Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@H:4]1[NH:19][C:18](=[O:20])[C@@H:17]([CH2:21][S:22]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[NH:16][C:15](=[O:42])[C@@H:14]([CH3:43])[NH:13][C:12](=[O:44])[CH2:11][C@@H:10](/[CH:45]=[CH:46]/[CH2:47][CH2:48][S:49]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:9][C:8](=[O:69])[CH2:7][NH:6][C:5]1=[O:70])([CH3:3])[CH3:2].S([O-])([O-])(=O)=S.[Na+].[Na+].[Na+].[Cl-]>C(Cl)Cl.CO>[CH:1]([C@H:4]1[NH:19][C:18](=[O:20])[C@@H:17]2[NH:16][C:15](=[O:42])[C@@H:14]([CH3:43])[NH:13][C:12](=[O:44])[CH2:11][C@@H:10]([CH:45]=[CH:46][CH2:47][CH2:48][S:49][S:22][CH2:21]2)[O:9][C:8](=[O:69])[CH2:7][NH:6][C:5]1=[O:70])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](C)NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)CNC1=O
Agent: CC(C)[C@H]1NC(=O)[C@H]2CSSCC/C=C/[C@H](CC(=O)N[C@H](C)C(=O)N2)OC(=O)CNC1=O
Agent: O=S([O-])([O-])=S
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)[C@H]1NC(=O)[C@H]2CSSCCC=C[C@H](CC(=O)N[C@H](C)C(=O)N2)OC(=O)CNC1=O
Reaction time: 0.5 h

