Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[CH3:25]>CS(C)=O.O>[Br:1][C:2]1[C:3](=[O:8])[N:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=2[CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]cccc1Br
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
44.5 g (280 mmol) of 3-bromopyridin-2(1H)-one are dissolved in 750 ml of anhydrous dimethyl sulphoxide, and 33.4 g (298 mmol) of potassium tert-butoxide are added a little at a time at room temperature. The suspension is stirred at this temperature for 1 h, 38.5 g (280 mmol) of 1-fluoro-2-methyl-4-nitrobenzene are then added and the reaction solution is heated at 80° C. for 20 h. The solution is allowed to cool and carefully diluted with water. The resulting crystalline precipitate is filtered off, washed with a little water and dried under reduced pressure. This gives 62 g (80% of theory) of the desired product.
Reaction SMILES: [CH2:1]=[C:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[OH:23]O.[OH-].[Na+].O>CO>[O:23]1[C:19]23[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]12)[C@@H:13]1[C@H:4]([C@H:5]2[C@@:9]([CH2:11][CH2:12]1)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]2)[CH2:3][C:2]3=[CH2:1]
Reactant: OO
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C=C12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C3OC132
Reaction time: 24 h
Yield: 80 %

Procedure:
To a solution of 6-methylenandrost-4-ene-3,17-dione (5 g, 16.7 mmole) in methanol (200 ml) cooled at 0° C. is added a cold 36% hydrogen peroxide solution (17 ml) and a cold 2% sodium hydroxide aqueous solution. The resulting reaction mixture is stirred at 0°-5° C. during 24 hrs, then it is poured into iced water (1400 ml) with vigorous stirring. The resulting precipitate is filtered, washed with water and dried in vacuo. There are obtained 4.2 g (80% yield) of the title compound,
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Fc1ccc(-c2cccc3[nH]ccc23)cc1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To the suspension of 4-(4-fluoro-phenyl)-1H-indole (2.28 g, 10.79 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (147 mL) was added pyridinium tribromide (90% purity from Aldrich, 11.51 g, 32.38 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (108 mL). Zinc dust (10.52 g, 162 mmol) was added to the reaction mixture portionwise, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated and the syrupy residue was suspended in water for 4 hour. The solid product was precipitated out, filtered, and washed repeatedly with water to remove the zinc salt and pyridine salt. After high vacuum dry, a pure product (2.40 g, 98%) was obtained.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[CH:32]1([C:35]2[C:36]([NH:52][C@@H:53]3[C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[CH2:55][C@@H:54]3[OH:62])=[N:37][C:38]([CH:49]3[CH2:51][CH2:50]3)=[C:39]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=3[Cl:48])[N:40]=2)[CH2:34][CH2:33]1>>[CH:32]1([C:35]2[C:36]([NH:52][C@@H:53]3[C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[CH2:55][C@@H:54]3[O:62][CH2:2][CH3:3])=[N:37][C:38]([CH:49]3[CH2:50][CH2:51]3)=[C:39]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=3[Cl:48])[N:40]=2)[CH2:33][CH2:34]1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: O[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.80-1.07, 1.17-1.20, 1.67, 1.79, 3.14-3.20, 3.46-3.50, 3.70-3.72, 4.35, 5.72, 5.97, 7.24-7.50; MS (ESI+) for C27H27Cl2N3O m/z 480 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=O.C(Cl)(=O)C([Cl:13])=O>C(Cl)Cl.CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([Cl:13])=[O:9]
Reactant: O=C(O)C1CCCCO1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CCCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.6 %

