Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][CH:66]([CH2:72][C:73]([F:76])([F:75])[F:74])[C:67](=[O:71])[C:68]([NH2:70])=[O:69])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29]C(C)(C)C)=[O:23])[CH2:14][C:15](=[O:21])[O:16]C(C)(C)C)=[O:11])=[O:7])(C)(C)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][CH:66]([CH2:72][C:73]([F:74])([F:76])[F:75])[C:67](=[O:71])[C:68]([NH2:70])=[O:69])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:52])([CH3:54])[CH3:53])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:29])[OH:34])=[O:23])[CH2:14][C:15](=[O:16])[OH:21])=[O:11])([OH:7])=[O:5]
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(F)(F)F)C(=O)C(N)=O)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(F)(F)F)C(=O)C(N)=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
80 mg (0.074 mmol) of 3(RS)-[[N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-αaspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-5,5,5-trifluoro-2-oxovaleramide were dissolved in 3 ml of trifluoroacetic acid and the solution was stirred at room temperature for 30 minutes. The solution was then diluted with 10 ml of toluene and the solvent was removed by evaporation. The residue was purified by reverse-phase high-pressure liquid chromatography on a Dynamax C18 column (5 micron, 300A, 21.4×50 mm). The elution gradient comprised 90% SSA 10% SSB to 95% SSB 5% SSA over 8.5 minutes (SSA is 0.1% trifluoroacetic acid in water; SSB is 0.1% trifluoroacetic acid in 70% acetonitrile and 30% water). After lyophilization overnight there were obtained 12 mg of 3(R or S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-5,5,5-trifluoro-2-oxo-valeramide (diastereoisomer A); MS: m/e 916.3 [M+H]+, which was eluted first, and 8 mg of 3(R or S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-5,5,5-trifluoro-2-oxo-valeramide (diastereoisomer B); MS: m/e 916.2 [M+H]+, which was eluted subsequently.
Reaction SMILES: [NH:1]([C:5]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:21])[NH:10]2)[C:2]([CH3:4])=[O:3].[N+](C1C(OCCCCBr)=CC=C2C=1C=CC(=O)N2)([O-])=O.C(OC(=O)C)(=O)C.[C:49]1([SH:55])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(O)(=O)C.[Zn]>[NH:1]([C:5]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:55][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:21])[NH:10]2)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1c(OCCCCBr)ccc2[nH]c(=O)ccc12
Reactant: Sc1ccccc1
Agent: O=c1ccc2c([N+](=O)[O-])c(OCCCCBr)ccc2[nH]1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(OCCCCSc2ccccc2)ccc2[nH]c(=O)ccc12

Procedure:
Prepared analogous to Example 122 from 5-acetamino-6-(4-bromo-butoxy)-carbostyril [prepared by reduction with zinc in acetic acid of 5-nitro-6-(4-bromo-butoxy)-carbostyril in the presence of acetic acid anhydride] and thiophenol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5](=[O:22])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2/[CH:19]=[CH:20]/[CH3:21])[CH:7]=[CH:8][CH:9]=1.[H][H]>C1COCC1.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([N:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][CH2:2][OH:1])[C:5]2=[O:22])=[C:11]([CH2:19][CH2:20][CH3:21])[CH:12]=1
Reactant: [H][H]
Reactant: C/C=C/c1cc([N+](=O)[O-])ccc1-n1cccc(CCO)c1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1cc(N)ccc1-n1cccc(CCO)c1=O

Procedure:
520 mg (1.73 mmol) of the compound from Example 46A are dissolved in 10 ml of THF. 30 mg of palladium on carbon are added, and the mixture is hydrogenated at RT in a hydrogen atmosphere under atmospheric pressure. The mixture is then filtered through kieselguhr, the filter cake is washed three times with THF and the filtrate is freed from the solvent. The reaction product is reacted further without further purification. This gives 471 mg (89% of theory) of the desired product.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+]([C:18]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])([O-])=O.Cl>CN(C)C=O>[CH2:1]([S:8][C:18]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccc([N+](=O)[O-])c1SCc1ccccc1
Temperature: 0 °C

