Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].C(=O)(O)O.[NH2:8][C:9]([NH2:11])=[NH:10].C([O:14][C:15](=O)[C:16]([O:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=1[CH:30]([CH3:32])[CH3:31])=[CH:17]OC)C>CS(C)=O>[NH2:10][C:9]1[NH:11][C:15](=[O:14])[C:16]([O:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=2[CH:30]([CH3:32])[CH3:31])=[CH:17][N:8]=1
Reactant: CCOC(=O)C(=COC)Oc1cc(C)c(OC)cc1C(C)C
Reactant: N=C(N)N
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(C(C)C)c(Oc2cnc(N)[nH]c2=O)cc1C
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 22 %

Procedure:
To a solution of NaOMe [prepared from sodium ( 0.05 g, 2.17 mmol) in anhydrous methanol (5 ml)], was added guanidine carbonate. After 5 minutes, a solution of 2-(2-isopropyl-4-methoxy-5-methyl-phenoxy)-3-methoxy-acrylic acid ethyl ester (0.22 g, 0.713 mmol) in anhydrous DMSO (10 ml) was added. The mixture was heated at 120° C. for 3 hours and was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over anhydrous sodium sulfate. After removal of drying agent, the organic solution was concentrated under reduced pressure. The residue was purified with silica gel chromatography (5% methanol in methylene chloride/0.1% concentrated NH4OH) to yield 2-amino-5-(2-isopropyl-4-methoxy-5-methyl-phenoxy)-3H-pyrimidin-4-one as pale yellow solid (0.045 g, 22%). MS M+H=290.
Reaction SMILES: OO.[F:3][C:4]1[C:18]([F:19])=[C:17]([CH:20]=[O:21])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=1.C([O-])([O-])=[O:23].[K+].[K+].CS(C)=O>O>[F:3][C:4]1[C:18]([F:19])=[C:17]([CH:20]=[O:21])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([NH2:12])=[O:23])=[CH:9][N:8]=1
Reactant: N#Cc1ccc(Oc2ccc(C=O)c(F)c2F)nc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)c(F)c2F)nc1
Reaction time: 1 h
Yield: 148.1 %

Procedure:
Add 30% aq. H2O2 (7.95 ml) to a suspension of 6-(2,3-difluoro-4-formyl-phenoxy)-nicotinonitrile (2.07 g, 7.95 mmol), K2CO3 (550 mg, 3.98 mmol) and DMSO (20 ml) stirring in an ice/water bath. After one hour, pour the reaction mixture into water and extract with EtOAc. Wash the extract with water and brine before drying (MgSO4) and concentrating to give 6-(2,3-difluoro-4-formyl-phenoxy)-nicotinamide (1.64 g) as a white solid. 1HNMR (DMSO-d6): 10.14 (s, 1H), 8.58 (s, 1H), 8.33 (d, 1H), 8.07 (s, 1H), 7.74 (t, 1H), 7.55 (s, 1H), 7.33 (d, 1H), 7.27 (t, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:21][C:22]2[C:27]([Cl:28])=[CH:26][N:25]=[CH:24][C:23]=2[Cl:29])=[N:11][N:10]=1>CN(C=O)C>[Cl:29][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:28])[C:22]=1[CH2:21][C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:9]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[N:10][N:11]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(-n3ccnc3)c2c1
Temperature: 80 °C
Yield: 41.3 %