Procedure:
To a solution of tetrahydro-pyran-2-carboxylic acid (6.94 g, 47.96 mmol) in DCM (200 mL) are added oxalyl chloride (4.81 mL, 56.83 mmol) as a solution in DCM (50 mL) and DMF (3 drops). The reaction is stirred at room temperature for 18 h, then concentrated under reduced pressure to afford 7.1 g of tetrahydro-pyran-2-carbonyl chloride, which is used in the next step. Yield: 99%; by 58° C., 1 mm Hg; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.49-1.98 (5 H, m), 2.02-2.19 (1 H, m), 3.46-3.66 (1 H, m), 3.96-4.12 (1 H, m), 4.24 (1 H, dd, J=9.14, 3.20 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH2:28])[C:5]([N:7]1[CH2:12][CH2:11][C:10]2([CH2:20][C:19](=[O:21])[C:18]3[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=[CH:15][C:14]=3[CH2:13]2)[CH2:9][CH2:8]1)=[O:6].[N:29]([CH3:32])=[C:30]=[S:31]>O1CCCC1>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:7]2[CH2:12][CH2:11][C:10]3([CH2:20][C:19](=[O:21])[C:18]4[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=[CH:15][C:14]=4[CH2:13]3)[CH2:9][CH2:8]2)=[O:6])[CH:25]=[CH:26][C:27]=1[NH:28][C:30]([NH:29][CH3:32])=[S:31]
Reactant: CC(C)n1ncc2c1C(=O)CC1(CCN(C(=O)c3ccc(N)c(N)c3)CC1)C2
Reactant: CN=C=S
Solvent: C1CCOC1
Product: CNC(=S)Nc1ccc(C(=O)N2CCC3(CC2)CC(=O)c2c(cnn2C(C)C)C3)cc1N
Reaction time: 6 h
Yield: 27.1 %

Procedure:
A mixture of 1′-(3,4-diaminobenzoyl)-1-isopropyl-4,6-dihydrospiro[indazole-5,4′-piperidin]-7(1H)-one (0.1 g, 0.3 mmol) and isothiocyanatomethane (19 mg, 0.3 mmol) was dissolved in tetrahydrofuran (3 mL). The reaction was heated to reflux and stirred for 6 hours. The reaction mixture was concentrated, and the residue was poured into cold water. The solution was extracted with ethyl acetate (3×20 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to provide 1-(2-amino-4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-ylcarbonyl)phenyl)-3-methylthiourea (37 mg, 27%).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[NH:12][C:13](=[O:14])[C:8]=2[CH:7]=[CH:6]1)CC=C.[Mn]([O-])(=O)(=O)=[O:26].[K+].[CH3:31][C:32]([CH3:34])=[O:33]>O>[OH:33][CH:32]([CH2:34][OH:26])[CH2:31][CH2:1][N:5]1[C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[NH:12][C:13](=[O:14])[C:8]=2[CH:7]=[CH:6]1
Reactant: C=CCCn1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)nc21
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)=O
Agent: [K+]
Solvent: O
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)nc2c1ccn2CCC(O)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.4 %

Procedure:
A solution of 7-but-3-enyl-2-(4-trifluoromethyl-phenyl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (50.3 mg, 151 μmol) in acetone (1.2 mL) and water (0.4 mL) was treated with potassium permanganate (46.1 mg, 292 μmol). The reaction stirred at room temperature overnight. The reaction was filtered through a coarse sintered glass frit, rinsing with ethyl acetate. The filtrate was concentrated in vacuo and then partitioned between water (25 mL) and ethyl acetate (25 mL). The aqueous layer was back extracted with ethyl acetate (25 mL), and the combined organics were washed with a saturated aqueous sodium chloride solution (25 mL), dried over magnesium sulfate, filtered and rinsed with ethyl acetate, and concentrated in vacuo. Flash chromatography (24 g silica gel column, 1-10% methanol/methylene chloride) afforded 7-(3,4-dihydroxy-butyl)-2-(4-trifluoromethyl-phenyl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as a white solid (6.9 mg, 12.4%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.72 (s, 1H) 1.85-2.15 (m, 1H) 3.10-3.53 (m, 3H) 4.09-4.45 (m, 2H) 4.48-4.62 (m, 1H) 4.72 (d, J=5.09 Hz, 1H) 6.53 (d, J=3.20 Hz, 1H) 7.12-7.34 (m, 1H) 7.90 (d, J=8.29 Hz, 2H) 8.34 (d, J=8.48 Hz, 2H) 12.3.1 (s, 1H). LC-MS calcd. for C17H17F3N3O3 [(M+H)+] 368, obsd. 368.0.
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.Cl.O[N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>>[N:29]1([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: On1ccnc1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(COn2ccnc2)cc1)c1ccccc1
Yield: 87 %

