Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1C=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.C=C1CC[N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])CC1>C(Cl)Cl>[C:22]([O:21][C:19]([N:16]1[CH2:2][CH2:3][C:4]2([O:10][CH2:8]2)[CH2:5][CH2:6]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 25 °C
Reaction time: 15 h
Yield: 101.1 %

Procedure:
m-Chloroperbenzoic acid (1.14 g, 6.6 mmol) was added to a solution of tert-butyl 4-methylenepiperidine-1-carboxylate (1 g, 5.1 mmol) in CH2Cl2 (30 mL) at 0° C. The reaction mixture was stirred for 15 h at rt, diluted with CH2Cl2, washed with a saturated aqueous solution of NaHCO3 and brine, dried (Na2SO4), and evaporated to afford 1.1 g of the title compound which was used without further purification. 1H-NMR (400 MHz, CDCl3) δ ppm 3.74-3.65 (m, 2H), 3.45-3.38 (m, 2H), 2.68 (s, 2H), 1.82-1.75 (m, 2H), 1.48-1.41 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]=[O:25])=[CH:4][CH:3]=1.C[Si](C)(C)[C:28]([F:31])([F:30])[F:29].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[C:28]([F:31])([F:30])[F:29])=[CH:4][CH:3]=1
Reactant: Cc1cc(C#N)ccc1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)ccc1N1CCCn2c1nc1c(Cl)ccc(C(O)C(F)(F)F)c12
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
To a stirred solution of 4-(9-chloro-6-formyl-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl)-3-methylbenzonitrile (68.5 mg, 0.195 mmol) and trimethyl(trifluoromethyl)silane (86.5 μL, 0.585 mmol) in tetrahydrofuran (1.0 mL) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 19.5 μL, 0.0195 mL) at 0° C. After 10 min, hydrochloric acid (1.0 M, 0.3 mL) was added. After 30 min, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give the title compound as a pale yellow solid (67.4 mg, 0.160 mmol, 82%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-])=O)[CH:8]=2)[NH:3]1>CO.[Pd]>[NH2:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])([CH3:16])[C:11](=[O:12])[NH:10]2
Reactant: CC1(C)Nc2ccc([N+](=O)[O-])cc2NC1=O
Agent: [Pd]
Solvent: CO
Product: CC1(C)Nc2ccc(N)cc2NC1=O

Procedure:
A solution of 1,2-dihydro-2,2-dimethyl-6-nitro-3-(4H)-quinoxalinone(663 mg, 3 mmol) in CH3OH (10 ml) is hydrogenated with 50 psi H2 (g) at room temperature in the presence of a catalyst of 10% by weight palladium on charcoal (50 mg). After the starting material is consumed, the solution is filtered and concentrated in vacuo to yield 6-amino-1,2-dihydro-2,2-dimethyl-3-(4H)-quinoxalinone.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1([CH3:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH2:9][CH2:8]1.[N+:18]([O-])([OH:20])=[O:19]>>[CH3:6][C:7]1([CH3:17])[C:16]2[C:11](=[CH:12][C:13]([N+:18]([O-:20])=[O:19])=[CH:14][CH:15]=2)[NH:10][CH2:9][CH2:8]1
Reactant: O=[N+]([O-])O
Reactant: CC1(C)CCNc2ccccc21
Agent: O=S(=O)(O)O
Product: CC1(C)CCNc2cc([N+](=O)[O-])ccc21
Reaction time: 0.33 h

Procedure:
To 13 ml of H2SO4 (96%) cooled in a salt ice bath was added dropwise 4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (5.80 g, 36.0 mmol). The resulting slurry was stirred for 30 min, upon when concomitant addition of HNO3 (90%, 1.70 ml, 36.0 mmol) and H2SO4 (96%, 7 ml) was started, the addition was finished in 20 min, the mixture was stirred at 0° C. to 15° C. for 2 h, poured into ice, and extracted with EtOAc. The organic portion was washed with brine, condensed, and purified by flash column chromatography (0 to 10% of EtOAc in hexanes). The titled compound was obtained as a yellow oil. MS (ES+): 206.9 (M+H)+. Calc'd for C11H14N2O2—206.24.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]2[CH2:23][CH2:22][N:21]([CH3:24])[C:20]2=[O:25])[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].Br[C:27]1[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[N:31][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:36][N:35]([CH3:37])[C:33]([C:30]1[CH:29]=[CH:28][C:27]([O:1][C:2]2[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)[CH:15]=[C:16]([O:18][C@H:19]3[CH2:23][CH2:22][N:21]([CH3:24])[C:20]3=[O:25])[CH:17]=2)=[CH:32][N:31]=1)=[O:34]
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Reactant: CN(C)C(=O)c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N(C)C)nc3)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Yield: 23 %

