Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12][O:11][CH:10]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:9]1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC(C(=O)OCc2ccccc2)C1
Temperature: 80 °C
Yield: 95.5 %

Procedure:
In a 500-mL round-bottom flask, the 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (5.0 g, 22 mmol) was dissolved in DMF (75 mL). Benzyl bromide (3.6 ml, 30 mmol) was added via syringe, followed by potassium carbonate (4.8 g, 35 mmol). The sides of the glass were rinsed down with dmf (25 mL), and an air condenser was affixed, the reaction mixture was heated at 80° C. in an oil bath for 14 h. The reaction was cooled to ambient temperature and concentrated. The residue was transferred to a separatory funnel with 60% ether-hexane (300 mL), and the organic layer was extracted with water (75 mL), half-saturated brine (30 mL), and saturated brine (30 mL), then was dried over sodium sulfate and concentrated. The residue was purified through silica gel (500 mL) using 20% to 30% EtOAc-hexane to afford the title compound (6.81 g, 21 mmol). MS m/z 266 (M+1-isobutylene).
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl[CH2:22][CH2:23][OH:24]>C(O)C>[CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([S:15][CH2:22][CH2:23][OH:24])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCl
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCSc1nc2ccc(Cc3ccccc3)cc2[nH]1

Procedure:
5.75 g (24 mmoles) of 5-benzyl-benzimidazoline-2-thione, a solution of 1 g of sodium hydroxide and 8 ml of water, 2 ml (30 mmoles) of 2-chloroethanol and 30 ml of ethanol are refluxed for an hour. The reaction mixture is evaporated and extracted with water and dichloromethane, then the aqueous phase is extracted with dichloromethane. The residue of the combined organic phases is solidified under ether. After filtration and crystallization from ethyl acetate 4.63 g (68.1%) of title product are obtained. M.p.: 108°-109° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:19][S:20]([O:18][CH2:17][CH2:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:10]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCCO)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(CCCOS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A mixture of 3-(3-tert-butoxycarbonylaminophenyl)propanol (3.24 g, 12.9 mmol), methanesulfonylchloride (1.63 g, 14.2 mmol), triethylamine (1.44 g, 14.2 mmol) and ethyl acetate (50 ml) was stirred at room temperature for 1 hour. Then the reaction mixture was diluted with ethyl acetate and successively washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (50 g) with hexane-ethyl acetate (3:1) to give 3-(3-tert-butoxycarbonylaminophenyl)propyl methanesulfonate as a colorless oil (3.50 g, 82%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH2:27][NH:26][CH2:25][CH2:24]4)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8].[CH:31](=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH2:27][N:26]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:25][CH2:24]4)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1ccc2c(c1)CCNC2
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1ccc2c(c1)CCN(Cc1ccccc1)C2
Reaction time: 0.17 h
Yield: 48.6 %

Procedure:
A mixture of 25 mg (0.049 mmol) of 1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide, 0.0152 mL (0.15 mmol) of benzaldehyde and 0.6 mL of DMF was stirred for 10 min. 67 mg (0.3 mmol) of sodium triacetoxyborohydride was added and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was partitioned between dichloromethane (10 mL) and water (10 mL). The organic layer was separated and dried over sodium sulfate. Purification by column chromatography on silica gel gave 11.7 mg (49%) of 2-benzyl-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 492 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])c(NCc2ccccc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(N)c(NCc2ccccc2)c1
Reaction time: 4 h

Procedure:
To a solution of (3-benzylamino-4-nitro-phenyl)-carbamic acid tert-butyl ester E-1.5′ (5.000 g; 15 mmol) in ethanol (50.000 g) is added a solution of ammonium chloride (3.932 g, 73 mmol) in water (10 ml). The reaction mixture is then stirred at 70° C. for 20 min Iron powder (4.077 g; 73 mmol) is then added portionwise and the reaction is stirred for 4 h at reflux. The reaction mixture is filtered and washed with hot ethanol. The filtrate is concentrated under reduced pressure. Water is added and the mixture is extracted with 10% MeOH in DCM. The combined organic layer is dried over Na2SO4 and concentrated under reduced pressure. The product is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24])=[O:6])[CH:2]=[CH2:3].[CH:25](N(C(C)C)CC)(C)C.CI>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH3:25])[CH2:20][C:19]1=[O:24])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1CCNCC1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1CCN(C)CC1=O
Reaction time: 12 h

