Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29]Cl)[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[CH3:34][NH:35][CH2:36][CH:37]([C:39]1[N:40]([CH3:44])[CH:41]=[CH:42][CH:43]=1)[OH:38].O>CN(C=O)C>[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29][N:35]([CH2:36][CH:37]([OH:38])[C:39]4[N:40]([CH3:44])[CH:41]=[CH:42][CH:43]=4)[CH3:34])[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Reactant: CNCC(O)c1cccn1C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1cccn1C
Temperature: 90 °C
Yield: 63.5 %

Procedure:
N,N-Diisopropylethylamine (0.14 mL) and N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.150 g) were added to a solution of rac-2-(methylamino)-1-(1-methyl-1H-pyrrol-2-yl)ethanol (Preparation 48, 0.126 g) in DMF (10 mL). The reaction mixture was heated to 90° C. for 1 h. The mixture was allowed to cool to room temperature, poured into water (25 mL), and was extracted with CH2Cl2 (4×25 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The resulting oil was purified by column chromatography (CH2Cl2/methanol, 98/2) followed by recrystallization from ethyl acetate to yield 0.126 g the title compound as a white solid. Physical characteristics. M.p. 122-124° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 10.65, 8.55, 7.41-7.32, 6.89, 6.61-6.60, 5.85-5.83, 4.84, 4.74-4.69, 4.55, 3.91, 3.79-3.71, 3.58, 2.79-2.70, 2.31; 13C NMR (100 MHz, CDCl3) δ 173.7, 164.7, 153.2, 150.6, 141.1, 137.3, 132.8, 131.4, 128.9, 128.6, 123.4, 116.8, 114.8, 106.8, 106.6, 106.0, 61.9, 60.8, 54.3, 42.5, 41.9, 37.8, 34.1; MS (ESI+) m/z 483 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[C:3]=1[C:14]([NH2:16])=[O:15].C(N(CC)C(C)C)(C)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[N:34]=[C:35]=[O:36]>O1CCOCC1>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:35]([NH:34][C:28]3[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:27]=3[F:26])=[O:36])=[CH:11][CH:12]=2)[C:3]=1[C:14]([NH2:16])=[O:15]
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: NC(=O)c1c(-c2ccc(N)cc2)nsc1N
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3nsc(N)c3C(N)=O)cc2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.7 %

Procedure:
A mixture of 5-amino-3-(4-aminophenyl)isothiazole-4-carboxamide (18 mg, 0.079 mmol), N,N-diisopropylethylamine (0.034 mL, 0.20 mmol), and 2-fluoro-5-methylphenyl isocyanate (0.014 mL, 0.11 mmol) in 1.0 mL dioxane was reacted at room temperature for 2.5 hours. The reaction was quenched with 0.5 mL MeOH, stirred 5 min at room temperature, and then evaporated. The residue was recrystallized from EtOAc/CHCl3 to give the title compound as a pale yellow solid (27 mg, 88%).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:26][C:14]=3[N:13]=2)=[C:8]([F:31])[CH:7]=1.[Cl:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(=O)([O-])O.[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:2]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:3]=2[CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:15]4[CH:23]=[CH:24][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:26][C:14]=4[N:13]=3)=[C:8]([F:31])[CH:7]=2)=[CH:42][CH:41]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc([N+](=O)[O-])ccc3Br)cc1F)n2C1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc([N+](=O)[O-])ccc3-c3ccc(Cl)cc3)cc1F)n2C1CCCCC1
Yield: 90.1 %

