Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:9][C:10]3[C:11](=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:6][C:5]([Br:18])=[CH:4][N:3]=1.[C:19](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:18][C:5]1[CH:6]=[C:7]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:19])[C:11]=3[N:12]=2)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1-c1nc2c(O)cccc2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2oc(-c3cc(Br)cnc3N)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
TFA (20 ml) was added to the mixture. The resulting solution was stirred at 25° C. for 2 hours. The TFA was evaporated and the mixture was basified with a solution 7N of ammonia in methanol. The mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 1 to 2% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(2-amino-5-bromo-3-pyridyl)-1,3-benzoxazol-4-ol (1.040 g) as a solid. NMR Spectrum: (DMSOd6) 6.81 (d, 1H), 7.18 (d, 1H), 7.25 (dd, 1H), 7.94 (bs, 2H), 8.28 (d, 1H), 8.30 (d, 1H), 10.47 (bs, 1H); Mass spectrum: M+H+ 306-308 Iodomethane (0.5 ml) was added to a stirred suspension 2-(2-amino-5-bromo-3-pyridyl)-1,3-benzoxazol-4-ol (820 mg) and potassium carbonate (1111 mg) in DMF (5 ml). The resulting suspension was stirred at 25° C. for 3 hours. The DMF was evaporated under reduce pressure. The mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 20 to 50% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 5-bromo-3-(4-methoxy-1,3-benzoxazol-2-yl)pyridin-2-amine (480 mg) as a solid. NMR Spectrum: (CDCl3) 4.08 (s, 3H), 6.84 (d, 1H), 6.93 (bs, 2H), 7.20 (d, 1H), 7.31 (dd, 1H), 8.23 (d, 1H), 8.38 (d, 1H); Mass spectrum: M+H+ 319-321
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[C:18]([CH2:20][CH3:21])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][C@@H:8]1[OH:22])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][CH2:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[C:18]([CH2:20][CH3:21])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][C@@H:8]1[OH:22]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CCCN=[N+]=[N-])O2)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CCCN)O2)c(=O)[nH]c1=O
Yield: 89.7 %

Procedure:
A solution of 0.28 g of 5'-(2-azidoethyl)-2',5'-dideoxy-5-ethyluridine in 50 ml of ethanol was hydrogenated over 50 mg of 10% palladium-on-carbon catalyst for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated to dryness to give 0.23 g of 5'-(2-aminoethyl)-2',5'-dideoxy-5-ethyluridine in the form of a colorless oil which crystallized upon standing.
Reaction SMILES: [CH:1]([N:4]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]([NH:20][C:21]2[NH:22][N:23]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=3)[CH:25]=2)=[O:19])=[N:16][CH:17]=1>CS(C)=O.CO>[CH3:35][O:34][C:32]1[CH:33]=[C:28]([CH2:27][CH2:26][C:24]2[CH:25]=[C:21]([NH:20][C:18]([C:15]3[CH:14]=[N:13][C:12]([N:7]4[CH2:8][CH2:9][CH2:10][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:17][N:16]=3)=[O:19])[NH:22][N:23]=2)[CH:29]=[C:30]([O:36][CH3:37])[CH:31]=1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Reactant: CC(C)N1CCCNCC1
Solvent: CS(C)=O
Solvent: CO
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCCN(C(C)C)CC4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
1-isopropyl-1,4-diazepane (228 mg, 1.60 mmol) was added to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (310 mg, 0.80 mmol) in DMSO (4.00 ml) at 25° C. The resulting solution was stirred at room temperature for 2 hours. The reaction was incomplete so the temperature was increased to 60° C. and the reaction mixture was stirred for a further 2 h. The reaction was still incomplete so the reaction mixture was stirred for a further 18 h at room temperature. The reaction mixture was diluted with MeOH (5 ml) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford crude product as an orange dry film. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (167 mg, 42%) as a pale yellow solid.
Reaction SMILES: [CH:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(Cl)(Cl)Cl.[N+](C1C=C([N+]([O-])=O)C=CC=1C([O-])=O)([O-])=[O:16]>CCCCCC.C(O)(C)C>[C@@H:4]12[CH2:3][CH2:2][CH2:1][C@@H:9]1[CH2:8][CH2:7][CH2:6][C@@H:5]2[OH:16]
Reactant: OC1CCc2ccccc21
Reactant: O=C([O-])c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: O[C@H]1CCC[C@H]2CCC[C@H]21

