Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:27][O:28][Si](C(C)(C)C)(C)C)[C@@H:10]([NH:20][S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([Cl:19])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.C1C=CN=CC=1.F>C1COCC1>[Si:1]([O:8][C@H:9]([CH2:27][OH:28])[C@@H:10]([NH:20][S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([Cl:19])[CH:13]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[S@](=O)N[C@@H](Cc1cc(F)cc(Cl)c1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: *CC(*)C
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)[S@](=O)N[C@@H](Cc1cc(F)cc(Cl)c1)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 50 mL polypropylene bottle containing (S)—N-((2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-(3-chloro-5-fluorophenyl)butan-2-yl)-2-methylpropane-2-sulfinamide (350.00 mg, 618 μmol) was added THF (10 mL ) and the mixture was allowed to stir at 0° C. for 5 minutes. At this time, PYRIDINE (2699 μl, 33371 μmol) was added via syringe before the addition of HF-Pyridine, 70% HF 30% pyr (1782 μl, 19775 μmol) via a syringe. The reaction was allowed to stir at this temp for 2 h and then quenched by pouring into sodium bicarbonate (sat 150 ml). The aq. layer was extracted with EtOAc 94×75 mL). The combined organics were washed with HCl (0.1 N, 3×100 mL), bicarbonate (sat, 100 mL), brine and dried with sodium sulfate. The dried solution was filtered and concentrated to give a yellow oil which was purified on a 40 g ISCO column to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH2:10][CH2:9][C:8]=2[C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1C=CC=CC=1>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]=2[C:19](=[O:28])[C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)C2=C(c3ccccc3)c3ccc(OC)cc3CC2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: COc1ccc(C(=O)c2ccc3cc(OC)ccc3c2-c2ccccc2)cc1
Yield: 40.7 %

Procedure:
To 11.1 g (30 mmol) of 1-phenyl-2-(4-methoxybenzoyl)-3,4-dihydro-6-methoxynaphthalene dissolved in benzene was added DDQ (9 g, 40 mmol). The mixture was heated to reflux for two hours and filtered while hot through silica gel. The silica gel was washed three times with ethyl acetate. The ethyl acetate washings and the benzene solution were combined and evaporated to dryness. The residue was crystallized from hot methanol, which yielded 4.5 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](N1C=CN=C1)([N:19]1C=CN=[CH:20]1)=O.C(N(CC)CC)C.Cl.CNC>CN(C)C=O>[CH3:17][N:19]([CH3:20])[C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8.1 %

Procedure:
To a solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (10 g, 43.6 mmol) in N,N-dimethylformamide (150 mL) was added 1,1′-carbonyldiimidazole (14.13 g, 87.23 mmol). The reaction mixture was stirred at room temperature for 10 min. Triethylamine (18.3 mL, 130.2 mmol) and dimethylamine hydrochloride (7.1 g, 87.2 mmol) were then added sequentially. The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was treated with cold water and was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified via flash chromatography to afford (R)-tert-butyl 3-(dimethylcarbamoyl)piperidine-1-carboxylate (0.9 g, 80%). MS (ES+APCI) (M+H) 257.1; LCMS retention time: 2.829 min (Method D1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH:24]([F:26])[F:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH:24]([F:26])[F:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:27][C:28]3[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[CH:30][CH:29]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CCC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O

