Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][C:22]1[C:23]([NH2:37])=[N:24][CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1>>[NH2:37][C:23]1[N:24]=[CH:25][C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:27][C:22]=1[CH3:21]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cnc(N)c(C)c3)ccn2c1=O

Procedure:
Methyl 8-(6-amino-5-methylpyridin-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (96.2 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded quantitatively the title compound as a yellow solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](O)(=[O:9])/[CH:6]=[CH:7]/[CH3:8].[CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:8][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5](=[O:9])[CH2:6]1
Reactant: C/C=C/C(=O)O
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC1CC(=O)c2ccccc21

Procedure:
To 31.8 g of aluminum chloride, 6.8 g of crotonic acid and 50.0 ml of benzene were added and the mixture was reacted under reflux for 5 hours. After filtering the reaction solution, benzene was removed from the filtrate by distillation and the residue was distilled in a vacuum (120°-123° C./12 mmHg) to obtain 9.7 g of 3-methyl-1-indanone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH:16]=[N:17]O)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH2:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(O)cc1C=NO
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN
Reaction time: 16 h
Yield: 29.3 %

Procedure:
A solution of 3-[4-hydroxy-2-(hydroxyimino-methyl)-phenyl]-acrylic acid tert-butyl ester (0.50 g, 1.9 mmol) in ethanol (50 mL) was treated with 10% palladium on carbon (0.25 g). The resulting suspension was treated with hydrogen using a Parr shaker apparatus at ambient temperature and 50 psi for 16 h. The reaction mixture was filtered through Celite, rinsed with ethanol (20 mL), and concentrated. The residue was dissolved in ethyl acetate (50 mL) and washed with 10% K2CO3 solution (2×25 mL) and 1N NaOH (2×25 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was crystallized from isopropyl acetate to give the title compound (0.14 g, 40%), mp 154-157° C. 1H NMR (CD3OD): δ 1.37 (s, 9H), 2.44-2.50 (t, 2H), 2.80-2.85 (t, 2H), 3.75 (s, 2H), 4.83 (s, 3H), 6.57-6.63 (dd, 1H), 6.75-6.77 (d, 1H), 6.95-7.00 (d, 1H). MS (ES+) m/z 252.1 ([M+H]+). MS (ES−) m/z 250.2 ([M−H]−). Anal. Calculated for C14H21NO3: C: 66.9069; H: 8.4222; N: 5.5731. Found: C: 66.57; H: 8.29; N: 5.60.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[SH:12].[CH3:13][C:14]1([CH3:29])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=[C:18]([C:26](Cl)=[O:27])[CH:17]=[CH:16][C:15]1=2>C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[S:12][C:26]([C:18]1[CH:17]=[CH:16][C:15]2[C:14]([CH3:29])([CH3:13])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]=2[CH:19]=1)=[O:27]
Reactant: COC(=O)c1ccc(C)c(S)c1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Cl)ccc21
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)c(SC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Yield: 88.3 %

