Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:11]([N:18]1[CH2:24][CH:23]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:22]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([F:41])[CH:35]=2)[O:21][CH2:20][C:19]1=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[CH2:11]([N:18]1[CH2:24][CH:23]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:22]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([F:41])[CH:35]=2)[O:21][CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1CN(Cc2ccccc2)C(=O)COC1c1ccc(Cl)c(F)c1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC1CN(Cc2ccccc2)CCOC1c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution of aluminum(III) chloride (5.28 g) in THF (396 mL) was added, under a nitrogen stream, lithium aluminum hydride (4.51 g) under ice-cooling, and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added dropwise a solution of (6RS,7SR)-4-benzyl-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-3-one (31.5 g) in THF (264 ml), and the mixture was stirred at 0° C. for 2 hr. To the reaction mixture was added aqueous potassium sodium (+)-tartrate tetrahydrate (93.0 g) solution at 0° C., and the mixture was stirred at room temperature overnight, and filtered through celite. The obtained oil was diluted with ethyl acetate, and the mixture was washed with distilled water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (26.4 g).
Reaction SMILES: C(C1N(CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)C(C(OCOP(OC)(O[C@H]2CO[C@@H]3[C@H](O[N+]([O-])=O)CO[C@H]23)=O)=O)=C(Cl)N=1)CCC.[CH2:70]([C:74]1[N:75]([CH2:92][C:93]2[CH:98]=[CH:97][C:96]([C:99]3[CH:104]=[CH:103][CH:102]=[CH:101][C:100]=3[C:105]3[N:109](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:108]=[N:107][N:106]=3)=[CH:95][CH:94]=2)[C:76]([C:80]([O:82][CH2:83][P:84]([O:89][CH2:90][CH3:91])([O:86][CH2:87][CH3:88])=[O:85])=[O:81])=[C:77]([Cl:79])[N:78]=1)[CH2:71][CH2:72][CH3:73]>>[CH2:70]([C:74]1[N:75]([CH2:92][C:93]2[CH:98]=[CH:97][C:96]([C:99]3[CH:104]=[CH:103][CH:102]=[CH:101][C:100]=3[C:105]3[NH:109][N:108]=[N:107][N:106]=3)=[CH:95][CH:94]=2)[C:76]([C:80]([O:82][CH2:83][P:84]([O:89][CH2:90][CH3:91])([O:86][CH2:87][CH3:88])=[O:85])=[O:81])=[C:77]([Cl:79])[N:78]=1)[CH2:71][CH2:72][CH3:73]
Reactant: CCCCc1nc(Cl)c(C(=O)OCP(=O)(OCC)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCc1nc(Cl)c(C(=O)OCOP(=O)(OC)O[C@H]2CO[C@H]3[C@@H]2OC[C@H]3O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCc1nc(Cl)c(C(=O)OCP(=O)(OCC)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
The title compound was prepared by following step E in Example 13, except that the reagent [(methoxy{[(3S,3aS,6R,6aS)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl]oxy}phosphoryl)oxy]methyl 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate was replaced by (diethoxyphosphoryl)methyl 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate. 1H NMR (500 MHz, CDCl3) δ 8.00 (dd, J=7.7, 1.3 Hz, 1H), 7.57 (t, J=7.4 Hz, 1H), 7.50 (td, J=7.6, 1.4 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.12 (d, J=8.2 Hz, 2H), 6.87 (d, J=8.0 Hz, 2H), 5.45 (s, 2H), 4.48 (d, J=8.9 Hz, 2H), 4.11 (quintet, J=7.3 Hz, 4H), 2.71 (t, J=7.8 Hz, 2H), 1.73 (quintet, J=7.7 Hz, 2H), 1.39 (sextet, J=7.4 Hz, 2H), 1.30 (t, J=7.1 Hz, 6H), 0.90 (t, J=7.5 Hz, 3H); LC-MS: m/z 587.1 (M+H).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4](Cl)=[CH:3][CH:2]=1.[NH2:9][C@@H:10]([C:21]([OH:23])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1>>[C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([NH:9][C@@H:10]([C:21]([OH:23])=[O:22])[CH2:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: Cc1ccc(N[C@H](Cc2c[nH]c3ccccc23)C(=O)O)cc1
Yield: 82 %

