Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:6][CH:7]=1.[CH:13]([NH:15][NH2:16])=O>C(O)CCC>[S:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:13]=[N:15][N:16]=2)[N:4]=1
Reactant: Clc1ccc(-c2cccs2)nn1
Reactant: NNC=O
Solvent: CCCCO
Product: c1csc(-c2ccc3nncn3n2)c1

Procedure:
A mixture of 1.0 g. of 3-chloro-6-(2-thienyl)pyridazine and 0.6 g. of formic acid hydrazide in 50 ml. of n-butyl alcohol is heated at the reflux temperature for 18 hours. The volatiles are removed and the residue is partitioned between dilute aqueous sodium hydroxide and methylene chloride. The organic layer is dried over anhydrous sodium sulfate, filtered and evaporated. The residue is recrystallized from methylene chloride:hexane to afford a tan solid. The solid is recrystallized from acetone:hexane to give 0.5 g. of the desired product as cream colored crystals, m.p. 155°-159° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:14][S:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[C:34]([O:38][CH3:39])(=[O:37])[CH:35]=[CH2:36]>CN(C=O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:2](/[CH:36]=[CH:35]/[C:34]([O:38][CH3:39])=[O:37])=[C:3]([CH:4]=[O:5])[CH:6]=3)=[C:16]([C:17]([F:20])([F:19])[F:18])[S:15][N:14]=2)=[CH:22][CH:23]=1
Reactant: O=Cc1cc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)ccc1Br
Reactant: C=CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)cc1C=O
Temperature: 105 °C
Yield: 41.2 %

Procedure:
2-Bromo-5-((3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methoxy)benzaldehyde (300 mg, 0.63 mmol), dichlorobis(tri-o-tolyphosphine) palladium (35 mg, 0.045 mmol), potassium carbonate (174 mg, 1.26 mmol) in DMF (2 mL) was purged under reduced pressure and backfilled with argon gas. Methyl acrylate (0.114 mL, 1.26 mmol) was added and heated at 105° C. for 3 hrs. The reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was washed with ethyl acetate. The organic layers were washed with water and brine, dried, filtered, and the filtrate was then concentrated. The resultant residue was purified by column chromatography on a 50 g silica gel column, eluting with 0-20% ethyl acetate/heptanes, to give compound 267b as a yellow solid (125 mg, 41% yield).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH2:17][C:18]#N)[S:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl.C(N(CC)CC)C.ClC(OCC)=[O:32].[BH4-].[Na+]>C(O)C.O.O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH2:17][CH2:18][OH:32])[S:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cl
Reactant: N#CCc1cc(C#CCCCc2ccccc2)cs1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: OCCc1cc(C#CCCCc2ccccc2)cs1
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
[4-(5-Phenylpent-1-ynyl)thiophen-2-yl]acetonitrile (321 g, 12.1 mmol) obtained in Example 25(c) was dissolved in ethanol (15 ml), and potassium hydroxide (1.70 g, 30.2 mmol) in water (15 ml) was added thereto in an ice bath followed by heating under reflux for 2 hours. After the reaction solution was acidified with 1N hydrochloric acid, the resulting solution was extracted with ethyl acetate. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (15 ml), and triethylamine (1.69 ml, 12.1 mmol) was added thereto. To the reaction solution was added dropwise ethyl chloroformate (1.21 ml, 12.7 mmol) in tetrahydrofuran (15 ml) in an ice bath, and the reaction mixture was stirred for 30 minutes under cooling with ice in a nitrogen atmosphere. After this reaction solution was filtered, the obtained filtrate was added slowly to an aqueous solution (10 ml) of sodium borohydride (2.29 g, 60.5 mmol) in an ice bath, and then the mixture was stirred for 3 days at room temperature. After the reaction solution was cooled down, acidified with 1N hydrochloric acid, and the resulting solution was extracted with ethyl acetate, and then the ethyl acetate layer was washed with a 1N aqueous sodium hydroxide solution and then with a saturated aqueous sodium chloride solution The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=10:1-4:1) to afford the title compound (2.74 g, 84% yield).
