Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22]([OH:24])=O)[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:4]=1[CH3:36])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C@@H:8]2[C:3]([C:1]#[N:2])=[C:4]([CH3:36])[N:5]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=3)[C:6](=[O:25])[N:7]2[CH2:21][C:22]([N:65]2[CH2:66][CH2:67][CH:62]([OH:61])[CH2:63][CH2:64]2)=[O:24])=[C:10]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:11]=1)#[N:16]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OC1CCNCC1
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: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)N2CCC(O)CC2)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 97.4 %

Procedure:
The reaction was carried out under argon. 2-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (45 mg, 87 μmol; Example 21) was initially charged in DMF (1.5 ml), HATU (165 mg, 434 μmol, 5 eq.) was added at 0° C. and the mixture was stirred for 20 min. 4-Hydroxypiperidine (43.9 mg, 434 μmol, 5 eq.) and N,N-diisopropylethylamine (56 mg, 434 μmol, 5 eq.) were then added, and the mixture was stirred at RT for 16 h until complete conversion had been achieved (HPLC control). The reaction mixture was then concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (51 mg, 98% of theory).
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19][C:20]1([CH2:33][CH2:34][OH:35])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[Si:1]([O:35][CH2:34][CH2:33][C:20]1([OH:19])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CCO)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(O)(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A solution of 21.50 ml (82.50 mmol) of tert-butyldiphenylsilyl chloride in 15 ml of dichloromethane is added dropwise, under an inert atmosphere, to a solution of 18.4 g (75 mmol) of tert-butyl 4-hydroxy-4-(2-hydroxyethyl)-1-piperidinecarboxylate, obtained in step 12.1, and 11.60 ml (82.50 mmol) of triethylamine in 100 ml of dichloromethane, cooled to about 0° C. The mixture is allowed to warm to room temperature and stifling is then continued for 12 hours. Saturated aqueous ammonium chloride solution is added to the reaction medium. The aqueous phase is separated out and extracted twice with dichloromethane, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica gel, eluting with a 10/90 and then 20/80 mixture of ethyl acetate and cyclohexane.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:13]=3)[CH2:18]2)=[O:29])=[CH:26][CH:25]=1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCc3cc(N4CC[C@H](N5CCC[C@@H]5C)C4)ccc3C2)cc1

Procedure:
To a solution of 6-((2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline in DCM (7 mL) was added 4-Methoxy-benzoyl chloride in DCM, followed by triethylamine. The reaction was quenched with aq. NaHCO3 and DCM work up. The crude product was purified on a silica gel column to obtain the title compound.
Reaction SMILES: Br[C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.[C-:21]#[N:22].[Na+]>CN(C)C=O.O>[C:21]([C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1)#[N:22]
Reactant: Cc1cc2c(cc1Br)C(c1ccccn1)=NC(C)(C)O2
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1C#N)C(c1ccccn1)=NC(C)(C)O2
Reaction time: 0.25 h
Yield: 20.9 %

Procedure:
Cuprous cyanide (1.1 g) was added to a solution of Compound 46 (2.0 g) in dimethylformamide (5 ml) and the mixture was heated under reflux for 23 hours. The reaction mixture was air-cooled. The mixture was then added to a solution of sodium cyanide (2.2 g) in water (6.5 ml), and the mixture was stirred for 15 minutes. The mixture was extracted with ethyl acetate, successively washed with aqueous 5% sodium cyanide solution and saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off. The resulting crude product was washed with ether/isopropyl ether to obtain 6-cyano-2,2,7-trimethyl-4-(2-pyridyl)-2H-1,3-benzoxazine (0.35 g) (Compound 64).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][N:6]=[C:7]([CH3:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[CH3:17][NH2:18]>>[CH3:15][C:7](=[N:6][O:5][CH2:4][C:3]([NH:18][CH3:17])=[O:2])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: CN
Reactant: COC(=O)CON=C(C)c1ccc(Cl)cc1
Product: CNC(=O)CON=C(C)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A mixture of 5.0 g of the [(α-methyl-4-chlorobenzylidene amino)oxy] acetic acid methyl ester obtained by the method described in example 3 and 40 ml of 35% aqueous methylamine solution was stirred for 2 hours. The precipitated solid substance was then dissolved by thrice extracting the mixture with an ether chloroform mixture. The extract was washed thrice with water, dried over anhydrous sodium sulfate and then concentrated by evaporation. Crystallisation of the residue from a benzene petroleum ether mixture yielded the above substance. Melting point 115° C.-116° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:15](O)=[O:16].CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH:6][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:12]([O:11][CH3:10])[CH:13]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CO)NC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.6 %

