Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[C:38]([O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][N:48]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:47][CH2:46]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and piperidin-4-yl-carbamic acid tert-butyl ester according to conditions described in general procedure C. Mp: 211-212° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.18-1.14 (m, 2 H), 1.34 (s, 9H), 1.57-1.61 (m, 8 H), 2.80 (t, J=12.8 Hz, 2 H), 3.21-3.34 (m, 6 H), 4.19 (bs, 1 H), 6.19 (d, J=5.5 Hz, 1 H), 6.76 (d, J=7.6 Hz, 1 H), 6.94-6.98 (m, 1 H), 7.14 (d, J=9.1 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.54-7.61 (m, 3 H), 7.81-7.83 (m, 1 H), 7.96-7.99 (m, 1 H), 8.24 (d, J=5.5 Hz, 1 H), 10.44 (s, 1 H).
Reaction SMILES: [OH:1][CH:2]([CH2:26][CH2:27][CH2:28][OH:29])/[CH:3]=[CH:4]/[CH:5]=[C:6]1[C:10](=[O:11])[C:9]([S:12][CH3:13])=[CH:8][C:7]1([OH:25])[CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:30](Cl)(=[O:32])[CH3:31].[Cl-].[Na+].[O:36](CCCCC1C(=O)CCC=1)[C:37]1C=CC=C[CH:38]=1>ClCCl.C(N(CC)CC)C>[C:30]([O:1][CH:2]([CH2:26][CH2:27][CH2:28][O:29][C:37](=[O:36])[CH3:38])/[CH:3]=[CH:4]/[CH:5]=[C:6]1[C:10](=[O:11])[C:9]([S:12][CH3:13])=[CH:8][C:7]1([OH:25])[CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:32])[CH3:31]
Reactant: O=C1CCC=C1CCCCOc1ccccc1
Reactant: CSC1=CC(O)(CCCCOc2ccccc2)C(=C/C=C/C(O)CCCO)C1=O
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC1=CC(O)(CCCCOc2ccccc2)C(=C/C=C/C(CCCOC(C)=O)OC(C)=O)C1=O
Yield: 43 %

Procedure:
To a solution of 23 mg of 5-[(E)-4,7-dihydroxy-2-heptenylidene]-4-hydroxy-2-methylthio-4-(4-phenoxybutyl)-2-cyclopentenone obtained in Example 91 dissolved in 2 ml of dichloromethane was added 200 μl of triethylamine. Under ice-cooling and stirring. 20 μl of acetylchloride was added, and the mixture was stirred at 0° C. for 2 hours. Saturated aqueous sodium chloride was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtrate and concentrated, followed by silica gel column chromatography to give 11 mg (yield 43%) of 5-[(E)-4,7-diacetoxy-2-heptenylidene]-4-hydroxy-2-methylthio-4-(4-phenoxybutyl)-2-cyclopentenone (J) and 4 mg (yield 17%) of 5-[(E)-4,7-diacetoxy-2-heptenylidene]-4-acetoxy-2-methylthio-4-(4-phenoxybutyl-2-cyclopentenone (K).
Reaction SMILES: [C:1]1([C@@:7]([NH2:19])([CH3:18])[CH2:8][CH2:9][NH:10][C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:18][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]([C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)[C:28](=[O:30])[NH:19]1
Reactant: Cc1cccc(NCC[C@@](C)(N)c2ccccc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(N2CCC(C)(c3ccccc3)NC2=O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
To a solution of (R)-3-phenyl-N1-m-tolylbutane-1,3-diamine (50 mg, 0.2 mol) and Et3N (60 mg, 0.6 mmol) in CH2Cl2 (3 mL) was added triphosgene (24 mg, 0.08 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and concentrated. The residue was purified by preparative HPLC to give 4-methyl-4-phenyl-1-m-tolyl-tetrahydro-pyrimidin-2-one (8 mg, 14%). LC-MS Method 1 tR=1.13 min, m/z=281; 1H NMR (CDCl3): 1.65 (s, 3H), 2.15-2.23 (m, 1H), 2.25 (s, 3H), 2.27-2.47 (m, 1H), 3.20-3.22 (t, 1H), 3.37-3.40 (d, 1H), 6.89-6.92 (m, 2H), 6.99-7.01 (m, 1H), 7.15-7.17 (m, 1H), 7.25-7.27 (m, 1H), 7.7.31-7.38 (m, 4H), 7.83 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)=O)=[CH:4][C:3]=1[F:17].[C:18]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[F:17]
Reactant: O=C1CCCCCC1
Reactant: O=C(c1cccc(O)c1)c1ccc(Br)c(F)c1
Product: Oc1cccc(C(=C2CCCCCC2)c2ccc(Br)c(F)c2)c1
Yield: 93 %