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-(2-oxo-piperazin-1-yl) methyl-4-(methanesulfonyloxy)pyrrolidine (6.37 g) in dichloromethane (60 ml) were added N,N-diisopropyl-N-ethylamine (3.38 ml) and methyl iodide (1.64 ml) under ice cooling with stirring, and the mixture was allowed to stay in a refrigeration for 12 hours. The mixture was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of ethyl acetate, methanol and isopropylamine (10:1:0.3 v/v/v) to give (2S,4R)-1-allyloxycarbonyl-2-(2-oxo-4-methylpiperazin-1-yl) methyl-4-(methanesulfonyloxy)pyrrolidine (3.19 g).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]([N:9]([CH3:24])[C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18]OS(C)(=O)=O)[CH2:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[CH2:27]([NH:29][CH2:30][CH2:31][O:32][CH3:33])[CH3:28]>CO>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7](=[O:8])[N:9]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18][N:29]([CH2:27][CH3:28])[CH2:30][CH2:31][O:32][CH3:33])[CH2:12][CH2:11]2)[CH3:24])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Reactant: CCNCCOC
Solvent: CO
Product: CCN(CC#C[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1)CCOC
Temperature: 25 °C

Procedure:
A solution of 200 mg (corresponds to 0.43 mmol) of trans-Methanesulfonic acid 3-{4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexyl}-prop-2-ynyl ester in 4.3 ml of methanol was cooled to 0° C., treated with 0.44 ml (1 mmol) of Ethyl-(2-methoxy-ethyl)-amine and stirred over night at RT. The solvent was evaporated and the residue extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried with Na2SO4, filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 99:1) gave 144 mg (83%) of pure trans-(4-{3-[Ethyl-(2-methoxy-ethyl)-amino]-prop-1-ynyl}-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester, MS: 407 (MH+, 1Cl). The following compounds were prepared from the corresponding mesylates and secondary amines:
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH:17][C@@H:18]3[CH2:22][C@H:21]([CH2:23][O:24][S:25]([NH:28]C(=O)OC(C)(C)C)(=[O:27])=[O:26])[C@@H:20]([OH:36])[CH2:19]3)[CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[S:25](=[O:27])(=[O:26])([O:24][CH2:23][C@H:21]1[CH2:22][C@@H:18]([NH:17][C:13]2[CH:12]=[C:11]([NH:10][C@@H:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)[N:16]=[CH:15][N:14]=2)[CH2:19][C@@H:20]1[OH:36])[NH2:28]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)OC[C@H]1C[C@@H](Nc2cc(N[C@H]3CCc4ccccc43)ncn2)C[C@@H]1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)OC[C@H]1C[C@@H](Nc2cc(N[C@H]3CCc4ccccc43)ncn2)C[C@@H]1O
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
To a solution of tert-butyl ({[(1R,2S,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2-hydroxycyclopentyl]methoxy}sulfonyl)carbamate (50.0 mg, 0.0962 mmol) in DCM (2.00 mL) was added trifluoroacetic acid (0.500 mL, 6.49 mmol), and the mixture was stirred for 30 min. The mixture was concentrated in vacuo and the residue was purified via silica gel chromatography eluting with 10% MeOH in DCM, and the product was dissolved in MeOH and treated with solid NaHCO3. The suspension was filtered and the filtrate was purified via silica gel chromatography eluting with 10% MeOH/DCM to afford the title compound as an amorphous solid (12.0 mg, 30%). 1H NMR (CD3OD, 400 MHz) δ: 7.94 (s, 1H), 7.29-7.12 (m, 4H), 5.53 (s, 1H), 5.32 (bs, 1H), 4.23-4.08 (m, 4H), 3.06-2.96 (m, 1H), 2.93-2.82 (m, 1H), 2.61-2.50 (m, 1H), 2.45-2.34 (m, 1H), 2.26-2.15 (m, 1H), 2.08-1.98 (m, 1H), 1.95-1.78 (m, 2H), 1.37-1.25 (m, 2H) ppm. LC/MS: Rt=1.29 min, ES+ 420. (AA standard).
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][Zn+])#[N:3].Cl[C:10]1[N:15]=[N:14][C:13]([NH:16][C:17](=[O:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.Cl>CCOC(C)=O.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:10]1[N:15]=[N:14][C:13]([NH:16][C:17](=[O:25])[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH:11]=1)#[N:3]
Reactant: O=C(Cc1ccccc1)Nc1ccc(Cl)nn1
Reactant: N#CCCCC[Zn+]
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: CCOC(C)=O
Product: N#CCCCCc1ccc(NC(=O)Cc2ccccc2)nn1
Temperature: 19 °C
Reaction time: 4 h
Yield: 60.2 %

