Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1.[CH3:21][NH:22][C:23]1[C:28]([CH3:29])=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]([N:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)[C:2]([C:26]2[CH:25]=[N:24][C:23]([NH:22][CH3:21])=[C:28]([CH3:29])[CH:27]=2)=[N:3]1)([CH3:20])[CH3:19]
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)cc1C
Reactant: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CNc1ncc(-c2nn(C(C)C)cc2-c2ccnc(NC[C@H](C)O)n2)cc1C
Temperature: 85 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
To a solution of (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-1-3) (1 g, 2.58 mmol) in toluene (30 mL) and EtOH (10 mL) were added N,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (B-4-3) (2 g, 6.3 mmol in theory) and 2 N aq. Na2CO3 (4 mL). The resulting mixture was degassed under N2 for 2 minutes. Then Pd(PPh3)4 (0.3 g, 0.26 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90° C. and stirred overnight. MS showed the reaction was complete and the mixture was cooled. The organic layer was separated and concentrated. The residue was purified by prep. HPLC to afford (2S)-1-(4-(1-isopropyl-3-(5-methyl-6-(methylamino)pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-4) (0.167 g, 16.98%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:9])[CH:8]=1)[NH2:5].[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl.Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][S:11]([CH3:10])(=[O:13])=[O:12])[CH:6]=[C:7]([I:9])[CH:8]=1
Reactant: Nc1cc(F)cc(I)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cc(F)cc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
Dissolve 3-fluoro-5-iodoaniline (600 mg, 2.53 mmol) (prepared as described in published PCT International Application WO96/23783 A1, published Aug. 8, 1996), methanesulfonyl chloride (896 mg, 7.83 mmol), triethylamine (1.91 g, 18.9 mmol), and N,N-dimethylamino-4-pyridine (31 mg, 0.253 mmol) in CH2Cl2 (10 mL) and stir at room temperature overnight. Dilute with 1.00N aqueous HCl (20 mL) and extract into ethyl acetate. Dry (MgSO4) and concentrate organics to a yellow solid. Dissolve solid in THF (50 mL) and add 1.0M tetrabutylammonium fluoride (2.8 mL). Heat to reflux for 3.5 h. Cool to room temperature, dilute with H2O, and extract into ethyl acetate. Dry (MgSO4) and concentrate organics. Chromatograph on silica gel (40 g), eluting with 20% to 35% ethyl acetate/hexanes affords 618 mg (78%) of the title compound as a white solid. MS (ES) 314 (M−H); HPLC shows 100% purity.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[F:10][CH:11]([F:14])[CH2:12][OH:13].CC(C)([O-])C.[K+].O>C1COCC1>[Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([O:13][CH2:12][CH:11]([F:14])[F:10])=[CH:6][CH:7]=1
Reactant: OCC(F)F
Reactant: Cc1nc(Br)ccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(OCC(F)F)ccc1Br
Temperature: 70 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
To a mixture of 3,6-dibromo-2-methylpyridine (2.00 g, 7.97 mmol) and 2,2-difluoroethanol (981 mg, 12.0 mmol) in THF (100 mL) is added potassium tert-butoxide (1.34 g, 12.0 mmol), and the mixture is stirred at 70° C. for 12 hours. After cooling to room temperature, the resulting mixture is poured to water (200 mL). The aqueous layer is extracted with ethyl acetate (200 mL×2). The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (8:1) to give 1.94 g (97% yield) of the title compound as colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:3]=1.[CH3:16][NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1)=[O:19].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(Cl)Cl>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:3]=[C:2]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:18]([NH:17][CH3:16])=[O:19])=[CH:26][CH:25]=2)[N:7]=1
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CNC(=O)Nc1ccc(-c2nc(Cl)nc(N3CCOC[C@@H]3C)n2)cc1
Temperature: 90 °C