Procedure:
A solution of imidazole (0.814 g, 11.21 mmoles) in dry DMF (30 ml) was stirred under N2 at room temperature and added with NaH (8.46 mmoles). After 30 minutes 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (2 g, 5.64 mmoles), prepared as described in example 45, in dry DMF (30 ml) was added. The mixture was heated at 80° C. for 3.5 hours, cooled, poured into water/ice and extracted three times with CH2Cl2. The organic phase was washed with water, anhydrified and concentrated to give a solid which was flash chromatographed (eluent: ethyl acetate) yielding 0.9 g of the title compound (yield: 50%). m.p. 250° C.
Reaction SMILES: [CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)([CH3:4])=[O:3].[I:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:28](Cl)=[O:29].C(N(C(C)C)CC)(C)C.[I-]>ClCCl>[CH3:4][P:2]([CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH2:12][C:13]2[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][C:16]([NH:17][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:33]([CH3:34])=[C:25]([I:24])[CH:26]=3)=[CH:15][CH:14]=2)[CH2:10][CH2:11]1)([CH3:1])=[O:3]
Reactant: CP(C)(=O)CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1I
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(CP(C)(C)=O)CC3)c(C(F)(F)F)c2)cc1I
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-({4-[(dimethylphosphoryl)methyl]piperazin-1-yl}methyl)-5-(trifluoromethyl)aniline (yellow solid, 3.66 mmole, 1.0 eq.) was dissolved in 15 mL anhydrous dichloromethane. 3-Iodo-4-methylbenzoyl chloride (1.58 grams, 5.64 mmole, 1.54 eq.) was added in one portion. At 0° C., under N2 protection, diisopropylethyl amine (2.4 mL, 14.0 mmole, 3.8 eq.) was added dropwise in 3 minutes. The reaction mixture was stirred at 0° C. under N2 for 30 minutes. It was then evaporated to remove most of the volatile components. The residue was purified via column chromatography (elution sequence: 100% dichloromethane—1% MeOH/dichloromethane/sat.NH3—10% MeOH/dichloromethane/sat.NH3), 40 mg of light yellow color oil was obtained and identified as the desire iodide. MS (LC/MS): 592.3 [M-].
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:13][C@@H:12]3[C@H:8]2[CH2:9][N:10]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O>[N+](C)([O-])=O.O>[N+:18]([C:4]1[CH:3]=[CH:2][C:1]([C@@H:7]2[CH2:13][C@@H:12]3[C@H:8]2[CH2:9][N:10]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:11]3)=[CH:6][CH:5]=1)([O-:20])=[O:19]
Reactant: CCC(=O)N1C[C@@H]2C[C@@H](c3ccccc3)[C@@H]2C1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CCC(=O)N1C[C@@H]2C[C@@H](c3ccc([N+](=O)[O-])cc3)[C@@H]2C1
Temperature: -8 °C
Yield: 106.2 %

Procedure:
1.0 g of 1-((1R,5S,6R)-6-Phenyl-3-aza-bicyclo[3.2.0]hept-3-yl)-propan-1-one (4.36 mmol) were dissolved in 12 ml of nitromethane. At −8° C., a mixture of 0.3 ml of nitric acid (65%, 4.36 mmol) and 4.6 ml of sulphuric acid (95%) in 0.76 ml of water were added dropwise within 45 minutes. Stirring at −8° C. was continued for 30 minutes, before 20 ml of ice water were added and the aqueous phase was extracted twice with diethyl ether, the combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 1.27 g of the product as a mixture of 2:1 para versus ortho substituted product which was used without further separation.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]Cl)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[OH:17][C:18]1[CH:29]=[CH:28][C:21]([C:22]([O:24][CH2:25][C:26]#[CH:27])=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][C:26]#[CH:27])=[O:23])=[CH:28][CH:29]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: ClCCC1CCN(c2ccc(Cl)nn2)CC1
Reactant: C#CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: C#CCOC(=O)c1ccc(OCCC2CCN(c3ccc(Cl)nn3)CC2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A mixture of 3.9 parts of 3-chloro-6-[4-(2-chloroethyl)-1-piperidinyl]pyridazine, 2.64 parts of (2-propynyl) 4-hydroxybenzoate, 2.76 parts of potassium carbonate and 75 parts of N,N-dimethylacetamide was stirred overnight at 110° C. After cooling, the reaction mixture was poured into 100 parts of water and the product was extracted with methylbenzene. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 5.2 parts (86.7%) of (2-propynyl) 4-[2-[1-(6-chloro-3-pyridazinyl)-4-piperidinyl]ethoxy]benzoate; mp. 122.0° C. (comp. 120).
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH:12]=[C:11]([CH:13]=O)[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:20][C:21]1[S:25][C:24]2[C:26]3([O:32][CH2:33][C:34]([F:36])([F:35])[C:23]=2[CH:22]=1)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[Cl:20][C:21]1[S:25][C:24]2[C:26]3([O:32][CH2:33][C:34]([F:35])([F:36])[C:23]=2[CH:22]=1)[CH2:27][CH2:28][N:29]([CH2:13][C:11]1[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:9][N:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:12]=1)[CH2:30][CH2:31]3
Reactant: CCOC(=O)c1nn(-c2ncccc2F)cc1C=O
Reactant: FC1(F)COC2(CCNCC2)c2sc(Cl)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)c1nn(-c2ncccc2F)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Reaction time: 0.17 h
Yield: 85.4 %