Procedure:
Racemic 19 (86 mg, 0.62 mmol) was dissolved in THF (5 mL), vinyl acetate (0.5 mL) was added. Amano lipase PS-30 (60 mg) was added and the resulting suspension was stirred at 23° C. until 50% conv. was reached (NMR) in ca. 6 h. The resulting suspension was diluted with Et2O and filtered on celite, the filter cake rinsed with Et2O. After evaporation of the remaining solvent, the residue was purified by column chromatography using hexanes/EtOAc (8:1, 6:1 then 4:1) to yield acetate 21 and the desired enantioenriched (−)-indanol (−)-19 (38.5 mg, 45% yield). [α]D20-28.3° (c 1.02, CHCl3), ([α]D20 lit. −27.2° (c 1.0, CHCl3).38 The enantiomeric excess of the 2,4-dinitrobenzoate derivative was determined to be 89.9% ee by chiral HPLC, Column ChiralPak IA, hexane/isopropanol (100/0 to 90/10, 15 min; 90/10 to 80/20, 15 min), 1 mL/min, Rt minor=16.58 min, Rt Major=19.5 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[Li].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:12]=[N:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:12]([NH:13][C:14]1[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=1)[C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(C=Nc2ccncc2)cc1OC
Reactant: [Li]c1nccs1
Product: COc1ccc(C(Nc2ccncc2)c2nccs2)cc1OC

Procedure:
The title compound is prepared in a similar manner to Examples 5, 6 and 7 by reacting 2-thiazolyl lithium (obtained from 2-bromothiazole and butyl lithium) with 4-(3,4-dimethoxybenzylideneamino)pyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].OC1C2N=NNC=2C=CC=1.CCN=C=NCCCN(C)C.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CN(C=O)C>[N:38]1([C:7]([C:6]2[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:9])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
In a round bottomed flask, 3-nitro-5-trifluoromethylbenzoic acid (5.0 g, 21.3 mmoles) was dissolved in 40 mL of dry DMF, to this solution was added hydoxybenzotriazole (5.8 g, 42.5 mmoles) and EDCI (8.2 g, 42.5 mmoles) and the solution stirred for 1 hour at room temperature. At the end of this time morpholine (2.2 g. 25.5 mmoles) was added and the reaction stirred overnight. The solution was then concentrated to dryness, and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined extracts dried with magnesium sulfate, filtered and concentrated. Chromatography with silica gel and eluting with a ethyl acetate/hexane gradient of 0-35% over 80 minutes gave morpholin-4-yl-(3-nitro-5-trifluoromethyl-phenyl)-methanone (1.8 g). 1H NMR (300 MHz, DMSO-d6) δ 8.6 (d, 2H), 8.3 (s, 1H), 3.8-3.6 (bm, 4H), 3.56 (b, 2H), 3.33 (bs, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC(S(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O)=CC=1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([O:20][CH2:39][C:40]([F:43])([F:42])[F:41])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: COc1ccc(O)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc(OCC(F)(F)F)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 51.9 %

Procedure:
A mixture of 2.83 g of Compound 6A, 6.05 g of cesium carbonate and 2.95 g of 2,2,2-trifluoroethyl p-toluenesulphonate in 60 mL of acetonitrile was refluxed for 16 hours while stirring. The solvent was evaporated off at reduced pressure, 90 mL of brine was added to the residue, and the mixture was extracted with ethyl acetate (3×40 mL). The organic layer was washed with water (3×20 mL) and of brine (20 mL) and dried over sodium sulphate. The solvent was removed at reduced pressure and the residue purified by flash chromatography in a petroleum ether/ethyl acetate gradient (95:5 to 80:20). The solvents were removed in vacuo to yield 1.86 g (52%) of Compound 6B as a white solid. M.p. (98) 102-105° C.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH3:6][C:7]1[N:12]=[C:11]([NH:13][C:14](=[S:16])[S-:15])[CH:10]=[CH:9][CH:8]=1.C([NH+](CC)CC)C.C(O)C>CN(C)C=O>[OH:5][C:3]1([CH3:4])[CH2:2][S:16][C:14](=[S:15])[N:13]1[C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:6])[N:12]=1
Reactant: CC(=O)CCl
Reactant: Cc1cccc(NC(=S)[S-])n1
Agent: CC[NH+](CC)CC
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1cccc(N2C(=S)SCC2(C)O)n1
Temperature: 2 °C
Reaction time: 3 h