Procedure:
A mixture of (S)-4-(4,6-dichloro-1,3,5-triazin-2-yl)-3-methylmorpholine (step (i) example 1) (4 g, 16.1 mmol), 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (4.67 g, 16.1 mmol), bis(triphenylphosphene)palladium(II) dichloride (0.66 g, 0.8 mmol) and 2M Na2CO3 (8 ml, 19.6 mmol) in DME (32 ml) was heated in the microwave at 90° C. for 90 minutes. The mixture was diluted with DCM (200 mL), washed with water (200 mL), the organic layer passed through a PTFE hydrophobic frit and the solvent removed in vacuo to yield a black oil. The oil was purified by flash chromatography using Pet ether, EtOAc 0-100% gradient to yield an off-white solid of (S)-1-(4-(4-chloro-6-(3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea. (932 mg, 15%)
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH2:15][CH2:16][CH2:17][OH:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[OH:18][CH2:17][CH2:16][NH:15][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(NCCO)CC1
Yield: 89 %

Procedure:
A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (15 g), 2-aminoethanol (14 ml), acetic acid (6.6 ml) in 1,2-dichloroethane (300 ml) was mixed at room temperature for 1 hour, and then sodium triacetoxyborohydride (49 g) was added thereto, followed by mixing at room temperature for 15 hours. pH of the aqueous layer was adjusted to about 12 by adding a 1 N aqueous sodium hydroxide solution to the reaction mixture, and then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound as a colorless oil (18 g, 89%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:46])([CH3:45])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:44])([C@@:13]3([CH3:43])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][S:38](=[O:42])(=[O:41])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.CC1(C)C(C)(C)OB([C:57]2[CH2:62][CH2:61][CH:60]([CH2:63][C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH2:59][CH:58]=2)O1>>[O:42]=[S:38]1(=[O:41])[CH2:39][CH2:40][N:35]([CH2:34][CH2:33][NH:32][C@:16]23[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]2[C@@H:18]2[C@@:13]([CH3:43])([CH2:14][CH2:15]3)[C@@:12]3([CH3:44])[C@@H:21]([C@:22]4([CH3:25])[C@@H:9]([CH2:10][CH2:11]3)[C:8]([CH3:45])([CH3:46])[C:7]([C:57]3[CH2:62][CH2:61][CH:60]([CH2:63][C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH2:59][CH:58]=3)=[CH:24][CH2:23]4)[CH2:20][CH2:19]2)[CH2:36][CH2:37]1
Reactant: CCOC(=O)CC1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(CC(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 42.7 %

Procedure:
The title compound was prepared following the method described in step 1 for the preparation of Example 1, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)acetate as the reactants. The product was obtained as a mixture of diasteromers in 42.7% yield. MS: m/e 737.65 (M+H)+, 2.939 min (method 8). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.32 (br. s., 1H), 5.19 (d, J=5.8 Hz, 1H), 4.72 (d, J=1.8 Hz, 1H), 4.61 (d, J=1.5 Hz, 1H), 4.21-4.09 (m, 2H), 3.15-2.96 (m, 8H), 2.77-2.54 (m, 4H), 2.52-2.40 (m, 1H), 2.34-2.08 (m, 4H), 2.03-1.72 (m, 7H), 1.70 (s, 3H), 1.61-1.39 (m, 9H), 1.39-1.19 (m, 10H), 1.12-1.04 (m, 7H), 1.01-0.97 (m, 6H), 0.96-0.91 (m, 3H), 0.87 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=[O:5].[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>N1C=CC=CC=1>[C:19]([O:1][C:2]1[CH:17]=[C:16]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][C:7]=1[O:13][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:5])(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)c2ccc(OC(=O)C(C)(C)C)cc2OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1