Procedure:
In a manner analogous to Example 1(a), starting with 1.83 g (10 mmol) of methyl 3-mercapto-4-methyl benzoate, 1.5 ml of triethylamine and 2.76 g (11 mmol) of 5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphtoyl chloride, methyl 4-methyl-3-(5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphtoylthio)-benzoate (3.50 g; 88%) is produced.
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)(=[O:10])[CH3:9].[CH3:17][C:18]1([CH3:32])[O:22][C@H:21]([C:23]2[C:24]([F:31])=[C:25]([CH:28]=[CH:29][CH:30]=2)[CH:26]=[O:27])[CH2:20][O:19]1.Cl>C1COCC1>[CH3:17][C:18]1([CH3:32])[O:22][C@H:21]([C:23]2[C:24]([F:31])=[C:25]([CH:26]([OH:27])[CH2:9][C:8]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[O:10])[CH:28]=[CH:29][CH:30]=2)[CH2:20][O:19]1
Reactant: CC(=O)c1cccnc1
Reactant: CC1(C)OC[C@@H](c2cccc(C=O)c2F)O1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](c2cccc(C(O)CC(=O)c3cccnc3)c2F)O1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
In a stream of argon, anhydrous THF solution containing 0.72 ml of N,N-diisopropylamine was cooled to about −70° C., 3.3 ml of 1.54 M n-butyl lithium-hexane solution was added dropwise thereto, and then the reaction liquid was risen to about −15° C. The reaction liquid was again cooled to about −70° C., mixed with 0.54 ml of 3-acetylpyridine and then stirred at the same temperature for about 30 minutes, and subsequently, 5 ml of anhydrous THF solution containing 1.1 g of 3-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluorobenzaldehyde was gradually added dropwise thereto. After stirring at −70° C. for about 20 minutes and then at about −30° C. for about 3 hours, this was mixed with an appropriate amount of 0.2 M hydrochloric acid aqueous solution and subjected to several times of extraction operation with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate, and then the solvent was evaporated and the thus formed residue was isolated and purified by a silica gel column chromatography to obtain 0.77 g (45%) of 3-[3-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluorophenyl]-3-hydroxy-1-pyridin-3-yl-propan-1-one as a colorless oil from an ethyl acetate-hexane (7:3) eluate. FA: 346
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=O)[C:5]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[C:5]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CN1CCNCC1
Reactant: COC(=O)COc1c(C=O)cc(Cl)cc1C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)COc1c(CN2CCN(C)CC2)cc(Cl)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
A solution of methyl 5-chloro-3-formyl-2-(2-methoxy-2-oxoethoxy)benzoate (0.99 g, 3.5 mmol) in methylene chloride (30 mL) was added with N-methylpiperazine (0.38 g, 3.8 mmol), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0° C., and then added portionwise with sodium triacetoxyborohydride (0.12 g, 5.5 mmol). After completion of the addition, the reaction mixture was warmed to room temperature, and stirred for 12 hours. The reaction mixture was added with water, the mixture was extracted with ethyl acetate, and the organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (99:1→95:5)) to obtain methyl 5-chloro-2-(2-methoxy-2-oxoethoxy)-3-[(4-methylpiperazin-1-yl)methyl]benzoate (1.2 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[CH3:8][C:5]1[CH:4]=[C:3]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:2]([N:1]=[C:15]=[S:16])=[CH:7][CH:6]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1ccc(N)c(-c2ccccc2)c1
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(N=C=S)c(-c2ccccc2)c1

Procedure:
Reaction of 2-amino-5-methylbiphenyl (7 g) with thiophosgene (5.7 g) in a mixture of dioxan (20 ml) and water (50 ml) at 0°-5° C. for 30 minutes and at ambient temperature for 1 hour gave 5-methyl-2-biphenylyl isothiocyanate as a yellow oil.
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[C:8]([NH:10][C@@H:11]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=1)[C@H:12]([OH:26])[CH2:13][NH:14][C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[CH:19]=2)[CH2:17][CH2:16]1)=[O:9])[CH:2]=[CH2:3].CC(O)=[O:41].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl.CCOCC>[CH2:1]([S:4]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[C:8]([NH:10][C@@H:11]([CH2:27][C:28]1[CH:29]=[C:30]([F:35])[CH:31]=[C:32]([F:34])[CH:33]=1)[C@H:12]([OH:26])[CH2:13][NH:14][C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[CH:19]=2)[CH2:17][CH2:16]1)=[O:9])=[O:41])[CH:2]=[CH2:3]
Reactant: C=CCSc1cccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNC2(c3cccc(CC)c3)CC2)c1
Reactant: CC(=O)O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCS(=O)c1cccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNC2(c3cccc(CC)c3)CC2)c1
Reaction time: 0.5 h