Procedure:
116 mg (0.30 mmol) of 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}butanoic acid (racemate) and 64 mg (0.33 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 127 mg (75% of theory)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([O:13][CH3:14])[C:6]([O:11][CH3:12])=[CH:7][C:8]=1[CH2:9]Cl.[OH-].[Na+].C1(C)C=CC=CC=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH2:33])=[CH:27][CH:26]=1>O>[CH3:14][O:13][C:5]1[CH:4]=[C:3]2[C:8](=[CH:7][C:6]=1[O:11][CH3:12])[CH2:9][N:33]([CH2:32][CH2:31][C:28]1[CH:29]=[CH:30][C:25]([NH2:24])=[CH:26][CH:27]=1)[CH2:2]2
Reactant: NCCc1ccc(N)cc1
Reactant: COc1cc(CCl)c(CCl)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)CN(CCc1ccc(N)cc1)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4,5-Bischloromethyl veratrol (2.35 g: S. H. Wood, M. A. Peny and C. C. Tung, J. A. C. S. (1950), 72, 2989-2991) was added at room temperature to a stirred suspension of 50% aqueous sodium hydroxide (5 ml), toluene (25 ml), 4-aminophenylethylamine (1.5 g) and Aliquat (0.2 g). The heterogeneous mixture was stirred at room temperature for 16 hours, poured in water and extracted with methylene chloride. The organic layer was dried and the solvent evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with methylene dichloride/methanol (95:5) to give the title compound as a solid (0.6 g), MP: 150°. NMR includes signals at d 2.7(4H,m,Ph--CH2 --CH2 --N); 4.6(2H,bs,NH2); 3.7(6H,s,2×OCH3); 3.8(4H,s,2×N--CH2Ph); 6.2-7.0(6H,m,aromatics).
Reaction SMILES: [C:1]([C:3]([C@@H:16]1[CH2:20][CH2:19][N:18](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].Br.C1(O)C=CC=CC=1>ClCCl>[C:1]([C:3]([C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)N2CC[C@@H](C(C#N)(c3ccccc3)c3ccccc3)C2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: ClCCl
Product: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Temperature: 25 °C

Procedure:
A mixture containing 3-(S)-(+)-(1-cyano-1,1-diphenylmethyl)-1-tosylpyrrolidine (49 g--see Preparation 6(B)), 48% aqueous hydrobromic acid (500 ml) and phenol (50 g) was heated under reflux for 1.25 hours then allowed to cool to room temperature. The mixture was extracted with ether (50 ml) to remove an upper layer of purple oil, then with 2:1 ether/hexane (150 ml). The aqueous layer was extracted with dichloromethane (4×100 ml), the dichloromethane extracts were combined, washed with 10% aqueous sodium hydroxide (3×50 ml), then dried (MgSO4) and concentrated in vacuo to give an oil. The original ether extract was concentrated in vacuo to give an oil which was dissolved in dichloromethane (100 ml) and washed with 10% aqueous sodium hydroxide (3×50 ml). The dichloromethane solution was dried (MgSO4) and concentrated in vacuo to give an oil which was combined with that obtained from the initial dichloromethane extraction. The combined oils were then dissolved in dichloromethane (200 ml) and washed with 10% aqueous sodium hydroxide solution (2×50 ml). The dichloromethane solution was dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield, 24.3 g, [α]D25 +6.0° (c 1.0, CH2Cl2).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[H][H]>CS(C)=O.CO.[Pd]>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: [H][H]
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: CN1CCN(c2ccc(N)cc2)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
Potassium carbonate (1.9 g, 14.2 mmol) was added to a mixture of 1-fluoro-4-nitrobenzene (1 g, 7.1 mmol) and 1-methyl-piperazine (0.94 mL, 8.5 mmol) in methyl sulfoxide (DMSO, 5 mL). The mixture was stirred at 80° C. for 3 hours. After cooling down, the residue was extracted into EtOAc. The organic layer was washed with water, brine and then dried with Na2SO4. Removal of the solvent in vacuo yielded an orange solid. The solid was dissolved in 25 mL of methanol and palladium on carbon (10% Pd/C, 50 mg) was added slowly. The system was sealed and blanketed with hydrogen. The mixture was stirred at rt for 16 hours under hydrogen. The catalyst was filtered through a celite pad and the solvent was evaporated to leave a dark purple solid (1.3 g, 80%). 1H NMR (300 MHz, CD3OD) δ (ppm): 6.90 (m, 2H), 6.81 (m, 2H), 3.38 (m, 4H), 3.26 (m, 4H), 2.93 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:4]=1[CH3:13].C(Cl)(Cl)(Cl)Cl.[Br:19]Br>CC(O)=O>[Br:19][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:13])[C:5]=1[C:9]([F:10])([F:11])[F:12]
Reactant: COc1cccc(C(F)(F)F)c1C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)c(C(F)(F)F)c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask, was placed 1-methoxy-2-methyl-3-(trifluoromethyl)benzene (700 mg, 3.68 mmol, 1.00 equiv), CCl4 (3.0 mL). The mixture was cooled to 0° C. Br2 (698 mg, 4.37 mmol, 1.19 equiv) and AcOH (0.5 mL) were added. The resulting solution was stirred for 1 h at 30° C. The reaction process was monitored by TLC (Petroleum ether). The reaction was then quenched by the addition of 10 mL of saturated sodium bicarbonate. The resulting solution was extracted with 3×10 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether. This resulted in 0.7 g (71%) of 1-bromo-4-methoxy-3-methyl-2-(trifluoromethyl)benzene as yellow oil.
Reaction SMILES: Cl.[C:2]([NH2:8])(=[NH:7])[CH2:3][CH2:4][CH2:5][CH3:6].[CH2:9]([CH:11]([C:17]([CH3:19])=O)[C:12](OCC)=[O:13])[CH3:10].C(N(CC)CC)C>CN(C=O)C.[Cl-].[Na+].O>[CH2:3]([C:2]1[NH:8][C:12](=[O:13])[C:11]([CH2:17][CH3:19])=[C:9]([CH3:10])[N:7]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(=N)N
Reactant: CCOC(=O)C(CC)C(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCc1nc(C)c(CC)c(=O)[nH]1

