Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=2[C:9]=1[C:10]([C:12]1[CH:17]=[C:16](I)[C:15]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[C:14](I)[CH:13]=1)=[O:11])[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>CO.[Pd](Cl)Cl>[CH2:1]([C:5]1[O:6][C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=2[C:9]=1[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:14][CH:13]=1)[OH:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1cc(I)c(OCCN(CC)CC)c(I)c1
Agent: Cl[Pd]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCc1oc2ccccc2c1C(O)c1ccc(OCCN(CC)CC)cc1
Yield: 50 %

Procedure:
One mmole (645 mg) of the ketone, (2-n-butyl-3-benzofuranyl)[4-[2-(diethylamino)ethoxyl]-3,5-diiodophenyl]methanone is dissolved in 10 ml of methanol. Palladium dichloride (2 mmole, 354 mg) is added and the mixture is agitated to suspend the palladium dichloride. The temperature of the mixture is adjusted to 20° C. Sodium borohydride (10 mmole, 379 mg) is added and stirring is continued until reaction is complete (~1 hour). The palladium dichloride is removed by filtration and water is added to the filtrate. An ether extraction is performed and the product is removed from the ether phase by evaporation under reduced pressure. The produce is purified by chromatography (silica gel using methylene chloride) and results in >50% yield of the product, m.p. 203° C. (decomposes).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:24]2[CH:23]=[C:22]3[C:25]4[C:30]([CH:31]=[C:21]3[NH:20][C:19]=2[C:18]([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[CH:16]2)=[CH:29][CH:28]=[CH:27][CH:26]=4.[C:42](O[Na])(C)(C)C.CI>C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:24]2[CH:23]=[C:22]3[C:25]4[C:30]([CH:31]=[C:21]3[N:20]([CH3:42])[C:19]=2[C:18]([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[CH:16]2)=[CH:29][CH:28]=[CH:27][CH:26]=4
Reactant: c1ccc2cc(-c3c4ccccc4c(-c4ccc5ccccc5c4)c4[nH]c5cc6ccccc6c-5cc34)ccc2c1
Reactant: CC(C)(C)O[Na]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1c2cc3ccccc3c-2cc2c(-c3ccc4ccccc4c3)c3ccccc3c(-c3ccc4ccccc4c3)c21
Reaction time: 0.5 h

Procedure:
7.4 g (14.2 mmol) of 6,11-di(2-naphthyl)-12-H-12-aza-indeno[1,2-b]anthracene was dissolved with 70 ml of THF in a 250 ml flask, and 1.64 g (17.0 mmol) of t-BuONa was added thereto and then, 2.4 ml (17.0 mmol) of CH3I was slowly added thereto at room temperature. After 30 minutes, a solvent was removed to obtain a solid, and the solid was hot filtered twice using dichlorobenzene, and re-crystallized three times using dichlorobenzene. Then, the resultant solid was dried under reduced pressure, thereby producing 6,11-di(2-naphthyl)-12-methyl-12-aza indeno[1,2-b]anthracene (3.5 g, 46%) that was white yellow.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:24]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:24])=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)nc2cc(C(F)(F)F)ccc2c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Cl)nc2cc(C(F)(F)F)ccc2c1C
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of 15.0 g (50.1 mmol) 2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in POCl3 (46 ml) was heated to 100° C. for 2 h. After cooling of the RS to RT, it was diluted with EtOAc and neutralised with a sat. aq. NaHCO3 sol. The organic phase was separated and washed with brine, dried over MgSO4 and concentrated in a vacuum. 15.4 g (48.5 mmol, 97%) 2-chloro-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: [NH:1]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@H:2]([C:4]([NH:6][C@H:7]([C:13]([NH:15][C@H:16]([C:26]([NH:28][CH2:29][C:30]([NH:32][C@H:33]([C:38]([NH:40][CH2:41][C:42]([O:44]CC1C=CC=CC=1)=[O:43])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])=[O:27])[CH2:17][O:18]CC1C=CC=CC=1)=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[NH2:11])=[O:5])[CH3:3]>CC(O)=O.[Pd]>[NH:1]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@H:2]([C:4]([NH:6][C@H:7]([C:13]([NH:15][C@H:16]([C:26]([NH:28][CH2:29][C:30]([NH:32][C@H:33]([C:38]([NH:40][CH2:41][C:42]([OH:44])=[O:43])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])=[O:27])[CH2:17][OH:18])=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[NH2:11])=[O:5])[CH3:3]
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O

