Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C([O:45][C:46](=[O:57])[NH:47][CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([NH2:56])=[CH:52][CH:51]=1)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@@H:9]([C:28]([NH:56][C:53]3[CH:52]=[CH:51][C:50]([CH2:49][CH2:48][NH:47][C:46](=[O:57])[OH:45])=[CH:55][CH:54]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])=[C:16]([F:22])[CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CCNC(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 1.5 h

Procedure:
To a solution of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (51.1 mg, 0.11 mmol) in dichloromethane (3 mL) were added DIPEA (71.2 mg, 0.55 mmol), [2-(4-AMINO-PHENYL)-ETHYL]-CARBAMIC ACID TERT-BUTYL ESTER (52.3 mg., 0.22 mmol, Chem-Impex) and HATU (77.8 mg, 0.20 mmol) (The acid, DIPEA, and HATU were added in thirds at 20 min intervals). After 90 mins, the reaction was diluted with dichloromethane, washed with water and saturated sodium chloride and purified by silica gel chromatography with ethyl acetate and n-hexanes to give chiral [2-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-ethyl]-carbamic acid tent-butyl ester (40.6 mg., 54.2%) as a white lyophilized solid. HRMS (ES+) m/z Calcd C36H40Cl2F2N4O3+H [(M+H): 685.2519. Found: 685.2517.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])[CH:8]=[CH:9][C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:23]1([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:33][CH:32]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.P(Br)(Br)Br.Cl>N1C=CC=CC=1>[C:17]([C:14]1[CH:13]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:15]=1[OH:16])[CH:8]=[CH:9][C:10]([N:26]1[CH2:27][CH2:28][N:23]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:33][CH:32]=2)[CH2:24][CH2:25]1)=[O:11])([CH3:19])([CH3:20])[CH3:18]
Reactant: CCOC(=O)Cc1ccc(CCN2CCNCC2)cc1
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Agent: BrP(Br)Br
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)Cc1ccc(CCN2CCN(C(=O)C=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)cc1
Reaction time: 2 h

Procedure:
A solution of 14.0 g. (51 mmole) 3,5-di-tert.-butyl-4-hydroxycinnamic acid and 17.7 g. (51 mmole) ethyl 4-[2-(piperazin-1-yl)-ethyl]-phenylacetate dihydrochloride in 150 ml. anhydrous pyridine is mixed dropwise, with ice cooling, with a solution of 3.57 g. (26 mmole) phosphorus tribromide in 20 ml. pyridine. Stirring is continued for 2 hours, with ice cooling, and the reaction mixture then left to stand for 12 hours at ambient temperature, whereafter it is poured on to ice and extracted with ethyl acetate. The extracts are dried and evaporated, the residue is taken up in diethyl ether and the hydrochloride is precipitated with hydrogen chloride-containing diethyl ether. After recrystallisation from a mixture of ethanol and water, to which has been added some concentrated hydrochloric acid, there are obtained 14.5 g. (47%) of hydrochloride of the desired compound; m.p. 111°-113° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:39])[CH2:33][CH2:34][O:35][CH:36]([CH3:38])[CH3:37]>>[CH3:37][CH:36]([O:35][CH2:34][CH2:33][C:32]1[N:39]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[O:28][N:31]=1)[CH3:38]
Reactant: CC(C)OCCC(N)=NO
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Product: CC(C)OCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
100 mg (0.24 mmol) of the compound from Example 100A and 60 mg (0.37 mmol) of the compound from Example 65A were reacted according to the General Method 2. Yield: 54 mg (42% of theory)
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=4)[CH2:23][CH2:22][C:21]([C:33]([O:35]C)=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl.O1CCC[CH2:43]1>CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH:31]([CH3:32])[CH3:43])[CH:30]=4)[CH2:23][CH2:22][C:21]([C:33]([OH:35])=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cnn(CC)c2)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cnn(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-[(1-ethylpyrazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylate (392 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 3 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutral, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-[(1-isopropylpyrazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (229 mg) as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]3[O:16][CH2:17][O:18][C:12]=3[CH:11]=2)[C:5]([C:19]([O:21]C)=[O:20])=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]3[O:16][CH2:17][O:18][C:12]=3[CH:11]=2)[C:5]([C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1COc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Br)cc1COc1ccc2c(c1)OCO2