Procedure:
A mixture of 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide (Intermediate 18) (206 mg, 0.6 mmol), 5-bromo-N,N-dimethyl-pyridine-2-carboxamide (CAS no. 845305-86-4) (165 mg, 0.72 mmol), cesium carbonate (587 mg, 1.8 mmol) and tris(triphenylphosphine)copper bromide (CAS no. 15709-74-7) (112 mg, 0.12 mmol) in N,N-dimethylacetamide (5 mL) was stirred at 160° C. for 6 hours. The N,N-dimethylacetamide was evaporated under reduced pressure and the residue was dissolved in water (20 mL) extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica eluting with 0-5% methanol in DCM. The resulting compound was dissolved in ethyl acetate (110 mL), washed with citric acid (1N, 10 mL), water (10 mL) and brine (10 mL), dried (MgSO4) and the solvent evaporated to afford the product (67 mg, 23%). 1H NMR δ (300 MHz, CDCl3) 2.14-2.26 (m, 1H), 2.52-2.67 (m, 1H), 2.55 (s, 3H), 2.94 (s, 3H), 3.15 (s, 6H), 3.34-3.57 (m, 2H), 4.94 (t, 1H), 6.97 (s, 1H), 7.23 (s, 1H), 7.40 (d, 1H), 7.46 (s, 1H), 7.72 (s, 1H), 8.14 (s, 1H), 8.38 (s, 1H), 8.58 (s, 1H), 9.52 (s, 1H); m/z 491 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[NH2:11][CH2:12][C:13]1[N:17]([CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[N:16]=[C:15]([CH2:28][CH3:29])[C:14]=1[O:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=1.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>CO.O.ClCCl>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:11][CH2:12][C:13]2[N:17]([CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[N:16]=[C:15]([CH2:28][CH3:29])[C:14]=2[O:30][C:31]2[CH:32]=[C:33]([Cl:38])[CH:34]=[C:35]([Cl:37])[CH:36]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCc1nn(CCNC(=O)OC(C)(C)C)c(CN)c1Oc1cc(Cl)cc(Cl)c1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCc1nn(CCNC(=O)OC(C)(C)C)c(CNCc2ccc(C#N)cc2)c1Oc1cc(Cl)cc(Cl)c1
Reaction time: 4 h
Yield: 58 %

Procedure:
A mixture of 4-cyanobenzaldehyde (50 mg, 0.380 mmol), the amine of Example 138 (172 mg, 0.400 mmol), magnesium sulphate (200 mg) and dichloromethane (4 ml) was stirred at room temperature for 4 days. The mixture was filtered and the filtrate was concentrated under reduced pressure to leave a yellow oil. The oil was dissolved in methanol (4 ml) and sodium borohydride (18 mg, 0.480 mmol) was added with vigorous stirring. Once the addition was complete the reaction was stirred for 4 hours and then water (2 ml) was added. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (50 ml). The resulting solution was washed with 1M aqueous potassium carbonate solution (20 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (99:1, by volume) then dichloromethane:methanol (95:5, by volume) to provide the title compound (120 mg) as a colourless oil.
Reaction SMILES: Cl.[CH2:2]([NH2:7])[CH2:3][CH2:4][C:5]#[CH:6].[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.C(N(CC)CC)C>ClCCl>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:7][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: C#CCCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.2 %

