Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[OH:10])#[N:2].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[O:10][CH2:11][CH:13]1[O:15][CH2:14]1)#[N:2]
Reactant: N#Cc1ccc(Cl)cc1O
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N#Cc1ccc(Cl)cc1OCC1CO1
Yield: 75.7 %

Procedure:
2-Cyano-5-chlorophenol (3.0 g), epichlorohydrin (6.0 g) and anhydrous potassium carbonate (4.2 g) were heated with stirring in ethanol for 2 hours. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 3.1 g of 1-(2-cyano-5-chlorophenoxy)-2,3-epoxypropane.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1.O>[CH3:19][S:20]([N:16]1[CH:17]=[CH:18][C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)=[N:15]1)(=[O:22])=[O:21]
Reactant: c1ccc(Oc2ccc(-c3cc[nH]n3)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)n1ccc(-c2ccc(Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of 3-(4-phenoxyphenyl)-1H-pyrazole (125 mg, 0.529 mmol) in pyridine (10 mL) at room temperature was added neat methanesulfonyl chloride (50 μL, 0.64 mmol). After stirring overnight at room temperature, the reaction was diluted with water. Column chromatography afforded 152 mg (91%) of the title compound as white solid, mp 136° C. 1H NMR (CDCl3): δ 8.06 (d, J=3.0 Hz, 1H), 7.84 (d, J=8.7 Hz, 2H), 7.37 (t, J=8.7 Hz, 2H), 7.14 (t, J=7.5 Hz, 1H)), 7.06 (d, J=8.7 Hz, 2H), 7.06-7.04 (m, 2H), 6.72 (d, J=3.0 Hz, 1H), 3.38 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]([CH2:13][OH:14])[CH2:11][CH2:10][CH:9]1[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I.O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]([CH2:13][O:14][CH3:26])[CH2:11][CH2:10][CH:9]1[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC(CO)N1Cc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCC1CCC(CO[Si](C)(C)C(C)(C)C)N1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 1-benzyl-2-t-butyldimethylsilyloxymethyl-5-hydroxymethylpyrrolidine (10 g) in tetrahydrofuran (100 ml) was added portionwise sodium hydride (2.3 g) at 0° C. The mixture was stirred at the same temperature for 30 minutes. And then methyl iodide was added to the mixture. After stirring for an hour at room temperature, water and ethyl acetate was added thereto. The aqueous layer was separated and washed twice with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate, water and brine successively, dried over magnesium sulfate and evaporated under reduced pressure to give 1-benzyl-2-t-butyldimethylsilyloxymethyl-5-methoxymethylpyrrolidine (9.99 g).
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH:9]([CH2:12][C:13](O)=[O:14])[S:8][CH:7]1[C:16]1[S:17][C:18]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:20]=1)(=[O:3])[NH2:2].[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH2:38][CH2:39][NH2:40])=[CH:30]1.C(P(=O)(OCC)OCC)#N.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH2:38][CH2:39][NH:40][C:13]([CH2:12][C@H:9]2[S:8][C@@H:7]([C:16]3[S:17][C:18]([C:21]#[C:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:19][CH:20]=3)[N:6]([CH2:5][CH2:4][C:1]([NH2:2])=[O:3])[C:10]2=[O:11])=[O:14])=[CH:30]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: NC(=O)CCN1C(=O)C(CC(=O)O)SC1c1ccc(C#Cc2ccccc2)s1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NC(=O)CCN1C(=O)[C@@H](CC(=O)NCCc2c[nH]c3ccccc23)S[C@H]1c1ccc(C#Cc2ccccc2)s1
Yield: 16.4 %

