Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.[CH3:31][C:32]1[C:36]([C:37]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[O:38])=[C:35]([CH3:45])[O:34][N:33]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:42]3[CH2:43][CH2:44][N:39]([C:37]([C:36]4[C:32]([CH3:31])=[N:33][O:34][C:35]=4[CH3:45])=[O:38])[CH2:40][CH2:41]3)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: Cc1noc(C)c1C(=O)N1CCNCC1
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)c2c(C)noc2C)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 34) was reacted with (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone to give [(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazol-1-yl]-[4-(3,5-dimethyl-isoxazole-4-carbonyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. LR-MS: 652.2 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](Cl)=[O:4].[NH2:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[N:29][C:30]=3[NH2:32])[N:25]([C@H:33]3[CH2:38][CH2:37][C@H:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)[N:24]=2)=[C:17]([F:46])[CH:16]=1>N1C=CC=CC=1>[NH2:32][C:30]1[N:29]=[CH:28][N:27]=[C:26]2[N:25]([C@H:33]3[CH2:38][CH2:37][C@H:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)[N:24]=[C:23]([C:18]3[C:17]([F:46])=[CH:16][C:15]([NH:14][C:3](=[O:4])[C:2]([CH3:13])([CH3:1])[CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[C:20]([O:21][CH3:22])[CH:19]=3)[C:31]=12
Reactant: CC(C)(Cc1ccccc1)C(=O)Cl
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1N
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1NC(=O)C(C)(C)Cc1ccccc1
Reaction time: 5 h

Procedure:
2,2-Dimethyl-3-phenylpropanoyl chloride (52 mg, 0.264 mmol) was added to a solution of trans-3-(4-amino-2-fluoro-5-methoxyphenyl)-1-[4-(4-methylpiperazino) cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 0.176 mmol) in pyridine (1.5 mL). After 5 hours, the solvent was evaporated and the residue was first purified by flash column chromatography chromatography using dichloromethane/methanol (95:5 to 85:15) as mobile phase then by preparatory LC/MS to give trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino) cyclohexyl]-1H-pyrazolo [3,4-d]pyrimidin-3-yl}-5-fluoro-2-methoxyphenyl)-2,2-dimethyl-3-phenylpropanamide (22 mg, 19%). 1H NMR (CDCl3-d) δ 1.33 (s, 6H), 1.57 (m, 2H), 1.92 (m, 2H), 2.15 (m, 6H), 2.30 (s, 3H), 2.49 (m, 4H), 2.66 (m, 3H), 2.95 (s, 2H), 3.84 (s, 3H), 4.76 (m, 1H), 5.51 (bs, 2H), 6.98 (d, J=6.86 Hz, 1H), 7.15 (m, 2H), 7.23 (m, 3H), 8.01 (s, 1H), 8.35 (s, 1H), 8.47 (d, J=11.88, 1H). LCMS LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=615.3, Rt=2.18 min.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:36]=[CH:35][C:6]([C:7](=[O:34])[CH2:8][CH2:9][NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[N:13](C(OC(C)(C)C)=O)[C:12]=2[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:36]=[CH:35][C:6]([C:7](=[O:34])[CH2:8][CH2:9][NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[NH:13][C:12]=2[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1c(NCCC(=O)c2ccc(C(F)(F)F)cc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccc(C(F)(F)F)cc1

Procedure:
Dissolve 3-[(p-trifluoromethylphenacyl)methylamino]-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole from above in methylene chloride (5 mL). Add trifluoracetic acid (3 mL) and stir for 5 hours. Concentrate the reaction in vacuo, dilute with ethyl acetate (100 mL), wash with saturated sodium carbonate, dry over magnesium sulfate, filter and concentrate in vacuo. Recrystallize the residue from ethyl acetate/hexane to yield the title compound (820 mg).
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:12](Cl)(=[O:21])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[C:12]([NH:11][NH:10][C:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])(=[O:21])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NNC(=O)c1ccccc1O
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: O
Product: O=C(C=Cc1ccccc1)NNC(=O)c1ccccc1O
Temperature: 20 °C
Reaction time: 9 h
Yield: 32.3 %