Reaction SMILES: Br.Br[CH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].Cl.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([SH:20])[N:15]=1.C(N(CC)CC)C>CCO>[Cl:11][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[CH2:3][S:20][C:16]1[N:15]=[C:14]([CH3:13])[CH:19]=[CH:18][N:17]=1
Reactant: Cc1ccnc(S)n1
Reactant: Clc1cncc(Cl)c1CBr
Agent: Br
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccnc(SCc2c(Cl)cncc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
A mixture of 4-(bromomethyl)-3,5-dichloropyridine hydrobromide (1.3 g, 5.0 mmol), 4-methylpyrimidine-2-thiol hydrochloride (543 mg, 3.3 mmol), and triethylamine (1.8 mL, 12.9 mmol) in absolute EtOH (35 mL) was stirred at room temperature overnight. The mixture was evaporated, co-evaporated with EtOAc (10 mL), and dried in vacuo. The solid residue was treated with water (75 mL). The mixture was extracted with 50% ethyl acetate/Et2O (75 mL). The organic extract was extracted with brine (2×75 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-4% MeOH/CH2Cl2), affording the title compound (800 mg, 85% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.45 (s, 3H), 4.70 (s, 2H), 7.17 (d, 1H, J=5.1 Hz), 8.54 (d, 1H, J=5.1 Hz), 8.67 (s, 2H); M+287.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@H:29]([CH3:34])[C:30]([O:32]C)=O)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[NH3:35]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@H:29]([CH3:34])[C:30]([NH2:35])=[O:32])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: N
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Solvent: CO
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)C(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
A solution of methyl (2R)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.55 mmol) in methanol (3 ml) was saturated with ammonia by bubbling gaseous ammonia into the solution for a few minutes. The tube containing the solution was sealed and the mixture was stirred for 48 hours at room temperature. The precipitate was filtered, washed with ether and dried to give the title compound as a white solid (165 mg, 65%); NMR Spectrum 1.66 (d, 3H), 5.14 (q, 1H), 5.77 (s, 2H), 6.94 (d, 1H), 7.02 (d, 1H), 7.30 (m, 1H), 7.36 (d, 1H), 7.55 (br s, 1H), 7.78-7.67 (m, 4H), 7.89 (br s, 1H), 8.15 (s, 1H), 8.52 (m, 3H), 10.80 (br s, 1H); Mass spectrum MH+ 440.
Reaction SMILES: [CH2:1]([O:8][CH2:9]/[CH:10]=[CH:11]\[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH2:1]([O:8][CH2:9]/[CH:10]=[CH:11]/[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C/C=C\COCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC/C=C/COCc1ccccc1
Temperature: 0 °C
Yield: 55.8 %

Procedure:
3.9 g of (Z)-4-benzyloxy-2-butenal was dissolved in 60 ml of ethanol, and 850 mg of sodium borohydride was added thereto at 0° C. under stirring. The mixture was stirred at 0° C. for 1.5 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The ethyl acetate solution was washed sequentially with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was subjected to distillation under reduced pressure (2.0 mmHg, 142° C.) to obtain 2.2 g of (E)-4-benzyloxy-2-buten-1-ol as colorless oily substance.
Reaction SMILES: [CH:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([NH:18][C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=3)=[O:20])=[C:13]([CH:17]=2)[C:14]([OH:16])=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:18][C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=3)=[O:20])=[C:13]([CH:17]=2)[C:14]([OH:16])=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(C#CC2CCCCC2)cc1C(=O)O)c1ccc(C2CCCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1ccc(CCC2CCCCC2)cc1C(=O)O)c1ccc(C2CCCCC2)cc1
Yield: 81 %

Procedure:
55 mg (0.13 mmol) of 5-(cyclohexylethynyl)-2-{[(4-cyclohexylphenyl)carbonyl]amino}benzoic acid obtained in Example 92 and 55 mg of Pd—C were stirred in ethanol (4 mL) at room temperature for 5 days. Thereafter, the mixture was filtered, and the filtrate was condensed, thereby giving 45 mg of the target 5-(2-cyclohexylethyl)-2-{[(4-cyclohexylphenyl)carbonyl]amino}benzoic acid (yield: 81%).