Procedure:
Chloroacetone (13.9 cc) is added to a solution of triethylammonium (6-methylpyrid-2-yl)dithiocarbamate (50.0 g) in dimethylformamide (250 cc) at a temperature between 15 and 23° C. The reaction is continued for 3 hours at 20°-23° C. After filtration and evaporation of the dimethylformamide under reduced pressure (0.1 mm.Hg) at 45° C., the residual oil is dissolved in ethyl acetate (500 cc); the organic solution is washed with distilled water (100 cc), dried over sodium sulphate, treated with decolorising charcoal (2 g) and evaporated. The crystals obtained (38.0 g; m.p. 150°-153° C.) are dissolved in boiling ethanol (520 cc). After 2 hours cooling at 2° C., the resulting crystals are separated by filtration, washed twice with ice-cold ethanol (total 80 cc) and dried under reduced pressure (0.1 mm.Hg) at 45° C. 4-Hydroxy-4-methyl-3-(6-methylpyrid-2-yl)-thiazolidine-2-thione (24.9 g), melting at 156° C., is obtained.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][C@H:6]1[C:30](O)=[O:31])(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.C[Si]([CH:43]=[N+:44]=[N-:45])(C)C>C(Cl)Cl.CN(C=O)C.CCCCCC>[N+:44](=[CH:43][C:30]([C@@H:6]1[CH2:7][C@@H:8]([S:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9][N:5]1[S:2]([CH3:1])(=[O:3])=[O:4])=[O:31])=[N-:45]
Reactant: CS(=O)(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CS(=O)(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1C(=O)C=[N+]=[N-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 27.1 %

Procedure:
A solution of 25 g (93 mmol) (2S,4R)-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid in 265 ml CH2Cl2 at 0° C. was treated with 2 drops of DMF followed by 8 ml (99 mmol) oxalylchloride. After 15 min at 0° C. the reaction was stirred 2 h at room temperature, evaporated and dissolved in 260 ml THF/CH3CN 1:1. 58.5 ml (117 mmol) 2M trimethylsilyldiazomethane solution in hexane was then added at 0° C. The reaction was stirred 16 h at room temperature, evaporated and poured in H2O/EtOAc. The organic phase was dried over Na2SO4, evaporated and purified by flash column chromatography on silica gel with hexane/EtOAc (7:3 to 1:1) to give 12.4 g (48%) of (2S,4R)-2-diazo-1-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-yl)-ethanone, MS: 509 (M+NH4+).
Reaction SMILES: FC1C=C(C2CC(=O)C3C(=CC=C(O)C=3)O2)C=CC=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[C:28](=[O:30])[CH3:29].[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:33]=1[CH:34]=O>>[OH:27][C:24]1[CH:23]=[C:22]2[C:21](=[CH:26][CH:25]=1)[O:20][CH:34]([C:33]1[C:32]([F:31])=[CH:39][CH:38]=[CH:37][C:36]=1[F:40])[CH2:29][C:28]2=[O:30]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: O=Cc1c(F)cccc1F
Agent: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Product: O=C1CC(c2c(F)cccc2F)Oc2ccc(O)cc21