Procedure:
The general McMurry protocol, described for 14 was followed. Reaction of (4-bromo-3-fluorophenyl)(3-hydroxyphenyl)methanone (196) (0.860 g, 2.3 mmol) and cycloheptanone (0.814 mL, 6.87 mmol) afforded 0.80 g, (93%) of the title compound 197 as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.89 (app t, J=7.5 Hz, 1H), 7.17 (app t, J=7.8 Hz, 1H), 6.96 and 6.92 (dd, J1=9.6 Hz, J2=1.8 Hz, 1H), 6.86 and 6.84 (dd, J1=8.1 Hz, J2=1.8 Hz, 1H), 6.73 (app br d, J=8.1 Hz, 1H), 6.70 and 6.68 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 6.61 (app t, J=1.8 Hz, 1H), 4.86 (s, 1H), 2.31 (br s, 4H), 1.59 (br s, 8H).
Reaction SMILES: Br[C:2]1[CH:21]=[N:20][C:5]2[O:6][C:7]3[C:12]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[N:11][C:10](Cl)=[N:9][C:8]=3[C:4]=2[CH:3]=1.[NH:22]1[C:30]2[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[C:25]=2[CH:24]=[CH:23]1.C(=O)([O-])O.[Na+].[CH2:39](O)[CH3:40]>O.C1(C)C=CC=CC=1>[NH:22]1[C:30]2[C:25](=[C:26]([C:10]3[N:11]=[C:12]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:7]4[O:6][C:5]5[N:20]=[CH:21][C:2]([C:40]6[CH:39]=[CH:28][CH:29]=[C:30]7[C:25]=6[CH:24]=[CH:23][NH:22]7)=[CH:3][C:4]=5[C:8]=4[N:9]=3)[CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1
Reactant: Clc1nc(N2CCOCC2)c2oc3ncc(Br)cc3c2n1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1cc(-c2cnc3oc4c(N5CCOCC5)nc(-c5cccc6[nH]ccc56)nc4c3c2)c2cc[nH]c2c1
Temperature: 120 °C

Procedure:
Under Ar(g) to a mixture of compound 5 (8 mg, 0.022 mnnol), indole-4-boronic acid (10.5 mg, 0.065 mmol), dichloro-bis(triphenylphosphine)palladium (11) (1.5 mg, 0.002 mmol) and sodium hydrogen carbonate (8 mg, 0.097 mmol) was added ethanol (1 mL) followed by toluene (1.6 mL) and then water (0.5 mL). The reaction mixture was then heated in a microwave at 120° C. (300 W) for 1 h, and was subsequently cooled to rt; the mixture was then partitioned between CH2Cl2 and water, and the organic layer was separated, dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 20-40% EtOAc/Hex) furnished E (2.7 mg, 0.005 mol, 25%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH:12]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C@H:13]([C:23]([OH:25])=O)[CH2:14][CH2:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(Cl)Cl.[CH2:39]1COC[CH2:40]1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:23](=[O:25])[C@@H:13]([NH:12][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:14][CH2:15][C:16]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:22])[CH:10]([CH2:39][CH3:40])[CH2:11]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)N1CCNCC1
Reactant: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)C(CC)C1

Procedure:
This compound was prepared using a method analogous to that of Example 22. step 22.1, intermediate 23.1 replacing 1-(ethoxycarbonyl)piperazine, and Z-(L)-Glu(OtBu)-OH replacing Boc-β-cyano-(L)-Ala-OH, but in DCM/THF (10 ml, 1:1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.C[N-]OC.[Li][CH2:16][CH2:17][CH2:18][CH3:19]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8](=[O:10])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:2]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: [Li]CCCC
Agent: C[N-]OC
Product: CCCCC(=O)Cc1cccnc1