Reaction SMILES: [Cl-].[Li+].[CH:3]([Mg]Cl)=[CH2:4].[C:7]1(=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8]1>C1COCC1.[Cu]Cl>[CH:3]([C:7]1([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8]1)=[CH2:4]
Reactant: C=C[Mg]Cl
Reactant: CCOC(=O)C=C1CC1
Agent: Cl[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC1(CC(=O)OCC)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Under argon, 0.55 g (5.53 mmol) of copper(I) chloride and 0.59 g (13.82 mmol) of lithium chloride are suspended in 150 ml of anhydrous THF. The reaction mixture is cooled to −78° C., 48.8 ml (82.95 mmol) of vinylmagnesium chloride solution (1.7 M in THF) are added and the mixture is stirred for 10 minutes. Over a period of 30 min, a solution of 8.72 g (69.12 mmol) of ethyl cyclopropylideneacetate (Example 1A) in 50 ml of anhydrous THF is then added dropwise. After the addition is ended, the cooling bath is replaced by an ice/acetone bath. After a further 15 min, the reaction is terminated by dropwise addition of 100 ml of 1 N hydrochloric acid. The reaction mixture is saturated with sodium chloride, and 100 ml of a saturated sodium chloride solution which contains 5 ml of a 25% strength aqueous ammonia solution are then added. The mixture is filtered through Celite. The filtrate is washed with ammoniacal sodium chloride solution until the aqueous phase remains colorless. The organic phase is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the solvent and kugelrohr distillation of the residue at 150° C. and 15 mbar gives 7.10 g (67% of theory) of the title compound as a colorless liquid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:30])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[Br:29][C:25]1[CH:24]=[C:23]([C:21]2[CH2:20][C:19](=[O:30])[NH:18][C:9]3[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(Br)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(Br)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
) The title compound was prepared from the above described {2-[3-(3-bromo-phenyl)-3-oxo-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (1.152 g, 2.30 mmol) and TFA (10 mL) according to general procedure I step 2. Obtained as a light yellow solid (0.730 g, 82%). MS (ISP) 383.0 [(M+H)+] and 385.0 [(M+2+H)+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][N:3]=1.[C:16](Cl)(=[O:26])[C:17]1[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:19](Cl)=[O:20]>N1C=CC=CC=1.CCOC(C)=O>[C:12]([O:11][C:9]([NH:8][C:5]1[CH:6]=[N:7][C:2]([N:1]2[C:19](=[O:20])[C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16]2=[O:26])=[N:3][CH:4]=1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1cnc(N)nc1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cnc(N2C(=O)c3ccccc3C2=O)nc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of N-(2-aminopyrimidin-5-yl)(tert-butoxy)carboxamide (0.237 g, 1.0 mmol) in pyridine (1 mL) was added phthaloyl dichloride (0.144 mL, 1.0 mmol). The resulting suspension was stirred at 45° C. for 2 hr, diluted with EtOAc, washed with water and brine, dried and concentrated in vacuo to give crude (tert-butoxy)-N-[2-(1,3-dioxobenzo[c]azolidin-2-yl)pyrimidin-5-yl]carboxamide (0.31 g). ES-MS (M+H)+=341; (M+H−tBu)+=285.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18]O)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[Br:27]P(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][Br:27])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CO)cc2C1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(CBr)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a solution of 0.380 mmol of tert-butyl-7-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate in 2.5 ml CH2Cl2 were added at 0° C. 1.139 mmol Et3N and 0.456 mmol tribromophosphine. The mixture was allowed to warm to room temperature and stirred for 1 h. To the reaction mixture were added saturated NaHCO3 solution and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed, dried over MgSO4 and filtered. Evaporation of the solvent gave 105 mg of crude material that was purified by flash chromatography to yield 76 mg of colorless oil (61.3%).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[C:11](Cl)=[O:12])([CH3:3])[CH3:2].[OH-].[NH4+:15]>>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[C:11]([NH2:15])=[O:12])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C(=O)Cl
Agent: [OH-]
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C(N)=O
Reaction time: 8 h

Procedure:
A 250 mL flask was purged with nitrogen, left under a nitrogen atmosphere, and charged with 13.0 g (0.0641 mol) of (1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarbonyl chloride. While stirring 130 mL of 29% ammonium hydroxide solution was added to the flask. A white precipitate quickly formed, and after stirring overnight the fine white slurry was suction filtered. The filter cake was washed with water (3×50 mL) then dried in a vacuum oven (RT, 5 mm Hg, 3 days) to provide (1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide as a white solid with the following spectroscopic properties.