Procedure:
1.50 g Boc-Ala-Gln-Ser(Bzl)-Gly-Leu-Gly-OBzl was dissolved in 100 ml AcOH and subjected to 8 hours of catalytic reduction in the presence of Pd-black as a catalyst. After filtering the catalyst, the reduced solution was concentrated; the resulting residue was precipitated with ether and collected by filtration.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)=O>[Pd].S(=O)(=O)(O)O.C(O)(=O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1
Reactant: COc1ccc(C(=O)CCCCCBr)cc1OC
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(CCCCCCBr)cc1OC
Reaction time: 9 h
Yield: 91.3 %

Procedure:
A mixture of 32.9 g of 1-(6-bromo-1-oxohexyl)-3,4-dimethoxybenzene, 3.0 g of 10% palladium on carbon and 5 drops of concentrated sulfuric acid in 200 mL of acetic acid was shaken under hydrogen pressure for 9 hours in a Parr hydrogenator at an initial pressure of 55 psi. The reaction mixture was filtered through Celite and the filtrate was concentrated at reduced pressure. The residue was purified by HPLC using 10% ethyl acetate-hexane to give 28.7 g (91% yield) of 1-(6-bromohexyl)-3,4-dimethoxybenzene as an oil. The nmr spectrum was consistent with the structure and the low resolution mass spectrum showed the molecular ion at m/z 300 (C14H21BrO2).
Reaction SMILES: [CH3:1][C:2]1([CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:6](=[O:7])[NH:5][NH:4][C:3]1=[O:8].[C:18]([O:24][CH3:25])(=[O:23])[CH:19]=[CH:20][CH:21]=[CH2:22].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>ClCCl>[CH3:1][C:2]1([CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:6](=[O:7])[N:5]2[CH2:22][CH:21]=[CH:20][CH:19]([C:18]([O:24][CH3:25])=[O:23])[N:4]2[C:3]1=[O:8]
Reactant: C=CC=CC(=O)OC
Reactant: CC1(CCOC2CCCCO2)C(=O)NNC1=O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: ClCCl
Product: COC(=O)C1C=CCN2C(=O)C(C)(CCOC3CCCCO3)C(=O)N12
Temperature: 25 °C
Yield: 38.4 %

Procedure:
(B)(b) A mixture of 14.52 g (0.06 mol) of 4-methyl-4-[2-(tetrahydro-2-pyranyloxy)ethyl]pyrazolidine-3,5-dione and 6.72 g (0.066 mol) of methyl penta-2,4-dienoate in 150 ml of dry dichloromethane was stirred at room temperature under a stream of nitrogen. A solution of 26.64 g (0.06 mol) of lead tetraacetate in 100 ml of dry dichloromethane was added dropwise, the blue color being allowed to fade between additions. When the addition was complete and no blue color persisted, the resulting suspension was filtered. The filtrate was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and evaporated to give 8.12 g (38%) of methyl 2,3,5,8-tetrahydro-2-methyl-1,3-dioxo-2-[2-(tetrahydro-2-pyranyloxy)ethyl]-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate having a melting point of 126.5°-127.6° C. (from diethyl ether).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[F-].[CH2:12]([N+](CCCC)(CCCC)CCCC)CCC.CI>O1CCCC1>[CH3:12][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cnc2c(N)ncnc21

Procedure:
Adenine (2.0 g, 14.8 mmol), tetrahydrofuran (100 mL) and tetrabutyl-ammonium-fluoride solution in 1.0 M tetrahydrofuran (37 mL, 37 mmol) were added in 300 mL mad apple-type flask with a magnetic stirrer. Methyl-iodide (2.72 mL) added drop wise to the solution in 10 minutes during stirring and allowed to stir for 2.5 hr. The reaction solution was evaporated under reduced pressure. The residues were dissolved in methanol and filtered. The filtrate was added ethanol-water mixture. The object was recrystallized in ethanol-water mixture to give white solids (1.0 g, yield, 45%). 1H NMR (400 MHz, DMSO-d6): δ 3.70 (s, 3H), 7.15 (br, 2H), 8.07 (s, 1H), 8.13 (s, 1H), 13C NMR (100 MHz, DMSO-d6): δ 29.3, 118.6, 141.3, 149.8, 152.4, 155.9; MS (ESI+)calcd for C6H7N5+(M+H+) 150.0774, found 150.0914.
Reaction SMILES: [OH-].[Na+].Cl.[CH2:4]([O:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[NH:21][CH2:22][C:23]1([C:29]([O:31]CC)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)[CH3:5]>C(O)C.O>[CH2:4]([O:6][CH2:7][C:8]1[N:21]([CH2:22][C:23]2([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=1)[CH3:5]
Reactant: CCOCC(=O)Nc1cnc2ccccc2c1NCC1(C(=O)OCC)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(C(=O)O)CCCCC1
Yield: 69 %