Procedure:
A solution of 3.0 g valeramidine hydrochloride, 3.47 g ethyl 2-ethylacetoacetate, and 5.8 mL triethylamine in 20 mL DMF was heated to 120° C. for 18 hours. The mixture was diluted with brine and extracted three times with ether. The combined organic material was washed with brine, was dried over MgSO4, was stripped of solvent in vacuo, and then was still flash chromatographed in 3% MeOH in CH2Cl2 to give the title compound as a white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([Si:9]([CH3:12])([CH3:11])[CH3:10])[CH:8]=1.[CH:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)=O.[OH-].[Na+].Cl>C1COCC1.O>[CH3:11][Si:9]([CH3:10])([CH3:12])[C:7]1[CH:6]=[C:5]([C:13](=[O:15])[CH:14]=[CH:18][C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH:4]=[C:3]([Si:2]([CH3:16])([CH3:1])[CH3:17])[CH:8]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1cc([Si](C)(C)C)cc([Si](C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(C(=O)C=Cc2ccc(C(=O)O)cc2)cc([Si](C)(C)C)c1
Yield: 65.7 %

Procedure:
Under ice-cooling, to a solution of 114 mg (0.43 mmol) of 3',5'-bis(trimethylsilyl)acetophenone and 70 mg (0.43 mmol) of methyl 4-formylbenzoate in 3 ml of THF was added a solution of 40 mg (1.00 mmol) of NaOH in 2 ml of H2O with stirring, and the mixture was stirred in an atmosphere of prepurified argon overnight. The reaction mixture was further added to 39 mg of NaOH, stirred for 2 days, and then the solution was adjusted with 2N-HCl to pH≤7 and extracted with ethyl acetate. The extract was dried and evaporated. The residue was purified by column chromatography using methylene chloride-methanol (10:1) as an eluant to give 112 mg of the desired compound (yield 66%), which was recrystallized from a mixture of ethyl acetate and n-hexane to give 98 mg of pale yellow prisms, m.p. 194°-195.5° C. (yield 57%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]([NH:9][C:10](=[O:18])[CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[C:35](Cl)=[O:36]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10](=[O:18])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:40]([O:41][CH3:42])=[C:32]([O:31][CH3:30])[CH:33]=3)[CH2:14][CH2:13]2)=[CH:19][CH:20]=1)=[O:4]
Reactant: COC(=O)c1ccc(NC(=O)CN2CCNCC2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)CN2CCN(C(=O)c3ccc(OC)c(OC)c3)CC2)cc1
Reaction time: 2 h