Procedure:
The title compound was prepared as its TFA salt in 87% yield as a solid using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 1-hydroxyimidazole, hydrochloride. 1H NMR (400 MHz; CDCl3): δ 3.42 (br s, 3H), 5.21 (s, 2H), 6.95 (s, 1H), 7.16-7.45 (m, 10H), 8.28 (br s, 1H); HPLC-MS: m/z=324.1 (M+1); Rt=1.92 min.
Reaction SMILES: [CH3:1][CH3:2].[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4]>>[CH2:4]=[CH:3][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:1]=[CH2:2]
Reactant: CC
Reactant: CCc1ccccc1
Product: C=C
Product: C=Cc1ccccc1

Procedure:
U.S. Pat. No. 6,031,143 and its corresponding EP 0 905 112 describe an integrated process for producing styrene by feeding benzene and recycled ethylene to an alkylation reactor to produce ethylbenzene, mixing the alkylation effluent with ethane and feeding the mixture to a dehydrogenation reactor containing a catalyst capable of contemporaneously dehydrogenating ethane and ethylbenzene. The resulting product is separated to produce a stream of styrene and ethylene, with ethylene being recycled to the alkylation reactor. The dehydrogenation reactor is preferably a fluidized bed reactor connected to a fluidized bed regenerator from which the catalyst is circulated between the regenerator and the dehydrogenation reactor in countercurrent flow. That is, catalyst is introduced to the dehydrogenation reactor from the top and slowly descends to the bottom in countercurrent with the gas phase reactants which are rising through the reactor. During this descent, the catalyst is deactivated. The deactivated catalyst is removed from the bottom of the dehydrogenation reactor and transported to the top of the regenerator where it descends to the bottom in countercurrent flow with hot air which is rising. During this descent, the carbonaceous residue present on the catalyst is burnt and the regenerated catalyst is collected at the bottom of the regenerator where it is subsequently circulated back to the top of the dehydrogenation reactor.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][C:8](Cl)=[O:9].[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:24](=S)=S>>[Cl:5][CH2:6][CH2:7][C:8]([C:14]1[CH:15]=[CH:16][C:11]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:12][CH:13]=1)=[O:9]
Reactant: O=C(Cl)CCCl
Reactant: O=C(O)CCCCc1ccccc1
Reactant: S=C=S
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)CCCCc1ccc(C(=O)CCCl)cc1
Reaction time: 0.25 h