Procedure:
Sodium hydroxide (2.71 g, 67.7 mmol) was added to a solution of ethyl 1-[({3-[(ethoxyacetyl)amino]quinolin-4-yl}amino)methyl]cyclohexanecarboxylate hydrochloride (10.15 g, 22.6 mmol) in 9:1 ethanol/water (30 mL), and the solution was heated at reflux for several hours. The ethanol was removed under reduced pressure, and the resulting solution was diluted with water and adjusted to pH 4 to 5 with the addition of 3 M hydrochloric acid. The mixture was then extracted several times with dichloromethane The aqueous fraction was adjusted to pH 7 and extracted several more times with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 5.73 g of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanecarboxylic acid.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[Br:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:8]([C:9](OC)=[O:10])=[CH:7][C:6]=1[O:17][CH3:18].[BH4-].[Na+].Cl>C(O)C.O1CCCC1>[Br:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:8]([CH2:9][OH:10])=[CH:7][C:6]=1[O:17][CH3:18]
Reactant: COC(=O)c1cc(OC)c(Br)c(OC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(CO)cc(OC)c1Br
Reaction time: 9 h
Yield: 96.6 %

Procedure:
To a solution of calcium chloride (46.5 kg) in ethanol (336 L) were added tetrahydrofuran (672 L) and methyl 4-bromo-3,5-dimethoxybenzoate (96.0 kg) to obtain a suspension. To the suspension was added sodium borohydride (31.7 kg) by portions at room temperature, and the mixture was stirred for about 9 hours at temperature of room temperature to 45° C. The reaction mixture was added dropwise to aqueous HCl solution and stirred for about 16 hours at room temperature. Organic solvent was removed in vacuo, and water (1440 L) was added to the residue and stirred for 1 hour at 50° C. After cooling, the crystalline precipitates were collected by filtration and dried to yield 4-bromo-3,5-dimethoxybenzyl alcohol (83.3 kg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][C@@H:17]([C:20]([O:22]CC)=[O:21])[CH2:16][C@@H:15]1[NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])=[O:12])=[CH:5]2.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][C@@H:17]([C:20]([OH:22])=[O:21])[CH2:16][C@@H:15]1[NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])=[O:12])=[CH:5]2
Reactant: CCOC(=O)[C@@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCc2nc(C(=O)N[C@H]3C[C@H](C(=O)O)CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reaction time: 12 h
Yield: 82 %

Procedure:
The compound (916 mg) obtained in Example 49 was suspended in a mixed solvent of ethanol (10 ml) and tetrahydrofuran (8 ml), and a 1N aqueous solution (3.3 ml) of sodium hydroxide was added at room temperature to stir the mixture for 12 hours at the same temperature. After adding 1N hydrochloric acid (3.3 ml), the solvent was distilled off under reduced pressure, and the residue was washed with water and diethyl ether to obtain the title compound (712 mg).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH:15]([C:17]3([NH2:21])[CH2:20][O:19][CH2:18]3)[CH3:16])[NH:13][CH:14]=2)=[CH:6][CH:5]=1>C(O)C>[F:23][C:2]([F:1])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C@@H:15]([C:17]3([NH2:21])[CH2:18][O:19][CH2:20]3)[CH3:16])[NH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: CC(c1nc(-c2ccc(OC(F)(F)F)cc2)c[nH]1)C1(N)COC1
Solvent: CCO
Product: C[C@@H](c1nc(-c2ccc(OC(F)(F)F)cc2)c[nH]1)C1(N)COC1
Reaction time: 0.17 h

Procedure:
Racemic 3-(1-{4-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}ethyl)oxetan-3-amine (Example 9, 0.243 g, 0.743 mmol) was dissolved in ethanol (1 mL). Enantiomers were separated by chiral preparative HPLC under basic conditions at ambient temperature on a Chiralpak AD-H column (250*, 20 mm i.d) supplied by Daicel Chemical Industries. A flow rate of 18 mL/min was used with mobile phase A: heptane and B: IPA+0.1% diethylamine (v/v). Two Agilent 1200 prep pumps supplied a mobile phase with a composition of 20% B. Run time was 10 minutes per 0.1 mL injection volume. Detection was achieved using an Agilent 1200 multiple wavelength UV absorbance detector set at 220 nm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.[Li]CCCC.[C:17]1(OS(C(F)(F)F)(=O)=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.[Cl-].[Li+]>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]1([C:9]2[S:8][C:7]3[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH:10]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: COc1ccc2ccsc2c1
Reactant: O=S(=O)(OC1=CCCCC1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2cc(C3=CCCCC3)sc2c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 68.1 %