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27](O)([CH2:29][CH3:30])[CH3:28])=[CH:26][C:21]=2[O:20][CH2:19]1>C1C=CC=CC=1>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27]([S:1][CH2:2][C:3]([OH:5])=[O:4])([CH3:28])[CH2:29][CH3:30])=[CH:26][C:21]=2[O:20][CH2:19]1
Reactant: O=C(O)CS
Reactant: CCC(C)(O)c1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCC(C)(SCC(=O)O)c1ccc2c(c1)OCO2
Yield: 35.4 %

Procedure:
50 ml of benzene, 1.29 g of mercaptoacetic acid and a catalytic amount of p-toluenesulfonic acid monohydrate were added to 2.27 g of 2-(1,3-benzodioxol-5-yl)-2-butanol (crude oil). The obtained mixture was heated under reflux for 11 hours and cooled, followed by the addition of benzene. The obtained mixture was washed with water, followed by the addition of a 1N aqueous solution of sodium hydroxide. The alkaline layer was separated, washed with ethyl acetate, acidified with concentrated hydrochloric acid and extrated with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography (chloroform) to obtain 1.11 g of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@@:8]2([CH3:20])[N:16]=[C:15]([NH2:17])[C:11]3([CH2:14][CH2:13][CH2:12]3)[S:10](=[O:19])(=[O:18])[CH2:9]2)[CH:7]=1.N>CO.[Pd]>[F:21][C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=1[C@@:8]1([CH3:20])[N:16]=[C:15]([NH2:17])[C:11]2([CH2:12][CH2:13][CH2:14]2)[S:10](=[O:19])(=[O:18])[CH2:9]1
Reactant: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)C2(CCC2)C(N)=N1
Agent: [Pd]
Agent: N
Solvent: CO
Product: C[C@@]1(c2ccccc2F)CS(=O)(=O)C2(CCC2)C(N)=N1
Temperature: 23 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a solution of (R)-7-(5-bromo-2-fluoro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]non-8-en-9-ylamine (555 mg, 1.48 mmol, Eq: 1.00) in methanol (50 ml) and ammonia (7 N in MeOH) (634 μl, 4.44 mmol, Eq: 3.0) was added at 23° C. under inert atmosphere Pd/C 10% (157 mg, 148 μmol, Eq: 0.1). The suspension was set under hydrogen (balloon) and stirred at 23° C. for 2 hours. The catalyst was filtered off, washed three times with methanol/dichloromethane (1:1) and evaporated. The residue was extracted with dichloromethane and sat NaHCO3-sol. The organic layer was dried over Na2SO4, filtered and evaporated to give the pure (R)-7-(2-fluoro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]non-8-en-9-ylamine (385 mg, 1.3 mmol, 87.8% yield) as a white solid. MS (ISP): m/z=297.5 [M+H]+.