Procedure:
3.3 Grams of p-methoxycarbonyl-α-(1-piperazinyl)acetanilide and 1.7 g of potassium carbonate were dissolved in 50 ml of DMF, then a methylene chloride solution containing 2.7 g of 3,4-dimethoxybenzoyl chloride was added dropwise thereto under ice-cooled condition with stirring. The reaction was continued at the same temperature for 2 hours, then to the reaction mixture was added 100 ml of methylene chloride, and the methylene chloride layer was washed with water, 5%-sodium bicarbonate aqueous solution, next with potassium carbonate aqueous solution, and was dried. Methylene chloride was removed by distillation, the residue obtained was purified by a silica gel column chromatography to obtain 3.3 g of p-methoxycarbonyl-α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide in the form of oily substance.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[C:31]([Cl:34])(=[O:33])[CH3:32]>CN(C=O)C>[ClH:34].[C:31]([NH:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1)(=[O:33])[CH3:32]
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
50 mg (0.12 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzo-thiophene-2-carboxamide dihydrochloride are initially charged in 0.3 ml of DMF, and 18.7 mg (0.18 mmol) of triethylamine and 11.6 mg (0.15 mmol) of acetyl chloride are added. After 16 h of stirring at RT, a further 18.7 mg (0.18 mmol) of triethylamine and 11.6 mg (0.15 mmol) of acetyl chloride are added. After a further 12 h of stirring at RT, the supernatant solution of the reaction mixture is purified by preparative HPLC. The product fractions are concentrated and the residue is dissolved in a mixture of methanol and 4M HCl in dioxane, then reconcentrated and dried under high vacuum. 8 mg (17.1% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:23][I:24]>>[I-:24].[CH3:23][P+:8]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CI
Reactant: Clc1ccc(P(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Product: C[P+](c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: [I-]
Yield: 92.9 %

Procedure:
Starting from 8.28 g (22.6 mmol) of tris(4-chlorophenyl)phosphine and 5.7 g (40 mmol, 1.8 eq) of methyl iodide, 10.64 g (21.0 mmol, 92.8%) of methyltris(4-chlorophenyl)phosphonium iodide was obtained: mp>250° C.
Reaction SMILES: [F:1][CH2:2][S:3](Cl)(=[O:5])=[O:4].S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25]Cl)=[N:23][CH:24]=1>O.C(O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][S:3]([CH2:2][F:1])(=[O:5])=[O:4])=[N:23][CH:24]=1
Reactant: ClCc1ccc(Br)cn1
Reactant: O=S(=O)(Cl)CF
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)(CF)Cc1ccc(Br)cn1
Temperature: 100 °C
Yield: 15.2 %

Procedure:
Commercially available fluoromethanesulfonyl chloride (975 mg, 7.36 mmol) is added dropwise to a solution of sodium sulfite (1.85 g, 14.7 mmol) and sodium bicarbonate (1.24 g, 14.7 mmol) in water (2 mL). The reaction mixture is heated in a microwave reactor to 100° C. for 20 minutes. After cooling to room temperature commercially available 5-bromo-2-(chloromethyl)pyridine (894 mg, 3.68 mmol) in ethanol (2 mL) is added. The mixture is heated in a microwave reactor to 100° C. for 20 minutes. The reaction mixture is cooled to 0° C. and the solid filtered off and discarded. The filtrates are diluted with saturated sodium carbonate (10 mL), extracted with tertiarybutyl methyl ether (50 mL). The organic layer is separated, dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give the title compound (150 mg): m/z 268.9 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([NH2:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1>C(O)=O>[CH:1]([NH:18][CH:14]([C:11]1[CH:10]=[CH:9][CH:8]=[CH:13][CH:12]=1)[C:15]([OH:17])=[O:16])=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H](C(=O)O)c1ccccc1
Solvent: O=CO
Product: O=CNC(C(=O)O)c1ccccc1
Reaction time: 0.5 h

Procedure:
40.8 ml. of acetic anhydride are cooled to 0°-5° and 54.4 ml. of formic acid are added dropwise with stirring at this temperature. The mixture is let stand for 30 minutes at this temperature and then 15.2 g. (0.1 mol.) of D-phenylglycine are added. After about 10 minutes, a clear solution results and after an additional 15 minutes α-(formylamino)benzeneacetic acid crystallizes. The temperature is allowed to rise to room temperature and 300 ml. of ice water are added. The mixture is then stirred for five minutes, filtered under suction, washed with water and dried, yield 11.4 g., m.p. 170°-175°. The product, α-(formylamino)benzeneacetic acid, is recrystallized from ethanol. The melting point remains unchanged.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7]([CH3:9])=[CH:6]O[CH:4]1OC)[CH3:2].[N+:12]([O-])([O-])=O.[NH4+]>O.C(O)(=O)C.[N+]([O-])(O)=O>[CH2:1]([C:3]1[CH:4]=[N:12][CH:6]=[C:7]([CH3:9])[CH:8]=1)[CH3:2]
Reactant: CCC1CC(C)=COC1OC
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CCc1cncc(C)c1
Reaction time: 0.25 h
Yield: 66 %