Procedure:
Pent-4-yn-1-amine hydrochloride (5.48 g, 45.8 mmol) was added to a 6° C. solution of 2,4-dichloro-3-nitroquinoline (10.6 g, 43.6 mmol) and triethylamine (15.2 mL, 109 mmol) in dichloromethane (100 mL). After 30 minutes, the solution was allowed to warm to room temperature. After 5 hours, the volatiles were removed under reduced pressure and the solid residue was triturated with water and isolated by filtration. The filter cake was rinsed with water and toluene and was allowed to dry for several days to yield 2-chloro-3-nitro-N-pent-4-ynylquinolin-4-amine as an orange solid (13.16 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[CH:15][C:14]([C:27]([F:30])([F:29])[F:28])=[N:13]2)=[CH:8][CH:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:3][CH2:4][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=3)=[CH:15][C:14]([C:27]([F:28])([F:29])[F:30])=[N:13]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(CO)cc2)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A mixture of 1-[4-(ethoxycarbonyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (2.4 g) and lithium aluminum hydride (0.25 g) in tetrahydrofuran (20 ml) was stirred at 55° C. for 2 hours. The reaction was quenched with methanol and water, and the mixture was filtered. The filtrate was concentrated and the residue was dissolved in a mixture of ethyl acetate and tetrahydrofuran. The solution was washed with water, dried, and evaporated. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (20:1).to give a white powder of 1-[4-(hydroxymethyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (1.3 g).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[CH2:8][C:9]#[N:10].[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O)=O>C(O)C>[C:15]1(=[C:8]([C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH3:4])[C:9]#[N:10])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccccc1CC#N
Reactant: O=C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CCO
Product: COc1ccccc1C(C#N)=C1CCCCC1
Temperature: 85 °C
Yield: 36.4 %

Procedure:
Sodium methylate (5.40 g, 0.10 mol) is dissolved in ethanol (70 ml) and 2-methoxy benzylcyanide (14.70 g, 0.10 mol) is added over 2 min. Cyclohexanone (9.80 g, 0.10 mol) is added to the white suspension. The resulting mixture is heated to 85° C. (bath) for 4.5 h. Under icecooling, formic acid (5.0 ml) is added dropwise, upon which the mixture turns colourless. Standard aqueous workup as described in example 1, followed by a short path distillation at 0.05 mbar/137-146° C. yields 8.28 g of product (37% yield) as a viscous oil, from which a crystalline byproduct is separated via crystallization from hexane. The mother liquor is concentrated and the residue subjected to a fine distillation at 0.05 mbar/136° C. to yield the product as colourless oil (1.81 g, 8%).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]2[CH2:13][CH2:14][CH2:15][C:16](=[O:17])[C:4]=12.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][CH:15]1[CH2:14][CH2:13][C:5]2=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[S:7][C:3]([S:2][CH3:1])=[C:4]2[C:16]1=[O:17]
Reactant: CCOC(=O)c1sc(SC)c2c1CCCC2=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1sc(SC)c2c1CCC(Br)C2=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 87.1 %

Procedure:
Ethyl 4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (25.12 g) was dissolved in chloroform (400 ml); a solution of bromine (15.59 g) in chloroform (20 ml) was added dropwise at room temperature over a period of 30 minutes. After the reaction mixture was stirred at room temperature for 40 minutes, it was washed with a 2% aqueous solution of sodium sulfite (400 ml), water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried (MgSO4), after which the solvent was distilled off to yield ethyl 5-bromo-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (28.27 g, 87.1%), which was then recrystallized from ethyl acetate-hexane. Light-yellow prisms. Melting point 147-148° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25].C(N1C=CN=C1)(N1C=CN=C1)=O>>[CH2:18]([CH:12]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][C:38]([C:35]2[CH:36]=[CH:37][C:32]([C:29]3[CH:30]=[CH:31][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:27][CH:28]=3)=[CH:33][CH:34]=2)=[O:39])=[CH:6][CH:7]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:19][CH2:20][CH3:21]
Reactant: COC(=O)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CCCCC(Cc1ccc(OCCN)cc1)C(=O)OCC
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(C(=O)OC)cc3)cc2)cc1)C(=O)OCC
Yield: 37.8 %