Procedure:
To 50 ml of N-dimethylacetamide were added 5.0 g of salicyloylhydrazine and 5.5 g of cinnamoyl chloride, and the mixture was stirred at 20° C for 9 hours. The reaction mixture was then poured into 2 liters of water, and the produced precipitate was collected by filtration and washed with water. The so obtained product was then recrystallized twice from acetic acid and dried under reduced pressure to yield 3 g of N-cinnamoyl-N'-salicyloylhydrazine as white crystals, m.p. 271° C. Analysis: Calculated for C16H14N2O3 ; C, 68.09%, H, 4.96%; N, 9.93%, Found: C, 68.08%; H, 4.81%; N, 9.08%.
Reaction SMILES: CC(C1C=CC=C(Cl)C=1)=O.CC1(C2C=CC=C(Cl)C=2)C=CC=C(C=CC#N)C1.[2H][2H].[CH3:31][CH:32]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)[CH2:33][CH2:34][NH2:35].[CH3:43][O:44][C:45]1[CH:46]=[C:47]([C:51](=O)[CH3:52])[CH:48]=[CH:49][CH:50]=1.C([BH3-])#N.[Na+]>[OH-].[Pd+2].[OH-].CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)(=O)C>[CH3:31][CH:32]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)[CH2:33][CH2:34][NH:35][CH:51]([C:47]1[CH:48]=[CH:49][CH:50]=[C:45]([O:44][CH3:43])[CH:46]=1)[CH3:52]
Reactant: CC(CCN)c1cccc(Cl)c1
Reactant: COc1cccc(C(C)=O)c1
Agent: [Pd+2]
Agent: [Ti+4]
Agent: CC(=O)c1cccc(Cl)c1
Solvent: CC(=O)O
Product: COc1cccc(C(C)NCCC(C)c2cccc(Cl)c2)c1

Procedure:
In a similar fashion, 3-chloroacetophenone was used to prepare 3-methyl-3-(3-chlorophenyl)cinnamonitrile. The nitrile was catalytically reduced (palladium hydroxide, acetic acid, 60 p.s.i. hydrogen 2 hr) to generate 3-methyl-3-(3-chlorophenyl)propylamine. An equal molar amount of the amine, 3′-methoxyacetophenone and 1.25 molar equivalents titanium(IV) isopropoxide were mixed 4 hr at rt and the intermediate imine treated with an ethanolic sodium cyanoborohydride (5 ml of 1 M, 5 mmol). Work-up and chromatography afforded N-[3-methyl-3-(3-chlorophenyl)propyl]-1-(3-methoxyphenyl)ethylamine, 4Z/5A, as an oil; m/z (rel. int.) 283 (M+, 17), 268 (71), 164 (13), 135 (100), 121 (21), 105 (27), 91 (26), 77 (14).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18](C3C=CC=CN=3)C)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](CN2CCN(C(OC(C)(C)C)=O)CC2)=[CH:30][CH:29]=1.C(O)(C(F)(F)F)=O.BrC1C(Cl)=C([N+]([O-])=O)C(N)=NC=1>CC(O)C.CCN(C(C)C)C(C)C.C(Cl)Cl>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:31]3[CH:32]=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CC(c1ccccn1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: COc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cn1
Agent: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cn1