Procedure:
A mixture of [3-(2-carbamoyl-ethyl)-4-oxo-2-(5-phenylethynyl-thiophen-2-yl)-thiazolidin-5-yl]-acetic acid (1.36 g,3.28 mmol), 3-indolylethylamine (0.77 g, 4.8 mmol), diethyl cyanophosphonate (0.781 g, 4.8 mmol) and diisopropylethylamine (0.62 g, 4.8 mmol) was stirred in DMF (50 mL) for three hours at room temperature. The mixture was poured into water (100 mL). The product was extracted into ethyl acetate (2×100 mL). The extract was washed successively with sat. NaHCO3, H2O, brine, and then dried (MgSO4). The solvent was evaporated to a brown gum, which was washed twice with methanol to remove the dark color to provide the title compound as an off-white solid (0.3 g, 16.8%). 1H NMR (DMSO-d6) δ 10.8 (s, 1H), 8.19-8.23 (t, 1H), 7.51-7.55 (m, 3H), 7.33-7.46 (m, 4H), 7.27-7.31 (m, 3H), 7.14-7.15 (d, 1H, J=2.2 Hz), 7.02-7.07 (t, 1H), 6.91-6.98 (m, 2H), 6.13 (s, 1H ), 4.15-4.20 (dd, 1H, J=3.1 Hz ), 3.55-3.64 (m, 1H), 3.27-3.41 (m, 2H), 2.97-3.07 (m, 2H), 2.79-2.84 (t, 2H), 2.60 (s, 1H), 2.55-2.56 (d, 1H, J=4.7 Hz), 2.35-2.45 (m,1H), 2.08-2.18 (m, 1H), 95% cis based on peaks at δ 6.13 and 4.15-4.20); MS(ESI)557[M+H]+.FTIR(ATR) 1620, 1660 cm−1.Anal.(C30H28N4O3S2) calc. C, 64.72; H, 5.07; N, 10.06. Obs. C, 64.55; H, 4.98; N, 9.93.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([F:16])([F:15])[F:14])=[N:10][C:9]=2[C:17]([O:19]CC)=[O:18])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]([F:16])([F:14])[F:15])=[N:10][C:9]=2[C:17]([OH:19])=[O:18])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(C(F)(F)F)oc1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(C(F)(F)F)oc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
Compound ethyl 5-(4-fluorophenyl)-2-(trifluoromethyl)oxazole-4-carboxylate (150 mg, 0.49 mmol) was dissolved in THF (4.6 mL) and cooled on ice. To this solution is added LiOH (13 mg, 0.31 mmol) in water (1.5 mL) and the mixture was stirred for 1 hr then warmed to room temperature and stirred overnight. The THF was evaporated, and H2O (10 mL) was added and the solution then acidified with 1 N HCl and extracted in EtOAc (3×15 mL). The organic fractions were dried over Na2SO4 and concentrated. The crude material was fractionated by SiO2 chromatography (DCM to 90% DCM/10% MeOH gradient, the desired product elutes in 7% MeOH) to afford a white solid (17 mg, 11% yield). 1HNMR (400 MHz, MeOD, CDCl3): d 8.17 (m, 2H), 7.14 (t, 2H, J=8 Hz).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([O:19][CH3:20])=[CH:8][CH:9]=[C:10]2[C:15]=1[NH:14][C:13](=[O:16])[C:12]([CH2:17][NH2:18])=[CH:11]2)[CH2:2][CH2:3][CH3:4].[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1.CO.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[C:7]([O:19][CH3:20])=[CH:8][CH:9]=[C:10]2[C:15]=1[NH:14][C:13](=[O:16])[C:12]([CH2:17][NH:18][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=1)=[O:30])=[CH:11]2)[CH2:2][CH2:3][CH3:4]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCCCOc1c(OC)ccc2cc(CN)c(=O)[nH]c12
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCOc1c(OC)ccc2cc(CNC(=O)Nc3ccc(F)cc3)c(=O)[nH]c12
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
8-Butoxy-3-aminomethyl-7-methoxy-2-oxo-1,2-dihydroquinoline (56.6 mg, 0.205 mmol) obtained in Example 7-2 was dissolved in chloroform (1 ml), and 4-fluorophenyl isocyanate (25.6 μl, 0.225 mmol) was successively added thereto while being cooled with ice. The mixture was stirred at the same temperature for 30 minutes, to which methanol (30 μl) and triethylamine (30 μl) were added, and was further stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resultant residue was washed with toluene to give the title compound (73 mg, yield 86%) as colorless crystals (Table 31).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([CH:7]=[N:8]O)[C:5]([OH:11])=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(OC(=O)C)(=O)C.O.C(O)C>[C:7]([C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[OH:11])#[N:8]
Reactant: ON=Cc1cc(F)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: N#Cc1cc(F)ccc1O
Temperature: 25 °C
Yield: 87.5 %