Procedure:
Methyl 2-[4-(2-bromo-5-nitrobenzyloxy)-2-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylate (2.0 g) obtained in Example 336, 4-chlorophenylboronic acid (590 mg) and tetrakis(triphenylphosphine)palladium (396 mg) were suspended in dimethoxyethane (40 ml), and saturated aqueous sodium hydrogencarbonate solution (20 ml) was added, which was followed by refluxing under heating for 1 hr. The reaction mixture was allowed to cool, water was added and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (n-hexane:ethyl acatate=2:1) to give the title compound (1.9 g, yield 90%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Ca+2].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>C(Cl)Cl.C(Cl)Cl.CO>[N+:29]([C:26]1[CH:25]=[CH:24][C:23]([O:22][C:20](=[O:21])[NH:11][C:10]2[CH:12]=[CH:13][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:8][CH:9]=2)=[CH:28][CH:27]=1)([O-:31])=[O:30]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
A mixture of 4-morpholinoaniline (1.01 g, 5.68 mmol) and CaCO3 (743 mg, 7.42 mmol) (10 micron powder) was treated with a solution of 4-nitrophenyl chloroformate (1.49 g, 7.39 mmol) in DCM (7.5 mL) in one portion under air on an ice bath. The thick, easily stirred reaction slurry was stirred for 1-2 min on the ice bath before stirring at rt for 1 h. The slurry was then diluted with 9:1 DCM/MeOH (7.5 mL) and directly applied to a flash silica column (95:5 DCM/MeOH) to provide 0.7 g of material. This was further purified by trituration with hot toluene (25 mL) to afford the title compound as a light olive green powder (444 mg, 23%). 1H NMR (300 MHz, CDCl3) δ 8.28 (m, 2H), 7.42-7.31 (m, 4H), 6.95-6.85 (m, 3H), 3.86 (m, 4H), 3.13 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[CH2:4][CH2:3]1.[Br:17]Br>C(O)(=O)C>[Br:17][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:9][C:10]=1[N+:14]([O-:16])=[O:15]
Reactant: CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Reactant: BrBr
Solvent: CC(=O)O
Product: CN1CCN(c2ccc(Br)c([N+](=O)[O-])c2)CC1
Reaction time: 8 h