Procedure:
A solution of 2.4 g (0.01 mole) of 2,2',4,4'-tetrahydroxybenzophenone and 5 g (0.04 mole) of pivaloylchloride was warmed to 50° C. in 75 mls of dry pyridine for 2 hrs with a drying tube attached. The solvent was removed via rotary evaporator and the residue was partitioned between H2O and CH2Cl2 ; the organic layer was washed with dilute K2CO3 and dried over MgSO4. After removal of solvent via rotary evaporation, the title compound was crystallized from ethanol. 4 g. (69%) yield. M.P.~154°156° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[Cl-].[Na+].[OH-].[Na+].[O:11]1[CH:20]2[CH:12]1[CH2:13][C:14]1[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOCC>[N:1]1([C@@H:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:20][C@H:12]2[OH:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: c1ccc2c(c1)CC1OC21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O[C@@H]1Cc2ccccc2[C@H]1N1CCCC1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
A solution of 10.8 ml of pyrrolidine in 6.75 g of 2,3-epoxy-indane [described by Mousseron et al., Bull. de Soc. Chim. de France, 1946, p. 629-630] was slowly added to 10.8 ml of demineralized water and after increasing the temperature to 65° C., the mixture was stirred for 90 minutes at 65° C. 20 ml of demineralized water were then added and excess pyrrolidine was distilled off at reduced pressure to obtain an oil phase and an aqueous phase. The aqueouse phase was saturated with sodium chloride and 1 ml of 32% sodium hydroxide was added thereto. The mixture was extacted with ether and the ether phase was dried and evaporated to dryness under reduced pressure. The oil residue was chromatographed over silica and eluted with ethyl acetate containing 5% of triethylamine to obtain 8.81 g of trans (±) 2,3-dihydro-1-(pyrrolidin-1-yl)-1H-inden-2-ol.
Reaction SMILES: [NH3:1].[CH:2]1([C:5]2[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7](OC)[N:6]=2)[CH2:4][CH2:3]1>CO>[NH2:1][C:7]1[N:6]=[C:5]([CH:2]2[CH2:3][CH2:4]2)[N:10]=[C:9]([O:11][CH3:12])[N:8]=1
Reactant: COc1nc(OC)nc(C2CC2)n1
Reactant: N
Solvent: CO
Product: COc1nc(N)nc(C2CC2)n1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
Gaseous ammonia is blown through a solution of 5 g of 2-cyclopropyl-4,6-dimethoxy-1,3,5-triazine in 30 ml of methanol at room temperature until saturation is reached. The solution is then stirred in a bomb tube (autoclave) at 140° C. for 1 hour; it is subsequently cooled, and the reaction mixture is filtered to thus obtain 0.5 g of the title product as light-brown crystals, m.p. 156°-157° C.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4])([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NC(C)C)[nH]n1
Yield: 13 %

Procedure:
As described for example 1b, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.32 mmol) was converted, using isopropylamine instead of morpholine, to the title compound (14 mg, 13%), which was obtained as a colorless oil. MS: m/e=341.3 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)[O:18][C:19]=2[CH3:20])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(C(C)(C)C)cc3)c(C)o2)cc1
Agent: Cl
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(C(C)(C)C)cc1
Yield: 89.4 %

Procedure:
Method C. Reaction of benzoate 22 (97 mg, 0.23 mmol) and 6 M HCl (5 mL) gave acid 23 (85 mg, 89%) as a white solid: mp (H2O) 220-222° C.; 1H NMR δ 13.15 (br s, 1 H, CO2H), 8.02 (dd, J=8.7, 1.9Hz, 2 H, H-2, H-6), 7.88 (ddd, J=8.7, 1.9, 1.5Hz, 2 H, H-3, H-5), 7.70 (ddd, J=8.6, 2.0, 1.9Hz, 2 H, H-2′, H-6′), 7.63 (ddd, J=8.6, 2.0, 1.9Hz, 2 H, H-3′, H-5′), 4.64 (s, 2 H, CH2SO2), 2.14 (s, 3 H, CH3), 1.29 [s, 9 H, C(CH3)3]; MS m/z 415.5 (MH+, 100%). Anal. calcd for C22H23NO5SH2O: C, 61.24; H, 5.84; N, 3.25. Found: C, 61.32; H, 5.50; N, 3.14%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH2:14][CH2:15][CH2:16][OH:17])[CH:3]=1.[NH2:18][NH2:19]>O1CCOCC1>[NH:18]([C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH2:14][CH2:15][CH2:16][OH:17])[CH:3]=1)[NH2:19]
Reactant: NN
Reactant: OCCCc1cc(Cl)cc(N2CCOCC2)n1
Solvent: C1COCCO1
Product: NNc1cc(CCCO)nc(N2CCOCC2)c1
Yield: 87.6 %

