Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:9]=2[C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:22][S:23]([C:26]1[S:30][C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:28][CH:27]=1)(=[O:25])=[O:24]>>[CH:1]1([O:7][C:8]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:9]=2[C:10]([N:34]2[CH2:35][CH2:36][N:31]([C:29]3[S:30][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:27][N:28]=3)[CH2:32][CH2:33]2)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)c1cnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(OC2CCCCC2)c(C(=O)O)c1
Agent: Cl
Product: CS(=O)(=O)c1ccc(OC2CCCCC2)c(C(=O)N2CCN(c3ncc(S(C)(=O)=O)s3)CC2)c1
Yield: 38 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclohexyloxy-5-methanesulfonyl-benzoic acid (Example A7) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 21(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a light red crystalline solid (yield 38%). MS (m/e): 528.3 (M+H+, 100%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]2[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:15]=1>CN(C=O)C>[I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:14]2[N:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]3[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:15]=2)=[CH:4][CH:3]=1
Reactant: COc1ncccc1Nc1cc(Cl)ncn1
Reactant: Ic1ccc2cn[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncccc1Nc1cc(-n2ncc3ccc(I)cc32)ncn1
Temperature: 110 °C
Reaction time: 18 h
Yield: 65.9 %

Procedure:
To a solution of 6-iodo-1H-indazole (100 mg, 0.41 mmol) in DMF (5 mL) was added NaH (60% oil dispersion, 32.78 mg, 0.82 mmol)) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes before the addition of 6-chloro-N-(2-methoxypyridin-3-yl)pyrimidin-4-amine (126.7 mg, 0.55 mmol). The reaction mixture was then stirred at 110° C. for 18 hr. The reaction mixture was then cooled to RT, quenched by the addition of water (2 ml), EtOAc (a few drops) was added and the resultant precipitate was collected by suction filtration and thoroughly dried under high vacuum to give the title compound (120 mg, LC-MS: m/z=+444.90). This compound of 62% purity LC-MS (UV) was used without further purification.
Reaction SMILES: C[C:2]([CH3:18])(C)[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([OH:16])=[O:15])[NH:9]2.[CH3:19][CH:20](C)[CH2:21]CCO>>[CH3:19][CH:20]([CH3:21])[CH2:18][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([OH:16])=[O:15])[NH:9]2
Reactant: CC(C)(C)COc1cccc2[nH]c(C(=O)O)cc12
Reactant: CC(C)CCCO
Product: CC(C)CCCOc1cccc2[nH]c(C(=O)O)cc12

Procedure:
This compound is synthesized analogously to (85) from 4-methyl-pentan-1-ol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH2:37][O:38][CH3:39])=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)=[N:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH2:37][O:38][CH3:39])=[N:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)=[N:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: COCc1nc(-c2ccc(OC(F)(F)F)cc2)ncc1CCl
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(OC(F)(F)F)cc3)nc2COC)cc1C

Procedure:
In analogy to the procedure described in example 113A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-methoxymethyl-2-(4-trifluoromethoxy-phenyl)-pyrimidine (example 155E]) to give the title compound as brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH:9]([N:12]([CH3:14])[CH3:13])[CH2:10][CH3:11])=[CH:4][CH:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[C:9]([N:12]([CH3:13])[CH3:14])([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH3:11])=[CH:6][CH:7]=1
Reactant: CCC(C(=O)c1ccc(F)cc1)N(C)C
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(F)cc1)N(C)C

Procedure:
100 g (0.48 mol) of 1-(4-fluorophenyl)-2-dimethylamino-butan-1-one (crude product from A) are dissolved in 330 ml of acetonitrile. 98.1 g (0.57 mol) of benzyl bromide are slowly added dropwise, with stirring. After the mixture has been stirred at room temperature for 12 hours, the solvent is distilled off in vacuo. The residue is dissolved in 500 ml of water and the solution is heated to 55°-60°. 113 g of a 34% NaOH solution (0.96 mol) are added dropwise at this temperature and the mixture is subsequently stirred for 30 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:16]=[CH:15][S:14][C:13]=2Br)=[O:11])[C:5]([OH:8])=[CH:6][CH:7]=1.[C:18](=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:13]3[S:14][C:15]([CH3:18])=[CH:16][C:12]=3[C:10](=[O:11])[NH:9][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1cc(F)ccc1O)c1ccsc1Br
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc2c(s1)Oc1ccc(F)cc1NC2=O
Temperature: 140 °C
Reaction time: 1 h
Yield: 13.5 %

