:50]([OH:49])[CH2:67][C@H:66]2[CH3:68]
Reactant: COC[C@]12[C@@H](CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]31)C[C@@H](OC(C)=O)C[C@H]2C
Agent: C[C@]12CC[C@H]3[C@@H](CC[C@H]4C[C@@H](O[Si](c5ccccc5)(c5ccccc5)c5ccccc5)CC[C@@]43CO)[C@@H]1CCC2=O
Solvent: CC(=O)O
Product: COC[C@]12[C@@H](CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]31)C[C@@H](O)C[C@H]2C

Procedure:
Substituting 3β-(1'-cyclopentenyloxy)-19-hydroxy-5α-androstan-17-one acetate, 19-hydroxy-3β-triphenylsiloxy-5α-androstan-17-one acetate and 19-methoxy-1β-methyl-5α-androstane-3β,17β-diol diacetate for the 19-hydroxy-3β-(2'-tetrahydropyranyloxy)-5α-androstan-17-one acetate above results in the preparation of 3β-(1'-cyclopentenyl-oxy)-19-hydroxy-5α-androstan-17-one, 19-hydroxy-3β-triphenylsiloxy-5α-androstan-17-one and 19-methoxy-1β-methyl-5α-androstane-3β,17β-diol, respectively.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](/[CH:21]=[CH:22]/[C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16]([O:18]CC)=[O:17])=[CH:10]2)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C>[C:1]([C:5]1[CH:6]=[C:7](/[CH:21]=[CH:22]/[C:23](=[O:31])[C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(/C=C/C(=O)c3ccc(C)cc3)cc(C(C)(C)C)c2oc1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C(=O)/C=C/c2cc(C(C)(C)C)c3oc(=O)c(C(=O)O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of (E)-ethyl 8-tert-butyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxylate (0.5 g, 1.19 mmol) in ethanol (50 mL) was added 10% aqueous KOH (10 mL), and the mixture was vigorously stirred for 1 h at room temperature. After completion of the reaction, the solvents were removed and the residue was acidified with dilute hydrochloric acid (HCl) (2 N). The precipitate was separated by filtration and dried over vacuum. The residue was washed with methanol to give (E)-8-tert-butyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxylic acid of Formula V (0.31 g, 64% yield).
Reaction SMILES: O=[O+][O-].[O:4]=O.[CH2:6]([C:13]1[O:19][C@@H:18]2[C@@H:15]([C:16](=[O:24])[N:17]2[CH:20]=C(C)C)[N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CSC>ClCCl>[CH2:6]([C:13]1[O:19][C@@H:18]2[C@@H:15]([C:16](=[O:24])[N:17]2[CH:20]=[O:4])[N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)=CN1C(=O)[C@H]2N=C(Cc3ccccc3)O[C@H]21
Reactant: O=O
Agent: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: O=CN1C(=O)[C@H]2N=C(Cc3ccccc3)O[C@H]21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
An ozone-oxygen mixture was passed through a solution, cooled to -70° C., of 2.56 g (10 millimols) of (1S,5R)-3-benzyl-6-(2-methylprop-1-enyl)-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one (R. J. Stoodley et al., J. C. S. Perkin I 1974, 181) in 75 ml of anhydrous dichloromethane, until a blue coloration was obtained. Thereafter, flushing with nitrogen was carried out for 10 minutes, and 5.9 ml (80 millimols) of dimethyl sulphide were then added at -70° C. The mixture was stirred for 1 hour at 0° C. and for 1 hour at room temperature, and then evaporated down in vacuo. The residue was dissolved in dichloromethane, and the solution was washed with saturated NaHCO3 solution and water, and dried over MgSO4. After the solvent had been removed in vacuo, the residue was triturated with ether. 1.2 g (52%) of (1S,5R)-3-benzyl-6-formyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one were obtained as colorless crystals, melting point 90°-92° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:15][C:14]=2[CH3:27])[CH3:12])=[CH:6][C:5]=1C.C([Si](C)(C)[O:35][C:36]1C=C[C:39](NC)=[C:38](C)[CH:37]=1)(C)(C)C.COC(=O)C1C=CC(C=O)=CC=1OCCCC>>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])=[CH:15][C:14]=2[CH3:27])[CH3:12])=[CH:6][C:5]=1[O:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: COC(=O)c1ccc(CN(C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2C)cc1C
Reactant: CNc1ccc(O[Si](C)(C)C(C)(C)C)cc1C
Agent: CCCCOc1cc(C=O)ccc1C(=O)OC
Product: CCCCOc1cc(CN(C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2C)ccc1C(=O)OC