Procedure:
The same procedure is used as in Example 1, p-toluyl chloride and D-tryptophane being used. Yield 82%. Melting point 146.5° to 147.5° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([OH:17])[CH:10]=1)=[O:7].[CH2:18](OC1C=C(O)C=CC=1OC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.O1C=CC=C1C(Cl)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1)=[O:7]
Reactant: COc1ccc(OC(=O)c2ccco2)cc1O
Reactant: COc1ccc(O)cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1ccco1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(OC(=O)c2ccco2)cc1OCc1ccccc1

Procedure:
The compound 3-hydroxy-4-methoxyphenyl 2-furoate was made as follows. An amount of 2.00 gms. of 3-benzyloxy-4-methoxyphenol, 1.00 gms. of triethylamine and 0.10 gms of 4-dimethylaminopyridine were dissolved in 100 ml. of methylene chloride at 0° C. and stirred. To the mixture was added 1.16 gms. of 2-furoyl chloride and the mixture was stirred overnight. The mixture was then washed wth equal volumes of 1 M hydrochloric acid, saturated sodium bicarbonate and water. The mixture was then dried over magnesium sulfate and the solvent evaporated to yield 3-benzyloxy-4-methoxyphenyl 2-furoate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:12])=[C:4]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]=[N:6][CH:7]=1.[CH2:13](OC(OCC)OCC)C>>[Cl:1][C:2]1[C:3]2[N:12]=[CH:13][N:8]([CH:9]3[CH2:10][CH2:11]3)[C:4]=2[N:5]=[N:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1c(Cl)cnnc1NC1CC1
Product: Clc1cnnc2c1ncn2C1CC1
Yield: 48 %

Procedure:
A mixture of 5-chloro-N-3-cyclopropylpyridazine-3,4-diamine (Preparation 90, 10.0 g, 54 mmol) and triethylorthoformate (120 mL) were heated to reflux for 3 hours. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with CH2Cl2:MeOH 98:2 to afford the title compound as a brown solid in 48% yield, 5 g.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]([NH:18][C:19]2[CH:24]=[C:23]([NH:25][C:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH:29]=3)=[O:27])[CH:22]=[CH:21][C:20]=2[CH3:40])=[O:17])=[CH:12][CH:11]=1>O>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:10]1[N:15]=[CH:14][C:13]([C:16]([NH:18][C:19]2[CH:24]=[C:23]([NH:25][C:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)[CH:29]=3)=[O:27])[CH:22]=[CH:21][C:20]=2[CH3:40])=[O:17])=[CH:12][CH:11]=1
Reactant: CN(C)CCCCN
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccc(Cl)nc1
Solvent: O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccc(NCCCCN(C)C)nc1
Temperature: 100 °C