Procedure:
To a solution of N-(3-fluoro-6-hydroxyphenyl)-2-bromo-3-thiophenecarboxamide (3.3 g) in dimethyl sulfoxide (100 ml) was added potassium carbonate (2.8 g) and the mixture was stirred at 140° C. for 1 hour. The reaction system was cooled to room temperature and the reaction mixture was poured into diluted hydrochloric acid under ice-cooling. The precipitated crystals were collected by filtration, dissolved in chloroform, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=99.5:0.5). The solvent was evaporated under reduced pressure. To the residue was added ethyl acetate and the precipitated crystals were collected by filtration to give 7-fluoro-2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (350 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[NH2:30][CH2:31][C:32]1([CH2:35][OH:36])[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:36][CH2:35][C:32]1([CH2:31][NH:30][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:10]2)=[O:28])[CH2:34][CH2:33]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: NCC1(CO)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCC2(CO)CC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol) prepared in Example 1d, (1-aminomethyl-cyclopropyl)-methanol (30.3 mg, 0.3 mmol), HATU (76.0 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of MeCN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-hydroxymethyl-cyclopropylmethyl)-amide (23.9 mg, 24.7%) as a white powder.
Reaction SMILES: C([C:3]1([C:33]([O-:35])=[O:34])[C:8]2[C:9]3[CH:15]=[C:14]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:18])=[O:17])[CH:13]=[C:12]([Cl:25])[C:10]=3[O:11][C:7]=2[CH2:6][CH2:5][N:4]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])C.O.[OH-].[Li+].Cl>O.O1CCCC1>[C:29]([O:28][C:26]([N:4]1[CH2:5][CH2:6][C:7]2[O:11][C:10]3[C:12]([Cl:25])=[CH:13][C:14]([S:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)(=[O:17])=[O:18])=[CH:15][C:9]=3[C:8]=2[CH:3]1[C:33]([OH:35])=[O:34])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCC1(C(=O)[O-])c2c(oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc23)CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c2C1C(=O)O
Reaction time: 2 h
Yield: 135.5 %

Procedure:
To a stirred solution of the product of Example 85, step C (80 mg, 0.12 mmol) in water (5 mL) and tetrahydrofuran (5 mL) was added lithium hydroxide monohydrate (84 mg, 2.0 mmol) at ambient temperature. After 2 h, 1 M HCl solution (3 mL) was added. The mixture was extracted with dichloromethane (2×10 mL) and the combined organic extracts were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give 2-(tert-butoxycarbonyl)-6-chloro-8-(phenylsulfonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine-1-carboxylic acid (80 mg, 99%) as a colorless oil which was used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH2:28][CH3:29])([CH3:27])[CH3:26])=[CH:21][C:20]=1[C:30]([CH2:33][CH3:34])([CH3:32])[CH3:31])=[O:13].[N+:35]([O-])([OH:37])=[O:36].CO>C(O)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:35]([O-:37])=[O:36])=[CH:4][C:3]=1[C:12]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH2:28][CH3:29])([CH3:26])[CH3:27])=[CH:21][C:20]=1[C:30]([CH2:33][CH3:34])([CH3:32])[CH3:31])=[O:13]
Reactant: CCC(C)(C)c1ccc(OCCCNC(=O)c2ccc3ccccc3c2O)c(C(C)(C)CC)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CO
Product: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc([N+](=O)[O-])c3ccccc3c2O)c(C(C)(C)CC)c1