Procedure:
A solution of 1-methyl-4-(3-nitrophenyl)piperazine (EP0533267A) (1.0 g; 4.5 mmol) in glacial acetic acid (25 ml) was treated with bromine (0.23 ml; 1 equivalent). The reaction mixture was stirred at 75° overnight, then cooled, filtered, and the yellow sticky solid was partitioned between potassium carbonate (aq) and 2% methanol in dichloromethane. The organic phase was dried (Na2SO4) and evaporated under reduced pressure to leave the title compound (D26) as a viscous orange oil (928 mg, 68%) MH+=300/302.
Reaction SMILES: [Cl:1][C:2]([Cl:14])([Cl:13])[CH2:3][O:4][C:5]([NH:7][C:8]1[CH:12]=[CH:11][O:10][N:9]=1)=[O:6].O[CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH2:34][CH2:33][N:32]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:31][CH:30]=3)=[C:25]([F:42])[CH:24]=2)[CH2:18]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[O:10]1[CH:11]=[CH:12][C:8]([N:7]([CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH2:31][CH:30]=4)=[C:25]([F:42])[CH:24]=3)[CH2:18]2)[C:5]([O:4][CH2:3][C:2]([Cl:1])([Cl:13])[Cl:14])=[O:6])=[N:9]1
Reactant: O=C(Nc1ccon1)OCC(Cl)(Cl)Cl
Reactant: O=C1O[C@@H](CO)CN1c1ccc(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=C1O[C@@H](CN(C(=O)OCC(Cl)(Cl)Cl)c2ccon2)CN1c1ccc(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-(2,2,2-trichloroethyloxycarbonylamino)isoxazole (1.30 g, 5.0 mmol), 5(R)-hydroxymethyl-3-(3-fluoro-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one (WO 97/30995; 1.91 g, 5.0. mmol) and tributylphosphine (1.52 g, 7.5 mmol) in dry tetrahydrofuran (50 ml) under a nitrogen atmosphere at 0° C., was added 1,1′-(azodicarbonyl)dipiperidine (1.89 g, 7.5 mmol) in dry tetrahydrofuran (15 ml). The solution was stirred at 0° C. for 30 minutes before being allowed to come to room temperature and it was then stirred for 2 days. The mixture was filtered, concentrated by rotary evaporation and chromatographed by MPLC (30% ethyl acetate/hexane, ICN Alumina N 32-63), and triturated with ether to give the title compound as a white amorphous solid (1.62 g, 52%). NMR: 2.41 (m, 2H), 2.60 (t, 2H), 3.15 (m, 2H), 3.90 (dd, 1H), 4.18 (m, 2H), 4.37 (dd, 1H), 5.04 (dd, 3H), 5.95 (broad s, 1H), 6.88 (s, 1H), 7.32 (m, 3H), 8.89 (s, 1H); m/z ES+ (M+H)=623.
Reaction SMILES: C1(=O)[N:5]([C@H:6]2[C@@H:9](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:7]2=[O:25])C(=O)C2=CC=CC=C12.CNN>C(COC)OC>[NH2:5][C@H:6]1[C@@H:9](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]([Si:18]([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:20])[CH3:19])[C:7]1=[O:25]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](N2C(=O)c3ccccc3C2=O)[C@H]1/C=C/c1ccccc1
Agent: CNN
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](N)[C@H]1/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 5 ml of dimethoxyethane is suspended 440 mg of cis-3-phthalimido-4-(E)-styryl-1-(tert-butyldimethylsilyl)-2-oxoazetidine and after addition of 0.26 ml of methylhydrazine, the mixture is stirred at room temperature for 30 minutes. The solvent is then distilled off under reduced pressure and the residue is dissolved by addition of 5 ml of methylene chloride and allowed to stand overnight. The precipitate is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography [eluent:chloroform-ethyl acetate (6:4)] to give an oil of cis-3-amino-4-(E)-styryl-1-(tert-butyldimethylsilyl)-2-oxoazetidine. This oil is dissolved in 10 ml of tetrahydrofuran and under ice-cooling and stirring, 0.2 ml of triethylamine is added, followed by addition of 0.212 g of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl chloride hydrochloride. The mixture is stirred under ice-cooling for 10 minutes and then at room temperature for 30 minutes, after which the reaction mixture is shaken with ethyl acetate and water. The ethyl acetate layer is taken, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is purified by silica gel column chromatogtaphy [eluent:chloroform-ethyl acetate (7:3)] and crystallized from ether to give cis-[2-(2-chloroacetamido-4 -thiazolyl)-2-methoxyiminoacetamido]-4-(E)-styryl-1-(tert-butyldimethylsilyl)-2-oxoazetidine (sin-isomer), melting at 228°-231° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.CO.[BH4-].[Na+].[OH-].[K+]>O.C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)c2ccccc12
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(Cl)c2ccccc12

