Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].[CH2:25]([C:27]1[CH:28]=[N:29][C:30](Cl)=[N:31][CH:32]=1)[CH3:26].CCN(C(C)C)C(C)C>C(O)(C)C>[CH2:25]([C:27]1[CH:28]=[N:29][C:30]([NH:1][CH2:2][C@H:3]2[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[N:13]=[C:14]([CH3:24])[S:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:11])=[N:31][CH:32]=1)[CH3:26]
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Reactant: CCc1cnc(Cl)nc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(NC[C@H]2[C@@H](C)CCCN2C(=O)c2nc(C)sc2-c2ccc(F)cc2)nc1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A mixture of rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 5-ethyl-2-chloropyrimidine, and DIPEA in isopropanol was stirred at 110° C. for 18 h. The reaction was cooled and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 454.02 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:15][C:14]([OH:16])=[C:13]([CH2:17][C:18]3[N:28]=[C:21]4[N:22]=[C:23](C)[CH:24]=[C:25](C)[N:20]4[N:19]=3)[C:12](=[O:29])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:35]1([C:38]#[N:39])[CH2:37][CH2:36]1.[Cl:40]C1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C(CC)C=1OC.CC1C=NC2N(N=C(C=O)N=2)C=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:15][C:14]([OH:16])=[C:13]([CH2:17][C:18]3[N:28]=[C:21]4[N:22]=[CH:23][C:24]([Cl:40])=[CH:25][N:20]4[N:19]=3)[C:12](=[O:29])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:35]1([C:38]#[N:39])[CH2:36][CH2:37]1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OC
Reactant: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(C5(C#N)CC5)c(Cl)c4)(C4CCCC4)OC3=O)nc2n1
Agent: Cc1cnc2nc(C=O)nn2c1
Product: N#CC1(c2ccc(CCC3(C4CCCC4)CC(O)=C(Cc4nc5ncc(Cl)cn5n4)C(=O)O3)cc2Cl)CC1

Procedure:
The title compound was prepared analogously to Example B(97), 1-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrile was substituted in place of 6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione in that example and 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in place of the 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in that example. 1H NMR (400 MHz, CDCl3) δ: 1.16-1.18 (m, 2H), 1.19-1.5 (m, 8H), 1.51-1.53 (m, 2H), 1.86-1.89 (m, 2H)), 2.16-2.29 (m, 1H), 2.35-2.47 (m, 3H), 2.59 (d, J=17 Hz, 1H), 3.56 (d, J=16 Hz, 1H), 3.65 (d, J=16 Hz, 1H), 7.08 (d, J=7.8, 1 Hz, 1H), 7.20-7.23 (m, 2H), 8.70 (d, J=2.5 Hz, 1H), 9.41 (d, J=2.5, 1.1 Hz, 1H), 10.7 (s, 1H). C28H27Cl2N5O3.0.25: C, 60.38; H, 4.98; N, 12.57. Found: C, 60.30; H, 4.80; N, 12.53. MS (ESI): 552.2(M+H+).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]([CH2:24][CH2:25][CH3:26])[C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]3[C:21](O)=[O:22])=[O:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)([Cl:29])=O>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]([CH2:24][CH2:25][CH3:26])[C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]3[C:21]([Cl:29])=[O:22])=[O:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCN(C(=O)C1CCCCC1C(=O)O)c1ccc(-n2ccnc2)cc1
Reactant: O=S(Cl)Cl
Product: CCCN(C(=O)C1CCCCC1C(=O)Cl)c1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Preparation 15, react 2-[[[4-(1H-imidazol-1-yl)phenyl](propyl)amino]carbonyl]cyclohexanecarboxylic acid with thionyl chloride to obtain the title compound.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[OH-].[NH4+:15]>C(O)(C)C>[NH2:15][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1
Reactant: [NH4+]
Reactant: N#Cc1ccc(OCC2CO2)cc1
Agent: [OH-]
Solvent: CC(C)O
Product: N#Cc1ccc(OCC(O)CN)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46 %