Procedure:
100 g of 1-hydroxy-N-[γ-(2,4-di-tert-amylphenoxy)propyl]-2-naphthamide was dissolved in 1 liter of acetic acid and nitrated at 15°-18° C. using 23 g of a 60% nitric acid aqueous solution. After the completion of the reaction, 1 liter of methanol was added thereto and precipitated crystals were separated by filtration. After recrystallization from a 2:1 by volume solvent mixture composed of ethyl acetate and methanol, 70 g of the titled compound was obtained. The melting point was 209°-210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[C:6]([CH3:19])[C:7]=1[O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1.C([O-])(=[O:26])C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[C:6]([CH3:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:26])[NH:11][N:10]=1
Reactant: CC(=O)[O-]
Reactant: Cc1cc(CC(=O)O)cc(Cl)c1Oc1cc(C(C)C)c(Cl)nn1
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(CC(=O)O)cc(Cl)c1Oc1cc(C(C)C)c(=O)[nH]n1
Temperature: 105 °C
Reaction time: 0.25 h
Yield: 31.7 %

Procedure:
A solution of [3-chloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-5-methyl-phenyl]-acetic acid (9b) (1.0 g, 2.81 mmol) in glacial acetic acid (30 mL) was treated with sodium acetate (808 mg, 9.83 mmol) at room temperature. The reaction mixture was heated to 105° C. for 24 h. At this time, the reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting residue was diluted with water, brought to pH=10 by the addition of a 1N aqueous sodium hydroxide solution and was extracted with ethyl acetate. The ethyl acetate layer was discarded. The water layer was acidified by the addition of a 3N aqueous hydrochloric acid solution and was extracted with ethyl acetate. The organic layers were combined, washed with water and a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting solid was dissolved in methylene chloride and methanol and then was absorbed onto silica. The preabsorbed solid was purified by column chromatography using silica gel eluted with 20% ethyl acetate in hexanes containing 2% glacial acetic acid. The desired fractions were concentrated as several separate batches and placed under high vacuum for 15 min. The solid was diluted with a 1:1 methylene chloride:hexanes solution. This process was performed three times. The solid was dried under high vacuum overnight. The solid was then slurried in acetonitrile, filtered, and dried in the vacuum oven at 80° C. overnight to afford [3-chloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-5-methyl-phenyl]-acetic acid (10b) (300 mg, 32%) as a white solid; EI(+)-HRMS m/z calcd for C16H17ClN2O4 (M+H)+ 337.0950, found 337.0949. Molecular Weight=336.7779; Exact Mass=336.0877
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4](F)[N:3]=1.CO.[CH3:12][NH:13][CH3:14]>[Cl-].[Na+].O>[Br:1][C:2]1[N:3]=[C:4]([N:13]([CH3:14])[CH3:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(F)c(Br)n1
Reactant: CNC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)c1ccc(F)c(Br)n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
2-Bromo-3,6-difluoro-pyridine (300 mg, 1.5 mmol) was dissolved in a 2M solution of dimethylamine in MeOH (7.8 mL, 15.56 mmol) and stirred at 80° C. in a sealed tube for 16 hours. The mixture was treated with brine and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield (6-bromo-5-fluoro-pyridin-2-yl)-dimethyl-amine as a dark oil that was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].P(OCC)(OCC)([S-])=[S:16]>O1CCCC1.O>[C:1]([C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])(=[S:16])[NH2:2]
Reactant: COC(=O)c1cc(C#N)c(C)cc1C
Reactant: CCOP(=S)([S-])OCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C(N)=S)c(C)cc1C
Temperature: 85 °C
Reaction time: 48 h
Yield: 57.1 %

Procedure:
To a round-bottom flask was added a solution of methyl 5-cyano-2,4-dimethylbenzoate (compound 2.3, 1.78 g, 9.41 mmol, 1.00 equiv) in tetrahydrofuran/H2O (30/3 mL). O,O′-diethyl dithiophosphate (3.30 g, 17.7 mmol, 2.00 equiv) was added and the resulting mixture was stirred for 2 days at 85° C. (CAUTION: significant gas evolution occurs—this and all other reactions described herein should be carried out in well ventilated fume hoods). After cooling to ambient temperature, the mixture was extracted with 2×50 mL of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:10) as eluent to furnish 1.20 g (57%) of the title compound as a yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[N:13]=[CH:12][C:11]=1[C:23]#[N:24].C(=O)(O)[O-].[Na+]>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(I)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(I)c1
Yield: 82.9 %

