Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[CH3:4][N:5]([CH2:10][CH2:11][CH3:12])[C:6]([NH:8][CH3:9])=[O:7].[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(Cl)(Cl)Cl>[CH3:4][N:5]([CH2:10][CH2:11][CH3:12])[C:6]([N:8]([CH3:9])[C:20]([NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21])=[O:7]
Reactant: O=C=Nc1ccccc1
Reactant: CCCN(C)C(=O)NC
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCN(C)C(=O)N(C)C(=O)Nc1ccccc1
Reaction time: 15 h
Yield: 74.6 %

Procedure:
Into 300 ml of anhydrous dichloromethane, 13.0 g (0.1 mol) of 1,3-dimethyl-1-propylurea and 12.0 g (0.1 mol) of phenylisocyanate were added and dissolved. The mixture was ice-cooled under stirring and 26.0 g (0.1 mol) of stannic chloride was added drop-wise. The reaction was then continued at a room temperature for 15 hours and the precipitate formed was separated by filtration. The precipitate thus obtained was added into a mixture of 60 ml of 20% hydrochloric acid/120 ml of chloroform and the stirring was continued until the mixture became transparent. Then the chloroform layer was separated and was washed with water and the chloroform layer was dried with anhydrous sodium sulfate. The chloroform was removed by distillation under reduced pressure and the residue thus obtained was recrystallized from ligroin to obtain 18.6 g (yield: 75%) of 1,3-dimethyl-1-propyl-5-phenylbiuret having a melting point of 63° to 64° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[NH:12][N:11]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].I[CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[CH:27]1([N:12]2[C:13]3=[N:14][CH:15]=[N:16][C:17]([NH2:19])=[C:18]3[C:10]([C:4]3[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([F:1])[CH:3]=3)=[N:11]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: IC1CCCC1
Reactant: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)cc(-c2nn(C3CCCC3)c3ncnc(N)c23)c1
Temperature: 25 °C

Procedure:
3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (BA75, 100 mg, 0.386 mmol) was dissolved in DMF (10 ml). K2CO3 (250 mg, 1.54 mmol) was added and reaction was stirred at room temperature under an argon atmosphere. Iodocyclopentane (0.134 ml, 1.16 mmol) was added with a syringe and reaction was stirred for 2 hours. Solid K2CO3 was removed by filtration. Solvent was partially removed in vacuo. Sodium citrate (50 ml) was added and reaction was extracted with EtOAc. Organic phases concentrated in vacuo and purified using by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA79.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][CH2:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][CH2:23][NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21]
Reactant: NCCCO
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCCCO)cc2c1=O
Yield: 68.5 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 3-amino-propan-1-ol according to the GPA affording 24.1 mg (68.5%) of a red powder. Rt=3.09 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1.C(O)(C(F)(F)F)=O>C1COCC1.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>[F:19][C:18]([F:20])([F:21])[CH:17]([C:14]1[CH:15]=[CH:16][C:11]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:12][CH:13]=1)[OH:22]
Reactant: Fc1cccc([Mg]Br)c1
Reactant: OC(c1ccc(Br)cc1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: OC(c1ccc(-c2cccc(F)c2)cc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To Pd(PPh3)4 (2.1 g, 1.823 mmol) was added 3-fluorophenylmagnesium bromide (55 mls, 1.0 M in THF, 55 mmol) at 0° C. over 15 minutes. The ice bath was removed and the mixture was stirred for 30 minutes. 1-(4-Bromophenyl)-2,2,2-trifluoroethanol (4.65 g, 18.23 mmol) in THF (50 mls) was added over 10 minutes. The mixture was heated to reflux for 3 hours and was shown complete by LC (Sunfire column, TFA). The mixture was cooled, quenched with H2O, rotary evaporated to remove most of the THF, and extracted 3 times with CH2Cl2. The organics were combined washed with brine, dried over MgSO4, and concentrated. Chromatography (SiO2, CH2Cl2) gave 4.64 g of 2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethanol. Yield 94%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1>CC1C=CC=CC=1C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:9]=1
Reactant: Brc1cccnc1
Reactant: C1CNCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: c1cncc(N2CCNCC2)c1
Temperature: 120 °C
Yield: 86 %