Procedure:
3-(allylthio)-N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)benzamide (325 mg, 0.606 mmol) was dissolved in CH2Cl2 (10 mL) and AcOH (1 mL)and treated with mCPBA (104 mg, 0.606 mmol). The reaction mixture was stirred for 2.5 h, at which time more mCPBA (20 mg, 0.11 mmol) was added and stirring continued for 30 min. more. The organic layer was diluted with Et2O and washed with 15% sodium thiosulfite solution. The organic was washed with brine, then dried (MgSO4) and concentrated to give an oil, which was chromatographed with 25% to 50% EtOAc in hexanes to give the title compound. (LRMS (M+H) m/z 553.8)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=2)[C:9]2[C:10]([C:17]([OH:19])=O)=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)=[CH:4][CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=3)[C:17](=[O:19])[N:20]2[C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(NC(c2ccc(Cl)cc2)c2cn(C(C)C)nc2C(=O)O)cn(C)c1=O
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N2C(=O)c3nn(C(C)C)cc3C2c2ccc(Cl)cc2)cn(C)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)((1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)methyl)-1-isopropyl-1H-pyrazole-3-carboxylic acid (Step 41.5). tR: 4.05 min (HPLC 1); tR: 0.90 min (LC-MS 2); ESI-MS: 397 [M+H]+ (LC-MS 2); Rf=0.60 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.47 (m, 6H) 1.90 (s, 3H) 3.34 (s, 3H) 4.54-4.65 (m, 1H) 6.12 (s, 1H) 7.17-7.24 (m, 2H) 7.30-7.39 (m, 3H) 7.69 (d, J=2.7 Hz, 1H) 7.85 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=2)[CH2:4]1.[C:16]1([C:22]2[O:23][C:24]([C:30]([F:33])([F:32])[F:31])=[C:25]([C:27](O)=[O:28])[N:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]2[N:8]=[CH:9][C:10]([NH:13][C:27]([C:25]3[N:26]=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:23][C:24]=3[C:30]([F:32])([F:33])[F:31])=[O:28])=[CH:11][CH:12]=2)[CH2:4]1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: COC1CN(c2ccc([N+](=O)[O-])cn2)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: COC1CN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)C1
Yield: 21.5 %

Procedure:
2-(3-Methoxy-azetidin-1-yl)-5-nitro-pyridine (120 mg, 0.5 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (141 mg, 0.55 mmol), Et3N (352 uL, 2.5 mmol) and BOP (232 mg. 0.525 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-methoxy-azetidin-1-yl)-pyridin-3-yl]-amide as a light green solid (45 mg). ES-MS calcd for C20H17F3N4O3 (m/e) 418.38, obsd 419.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]#[CH:22])[C:17](O)=[O:18])[C:10](=[O:23])[CH:9]=2)[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]#[CH:22])[C:17]([NH:26][C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=3)=[O:18])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: C#CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: C#CCC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
295 mg (purity 85%, 0.70 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]pent-4-ynoic acid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 91 mg (24% of theory)
Reaction SMILES: Cl[C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C@:11]1([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:13][O:12]1.C(=O)([O-])O.[Na+]>C(O)C>[CH3:13][C@@:11]1([CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:20]2)[O:12][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: CCOC(=O)C1CCN(C[C@@]2(C)CO2)CC1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Yield: 19.6 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (3.7 g, 25.1 mmol), ethyl (S)-1-(2-methyloxiran-2-ylmethyl)piperidine-4-carboxylate (4.8 g, 21.1 mmol) and sodium hydrogencarbonate (2.2 g, 25.1 mmol) in ethanol (25 ml) were stirred under reflux overnight. The reaction mixture was concentrated under reduced pressure. To the residue, water was added, and the solution was extracted with methylene chloride. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) and crystallized from diethyl ether to afford ethyl (S)-1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidine-4-carboxylate (1.4 g, yield 20%) as a white powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[N:7][C:8]=1[Cl:9].C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:30]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[N:7][C:8]=1[Cl:9])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CN)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CNC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To 5-aminomethyl-6-chloro-3-(1-BOC-2-(S)-azetidniylmethoxy)pyridine from step 92b (0.262 g, 0.80 mmol) was added CH2Cl2 (10 mL), triethylamine (0.1619 g, 1.60 mmol) and benzoyl chloride (0.1349 g, 1.0 mmol). The mixture was stirred at room temperature overnight, then concentrated under vacuum. The residue was chromatographed (silica gel; CH2Cl2 /MeOH, 9/1) to afford a light brown foam (0.267 g, 77%). MS (CI/NH3) m/z 432.00 (M+H+), 449.00 (M+NH4+). 1H NMR (CDCl3, 300 MHz): 1.57 (s, 9H), 2.25-2.37 (m, 2H), 3.87 (t, J=7.1 Hz, 2H), 4.11 (dd, J=2.7, 9.80 Hz, 1H), 4.31-4.39 (m, 1H), 4.49-4.55 (m, 1H), 4.68 (d, J=8.5 Hz, 2H), 6.75 (m, 1H), 7.42-7.56 (m, 4H), 7.79-7.82 (m, 2H), 8.03 (d, J=3.1 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].BrC1C=CC(Cl)=CC=1[CH2:20][O:21][CH2:22]OC>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[CH2:4][O:5][CH2:20][O:21][CH3:22]
Reactant: COCOCc1cc(Cl)ccc1Br
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Product: COCOCc1cc(C)ccc1Br