Procedure:
Dichloromethane (80 mL) was added to serine methyl ester hydrochloride (2.64 g, 17 mmol), 3-methoxy-4-nitrobenzoic acid (3 g, 15.2 mmol), WSC hydrochloride (3.83 g, 20 mmol), DMAP (0.18 g, 1.5 mmol) and N,N-diisopropylethylamine (2.58 g, 20 mmol), and the mixture was stirred at room temperature for one day. The reaction solution was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/2, 1/1, 2/1, 1/0) to obtain 3.11 g of the title compound as a colorless solid (69%).
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]2=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:3])[CH3:2].[Br:28]Br.Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:28][CH2:2][C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]2=[C:6]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:5]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:3]
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(C)=O)CCN(C)C2=O
Reactant: BrBr
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(=O)CBr)CCN(C)C2=O

Procedure:
A solution of ethyl 6-acetyl-8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (0.50 g, 1.35 mmol; Example 7, step 7), bromine (0.24 g, 1.49 mmol), 33% hydrobromide in glacial acetic acid (10 drops) in chloroform (15 mL) was stirred at room temperature for 6 hours. The mixture was treated with aqueous sodium bicarbonate and diluted with chloroform. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 20 to 80% ethyl acetate in hexane to afford the title compound. ES MS M+1=407, 409
Reaction SMILES: C(C1C=CC([CH:15]2[CH:20]([NH2:21])[CH2:19][CH:18]=[CH:17][CH2:16]2)=CC=1)=CC1C=CC=CC=1.Cl[C:23]([O:25][C:26]1C=CC=C[CH:27]=1)=[O:24]>C(Cl)Cl.N1C=CC=CC=1>[C:20]1([NH:21][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NC1CC=CCC1c1ccc(C=Cc2ccccc2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 170.3 %

Procedure:
To a stirred solution of 6-(4'-styrylphenyl)cyclohex-3-enylamine (0.44 g, 1.66 mmol) in methylene chloride (21 mL) and pyridine (10 mL) at 0° C. is added phenyl chloroformate (0.25 g, 1.6 mmol). The reaction is warmed to room temperature and partitioned between methylene chloride and water. The organic extracts are washed with brine, dried (MgSO4) and evaporated. The residue is triturated with diethyl ether and purified by flash chromatography (2% diethyl ether/toluene) to give the intermediate phenyl urethane (0.45 g, 70%); Rf=0.26. MS (FAB+ion) m/z 396 (M+H).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N+](=C)=[N-].Br.[C:16]([O:20][C:21]([N:23]1[CH2:31][CH2:30][CH:26]([C:27](=[S:29])[NH2:28])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CCO>[CH2:4]([C:3]1[S:29][C:27]([CH:26]2[CH2:30][CH2:31][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:24][CH2:25]2)=[N:28][CH:2]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Agent: Br
Agent: C=[N+]=[N-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(Cc3ccccc3)s2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To a solution of 65 mg of 1-bromo-3-phenyl-2-propanone (from reacting the acid chloride with diazomethane followed by hydrogen bromide) in 4 ml EtOH was added 74 mg of 1-boc-isonipecot-thioamide (from Step A). The reaction was stirred for 2 hours at 80° C. The solvent was then evaporated under reduced pressure. The residue was purified by flash chromatography with 10% EtOAc in hexane to give 37 mg of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1.[CH2:21]([Si:23]([CH2:27][CH3:28])([CH2:25][CH3:26])Cl)[CH3:22]>C1COCC1>[Br:13][C:14]1[CH:19]=[C:18]([Si:23]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:21][CH3:22])[C:17]([F:20])=[CH:16][N:15]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(Br)ncc1F
Temperature: -75 °C
Reaction time: 1 h