Procedure:
Add 16.07 gm. (0.044 mole) of methyl 5-bromo-α-(3,4methylenedioxyphenoxy)-o-toluate to a solution of 3.52 gm. (0.088 mole) of sodium hydroxide in 24 ml. of water and 212 ml. of methanol. Heat the mixture under reflux for 1 hour. Remove the methanol under vacuum and dissolve the residue in 225 ml. of water. Acidify with concentrated hydrochloric acid to the congo red end point. Separate the solids by filtration and dry (yield 14.14 gm., m.p. 167°-177° C.). Recrystallize from ethanol-water to obtain pure product as tan needles (m.p. 177°-180° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=3)(=[O:22])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CI.[C:34](=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:19]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=3)(=[O:21])=[O:22])[CH3:34])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2NS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CN([C@@H]1CCCc2c(OCC(=O)OC(C)(C)C)cccc21)S(=O)(=O)c1ccc(F)c(Cl)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 88.7 %

Procedure:
To a solution of [(R)-5-(3-chloro-4-fluoro-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (example 2-2, method D, 2nd step) (400 mg, 0.85 mmol) in acetonitrile (15 mL) was added methyl iodide (182 mg, 1.28 mmol) and potassium carbonate (350 mg, 2.53 mmol). The reaction mixture was stirred at 70° C. for 5 hours, then cooled to room temperature and filtered through a glass funnel. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (gradient elution, 0-10% methanol in dichloromethane) to afford {(R)-5-[(3-chloro-4-fluoro-benzenesulfonyl)-methyl-amino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid tert-butyl ester (365 mg, 89%) as a yellow oil. MS cald. for C23H27ClFNO5S 483, obsd. 484 (ESI+) [(M+H)+].
Reaction SMILES: ClC1C=CC=C2C=1NC([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=C2.[CH3:20][C:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH:22]=1>>[CH3:20][C:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][C:22]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: Cc1coc2ccccc12
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)oc2ccccc12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 3-methyl-benzofuran.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:4]=1.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:29][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:5]([CH:4]=1)[O:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: NCCc1ccccc1
Reactant: COc1ccc(C=O)c(OCCCN2CCOCC2)c1
Solvent: Cc1ccccc1
Product: COc1ccc(C=NCCc2ccccc2)c(OCCCN2CCOCC2)c1
Yield: 81.4 %

Procedure:
4-Methoxy-2-[3-(4-morpholinyl)propoxy]benzaldehyde (29.7 g) and 13.0 g of phenethylamine are reacted in 110 ml of toluene following the procedure described in Example 1B, yielding 33.1 g of the title compound, boiling point 240°-245° C. at 0.1-0.2 mm of Hg.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]([CH3:32])([CH2:11][C:12](=[O:31])[NH:13][C:14]1[CH:15]=[N:16][C:17]([O:20][C:21](=[O:30])[N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:19]=1)[CH2:7][C:8]([OH:10])=O.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>ClCCl>[CH3:5][C:6]([CH3:32])([CH2:7][C:8]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:10])[CH2:11][C:12]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:30])[N:22]([CH3:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:16][CH:15]=1)=[O:31]
Reactant: C1COCCN1
Reactant: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)CC(=O)O)cn1)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)CC(=O)N2CCOCC2)cn1)c1ccccc1
Reaction time: 0.17 h
Yield: 63 %