Procedure:
5-Fluorosalicylaldoxime (20.2 g, 0.13 mol) was dissolved in acetic anhydride (100 ml), followed by refluxing for 5 hours, distilling off acetic anhydride under reduced pressure after completion of the reaction, adding to the remaining oily material, a solution of KOH (20 g) dissolved in water (100 ml) and ethanol (100 ml), heating the mixture at 80° C. for 2 hours, allowing to cool down to room temperature, adding 6N-hydrochloric acid (50 ml) and water (200 ml) to deposit crystals, filtering the crystals, and recrystallizing from methanol (30 ml) to obtain acicular crystals (15.6 g). M.p. 121°~122° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:44])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C@:17](O)([CH2:18][C@@H:19]([O:37][C:38](=[O:42])[N:39]([CH3:41])[CH3:40])[CH2:20][C@@H:21]3[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.[C:45](=[O:50])([O:48]C)[O:46][CH3:47]>S(=O)(=O)(O)O>[CH3:44][C:2]1([CH3:1])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:37][C:38](=[O:42])[N:39]([CH3:41])[CH3:40])[CH2:20][C@@H:21]3[O:29][Si:30]([C:33]([CH3:35])([CH3:36])[CH3:34])([CH3:31])[CH3:32])=[CH:16][C@H:15]4[O:50][C:45]([O:46][CH3:47])=[O:48])[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]4(O)C[C@@H](OC(=O)N(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: COC(=O)OC
Agent: O=S(=O)(O)O
Product: COC(=O)O[C@@H]1C=C2C[C@@H](OC(=O)N(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12

Procedure:
In 10 ml of dimethyl carbonate was dissolved 350 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α-(tert-butyldimethylsilyl)oxy-3β-(N,N-dimethylcarbamoyl)oxypregn-6-en-5α-ol, followed by addition of one drop of concentrated sulfuric acid. The mixture was stirred in an atmosphere of argon gas under ice-cooling for 1 hour. The reaction mixture was then worked up in the same manner as Example 132 to give 95 of 20-(5,5-dimethyl- 1,3-dioxan-2-yl)-1α-(tert-butyldimethylsilyl)oxy-3β-(N,N-dimethylcarbamoyl)oxy-7α-(methoxycarbonyl)oxypregn-5-ene showing the following physical properties.
Reaction SMILES: [CH3:1][N:2]1[C@H:6]2[C:7](C(OC)=O)=[CH:8][CH2:9][C@@H:3]1[CH2:4][CH2:5]2.CC1C=CC=CC=1[Mg]Br.FC(F)(F)C(O)=O.Cl.[NH4+].[OH-]>CCOCC.O>[C@@H:3]12[N:2]([CH3:1])[C@@H:6]([CH2:5][CH2:4]1)[CH2:7][CH2:8][CH2:9]2
Reactant: COC(=O)C1=CC[C@@H]2CC[C@H]1N2C
Agent: Cc1ccccc1[Mg]Br
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CN1[C@@H]2CCC[C@H]1CC2
Temperature: -78 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
The anhydroecgonine methyl ester 1 (leq.) is dissolved in 25 ml of anhydrous ether and then added to 5 eq. of (methylphenyl) magnesium bromide at −40° C. After 3 hours of mechanical stirring, the mixture is cooled to −78° C. and treated drop by drop with a solution of 5 ml of trifluoroacetic acid diluted in 25 ml of anhydrous ether. After one hour's stirring, the mixture is brought to 0° C. and then treated with 70 ml of water and 26 ml of concentrated HCl. The aqueous phase is then treated with NH4OH and extracted with ether (3×40 ml). The different organic phases are collected, washed in brine, dried on Na2SO4 and evaporated to produce compound 2 with a yield of 30%.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[O:12]1[CH:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[Cl:11][C:10]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:13][CH:14]([OH:12])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:7]=[N:6][C:5]=2[CH:9]=1
Reactant: CC(C)(C)C1CO1
Reactant: Clc1cc2nc[nH]c2cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(O)Cn1cnc2cc(Cl)c(Cl)cc21
Temperature: 160 °C
Yield: 73.3 %

Procedure:
A large (2-5 mL) microwave reactor flask was charged with 5,6-dichlorobenzimidazole (571 mg, 3.1 mmol), 1,2-epoxy-3,3-dimethylbutane (307 mg, 3.1 mmol), powdered anhydrous potassium carbonate (424 mg, 3.1 mmol) and DMF (1.5 mL). The reaction was then heated in a microwave reactor for 6 minutes at 160° C. The reaction was then diluted with ethyl acetate and extracted with water three times. The organics were dried over MgSO4 and the solvent was removed. The residue was crystallized from CH2Cl2 to afford 653 mg (73%) of product as a white solid: 1H NMR (DMSO, 400 MHz) δ 1.06 (s, 9H), 3.47 (dd, 1H, J1=2.0, J2=10.4), 4.08 (dd, 1H, J1=10.5, J2=14.4), 4.47 (dd, 1H, J1=2.0, J2=14.4), 7.75 (s, 1H), 7.79(s, 1H), 8.23 (s, 1H); HPLC-MS calcd. for C21H22Cl2N4O2 (M+H+) 287.1, Found 287.3.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:6][C:7]([C:9]2[C:17]3[CH:16]=[C:15]([C:18]4[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][C:29]5([CH2:36][CH3:37])[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[N:19]=4)[S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])CC1.Cl.Cl.CNC(C1C2C=C(C3C([Cl:59])=CN=C(NCCCC4(CC)CCNCC4)N=3)SC=2C=CC=1)=O>>[ClH:24].[ClH:59].[CH3:3][NH:6][C:7]([C:9]1[C:17]2[CH:16]=[C:15]([C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][C:29]4([CH2:36][CH3:37])[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)[N:19]=3)[S:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CCC1(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CCN(C)CC1
Reactant: CCC1(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC)cccc4s3)n2)CCNCC1
Agent: Cl
Product: CCC1(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC)cccc4s3)n2)CCN(C)CC1