Procedure:
6-Hydroxy-2-(2,6-Difluorophenyl)chroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 3.0 g of 2′,5′-dihydroxyacetophenone and 2.6 ml of 2,6-difluorobenzaldehyde. The product was triturated from ethanol. 1H NMR (400 MHz, d6-DMSO) δ: 7.55 (m, 1H) 7.22-7.18 (m, 2H), 7.14 (d, 1H, J 3.0 Hz), 7.03 (dd, 1H, J 8.9, 3.0 Hz), 6.93 (d, 1H, J 8.9 Hz), 5.84 (dd, 1H, J 14.0, 3.0 Hz), 3.38 (dd, 1H, J −17.0, 14.0 Hz), 2.80 (dd, 1H, J −17.0, 3.0 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]([CH3:31])[C:29](=[O:32])[O:28][CH2:27][CH2:26][C:25]=2[CH:33]=1>CC(O)C>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[N:30]([CH3:31])[C:29](=[O:32])[O:28][CH2:27][CH2:26][C:25]=3[CH:33]=2)=[N:3][CH:4]=1
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl
Temperature: 120 °C
Yield: 70.1 %

Procedure:
A mixture of 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methylbenzamide (50 mg, 0.17 mmol), 2-amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (49 mg, 0.25 mmol) and camphorsulformic acid (4 mg, 0.02 mmol) in IPA (5 mL) was microwave-heated at 120° C. for 3.5 h. The mixture was concentrated and chromatographed with preparative TLC (methylene chloride and ethyl acetate (4:1)) to give 54 mg of 2-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (71%): 1H NMR (300 MHz, CDCl3) δ 8.33 (d, 1H), 7.95 (s, 1H), 7.56 (d, 1H), 7.43 (dd, 1H), 7.34 (d, 1H), 7.26 (m, 1H), 7.1 (t, 1H), 7.05 (d, 1H). 4.35 (t, 2H), 3.3 (s, 3H), 2.9 (s, 3H), 2.85 (t, 2H); MS (m/e): 453.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20](/[CH:22]=[N:23]/O)[CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.CS(Cl)(=O)=O>N1C=CC=CC=1.C(OCC)(=O)C.[O-]S([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([C:22]#[N:23])[CH:21]=1)[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(Br)cc(/C=N/O)c2)CC1
Agent: [Cu+2]
Agent: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Br)cc(C#N)c2)CC1
Temperature: 60 °C

Procedure:
To a solution of tert-butyl 4-{3-bromo-5-[(E)-(hydroxyimino)methyl]phenoxy}piperidine-1-carboxylate (157 mg, 0.393 mmol) in pyridine (1.2 mL) was added methanesulfonyl chloride (0.12 mL, 1.6 mmol). The reaction mixture was heated at 60° C. for 2 hours. The reaction solution was diluted with ethyl acetate and saturated CuSO4 solution. The organic layer was washed with CuSO4 twice, 1N HCl, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column to give the desired product as white solid. LCMS (M+H)+: 381.1, 383.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH: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])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31](=[O:41])[C:32]1[CH:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:29][O:30][C:31](=[O:41])[C:32]1[CH:37]=[CH:36][C:35]([C:38]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[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:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:39])=[CH:34][CH:33]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (100.0 mg, 0.23 mmol), 4-chlorocarbonyl-benzoic acid methyl ester (60.0 mg, 0.30 mmol), iPr2NEt (0.12 mL, 0.69 mmol) in CH2Cl2 (5 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and the residue was purified by flash column (1%-15% AcOEt in Hex) to give rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-benzoic acid methyl ester (132.0 mg, 98.0%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].BrC[C:23]1[S:24][C:25]([O:28][CH2:29][CH3:30])=[N:26][N:27]=1.C(OCC)(=O)C>CC(C)=O>[CH2:29]([O:28][C:25]1[SH:24]([CH3:15])[C:23]([O:14][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)=[N:27][N:26]=1)[CH3:30]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CCOc1nnc(CBr)s1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC1=NN=C(Oc2ccc(Oc3ccccc3)cc2)[SH]1C
Yield: 74.2 %