Procedure:
In a similar manner to that described in Example 5, a reaction was carried out using ethyl 3-[4-(2-aminoethoxy)phenyl]-2-butylpropionate (375 mg), which is the product of Reference example 6, 4′-methoxycarbonylbiphenyl-4-carboxylic acid (328 mg) and carbonyldiimidazole (225 mg) and the reaction mixture was treated to afford the title compound (257 mg) as colorless crystals.
Reaction SMILES: [C:1](N)(=O)C(C)=C.[Na].N(C(C#N)(C)CCC(O)=O)=NC(C#N)(C)CCC(O)=O.C(OCC)(=O)C=C.[C:35]([O:40][CH2:41][CH:42]1O[CH2:43]1)(=[O:39])[C:36]([CH3:38])=[CH2:37]>O>[C:35]([O:40][CH2:41][CH:42]([CH3:43])[CH3:1])(=[O:39])[C:36]([CH3:38])=[CH2:37]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: C=C(C)C(N)=O
Agent: C=CC(=O)OCC
Agent: CC(C#N)(CCC(=O)O)N=NC(C)(C#N)CCC(=O)O
Agent: [Na]
Solvent: O
Product: C=C(C)C(=O)OCC(C)C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
is added within 3 hours at 80° C. Thereafter a solution of 10 g of methacrylamide and 0.6 g of the sodium salt of 4,4'-azobis-(4-cyanovaleric acid) in 300 ml of water and a monomer mixture consisting of 50 g of ethyl acrylate and 45 g of glycidyl methacrylate are added simultaneously. After stirring for 60 minutes at 80° C. one obtains a coagulate-free dispersion with a solid content of 20%.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[CH3:12][NH2:13]>C(O)C.O>[CH3:12][NH:13][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CCO
Solvent: O
Product: CNCC(O)COc1ccccc1

Procedure:
To a solution of 1,2-epoxy-3-phenoxypropane (15 g), in ethanol (50 ml) was added 25-30% methylamine in water (50 ml) and the mixture heated under reflux for 1 h. The ethanol was removed in vacuo and the residue acidified with 2 N hydrochloric acid. The aqueous solution was extracted with ether acetate then made alkaline with 2 N sodium hydroxide and extracted into ether. The combined ethereal extracts were dried (Na2SO4), filtered and evaporated to give a semi-solid (14.8 g). The product was distilled in vacuo to give the title compound as white crystals b.p. 110°/0.07 mm, m.p. 74°-77° (9 g).
Reaction SMILES: [C:1]1([CH:11]=[CH:12][C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>[Pd].O1CCCC1>[C:1]1([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1cccc2ccccc12
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)CCc1cccc2ccccc12
Reaction time: 18 h
Yield: 99 %

Procedure:
10% Palladium on carbon (1.00 g) was added to a suspension of 3-(1-naphthyl)acrylic acid (50.0 g) in tetrahydrofuran (500 ml). The mixture was hydrogenated at 6 atmospheres for 18 hours then filtered through a kieselguhr pad washing with ethyl acetate (3×10 ml). The filtrate was evaporated under reduced pressure to give the subtitle compound (50.0 g) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([S:26][Si](C(C)C)(C(C)C)C(C)C)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[N:13]=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].[OH-].[K+].Cl[CH:58]([F:60])[F:59]>C1COCC1.O>[F:59][CH:58]([F:60])[S:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:16]=[CH:15][C:14]([CH:12]3[CH2:11][O:10][C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[N:13]3)=[CH:19][CH:18]=2)=[CH:21][CH:22]=1
Reactant: CC(C)[Si](Sc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cc1)(C(C)C)C(C)C
Reactant: FC(F)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(F)c1C1=NC(c2ccc(-c3ccc(SC(F)F)cc3)cc2)CO1
Reaction time: 0.08 h

Procedure:
To a solution of 10.9 g of the title compound of Step B in 20 mL of THF was added 23 mL of a commercial 1.0 M solution of n-Bu4NF in THF (containing 5% water) at 15 to 20° C. (water bath cooling) under a nitrogen atmosphere. After 5 minutes, 5.9 g of freshly-ground KOH was added, and then excess Freon® 22 (chlorodifluoromethane) was added through a subsurface tube at a rate sufficient to maintain a slight overpressure. After 20 to 30 minutes, the gas addition was stopped, and the reaction mixture was poured into ice-cold aqueous NH4Cl and extracted with ethyl acetate. The organic phase was washed with water and saturated aqueous NaCl, dried over MgSO4, and concentrated under vacuum. The residue was adsorbed onto silica gel, applied to a column of silica gel and eluted with hexanes/ethyl acetate (4:1 to 3:1 v:v) to obtain an oil. The oil crystallized upon trituration with ether and hexane to produce a white solid that was dried to provide 6.2 g of the title compound of Step C, a compound of this invention, melting at 72-76° C. 1H NMR (CDCl3, 300 MHz) δ 4.3-4.4 (m,1H), 4.8 (m,1H), 5.5 (m,1H), 6.85 (m,1H), 7.0 (m, 2H), 7.4-7.7 (m,9H).
Reaction SMILES: [N:1]([CH:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]1)=[C:2]=S.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21].[S]>[Hg]=O.C(#N)C>[O:21]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:2]1[NH:1][CH:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]1
Reactant: CCOC(=O)N1CCC(N=C=S)C1
Reactant: Nc1ccccc1O
Agent: O=[Hg]
Agent: [S]
Solvent: CC#N
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3o2)C1
Yield: 64 %