Procedure:
To a solution of 6-methoxybenzo[b]thiophene (362 mg, 2.21 mmol) in 5.5 mL of THF at −20° C. was added dropwise 2.5 M nBuLi (0.97 mL, 2.4 mmol) and the reaction was stirred at 0° C. for 40 minutes and was then warmed to room temperature for 30 minutes. Next, ZnCl2 (390 mg, 2.87 mmol) in 2.5 mL of THF was added by cannula and the reaction was stirred at room temperature for 15 minutes. At this point, Pd(Ph3P)4 (102 mg), trifluoromethanesulfonic acid cyclohex-1-enyl ester (0.6 gm, 2.93 mmol)3 and anhydrous lithium chloride (0.28 gm, 6.63 mmol) were added and then the reaction mixture was stirred for 16 hrs. at room temperature. The tetrahydrofuran was removed in vacuo and the residue diluted with water and extracted with ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was chromatographed on silica gel using hexanes as the eluant to yield 368 mg of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[CH2:21][CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)=O)(C)(C)C>>[Cl:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)/[CH:23]=[CH:22]/[CH2:21][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][NH:15]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC=Cc1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(/C=C/CC2CCCCN2)c1
Yield: 24 %

Procedure:
Stage b) Deprotection with trifluoroacetic acid is carried out according to the method of Preparation 2A, Stage b). The product obtained is a mixture of the Z and E isomers. Elution with a 90:10 v/v mixture of methylene chloride and 10% ammoniacal methanol by the Chromatoflash technique on silica furnishes the E isomer in the most polar fractions. The intermediate fractions are chromatographed a second time under the same conditions. All of the fractions with a high E-isomer content are combined, and, as described with regard to Preparation 2B, Stage b), are converted to the hydrochloride, which is recrystallized in isopropanol, then treated in an alkaline medium, extracted with ether and concentrated to furnish (E)-2-(m-chlorocinnamyl)piperidine with a yield of 24%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([NH2:18])=[S:17].BrBr>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]2[N:15]=[C:16]([NH2:18])[S:17][C:5]=2[C:6]([CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2CCOCC2)cc1NC(N)=S
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2CCOCC2)c2sc(N)nc12
Yield: 48.8 %

Procedure:
To a stirred solution of 1.90 g (7.13 mmol) [2-methoxy-5-(tetrahydro-pyran-4-yl)-phenyl]-thiourea in 50 ml chloroform was added dropwise 0.37 ml (7.22 mmol) bromine and the mixture heated at reflux for 18 hours. The mixture was then concentrated in vacuo. The residue was recrystallised from ethyl acetate to afford 920 mg (49%) 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine as a white solid. ES-MS m/e (%): 265 (M+H+, 100).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][N:7]=1.CSC(=N)N[N+]([O-])=O.S1C=CC(CSC[CH2:27][NH:28][C:29]([NH:31][N+:32]([O-:34])=[O:33])=N)=N1.CNC(=N[N+]([O-])=O)SC>>[S:8]1[CH:9]=[CH:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:29]([NH:28][CH3:27])=[N:31][N+:32]([O-:34])=[O:33])=[N:7]1
Reactant: N=C(NCCSCc1ccsn1)N[N+](=O)[O-]
Reactant: NCCSCc1ccsn1
Agent: CNC(=N[N+](=O)[O-])SC
Agent: CSC(=N)N[N+](=O)[O-]
Product: CNC(=N[N+](=O)[O-])NCCSCc1ccsn1

Procedure:
Reacting 3-[(2-aminoethyl)thiomethyl]isothiazole with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-[2-(3-isothiazolylmethylthio)ethyl]-N'-nitroguanidine and reaction of the same starting material with N,S-dimethyl-N'-nitroisothiourea by the procedure of Example 2(iii) gives N-[2-(3-isothiazolylmethylthio)ethyl]-N'-methyl-N"-nitroguanidine.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH:7][CH3:6])=[CH:11][CH:12]=2)=[CH:18][C:19]=1[C:24]([F:25])([F:26])[F:27]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reaction time: 8 h