Procedure:
Using the method of 2-{5-chloro-2-[3-(4-ethyl-1-methylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-{5-chloro-2-[3-(4-ethylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methylamide di-hydrochloride and isolated as a yellow solid. ES+(m/z) 486 (35Cl) and 488 (37Cl) [M(free base)+H].
Reaction SMILES: O[CH:2]([C:4]1[O:5][C:6](=[O:20])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].CS([Cl:25])(=O)=O>C(Cl)Cl>[Cl:25][CH:2]([C:4]1[O:5][C:6](=[O:20])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccccc1
Solvent: ClCCl
Product: CC(Cl)c1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 49.8 %

Procedure:
3-(1-Hydroxyethyl)-4-phenyl-1H-isochromen-1-one (intermediate B1, 300 mg, 1.27 mmol), Methane sulfonyl chloride (516 mg, 4.51 mmol), TEA (0.62 mmol, 4.5 ml) were reacted in DCM (10 ml) at RT. Solvent was then removed under reduced pressure to give the title compound (180 mg). This was used in next step without any further purification.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Mn+2:6].C1C2=C3C(C(C4C2=CC=CC=4)=O)=CC=C(C2C4C5C(=CC=2)C(=O)C2C(=CC=CC=2)C=5C=CC=4)C3=CC=1>S(=O)(=O)(O)O>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Mn+3:6].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Mn+3:6]
Reactant: [Mn+2]
Agent: O=C1c2ccccc2-c2cccc3c(-c4ccc5c6c(cccc46)-c4ccccc4C5=O)ccc1c23
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: [Mn+3]

Procedure:
A process according to claim 1, wherein manganese(II) sulfate is oxidised anodically in 80 to 90% sulfuric acid, in the presence of 4,4'-bibenzanthrone, to give manganese(III) sulfate, which acts in situ as an oxidising agent and converts 4,4'-bibenzanthrone into dioxoviolanthrone.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:19][NH:18][N:17]=2)[C:10]=1[F:27])C1C=CC=CC=1.[F:35][C:36]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:37]=1[CH:38]=O.C([BH3-])#N.[Na+].C([O-])([O-])=O.[Na+].[Na+]>CO.C(O)(=O)C.O>[F:35][C:36]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:37]=1[CH2:38][NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:19][NH:18][N:17]=2)[C:10]=1[F:27]
Reactant: O=Cc1cc(F)ccc1F
Reactant: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1-c1n[nH]cc1-c1ccncc1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Fc1ccc(F)c(CNc2ccc(F)c(-c3n[nH]cc3-c3ccncc3)c2F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.5 %

Procedure:
Dibenzyl-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amine (prepared as described in Example 22) (150 mg, 0.551 mmol) was dissolved in a 1:1:1 mixture of methanol, acetic acid and water (18 mL). Freshly distilled 2,5-difluorobenzaldehyde (0.180 mL, 1.653 mmol, 3 eq) was then added, followed by sodiumcyanoborohydride (2.424 mmol, 4.4 eq) and the mixture was stirred at room temperature for 5 hours. It was then poured into water, basified to pH 10 by addition of a saturated aqueous solution of Na2CO3 and extracted with ethyl acetate (3×30 mL). The combine dorganic layers were washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (DCM/MeOH 96:4) to give 124 mg (85%) of (2,5-difluoro-benzyl)-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amine a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.Cl[CH2:11][CH2:12][N:13]([CH2:21][CH2:22]Cl)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14]([N:13]1[CH2:21][CH2:22][C:7]([C:8]#[N:9])([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:11][CH2:12]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: N#CCc1ccncc1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccncc2)CC1