Procedure:
A 1000 mL three-neck flask fitted with internal temperature probe and addition funnel was flushed with Ar(g). Under positive Argon pressure 4-cyanobutylzinc bromide (0.5M in THF, 500 mL, 250 mmol) was charged into the addition funnel then added to the reaction vessel at room temperature. Solid N-(6-chloropyridazin-3-yl)-2-phenylacetamide (20.6 g, 83.3 mmol) was added to the stirred solution at RT under Ar(g) flow, followed by the addition of NiCl2(dppp) (4.52 g, 8.33 mmol). The resulting mixture was stirred at 19° C. for 240 minutes and then quenched with ethanol (120 mL). Water (380 mL) added to the stirred red solution, giving a thick precipitate. Ethyl acetate (760 mL) added and stirred well for 30 minutes. The solids were removed by filtration through a pad of celite. The mother liquor was then transferred to a separatory funnel and the organic layer was washed with H2O (380 mL), 0.5% ethylenediaminetetraacetic acid solution (380 mL) and again with H2O (380 mL). The organic layer was concentrated by rotoevaporation. Resulting red oil was redissolved in EtOAc (200 mL) and 1M HCl (380 mL) was added to the well stirred flask. After 30 minutes the mixture was transferred to separatory funnel and the aqueous layer collected. The organic layer was extracted with 1M HCl (2×380 mL). The aqueous layer's pH was then adjusted to ˜7 using 7.5% sodium bicarbonate solution and the pale yellow precipitate was collected by suction filtration, rinsed with water (200 mL) and diethyl ether (2×200 mL). The solid was dried overnight under high vacuum to afford N-(6-(4-cyanobutyl)pyridazin-3-yl)-2-phenylacetamide (1023, 14.76 g). 1H NMR (300 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.23 (d, J=9.036 Hz, 1H), 7.59 (d, J=9.246 Hz, 1H), 7.32 (m, 5H), 3.79 (s, 2H), 2.90 (t, J=7.357 Hz, 2H), 2.56 (t, J=7.038 Hz, 2H), 1.79 (t, J=7.311 Hz, 2H), 1.63 (t, J=7.01 Hz, 2H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.N1CCCCC1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:16]/[C:17]([OH:19])=[O:18])[S:5][CH:6]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(Br)cs1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1cc(Br)cs1
Temperature: 100 °C
Yield: 100 %

Procedure:
4-Bromothiophenecarboxaldehyde (2.5 g, 13.1 mmol) was placed in a 25 ml round bottomed flask and charged with piperidine (0.14 ml, 0.11 mmol) and pyridine (7.1 ml). Malonic acid was then added (2.21 mg, 21.2 mmol) and the reaction heated to 100° C. and maintained for 24 h. The reaction was then allowed to cool to room temperature and the solvent removed in vacuo. The remaining residue was acidified with concentrated HCl to pH 3 and the solid collected, filtered and washed with distilled water (20 ml). It was then air and oven dried to yield a yellow solid (3.04 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1([CH2:23][CH2:24][CH2:25][CH:26]([NH:36][C:37](=[O:47])[C@H:38]([CH2:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[NH2:39])[CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:30]1([CH2:29][CH2:28][CH2:27][CH:26]([NH:36][C:37](=[O:47])[C@H:38]([CH2:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[NH:39][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH2:25][CH2:24][CH2:23][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: N[C@@H](Cc1cccnc1)C(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N[C@@H](Cc2cccnc2)C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (0.66 g; 2.89 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 3-(3-Pyridyl)-alanine [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (85) (1.00 g; 2.41 mmol), N,N-diisopropylethylamine (0.68 g; 5.29 mmol) and PyBOP (1.50 g; 2.89 mmol) are added sequentially. The reaction is stirred for 5 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (80%→100% ethyl acetate in hexanes) affording the desired product (86) as a white solid. ESMS: MH+ 627.6
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][NH2:22])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:23](OC)(=[O:28])[CH2:24][C:25]([CH3:27])=O>CCO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21]4[C:23](=[O:28])[CH2:24][C:25]([CH3:27])=[N:22]4)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Reactant: COC(=O)CC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC1=NN(c2cc(-c3ccnc(Nc4cccc(Cl)c4)n3)ccn2)C(=O)C1
Yield: 92.4 %

Procedure:
A mixture of (3-Chloro-phenyl)-[4-(2-hydrazino-pyridin-4-yl)-pyrimidin-2-yl]-amine (3.14 g, 0.010 mol) and Methyl acetoacetate (1.28 g, 0.010 mol) in EtOH (30 ml) and Acetic acid (30 ml) is stirred at reflux for one hour. At room temperature the resulting precipitate is filtered with suction to yield the title compound,(3.50 g, 92%) m.p. 149–150° C.
Reaction SMILES: CC([O:5][CH2:6][C:7]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH:16]([CH3:18])[CH3:17])[O:9][N:8]=1)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:5][CH2:6][C:7]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH:16]([CH3:18])[CH3:17])[O:9][N:8]=1
Reactant: COC(=O)c1c(COC(C)(C)C)noc1C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(CO)noc1C(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77.9 %