Procedure:
A mixture of 3.10 ml (25.7 mmol) 3-iodoaniline, 200 ml ethanol, and 5.00 g (21.4 mmol) 4-chloro-6-nitro-quinoline-3-carbonitrile was heated to reflux under N2 for 3½ hours. Cooled and made basic with a saturated sodium bicarbonate. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane and collected. Air dried, washed solids with water, and dried in vacuo. Dissolved solids in 400 ml ethyl acetate, stirred with Darco, filtered and removed solvent. Dried solids in vacuo to give 7.38 g of yellow solid: mass spectrum (electrospray m/e): M+H=417.0.
Reaction SMILES: C(C1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)C.[C:36]([CH2:40][C:41](Cl)=O)([CH3:39])([CH3:38])[CH3:37]>>[CH3:12][C:8]1[N:7]=[C:6]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)(=[O:27])=[O:28])=[O:24])=[CH:18][CH:19]=3)[C:41]([CH2:40][C:36]([CH3:37])([CH3:38])[CH3:39])=[N:4][C:5]2=[C:10]([CH3:11])[CH:9]=1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(C)(C)CC(=O)Cl
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(CC(C)(C)C)nc4c(C)cc(C)nc43)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl]ethanol (step 4 of Example 1) and tert-butylacetyl chloride.
Reaction SMILES: [NH2:1][C:2](=[S:14])[C:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:5])[CH3:4].CO[C:17](OC)([N:19]([CH3:21])[CH3:20])[CH3:18]>C(Cl)Cl>[C:9]([O:8][C:7](=[O:13])[NH:6][C:3]([CH3:5])([CH3:4])[C:2]([N:1]=[C:17]([N:19]([CH3:21])[CH3:20])[CH3:18])=[S:14])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(C)(OC)N(C)C
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(N)=S
Solvent: ClCCl
Product: CC(=NC(=S)C(C)(C)NC(=O)OC(C)(C)C)N(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of tert-butyl 1-amino-2-methyl-1-thioxopropan-2-ylcarbamate (Example 12 b, 0.218 g, 1 mmol) and 1,1-dimethoxy-N,N-dimethylethanamine (CAN 18871-66-4, 0.16 g, 1.2 mmol) in methylene chloride (10 mL) was stirred at room temperature for 24 h. Then it was concentrated to give crude product, which was used directly in the next step without further purification (0.28 g, 98%) as yellow oil; MS (EI): m/e 288.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:46])([CH:43]([F:45])[F:44])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH:41]=[N:40][NH:39][C:38]4=[O:42])=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:39]1[C:38](=[O:42])[N:37]([C:34]2[CH:33]=[CH:32][C:31]([N:28]3[CH2:27][CH2:26][N:25]([C:22]4[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:46])[CH:43]([F:44])[F:45])=[CH:24][CH:23]=4)[CH2:30][CH2:29]3)=[CH:36][CH:35]=2)[CH:41]=[N:40]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ncn1-c1ccc(N2CCN(c3ccc(OCC(F)(F)C(F)F)cc3)CC2)cc1
Product: C[C@@H](n1ncn(-c2ccc(N3CCN(c4ccc(OCC(F)(F)C(F)F)cc4)CC3)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 21.4 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.31 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.50 g of 4-[4-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1-piperazinyl]phenyl]-3(2H,4H)-1,2,4-triazolone, 0.15 g of 2-[(1R,2S)-2-(2,4-difluorophenyl)- 2,3-epoxy-1-methylpropyl]-4-[4-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1-piperazinyl]phenyl]-3(2H,4H)-1,2,4-triazolone was obtained as a colorless powder.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].C(OCC)C>CCCCC>[CH2:9]([N:13]([CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)CCBr
Reactant: CCCCNCCCC
Solvent: CCCCC
Solvent: CCOCC
Product: CCCCN(CCCC)CCC(=O)OCC
Reaction time: 2 h