Procedure:
3-(4-Chloro-6-morpholin-4-yl-pyrid-2-yl)-propan-1-ol (19.4 mmol) is dissolved in dioxane (30 mL). To the reaction mixture is added anhydrous hydrazine (10 mL, 300 mmol). The reaction is then heated at reflux for five hours. The solvent is removed under reduced pressure, and the crude solid is dissolved in a mixture of dichloromethane (800 mL) and 10% potassium carbonate (40 mL). The organic layer is isolated, dried with sodium sulfate, and evaporated to yield crude 3-(4-hydrazino-6-morpholin-4-yl-pyrid-2-yl)-propan-1-ol (4.3 g., 17 mmol).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@:10]1([CH:50]1[CH2:52][O:51]1)[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:54]>CO.O1CCCC1>[NH2:54][CH2:52][CH:50]([C@:10]12[O:32][C@:13]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)([O:12][CH2:11]1)[C@H:14]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C@@H:15]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:51]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@@](C5CO5)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(O)CN)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(oxiran-2-yl)-6,8-dioxabicyclo[3.2.1]octane 10a (0.4 g, 0.56 mmol) in a methanol/tetrahydrofuran mixture (v/v=1/2, 9 mL) was added ammonium hydroxide (2 mL, 10 mmol). The mixture was heated to 55° C. and stirred for 16 hours. The resulting mixture was extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=6/1 to give the title compound 10b as colourless oil (0.21 g, 51.2%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.48 (m, 2H), 7.40 (m, 1H), 7.33 (m, 4H), 7.26 (m, 6H), 7.18 (m, 3H), 7.05 (m, 2H), 7.04 (m, 2H), 6.85 (m, 2H), 4.90 (m, 1H), 4.77 (m, 3H), 4.26 (d, 1H), 4.11 (d, 2H), 4.00 (m, 2H), 3.91 (m, 3H), 3.85 (t, 1H), 3.71 (m, 4H), 2.71 (m, 1H), 2.56 (m, 1H), 1.26 (t, 3H).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[C:9](Cl)(=[O:13])[C:10]([CH3:12])=[CH2:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:8][C:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][C:2]=1[C:9](=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)C(=O)Cl
Reactant: Cc1ccc(C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=C(C)C(=O)c1cc(C)ccc1C

Procedure:
Paraxylene (1 mL), methacryloyl chloride (110 mg), and aluminium chloride (160 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (140 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[C:11]12([CH:21]3[CH2:25][CH2:24][CH2:23][NH:22]3)[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C>[C:11]12([CH:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:6]3[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[C:3]=3[C:4]#[N:5])[CH2:20][CH:15]3[CH2:14][CH:13]([CH2:19][CH:17]([CH2:16]3)[CH2:18]1)[CH2:12]2
Reactant: C1CNC(C23CC4CC(CC(C4)C2)C3)C1
Reactant: N#Cc1c(F)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1c(Br)cccc1N1CCCC1C12CC3CC(CC(C3)C1)C2
Temperature: 130 °C