Procedure:
Thionylchloride (237 microL, 3.27 mmol) was added to a stirred solution of 3,3-dimethyl-4-[6-(methyl-phenyl-carbamoyloxy)-pyridin-3-ylcarbamoyl]-butyric acid (0.63 g, 1.63 mmol) in dichloromethane (10 mL). After stirring for 10 minutes the solution was divided into 4 equal portions of acid chloride. To one portion was added morpholine (0.5 mL) and after stirring for 2 hours at room temperature the crude product was purified by flash column chromatography (SiO2), yielding the title compound (117 mg, 63% yield).
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:12])=[N+:7]([O-])[CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].C([O-])([O-])=[O:14].[K+].[K+]>CC(OC(C)=O)=O.CO>[CH2:1]([C:5]1[C:6]([CH2:12][OH:14])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(CC(C)C)ccc[n+]1[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CC(C)Cc1cccnc1CO
Temperature: 100 °C
Reaction time: 16 h

Procedure:
3-Isobutyl-2-methyl-pyridine-1-oxide (821 mg, 4.97 mmol) was dissolved in Ac2O (10 mL) and stirred at 100° C. for 16 hours. The Ac2O was removed under reduced pressure and the resulting brown oil was quenched with saturated NaHCO3 (30 mL) and extracted with CH2Cl2 (6×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to yield a brown oil. Purification was avoided at this step due to the identical Rf values of the two products formed. The brown oil was dissolved in MeOH (20 mL) and powdered K2CO3 (2.05 g) was added. The mixture was stirred at room temperature for 2.5 hours. The solid was removed via suction filtration and the filtrate was concentrated in vacuo to give a brown oil. Purification via column chromatography on silica gel (CH2Cl2:MeOH, 95:5, v/v) afforded (3-isobutyl-pyridin-2-yl)-methanol as a yellow oil (383 mg, 78%, 2-steps). 1H NMR (CDCl3) δ 0.93 (d, 6H, J=6.0 Hz), 1.86 (m, 1H), 2.38 (d, 2H, J=6.0 Hz), 4.73 (s, 2H), 4.90 (br s, 1H), 7.18 (dd, 1H, J=9.0, 3.0 Hz), 7.45 (d, 1H, J=9.0), 8.41 (d, 1H, J=6.0 Hz).
Reaction SMILES: C(O)(=O)C.[Br:5]N1C(=O)CCC1=O.[CH2:13]([CH:15]([C:18]1[N:23]2[N:24]=[C:25]([CH3:38])[C:26]([C:27]3[S:31][C:30]([C:32]4[N:33]([CH3:37])[N:34]=[CH:35][N:36]=4)=[N:29][CH:28]=3)=[C:22]2[N:21]=[C:20]([CH3:39])[CH:19]=1)[CH2:16][CH3:17])[CH3:14]>C(#N)C>[Br:5][C:28]1[N:29]=[C:30]([C:32]2[N:33]([CH3:37])[N:34]=[CH:35][N:36]=2)[S:31][C:27]=1[C:26]1[C:25]([CH3:38])=[N:24][N:23]2[C:18]([CH:15]([CH2:16][CH3:17])[CH2:13][CH3:14])=[CH:19][C:20]([CH3:39])=[N:21][C:22]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(CC)c1cc(C)nc2c(-c3cnc(-c4ncnn4C)s3)c(C)nn12
Solvent: CC(=O)O
Solvent: CC#N
Product: CCC(CC)c1cc(C)nc2c(-c3sc(-c4ncnn4C)nc3Br)c(C)nn12
Temperature: 22 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Add acetic acid (1 mL) and N-bromosuccinimide (4.1 g, 22 mmol) to a solution of 7-(1-ethyl-propyl)-2,5-dimethyl-3-[2-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiazol-5-yl]-pyrazolo[1,5-a]pyrimidine (8 g, 21 mmol) in acetonitrile (80 mL). Stir the mixture 2 h at 22° C. Then evaporate the solvent and add water (50 mL) and methyl-t-butyl ether (100 mL) to the resulting residue. Separate the organic portion, dry over sodium sulfate, filter, and evaporate the solvent. Recrystallize the resulting residue from isopropyl alcohol to afford the title compound (8.7 g, 90%). ES/MS (m/z): (79Br/81Br) 460/462 (M+1)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH2:10])[CH3:2].O.[Br:12]Br>Cl>[Br:12][C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([NH2:10])=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: CCc1cccc(C)c1N
Reactant: BrBr
Agent: Cl
Solvent: O
Product: CCc1cc(Br)cc(C)c1N