Procedure:
To a vigorously stirring solution of 12 (1120 mg, 4.42 mmol) in CH2Cl/MeOH (9:1, 1000 mL) was added the protected dithiol 8A (430 mg, 0.44 mmol) in CH2Cl2/MeOH (9:1, 500 mL) dropwise over 30 minutes. After stirring for a further 30 minutes, 0.1M sodium thiosulfate (300 mL) and sat. NaCl (100 mL) were added, extracting with CH2Cl2 (3×100 mL). The combined organic extract was dried (MgSO4), filtered, and solvent removed. The residue was purified by flash chromatography (eluent 1-6% MeOH/CH2Cl2) to give 9A (205 mg, 0.42 mmol, 96%) as a white solid: [α]22D −98.0 (c 0.50, CHCl3); IR νmax 3300, 2477, 1734, 1659, 1526, 1446 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=6.5 Hz, 1H), 7.33 (t, J=5.3 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 6.60 (d, J=3.8 Hz, 1H), 5.95 (dtd, J=16.1, 6.5, 2.0 Hz, 1H), 5.80-5.70 (m, 2H), 4.85 (ddd, J=9.8, 8.5, 3.8 Hz, 1H), 4.21 (qd, J=7.3, 3.8 Hz, 1H), 4.11 (d, J=5.3 Hz, 2H), 3.44 (dd, J=15.6, 10.0 Hz, 1H), 3.20 (dd, J=10.3, 6.8 Hz, 1H), 3.01-2.95 (m, 2H), 2.92 (dd, J=15.6, 4.0 Hz, 1H), 2.85-2.58 (m, 5H) 1.49 (d, J=7.5 Hz, 3H), 0.98 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.5 Hz, 3H); 13C NMR 100 MHz 173.3 (C), 171.6 (C), 171.0 (C), 169.4 (C), 168.2 (C), 130.4 (CH), 130.3 (CH), 69.8 (CH), 64.9 (CH), 54.5 (CH), 52.0 (CH), 42.4 (2×CH2), 38.7 (CH2), 38.6 (CH2), 32.7 (CH2), 27.5 (CH), 20.8 (CH3), 20.1 (CH3), 16.7 (CH3); LRMS (ES+) m/z 995 (50%, [2M+Na]+), 509 (80%, [M+Na]+), 487 (100%, [M+H]+); HRMS m/z 509.1495 (M+Na)+ expected 509.1499.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:12].[Cl:22][CH2:23][C:24](Cl)=[O:25].Cl>ClCCCl>[Cl:22][CH2:23][C:24]([C:9]1[CH:8]=[C:7]([C:11](=[O:12])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[N:6]([CH3:5])[CH:10]=1)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: Cn1cccc1C(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1cc(C(=O)CCl)cc1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
A 210 g (1.57 mole) sample of AlCl3 was added in portions to a solution of 145.4 g (0.63 mole) of (1 -methyl-1H-pyrrol-2-yl)(4-nitrophenyl)-methanone (1) in 450 mL of 1,2-dichloroethane (DCE). A solution of 125 mL (1.57 mole) of chloroacetyl chloride in 200 mL of DCE was added dropwise. The mixture was stirred 1 h at room temperature. The reaction was poured into 1N HCl and ice, the organics were separated, washed with H2O, 1N NaOH, H2O, brine and dried (MgSO4). The solvent was evaporated in vacuo and the residue was recrystallized from EtOAc/EtOH to give 116.2 g of solid. mp 173°-176° C. Mass spectrum (Cl-CH4) m/z 307 (M+1). NMR (Me2SO-d6)δ 8.4 (d, 2 H); 8.2 (s,1 H); 8.0 (d, 2 H); 7.1 (s, 1 H); 4.8 (s, 2 H); 4.0 (s, 3 H). Anal calcd for C14H11CIN2O4 : Calcd: C, 54.83; H, 3.61; N, 9.13. Found: C, 55.11;H, 3.70; N, 9.10.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)=[O:13])[C:3]([O:5]C)=[O:4].[NH4+].[OH-]>O>[NH2:1][C@@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)=[O:13])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)C1CC(=O)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: N[C@@H](CCCCNC(=O)C1CC(=O)C1)C(=O)O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
(S)-methyl 2-amino-6-(3-oxocyclobutanecarboxamido)hexanoate (0.297 g) and 18 mL H2O were put in a 40 mL glass vial. To the resulting clear solution was added 2.2 mL 1N NH4OH, and the reaction was shaken at ambient temperature for 22 hours, at which time the LCMS analysis revealed a complete reaction. The reaction mixture was frozen and lyophilized, affording (S)-2-amino-6-(3-oxocyclobutanecarboxamido)hexanoic acid (TU3205-030) as colorless crystals. MS (ESI+): m/z 243.20 (MH+).
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21]CC3OC3)=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1)C1OC1.C(O)(=O)C=C.C(C1CC(=O)OC1=O)=CCCCCCC>>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)([CH3:14])[CH3:13])=[CH:10][CH:11]=1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Agent: C=CC(=O)O
Agent: CCCCCCC=CC1CC(=O)OC1=O
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reaction time: 2 h

Procedure:
10.54 g of bisphenol A diglycidyl ether was heated to 70 C. under stirring and then 4.46 g acrylic acid was added slowly under nitrogen atmosphere. After maintaining the reaction at 70 C. for 2 hours, 13.0 g of 2-octen-1-ylsuccinic anhydride was added and then the temperature was raised to 80 C. under mechanical stirring. The reactants are stirred at 80 C. for 2-3 hours to complete the reaction.
Reaction SMILES: [O:1]([CH2:19][CH:20]([CH3:48])[CH2:21][CH2:22][CH2:23][C:24]([CH3:47])([OH:46])[C:25](=[O:45])[CH2:26][CH2:27][C:28]1([O:44][CH2:43][CH2:42][O:41]1)[CH2:29][O:30][S:31]([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C.[CH3:56][S:57]([CH3:59])=O>>[O:1]([CH2:19][CH:20]([CH3:48])[CH2:21][CH2:22][CH2:23][C:24]([CH3:47])([O:46][CH2:56][S:57][CH3:59])[C:25](=[O:45])[CH2:26][CH2:27][C:28]1([O:41][CH2:42][CH2:43][O:44]1)[CH2:29][O:30][S:31]([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CS(C)=O
Reactant: Cc1ccc(S(=O)(=O)OCC2(CCC(=O)C(C)(O)CCCC(C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)OCCO2)cc1
Solvent: CC(=O)OC(C)=O
Product: CSCOC(C)(CCCC(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)CCC1(COS(=O)(=O)c2ccc(C)cc2)OCCO1
Reaction time: 20 h
Yield: 91 %