Procedure:
Ethyl 3-bromopropionate (18.0 g; 0.10 mol) was added carefully to di-n-butylamine (25.8 g; 0.20 mol), followed by stirring for 2 hours. Then diethyl ether (200 ml) and pentane (200 ml) were added. The precipitate was filtered off, the filtrate was evaporated and the residue was distilled at sub-atmospheric pressure. The yield was 7.0 g (31%).
Reaction SMILES: [CH3:1][N:2]1[C:15]2[CH:14]=[C:13]([CH:16]([CH2:26][CH:27]3[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]3)[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[O:18])[CH:12]=[CH:11][C:10]=2[S:9](=[O:35])(=[O:34])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.Cl.[NH2:37][OH:38]>CO>[OH:38][N:37]=[C:30]1[CH2:31][CH2:32][CH:27]([CH2:26][CH:16]([C:13]2[CH:12]=[CH:11][C:10]3[S:9](=[O:34])(=[O:35])[C:8]4[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=4)[N:2]([CH3:1])[C:15]=3[CH:14]=2)[C:17]([NH:19][C:20]2[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=2)=[O:18])[CH2:28][CH2:29]1
Reactant: NO
Reactant: CN1c2ccccc2S(=O)(=O)c2ccc(C(CC3CCC(=O)CC3)C(=O)Nc3ccn(C)n3)cc21
Agent: Cl
Solvent: CO
Product: CN1c2ccccc2S(=O)(=O)c2ccc(C(CC3CCC(=NO)CC3)C(=O)Nc3ccn(C)n3)cc21

Procedure:
67 mg of 2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(4-oxocyclohexyl)propionamide and 14 mg of hydroxylamine hydrochloride are dissolved in 13 ml of methanol and heated at the boil under reflux for three hours. The methanol is then removed under reduced pressure, and the resulting residue is taken up in a mixture of 20 ml of ethyl acetate and 10 ml of water. The organic phase is washed twice with in each case 10 ml of water, dried over MgSO4, concentrated under reduced pressure and then lyophilized. This gives 49 mg of 3-(4-hydroxyiminocyclohexyl)-2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)propionamide.
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:7][C:6]1=[O:22])(=O)[CH2:2][CH3:3].[CH2:23]([O:25][NH2:26])[CH3:24]>CO>[CH2:23]([O:25][NH:26][C:1](=[C:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:7][C:6]1=[O:22])[CH2:2][CH3:3])[CH3:24]
Reactant: CCC(=O)C1C(=O)CC(CCSc2ccc(Cl)cc2)CC1=O
Reactant: CCON
Solvent: CO
Product: CCONC(CC)=C1C(=O)CC(CCSc2ccc(Cl)cc2)CC1=O
Yield: 55.5 %

Procedure:
1.6 g of 2-propionyl-5-[2-(4-chlorophenylthio)ethyl]cyclohexane-1,3-dione was allowed to react with 0.8 g of ethoxyamine at room temperature for 16 hours in 60 ml of methanol. After completion of the reaction, the resulting reaction solution was treated as in Example 1 to obtain oily product. Purification of the oily product by column chromatography gave 1 g of the desired compound as colorless oily material.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[OH-:23].[K+].O>C(O)(C)(C)C>[C:1]([C:3]1[C:8]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:23])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1C#N
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1C(N)=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of (R)-tert-butyl 2-((2-cyanopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate (3.62 g, 11.9 mmol, EXAMPLE 1 Step 1) in tert-butanol (110 mL) was added potassium hydroxide pellet (10.0 g, 179 mmol) at room temperature. The resulting mixture was stirred at 80° C. for 0.5 h. After cooling to room temperature, the mixture was poured into water, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residual oil was purified by silica gel column chromatography (dichloromethane to methanol/dichloromethane 1:15) to give 3.43 g (90%) of the title compound as a white amorphous powder.