Procedure:
In another example of the general procedure (scheme 2), readily available pyridin-3-yl-acetic acid (10) is converted to the N-methyl-N-methoxyamide derivate (12), which is reacted with BuLi to produce 1-pyridin-3-yl-hexan-2-one (13). N,N-dimethylformamide dimethylacetal treatment of 13 furnished the enamine (14) which is converted to the pyrazol (15). The synthesis of 3-(4-Butyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (16) is illustrated in scheme 2 according to the two step sequence shown in scheme 1.
Reaction SMILES: [N-]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:6]1[C:19]2[C:10](=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([C:20]([OH:22])=O)=[CH:8][CH:7]=1.[NH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][CH2:30][NH2:31]>>[CH:6]1[C:19]2[C:10](=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([C:20]([NH:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][CH2:30][NH:31][C:20]([C:9]2[C:2]3[C:19](=[CH:18][C:5]4[C:4]([N:3]=3)=[CH:17][CH:12]=[CH:13][CH:14]=4)[CH:6]=[CH:7][CH:8]=2)=[O:22])=[O:22])=[CH:8][CH:7]=1
Reactant: c1c[n-]cn1
Reactant: NCCCNCCCN
Reactant: O=C(O)c1cccc2cc3ccccc3nc12
Product: O=C(NCCCNCCCNC(=O)c1cccc2cc3ccccc3nc12)c1cccc2cc3ccccc3nc12
Yield: 80 %

Procedure:
Similar reaction of acridine-4-carboxylic acid imidazolide with N,N-bis(3-aminopropyl)amine as above, followed by purification of the product by chromatography on alumina-90, eluting with CH2Cl2 /MeOH (20:1), gave bis[3-(acridine-4-carboxamido)propyl]amine (35) (80%) as an oil. 1H NMR [(CD3)2SO] δ 11.40 (t, J=5.4 Hz, 2 H, 2×CONH), 9.19 (s, 2 H, H-9), 8.71 (d, J=7.1 Hz, 2 H, H-3), 8.32 (d, J=8.5 Hz, 2 H, ArH), 8.18-8.00 (m, 4 H, ArH), 7.83-7.62 (m, 4 H, ArH), 7.51 (t, J=7.5 Hz, 2H, ArH), 3.64 (q, J=6.0 Hz, 4H, 2×CONHCH2) 2.86 (t, J=6.7 Hz, 4H, CH2NHCH2) 1.92 (quint, J=6.5 Hz, 4 H, 2×CH2CH2CH2). Crystallization from MeOH/EtOAc/HCl gave the trihydrochloride salt, mp 171-173° C. Anal. (C34H31N5O2.2HCl.2H2O) C, H, N, Cl.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([N+:12]([O-])=O)=[C:10]([N+:15]([O-])=O)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]>CO.[Pd]>[CH3:1][O:2][C:3]1[C:11]([NH2:12])=[C:10]([NH2:15])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1c(C(=O)O)ccc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1c(C(=O)O)ccc(N)c1N

Procedure:
2-methoxy-3,4-dinitrobenzoic acid (1.0 g) was dissolved in methanol (50 mL) and treated with 100 mg 10% palladium on carbon. The reaction mixture was purged with nitrogen and placed in an ice bath. Upon treatment with 5 mL formic acid, brisk effervescence was noticed which subsides upon further cooling. The reaction mixture was filtered through celite and concentrated to give a tan solid. (Decolorization occurs rapidly upon keeping) EIMS M+182, Exp. 182.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:12](=O)(O)[O-].[Na+]>CO.O>[OH:1][C:2]1[C:3]([C:8]([O:10][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ncccc1O