Procedure:
This was prepared using the same procedure as for 5-bromo-3-nitro-4-(4-(1-(pyridin-2-yl)ethyl)piperazin-1-yl)pyridin-2-amine, but here using tert-butyl 4-((6-methoxypyridin-3-yl)methyl)piperazine-1-carboxylate (1.1 eq, 0.54 mmol, 165 mg), TFA (1 mL) and CH2Cl2 (3 mL), then 5-bromo-4-chloro-3-nitropyridin-2-amine (123 mg, 0.49 mmol) in iPrOH (3.5 mL) and DIPEA (1 mL). Filtration and washing as previously described gave the product (89 mg, 40% for two steps) as a yellow solid; δH (500 MHz, DMSO-d6) 2.50 (hidden by DMSO peak, s, br, 4H, piperazine N(CH2)2), 3.05 (s, br, 4H, piperazine N(CH2)2), 3.48 (s, 2H, NCH2), 3.84 (s, 3H, OCH3), 6.80 (d, J=8.5 Hz, 1H, pyridine H-5), 6.98 (s, br, 2H, NH2), 7.66 (dd, J=8.5, 2.3 Hz, 1H, pyridine H-4), 8.07 (d, J=1.1 Hz, 1H, pyridine H-2), 8.16 (s, 1H, bromopyridine H-6); LC (Method B)-MS (ESI, m/z): Rt=2.33 min—423, 425 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 423.0777, calculated for C16H19BrN6O3 (M+H)+: 423.0780.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)=[O:5].[CH2:26]1COCC1.C[Li]>CCOCC>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:10]=[C:6]2[C:4](=[O:5])[CH3:26])=[CH:23][CH:22]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1ccc(-c2ccccc2)n1Cc1ccc(F)cc1
Agent: [Li]C
Solvent: CCOCC
Product: CC(=O)c1ccc(-c2ccccc2)n1Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 1-(4-fluorobenzyl)-5-phenyl-1H-pyrrole-2-carboxylic acid methoxy-methylamide AV-7-1 (0.726 g, 2.16 mmol) and dry THF (20 mL). This solution was cooled to −78° C. and methyllithium (3.39 mL of a 1.4 M solution in Et2O, 4.75 mmol). The mixture was stirred 30 min at −78° C. then the reaction was quenched with saturated aqueous NH4Cl solution. The mixture was warmed to room temperature and stirred 2 h. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic fractions were dried (MgSO4), filtered and concentrated in vacuo. The crude product was chromatographed on silica gel using 15% EtOAc in hexanes as eluant to give 1-[1-(4-fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]ethanone AV-8-1 as an oil. 1H NMR (CDCl3) δ 2.42 (3H, s), 5.59 (2H, s), 6.29 (1H, d, j=4.2 Hz), 6.78 to 6.91 (4H, m), 7.12 (1H, d, j=4.2 Hz), 7.29 (2H, m), 7.38 (3H, m).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([O:10]CC)=O)[CH3:2].[NH3:13]>CO>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([NH2:13])=[O:10])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCCN1CC
Reactant: N
Solvent: CO
Product: CCN1CCC[C@H]1C(N)=O
Temperature: 50 °C

Procedure:
Ethyl (-)-(S)-1-ethyl-2-pyrrolidinecarboxylate (3.4 g, 0.02 mol) was added to a cooled solution of MeOH (10 ml) and liquid NH3 (10 ml) in a stainless steel reaction bottle containing 3 g of 3 Å molecular sieves. The bottle was heated at 50° C. for 20 h. After cooling the solvent was allowed to evaporate. The product was dissolved in dry MeOH, filtered and the filtrate was evaporated under reduced pressure to give the title compound as white crystals in a quantitative yield (2.8 g). Recrystallization from n-hexane afforded 2.5 g (88%) of the amide, mp 107°-108° C. [α]D25 =-119° (c=0.5 MeOH). The enantiomeric purity was determined to 99.7% S-isomer.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=O)[O:31]C.[H-].[K+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[C@H:17]([C:30]([O:29][CH3:28])=[O:31])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: COC(=O)OC
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@]2(C)C1=O
Yield: 90 %