Procedure:
2-Ethyl-6-methyl-phenylamine (14 mL, 100 mmol) was dissolved in concentrated hydrochloric acid (30 mL) and water (220 mL) and cooled to 0° C. To this was added bromine (5.1 mL, 1 equiv.) dropwise. There was rapid formation of a white precipitate. The precipitate was filtered and washed with diethyl ether. The precipitate was suspended in water and neutralized with aqueous potassium carbonate. An oil formed which was extracted into diethyl ether. The ethereal was dried over potassium carbonate, filtered, and concentrated to give 7.0 g (33%) as a purple oil which was used without purification. Mass spec.: 214.01 (MH)+.
Reaction SMILES: C([Li])CCC.[C:6]([N:13]1[CH2:16][C:15](=[O:17])[CH2:14]1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl.[CH2:19]([O:26][C:27]1[CH:32]=[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=[CH:29][C:28]=1Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.CCCCCC>[C:9]([O:8][C:6]([N:13]1[CH2:16][C:15]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:32][C:31]=2[O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([OH:17])[CH2:14]1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Brc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
In a 100 ml three-necked flask, 5 g of 2,4-bis(benzyloxy)-1-bromobenzene are dissolved in 60 ml of tetrahydrofuran. The mixture is cooled to −70° C. and then 11.4 ml of 2.5M n-butyllithium in hexane are added. The reaction medium is stirred at −70° C. for 1 hour, and then 2.8 g of 1-Boc-azetidine-3-one dissolved in 4 ml of THF are added dropwise. The reaction medium is stirred at −70° C. for 2 hours and then left at ambient temperature overnight. The reaction medium is poured into 40 ml of a 2M solution of hydrochloric acid and then extracted with 100 ml of ethyl acetate. The organic phases are combined, washed with 50 ml of water and then dried over magnesium sulphate and evaporated.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@H:9]1[C:17]2[C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[N:15][CH:14]=[N:13][C:12]=2[C:11](=[O:31])[CH2:10]1.O[C@H]1C2N=CN=C(N3CCN(C(OC(C)(C)C)=O)CC3)C=2[C@H](C)C1>C(Cl)Cl>[OH:31][C@@H:11]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:17]=2[C@H:9]([CH3:8])[CH2:10]1
Reactant: C[C@@H]1CC(=O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Reaction time: 0.08 h
Yield: 95.4 %

Procedure:
Triethylamine (4.33 mL, 31.1 mmol; degassed with nitrogen 30 minutes prior to use) and formic acid (1.36 mL, 36.1 mmol; degassed with nitrogen 30 minutes prior to use) were added to a solution of (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (9.75 g, 29.3 mmol) in DCM (210 mL; degassed with nitrogen 30 minutes prior to use). The mixture was stirred for 5 minutes, then a Ru catalyst (0.0933 g, 0.147 mmol) was added. The reaction was stirred under positive nitrogen pressure overnight (18 hours). The reaction mixture was concentrated to dryness and dried on high vacuum. The impure material was flashed on Biotage 65M loaded 1:1 DCM:ethyl acetate 500 mL flushed, then 1:4 DCM:ethyl acetate until product (2nd spot), then gradient to neat ethyl acetate, then 25:1 DCM:MeOH eluted rest of product. The fractions were combined and concentrated on a rotary evaporator. The residue was concentrated again from DCM/hexanes to give a mixture of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (major) and tert-butyl 4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (minor) (9.35 g, 95.3% yield) as a foam. LC/MS (APCI+) m/z 335 [M+H]+. 1H NMR (CDCl3) shows 88% diastereoselectivity by integration of carbinol methine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH2:17][O:18][C:19](=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:14]=[CH:13]1)[N:8]=[C:7]([C:28]([O:30]CC)=[O:29])[C:6](=[O:33])[NH:5]2.[OH-].[Li+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH2:17][O:18][C:19](=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:14]=[CH:13]1)[N:8]=[C:7]([C:28]([OH:30])=[O:29])[C:6](=[O:33])[NH:5]2
Reactant: CCOC(=O)c1nc2cc(-n3cnc(COC(=O)Nc4ccccc4)c3)c(Cl)cc2[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccccc1)OCc1cn(-c2cc3nc(C(=O)O)c(=O)[nH]c3cc2Cl)cn1
Temperature: 50 °C
Reaction time: 1.25 h
Yield: 38.6 %