Procedure:
0.76 g of 4-phenoxy phenol was dissolved in 10 ml of acetone followed by adding 0.6 g of anhydrous potassium carbonate and 1.0 g of 2-bromomethyl-5-ethoxy-1,3,4-thiadiazole. The resulting mixture was refluxed with stirring and heated for 2 hours. After cooling, 100 ml of ethyl acetate was added followed by washing with water for two times, and the resulting ethyl acetate layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled over under reduced pressure, and the residue was purified by chromatography on silica gel to obtain 1.0 g of the compound No. 1 described in Table 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](Cl)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:14]([CH3:13])[C@H:15]2[CH2:34][N:19]3[C:20]4[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]3[CH2:17][CH2:16]2)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(Cl)Cc1ccc(F)c(F)c1
Product: CN(C(=O)Cc1ccc(F)c(F)c1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from (3,4-difluorophenyl)acetyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 413.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([NH2:27])[CH:20]=3)=[CH:17][N:16]=[N:15]2)[CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11].[CH2:28]([N:30](CC)[CH2:31]C)C.ClC(Cl)([O:38][C:39](=O)[O:40]C(Cl)(Cl)Cl)Cl>ClCCl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([N:14]2[C:18]([C:19]3[CH:20]=[CH:21][C:22]([N:30]([CH3:31])[CH3:28])=[CH:23][CH:24]=3)=[CH:17][N:16]=[N:15]2)[CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11].[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[N:14]([C:6]3[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)[N:15]=[N:16][CH:17]=2)=[CH:20][C:21]=1[NH:27][C:39](=[O:38])[O-:40]
Reactant: CCN(CC)CC
Reactant: COc1ccc(-c2cnnn2-c2cc(OC)c(OC)c(OC)c2)cc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: COc1cc(-n2nncc2-c2ccc(N(C)C)cc2)cc(OC)c1OC
Product: COc1ccc(-c2cnnn2-c2cc(OC)c(OC)c(OC)c2)cc1NC(=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(3,4,5-trimethoxy-phenyl)-5-(3-amino-4-methoxy-phenyl)-1H-[1,2,3]triazole hydrochloride (300 mg) and triethylamine (0.22 mL, 1.60 mmol) in dichloromethane (3 mL) is added slowly to a solution of triphosgene (77 mg, 0.26 mmol) in dichloromethane (5 mL) at 0° C. under nitrogen atmosphere. The reaction mixture is stirred for 30 min at room temperature, and then cooled to 0° C. before the addition of PEG (1.53 g, 0.76 mmol) and triethylamine (0.12 mL, 0.77 mmol) in 2 ml of dichloromethane. The resulting reaction mixture is stirred for 3 h. and washed with NaHCO3 solution. The aqueous layer is extracted with dichloromethane (2×), and the combined organic layers are washed with saturated NaCl solution, dried over Na2SO4 and evaporated. The crude product is purified by silica gel column chromatography (20% MeOH in EA) to give desired product PEG-2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)phenylcarbamate.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].N1CCCCC1.[CH:14]1([NH:17][C:18]2[N:23]3[N:24]=[CH:25][C:26]([CH:27]=O)=[C:22]3[N:21]=[C:20]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)[CH:19]=2)[CH2:16][CH2:15]1>C(O)C.O>[CH:14]1([NH:17][C:18]2[N:23]3[N:24]=[CH:25][C:26](/[CH:27]=[C:7]4/[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1]/4)=[C:22]3[N:21]=[C:20]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)[CH:19]=2)[CH2:16][CH2:15]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Nc3cccc(F)c3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: O
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(Nc4cccc(F)c4)nc23)N1
Temperature: 80 °C
Reaction time: 15 h
Yield: 27.6 %

Procedure:
Hydantoin (69 mg, 0.69 mmol) and piperidine (69 μL, 0.69 mmol) were added to 7-(cyclopropylamino)-5-(3-fluorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (72 mg, 0.23 mmol) dissolved in ethanol (1.1 mL). The reaction was heated at 80° C. After 15 h, the reaction was cooled to r.t., diluted with water (5 mL), and the precipitate was collected and washed with 1:1 ethanol:water (5 mL). The bright yellow solid was dried in vacuo to give (Z)-5-((7-(cyclopropylamino)-5-(3-fluorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (25 mg, 10% over 3 steps). LCMS (M+1=507)