Procedure:
4-(Oxiranylmethoxy)benzonitrile (from step (i) above; 100 g, 0.57 mol) was added to a mixture of concentrated aqueous ammonium hydroxide (500 mL) and iso-propanol (300 mL). The resulting slurry was stirred at room temperature for 3 days. The reaction mixture was filtered to remove the insoluble by-product, and the filtrate was concentrated in vacuo to give a crude product, which was crystallised from acetonitrile to yield 50 g (46%) of the sub-title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:11][S:12]([OH:15])(=O)=[O:13]>S(=O)(=O)(O)N>[C:9]1([S:12]([Cl:11])(=[O:15])=[O:13])[C:10]2[CH:1]=[CH:2][CH:3]=[C:4]([S:12]([Cl:11])(=[O:15])=[O:13])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc2ccccc2c1
Agent: NS(=O)(=O)O
Product: O=S(=O)(Cl)c1cccc2c(S(=O)(=O)Cl)cccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.8 %

Procedure:
64.1 g (0.5 mol) of naphthalene are introduced with ice cooling into 640.7 g (5.5 mol) of chlorosulfonic acid, to which 1 g of sulfamic acid has been added. The mixture is then stirred at room temperature for 4 hours. The reaction mixture is added dropwise to ice water, and the precipitated crystals are filtered off with suction and washed with water. 172.1 g of naphthalene-1,5-disulfonyl chloride having a water content of 26.5% and a chloride content of 71.6%, corresponding to 123.2 g (75.7%), are obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[S:19][CH2:20][C:21]#[N:22]>C1COCC1>[C:21]([CH2:20][S:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:1](=[O:3])[CH3:2])#[N:22]
Reactant: CC(=O)Cl
Reactant: N#CCSc1cc(F)ccc1N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(F)cc1SCC#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (1.9 ml) in THF (10 ml) and subsequently pyridine (2.15 ml) in THF (10 ml) was added to a stirred solution of (2-amino-5-fluoro-phenylsulfanyl)acetonitrile (4.39 g) in THF (40 ml) at 0° C. The mixture was stirred at 0° C. for 1 h. Then the solvent was removed in vacuo and the residue was triturated with water (100 ml). The precipitate was filtered off and dried. Crude yield 4.45 g (82%); mp 97-100° C. The title compound could be further purified by recrystallization from 96% ethanol; mp 100.5-101.5° C.; 1H-NMR (DMSO-d6), δ (ppm): 9.68 (s, 1H, NH), 7.50-7.30 (m, 2H, Ar—H), 7.23-7.07 (m, 1H, Ar—H), 4.26 (s, 2H, CH2), 2.05 (s, 3H, CH3); IR (KBr) ν (cm−1): 3239 (NH), 2244 (C≡N), 1641 and 1579 (amide).
Reaction SMILES: [CH:1]([Cl:4])(Cl)Cl.[CH2:5]=[C:6]1[C@H:12]([CH3:13])[O:11]C(O)[CH2:8][C@@H:7]1[NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH2:5]=[C:6]1[C@H:12]([CH3:13])[O:11][CH:1]([Cl:4])[CH2:8][C@@H:7]1[NH:14][C:15](=[O:20])[C:16]([F:18])([F:19])[F:17]
Reactant: ClC(Cl)Cl
Reactant: C=C1[C@@H](NC(=O)C(F)(F)F)CC(O)O[C@H]1C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C=C1[C@@H](NC(=O)C(F)(F)F)CC(Cl)O[C@H]1C
Reaction time: 8 h
Yield: 90 %