Procedure:
{2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.08 g, 2.51 mmol, 1 eq) was dissolved in dry DCM (10 ml) under argon atmosphere and TFA (961 μl, 5 eq) was added. Reaction mixture was stirred for overnight. In the reaction mixture was added more DCM (15 ml) and was extracted with saturated NaHCO3 (3×15 ml) and brine. Organic layer was dried over anhydrous Na2SO4, filtered and evaporated to give a crude product. Crude product was purified via Biotage SP-1 Snap Si 25 g; 25 ml/min; UV Wavelength (Collection: 254 nm; Monitor: 290 nm) in the gradient of MeOH in DCM: 2% for 1.5 CV, 2-10% for 20 CV. The appropriate fractions were combined and product 2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (501 mg, yield=58.1%, purity 96%). [M+H]+=330.75 1H NMR (300 MHz; CDCl3) δ/ppm 2.47 (s, 3H), 2.78-2.92 (m, 4H), 6.91-7.10 (m, 3H), 7.19-7.33 (m, 3H), 7.41 (d, J=8.99 Hz, 1H)
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16](O)[CH:17]2[CH2:22][CH2:21][O:20][N:19]([CH3:23])[C:18]2=[O:24])[N:6]=1)([CH3:4])[CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[N:8]=[C:7](/[CH:16]=[C:17]2/[C:18](=[O:24])[N:19]([CH3:23])[O:20][CH2:21][CH2:22]/2)[N:6]=1)([CH3:1])[CH3:3]
Reactant: CN1OCCC(C(O)c2nc(C(C)(C)C)c(O)c(C(C)(C)C)n2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN1OCC/C(=C\c2nc(C(C)(C)C)c(O)c(C(C)(C)C)n2)C1=O
Yield: 30 %

Procedure:
A mixture of 0.70 g (2.0 mmol) of 4-[[4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]hydroxymethyl]tetrahydro-2-methyl-2H-1,2-oxazin-3-one, Example 7, and 0.040 g (0.20 mmol) of p-toluenesulfonic acid monohydrate in 15 mL of toluene was stirred at reflux for 18 hours. The cooled reaction mixture was evaporated, and the residue was purified by flash chromatography (silica gel, 15% ethyl acetate in hexane elution) to yield 0.20 g (31%) of the title compound, mp 180°-181° C.; 1H NMR (deuteriochloroform) δ 1.46 (s, 18H), 3.36 (s, 3H), 3.46 (m, 2H), 4.21 (m, 2H), 5.25 (s, 1), 7.73 (s, 1H); MS m/e 334 (M+ +1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][C:10]=2[CH3:22])[CH:5]=[N:6][C:7]=1Cl.[CH3:23][B-](F)(F)F.[K+].C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][C:10]=2[CH3:22])[CH:5]=[N:6][C:7]=1[CH3:23]
Reactant: C[B-](F)(F)F
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1-c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1-c1cnc(C)c(Cl)c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A suspension of tert-butyl 4-(5,6-dichloropyridin-3-yl)-3-methylbenzoate (Step A, 650 mg, 1.92 mmol), potassium methyltrifluoroborate (234 mg, 1.92 mmol), Cs2CO3 (1.88 g, 5.77 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (157 mg, 0.192 mmol), dioxane (4 mL) and water (0.25 mL) was flushed with nitrogen and stirred at 110° C. for 2 hours. After cooling down, the mixture was filtered over celite. The filter cake was washed with ethyl acetate and further diluted with ethyl acetate and water. After separating the layers, the organic was washed with brine. The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated. The crude isolate was purified by silica gel chromatography (0 to 80% ethyl acetate/hexane) to give the titled compound as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.38 (d, J=1.9 Hz, 1H), 7.94 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.27 (d, J=7.9 Hz, 1H), 2.7 (s, 3H), 2.35 (s, 3H), 1.64 (s, 9H).
Reaction SMILES: [CH:1]([C:4]1[O:8][N:7]=[C:6]([C:9](OCC)=[O:10])[CH:5]=1)([CH3:3])[CH3:2].[BH4-].[Na+].O>C(O)C>[CH:1]([C:4]1[O:8][N:7]=[C:6]([CH2:9][OH:10])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)C)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)c1cc(CO)no1
Temperature: 25 °C
Reaction time: 10 h
Yield: 94.6 %

Procedure:
20.76 g of ethyl 5-i-propyl-isoxazole-3-carboxylate was dissolved in 200 ml of ethanol, and 4.20 g of sodium borohydride was then added. The mixture was stirred at room temperature for 10 hours. After 50 ml of water was added, the reaction mixture was concentrated to 50 ml under reduced pressure. The concentrated solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 15.13 g of (5-i-propyl-isoxazol-3-yl)methanol.