Procedure:
A mixture of 55 parts of ethyl 3-isothiocyanato-1-pyrrolidinecarboxylate, 23.6 parts of 2-aminophenol and 320 parts of acetonitrile was stirred and refluxed for 4 hours. Then there were added 93 parts of mercury(II) oxide and 0.5 parts of sulfur while stirring vigorously. The reaction mixture was stirred and refluxed overnight. After cooling, the mixture was filtered over diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 38 parts (64%) of ethyl 3-[(2-benzoxazolyl)amino]-1-pyrrolidinecarboxylate as a residue (38).
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH:10]([OH:29])[CH2:11][O:12][C:13]2[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]3[C:16]([CH:17]=[CH:18][C:19]([C:26]([OH:28])=[O:27])=[CH:20]3)=[CH:15][CH:14]=2)=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+:40]>>[C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH:10]([OH:29])[CH2:11][O:12][C:13]2[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]3[C:16]([CH:17]=[CH:18][C:19]([C:26]([O-:28])=[O:27])=[CH:20]3)=[CH:15][CH:14]=2)=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2].[Na+:40]
Reactant: CCCc1c(OCC(O)COc2ccc3ccc(C(=O)O)cc3c2CCC)ccc(C(C)=O)c1O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCc1c(OCC(O)COc2ccc3ccc(C(=O)[O-])cc3c2CCC)ccc(C(C)=O)c1O
Yield: 85.7 %

Procedure:
7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-8-propylnaphthalene-2-carboxylic acid (9.377 g) was treated with an aqueous solution of sodium bicarbonate (1.640 g) and the resulting solution was freeze-dried to afford sodium 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-8-propylnaphthalene-2-carboxylate (8.4 g).
Reaction SMILES: [C:1]1([S:7]([CH:10]=[CH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH3:27])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=O.CS(O)(=O)=O>[Pd].O>[CH3:27][N:23]1[CH2:24][CH2:25][CH2:26][C@@H:22]1[CH2:21][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([CH2:11][CH2:10][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:8])=[O:9])[CH:13]=2)[NH:17][CH:16]=1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(C=CS(=O)(=O)c3ccccc3)cc12
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Solvent: O
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(CCS(=O)(=O)c3ccccc3)cc12
Yield: 109.4 %

Procedure:
(R)-5-(2-Phenylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (200 kg dry equivalent) and acetone (1186.5 kg) were charged to a dry, glass lined vessel. De-ionised water (300 kg), further acetone (237 kg), methanesulphonic acid (55 kg) and a slurry of palladium on carbon (22.4 kg dry equivalent) in de-ionised water (200 kg) were added and the mixture was hydrogenated under an atmosphere of hydrogen gas. The reaction slurry was filtered to remove the catalyst. De-ionised water (1300 kg) and 48% aqueous sodium hydroxide solution (60 kg) were added to precipitate the product, which was isolated by filtration and washed with a mix of de-ionised water (210 kg), acetone (83 kg) and further de-ionised water (710 kg) to yield 3-{[1-methylpyrrolidin-2(R)-yl]methyl}-5-(2-phenylsulphonylethyl)-1H-indole (220 kg wet, 157.65 kg when dry, 78.41%).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[CH2:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C>O1CCCC1>[CH2:11]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:21][CH:22]=1)[CH2:12][CH2:13][CH3:14]
Reactant: C#Cc1ccc(N)nc1N
Reactant: CCCCOCc1ccc(CC(Cl)=NO)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCOCc1ccc(Cc2cc(-c3ccc(N)nc3N)on2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.3 %

Procedure:
To a solution of 3-ethynyl-pyridin-2,6-diamine (14.6 mg, 0.11 mmol) described in Manufacturing Example 13-1-3 and 4-butoxymethyl-phenyl-acetohydroximoyl chloride (28 mg, 0.11 mmol) described in Manufacturing Example 4-1-4 in tetrahydrofuran was added triethylamine (31 μL, 0.22 mmol), which was stirred for 4 hours at room temperature. The reaction solution was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1) and then purified again by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (6.7 mg, 13%) as a trifluoroacetic acid salt.