Procedure:
To a solution of ethyl 1-(3-fluoro-2-pyridyl)-4-formyl-pyrazole-3-carboxylate (342.5 mg) in 1,2-dichloroethane (6.7 mL), 2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine] (280 mg, 1 mmol) is added. The mixture is stirred for 10 min. Then, sodium triacetoxyborohydride (442 mg) is added and the mixture is stirred overnight at room temperature. Sodium bicarbonate (saturated aqueous solution) is added and the organic phase extracted with dichloromethane, dried over magnesium sulfate and solvent evaporated in vacuo. Crude is purified by normal phase Isco chromatography using as eluent ethyl acetate and hexane to give 450 mg of ethyl 4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-1-(3-fluoro-2-pyridyl)pyrazole-3-carboxylate. MS (m/z): 527 (M+1).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[C:14]1[CH:15]=[C:16]([CH2:20][C:21]#[N:22])[CH:17]=[CH:18][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:42][CH2:43][CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49]>O1CCCC1.C(OCC)(=O)C>[C:21]([CH2:20][C:16]1[CH:17]=[CH:18][CH:19]=[CH:14][C:15]=1[O:42][CH2:43][CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])#[N:22]
Reactant: N#CCc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCOc1ccccc1CC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl azodicarboxylate (6.2 ml, 39.4 mmol) was added dropwise to an ice-cooled solution of 3-hydroxyphenyl acetonitrile (preparation 126) (4.2 g, 31.5 mmol), triphenylphosphine (10.34 g, 39.4 mmol) and tert-butyl 2-hydroxyethylcarbamate (5.4 ml, 34.9 mmol) in tetrahydrofuran (70 ml), and once addition was complete, the reaction was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (400 ml), washed with 1N NaOH solution, water, brine, then dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate:pentane (30:70) as eluant to give the desired product as a yellow/green oil, that crystallised on standing, (5.88 g, 68%).
Reaction SMILES: COC(=O)[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.NC1[NH:77][N:76]=[N:75][N:74]=1>CN(C)C=O>[Cl:36][C:8]1[CH:9]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])[C:11]([Cl:13])=[CH:12][C:7]=1[C:6]([NH:5][C:4]1[NH:77][N:76]=[N:75][N:74]=1)=[O:37]
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: Nc1nnn[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nnn[nH]1)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 22 %

Procedure:
To a solution of 0.20 g (0.41 mmol) 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) in 2 mL N,N-dimethylformamide were added 0.165 g (0.43 mmol) O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 0.21 mL (1.24 mmol) N,N-diisopropylethylamine. To the yellow solution 0.037 g (0.43 mmol) 5-amino-1H-tetrazole (commercially available, CAS RN 4418-61-5) was added and the solution was stirred at room temperature for 3.25 hours. Then the solution was heated to 60° C. and stirred at this temperature for 88 hours. After filtration over a syringe micro filter, the reaction mixture was purified by preparative HPLC (Phenomenex Gemini column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give the desired compound as a light brown solid (0.051 g, 22%). MS (ESI): m/z=551.11 [M+H]+.
Reaction SMILES: C([BH3-])#N.[Na+].[NH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][CH2:6]1.C(O[C:20]1(O[Si](C)(C)C)[CH2:22][CH2:21]1)C.C(O)(=O)C>C1COCC1.CO>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][CH:8]1[CH2:9][CH2:10][N:5]([CH:20]2[CH2:22][CH2:21]2)[CH2:6][CH2:7]1)[CH3:16]
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CCOC(=O)CC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CC1CCN(C2CC2)CC1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
Sodium cyanoborohydride (2.2 g) was added to a mixture of ethyl 4-piperidine acetate (2.0 g), (1-ethoxycyclopropoxy)trimethylsilane (6.1 g), acetic acid (6.7 mL), a molecular sieve 3A (2.0 g), MeOH (20 mL), and THF (20 mL) at room temperature, and the mixture was stirred at 65° C. for 6 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. After EtOAc was added to the residue, the mixture was stirred, and the insoluble material was separated by filtration. After water was added to the filtrate, potassium carbonate was added to alkalify the mixture. Extraction was performed on the mixture using EtOAc, and the extract was washed with a saturated aqueous NaHCO3 solution and saturated brine. The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH=100:0 to 95:5), whereby ethyl(1-cyclopropylpiperidin-4-yl)acetate (2.1 g) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([C@@H:6]([OH:36])[C:7]([NH:9][CH2:10][CH2:11][C:12]([NH:14][CH2:15][CH2:16][S:17][S:18][CH2:19][CH2:20][NH:21][C:22]([CH2:24][CH2:25][NH:26][C:27]([C@H:29]([OH:35])[C:30]([CH2:33][OH:34])([CH3:32])[CH3:31])=[O:28])=[O:23])=[O:13])=[O:8])([CH2:4][OH:5])[CH3:3].C[O:38][C:39](OC)([CH3:41])[CH3:40]>FC(F)(F)C(O)=O.CC(C)=O>[CH3:3][C:2]([C@@H:6]([OH:36])[C:7]([NH:9][CH2:10][CH2:11][C:12]([NH:14][CH2:15][CH2:16][S:17][S:18][CH2:19][CH2:20][NH:21][C:22]([CH2:24][CH2:25][NH:26][C:27]([C@H:29]([OH:35])[C:30]([CH2:33][OH:34])([CH3:31])[CH3:32])=[O:28])=[O:23])=[O:13])=[O:8])([CH2:4][OH:5])[CH3:1].[CH2-:40][C:39]([CH3:41])=[O:38]
Reactant: COC(C)(C)OC
Agent: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)CO
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: [CH2-]C(C)=O
Reaction time: 48 h