Procedure:
11-t-Butyldiphenylsiloxy-6,10-dimethyl-2,2-ethylenedioxy-6-hydroxy-5-oxo-1-tosyloxyundecane (1.15 g) is dissolved in dimethyl sulfoxide (8.15 ml), acetic anhydride (8.15 ml) is added and the resulting solution is stirred for 20 hours. The solvents are removed in vacuo below 70° C. and the residue is partitioned between ether and saturated sodium bicarbonate solution. The organic layer is washed with brine and dried (sodium sulfate). The solvent is removed in vacuo to give 11-t-butyldiphenylsiloxy-6,10-dimethyl-2,2-ethylenedioxy-6-methylthiomethoxy-5-oxo-1-tosyloxyundecane (1.13 g, 91%) as a yellow oil; nmr (CDCl3,δ) 0.88 (d, CH3CH), 1.04 [s, (CH3)3 -C], ##STR29## 2.17 (s, SCH3), 2.42 (s, CH3 -Ph), 3.42 (d, OCH2CH), 3.89 (s, OCH2CH2O and TsOCH2C), 4.41 (s, OCH2S), 7.2-7.9 (aromatic H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([NH2:14])=[O:13])=[CH:6][CH:5]=1.[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:14]=[C:12]([CH:11]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:15])([F:16])[F:1])=[CH:9][CH:8]=2)[O:13][CH:21]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)C=Cc1ccc(OC(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1

Procedure:
4.28 g (18.5 mmol) 3-(4-Trifluoromethoxy-phenyl)-acrylamide, 2.80 g (22.2 mmol) 1,3-dichloroacetone and 30.0 ml toluene were kept at reflux temperature for 16 h with continuous removal of water by use of a Dean-Stark trap. After removal of solvents in vacuo, the residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 20:1). All fractions containing the product were concentrated to a volume of 10 ml and the crystallized material isolated by filtration, washed with cold heptane and dried. 1.75 g (31%) 4-Chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]([C:27]([CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1)=[O:28])[NH2:26].[CH2:42]([O:49][N:50]1[C:56](=[O:57])[N:55]2[CH2:58][C@H:51]1[CH2:52][CH2:53][C@H:54]2[C:59](O)=[O:60])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:42]([O:49][N:50]1[C:56](=[O:57])[N:55]2[CH2:58][C@H:51]1[CH2:52][CH2:53][C@H:54]2[C:59]([NH:26][NH:25][C:27]([CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1)=[O:28])=[O:60])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 12 h
Yield: 60.5 %