Procedure:
In a stirring flask equipped with a reflux condenser are placed 9.3 g of AlCl3, 10 ml of CS2 and 1.98 ml of β-chloropropionyl chloride. To this mixture are added dropwise at room temperature within 5 minutes 3.61 g of 5-phenylvaleric acid (rinsing is carried out with 2 ml of CS2). The reaction mixture is subsequently stirred for a further 15 minutes, warmed slightly and then cooled. The reaction mixture is then pipetted into a stirred mixture of ice, water and ether. The organic phase is washed neutral with bicarbonate solution and water. After drying over MgSO4 the solvent is removed and 5.03 g of crystalline product are thus obtained.
Reaction SMILES: NC1C(C#N)=C(N2CCC(C3N(CCNCC4CC4)[CH:18]=[C:19]([C:21]4C=CC(F)=C(C)C=4)[N:20]=3)CC2)N=CN=1.C(N)(C)C.[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]([N:47]2[CH2:52][CH2:51][CH:50]([C:53]3[N:54]([CH2:69][CH2:70]OS(C)(=O)=O)[CH:55]=[C:56]([C:58]4[CH:63]=[CH:62][C:61]([F:64])=[C:60]([C:65]([F:68])([F:67])[F:66])[CH:59]=4)[N:57]=3)[CH2:49][CH2:48]2)[C:42]=1[O:76][CH2:77][CH3:78].NC1N=CN=C(N2CCC(C3N(CCOS(C)(=O)=O)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)C=1C#N>>[CH2:77]([O:76][C:42]1[C:41]([NH2:40])=[N:46][CH:45]=[N:44][C:43]=1[N:47]1[CH2:52][CH2:51][CH:50]([C:53]2[N:54]([CH2:69][CH2:70][NH:20][CH:19]([CH3:21])[CH3:18])[CH:55]=[C:56]([C:58]3[CH:63]=[CH:62][C:61]([F:64])=[C:60]([C:65]([F:67])([F:66])[F:68])[CH:59]=3)[N:57]=2)[CH2:49][CH2:48]1)[CH3:78]
Reactant: Cc1cc(-c2cn(CCNCC3CC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Reactant: CCOc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCOS(C)(=O)=O)CC1
Agent: CS(=O)(=O)OCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Solvent: CC(C)N
Product: CCOc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNC(C)C)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using isopropylamine and methanesulfonic acid 2-[2-[1-(6-amino-5-ethoxy-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-imidazol-1-yl]-ethyl ester instead of cyclopropylmethylamine and methanesulfonic acid 2-[2-[1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-imidazol-1-yl]ethyl ester. LC-MS: (M+1=536, obsd.=536).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[C:4]([O:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1.[OH:16][CH2:17][C@@H:18]1[C@:27]2([CH3:28])[C@H:22]([C:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][CH2:26]2)[CH2:21][CH2:20][C@@:19]1([CH3:32])[OH:31].C([O-])([O-])=O.[Cs+].[Cs+].COCCOCCOC>CCOC(C)=O.[Cu]I.C1(C)C=CC=CC=1>[CH3:14][CH:13]([O:12][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=1)[O:16][CH2:17][C@@H:18]1[C@:27]2([CH3:28])[C@H:22]([C:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][CH2:26]2)[CH2:21][CH2:20][C@@:19]1([CH3:32])[OH:31])[CH3:15]
Reactant: CC1(C)CCC[C@]2(C)[C@@H](CO)[C@](C)(O)CC[C@@H]12
Reactant: CC(C)Oc1cc(I)cc(OC(C)C)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOCCOC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)Oc1cc(OC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)cc(OC(C)C)c1
Temperature: 120 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
In a sealed tube purged with nitrogen, compound (47) (1.85 g, 5.78 mmol), (1S,2R,4aS,8aS)-1-(hydroxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (3) (1.26 g, 5.25 mmol), Cs2CO3 (2.56 g, 7.87 mmol), 3,4,7,8-tetramethyl-[1,10]-phenylthroline (0.25 g, 1.0 mmol), CuI (0.10 g, 0.70 mmol), diglyme (5 mL) and toluene (20 mL) were placed. The reaction mixture was stirred at 120° C. for 18 h. The reaction was cooled to room temperature, diluted with EtOAc (600 mL) and washed with water (200 mL). The solid material was removed by filtration. The organic layer was separated, dried (Na2SO4) and concentrated. Purification by column chromatography on silica gel (Hexanes/EtOAc, 4:1) gave (1S,2R,4aS,8aS)-1-[3,5-bis(propan-2-yloxy)phenoxymethyl]-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (48) (1.50 g, 66%) as a colourless oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:28][CH:29]([CH3:33])[CH2:30][CH:31]=O.[BH4-].[Na+]>CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([CH2:31][CH2:30][CH:29]([CH3:33])[CH3:28])[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)CC=O
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCN1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 36 %