Procedure:
To a solution of 3-hydroxypyridine-2-carboxylic acid (100 g, 719 mmol) in anhydrous methanol (300 ml) was added dry HCl gas until the saturation point of the solution was achieved. The reaction was heated to reflux for 15 h and then cooled and degassed with argon. The solution was concentrated in vacuo to give a white solid which was dissolved in water (250 ml). The pH of the solution was adjusted to ˜7.5 with the slow addition of solid sodium bicarbonate. The resulting suspension was extracted with EtOAc (2×300 ml), and the organic portion was dried over magnesium sulfate, filtered, and concentrated in vacuo to yield methyl 3-hydroxypyridine-2-carboxylate as an oily residue which crystallized on standing (99.2 g).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)C.B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:14][O:13][C:9]1[CH:10]=[CH:11][C:12]2[CH:4]=[CH:5][S:6][C:7]=2[CH:8]=1
Reactant: CCOC(CSc1cccc(OC)c1)OCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc2ccsc2c1
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
A solution of 1-[(2,2-diethoxy)ethylthio]-3-methoxybenzene (13.0 g, 0.051 mol) in CH2Cl2 (100 ml) was added dropwise to a solution of BF3.Et2O (6.7 ml, 0.054 mol) in CH2Cl2 (1000 ml) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 0.5 hours, treated with aqueous NaHCO3 solution, and stirred until both phases were clear. The CH2Cl2 layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give 8.68 g of an approximately 10:1 mixture of 6- and 4-methoxybenzo[b]thiophene as a dark brown oil. Purification by vacuum distillation (bp=65°-7° C. at 0.3 mmHg) gave 5.58 g of pale yellow oil. Major isomer: 'H NMR, δ :(CDCl3):3.85 (3H, s, --OCH3); 6.98 (1H, dd, J=4.5, H5); 7.23 (2H, s, H2, H3); 7.35 (1H, d, J=1.5, H7); 7.68 (1H, d, J=4.5, H4).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CN=C1.C(O)C>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12][O:13][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(NCCO)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)[Si](OCCNC(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Subsequently, to a solution of (2-hydroxyethyl)carbamic acid benzyl ester (5.37 g, 27.5 mmol) in dimethylformamide (160 ml) were added t-butyldiphenylsilyl chloride (8.6 ml, 33.0 mmol) and imidazole (2.3 g, 33.8 mmol) in an ice bath, and the mixture was stirred at room temperature overnight. After checking the completion of the reaction, ethanol was added thereto and the reaction mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (5:1) as the eluant to afford [2-(t-butyldiphenylsilyloxy)ethyl]carbamic acid benzyl ester (11.93 g, yield 100%) as a colorless and transparent syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C@H:9]2[C@@H:13]([CH2:14][OH:15])[O:12][C:11]([CH3:17])([CH3:16])[N:10]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:5]=[CH:4][N:3]=1.[CH3:25][C:26]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])[CH3:27].N1C=CN=C1>>[Si:29]([O:15][CH2:14][C@H:13]1[O:12][C:11]([CH3:17])([CH3:16])[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:9]1[CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)([C:26]([CH3:28])([CH3:27])[CH3:25])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccnc(Cl)c2)[C@@H](CO)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccnc(Cl)c2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C

Procedure:
The title compound was synthesized in a manner analogous to Example 475, step I via (4S,55)-tert-butyl 4-((2-chloropyridin-4-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate in the presence of TBSCl and imidazole and was used without further purification. Step 2: (4S,5S)-tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-4-((2-chloro-6-methylpyridin-4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:14][C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[C:19](Cl)[N:18]2[N:25]=[CH:26][N:27]=[C:17]2[N:16]=1>C(Cl)Cl>[Cl:14][C:15]1[C:20]([CH:21]([CH3:22])[CH3:23])=[C:19]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:18]2[N:25]=[CH:26][N:27]=[C:17]2[N:16]=1
Reactant: CC(C)c1c(Cl)nc2ncnn2c1Cl
Reactant: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1c(Cl)nc2ncnn2c1NC1CCCC1
Yield: 76 %