Procedure:
This compound was made from 2-bromo-5-methylbenzoic acid in the same manner as compound 18d: 1H NMR (300 MHz, DMSO-d6) δ (ppm) 2.27 (s, 3H), 3.30 (s, 3H), 4.51 (s, 2H), 4.68 (s, 2H), 7.05 (dd, J=7.9, 2.3 Hz, 1H), 7.30 (d, J=1.5 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H).
Reaction SMILES: [C:1](=[O:4])([O-])O.[Na+].F[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C>>[CH2:1]([OH:4])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: O=C([O-])O
Reactant: CCCCCCCCCCCCF
Agent: [Na+]
Product: CCCCCCCCCCCCO

Procedure:
93 mg (0.5 mmol) of dodecanol purified by distillation, 0.39 g (0.6 mmol, 1.2 equivalents) of N,N-diethyl-α,α-difluoro-[4-(1H,1H,2H,2H-perfluorodecyl)benzyl]amine (compound c) produced in Example 1, and 0.5 ml of heptane were put into a container formed of PFA (tetrafluoroethylene/perfluoroalkyl vinyl ether copolymer), and reacted in a nitrogen atmosphere at 100° C. for 3 hours. After the reaction, an aqueous saturated sodium hydrogencarbonate solution was added thereto for neutralization, and then the product was extracted out with dichloromethane. The solvent was evaporated away, followed by purification through silica gel column chromatography (solvent: dichloromethane/diethyl ether mixed solvent) to give a product. The main product was 1-fluorododecane, and its yield was 86%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH3:13])=[C:5]2[C:14]([OH:16])=O.S(Cl)([Cl:19])=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH3:13])=[C:5]2[C:14]([Cl:19])=[O:16]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)c2cc(Cl)ccc2[nH]c1=O
Product: Cc1c(C(=O)Cl)c2cc(Cl)ccc2[nH]c1=O