Procedure:
A solution of 3-benzyloxy-1,3,5(10)-estratrien-17-one (2) (4.00 g, 11.1 mmol) in dry THF (5 mL) was added over a period of 30 min to a solution of dimethylcarbonate (2.34 mL, 27.8 mmol) and potassium hydride (1.42 g, 34.7 mmol) in dry THF (40 mL). Then, the mixture was heated to reflux for a period of 3 h. Most of the solvent was then evaporated and the residue was diluted with ethyl acetate (100 mL) and treated with a saturated ammonium chloride solution (50 mL). The organic phase was washed with water (6×40 mL), dried and evaporated to give a yellowish solid. Trituration of the residue with a mixture of acetone:hexanes (1:1) yielded the title compound in 90% yield as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14](O)=[O:15])=[C:9]2[CH3:17])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:31])=O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([Cl:31])=[O:15])=[C:9]2[CH3:17])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C(=O)O)c(C)n1-c1ccc(F)cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)Cl)c(C)n1-c1ccc(F)cc1C(F)(F)F
Temperature: 1.5 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of 1-[4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carbaldehyde (1.5 g, 5.3 mmol) in acetone (150 mL) was added a 0.3 M solution of KMnO4 (150 mL). The reaction mixture was stirred 3 h at room temperature and then was charged with 10% H2O2 (5 mL). After 15 minutes the reaction mixture was filtered and the filtrate was concentrated in vacuo to remove acetone. The remaining aqueous suspension was acidified with acetic acid. The precipitates were recovered by filtration and dried under high vacuum to afford 1-(4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxylic acid (0.99 g, 62%) as a faintly yellow powder; 1H NMR (CDCl3): δ 7.56 (dd, J=8, 3 Hz, 1H), 7.41 (m, 1H), 7.27 (dd, J=5, 8 Hz, 1H), 6.42 (s, 1H), 2.21 (s, 3H), 1.90 (s, 3H); MS (ESI) m/z 302 [M+H]+. To a suspension of 1-(4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxylic acid (0.65 g, 2.16 mmol) in anhyd toluene (5.0 mL) cooled to 0-3° C. were added thionyl chloride (0.25 mL) and DMF (20 μL). The reaction mixture was allowed to warm to room temperature where it remained for 3 h and then was concentrated in vacuo. The residue was evaporated twice from 5 mL of toluene to remove thionyl chloride and then was triturated in 3 mL of hexanes. The solids were removed by filtration and the filtrate was concentrated under reduced pressure and dried under high vacuum to afford the title compound (0.44 g, 64%) as a pale brown solid; 1H NMR (CDCl3): δ 7.59 (dd, J=8, 3 Hz, 1H), 7.44 (m, 1H), 7.27 (dd, J=5, 8 Hz, 1H), 6.51 (s, 1H), 2.17 (s, 3H), 1.89 (s, 3H); MS (ESI) m/z 320 [M+H]+.
Reaction SMILES: O[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[N:3]=1.C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)[Cl:28]>>[Cl:28][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc2nccn2c(O)n1
Solvent: CCN(CC)c1ccccc1
Product: COC(=O)c1cc2nccn2c(Cl)n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Methyl 5-hydroxyimidazo[1,2-c]pyrimidine-7-carboxylate (4.0 g, 21 mmol) and N,N-diethylaniline (6.6 mL, 41 mmol) were suspended in POCl3 (80 mL, 870 mmol) and heated at 50° C. for 30 minutes. The reaction mixture remained heterogeneous, so the temperature was raised to 100° C. After 30 minutes, LCMS analysis showed mostly the title compound, along with 5,7-dichloroimidazo[1,2-c]pyrimidine (which was presumably formed from 7-chloroimidazo[1,2-c]pyrimidin-5-ol carried through from the previous step). The reaction mixture was cooled to ambient temperature and concentrated down to remove the POCl3. The residue was cooled in an ice bath and quenched carefully with water. Solid K2CO3 was added to neutralize the solution to pH 7, which was then extracted with DCM. The combined organic layers were filtered through a Biotage phase separator cartridge and washed with DCM. The filtrate was concentrated down to a thick dark greenish brown residue. While sitting overnight, a precipitate formed. The resultant solid was triturated in DCM and Et2O to give afford methyl 5-chloroimidazo[1,2-c]pyrimidine-7-carboxylate (6.4 g, 21 mmol, 100% yield) as a brick-red solid. The solid was 70% pure, but could not be purified at this stage due to its insolubility. The crude material was used directly in the next step. MS (apci) m/z=212.2 (M+H).
Reaction SMILES: [CH2:1]([CH:3]1[C:8]2([C:12](=[O:13])[CH2:11][CH2:10][CH2:9]2)[CH2:7][CH:6]=[C:5]([CH3:14])[CH2:4]1)[CH3:2].COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([CH:3]1[C:8]2([CH:12]([OH:13])[CH2:11][CH2:10][CH2:9]2)[CH2:7][CH:6]=[C:5]([CH3:14])[CH2:4]1)[CH3:2]
Reactant: CCC1CC(C)=CCC12CCCC2=O
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC1CC(C)=CCC12CCCC2O
Yield: 95.6 %

