Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:8]=[C:9]([C:19]([OH:21])=O)[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)=[O:6])[CH2:2][CH3:3].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.C[Si]([CH:39]=[N+:40]=[N-:41])(C)C>C1(C)C=CC=CC=1.CCOCC.CN(C=O)C>[CH2:1]([NH:4][C:5]([C:7]1[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:10]=[C:9]([C:19](=[O:21])[CH:39]=[N+:40]=[N-:41])[CH:8]=1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCNC(=O)c1cc(C(=O)O)cc(-c2ccccc2)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCNC(=O)c1cc(C(=O)C=[N+]=[N-])cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
68E (194 mg, 0.69 mmol) was suspended in 1.5 mL of toluene with 11 μL of dry DMF. Oxalyl chloride (72 μL, 0.82 mmol) was then added dropwise at 0° C. leading to a gas evolution. After the addition, the reaction was stirred at room temperature for 2 hours. After that time, the reaction mixture was concentrated. The residue was dissolved in THF. At 0° C., triethylamine (95 μL, 0.69 mmol) was added followed by trimethylsilyldiazomethane (582 μL of a 2 M solution in Et2O). The reaction was then stirred at room temperature for 16 hours. The reaction mixture was then concentrated and the residue was purified using SiO2 with CH2Cl2/AcOEt 98:2 to 85:15. An orange oil was obtained (100 mg, 48%). NMR 1H (ppm, CDCl3): 8.14 (t., J4=1.68 Hz, 1H), 8.06 (t., J4=1.60 Hz, 1H), 8.03 (t., J4=1.68 Hz, 1H), 7.59-7.55 (m, 2H), 7.46-7.34 (m, 3H), 6.51 (br.s., 1H), 6.01 (s, 1H), 3.46-3.39 (m, 2H), 1.64 (sext., J3=7.24 Hz, 2H), 0.97 (t., J3=7.37 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[N:6][C:5]1=[O:16].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:29][O:28][C:24]1[CH:23]=[C:22]2[C:27]([C:18]([O:1][CH2:2][CH2:3][N:4]3[CH:9]=[C:8]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:7]=[N:6][C:5]3=[O:16])=[CH:19][CH:20]=[N:21]2)=[CH:26][CH:25]=1
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: O=c1ncc(-c2ccccc2)cn1CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Product: COc1ccc2c(OCCn3cc(-c4ccccc4)cnc3=O)ccnc2c1
Temperature: 80 °C
Yield: 30.8 %

Procedure:
To a 10 mL round bottomed flask was added 1-(2-hydroxyethyl)-5-phenylpyrimidin-2(1H)-one (0.043 g, 0.20 mmol), 4-chloro-7-methoxyquinoline (0.042 g, 0.22 mmol), toluene (2.0 mL) and cesium carbonate (0.071 g, 0.22 mmol). The reaction was carefully evacuated and then backfilled with N2. This was repeated twice. Then racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (0.020 g, 0.050 mmol) and palladium(II) acetate (0.0089 g, 0.040 mmol) were added. The reaction was again carefully evacuated and then backfilled with N2. This was repeated twice. The mixture was then heated at 80° C. for 3 h. After cooling to room temperature, the mixture was poured into aq. NaHCO3 (50 mL) and extracted with EtOAc (100 mL). This produced a bad emulsion so the mixture was filtered through Celite. The Celite plug was eluted with 10% MeOH/CH2Cl2 and the aqueous phase was extracted with 25% iPrOH/CHCl3. The EtOAc extract, MeOH/CH2Cl2 eluent and the iPrOH/CHCl3 extracts were combined, dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0 to 1% MeOH (2M in NH3)/CH2Cl2 afforded 1-(2-(7-methoxyquinolin-4-yloxy)ethyl)-5-phenylpyrimidin-2(1H)-one (0.023 g, 31% yield) as an off-white solid. MS (ESI, pos. ion.) m/z: 374 (MH+). Calc'd exact mass for C22H19N3O3: 373. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.87 (s, 3 H), 4.50 (t, J=4.8 Hz, 2 H), 4.59 (t, J=4.9 Hz, 2 H), 6.93 (d, J=5.3 Hz, 1 H), 7.02 (dd, J=9.2, 2.5 Hz, 1 H), 7.29 (d, J=2.5 Hz, 1 H), 7.37 (t, J=7.3 Hz, 1 H), 7.47 (t, J=7.6 Hz, 2 H), 7.60 (d, J=7.4 Hz, 2 H), 8.00 (d, J=9.2 Hz, 1 H), 8.63 (d, J=5.1 Hz, 1 H), 8.81 (d, J=3.5 Hz, 1 H), 8.97 (d, J=3.5 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1S(C(F)(F)F)(=O)=O)[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O-:27])(=[O:26])C.[K+]>CS(C)=O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[O:13])[CH:14]=[CH:15][C:16]=1[C:24]([OH:27])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(S(=O)(=O)C(F)(F)F)c(OCc2ccccc2)c1
Reactant: CC(=O)[O-]
Agent: [Fe+2]
Agent: [Pd+2]
Agent: [K+]
Solvent: CS(C)=O