Procedure:
Compound A2 (0.15 mmol, 60 mg), and 3-methyl-butyraldehyde (0.15 mmol, 13 mg) were dissolved in methanol (2 mL) and stirred for 5 minutes at room temperature. Then, sodium borohydride (0.18 mmol, 6.3 mg) was added at 0° C. The reaction was complete immediately upon addition of sodium borohydride. The mixture was quenched with saturated ammonium chloride solution (1 mL) followed by an extraction with dichloromethane. Removal of organic solvent in vacuo and purification by HPLC provided Compound A8 as a yellow solid (25 mg, 36%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.17 (s, 1H), 8.35 (s, 1H), 7.90 (d, 2H), 7.80 (d, 2H), 5.72 (s broad, 1H), 3.65 (m, 2H), 3.11 (m, 2H), 2.96 (m, 5H), 2.40 (m, 2H), 2.15 (m, 2H), 1.60 (m, 3H), 0.85 (d, 6H). LCMS (ESI), m/z 464.4 (M+H+, 100%).
Reaction SMILES: [CH3:1][NH:2][CH:3]=[O:4].[CH2:5]=O.[CH:7](=[O:11])[CH:8]([CH3:10])[CH3:9].Cl.[OH-].[Na+]>>[CH3:9][C:8]([CH3:10])([CH:7]=[O:11])[CH2:1][N:2]([CH3:5])[CH:3]=[O:4]
Reactant: CC(C)C=O
Reactant: CNC=O
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C=O)CC(C)(C)C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a round-bottom flask with a mounted reflux condenser and under nitrogen atmosphere, 59.7 g (1.00 mol) of N-methylformamide, 84.3 g (1.00 mol) of 36% aqueous formaldehyde, and 78.6 g (1.10 mol) of isobutyraldehyde were introduced while being stirred vigorously, mixed with 18.2 g of concentrated hydrochloric acid (slight exothermicity). After that, the mixture was heated to boiling in an oil bath (100° C.) and was kept boiling overnight. The clear, yellow reaction mixture was cooled to room temperature, neutralized with 2N NaOH, extracted twice with ethyl acetate; the combined organic phases were washed with brine, dried on MgSO4, and completely concentrated by evaporation in a rotary evaporator. The dark-yellow oil that was obtained was fractionated in a vacuum. The product distilled at an overhead temperature of 63° C. and a pressure of 4·10−2 mbar. Yield: 20.2 g (14% of theory) of colorless, slightly pungent-smelling liquid.
Reaction SMILES: [CH2:1]([C:3]([CH3:5])=[O:4])[CH3:2].CN1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12]>>[CH2:2]=[CH:1][C:3]1[CH:5]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:2]=[CH:1][C:3]([OH:4])=[O:12]
Reactant: CCC(C)=O
Reactant: CN1CCCC1=O
Product: C=CC(=O)O
Product: C=Cc1ccccc1

Procedure:
A true spherical silica fine particle (“SEAHOSTER KEP150”, produced by Nippon Shokubai K.K.) having an average particle size of 1.5 μm (10 parts), 2 parts of a dispersant polymer (“JONCRYL 611”, acrylic acid ester styrene copolymer, produced by Johnson Polymer), 16 parts of methyl ethyl ketone and 64 parts of N-methylpyrrolidone were mixed, and the resulting mixture was put in a 200 ml-volume polyethylene-made container together with 30 parts of glass bead having a diameter of 2 mm and dispersed for 2 hours by a paint shaker (manufactured by Toyo Seiki) to obtain a silica fine particle dispersion.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Yield: 94.8 %

Procedure:
A solution of piperazine-1-carboxylic acid tert-butyl ester (1.90 g, 10.2 mmol) and triethylamine (1.55 mL, 11.1 mmol) in CH3CN (9 mL) was treated with 1-bromomethyl-4-nitro-benzene (2.00 g, 9.26 mmol) as a solution in CH3CN (15 mL) at RT for 20 min. The mixture was concentrated in vacuo. The residue was taken up in CH2Cl2 (20 mL) and washed with water (1×20 mL). The aqueous layer was extracted with CH2Cl2 (2×20 mL), and the combined organic layers were washed with water (1×40 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue on a 50-g Isolute SPE column on a FlashMaster system with 10-25% EtOAc-hexane afforded the title compound (2.82 g, 95%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C16H23N3O4, 322.2 (M+H). found 321.9.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:25](=[O:26])[C:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:30][CH:29]=3)=[C:23]([CH2:42][CH2:43][CH3:44])[N:22]=[C:21]2[CH3:45])=[CH:16][CH:15]=1>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[C:25](=[O:26])[C:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[NH:3][C:4](=[O:7])[O:5][N:41]=4)=[CH:30][CH:29]=3)=[C:23]([CH2:42][CH2:43][CH3:44])[N:22]=[C:21]2[CH3:45])=[CH:18][CH:19]=1
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(F)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(-c2ccc(F)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.74 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C. for 30 min, 4′-{[1-(4-fluorophenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.47 g) was added, and the mixture was stirred at 90° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.26 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.49 g, 91%) as a colorless solid.