Procedure:
To a solution of the compound (76.0 mg, 162 μmol) of Example 42 in ethanol. (2 ml) were added 1 mol/L aqueous solution of lithium hydroxide (567 μl, 567 μmol) and water (1 ml), and the mixture was stirred for 75 minutes at 50° C. After cooling, water was added to the reaction mixture and the insolubles were filtered off. The filtrate was brought to pH4 with 3 mol/L hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and then air-dried, thereby obtaining 27.5 mg of title compound as light brown powder. Yield 39%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:35][CH2:34][CH2:33][N:32]([C:7](=[O:8])[C:6]4[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[C:11]([F:14])([F:13])[F:12])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:16][CH2:17]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCCNCC2)nn1
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Product: O=C(NCCC1CC1)c1ccc(N2CCCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 5-fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-[1,4]diazepan-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (60% yield). 1H NMR (CDCl3, 300 MHz) δ 8.07-7.85, 7.71-7.6, 7.23-7.08, 6.94-6.88, 6.34-6.31, 4.24-4.12, 3.98-3.73, 3.67-3.36, 3.29-3.25, 2.19-1.73, 1.53-1.46, 0.81-0.68, 0.48-0.4, 0.11-0.03. 13C NMR (CDCl3, 75 MHz) δ 167.3, 167.2, 165.7, 163.1, 162.9, 162.3, 158.9, 158.4, 144.8, 144.6, 137.1, 129.7-129.2, 127.4, 127.2, 125.0, 121.4, 116.7, 116.6, 116.4, 116.3, 114.9, 114.8, 114.6, 114.5, 111.5, 111.3, 48.8, 48.6, 47.6, 47.5, 45.8, 45.7, 44.1, 39.6, 34.5, 26.8, 25.4, 8.6, 4.2. MS (ES+) m/z 480.1 (M+1).
Reaction SMILES: [Mg].O1C[CH2:5][CH2:4][CH2:3]1.C(Cl)C=C.[CH:11]12[CH2:21][CH:17]([C:18](=[O:20])[CH2:19]1)[CH:16]1[CH:12]2[CH2:13][CH2:14][CH2:15]1>C(O)(=O)C>[CH2:5]([C:18]1([OH:20])[CH2:19][CH:11]2[CH2:21][CH:17]1[CH:16]1[CH:12]2[CH2:13][CH2:14][CH2:15]1)[CH:4]=[CH2:3]
Reactant: O=C1CC2CC1C1CCCC21
Reactant: C1CCOC1
Agent: [Mg]
Solvent: CC(=O)O
Solvent: C=CCCl
Product: C=CCC1(O)CC2CC1C1CCCC21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a one litre reaction vessel, equipped with a stirrer, a cooler and a dropping funnel, 26.4 g magnesium, 100 g tetrahydrofurane and 1 g allyl chloride were heated to about 40° C. to start the reaction. A mixture of 76.5 g allyl chloride, 250 g tetrahydrofurane and 150 g tricyclo [5,2,1,02,6 ] decan-8-one was added in four hours, keeping the temperature at 35°-40° C. The reaction mixture was stirred for an additional 30 minutes and subsequently poured into a mixture of 600 g of ice and 80 g of acetic acid. The layers were separated and the water layer extracted twice with toluene. The combined organic layers were washed with 5% soda solution until alkaline and subsequently with water until neutral. The organic solvent was removed by distillation under reduced pressure. The residue was distilled on a Vigreux head at 2 mm.Hg. The fraction boiling between 93° and 95° C. was collected.