Procedure:
A mixture of 4-dimethylaminobutylamine (5 ml) and 6-chloro-N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-3-carboxamide (0.181 g) was stirred and heated to 100° C. for 16 hours. The mixture was poured into water (50 ml) and stirred for 20 minutes. The resultant solid was isolated, washed with diethyl ether and under vacuum at 40° C. There was thus obtained the title compound (0.17 g); NMR Spectrum: (DMSOd6) 1.4-1.6 (m, 4H), 2.1 (s, 6H), 2.19 (s, 3H), 2.21 (m, 2H), 3.52 (m, 6H, 3.72 (m, 4H), 6.49 (d, 1H), 7.14 (m, 2H), 7.21 (m, 2H), 7.54 (d, 1H), 7.78 (s, 1H), 7.85 (d, 1H), 8.27 (d, 1H), 8.64 (s, 1H), 9.51 (s, 1H), 10.26 (s, 1H); Mass Spectrum M+H+ 532.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:28][C:29]([F:43])([F:42])[C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:41])[CH2:37][C:38](=O)[CH3:39])=[CH:32][CH:31]=1>>[CH3:39]/[C:38](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:37]/[C:36](=[O:41])[C:33]1[CH:34]=[CH:35][C:30]([C:29]([F:28])([F:42])[F:43])=[CH:31][CH:32]=1
Reactant: CC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1sc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: C/C(=C/C(=O)c1ccc(C(F)(F)F)cc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)sc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 290 mg (0.76 mmol) of Intermediate 47 and 150 mg (0.76 mmol) of Intermediate 24 to yield 140 mg (31% yield) of Example 10: TLC (DCM/MeOH, 4/1): Rf=0.47; 1H NMR (DMSO-d6, 300 MHz) δ11.52 (d, 1H, J=8.9), 7.96 (d, 2H, J=8.1), 7.80 (m, 2H), 7.72 (d, 2H, J=8.4 ), 7.42 (m, 3H), 7.10 (d, 2H, J=8.4), 6.80 (d, 2H, J=8.4), 5.61 (s, 1H), 4.20 (t, 2H, J=6.6), 4.15 (m, 1H), 3.17 (m, 1H), 3.05 (t, 2H, J=6.5), 2.77 (dd, 1H, J=13.6, 8.6), 2.41 (s, 3H), 1.69 (s, 3H); low resolution MS (ES+)m/e 595.0 (MH+).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:34])[C:11]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:15](=[O:28])[C:14]=12)C1C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][N:16]1[CH2:17][CH2:18][N:13]2[CH:12]=[C:11]([C:29]3[S:30][CH:31]=[CH:32][N:33]=3)[C:10](=[O:34])[C:9]([OH:8])=[C:14]2[C:15]1=[O:28]
Reactant: O=C1c2c(OCc3ccccc3)c(=O)c(-c3nccs3)cn2CCN1Cc1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2c(O)c(=O)c(-c3nccs3)cn2CCN1Cc1ccc(Cl)c(Cl)c1
Yield: 69.2 %