Procedure:
Prepare by the method of example 30.2 using 4-pyridylacetonitrile (10 mmol) and 2-chloro-N-(2-chloroethyl)-N-tert-butoxycarbonyl-ethanamine (11 mmol). Purify to give the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:36]([CH2:37][CH2:38][OH:39])=[C:35]([F:40])[CH:34]=[CH:33][C:10]=1[CH2:11][N:12]1[CH2:32][CH2:31][C:15]2([O:20][CH2:19][CH2:18][N:17]([C:21]([C:23]3[N:24]=[C:25]([CH:28]([CH3:30])[CH3:29])[S:26][CH:27]=3)=[O:22])[CH2:16]2)[CH2:14][CH2:13]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[F:8][C:9]1[C:10]([CH2:11][N:12]2[CH2:32][CH2:31][C:15]3([O:20][CH2:19][CH2:18][N:17]([C:21]([C:23]4[N:24]=[C:25]([CH:28]([CH3:30])[CH3:29])[S:26][CH:27]=4)=[O:22])[CH2:16]3)[CH2:14][CH2:13]2)=[CH:33][CH:34]=[C:35]([F:40])[C:36]=1[CH2:37][CH:38]=[O:39]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(F)c(CCO)c4F)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(F)c(CC=O)c4F)CC3)C2)cs1
Reaction time: 0.08 h

Procedure:
TFA (0.11 mL) was added to a solution of (9-(2,4-difluoro-3-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 45, step c) (0.7 g) in DCM (5 mL) at 0° C. and the resulting mixture stirred for 5 min. Dess-Martin periodinane (0.93 g) was then added and the mixture stirred at RT for 45 min. Saturated sodium thiosulphate solution (5 mL), saturated sodium bicarbonate solution (5 mL) and ethyl acetate (20 mL) was then added and the mixture stirred for 10 min. The aqueous layer was separated and extracted with ethyl acetate (20 mL). The combined organics were washed with brine, acidified with a few drops of acetic acid, the mixture dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a clear gum.
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)P(=O)(N(C)C)N(C)C.C(=O)(O)[O-].[Na+].[CH2:38](Br)[CH:39]=[CH2:40]>C(OCC)(=O)C>[CH2:40]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:11]=1)[CH:39]=[CH2:38]
Reactant: C=CCBr
Reactant: NS(=O)(=O)c1cc(C(=O)NNc2ccccc2)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCN(NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1
Temperature: 25 °C

Procedure:
In a three necked 1 liter round bottom reaction vessel equipped with a mechanical stirrer and reflux condenser were placed 48.8 g (0.15 mol) of the compound of Example 8 and 125 ml of hexamethylphosphorictriamide. The mixture was heated with stirring under nitrogen to 80°-85° C. To this solution 126 g (1.5 mol) of sodium bicarbonate powder was added portionwise followed by 20 g (0.17 mol) of allyl bromide. After 2.25 hours an additional 1.8 g (0.015 mol) of allyl bromide was added. After 29 hours of heating the reaction mixture was cooled to room temperature diluted with 700 ml of ethyl acetate, and the slurry was cross washed with water and diluted brine. The ethyl acetate was separated, dried with magnesium sulfate, clarified and taken to dryness under vacuum. The crude reaction mixture was crystallized from chloroform yielding 26.2 g of analytically pure product mp 99°-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][C@@H:7]([NH:12][CH2:13][C@H:14]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][N:15]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:8]([O:10]C)=[O:9])=[CH:4][CH:3]=1.O.[OH-].[Li+].S([O-])([O-])(=O)=O.[K+].[K+]>O1CCCC1.O>[C:27]([O:26][C:24]([N:15]1[C@@H:14]([CH2:13][NH:12][C@@H:7]([C:8]([OH:10])=[O:9])[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:32][CH:31]=2)[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)[C@@H](Cc1ccc(Cl)cc1)NC[C@H]1Cc2ccccc2CN1C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1CN[C@H](Cc1ccc(Cl)cc1)C(=O)O
Temperature: 0 °C

Procedure:
6.4 g of tert-butyl (3R)-3-({[(1R)-1-(4-chlorobenzyl)-2-methoxy-2-oxoethyl]amino}methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate are dissolved in 150 ml of a mixture of tetrahydrofuran/water/MeoH (1/1/1) at 0° C., and 0.99 g of lithium hydroxide hydrate is added. Stirring is maintained at 0° C. for 3 h. 0.5 g of lithium hydroxide hydrate is then added. The medium is maintained at 0° C. for 16 h. Potassium sulphate is added up to a pH of 7. The precipitate obtained is filter-dried and rinsed with diethyl ether. After drying over P2O5, 7.2 g of N-{[(3R)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]methyl}-4-chloro-D-phenylalanine are obtained.