Procedure:
10-Ethyl-8-methyl-spiro[4.5]dec-7-en-1-one (14 g; 0.073 mol) was dissolved in toluene (60 ml) and reduced using Vitride® in toluene; 40 ml) at 60-70° C. A partial conversion was observed: 22.1% ketones and 67.5% alcohols. Usual work-up (see above), followed by column chromatography on SiO2 (solvent: hexane/MTBE: 9/1) afforded 95.6% pure desired product, as a mixture of isomers.
Reaction SMILES: C(OC([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33]([NH:35][C@H:36]2[CH2:41][CH2:40][C@H:39]([C:42]([OH:44])=[O:43])[CH2:38][CH2:37]2)=[O:34])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.Cl.O1CCOCC1>O1CCOCC1>[C:11]1([C@H:9]([NH:8][CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:25][N:24]([C:33]([NH:35][C@H:36]3[CH2:41][CH2:40][C@H:39]([C:42]([OH:44])=[O:43])[CH2:38][CH2:37]3)=[O:34])[CH2:23]2)[CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)N[C@H]2CC[C@H](C(=O)O)CC2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NC[C@H]1CN(C(=O)N[C@H]2CC[C@H](C(=O)O)CC2)C[C@@H]1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 6.0 ml 1,4-dioxane solution of 175 mg of trans-4-({[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}amino)cyclohexane carboxylic acid was mixed with 1.0 ml of 4 M hydrogen chloride/1,4-dioxane at room temperature and stirred overnight at room temperature. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol), and the thus obtained solid was recrystallized from chloroform-diethyl ether to obtain 36 mg of trans-4-({[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}amino)cyclohexane carboxylic acid as a white solid.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][C@@:15]12[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][C@H:24]1[CH2:23][CH2:22][C@H:21]1[C@H:16]2[CH2:17][C@@H:18]2[CH2:32][CH2:31][C@H:30]([OH:33])[C@@:19]2([CH3:34])[CH2:20]1.CC(O)C>CC(C)=O.[Cl-].[Na+].O>[CH3:34][C@@:19]12[C:30](=[O:33])[CH2:31][CH2:32][C@H:18]1[CH2:17][C@@H:16]1[C@H:21]([CH2:22][CH2:23][C@H:24]3[C@@:15]1([CH3:14])[CH2:28][CH2:27][C:26](=[O:29])[CH2:25]3)[CH2:20]2
Reactant: C[C@]12C[C@H]3CC[C@@H]4CC(=O)CC[C@@]4(C)[C@@H]3C[C@@H]1CC[C@@H]2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: C[C@@]12CCC(=O)C[C@H]1CC[C@@H]1C[C@]3(C)C(=O)CC[C@H]3C[C@H]12
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
Jones reagent was added to a solution of compound 20 (480 mg, 1.66 mmol) in acetone (40 mL) at 0° C. until a brown-yellowish color persisted. After 10 min, 2-propanol (1.0 mL) was added and then brine (50 mL) was added. The product was extracted into EtOAc (50 mL×3). The combined extracts were dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 20% EtOAc in hexanes) to give compound 21 (461 mg, 96%): 1H NMR (CDCl3) δ 1.02 (s, 3H), 0.87 (s, 3H); 13C NMR (CDCl3) δ 220.1, 211.0, 48.2, 47.8, 47.6, 45.6, 45.4, 43.5, 40.9, 38.9, 37.6, 35.4, 34.0, 33.4, 29.9, 28.7, 23.8, 13.4; IR νmax 1734, 1714 cm−1.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[CH:3]=1.[Br:11][CH:12]([CH:15]=O)[CH:13]=O>>[CH3:10][O:9][C:7]([C:4]1[CH:3]=[C:2]2[N:1]=[CH:13][C:12]([Br:11])=[CH:15][N:6]2[N:5]=1)=[O:8]
Reactant: COC(=O)c1cc(N)[nH]n1
Reactant: O=CC(Br)C=O
Product: COC(=O)c1cc2ncc(Br)cn2n1

Procedure:
The title compound, brown solid, MS: m/e=256.0/254.1 (M+H+), can be prepared in accordance with the general method of example 9, step 1 from methyl 5-amino-1H-pyrazole-3-carboxylate and 2-bromomalonaldehyde.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C@H:9]([CH2:11][N:12]3[CH2:17][CH2:16][C:15]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=4)([OH:18])[CH2:14][CH2:13]3)[CH2:8][C:7]=2[CH:27]=1>CN(C=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C@H:9]([CH2:11][N:12]3[CH2:17][CH2:16][C:15]([CH2:19][C:20]4[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=4)([OH:18])[CH2:14][CH2:13]3)[CH2:8][C:7]=2[CH:27]=1
Reactant: COc1ccc2c(c1)C[C@@H](CN1CCC(O)(Cc3ccc(Cl)cc3)CC1)O2
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)C[C@@H](CN1CCC(O)(Cc3ccc(Cl)cc3)CC1)O2

Procedure:
The title compound, MS: m/e=374.2 (M+H+) [α]=+32.4° (c=1.0, DMF), >99% e.e. by chiral phase HPLC, was prepared from (S)-1-(5-methoxy-2,3-dihydro-benzofuran-2-ylmethyl)-4-(4-chloro-benzyl)-piperidin-4-ol.