Procedure:
A solution of diisopropylamine (25.3 g, 250 mmol) in 370 ml THF was cooled with a dry-ice acetone bath at −75° C. BuLi (100 ml, 250 mmol, 2.5 M in hexanes) was added dropwise while maintaining the temperature below −50° C. After the temperature of the mixture had reached −75° C. again, a solution of 2-bromo-5-fluoropyridine (36.7 g, 208 mmol) in 45 ml THF was added dropwise. The mixture was stirred for 1 h at −75° C. Triethylchlorosilane (39.2 g, 260 mmol) was added quickly. The temperature stayed below −50° C. The cooling bath was removed and the reaction mixture was allowed to warm to −15° C., poured onto aq. NH4Cl (10%). TBME was added and the layers were separated. The organic layer was washed with brine, dried with MgSO4.H2O, filtered and evaporated to give a brown liquid which was distilled at 0.5 mm Hg to yield the title compound as a slightly yellow liquid (b.p. 105-111° C.). HPLC: RtH11=2.284 min; ESIMS: 290, 292 [(M+H)+, 1Br]; 1H-NMR (400 MHz, CDCl3): 8.14 (s, 1H), 7.40 (d, 1H), 1.00-0.82 (m, 15H).
Reaction SMILES: [BrH:1].C(Cl)(Cl)=S.Br[C:7]1[C:16]([N:17]=[C:18]=[S:19])=[CH:15][CH:14]=[C:13]2[C:8]=1[N:9]=[CH:10][CH:11]=[N:12]2>O>[Br:1][C:16]1([N:17]=[C:18]=[S:19])[CH:15]=[CH:14][C:13]2[N:12]=[CH:11][CH:10]=[N:9][C:8]=2[CH2:7]1
Reactant: S=C=Nc1ccc2nccnc2c1Br
Reactant: Br
Agent: S=C(Cl)Cl
Solvent: O
Product: S=C=NC1(Br)C=Cc2nccnc2C1
Reaction time: 2 h
Yield: 90 %

Procedure:
The crude hydrobromide product described above (4.27 g, 14.0 mmol) was dissolved in 60 ml of water; thiophosgene (Aldrich, 1.28 ml, 16.8 mmol) was added in small portions with vigorous stirring. After 2 hours, the red color of the solution was discharged. The solid formed was filtered off and washed thoroughly with water. After drying in vacuo at 25° C., 3.38 g of brick red crystals were obtained, m.p. 157-8° C., representing a yield of 90%. A portion of this material was further purified by column chromatography to give white crystals, m.p. 157-8° C. Using various analytical procedures, these crystals were determined to be 5-bromo-6-isothiocyanatoquinoxaline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[O:5][C:6]1[C:7](Cl)=[N:8][CH:9]=[N:10][C:11]=1Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([NH2:29])(=[O:28])=[O:27]>C(OCC)(=O)C>[OH:2][CH2:3][CH2:4][O:5][C:11]1[N:10]=[CH:9][N:8]=[C:7]([NH:29][S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])(=[O:28])=[O:27])[C:6]=1[O:5][C:4]1[CH:14]=[CH:15][CH:16]=[CH:17][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1Oc1c(Cl)ncnc1Cl
Reactant: COc1ccccc1S(N)(=O)=O
Solvent: CCOC(C)=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccccc2OC)ncnc1OCCO

Procedure:
By reacting 5-(2-methoxyphenoxy)-4,6-dichloropyrimidine with o-methoxyphenylsulfonamide and thereafter with ethylene glycol Na, there was obtained N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]-o-methoxybenzenesulfonamide, m.p. 164°-165° C. (from ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][C:14]1=[O:19].[H-].[Na+].C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:13]2[CH2:18][CH2:17][O:16][CH2:15][C:14]2=[O:19])=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc(Br)cc1
Reactant: O=C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1COCCN1CCCOc1ccc(Br)cc1
Temperature: 75 °C
Reaction time: 5 h
Yield: 31.2 %

Procedure:
To a mixture of 1-bromo-4-(3-bromopropoxy)benzene (300 mg, 1.02 mmol) and morpholin-3-one (100 mg, 1.02 mmol) in DMF (6 mL) was added NaH (365 mg, 1.10 mmol). The mixture was stirred at 75° C. for 5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated to give the title compound (100 mg, 35%) as a yellow oil.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([F:18])=[C:13]([F:17])[CH:14]=2)[C:9]1=[O:19])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([F:18])=[C:13]([F:17])[CH:14]=2)[C:9]1=[O:19]
Reactant: CC=CCC1Cc2cc(F)c(F)cc2C1=O
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: O=CCC1Cc2cc(F)c(F)cc2C1=O
Reaction time: 0.67 h
Yield: 76 %

Procedure:
An ozone stream (2 g ozone/hour) was conducted for 40 minutes while stirring through a solution, cooled to -70°, of 5.3 g of (RS)-2-(2-buten-1-yl)-5,6-difluoro-1-indanone in 125 ml of anhydrous dichloromethane and 25 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 2.64 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 60 ml of dichoromethane and, after the addition of 10 ml of water and 10 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 80 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 40 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. There was obtained a yellow oil which was crystallized from diethyl ether/hexane. 3.82 g (76%) of (RS)-2-(2-oxoethyl)-5,6-difluoro-1-indanone were obtained as a white solid with m.p. 78°-81°.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.P(Cl)(Cl)([Cl:18])=O>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([Cl:18])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c(-c2ccco2)nc(N)[nH]c1=O
Solvent: ClCCl
Product: N#Cc1c(Cl)nc(N)nc1-c1ccco1
Temperature: 25 °C
Yield: 4.5 %