Procedure:
6.85 g (0.055 mol) of benzyl mercaptan are dissolved in 150 ml of dimethylformamide. The batch is then cooled to 0° C. and 15.2 g (0.11 mol) of potassium carbonate are added. 10.6 g (0.050 mol) of 2,3-dinitrobenzoic acid are then added in portions at from 0° to 5° C. and the internal temperature is afterwards raised to room temperature over a period of 24 hours. The reaction mixture is then poured onto ice/water and acidified with hydrochloric acid. The resulting product is filtered, washed with water and dried. Yield: 11.8 g (82% of the theoretical yield); m.p. 152°-153° C.
Reaction SMILES: [CH2:1]([NH:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[C:15]([OH:17])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]([CH3:9])[C:15]([C@H:11]1[CH2:12][CH2:13][CH2:14][O:10]1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1CCCO1
Reactant: CNCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)C(=O)[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
25.30 g of N-benzyl-N-methylamine are added to a solution of 20.00 ml of (R)-tetrahydrofuran-2-carboxylic acid in 200 ml tetrahydrofuran. Then a total of 67.10 g of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate are added batchwise while cooling with an ice bath and the reaction mixture is then stirred for about 48 hours at ambient temperature. The precipitate formed is suction filtered, the filtrate is evaporated, mixed with water and filtered again. The filtrate obtained is made alkaline with sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined ethyl acetate extracts are washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and evaporated down. A yellowish oil remains, which is further reacted without any further purification. Yield: 24.60 g (54% of theory); mass spectrum (ESI+): m/z=220 [M+H]+; Rf value: 0.62 (silica gel, ethyl acetate).
Reaction SMILES: [O:1]=[C:2]1[N:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C@H:4]2[C:13]3[C:18]([CH2:19][C@@H:3]12)=[CH:17][CH:16]=[CH:15][CH:14]=3.[CH3:20][NH:21][CH3:22].C1COCC1>>[CH3:20][N:21]([CH3:22])[C:2]([C@@H:3]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@@H:4]1[NH:5][C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:1]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2Cc3ccccc3[C@@H]21
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@@H]1Cc2ccccc2[C@@H]1NC(=O)OC(C)(C)C
Yield: 91 %

Procedure:
To tert-butyl rel-(2aR,7bR)-2-oxo-2,2a,3,7b-tetrahydro-1H-indeno[1,2-b]azete-1-carboxylate (200 mg, 0.77 mmol) was added 2.00 M dimethylamine in THF (1.90 mL, 3.80 mmol) in the sealed tube, and the mixture was microwaved at 120° C. for 30 minutes. The reaction mixture was concentrated under vacuum, and then the residue was washed with small amount of hexane to give the title compound (226 mg, 91%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH:9]([CH3:22])[C:10]([CH:12]1C(=O)OC(C)(C)[O:14][C:13]1=O)=[O:11])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C>[CH3:22][CH:9]1[CH2:8][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:23])[C:13](=[O:14])[CH2:12][C:10]1=[O:11]
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)C1C(=O)OC(C)(C)OC1=O
Solvent: CCOC(C)=O
Product: CC1CN(C(=O)OC(C)(C)C)C(=O)CC1=O
Temperature: 77 °C
Reaction time: 3 h

Procedure:
The tert-butyl[3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-methyl-3-oxopropyl]carbamate from Step 1 (5.19 g, 15.76 mmol) was dissolved in ethyl acetate (60.6 ml), heated to reflux (77° C.) and stirred for 3 hrs, then cooled to room temperature. The solvent was evaporated under vacuum to afford the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) 4.29 (dd, J=14.0, 5.0 Hz, 1H), 3.53 (m, 3H), 2.59 (m, 114), 1.56 (s, 9H), 1.20 (d, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:6]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:5]=[CH:4][CH:3]=1.I[CH2:29][CH2:30][OH:31].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:6]([N:16]([CH2:29][CH2:30][OH:31])[S:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cccc(F)c2/C=C/c2ccncc2)cc1
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(CCO)c2cccc(F)c2/C=C/c2ccncc2)cc1
Yield: 21.5 %