Procedure:
HATU (3.3 g, 8.7 mmol) and tert-butyl 4-(hydrazinecarbonyl)piperidine-1-carboxylate (2.29 g, 9.42 mmol) were added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (2.0 g, 7.25 mmol) in CH2Cl2 (50 mL) at 0° C. DIPEA (2.8 g, 21.8 mmol) was then added and the reaction mixture was stirred at 0° C. for 12 hrs. The reaction mixture was then washed with water and saturated sodium chloride and dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (10:1 DCM/MeOH) to give tert-butyl 4-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonyl)piperidine-1-carboxylate (2.2 g, 62%) as a white solid. ESI-MS (EI+, m/z): 502.2 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:29])([CH:26]([F:28])[F:27])[CH2:16][O:17][C:18]1[N:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=1.[OH-].[K+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:25][CH2:24][C:21]2[CH:22]=[N:23][C:18]([O:17][CH2:16][C:15]([F:29])([F:14])[CH:26]([F:28])[F:27])=[CH:19][CH:20]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1ccc(OCC(F)(F)C(F)F)nc1
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)n1ncc(OCc2ccc(OCC(F)(F)C(F)F)nc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
In 40 ml of N,N-dimethylformamide were dissolved 2.2 g of 2-t-butyl-4,5-dichloro-3(2H)-pyridazinone and 2.5 g of 6-(2,2,3,3-tetrafluoropropyloxy)-3-pyridine methanol, and thereto was added 0.7 g of powdery potassium hydroxide. The reaction mixture was stirred overnight at room temperature and poured into water. Then, procedures similar to those in Preparation Example 24 were conducted to obtain 3.6 g of 2-t-butyl-4-chloro-5-[{6-(2,2,3,3-tetrafluoropropyloxy)-3-pyridyl}-methyloxy]-3(2H)-pyridazinone, m.p. 112.0°~118.0° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C>C(O)C.[Ni]>[NH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:8]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9]
Reactant: O=C(NCc1cccc([N+](=O)[O-])c1)NC1CCCCC1
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1cccc(CNC(=O)NC2CCCCC2)c1
Reaction time: 2 h
Yield: 84.1 %

Procedure:
1-Cyclohexyl-3-(3-nitro-benzyl)-urea (4 g) was suspended in ethanol (70 ml) and Raney nickel (2 g) was added. Under stirring aqueous hydrazine solution (2.5 ml, 80%) was added. DMF was added (50 ml) and the reaction mixture was stirred for additional 2 h and filtered. The solution was evaporated i.v. affording the title compound (3 g, R1=0.43 DCM/ethanol 19:1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH2:34]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH2:35])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCCCCCCCCN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCCCCCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 12-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and octane-1,8-diamine. MS obsd. (ESI+) [(M+H)+] 481, 1H NMR (400 MHz, CD3OD) δ ppm 8.10-8.08 (dd, J=1.2 Hz, 1 H), 7.92 (s, 1 H), 7.86-7.84 (d, J=7.6 Hz, 1 H), 7.71-7.67 (m, 2 H), 7.61-7.55 (m, 2 H), 5.92 (s, 1 H), 5.28 (s, 2 H), 4.52 (s, 2 H), 3.75-3.73 (m, 2 H), 3.50-3.46 (t, 2 H), 2.93-2.83 (t, 2 H), 2.46 (s, 3 H), 1.74-1.64 (m, 4 H), 1.51-1.40 (m, 8 H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH2:16]>>[C:15]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1)([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:14]
Reactant: c1ccc2[nH]nnc2c1
Reactant: C=C(C)CC(C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(C)CC(C)(C)n1nnc2ccccc21
Temperature: 130 °C
Reaction time: 11 h