Procedure:
A mixture of 1.0 g of D-pantethine, 5 ml of 2,2-dimethoxypropane, 5 drops of trifluoroacetic acid and 5 ml of acetone was stirred for 2 days and then evaporated. The resulting white foam was purified by flash chromatography [dichloromethane:methanol (10:1)], giving 1.0 g of the desired compound as a white hygroscopic foam.
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH2:19][CH2:18][C@H:17]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@@H:16]3[CH2:15][CH2:14][C:13](=[O:20])[CH:12]=4)[C@@H:7]1[CH:6]=[CH:5][C:4]2=[O:21].[C:22]1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>O1CCOCC1.C(OC)(OC)OC>[CH3:22][O:20][C:13]1[CH2:14][CH2:15][C@H:16]2[C:11](=[CH:10][CH2:9][C@@H:8]3[C@@H:17]2[CH2:18][CH2:19][C@@:3]2([CH2:2][CH3:1])[C@H:7]3[CH:6]=[CH:5][C:4]2=[O:21])[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1C=CC2=O
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: COC(OC)OC
Product: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(OC)CC[C@@H]43)[C@@H]1C=CC2=O
Reaction time: 2.5 h
Yield: 1009.8 %

Procedure:
Under argon, 20.0 g of 18-methyl-4,15-estradiene-3,17-dione in 100 ml of 1,4-dioxane and 100 ml of trimethyl orthoformate is agitated with 800 mg of p-toluenesulfonic acid at 50° C. After 2.5 hours, 10 ml of pyridine is added and the solution extensively distilled under vacuum. The residue is dissolved in ethyl acetate, washed with water, and dried. Chromatography of the crude product with 0-20% ethyl acetate-hexane yields 14.0 g of 3-methoxy-18-methyl-3,5,15-estratrien-17-one, melting point 162.1° C. (from methanol).
Reaction SMILES: [Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([O:11][CH2:12]C2CCC[N+]2(C(C2C=CON=2)C(=O)N)C)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br-].OC[C@H]1CCC[N+]1(CC(=O)NC1C=CON=1)C.[Br-].OC1[CH2:60][CH2:59][N+:58]([CH3:71])([CH2:61][C:62](=[O:70])[NH:63][C:64]2[CH:69]=[N:68][CH:67]=[CH:66][N:65]=2)[CH2:57][CH2:56]1>>[Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:9]([O:11][CH:12]2[CH2:56][CH2:57][N+:58]([CH3:71])([CH2:61][C:62](=[O:70])[NH:63][C:64]3[CH:69]=[N:68][CH:67]=[CH:66][N:65]=3)[CH2:59][CH2:60]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C[N+]1(CC(=O)Nc2cnccn2)CCC(O)CC1
Reactant: C[N+]1(C(C(N)=O)c2ccon2)CCCC1COC(=O)C(O)(c1ccccc1)C1CCCCC1
Agent: C[N+]1(CC(=O)Nc2ccon2)CCC[C@@H]1CO
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2cnccn2)CCC(OC(=O)C(O)(c2ccccc2)C2CCCCC2)CC1