Procedure:
In tetrahydrofuran was dissolved 1.92 g of the compound obtained in Example 43, followed by addition of 1.72 g of 2-iodoethanol and 0.69 g of potassium carbonate. The mixture was refluxed overnight and after-treated to give crystals. This crystal crop was recrystallized from ethanol to provide 0.46 g of the title compound,(light yellow needles). m.p. 152-153° C.
Reaction SMILES: [CH2:1]([C:3]1([NH2:9])[CH2:8][O:7][CH2:6][O:5][CH2:4]1)[CH3:2].[OH-].[Na+].O.[Cl:13][CH2:14][C:15](Cl)=[O:16]>C(Cl)Cl>[Cl:13][CH2:14][C:15]([NH:9][C:3]1([CH2:1][CH3:2])[CH2:8][O:7][CH2:6][O:5][CH2:4]1)=[O:16]
Reactant: CCC1(N)COCOC1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCC1(NC(=O)CCl)COCOC1

Procedure:
Five and two-tenths g (0.04 mole) of 5-ethyl-5-amino-1,3-dioxane, 3.2 g (0.04 mole) of 50% sodium hydroxide, 10 ml of water, and 90 ml of methylene chloride were combined in a reaction flask. The mixture was cooled to below 35° C. Four and one-half g of chloroacetylchloride were added dropwise. The reaction mixture was stirred for one-half hour, washed with water and dried over magnesium sulfate. The solvent was vacuum stripped. Yield was 5.8 g of 5-chloroacetylamino-5-ethyl-1,3-dioxane. m.p.=89°-95° C. Structure was confirmed by NMR.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.CCN(CC)CC.Cl.[F:18][CH2:19][CH2:20][NH:21][CH3:22]>CN(C=O)C>[F:18][CH2:19][CH2:20][N:21]([CH3:22])[C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9]
Reactant: Cn1cc(C(=O)O)cn1
Reactant: CNCCF
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(CCF)C(=O)c1cnn(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl-1H-pyrazole-4-carboxylic acid (1.0 g, 7.93 mmol) was combined with DMF (10.0 ml) to give a colorless solution. Et3N (3.3 ml, 23.8 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (TBTU, 2.8 g, 8.72 mmol) were added and the reaction mixture was stirred at RT for 1 h. 2-Fluoroethyl-methylamine hydrochloride (991 mg, 8.72 mmol) was added and stirring was continued overnight. DMF was removed under HV and the crude product (5.93 g brown oil) was purified by chromatography with a 50 g SiO2—NH2 cartridge (CH2Cl2/MeOH 95:5). The resulting product was dried under HV at RT for 48 h. Yellow oil (1.40 g, 92%); MS: m/z=186.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19]([F:22])([F:21])[F:20])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH:8]=1)[NH2:7].Cl.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.[Zn]>[Cl:1][C:2]1[CH:8]=[C:6]([NH2:7])[C:5]([NH2:9])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:19]([F:21])([F:22])[F:20]
Reactant: Nc1cc(Cl)c(-c2ccc(Cl)cc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c(-c2ccc(Cl)cc2C(F)(F)F)cc1N
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-4-iodo-2-nitroaniline (2 g, 6.70 mmol) in dioxane (100 ml) and water (10 ml) which maintained with an inert atmosphere of nitrogen was added [4-chloro-2-(trifluoromethyl)phenyl]boronic acid (1.8 g, 8.02 mmol), K3PO4 (2.6 g, 12.24 mmol), Pd(PPH3)4 (0.78 g, 335.77 mmol) with stirring overnight at 95° C. in an oil bath. The resulting mixture was concentrated under vacuum to give a residue which was purified by a silica gel column, eluting with 2% to 3% acetate in petroleum ether to produce 5-chloro-4-[4-chloro-2-(trifluoromethyl)phenyl]-2-nitroaniline as a yellow solid (800 mg, 34%). Next, to a solution of 5-chloro-4-[4-chloro-2-(trifluoromethyl)phenyl]-2-nitroaniline (1.6 g, 4.56 mmol) in ethanol (50 ml) was added Zn powder (1.8 g, 27.69 mmol), hydrogen chloride (2 ml) with stirring for 2 h at 85° C. in an oil bath. The solution was poured into water (300 ml), adjusted to pH 8 with saturated aqueous sodium carbonate and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluting with 5% to 20% ethyl acetate in petroleum to produce 4-chloro-5-[4-chloro-2-(trifluoromethyl)phenyl]benzene-1,2-diamine as a crude red solid (560 mg, 76%). Finally, the solution of 4-chloro-5-[4-chloro-2-(trifluoromethyl)phenyl]benzene-1,2-diamine (100 mg, 0.31 mmol) in trifluoroacetic acid (5 m 1) and hydrogen chloride (1 ml) was stirred overnight at 80° C. in an oil bath. The mixture was quenched with water (100 ml), adjusted to pH 8 with saturated aqueous sodium carbonate solution and extracted with ethyl acetate (50 ml×3). The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to afford 5-chloro-6-[4-chloro-2-(trifluoromethyl)phenyl]-2-(trifluoro methyl)-1H-1,3-benzodiazole as a white solid (101.7 mg, 82%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][N:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC([N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1)=O)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>COCCOC.O.CCO>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:30]3[CH:31]=[N:27][NH:28][CH:29]=3)=[CH:14][N:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)cn2)CCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3cn[nH]c3)cn2)CCC1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 103.4 %