Procedure:
2-Bromo-6-fluorobenzonitrile (900 mg), 2-adamantan-1-yl-pyrrolidine (924 mg), and potassium carbonate (1244 mg) were added to dimethyl sulfoxide and the mixture was heated at 130° C. for 16 hours. The solution was cooled, diluted with ethyl acetate, washed twice with 1M HCl, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the crude material was concentrated under vacuum and purified on silica gel using 5% ethyl acetate (hexanes) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([CH3:11])[N:5]=[CH:4][N:3]=1.[CH2:12]([N:19]1[CH2:26][CH:25]2[CH:21]([CH2:22][NH:23][CH2:24]2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:12]([N:19]1[CH2:26][CH:25]2[CH2:24][N:23]([C:8]([C:7]3[C:2]([CH3:1])=[N:3][CH:4]=[N:5][C:6]=3[CH3:11])=[O:10])[CH2:22][CH:21]2[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(CN2CC3CNCC3C2)cc1
Reactant: Cc1ncnc(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncnc(C)c1C(=O)N1CC2CN(Cc3ccccc3)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
step 1—To a mixture of 4,6-dimethyl-pyrimidine-5-carboxylic acid (0.85 g, 5.58 mmol, T. J. Kress et. al. Heterocycles 1994 38:1375) and 4a (1.13 g, 5.58 mmol, C. J. Ohnmacht et al. J. Heterocycl. Chem. 1983 20:321) in DCM (25 mL) at RT was added sequentially EDCI (1.43 g, 6.7 mmol), HOBt (0.9 g, 6.7 mmol) and DIPEA (3.9 mL, 22.34 mmol) and the mixture was stirred overnight at RT. The reaction mixture was washed with 5% NaHCO3 solution, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with MeOH (containing 10% NH4OH)/DCM (0 to 4%) to afford 1.5 g of (5-benzyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4,6-dimethyl-pyrimidin-5-yl)-methanone: ms (ES+) m/z 337 (M+H)+. To a solution of amide from the previous step (1.5 g, 4.45 mmol) in MeOH (50 mL) was added ammonium formate (2.81 g, 44.58 mmol). Palladium on charcoal previously wetted with MeOH was slowly added and the mixture heated to reflux for 8 h. The catalyst was filtered and solvent evaporated. The residue was purified by flash chromatography on silica gel eluting with MeOH (containing 10% NH4OH)/DCM (0 to 4%) to afford 0.941 g of 44b: ms (ES+) m/z 247 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH2:13])[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[O:14]=[C:15]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][CH2:17][N:16]1[CH2:27][C:28](O)=[O:29].C(N=C=NCCCN(C)C)C>ClCCl>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([NH:13][C:28](=[O:29])[CH2:27][N:16]3[CH2:17][CH2:18][CH2:19][CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]3=[O:14])[CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Reactant: NC1(c2ccc(F)cc2)CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)C1=O)NC1(c2ccc(F)cc2)CCC1
Reaction time: 60 h

Procedure:
To a solution of 1-(4-fluorophenyl)cyclobutanamine hydrochloride (0.048 g, 0.236 mmol) and 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (Example 91D, 0.050 g, 0.214 mmol) in dichloromethane (0.5 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.049 mL, 0.279 mmol) (0.049 mL, 0.279 mmol), and the reaction was stirred for approximately 60 hours. The reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). The product was dissolved in a minimal ethyl acetate and hexanes was added which caused the product to precipitate from solution. Concentration gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.34-7.43 (m, 2H), 7.22-7.34 (m, 3H), 7.14-7.20 (m, 2H), 7.09-7.11 (br s, 1H), 6.97-7.03 (m, 2H), 4.03 (d, J=14.1 Hz, 1H), 3.87 (d, J=14.1 Hz, 1H), 3.69 (dd, J=7.9, 6.0 Hz, 1H), 3.51-3.60 (m, 1H), 3.39-3.48 (m, 1H), 2.47-2.60 (m, 4H), 1.78-2.17 (m, 6H); MS (ESI−) m/z 379 (M−H)−.