Procedure:
A 200 ml Kjeldahl flask equipped with a cooling condenser and a thermometer was charged with a solution of 22 g of piperazine in 20 ml of o-xylene, a solution of 6.72 g of 3-bromopyridine in 20 ml of o-xylene and a solution of 5.66 g of NaOBut in 20 ml of o-xylene, and further with a solution of 48 mg of palladium acetate in 15 ml of o-xylene (the ratio of palladium atom/heterocyclic aromatic halide=0.5% by mole). The flask was flushed with nitrogen for about 20 minutes while the content was stirred, and 0.2 ml of tri-tert.-butylphosphine was added. Then the mixture was heated to 120° C., and maintained at that temperature for 3 hours with stirring. After completion of the reaction, the same treatment as employed in Example 1 was conducted to give colorless oily 1-(3-pyridyl)piperazine. The yield was 86% by mole.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:11][OH:12])[CH:7]=[C:8]([F:10])[CH:9]=1.CI.N[C@H:16](C(O)=O)CCSC>CCOC(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([CH2:11][O:12][CH3:16])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: OCc1cc(F)cc(Br)c1
Reactant: CSCC[C@H](N)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: COCc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 231.1 %

Procedure:
NaH (60% dispersion in mineral oil, 245 mg, 6.12 mmol) was added to a solution of (3-bromo-5-fluorophenyl)methanol (1.195 g, 5.83 mmol) in 2-Me THF (20 mL). After gas evolution had ceased, MeI (0.455 mL, 7.29 mmol) was added and the resulting mixture was stirred at r.t. for 16 h. Another portion of NaH (50 mg, 2.1 mmol) and Met (0.10 mL, 1.6 mmol) were added and the mixture was heated to 60° C. for 2 h. The cooled mixture was diluted with EtOAc, washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (gradient of 0-15% EtOAc in heptane) to give 0.810 g (63% yield) of the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.30 (s, 3H), 4.38-4.46 (m, 2H), 7.18 (m, 1H), 7.37 (s, 1H), 7.44-7.50 (m, 1H); MS (EI) m/z 218 M′.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][CH2:20][C:21]2[O:25][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23][C:22]=2[CH:32]=O)=[CH:17][CH:16]=1.C(OP([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][CH2:20][C:21]2[O:25][C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:23][C:22]=2/[CH:32]=[CH:44]/[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:17][CH:16]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2oc(-c3ccccc3)nc2C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1nc(-c2ccccc2)oc1COc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 3 h
Yield: 47.8 %

Procedure:
To a mixture of 5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazole-4-carbaldehyde (1.0 g), ethyl diethylphosphonoacetate (0.52 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.10 g) at room temperature, and the mixture was stirred at the same temperature for 3 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl (2E)-3-[5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazol-4-yl]-2-propenoate as colorless crystals (0.55 g, yield 49%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 107-108° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([Sn](CCCC)(CCCC)[C:19]([O:21][CH2:22][CH3:23])=[CH2:20])CCC>[Cl-].C([N+](CC)(CC)CC)C.CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:19]([O:21][CH2:22][CH3:23])=[CH2:20])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: C=C(OCC)c1ncc(C(=O)OCC)cc1Cl
Temperature: 80 °C

Procedure:
To a suspension of ethyl 5,6-dichloronicotinate (5.26 g, 23.90 mmol) and tetraethylammonium-chloride (11.88 g, 71.7 mmol) in MeCN (50 mL) was added tributyl(1-ethoxyvinyl)stannane (9.50 g, 26.3 mmol) and PdCl2(PPh3)2 (0.671 g, 0.956 mmol). The reaction was sealed, heated at 80° C. for 5 hours. A dark color clear solution resulted. The reaction mixture was then cooled to 20° C., concentrated and diluted with EtOAc (200 mL), and washed with water (50 mL) and brine (50 mL). The organic was then dried (Na2SO4) and concentrated to give crude ethyl 5-chloro-6-(1-ethoxyvinyl)nicotinate. The residue was then dissolved in THF (100 mL) and HCl (20 mL, 3M in H2O) was added. The reaction mixture was stirred at 20° C. for 5 hours, and saturated NaHCO3 solution was added until pH=8. The mixture was then diluted with EtOAc (200 mL) and water (50 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organics was washed with brine (20 mL), dried (Na2SO4) and concentrated to afford the desired product (3.56 g). LCMS m/z 228.5 (M+H)+, Rt 0.83 min.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:24])[CH:18]([CH3:23])[CH:19]([CH3:22])[CH2:20][CH3:21])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:25]([OH:27])=[O:26].[CH2:28]([OH:35])C(N)(CO)CO.[CH3:36][OH:37]>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:24])[CH:18]([CH3:23])[CH:19]([CH3:22])[CH2:20][CH3:21])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:25]([O-:27])=[O:26].[OH:37][CH2:36][N+:7]([CH2:28][OH:35])([CH2:2][OH:1])[CH3:6]
Reactant: CO
Reactant: NC(CO)(CO)CO
Reactant: CCC(C)C(C)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)O)cnc3c2c1
Solvent: CN(C)C=O
Product: CCC(C)C(C)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)[O-])cnc3c2c1
Product: C[N+](CO)(CO)CO