Procedure:
9-Benzyloxy-2-(3,4-dichlorobenzyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (93 mg) was dissolved in trifluoroacetic acid (2 ml). After leaving at room temperature for 1.5 hr, the mixture was concentrated. Toluene was added to the residue and the mixture was concentrated again, which operations were performed twice. Ethyl acetate was added and the solid was collected by filtration to give 2-(3,4-dichlorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (53 mg).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:6][C:5]=1[O:21][CH3:22].[OH-].[Li+].Cl.O>C1COCC1.CO>[CH3:22][O:21][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[CH:8]=[C:9]([CH3:10])[C:4]=1[C:3]([OH:23])=[O:2]
Reactant: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)O
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a solution of 0.325 g (1.00 mmol) of 2-methoxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid methyl ester in 20 ml of THF/MeOH (1:1) was added 2.50 ml (2.50 mmol) of lithium hydroxide solution (1 molar in water) drop by drop and the reaction mixture was then heated up to reflux. After 8 hours, it was poured into crashed ice and acidified with HCl/H2O (1N) to pH 3.0 and then extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 0.24 g (77%) of the title compound as light yellow solid. MS: 310.0 (M−H−).
Reaction SMILES: [C:1](OC(C)(C)C)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)[NH2:17].CS(O)(=O)=O.O>C1(C)C(C)=CC=CC=1>[CH3:22][O:21][C:19]1[CH:20]=[C:14]([O:13][CH3:12])[CH:15]=[C:16]2[C:18]=1[C:3]([CH3:5])=[CH:2][C:1](=[O:6])[NH:17]2
Reactant: COc1cc(N)cc(OC)c1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1cc(OC)c2c(C)cc(=O)[nH]c2c1
Temperature: 125 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl acetoacetate (1.58 g) was heated to 120° C. and 3,5-dimethoxyaniline (1.53 g) dissolved in xylene (4 ml) was added The mixture was heated at 120-130° C. for 20 minutes and then cooled to room temperature. Methanesulfonic acid (2 ml) was added and the mixture was stirred at ambient temperature for 10 minutes. Water (40 ml) was added and the precipitate filtered and dried. Yield 1.31 g (60%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([C:21]2([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40].CO>C(OCC)(=O)C>[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:24]3[CH2:23][CH2:22][C:21]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)([O:27][C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=4)[CH2:26][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: FC(F)(F)c1ccc(OC2(c3ccccc3)CCNCC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(Oc2ccc(C(F)(F)F)cc2)(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-phenyl-4-(4-trifluoromethylphenoxy)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 49% overall yield. FDMS m/e=510 (M+ of free base). α[D]589 =-11.99 (c=0.42, methanol).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[N:18]([CH2:33][CH:34]3C[CH2:37][CH2:36][N:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=3)N=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([O-])=O.[NH4+:56]>CO.[Pd]>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:56]=[C:17]([CH:14]3[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]3)[N:18]([CH:33]3[CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:34]3)[CH:19]=2)=[CH:23][C:24]=1[C:29]([F:30])([F:32])[F:31]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCCC1Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCNCC2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
To a solution of 4-[1-(1-tert-butoxycarbonyl-pyrrolidin-2-ylmethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester (200.00 mg; 0.32 mmol; 1.00 eq.) in methanol 5 ml added trifluoro-acetic acid (54.24 mg; 0.48 mmol; 1.50 eq.), stirred at RT for 5 min, added ammonium formate (199.96 mg; 3.17 mmol; 10.00 eq.) and 200 mg wet 10% Pd/C, stirred at RT for 1 hr, lc-ms showed clean desired. Removed off solvent, added EA 50 ml, washed with Brine and 5% NaHCO3, dried, removed off solvent, got title compound 110 mg, yield 70%.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([C:10]1[NH:11][C:12]2[C:17]([C:18](=[O:21])[C:19]=1[CH3:20])=[CH:16][C:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=[C:14]([CH3:34])[CH:13]=2)[CH3:9].[OH-].[Na+].Cl[C:38]([O:40][CH3:41])=[O:39]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CC(N(C)C)=O>[C:38](=[O:39])([O:40][CH3:41])[O:21][C:18]1[C:17]2[C:12](=[CH:13][C:14]([CH3:34])=[C:15]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:25][CH:24]=3)[CH:16]=2)[N:11]=[C:10]([CH2:8][CH3:9])[C:19]=1[CH3:20]
Reactant: COC(=O)Cl
Reactant: CCc1[nH]c2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(=O)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCc1nc2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(OC(=O)OC)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Toluene (810 ml), 90 ml of dimethyl acetamide, 113.2 g of 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4(1H)-one, and 4.8 g of tetrabutylammonium bromide were added to a glass vessel equipped with a stirring device, a thermometer, and a reflux condenser and having a volume of 3000 ml, and the mixture was stirred at room temperature. A 48% aqueous sodium hydroxide solution (50 g) was added dropwise thereto at 30 to 35° C., and the mixture was stirred at the same temperature for one hr. After cooling to 10 to 15° C., 34 g of methyl chloroformate was added dropwise, and a reaction was allowed to proceed at the same temperature for one hr. Water was added to the reaction solution. After washing, toluene was removed by evaporation, and the precipitated solid was collected by a suction filter. The solid was dried in vacuo to give 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4-yl methyl carbonate (128 g, yield 98%). It was confirmed from the results of measurement of 1H-NMR that the compound thus obtained was a compound of No. 120 described in WO2006/013896 (patent document 1).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1.[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]=1[O:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=1)[CH3:28]
Reactant: COc1cccc(O)c1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2cccc(OC)c2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 51.2 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.8 g), 3-methoxyphenol (0.34 g), 8 M potassium hydroxide solution (0.34 mL) and dimethyl sulfoxide (10 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.45 g, 51%).
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[C:13]2[C:8](=[C:9]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:20]([N:17]1[CH2:18][CH2:19][N:14]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[CH:7]=[CH:6][NH:5]3)[CH2:15][CH2:16]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(N3CCN(Cc4ccccc4)CC3)cccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: c1ccc(CN2CCN(c3cccc4[nH]ccc34)CC2)cc1

Procedure:
To a solution of 1.2 gram (2.68 mmole) 1-triisopropylsilanyl-4-(4-benzyl-piperazin-1-yl)-1H-indole in 20 mL tetrahydrofuran was added 3 mL (3 mmole) 1.0 M tetrabutylammonium fluoride in tetrahydrofuran. After 2 hours the solution was concentrated under reduced pressure and the residue was partitioned between 25 mL ethyl ether and 10 mL 10% sodium carbonate. The organic phase was washed with 3×10 mL water, dried (magnesium sulfate), and concentrated. 4-(4-Benzyl-piperazin-1-yl)-1H-indole was isolated as the white hydrochloride salt from ethyl ether, 604 mg, m.p. 233-234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]I>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]2([CH2:10][C:11]([OH:13])=[O:12])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])=[CH:6][CH:7]=1
Reactant: ICCCCCI
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CC1(C(=O)c2ccc(Cl)cc2)CCCCC1
Temperature: 0 °C