Procedure:
To a solution of methyl 3-{[(1,1-dimethylethyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolecarboxylate (500 mg, 1.96 mmol) in dichloromethane (97 mL) was added trifluoroacetic acid (97 mL, 1.25 mol). The solution was stirred at ambient temperature for approximately 45 minutes and then concentrated. The residue was taken up with ethyl acetate and poured into saturated sodium bicarbonate. Solid sodium bicarbonate followed by solid sodium carbonate were added until the pH was basic. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 25% ethyl acetate in hexanes) to afford the methyl 3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (304 mg, 78%). 1H-NMR (400 MHz, DMSO-d6) δ 5.29 (t, J=6 Hz, 1H), 4.62 (d, J=6 Hz, 2H), 3.77 (s, 3H), 3.68 (septet, J=7 Hz, 1H), 1.25 (d, J=7 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(O)C>[CH2:23]([N:10]1[C:11]2[C@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccccc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 79.7 %

Procedure:
A solution of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 213 mg, 0.7 mmol), tetrabutylammonium iodide (271 mg, 0.7 mmol) and benzyl bromide (0.45 mL, 3.7 mmol) in dimethylformamide (1.4 mL) was heated at 100° C. in a sealed tube for 24 h and then left at room temperature for a further 24 h. The solvent was evaporated and ethyl acetate was added. The solution was washed with 10% aqueous sodium thiosulfate and brine, dried (sodium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc. Burlington, Wis.) with a RS-12G silica gel column, eluting with 10-100% ethyl acetate/hexanes, to give a light brown foam. This was dissolved in ethanol and the solution was treated with activated carbon (15 mg) and heated at 50° C. for 1 h. The mixture was filtered through Celite and the Celite was washed with ethanol. The combined filtrates were evaporated and the resulting foam was dried under high vacuum to give (4R,7S)-1-benzyl-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (220 mg, 80%) as an off-white solid. ES(+)-MS (M+H) 395.
Reaction SMILES: C([Zn]CC)C.[CH:6]1([C:9]#[CH:10])[CH2:8][CH2:7]1.[Li]CCCC.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26]>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[C@@:24]([OH:29])([C:10]#[C:9][CH:6]1[CH2:8][CH2:7]1)[C:25]([F:26])([F:27])[F:28]
Reactant: C#CC1CC1
Reactant: Cc1ccc(N)c(C(=O)C(F)(F)F)c1
Agent: CC[Zn]CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(N)c([C@@](O)(C#CC2CC2)C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of (1R,2S)—PNE (17.6%-w/w, 21.0 g, 18.0 mmol) in a THF/toluene mixture (9:1-w/w) was charged in a vessel at room temperature. A solution of diethylzinc in toluene (29.9%-w/w, 6.10 g, 14.8 mmol) was added at 17 to 25° C. and the mixture was aged at said temperature range for 30 min. A solution of cyclopropylacetylene in toluene (69.6%-w/w, 8.55 g, 90.0 mmol) was added at 18° C. and the resulting mixture was aged at 20° C. for 60 min. A solution of BuLi in toluene (3.09 mol/kg, 17.6 g, 54.4 mmol) and a solution of 1-(2-amino-5-methylphenyl)-2,2,2-trifluoroethanone (CN46217, 36.5%-w/w, 33.4 g, 60.0 mmol) in toluene/THF (1:1-w/w) were added in parallel to the reaction mixture at 20° C. within 3 h. The addition of BuLi was started 10 min in advance of the CN46217 addition. After completed addition of CN46217 the reaction mixture was stirred for 30 min at 20° C., then heated to 30° C. over a period of 60 min and aged for 6 h at 30° C. The reaction mixture was stirred at 0° C. overnight. HPLC (Method B) indicated 72.3% conversion and 96.7% enantiomeric purity. The reaction mixture was diluted with toluene (25.8 g) and quenched by addition of aqueous citric acid (1 M, 73.9 g). After stirring for 15 min the phases were separated and the aqueous phase was discarded. The organic phase was successively washed with water (9.1 g), aqueous NaHCO3 solution (5%-w/w, 24.0 g), and water (12.0 g). The organic phase was partially concentrated (60 g residual solution), diluted with toluene (30 g), and partially concentrated again (52 g residue). The residue was diluted with toluene (65 g), cooled to 5° C. and aged over night. The crystals were filtered, washed with cold (approx. 5° C.) toluene (10 g) and dried under vacuum at 40° C. The wet product (10.8 g) obtained as off-white solid with a purity of 99.2 and 100% ep according to method B. The crude product was purified by slurring it in a mixture of toluene (10 mL) and heptane (40 mL) at room temperature for 1 h, filtered and dried at 40° C. in vacuo. The product (compound of formula II, wherein R1 is trifluoromethyl, R2 is 2-cyclopropyl-ethynyl, R8 is 5-methyl, R9 is hydrogen and R10 is hydrogen) was obtained as white solid (10.6 g, 38 mmol, 64% yield) with a purity of 99.4% and 100% ep according to method B. The assay was 97.0%-w/w according to 1H-NMR.