Procedure:
To a suspension of 4-oxo-10-(2,3-dimethylpentanamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid (7.0 g) in N,N-dimethylformamide (93 ml) was added tris(hydroxymethyl)aminomethane (2.3 g) and methanol (47 ml) under stirring and stirred for 2 hours at ambient temperature. The insoluble materials was removed by filtration, and to the filtrate was added ether (60 ml) with stirring. The resultant precipitate was collected by filtration and washed with ether, and dried under reduced pressure to give tris(hydroxymethyl)methylammonium 4-oxo-10-(2,3-dimethylpentanamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (3.15 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[N:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:18]>C(Cl)(Cl)Cl.C(Cl)Cl>[F:1][C:2]1[CH:3]=[N+:4]([O-:18])[C:5]2[CH:6]=[CH:7][C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1ccc2ncc(F)cc2[nH]1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=c1ccc2c(cc(F)c[n+]2[O-])[nH]1

Procedure:
7-Fluoro-1,5-naphthyridin-2(1H)-one (1.280 g, 7.798 mmol) and m-chloroperoxybenzoic acid (2.123 g, ca. 1.2 eq. based on an mCPBA content of 75%) were stirred in chloroform (60 mL) at reflux overnight. Further mCPBA (0.420 g) was added and the mixture was stirred at reflux for an additional 6 hours. The mixture was diluted with DCM to a total volume of ca. 100 ml and filtered with suction. The solid collected was washed with DCM (2×20 mL) and air-dried to give 7-fluoro-1,5-naphthyridin-2(1H)-one 5-oxide as a tan solid (1.045 g, contaminated with ca. 12% starting material).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:26][Si:27]([CH2:30][CH2:31][O:32][CH2:33]Cl)([CH3:29])[CH3:28]>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]([CH2:33][O:32][CH2:31][CH2:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc([N+](=O)[O-])c3)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc([N+](=O)[O-])c3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (2.0 g, 6.4 mmol) in THF (30 mL), was added sodium hydride (180 mg, 7.50 mmol) at 0° C. The reaction was stirred for 1 hour at room temperature, then cooled back to 0° C., followed by the dropwise addition of SEMCl (1.28 g, 7.68 mmol). The solution was stirred for 4 hours at room temperature before being quenched by addition of 50 mL of a water/ice mixture. The resulting mixture was concentrated in vacuo, and the resulting solution was extracted with ethyl acetate (×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The reaction was then purified by chromatography using silica gel, eluting with 1-50% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford ethyl 4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a yellow oil. LRMS (ESI) calc'd for C21H27N4O5Si [M+H]+: 443, found 443.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([C:12]#[N:13])[C:4]=1[OH:14])#[N:2].[C:15](C1C=C([N+]([O-])=O)C=C(C#N)C=1N)#N.C(C1C=C([N+]([O-])=O)C=C(C#N)C=1Cl)#N.CO.[OH-].[Na+]>>[C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([C:12]#[N:13])[C:4]=1[O:14][CH3:15])#[N:2]
Reactant: N#Cc1cc([N+](=O)[O-])cc(C#N)c1N
Reactant: N#Cc1cc([N+](=O)[O-])cc(C#N)c1O
Agent: N#Cc1cc([N+](=O)[O-])cc(C#N)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C#N)cc([N+](=O)[O-])cc1C#N

Procedure:
2,6-Dicyano-4-nitro-phenol, used in Example 12, was prepared according to generally known processes: 2,6-dicyano-4-nitro-aniline is converted by a Sandmeyer reaction into 2,6-dicyano-4-nitro-chlorobenzene of melting point 218°-219.5°C, reacted with methanol/sodium hydroxide to give 2,6-dicyano-4-nitro-anisole of melting point 144°-148°C, and the latter subsequently split with sodium iodide in dimethylformamide to give 2,6-dicyano-4-nitro-phenol of melting point 228°-231°C. The last two stages correspond to a process indicated in Belgian Pat. No. 764,117.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:27]([OH:29])=O)[CH2:6][S:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].Cl.C(SCCN)(=O)C.Cl.[C:39]([S:47][CH2:48][CH2:49][NH2:50])(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl.CCOCC>[C:1]([NH:4][C@H:5]([C:27]([NH:50][CH2:49][CH2:48][S:47][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:29])[CH2:6][S:7][C:8]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: NCCSC(=O)c1ccccc1
Agent: CC(=O)SCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCSC(=O)c1ccccc1
Yield: 62 %