Procedure:
A solution of 0.51 g (2 mmol) of the intermediate VIII in 10 ml of acetic acid and 40 ml of water was heated at 100° C. for two hours, then evaporated to dryness to give 2,3,4,6-tetradeoxy-4-C-methylene-3-trifluoroacetamido-L-threo-hexopyranose (IX, 0.47 g, 99%) as a white solid: m.p. 168°-170° C., [α]D20° -160° (c=0.5, CHCl3). Treatment of IX (0.36 g, 1.5 mmol) in 25 ml of dry methylene dichloride with 4 ml of trifluoroacetic anhydride for 2 hours at 0° C. and 1 hour at 20° C. gave, after evaporation, the 1-0-trifluoroacetate (X), which was directly used for the preparation of the corresponding 1-chloro-derivative by treatment with dry hydrogen chloride in anhydrous diethyl ether at 0° C. After standing at 0° C. overnight, the reaction mixture was evaporated to dryness to give 2,3,4,6-tetradeoxy-4-C-methylene-3-trifluoroacetamido-L-threo-hexopyranosyl chloride (III-A, 0.35 g, 90%), suitable for the subsequent coupling reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=[CH:24]1)=O.CNC>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([N:23]([CH3:24])[CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.018 mole), and 1,1'carbonyldiimidazole (2.9 g, 0.018 mole), in anhydrous tetrahydrofuran (175 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 4 hours. The nitrogen flow was stopped and a solution of dimethylamine in tetrahydrofuran (72 ml of 0.5M) was added. The solution was stirred at room temperature under nitrogen for 1/2 hour. The reaction mixture was filtered, concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake was recrystallized from tetrahydrofuran-isopropyl ether, giving 4.5 g (70%). Recrystallization from isopropyl alcohol-isopropyl ether gave 4.0 g of cream colored needles, mp 144°-146° C.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[C@H:12]([CH:13]=[O:14])[O:11][C:10]([CH3:16])([CH3:15])[N:9]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH:25]1[CH2:28][CH2:27][CH2:26]1.[Mg].[Cl-].[NH4+]>O1CCCC1>[CH:1]1([CH2:7][C@H:8]2[C@H:12]([C@H:13]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[OH:14])[O:11][C:10]([CH3:16])([CH3:15])[N:9]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](C=O)OC1(C)C
Reactant: BrC1CCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@@H](O)C2CCC2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.8 %

Procedure:
A solution of 7.23 g (22.2 mmol) of t-butyl (4S,5R)-4-(cyclohexylmethyl)-5-formyl-2,2-dimethyl-3-oxazolidinecarboxylate in 150 ml of tetrahydrofuran is added dropwise within 40 minutes at 30° to a solution of the Grignard compound prepared from 15 g (111 mmol) of bromocyclobutane and 2.7 g (111 mgram atom) of magnesium shavings in 150 ml of tetrahydrofuran and the reaction mixture is subsequently stirred at room temperature overnight. Thereafter, the reaction mixture is poured into 300 ml of a saturated ammonium chloride solution and extracted three times with 600 ml of ether each time. The ether extracts are washed with ammonium chloride solution, dried, filtered and evaporated. The crude product (9.34 g) is chromatographed on 500 g of silica gel with a 92.5:7.5 mixture of toluene and ethyl acetate as the eluting agent, whereby there are obtained 2.44 g of t-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(S)-cyclobutylhydroxymethyl]-2,2-dimethyl-3-oxazolidinecarboxylate as an oil; MS: 381 (M)+, and 2.9 g of the epimeric compound t-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(R)-cyclobutylhydroxymethyl]-2,2-dimethyl-3-oxazolidinecarboxylate, likewise as an oil, MS: 381 (M)+.
Reaction SMILES: C([Mg]Br)C.[CH:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:15][O:16][CH:17](OC)[O:18][CH3:19]>C(OCC)C>[CH3:15][O:16][CH:17]([O:18][CH3:19])[C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C#CCCCCCCCC
Reactant: COC(OC)OC
Agent: CC[Mg]Br
Solvent: CCOCC
Product: CCCCCCCCC#CC(OC)OC