Procedure:
The title compound is prepared essentially according to the preparation of 4-({[4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-amino}-methyl)-2-methyl-benzoic acid methyl ester starting from [4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-amine and 2-butoxy-4-formyl-benzoic acid methyl ester. The title compound is obtained as syrup after workup and is used without further purification. LC-ES/MS m/e 472.3 (M+1).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:7]2[CH2:8][CH2:9][CH2:10][N:11]=[C:6]2[S:5][C:4]=1[C:12]([O:14]C(C)(C)C)=[O:13]>Cl>[ClH:1].[CH3:2][C:3]1[N:7]2[CH2:8][CH2:9][CH2:10][N:11]=[C:6]2[S:5][C:4]=1[C:12]([OH:14])=[O:13]
Reactant: CC1=C(C(=O)OC(C)(C)C)SC2=NCCCN21
Agent: Cl
Product: CC1=C(C(=O)O)SC2=NCCCN21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In 400 ml of 2N hydrochloric acid was suspended tert-butyl 3-methyl-6,7-dihydro-5H-thiazolo[3,2-a]-pyrimidine-2-carboxylate hydrochloride obtained in Example 26, followed by stirring at room temperature for 18 hours. The precipitated crystals were collected by filtration and washed successively with diethylether and acetone to yield 27.5 g of the titled compound.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=[O:20].C([O:24][C:25]1[CH2:30][CH2:29][CH2:28][C:27](=O)[CH:26]=1)(C)C.Cl>CCOCC.O>[CH3:13][N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([C:27]2[CH2:28][CH2:29][CH2:30][C:25](=[O:24])[CH:26]=2)[C:15]1=[O:20]
Reactant: CC(C)OC1=CC(=O)CCC1
Reactant: CN1CCCCC1=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: O
Product: CN1CCCC(C2=CC(=O)CCC2)C1=O
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (1.4 M in hexane, 120 ml) was treated at 20° C. under dry nitrogen with diisopropylamine (27 ml, 19.2 g) in dry ether (25 ml). The mixture was stirred for 10 minutes at 20° C. after completion of the addition and then 1-methyl-2-piperidone (20 g) in ether (25 ml) was added dropwise over 10 minutes. The mixture was stirred for a further 10 minutes, and then 3-isopropoxy-2-cyclohexenone (19.4 g) in ether (25 ml) was added dropwise over 10 minutes. The mixture was stirred at 20° C. for a further 2 hours and was then hydrolysed by the addition, dropwise at first, of a mixture of conc. hydrochloric acid (50 ml) and water (50 ml). The mixture was cooled in a water bath during the acidification to moderate the reaction. The mixture was cooled to room temperature (from 35° C.) and the organic phase was separated and dried (MgSO4). Removal of the solvent left a mobile yellow oil (0.63 g). The aqueous phase was extracted exhaustively with chloroform (10×40 ml) and the combined extracts were washed with water (100 ml), and saturated aqueous sodium chloride solution (100 ml), and dried (MgSO4). Evaporation left a pale green oil (25.79 g). The two fractions were combined and distilled, giving two fractions A, bp<120° C./1 mm (4.6 g), colourless, mobile liquid; and B, bp 150° C.-164° C./0.07 mm (14.46 g), yellow oil solidifying to a light yellow mass, mp 41°-62° C. Fraction A was identified by IR as slightly impure 1-methyl-2-piperidone (23% recovery), while fraction B was identified by IR and NMR as the title compound.
Reaction SMILES: [CH2:1]([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12](=[C:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[CH2:13]2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:35])=O>>[CH2:1]([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12](=[C:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:35])=[O:23])=[CH:20][CH:19]=1)[CH2:13]2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C(=C2CC3CCC(C2)N3CCc2ccccc2)c2ccccc2)cc1
Product: O=C(Cl)c1ccc(C(=C2CC3CCC(C2)N3CCc2ccccc2)c2ccccc2)cc1
Yield: 100.2 %

Procedure:
A mixture of 6 g (0.014 mole) of 4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3-ylidene)phenylmethyl]benzoic acid, 20 ml of CHCl2 and 3 mL (0.042 mole) of thionyl chloride were refluxed for 1.5 h. The solvent was evaporated in vacuo to give 6.2 g of 4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3-ylidene)phenylmethyl]benzoyl chloride. MS m/z (MH+) of CH3OH quench 437.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O.CC1(C)N([O])C(C)(C)CCC1>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4]
Reactant: COC(=O)C1CC(O)CN1Cc1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: COC(=O)C1CC(=O)CN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of a corresponding 1-benzyl-4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester in DCM, cooled at 0° C. is treated with trichloroisocyanuric acid and TEMPO, and then the reaction mixture is stirred at 0° C. for about 1 h. The mixture is diluted with DCM and washed with NaHCO3, HCl, and brine. The organic layer is dried and concentrated to afford the product 1-benzyl-4-oxo-pyrrolidine-2-carboxylic acid methyl ester (25)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:16]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)=[N:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>CCOC(C)=O>[CH3:15][NH:14][C:10]1[N:9]=[C:8]([C:7]2[C:2]([O:39][C:36]3[CH:35]=[CH:34][C:33]([CH2:32][C:25]4[C:26]5[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:22]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)=[N:23][N:24]=4)=[CH:38][CH:37]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Oc1ccc(Cc2nnc(-c3ccccc3)c3ccccc23)cc1
Reactant: CNc1nccc(-c2cccnc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CNc1nccc(-c2cccnc2Oc2ccc(Cc3nnc(-c4ccccc4)c4ccccc34)cc2)n1
Temperature: 130 °C

Procedure:
To a mixture of 4-(2-chloropyridin-3-yl)-N-methylpyrimidin-2-amine (0.0500 g, 0.23 mmol), 4-((4-phenylphthalazin-1-yl)methyl)phenol (0.071 g, 0.23 mmol) and cesium carbonate (0.15 g, 0.45 mmol) was added DMSO (0.5 mL). The resulting mixture was heated to 130° C. in a sealed tube for 15 hours, then diluted with EtOAc and extracted with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude concentrate was purified by Gilson reverse-phase HPLC (0.1% TFA in ACN/water; 15-95% ACN; 40 mL/min). Diluted product with DCM and extracted with saturated sodium bicarbonate. Dried organics over sodium sulfate, filtered and concentrated. Lyophilized concentrate to obtained N-methyl-4-(2-(4-((4-phenylphthalazin-1-yl)methyl)phenoxy)pyridin-3-yl)pyrimidin-2-amine as a white solid. MS m/z=497 [M+H]+. Calc'd for C31H24N6O: 496.58.