Procedure:
This compound was prepared in the manner of Step C, Example 1, using 2.1 grams (0.011 mole) of 4-chloronaphthalenecarbaldehye, 70 mL of methanol, 20 mL of THF, and 2 grams (0.054 mole) of sodium borohydride. This preparation differs in that sodium borohydride was used rather than a solution of potassium hydroxide in water. The yield of the title compound was 1.9 grams.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][C:19]=1[O:28][C:29]([F:32])([F:31])[F:30].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([N:12]2[CH2:13][CH2:14][CH2:15][C:16]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[CH:10][C:11]2=3)=[O:26])=[CH:20][C:19]=1[O:28][C:29]([F:30])([F:32])[F:31]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cc1ccc(Cl)c(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)c(OC(F)(F)F)c1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.023 g, 0.10 mmol), 4-chloro-3-(trifluoromethoxy)phenylacetic acid (0.025 g, 0.10 mmol) and Et3N (0.060 mL, 0.43 mmol) in DMF (0.6 mL) was added HATU (0.060 g, 0.15 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water and partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by reverse phase HPLC to afford the desired product (0.039 g, 85%). 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.44 (m, 3H), 7.12-7.22 (m, 4H), 3.90 (s, 2H), 3.76 (m, 2H), 2.80 (t, J=6.2 Hz, 2H), 2.02 (m, 2H); MS: (ES) m/z calculated for C21H16ClF4N3O2 [M+H]+ 454.1, found 454.1.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([N:6]1[CH:10]2[CH2:11][C:12]([CH2:14][CH:7]1[CH2:8][CH2:9]2)=O)=[O:5].[Cl-].[CH3:16][O:17][CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:16][O:17][CH:18]=[C:12]1[CH2:14][CH:7]2[N:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:10]([CH2:9][CH2:8]2)[CH2:11]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)N1C2CCC1CC(=O)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N1C2CCC1CC(=COC)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-carbethoxy-4-tropinone (1-1) (8.00 g, 40.6 mmol, Acros) and (methoxymethyl)tripheylphosphonium chloride (16.7 g, 48.7 mmol) in THF was added sodium bis(trimethylsilyl)amide (48.7 mL, 48.7 mmol, 1.0 N in THF) at 0° C. After stirring at room temperature overnight, the solvent was removed by rotary evaporation. The mixture was quenched with a saturated aqueous solution of NH4Cl, extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give a crude residue. Purification of the crude residue by flash chromatography over silica gel (gradient elution; 0%-20% ethyl acetate/hexanes as eluent) afforded (1-2) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]([OH:10])=[CH:8][CH:7]=[N:6]1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[C:26]([C:27]2[CH2:31][CH2:30][O:29][N:28]=2)=[C:25]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>COCCOC>[Cl:17][C:18]1[C:26]([C:27]2[CH2:31][CH2:30][O:29][N:28]=2)=[C:25]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:24]=[CH:23][C:19]=1[C:20]([C:8]1[CH:7]=[N:6][N:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[C:9]=1[OH:10])=[O:21]
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c(Cl)c1C1=NOCC1
Reactant: CC(C)(C)n1nccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)n1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C3=NOCC3)c2Cl)c1O
Reaction time: 8 h

Procedure:
2.32 g (0.02 mol) of 1-(1,1-dimethyl-1-ethyl)-5-hydroxy-1H-pyrazole and 2.3 g (0.02 mol) of potassium carbonate were added to a solution of 5.4 g (0.02 mol) of 2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl chloride in 100 ml of ethylene glycol dimethyl ether, and the mixture was stirred overnight. The mixture was subsequently refluxed for 3 hours, the solvent was distilled off, the residue was taken up in 300 ml of water and washed with methylene chloride and the aqueous phase was acidified to pH=3 using 10% strength hydrochloric acid. The precipitate was filtered off with suction and dried at 400° C. This gave 4.6 g (65% of theory) of 4-[2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl]-5-hydroxy-1-(1,1-dimethyl-1-ethyl)-1H-pyrazole].
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[ClH:23]>O1CCOCC1>[ClH:23].[CH2:21]([O:20][C:18]([C:5]1([CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C1(CC2CC2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1(CC2CC2)CCNCC1
Temperature: 25 °C

Procedure:
A mixture of 0.5 g (1.6 mmol) 1-tert-butyl 4-ethyl 4-(cyclopropylmethyl)piperidine-1,4-dicarboxylate (commercially available) in 20 mL dioxane was treated with 4 mL 4N HCl in dioxane and stirred at room temperature over night. The mixture was evaporated to dryness and used without further purification in the consecutive step.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:7][CH:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:5][CH2:4]1.[Si]([Cl:33])(C)(C)C>C(OCC)(=O)C>[ClH:33].[CH3:28][N:2]([CH3:1])[C:3]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:8][CH2:7][CH:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(c2[nH]c3ccccc3c2CCCO)CC1
Solvent: CCOC(C)=O
Product: Cl
Reaction time: 1 h

Procedure:
3-(2-(4-(Dimethylamino)-4-phenylcyclohexyl)-1H-indol-3-yl)propan-1-ol (polar diastereomer) (130 mg, 0.35 mmol) was dissolved in ethyl acetate (15 ml). Me3SiCl (88 μl, 0.7 mmol) was then added dropwise at RT and the mixture was stirred for 1 h. A white precipitate precipitated out. The precipitate was filtered off with suction, washed with ethyl acetate (2×5 ml) and then dried. Example 183 (125 mg, m.p. 210-214° C., 87%, NMR purity <95%) was a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([O:24]CC)=[O:23])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Na+].[Cl-]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCCC3c3cncc(F)c3)nc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1cnn2ccc(N3CCCC3c3cncc(F)c3)nc12
Reaction time: 120 h
Yield: 98.5 %