Procedure:
To freshly prepared ethyl magnesium bromide (from 61 mmoles bromoethane and 63 mmoles magnesium) was added 1-decyne (50 mmoles) in diethyl ether (10 ml) dropwise at ambient temperature. The reaction mixture was then heated at reflux for 2 hours. After cooling the reaction mixture, trimethylorthoformate (75 mmoles) in diethyl ether (10 ml) was added and the resultant mixture heated to distill off the diethyl ether. The resultant paste was taken up in anhydrous toluene (50 ml) and heated at reflux for 1 hour. The reaction mixture was poured into saturated ammonium chloride (50 ml) and then extracted with diethyl ether (3×50 ml). The organic phase was washed with water (3×20 ml) and dried over anhydrous magnesium sulfate. Evaporation of the organic phase afforded the desired product as an oil.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.N([O-])=O.[Na+].[ClH:18]>C(O)(=O)C.O>[Cl:18][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cl
Reactant: CCOc1ccc2nc(N)sc2c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOc1ccc2nc(Cl)sc2c1
Temperature: 30 °C
Reaction time: 0.33 h
Yield: 61.7 %

Procedure:
20 g (0.103 mol) of 2-amino-6-ethoxy-benzothiazole are dissolved in 100 ml of glacial acetic acid and 52 ml of concentrated hydrochloric acid and whilst cooling with ice the mixture is diazotised with 7.4 g (0.108 mol) of sodium nitrite in 15 ml of water. Then the solution of the diazonium salt is added batchwise to a suspension of 13.6 g (0.137 mol) of copper-I-chloride in 65 ml of concentrated hydrochloric acid and stirred for 20 minutes at 30° C. Then the mixture is diluted with 800 ml of ice water and the crystals formed are suction filtered. To purify them they are chromatographed on silica gel (eluant: petroleum ether/ethyl acetate=6:1). Yield: 61.7% of theory, Melting point: 60-61° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[C:20]1([C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[OH:23])[OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:14]1([CH2:13][CH2:12][CH2:11][CH2:10][O:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][O:21][C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[OH:23])=[CH:4][CH:5]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccc(OCCCCc2ccccc2)cc1
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccccc1OCc1ccc(OCCCCc2ccccc2)cc1
Yield: 48.5 %

Procedure:
In 1.5 ml of N,N-dimethylformamide were stirred 390 mg of 4-chloromethyl-1-(4-phenylbutoxy)benzene, 180 mg of catechol and 270 mg of potassium carbonate at room temperature overnight. The reaction mixture was dispersed in water and ethyl acetate and the dispersion was separated. The ethyl acetate layer washed subsequently with water and an aqueous saline solution, dried and concentrated. The obtained residue was applied to silica gel column chromatography and eluted with toluene to obtain 240 mg of o-[p-(4-phenylbutoxy)benzyloxy]phenol.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]([NH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH2:17])=[O:13].C(N(CC)CC)C>ClCCl>[CH3:10][O:11][C:12]([NH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH:17][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: COC(=O)NC(CN)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC(CNC(=O)c1ccccc1)c1ccccc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
0.22 g of benzoyl chloride was added to 10 ml of a solution of 0.25 g of N-(methoxycarbonyl)-1-phenylethylenediamine and 0.2 g of triethylamine in dichloromethane under ice cooling, and the mixture was stirred for 30 minutes at 5° C. and at room temperature for 3 hours. The reaction mixture was rinsed with water, the organic layer was dried over magnesium sulfate anhydrous, and the residual oily material obtained under a reduced pressure was purified by column chromatography on silica gel (2:1 hexane/ethyl acetate) to obtain 0.28 g of the title compound as colorless crystals.
Reaction SMILES: Cl[CH:2]([Cl:4])[CH3:3].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[S:16]1C2C(=O)[CH:22]=[CH:21][NH:20][C:19]=2[CH:18]=[CH:17]1>ClCCl>[Cl:4][C:2]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:18]=[CH:17][S:16][C:3]=12
Reactant: CC(Cl)Cl
Reactant: O=c1cc[nH]c2ccsc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1ccnc2ccsc12

Procedure:
30 ml of dichloromethane and 20 ml of dichloroethane in 250 ml round bottom flask were added with dimethylformamide (1.8 ml, 23.28 mmol) and oxalylchloride (2.9 ml, 33.86 mmol) was slowly dropped to the mixture at 0° C. After 4H-thieno[3,2-b]pyridine-7-one (1.6 g, 10.58 mmol) was added, the mixture was refluxed for 6 hours. After lowering the temperature to room temperature, the title compound of yellowish solid (1.7 g, 90%) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH2:15]([N:21]=[C:22]=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>C(Cl)Cl>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[O:1][C:22](=[O:23])[NH:21][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Oc1ccc2oc3ccccc3c2c1
Reactant: CCCCCCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)Oc1ccc2oc3ccccc3c2c1
Yield: 105.7 %