Procedure:
Following the method of Hull (J. Chem. Soc. 1957, 4845), a stirred suspension of 3.26 g (16.1 mmol) 2-amino-4-furan-2-yl-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile in 3.7 ml (40.3 mmol) phosphorus oxychloride was heated at reflux for 90 minutes. The reaction mixture was then cooled to room temperature, diluted with dichloromethane, and poured cautiously onto 100 ml rapidly stirred ice-water such that the temperature remained around 10° C. The phases were separated and the aqueous phase further extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate) afforded 0.16 g (4%) 2-amino-4-chloro-6-furan-2-yl-pyrimidine-5-carbonitrile as an orange crystalline solid. EI-MS m/e (%): 222 (M{37Cl}+, 34), 220 (M{35Cl}+, 100), 143 (30).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[CH:14]#[C:15][C@@H:16]([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>C(Cl)Cl>[C:6]([Si:10]([CH3:12])([CH3:11])[O:22][C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:15]#[CH:14])([CH3:9])([CH3:8])[CH3:7]
Reactant: C#C[C@@H](O)CCCCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C#C[C@H](CCCCC)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The procedure of Noyori (Suzuki, M., et al., J. Med. Chem. 41, 3084-3090 (1998)) was used. Imidazole (971 mg, 14.3 mmol) and t-butylchlorodimethylsilane (1.43 g, 9.51 mmol) were added to a solution of (S)-1-octyn-3-ol SI-8 (1.00 g, 1.16 ml, 7.92 mmol) in CH2Cl2 (18 ml), cooled to 0° C. The reaction mixture was then stirred at room temperature for 24 h before being poured into 1 M HCl (50 ml). The mixture was extracted with 40/60 petroleum ether (3×50 ml). The combined organic phases were washed with brine (50 ml) before being dried (MgSO4), filtered, and concentrated to give the title compound SI-7 (1.89 g, 99%) as a clear, colourless oil. Analytical data consistent with the literature (Nicolaou, K. C. et al., A. J. Am. Chem. Soc. 107, 7515-7518 (1985); Cmrecki, V. et al., Tetrahedron 66, 6550-6564 (2010)).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:8]=1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([C:5]1[CH:4]=[C:3]([CH2:2][Br:20])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)OCC)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(CBr)cc(C(=O)OCC)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of diethyl 5-(hydroxymethyl)benzene-1,3-dioate (3.5 g, 0.014 mol) and carbon tetrabromide (5.0 g, 0.015 mol) in 30 mL CH2Cl2, cooled to 0° C., was added dropwise a solution of triphenylphosphine (3.9 g, 0.015 mol) in 20 mL CH2Cl2. The reaction was stirred at 0° C. for 1.5 h, diluted with CHCl3, and washed with water and brine. Drying, solvent evaporation and flash chromatography (silica gel, 0-30% EtOAc/hexanes) gave diethyl-5-(bromomethyl)benzene-1,3-dioate. 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.25 (app d, J=1.6 Hz, 2H), 4.55 (s, 2H), 4.42 (q, J=7.1 Hz, 4H), 1.42 (t, J=7.1 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:35])[CH:3]=1.[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:27][CH2:28]2)=[O:22])=[C:4]([CH3:35])[CH:3]=1
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 28.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (47 mg, 0.10 mmol) obtained in step 2 and ethanesulfonamide (52 mg, 0.5 mmol), the title compound (16 mg, 28%) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][CH2:5][CH2:4][C:3]1([C:8]1[N:12]([CH3:13])[N:11]=[CH:10][CH:9]=1)O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[C:3]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][CH:9]=2)=[CH:4][CH2:5][CH2:6]1
Reactant: Cn1nccc1C1(O)CCCC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1nccc1C1=CCCC1(C)C
Yield: 89.7 %

Procedure:
A solution of the 2,2-dimethyl-1-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (630 mg, 3.24 mmol) prepared in Example 99a and p-toluenesulfonic acid hydrate (2.00 g, 10.5 mmol) in toluene (20 mL) was stirred for 8 hours under reflux, and the solvent was subjected to azeotropic distillation with water. After allowing to cool, water (50 mL) was added to the reaction solution, and an organic layer was extracted. The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=3:1) to yield the title compound (512 mg, 90%) as a brown oil.