Procedure:
With stirring, a mixture of 0.13 g (1.5 mmol) of cyclopentylamine and 0.15 g (1.5 mmol) of triethylamine in 10 ml of methylene chloride was added to a mixture of 0.34 g (1.5 mmol) of 5,7-dichloro-6-isopropyl-[1,2,4]-triazolo-[1,5-α]-pyrimidine (cf. Ex. 2) in 20 ml of methylene chloride. The reaction mixture was stirred at room temperature for 16 h and then washed with 5% strength hydrochloric acid. The organic phase was separated off, dried over sodium sulfate and filtered. The filtrate was freed from the solvent and the residue was purified chromatographically. This gave 0.32 g (1.14 mmol) of the title compound (melting point 139° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)#[N:2].[CH3:15][N:16]([CH:18]=O)[CH3:17]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:15][N:16]([CH3:18])[CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)#[N:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)Cc1ccc(C#N)cc1
Product: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
Combined ethyl 2-(4-cyanophenyl)acetate (25 g, 0.132 mol) with DMF-DEA (60 mL) and heated to 70° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated and then purified by flash chromatography to give the title compound (20 g, 62%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.71 (d, J=8.4 Hz, 2H), 7.59 (s, 1H), 7.29 (d, J=8.4 Hz, 2H), 4.03 (q, J=6.8 Hz, 2H), 2.67 (s, 6H), 1.13 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[S:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][N:7]=1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:15]2[CH2:16][CH2:17][CH:12]([N:2]([CH3:1])[C:3]3[S:4][C:5]([C:8]([F:11])([F:9])[F:10])=[N:6][N:7]=3)[CH2:13][CH2:14]2)=[CH:21][CH:20]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: CN(c1nnc(C(F)(F)F)s1)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: CN(c1nnc(C(F)(F)F)s1)C1CCN(Cc2ccc(F)cc2)CC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A mixture of methyl-piperidin-4-yl-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-amine (D2) (0.050 g, 0.19 mmol), 4-fluorobenzyl chloride (0.029 ml, 0.24 mmol) and diisopropylethylamine (0.050 ml, 0.28 mmol) in acetonitrile (3 ml) was stirred at 120° C. for 30 min., under microwave irradiation. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and extracted with a 10% solution of ammonium chloride (25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 0-1.5% ammonia in methanol (7M)/dichloromethane) to yield E1 (0.061 g, 87%) as a solid. C16H18F4N4S requires 374. Found 375 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[CH3:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH3:19][C:20]1[CH:25]=[C:24]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cccc(-c2nc(Nc3cc(C)[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-methyl-phenylboronic acid to give [1-(3-methyl-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 315(MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:19]([O-])=[O:20].[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH2:8][N:9]([N:19]=[O:20])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(Cc2ccccc2)CCNCC1
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1(Cc2ccccc2)CCN(N=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
To a solution of 4-ethoxycarbonyl-4-benzylpiperidine (495 mg) in water (5 mL) was added sodium nitrite (276 mg) and acetic acid (201 μL) and the mixture was stirred at room temperature overnight. To the reaction mixture was added an aqueous saturated sodium hydrogencarbonate solution and the mixture was stirred and extracted with chloroform. The extract was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=85/15 to 80/20) and dried in vacuo to give 4-ethoxycarbonyl-4-benzyl-1-nitrosopiperidine (565 mg, yield: 100%) as a colorless solid. To a solution of the product (565 mg) in methanol (3 mL) was added zinc powder (654 mg) and then added acetic acid (3 mL) under ice-cooling and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. To the residue was added an aqueous saturated sodium hydrogencarbonate solution and chloroform and the mixture was stirred and extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 1-amino-4-benzyl-4-ethoxycarbonylpiperidine (508 mg, yield: 97%) as a colorless viscidity.
Reaction SMILES: [CH2:1]([CH2:10][CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[NH:15][C:14]=1[C:24]([O:26]CC)=[O:25])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].O.O.[OH-].[Li+].Cl>O1CCCC1>[CH2:1]([CH2:10][CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[NH:15][C:14]=1[C:24]([OH:26])=[O:25])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCCC(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCCNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccccc1
Yield: 55.3 %

Procedure:
Mix 3-[(phenacyl)ethylamino]-2-carbethoxy-4,6-dichloroindole (600 mg, 1.48 mmol), water (10 mL) and tetrahydrofuran (10 mL). Add lithium hydroxide monohydrate (0.22 g, 5.18 mmol) and stir at room temperature for 24 hours. Heat to reflux for 5 hours then pour into 1N hydrochloric acid (100 mL). Extract into ethyl acetate, dry (MgSO4) and evaporate the solvent in vacuo to give the crude product (0.72 g) as a white solid. Recrystallize (ethyl acetate/hexane) to give the title compound (0.32 g, 57%); mp 254°-6° C.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:13]=[CH:14][CH:15]=1)=[N:5]2.[H-].[Na+].[CH3:23]I>CN(C)C=O>[CH3:23][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[CH:7]=[CH:8][C:9]3[N:4]([CH:3]=[N:2][N:1]=3)[N:5]=2)[CH:11]=1)[C:17](=[O:20])[O:18][CH3:19]
Reactant: CI
Reactant: COC(=O)Nc1cccc(-c2ccc3nncn3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)N(C)c1cccc(-c2ccc3nncn3n2)c1
Reaction time: 1 h

Procedure:
A mixture of 2.25 g of [3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]carbamic acid, methyl ester, 0.42 g of sodium hydride (50% in oil) and 200 ml of dimethylformamide was stirred under argon, for 1 hour and then 0.55 ml of methyl iodide was added. This mixture was stirred overnight, then treated as described in Example 1, giving 1.3 g of the desired product as tan crystals, mp 195°-199° C.