Procedure:
To benzotriazole (100 g.) melted, heated to 130° C. and stirred there was added aluminum chloride (0.1 g.) and the addition of diisobutylene drop by drop was begun. As the reaction mixture was cooled to 100° C. by refluxing olefin, addition was discontinued until consumption by alkylation allowed the temperature to rise to 120° C. where addition was resumed. This procedure was continued for 11 hrs. during which a total of 90 g. of diisobutylene was added. The reaction mixture was cooled, treated with water, extracted with benzene and filtered to remove solids. The benzene portion was separated, dried and stripped of solvent by rotary evaporation. The product N-tert-octylbenzotriazole was obtained as a tan semi-solid residue.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.F[C:14]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=1[C:16]#[N:17].Cl>CS(C)=O>[OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:14]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=3[C:16]#[N:17])[CH2:11][CH:6]2[CH2:5][CH2:4]1
Reactant: OCC1CCC2CNCCN2C1
Reactant: N#Cc1cc(F)ccc1F
Agent: Cl
Solvent: CS(C)=O
Product: N#Cc1cc(F)ccc1N1CCN2CC(CO)CCC2C1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
A mixture of 1.05 g (6.17 mmol) of (7RS,9aSR)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (U.S. Pat. No. 5,326,874) and 1.29 g (9.25 mmol) of 2,5-difluorobenzonitrile in 20 mL of DMSO was heated at 100° C. for 16 h. The mixture was cooled to room temperature, acidified with 1M HCl, washed with ether (3×), made basic with conc. ammonium hydroxide, and extracted with ethyl acetate (3×). The combined organic layers were washed with water (3×), dried (magnesium sulfate), filtered and evaporated. Purification by silica gel MPLC with 90:10 chloroform:methanol gave 0.51 g of (7RS,9aSR)-7-hydroxymethyl-2-(2-cyano-4-fluorophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [Li].[C:2]([O:5][CH2:6][CH3:7])(=[O:4])[CH3:3].[CH:8]([C:10]([CH2:12][CH3:13])=[CH2:11])=[O:9].[Cl-].[NH4+]>N.C(OCC)C>[CH2:12]([C:10]([CH:8]([OH:9])[CH2:3][C:2]([O:5][CH2:6][CH3:7])=[O:4])=[CH2:11])[CH3:13]
Reactant: CCOC(C)=O
Reactant: C=C(C=O)CC
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: CCOCC
Product: C=C(CC)C(O)CC(=O)OCC
Reaction time: 0.03 h
Yield: 23.6 %

Procedure:
2.2 g Lithium metal was dissolved in 200 ml of liquid ammonia containing a trace of ferric nitrate, and 21 g (23.5 ml) of ethyl acetate was added. The mixture was stirred for two minutes and 2-formylbut-1-ene (19 g) in diethyl ether (60 ml) was added over 10 minutes at the reflux temperature of the mixture. Stirring was continued for a further 30 minutes, a slight excess of ammonium chloride was added to the reaction mixture and the ammonia was evaporated off. The residue was extracted with diethyl ether, was washed with dilute hydrochloric acid and then with brine, was dried, was evaporated and was distilled at 110°-120° C./10 mm Hg to give 9.2 g (24%) of 2-ethyl-3-hydroxy-4-ethoxycarbonylbut-1-ene (approximately 90% pure).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:11]=1[CH3:12]
Reactant: C1CCNCC1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Product: Cc1c(N2CCCCC2)nc2cc(F)cc(F)c2c1Cl

Procedure:
Prepared according to Procedure G using 2,4-dichloro-5,7-difluoro-3-methylquinoline (300 mg, 1.21 mmol) and piperidine in to give 4-chloro-5,7-difluoro-3-methyl-2-(piperidin-1-yl)quinoline. Mass Spectrum (ESI) m/e=297.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH:13]1[CH2:18][CH2:17][CH:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[O:23]1CCC[CH2:24]1.C([Li])CCC.C1CCCCC1.CN(C)C=O.Cl.C([O-])(O)=O.[Na+]>>[C:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([O:12][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH:24]=[O:23])[CH:3]=3)[N:8]=2)[CH2:14][CH2:15]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(Br)ccc3n2)CC1
Reactant: C1CCOC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3n2)CC1
Reaction time: 0.25 h