Procedure:
8.4 g (0.04 mol) of 4-(4-chlorophenyl)-4-oxo-butyric acid are dissolved in 300 ml tetrahydrofuran, combined batchwise with 5.8 g (0.12 mol) of sodium hydride (50% in oil) and refluxed for 90 minutes. After the addition of 8.9 ml (0.06 mol) of 1,5-diiodopentane the reaction mixture is refluxed for a further 3 hours. After cooling the reaction mixture is stirred into ice water, the tetrahydrofuran is distilled off and the residue is extracted with methylene chloride. The aqueous phase is acidified with hydrochloric acid and extracted with methylene chloride. The combined organic extracts are dried and evaporated down. The residue is chromatographed on silica gel and eluted with methylene chloride+ethanol (1 to 2%).
Reaction SMILES: [CH3:1][S:2][CH2:3][C@H:4]1[O:8][C:7](=[O:9])[N:6]([NH:10]C(=O)OC(C)(C)C)[CH2:5]1.O1CCOCC1.C(OC(C)C)(C)C.[ClH:31]>C1COCC1>[ClH:31].[NH2:10][N:6]1[CH2:5][C@@H:4]([CH2:3][S:2][CH3:1])[O:8][C:7]1=[O:9]
Reactant: CSC[C@@H]1CN(NC(=O)OC(C)(C)C)C(=O)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CSC[C@@H]1CN(N)C(=O)O1
Temperature: 25 °C
Reaction time: 96 h
Yield: 85 %

Procedure:
To a solution of (S)-tert-butyl 5-(methylthiomethyl)-2-oxooxazolidin-3-ylcarbamate (374 mg, 1.426 mmol) in THF (2 mL), 4M HCl in dioxane (1.25 mL, 4.99 mmol) was added. The reaction was stirred at r.t. for 4 days and a white solid precipitated. The obtained product was filtered and triturated with hot diisopropyl ether affording the title compound (240 mg, 1.208 mmol). Yield=85%.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:7]1([N:1]2[CH2:4][CH:3]([OH:5])[CH2:2]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1ccccc1
Reactant: OC1CNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: OC1CN(c2ccccc2)C1
Temperature: 100 °C
Yield: 5 %

Procedure:
The mixture of azetidin-3-ol (2 mmol), bromobenzene (2 mmol), Pd(OAc)2 (0.1 mmol), 2-(di-tert-butylphosphino)biphenyl (0.2 mmol) and NaOtBu (3 mmol) in toluene (3 mL) was heated at 100° C. for 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (15 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10]CCC#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-]=[N+]=[N-].[Na+].Cl.C(N(CC)CC)C.Cl>CN1C(=O)CCC1.O>[CH2:1]([O:8][C:9](=[O:15])[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCNC(=O)OCc1ccccc1
Agent: Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
A mixture of (2-cyano-ethyl)-carbamic acid benzyl ester (2.6 g, 12.7 mmol), sodium azide (2.48 g, 38 mmol) and triethylamine hydrochloride (2.62 g, 19 mmol) in NMP (96 mL) was stirred at 100° C. under Ar. After 24 h, the reaction was cooled to room temperature. Additional sodium azide (1.24 g, 19 mmol) and triethylamine hydrochloride (1.3 g, 9.5 mmol) was added to the reaction mixture and the solution was heated to 100° C. under Ar. After 18 h, the reaction was diluted with water (100 mL). 1M HCl was added dropwise until the pH was slightly acidic (˜pH 4). The solution was extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (3×100 mL) and brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to yield a brown oil. Flash chromatography on silica gel (0-15% MeOH in CH2Cl2) yielded 1.1 g of crude 2-(1H-tetrazol-5-yl)-ethyl]-carbamic acid benzyl ester (˜70% pure).