Procedure:
156 parts of 3-ethyl-2,3-dihydro-2-methoxy-5-methyl-4H-pyran are dissolved in 25 parts of water, 300 parts of acetic acid and 2 parts of 60 percent strength nitric acid at 22° C. After 15 minutes, a solution of 80 parts of ammonium nitrate in 80 parts of water is added. The resulting solution is added to 800 parts of acetic acid at 110° C. in the course of 20 minutes, whilst stirring. The reaction mixture is left to cool, the acetic acid, water and methanol are distilled off, 200 parts of water are added to the residue and the solution is rendered alkaline with 25 percent strength ammonia solution. The 3-ethyl-5-methyl-pyridine is extracted with ether. Distillation gives 80 parts (66% of theory) of 3-ethyl-5-methyl-pyridine of boiling point 83° C./15 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:33])[NH:25][C:26]4[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=4)=[CH:20][C:19]=3[N+:34]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>O.C(O)C.C(OCC)(=O)C.[Fe]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:33])[NH:25][C:26]4[CH:27]=[CH:28][C:29]([Br:32])=[CH:30][CH:31]=4)=[CH:20][C:19]=3[NH2:34])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Sc3ccc(C(=O)Nc4ccc(Br)cc4)cc3[N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)n1ccc2cc(Sc3ccc(C(=O)Nc4ccc(Br)cc4)cc3N)ccc21
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A suspension of the product of Example 89D (75 mg, 0.132 mmol), iron powder (45.3 mg, 0.811 mmol), and ammonium chloride (46 mg, 0.864 mmol) in water (1 mL) and ethanol (2 mL) was heated at 95° for 30 minutes. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with water (2×25 mL) and brine (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum to afford the title compound as a yellow solid (65 mg, 92%).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][NH:16][C:17]1[N:22]2[N:23]=[C:24]([CH3:36])[C:25]([C:26]3[C:31]([Cl:32])=[CH:30][C:29]([C:33]#[N:34])=[CH:28][C:27]=3[Cl:35])=[C:21]2[N:20]=[C:19]([CH3:37])[CH:18]=1)[CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(C)(C)C>C(O)C>[ClH:32].[Cl:32][C:31]1[CH:30]=[C:29]([CH:28]=[C:27]([Cl:35])[C:26]=1[C:25]1[C:24]([CH3:36])=[N:23][N:22]2[C:17]([NH:16][CH2:15][CH2:14][NH:7][CH:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:18][C:19]([CH3:37])=[N:20][C:21]=12)[C:33]#[N:34]
Reactant: Cc1cc(NCCN(C(=O)OC(C)(C)C)C2CCOCC2)n2nc(C)c(-c3c(Cl)cc(C#N)cc3Cl)c2n1
Solvent: CCO
Product: Cc1cc(NCCNC2CCOCC2)n2nc(C)c(-c3c(Cl)cc(C#N)cc3Cl)c2n1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 268.9 %

Procedure:
To {2-[3-(2,6-Dichloro-4-cyano-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethyl}-(tetrahydro-pyran-4-yl)-carbamic acid tert-butyl ester (10 mg, 0.015 mmol) was added 2:1 ethanol/concentrated aqueous hydrochloric acid (1 mL). The reaction was stirred 3 hours at room temperature, concentrated under reduced pressure, and then concentrated 3 additional times from ethanol to give a solid that was triturated from ether to afford the title compound (10 mg, quantitative): +APcI MS (M+1)+459; 1H NMR (methanol-d4) δ: 8.06 (s, 2H), 6.90 (s, 1H), 2.62 (s, 3H), 2.32 (s, 3H).