Procedure:
A solution of 2-hydroxydibenzofuran (5.0 g, 27 mmol), hexyl isocyanate (4.1 g, 32 mmol) and triethylamine (3.0 mL, 22 mmol) in 75 mL of methylene chloride was stirred under nitrogen at room temperature overnight. The reaction was extracted with 1N HCl. The organic solution was dried (MgSO4) and the solvent removed under reduced pressure to give 8.89 g of an off-white solid. Recrystallization of the solid from isopropanol gave 5.48 g (65%) of the title compound as an off-white crystalline solid, mp 109°-110° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13][C@H:14]([C:19]([NH:21][CH2:22][C:23]#[N:24])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.BrC1C=C(C(N[C@H:38]([C:43]([NH:45][CH2:46][C:47]#N)=O)[CH2:39]C(C)C)C(F)(F)F)C=CC=1>>[C:23]([CH2:22][NH:21][C:19](=[O:20])[C@H:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:13][CH:8]([C:5]1[CH:6]=[CH:7][CH:2]=[C:3]([C:39]2[CH:38]=[CH:43][N:45]=[CH:46][CH:47]=2)[CH:4]=1)[C:9]([F:12])([F:11])[F:10])#[N:24]
Reactant: CC(C)C[C@H](NC(c1ccc(Br)cc1)C(F)(F)F)C(=O)NCC#N
Reactant: CC(C)C[C@H](NC(c1cccc(Br)c1)C(F)(F)F)C(=O)NCC#N
Product: CC(C)C[C@H](NC(c1cccc(-c2ccncc2)c1)C(F)(F)F)C(=O)NCC#N

Procedure:
Using the procedure described for example 8, where N2-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(cyanomethyl)-L-leucinamide was substituted for N2-[1-(3-bromophenyl)-2,2,2-trifluoroethyl]-N-(cyanomethyl)-L-leucinamide, the title compound was obtained as a colorless gum.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[N+:21]([O-])=O)[C:10]([C:29](OCC)=[O:30])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:20][O:19][C:15]1[C:14]2[NH:21][C:29](=[O:30])[C@:10]3([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:9][NH:8][CH2:12][C@@H:11]3[C:13]=2[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CN(Cc2ccccc2)CC1c1cccc(OC)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@@]12CNC[C@@H]1c1cccc(OC)c1NC2=O
Yield: 60.3 %

Procedure:
To a solution of diethyl 1-benzyl-4-(3-methoxy-2-nitrophenyl)pyrrolidine-3,3-dicarboxylate (200 mg, 0.44 mmol) in 20 mL of methanol was added 10% Pd/C catalyst (40 mg, 20% by wt). The mixture was placed on a Parr shaker under 50 psi of hydrogen for 18 h. The reaction was filtered through a pad of Celite and concentrated in vacuo. The residue was purified by flash chromatography (elution with 5% methanol/methylene chloride) to afford 77 mg (60%) of the title compound as a solid. LRMS (ESI): 291.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=1.[Li]CCCC.[C:17](=[O:19])=[O:18]>>[CH:7]1([N:5]2[CH:6]=[C:2]([C:17]([OH:19])=[O:18])[CH:3]=[N:4]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Brc1cnn(C2CCCC2)c1
Reactant: O=C=O
Agent: [Li]CCCC
Product: O=C(O)c1cnn(C2CCCC2)c1
Yield: 47 %