Procedure:
The coupling reaction of 7 (7.41 mmol) is carried out according to Method B described in the first synthetic route (example 1): S-acetylcysteamine hydrochloride was replaced by S-benzoylcysteamine hydrochloride (T. Wieland and E. Bokelman, Ann. Chem., 1952, 576, 20-34. After the various treatments, the expected compound is isolated by flash chromatography on a silica gel column (eluent: CH2Cl2/ether 15%). 12 is collected in the form of a colorless foam with a yield of 62%. Rf (AcOEt/petroleum ether, 7/3): 0.42. [α]D20=+10.8° (c 1.11, CHCl3).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][CH:4]=1.[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>BrC1C=CC(CC)=CC=1.O1CCCC1>[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][CH:4]=1)[OH:22])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCc1ccc(Br)cc1
Reactant: O=Cc1ccccc1OCc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.4 %

Procedure:
1-Bromo-4-ethylbenzene (6.69 g, 0.036 mol) was added to a suspension of magnesium (17.2 g) and tetrahydrofuran (50 mL) and heated to reflux. Subsequently, a tetrahydrofuran (300 mL) solution of 1-bromo-4-ethylbenzene (97.9 g, 0.529 mol) was added for two hours at room temperature. After stirred at room temperature for 1.5 hours, the reaction mixture was cooled to 4° C. and a tetrahydrofuran (100 mL) solution of 2-benzyloxybenzaldehyde (100 g, 0.471 mol) was added for one hour. After stirred for two hours, the reaction mixture was poured into a saturated ammonium chloride aqueous solution. After the mixture was extracted with ethyl acetate, the organic phase was washed with brine and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to obtain (2-benzyloxyphenyl)(4-ethylphenyl)methanol (152 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=S(=O)(Cc1ccncc1)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1ccncc1)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A toluene (5 ml) solution of the 4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained in Example 119, 1-benzylpiperidin-4-ol (103 mg, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) was heated under reflux for 3 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was added with 1-benzylpiperidin-4-ol (103 mg, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol), followed by heating under reflux for 22 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column. The fraction obtained from the methanol:methylene chloride (=1:10) eluate was concentrated under reduced pressure. The residue thus obtained was purified by high performance liquid chromatography (using a mixed solvent of water/acetonitrile/formic acid), whereby the title compound (40 mg, 35%) was obtained as an amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][C:14]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]([OH:25])[CH2:17]3)[CH2:13]2)=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].[OH-].[Na+]>N1C=CC=CC=1>[C:27]([O:25][CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]2([CH2:15][CH2:16][N:12]([CH2:11][CH2:10][CH2:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:26])[CH2:13]2)[CH2:17]1)(=[O:29])[CH3:28]
Reactant: O=C(CCCN1CCC2(CC(O)c3ccccc32)C1)c1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CC(=O)OC1CC2(CCN(CCCC(=O)c3ccc(F)cc3)C2)c2ccccc21

Procedure:
7.5 g of (1RS,3RS)-p-fluoro-4-(3-hydroxy-spiro[indane-1,3'-pyrrolidin]-1'-yl)butyrophenone are stirred at room temperature for 20 hours together with 15 cc of pyridine and 15 cc of acetic anhydride. The reaction mixture is then poured on ice, is made alkaline with 2 N caustic soda solution and is extracted thrice with 100 cc amounts of ether. The crude title compound obtained as oily residue after concentrating the ether phase by evaporation, is converted into the hydrogen fumarate form, which is recrystallized from ethanol/ether. M.P. of the hydrogen fumarate form of the title compound: 168°-170°.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C:5]2([CH2:11][CH2:10][N:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=4)[N:15]=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:4][C@@H:3]1[NH:24][C:25](=[O:31])[O:26]C(C)(C)C.Cl.[O:33]1CCOCC1>CO>[C:25](=[O:31])([O-:33])[O-:26].[NH2:24][C@H:3]1[CH2:4][C:5]2([CH2:11][CH2:10][N:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=4)[N:15]=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:6][C@H:2]1[OH:1]
Reactant: COc1ccc2nccc(N3CCC4(CC3)C[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C4)c2n1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COc1ccc2nccc(N3CCC4(CC3)C[C@@H](O)[C@@H](N)C4)c2n1
Product: O=C([O-])[O-]
Reaction time: 12 h
Yield: 47.4 %

Procedure:
To a solution of 1,1-dimethylethyl {(2S,3R)-3-hydroxy-8-[6-(methyloxy)-1,5-naphthyridin-4-yl]-8-azaspiro[4.5]dec-2-yl}carbamate (220 mg, 0.514 mmol) in MeOH (5 mL) at 25° C. was added a solution of 4M HCl in dioxane (900 μL, 3.60 mmol). After 12 h, the solution was concentrated and the residue neutralized using excess MP carbonate resin yielding the title compound (80 mg, 47%) as an orange oil: LCMS (ES) m/e 329 (M+H)+.