Procedure:
6-Bromo-2-(4-tert-butyl-cyclohexyloxy)-quinoline (115 mg, 0.317 mmol) in tetrahydrofuran (2.6 mL, 32 mmol) was added 2.0 M of n-butyllithium in cyclohexane (0.48 mL, 0.95 mmol) at −78° C. and was stirred for 15 min. N,N-dimethylformamide (0.12 mL, 1.6 mmol) was added and was stirred for 30 minutes. When the reaction completed, 1 M HCl was added and after 5 min at −78° C., sat. NaHCO3 was added and extracted with EtOAc. The organic layer was concentrated and purified by silica gel chromatography using PE/EA (0-50%) as eluent to give product as a gel (30.6 mg, 31%). LCMS Rt=2.49 min m/z=312.51 ([M+1], 100%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:13][CH2:12][CH2:11][CH2:10][C:5]=2[C:6]=1[C:7]([NH2:9])=[O:8].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:21][CH2:22][C:23]([NH:1][C:2]1[S:3][C:4]2[CH2:13][CH2:12][CH2:11][CH2:10][C:5]=2[C:6]=1[C:7]([NH2:9])=[O:8])=[O:24]
Reactant: O=C(Cl)CCl
Reactant: NC(=O)c1c(N)sc2c1CCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1c(NC(=O)CCl)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a mixture of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide (30 g, 0.153 mol) and triethylamine (18.5 g, 0.183 mol) in DCM (200 ml) was added chloro-acetyl chloride (20.57 g, 0.183 mol) slowly at 0° C., and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to half of the volume to afford the solid product which was filtered, washed with 10 ml of DCM and dried to provide 2-(2-chloro-acetylamino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid amide (35 g, 84%) as off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.65-1.75 (m, 4H), 2.58-2.72 (m, 4H), 4.49 (s, 2H), 7.29 (s, 1H), 7.42 (s, 1H), 12.23 (s, 1H); LC-MS: [M+H]=272.8, 275.1, 257.9 & 255.9 m/z.
Reaction SMILES: ClC(OCC(C)C)=[O:3].[C:9]([N:16]([CH2:18][C:19]([OH:21])=[O:20])[CH3:17])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CN1CCOCC1.[CH2:29]([NH2:39])[C:30]1[CH:38]=[CH:37][C:36]2[O:35][CH2:34][O:33][C:32]=2[CH:31]=1>C1COCC1>[C:29]([NH2:39])(=[O:3])[C:30]1[CH:38]=[CH:37][C:36]2[O:35][CH2:34][O:33][C:32]=2[CH:31]=1.[C:9]([N:16]([CH2:18][C:19]([OH:21])=[O:20])[CH3:17])([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10]
Reactant: CC(C)COC(=O)Cl
Reactant: NCc1ccc2c(c1)OCO2
Agent: CN(CC(=O)O)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: NC(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
Isobutyl chloroformate (226 μL, 1.73 mmol) was added to a solution of N-Boc sarcosine (1.73 mmol) and N-methylmorpholine (192 μL, 1.73 mmol) in THF. After two minutes, piperonylamine (216 mL, 1.73 mmol) was added and the mixture allowed to warm to room temperature. After thirty minutes, the reaction mixture was passed through a bed of Celite and all volatiles were removed under reduced pressure to yield N-Boc sarcosine piperonyl amide (531 mg, 95%) as a white solid. 1H NMR: (CDCl3) δ2.41 (s,3), 3.28 (s,2), 4.39 (d,2), 5.95 (s,2), 6.80 (m,3), 7.43 (bs,1), 9.04 (bs,1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH:21]=[CH:20][CH2:19]1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:33])C=1>>[C:11]([O:10][C:8](=[O:9])[N:7]([CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH:21]2[CH:20]([O:33]2)[CH2:19]1)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N(CCCC1CC=CCC1)C(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC(C)(C)OC(=O)N(CCCC1CCC2OC2C1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 89.8 %

Procedure:
N-tert-Butoxycarbonyl-(3-cyclohex-3-enyl-propyl)-carbamic acid tert-butyl ester (12.2 g, 29.4 mmol, corrected) was treated with 3-chloroperbenzoic acid (70% purity, 8.7 g, 35.3 mmol, corrected) according to the method of Example 7 Step B and stirred at room temperature for 4.5 hours. After work up the title compound (9.38 g, 90% yield) was obtained as light yellow oil.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f52) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.