Procedure:
Ethyl 5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.540 g, 1.52 mmol) was dissolved in MeOH (20 mL) and treated with 1N NaOH (13 mL). After stirring for 5 days, citric acid (solid) was added to acidify the mixture to pH 4-5. Saturated aqueous NaCl (10 mL) was added and the reaction mixture extracted with DCM and EtOAc. The combined organic layers were combined to afford 5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.49 g, 99% yield). MS (apci) m/z=328.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-:16])=[O:15])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.Br[CH2:26][C:27]1[CH:31]=[CH:30][S:29][CH:28]=1>>[CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[CH:3]=1
Reactant: BrCc1ccsc1
Reactant: COC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1=O
Product: COC(=O)Cn1c(C)cc(Cc2ccsc2)c([N+](=O)[O-])c1=O
Yield: 81 %

Procedure:
This compound is prepared from 5 g (13.4 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-[[(trifluoromethyl)sulphonyl]oxy]-1,2-dihydropyridine-1-acetate and 2.9 g (16.4 mmol) of 3-bromomethyl-thiophene according to the method described in 1.5. 3.5 g of product are obtained in the form of yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11](=O)[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])([O-])=O>CC(O)=O.[Fe]>[NH:1]1[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:10]=[C:11]1[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CCC(=O)Cc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)CCc1cc2ccccc2[nH]1
Yield: 84.8 %

Procedure:
The mixture of Methyl 5-(2-nitrophenyl)-4-oxopentanoate (4.29 g, 17.08 mmol) and Iron powder (6.0 g, 107 mmol) in AcOH (75 mL) was heated at reflux for 3 h. The crude mixture was concentrated under reduced pressure and diluted with ethyl acetate. The organic solution was washed with NaOH solution, brine, sodium sulfate, filtered, and concentrated. Purification via flash chromatography then afforded the title compound (3.1 g, 14.49 mmol, 85% yield). LCMS: rt=2.86 min, [M+H+]=204.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:4][CH:3]1Cl.[CH2:13]([NH2:16])[CH2:14][NH2:15]>>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2[N:10]=[C:9]([NH:15][CH2:14][CH2:13][NH2:16])[CH:8]=[CH:7][C:6]=2[CH2:11]1
Reactant: CN1c2ncccc2C=CC1Cl
Reactant: NCCN
Product: CN1CCc2nc(NCCN)ccc2C1
Temperature: 138 °C

Procedure:
The product from Step A was dissolved in 10 equiv. of ethylenediamine and heated at 138° C. in a sealed tube for 18 hrs. The excess ethylenediamine was removed by distillation to provide the title compound as a brown oil. MS (M+H)+=207.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][N:6]1[C:11](=[O:12])[C:10]([C:13]([O:15]CC)=[O:14])=[CH:9][N:8]=[CH:7]1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][N:6]1[C:11](=[O:12])[C:10]([C:13]([OH:15])=[O:14])=[CH:9][N:8]=[CH:7]1
Reactant: CCOC(=O)c1cncn(Cc2ccc(F)c(F)c2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cncn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 25 °C

Procedure:
To a solution of ethyl 1-(3,4-difluorobenzyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (470 mg, 1.597 mmol) in methanol (3195 μl) at 0° C., aqueous sodium hydroxide (1917 μl, 1.917 mmol, 1M) was added dropwise. After warming to room temperature over 2 h, the reaction mixture was concentrated under reduced pressure. To the residue, water (5 mL) and ethyl acetate (2.5 mL) were added. The aqueous layer was washed with ethyl acetate and then acidified to pH 1 with aqueous hydrochloric acid (1M). The aqueous layer was then extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford 1-(3,4-difluorobenzyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid as a white solid. LRMS (ESI) calc'd for (C12H9F2N2O3) [M+H]+, 267.1; found 267.0.