Procedure:
Using the procedure of Example B30, 4-bromo-1-cyclopentyl-1 H-pyrazole (9.0 g, 42 mmol), n-BuLi (2.5 M, 18.5 mL, 46.2 mmol) and CO2 were combined to provide 1-cyclopentyl-1 H-pyrazole-4-carboxylic acid (3.5 g, 47% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.31 (s, 1H), 7.85 (s, 1 H), 4.78 (m, 1 H), 1.70-2.56 (m, 8 H); MS (ESI) m/z: 181.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:14][NH2:15])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])=[O:4].[C:16]([CH2:19][C:20](=O)[CH3:21])(=O)[CH3:17].C(N(CC)CC)C>CO>[N+:11]([C:10]1[CH:9]=[CH:8][C:7]([N:14]2[C:20]([CH3:21])=[CH:19][C:16]([CH3:17])=[N:15]2)=[CH:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4])([O-:13])=[O:12]
Reactant: COC(=O)c1cc(NN)ccc1[N+](=O)[O-]
Reactant: CC(=O)CC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(-n2nc(C)cc2C)ccc1[N+](=O)[O-]

Procedure:
A solution of 2.84 g (10 mmol) of 3-methoxycarbonyl-4-nitro-phenylhydrazine, 1.0 g (10 mmol) of acetylacetone and 3.0 ml of triethylamine in 40 ml of methanol is stirred overnight at ambient temperature. Then it is evaporated to dryness, the residue is dissolved in about 50 ml of dichloromethane, the solution is washed with 5% sodium hydrogen carbonate solution, dried and evaporated down again. The crude product thus obtained is purified by column chromatography over silica gel (eluant: dichloromethane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:12][C:13](=[O:16])[CH2:14]Cl)([CH3:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.CC([O-])(C)C.[K+].CO>CC(O)(CC)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:11])[NH:12][C:13](=[O:16])[CH2:14][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(CO)(NC(=O)CCl)c1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Solvent: CO
Product: CC1(c2cccc(Br)c2)COCC(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of (RS)-N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide (5.36 g, 17 mmol) in 2-methyl-2-butanol (100 ml) was treated in one portion with potassium tert-butylate (6.66 g, 58 mmol). Initially, the temperature rose to 30° C.; the reaction mixture was left to cool to room temperature and stirring was continued for one hour. For the workup, the reaction mixture was treated with methanol (50 ml), then evaporated at reduced pressure. The residue was purified by chromatography on silica gel using a gradient of dichloromethane/methanol=100/0 to 75/25 as the eluent. 4.18 g (88%) of (RS)-5-(3-bromo-phenyl)-5-methyl-morpholin-3-one were obtained as a white solid. Mass (calculated) C11H12BrNO2 [270.128]; (found) [M+H]+=270 and [M+2+H]+=272.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:5]2[N:6]([CH:13]=[C:14]([C:16]3[N:17]=[N:18][N:19]([CH3:21])[N:20]=3)[CH:15]=2)[N:7]=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])[CH3:2].[OH:22]OS([O-])=O.[K+]>CC(C)=O.O>[CH2:1]([S:3]([C:4]1[C:5]2[N:6]([CH:13]=[C:14]([C:16]3[N:17]=[N:18][N:19]([CH3:21])[N:20]=3)[CH:15]=2)[N:7]=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:22])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CCSc1c(C(N)=O)cnn2cc(-c3nnn(C)n3)cc12
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCS(=O)c1c(C(N)=O)cnn2cc(-c3nnn(C)n3)cc12
Temperature: 23 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a solution of 4-(ethylthio)-6-(2-methyl-2H-tetrazol-5-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (64 mg, 0.211 mmol) in acetone (1.0 mL) was added oxone (285 mg, 0.464 mmol) in water (1.0 mL). The reaction mixture was stirred at 23° C. for 1 hr. The reaction mixture was added 5 ml of water and stirred for 10 minutes. The solid was collected as the desired product (57.4 mg, 85% yield). 1H NMR (400 MHz, methanol-d4) δ 8.59 (d, J=1.8 Hz, 1H), 8.52 (s, 1H), 8.27 (d, J=1.5 Hz, 1H), 4.46 (s, 3H), 3.55-3.42 (m, 2H), 1.53 (s, 3H). MS (ES+) m/z: 320.10 (M+H); HPLC retention time: 2.007 min (analytical HPLC Method F).