Procedure:
This compound is prepared by an analogous method to (1R/S,2R)-2-((R/S)-(2-Cyclohexyl-2-hydroxy-2-phenyl-acetoxymethyl)-1-(isoxazol-3-yl carbamoylmethyl)-1-methyl-pyrrolidinium bromide (Example 1) by replacing (1R/S,2R)-2-hydroxymethyl-1-(isoxazol-3-ylcarbamoyl-methyl)-1-methyl-pyrrolidinium bromide (Intermediate B) with 4-hydroxy-1-methyl-1-(pyrazin-2-ylcarbamoylmethyl)-piperidinium bromide (Intermediate H).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].[F:27][C:28]([F:39])([F:38])[CH2:29][O:30][C:31]1[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:37]([C:34]3[CH:35]=[N:36][C:31]([O:30][CH2:29][C:28]([F:39])([F:27])[F:38])=[CH:32][CH:33]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: Nc1ccc(OCC(F)(F)F)nc1
Product: O=C1N(c2ccc(OCC(F)(F)F)nc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
Off-white crystalline solid. MS (ESI): 504.1. (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chlorobenzenesulfonyl chlorid and 6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine.
Reaction SMILES: C(O[C:6](=[O:31])[NH:7][C@H:8]([C:10](=[O:30])[NH:11][C@H:12]([B:17]1[O:25][C@H:24]2[C@:19]([CH3:29])([C@H:20]3[CH2:26][C@@H:22]([CH2:23]2)[C:21]3([CH3:28])[CH3:27])[O:18]1)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:9])(C)(C)C.[C:32]1([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C@@H:39]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)C(O)=O)[CH:33]=1>>[C:32]1([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C@@H:39]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[C:6]([NH:7][C@H:8]([C:10](=[O:30])[NH:11][C@H:12]([B:17]2[O:25][C@H:24]3[C@:19]([CH3:29])([C@H:20]4[CH2:26][C@@H:22]([CH2:23]3)[C:21]4([CH3:27])[CH3:28])[O:18]2)[CH2:13][CH:14]([CH3:15])[CH3:16])[CH3:9])=[O:31])[CH:33]=1
Reactant: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc1
Reactant: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Product: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)cc1

Procedure:
The title compound is prepared as described in example 1 but using {(S)-1-[(R)-3-Methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester and (S)-2-(Biphenyl-3-ylamino)-3-(4-methoxy-phenyl)-propionic acid.
Reaction SMILES: [C:1](=[S:3])=[O:2].[CH3:4][CH:5]([CH3:7])[O-:6].[K+].[CH3:9][S:10][CH:11](Cl)[CH3:12]>C(OCC)C>[C:1](=[O:2])([S:3][CH:11]([S:10][CH3:9])[CH3:12])[O:6][CH:5]([CH3:7])[CH3:4]
Reactant: O=C=S
Reactant: CSC(C)Cl
Reactant: CC(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CSC(C)SC(=O)OC(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
In a two-necked round bottomed flask equipped with a gas introducing tube and a condenser, gaseous carbonyl sulphide (6 g or 0.1 mole) was introduced into a suspension of potassium isopropoxide (9.9 g or 0.1 mole) in diethyl ether (60 ml). The reaction mixture refluxed by the reaction heat. After the addition of carbonyl sulphide was completed, the mixture was cooled and the precipitate was collected by filtration and suspended in dichloromethane (100 ml). The suspension was cooled to 0°C and while stirring, 1-methylthio-1-chloroethane (11.0 g or 0.1 mole, prepared according to H. Bohme and H. Bentler, Chem. Ber. 89 (1956) pages 1464-1468) was added dropwise in 30 min. The mixture was then kept overnight at 0° C and filtered. The filtrate was dried over anhydrous magnesium sulphate. The solvent was evaporated off at 30°C and 10 mm Hg. Fractional distillation of the residue yielded 11.0 g (57%) O-isopropyl S-[1-methylthioethyl] thiocarbonate, b.p. 62-64°C at 0.1 mm Hg. nD20 = 1.4914. Infrared absorptions (liquid film) were at 2980, 2939, 2920, 2878, 2862, 2828, 1708, 1700, 1465, 1444, 1436, 1422, 1384, 1373, 1340, 1330, 1230, 1155, 1095, 1055, 974, 951, 911, 847, 810, 728, 697, 673, 520 and 510 cm-1. The NMR spectrum (in CCl4, internal standard Si (CH3)4) had signals at δ = 1.25 (doublet), δ = 1.62 (doublet), δ = 2.14 (singlet), δ = 4.32 (quadruplet) and δ = 5.01 ppm (septet).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18](=S)[NH2:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.[NH2:21][OH:22]>O1CCOCC1.C1COCC1>[OH:22][NH:21][C:18]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([C:10]2[CH:9]=[N:8][N:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:11]=2)[N:17]=1)=[NH:19]
Reactant: NO
Reactant: NC(=S)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N=C(NO)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
With heating, 0.4 g (1.4 mmol) of 6-(1-pyridin-3-yl-1H-pyrazol-4-yl)pyridine-2-carbothioamide were dissolved in 40 ml of dioxane-THF 1:3, 0.4 ml of hydroxylamine (50% strength aqueous solution, corresponds to 6.8 mmol) was added and the mixture was stirred at 60° C. for 1 h and then concentrated by evaporation. The crude product obtained in this manner was not purified any further.