Procedure:
6.5 g (0.027 mol) of the carboxylic acid prepared in Example 1 are dissolved in 80 ml of thionyl chloride and heated under reflux for two hours. For working-up, the reaction mixture is concentrated under reduced pressure on a rotary evaporator and the residue which remains is stirred with diethyl ether. The reaction product is filtered off and the solid obtained is dried in vacuo.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:7].[C:18]1([CH2:24][S:25](Cl)(=[O:27])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[C:18]1([CH2:24][S:25]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[C:6]([O:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:7])(=[O:27])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCCCc1cccnc1)C1CCCN1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCCc1cccnc1)[C@@H]1CCCN1S(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
A solution of 3-(3-Pyridyl)-1-propyl pyrrolidine-2-carboxylate (200 mg; 0.9 mmol) and α-toluenesulfonyl chloride (160 mg; 0.9 mmol) in methylene chloride (20 mL) was treated with triethylamine (90 mg; 0.9 mmol) and stirred for 2 hours at room temperature. The reaction mixture was filtered to remove solids and applied directly to a silica gel column, eluting with 50% ethyl acetate in hexane, to obtain 150 mg (43%) of Compound 4 (Table I) as a clear oil. 1H NMR (300 MHz, CDCl3): δ1.81-1.85 (m, 2H); 1.95-2.02 (m, 3H); 2.10-2.25 (m, 1H); 2.69-2.74 (t, 2H); 2.85-2.97 (m, 1H); 3.24-3.27 (m, 1H); 4.16-4.20 (m, 2H); 4.29 (d, 1H); 4.34 (m, 1H); 4.45 (d, 1H); 7.20-7.25 (m, 1H); 7.35 (m, 3H); 7.49-7.52 (m, 3H); 8.46 (s, 2H). Analysis calculated for C20H24N2O3S: C, 61.83; H, 6.23; N, 7.21. Found: C, 61.59; H, 6.24; N, 7.17.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>C(O)(C)(C)C.C(#N)C>[N+:12]([CH:15]=[C:16]([S:17][CH3:18])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])([O-:14])=[O:13]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CC#N
Solvent: CC(C)(C)O
Product: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Yield: 54.9 %

Procedure:
(a)(i) A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole (1.71 g) in t-butanol (30 ml) was added slowly to a solution of 1-nitro-2,2-bis methylthioethylene (1.66 g) in acetonitrile (20 ml) at room temperature. The solution was heated under reflux for 3 hours, evaporated to dryness and chromatographed on a column of silica gel with elution by anhydrous ether (250 ml) followed by acetone (500 ml). The acetone eluate was concentrated to low bulk to give 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene (1.58 g), m.p. 151°-153°. A sample recrystallised from acetonitrile had m.p. 152°-153°.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[Cl:24][C:25]1[N:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:31]([C:28]2[CH:29]=[N:30][C:25]([Cl:24])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH2:19][CH2:18]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
Diisopropylethylamine (1.34 ml, 8.14 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.5 g, 2.70 mmol) in DCM (20 ml) at room temperature. To this mixture was added 6-chloro-pyridine-3-sulfonyl chloride (0.57 g, 2.70 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (50 ml) and washed sequentially with HCl (1M solution, 20 ml), NaOH (1M solution, 20 ml) and brine (20 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the title compound (0.64 g, 65% yield) as a white solid. δH (500 MHz, DMSO) 8.76 (d, J=2.20 Hz, 1 H) 8.19 (dd, J=8.44, 2.57 Hz, 1 H) 7.82 (d, J=8.44 Hz, 1 H) 6.89 (d, J=7.70 Hz, 1 H) 3.48 (d, J=11.92 Hz, 2 H) 3.31 (br. s., 1 H) 2.59-2.68 (m, 2 H) 1.76 (d, J=10.27 Hz, 2 H) 1.30-1.46 (m, 11 H).
Reaction SMILES: Cl[C:2]1[N:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][C:7]([CH3:13])=[CH:6][CH:5]=2.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[C:10]2[CH:11]=[O:12]
Reactant: C1CNCCN1
Reactant: Cc1ccc2c(c1)c(C=O)c(Cl)n2-c1ccccc1
Product: Cc1ccc2c(c1)c(C=O)c(N1CCNCC1)n2-c1ccccc1
Yield: 63 %

Procedure:
2-Chloro-5-methyl-1-phenyl-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Example 2 to give 5-methyl-1-phenyl-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde as a pale yellow solid (63% yield).