Procedure:
To a mixture of [1-(5-iodo-pyridin-2-yl)-cyclobutyl]-carbamic acid tert-butyl ester (0.46 g, 1.23 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (0.4 g, 1.35 mmol), and PdCl2(dppf)Cl2.dichloromethane complex (0.2 g, 0.25 mmol) in DME/H2O/EtOH (4 mL, 7:3:2) in a sealable microwave tube was added 1M K3PO4 (1.5 mL, 1.5 mmol). The tube was sealed and heated in microwave at 100° C. for 10 minutes and then 120° C. for 20 minutes. 2M NaOH was added (2 mL) and stirred for 10 minutes. The solution was extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over MgSO4, filtered through diatomaceous earth, and concentrated. The crude oil was purified via normal phase flash chromatography on silica gel eluting with 0-6% MeOH/CH2Cl2, to afford {1-[5-(1H-pyrazol-4-yl)-pyridin-2-yl]-cyclobutyl}-carbamic acid tert-butyl ester (0.40 g) as a brown solid, m/z 315.5 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:11]2[C:12](=O)[NH:13][CH2:14][CH2:15][CH2:16][C:10]=2[NH:9][CH:8]=1)=[O:6])[CH2:2][CH3:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1>[CH2:1]([O:4][C:5]([C:7]1[C:11]2[C:12](=[S:19])[NH:13][CH2:14][CH2:15][CH2:16][C:10]=2[NH:9][CH:8]=1)=[O:6])[CH2:2][CH3:3]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCOC(=O)c1c[nH]c2c1C(=O)NCCC2
Solvent: c1ccncc1
Product: CCCOC(=O)c1c[nH]c2c1C(=S)NCCC2
Temperature: 80 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
A mixture of compound (500 mg) from Step 1 and P4S10(2.0 g) in 20 mL of pyridine is heated at 80° C. with stirring overnight. It is cooled and evaporated under vacuum, then diluted with water and stirred. The insoluble material is filtered and the mother liquid is extracted with CH2Cl2/EtOAc (1:4). The combined extract is washed with brine, dried and concentrated to give 120 mg of 4-thioxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-3-carboxylic acid propyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:4]2[CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20].C(N(CC)C(C)C)(C)C>C(O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH:20][C:2]1[CH:3]=[CH:4][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:6]2[N:7]=1
Reactant: NCc1cccc(F)c1
Reactant: COC(=O)c1cnn2cnc(Cl)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)c1cnn2ccc(NCc3cccc(F)c3)nc12
Yield: 80 %