Reaction SMILES: [Mg].II.[CH3:4][CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1.C[O:23][B:24]([O:27]C)[O:25]C.S(=O)(=O)(O)O>O1CCCC1>[CH3:4][CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([O:23][B:24]([OH:27])[OH:25])[CH:12]=[CH:13][CH:14]=1
Reactant: COB(OC)OC
Reactant: CC(C)CCCC(C)CCOc1cccc(Br)c1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CCOc1cccc(OB(O)O)c1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
Under an inert atmosphere, 7.5 g of magnesium and a small amount of iodine were charged in 100 ml of dried tetrahydrofuran in a three-necked flask. Using a dropping funnel, 90 g of the above-mentioned 3-(3,7-dimethyloctyloxy)-bromobenzene was dropped over 50 minutes. After completion of dropping, 200 ml of dried tetrahydrofuran was added, and the mixture was stirred while heating for 2 hours under reflux to prepare a Grignard reagent. After completion of heating, the reagent was left to cool to room temperature. Into a three-necked flask other than the above-mentioned flask was charged 38 g of trimethylboric acid and 300 ml of dried tetrahydrofuran, and the flask was cooled in a dry ice/aceton bath. Using a dropping funnel, the above-mentioned Grignard reagent solution was dropped over 35 minutes. After completion of dropping, the reaction solution was heated up to room temperature. The reaction solution was added to dilute sulfuric acid (sulfuric acid 12 ml/water 360 ml) and the mixture was stirred, then, bisected and the portions were extracted with 150 ml of ethyl acetate and 100 ml ethyl acetate, respectively. The organic layers were combined, then, trisected and respective portions were washed with 100 ml of water. The washed organic layers were combined and the solvent was distilled off by an evaporator, then, 100 ml of hexane was added to suspend a solid component and the suspension was filtrated. Further, the filtrated substance was washed with 100 ml of hexane. 63 g of 3-(3,7-dimethyloctyloxy)-phenylboric acid was obtained in the form of while solid. Under an inert atmosphere, into a three-necked flask was charged 60 g of the above-mentioned 3-(3,7-dimethyloctyloxy)-bromobenzene, 250 ml of toluene, 250 ml of water, 62 g of potassium carbonate and 1.2 g of tetrakis(triphenylphosphine) palladium complex. Argon was bubbled through the solution for 20 minutes to remove oxygen, then, 63 g of the above-mentioned 3-(3,7-dimethyloctyloxy)-phenylboric acid was added and the mixture was heated up to 90° C., and stirred for 8 hours while heating at the same temperature. After completion of heating, the mixture was left to cool to room temperature. The toluene layer was separated, then, a colored component was removed by silica gel column chromatography. The solvent was distilled off to obtain 98 g of an oily product. This is referred to as compound G.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].Br.Br[CH2:29][CH2:30][C:31]1[N:32]=[CH:33][NH:34][CH:35]=1>CN(C=O)C.O>[NH:34]1[CH:35]=[C:31]([CH2:30][CH2:29][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[C:7](=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:6][CH2:5]3)[N:32]=[CH:33]1
Reactant: CC(=C1CCc2cc(O)ccc2C1=O)c1ccccc1
Reactant: BrCCc1c[nH]cn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=C1CCc2cc(OCCc3c[nH]cn3)ccc2C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
The product obtained from Step 2 (0.180 g, 0.68 mmol) was dissolved in 5 mL of dry DMF and treated with K2CO3 (0.376 g, 2.72 mmol) and 4-(2-bromoethyl)imidazole hydrobromide (0.192 g, 0.75 mmol). After stirring overnight at room temperature, the reaction was diluted with water and extracted with EtOAc. The pooled extracts were washed well with aqueous 0.5N KOH, water and brine, and then dried, filtered, and concentrated. Purification of the residue (SiO2, 5% MeOH in DCM) afforded 0.120 g (49%) of the title compound as a light yellow foam. Conversion of this product to its HCl salt according to the method of Example 34 afforded 0.063 g of a light yellow powder, mp 170-172° C.: CI-MS m/e 359 (M+ +1).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28]COC)[CH:23]=3)[CH3:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CO>CO>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:21][C:22]3[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=3)[CH3:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCOc1cccc(CN(C)c2cnc(-c3ccccc3)c(-c3ccccc3)n2)c1
Agent: Cl
Solvent: CO
Product: CN(Cc1cccc(O)c1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a suspension of 0.91 g of 1-{[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]methyl}-3-(methoxymethoxy)benzene in 10 ml of methanol, 2 ml of a 18% hydrogen chloride-methanol solution was added. After stirring at room temperature for 2 hours, 1 ml of a 18% hydrogen chloride-methanol solution was further added and the mixture was continuously stirred for one hour. After the solvent was evaporated under reduced pressure, the reaction solution was neutralized by adding an aqueous saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The crude crystal was washed with diethyl ether and then dried to obtain 0.66 g of the desired compound as a colorless crystal having a melting point of 156 to 157° C.