Procedure:
A solution of methyl 5-chloropyrazolo[1,5-c]pyrimidine-3-carboxylate (240 mg, 1.1 mM, 1.0 equiv), 3-fluorobenzylamine (200 uL, 2.0 mM, 2.0 equiv), 30 mL of ethanol and 400 uL of N,N-diisopropylethylamine (2.0 mM, 2 equiv) were combined and heated under reflux for 4 hours. The mixture was concentrated and the product collected by filtration and washed with cold ethanol to give 271 mg (80%) of methyl 5-(3-fluorobenzylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate LCMS (ESI) m+H=301.2, 1H NMR (400 MHz, DMSO-d6) δ: 8.56 (d, 1H), 8.41 (m 1H), 8.17 (s, 1H), 7.35 (m, 3H), 7.08 (td, 1H), 6.44 (d, 1H), 4.61 (d, 2H), 3.74 (s, 3H).
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:35])=[C:18]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[N:31][CH:32]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1>C(Cl)Cl>[Cl:15][C:16]1[C:17]([CH3:35])=[C:18]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[N:31][CH:32]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1-c1ccc(C#N)nc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccc(C#N)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of cyanuric chloride (170 mg, 0.94 mmol) and N,N-dimethylformamide (73 μL, 0.94 mmol) was stirred at room temperature for 10 minutes and then a solution of 5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile (190 mg, 0.628 mmol) in methylene chloride (4 mL) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, then filtered and concentrated. The resultant crude product was used directly in the next step without further purification (110 mg, 55%). LCMS calculated for C16H15Cl2N2O (M+H)+: m/z=321.0; Found: 321.0
Reaction SMILES: C[O:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)=O)=O.[H-].C([Al+]CC(C)C)C(C)C.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:23]1([CH2:22][N:19]2[CH2:18][CH2:17][CH:16]([N:15]3[CH2:13][CH2:12][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[NH:5][C:3]3=[O:2])[CH2:21][CH2:20]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)Nc1ccccc1CC(=O)NC1CCN(Cc2ccccc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=C1Nc2ccccc2CCN1C1CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
5.00 g (13.11 mmol, 1.0 eq) 2-methoxycarbonylamino-N-[1-(phenylmethyl)-4-piperidinyl]-phenylacetamide from Example 3 are suspended in 50 ml of toluene and heated to 80° C. At this temperature 56.1 g (78.61 mmol, 6.0 eq) diisobutylaluminium hydride in toluene (20%) are metered in. After the addition has ended the reaction mixture is stirred for another 30 minutes at this temperature. After cooling to 10° C. the mixture is adjusted to pH=2.5 with hydrochloric acid. The precipitate formed is dissolved with sodium hydroxide solution and after phase separation the organic phase is washed with 50 ml of water. The organic phase is evaporated down in vacuo to an oil and combined with 50 ml of methanol.
Reaction SMILES: [C:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([P:29](=[O:40])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([F:28])[F:27])=[CH:22][CH:21]=1>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[C:36]([O:35][P:29]([C:26]([F:28])([F:27])[C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:2]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([P:29]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:40])([F:28])[F:27])=[CH:22][CH:21]=2)([C:3]([O:5][CH3:6])=[O:4])[C:1]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])=[CH:21][CH:22]=1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:40])([CH3:37])([CH3:38])[CH3:39]
Reactant: COC(=O)CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)(Cc1ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of benzyl methyl malonate (0.2 g) in DMF (8 mL), was added sequentially NaH (0.08 g, 60% in mineral oil), di(tert-butyl) [[4-(bromomethyl)phenyl](difluoro)methyl]phosphonate (0.83 g), and n-Bu4NI (0.08 g). The reaction mixture was stirred at room temperature for 2.5 h, then quenched with 20 mL of saturated aqueous NH4Cl solution and extracted with 50 mL of 1:1 hexane/EtOAc. The extract was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 2:1 hexane/EtOAc. First eluted was 1-benzyl 3-methyl 2-{4-[(di-tert-butoxyphosphoryl)(difluoro)methyl]benzyl}malonate (0.2 g), followed by the title compound (0.3 g) as an oil.