Product: O=Cc1ccc(C(=O)O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 3-benzyloxy-4-trifluoromethanesulfonylbenzaldehyde (350 mg, 0.97 mmol, 1 eq), potassium acetate (380 mg, 3.89 mmol, 4 eq), palladium (II) diacetate (32 mg, 0.05 mmol, 0.05 eq) and 1,1′-bis-(diphenylphosphino)ferrocene (dppf) (108 mg, 0.19 mmol, 0.2 eq) in anhydrous dimethylsulfoxide (6 mL) was purged with carbon monoxide and stirred for 5 min. The reaction mixture was then heated to 60□C. and stirred under a carbon monoxide balloon for 3 h. The solution was allowed to cool to room temperature, and acidified to pH 1 with 10% HCl and then extracted with ethyl acetate (2×20 mL). The organic extracts were combined and washed with brine, then extracted with saturated aqueous sodium bicarbonate (3×20 mL). The aqueous extracts were combined, washed with ethyl acetate (2×20 mL), acidified to pH 1 with 10% HCl and back extracted with ethyl acetate (2×20 mL). The organic solution was dried over sodium sulfate and evaporated in vacuo to give a cream coloured powder (146 mg, 59%). 1H NMR (CDCl3) δ10.08 (s, 1H, O═C—H), 5.39 (s, 2H, OCH2Ph).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]([CH3:18])=[C:11]([CH:17]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:2]=1.[C:19]([OH:28])(=[O:27])[C@@H:20]([C@H:22]([C:24]([OH:26])=[O:25])[OH:23])[OH:21].C(O)C>C(O)(=O)C.[Pt]=O>[C:19]([OH:28])(=[O:27])[C@@H:20]([C@H:22]([C:24]([OH:26])=[O:25])[OH:23])[OH:21].[NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]2[CH:8]=[CH:9][C:10]([CH3:18])=[C:11]([CH:17]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2]1
Reactant: CCOC(=O)c1cc(-c2cccnc2)ccc1C
Agent: O=[Pt]
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc([C@@H]2CCCNC2)ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.9 %

Procedure:
A 500 mL hydrogenation vessel was charged with 2.0 g platinum(II)oxide and purged with nitrogen. Ethyl 5-(3-pyridyl)-2-methylbenzoate (19.57 g, 81.10 mmol) was added as a solution in 200 mL acetic acid. The suspension was hydrogenated at 45 psi for 18 h. The catalyst was filtered through celite and the filter plug was washed with 200 mL acetic acid. The filtrate was concentrated under reduced pressure. The resultant oil was taken up in 500 mL water and made basic with 5N aqueous sodium hydroxide. This basic layer was extracted with ethyl acetate (2×500 mL) and the extracts were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was taken up in 200 mL hot ethanol. L-(+)-tartaric acid (12.17 g, 81.1 mmol) was added into the ethanol solution and was allowed to stir at ambient temperature for 48 h, forming a white precipitate that was collected by filtration. The white solid was recrystallized from hot 5% H2O/ethanol (300 mL) and then from 350 mL hot 20% H2O/ethanol to yield 11.25 g (35%, 95.8% ee) of (S)-ethyl 5-(3-piperidinyl)-2-methylbenzoate-L-tartaric acid salt as a white solid. The mother liquors were combined and concentrated under reduced pressure. The resultant oil was taken up in 300 mL water and made basic with 5N aqueous sodium hydroxide. This basic layer was extracted with ethyl acetate (2×300 mL) and the extracts were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was taken up in 200 mL hot ethanol. D-(−)-tartaric acid (6.82 g, 45.4 mmol) was added into the ethanol solution and was allowed to stir at ambient temperature for 48 h, forming a white precipitate that was collected by filtration. The white solid was recrystallized from hot 5% H2O/ethanol (300 mL) and then from 350 mL hot 20% H2O/ethanol to yield 13.51 g (42%, 100% ee) of (R)-ethyl 5-(3-piperidinyl)-2-methylbenzoate-D-tartaric acid salt as a white solid.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]1[S:38][CH:39]=[CH:40][N:41]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:32]5[CH2:36][CH2:35][CH2:34][CH:33]5[C:37]5[S:38][CH:39]=[CH:40][N:41]=5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: c1csc(C2CCCN2)n1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN5CCCC5c5nccs5)c4)cc23)CC1
Yield: 30.9 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-(2-pyrrolidinyl)-1,3-thiazole (132.4 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the title compound (20.0 mg, 30.4%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:22][C:21]([C:23](OCC)=[O:24])=[N:20][N:19]=2)[CH2:14][CH2:13]1)=[O:10].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:22][C:21]([CH2:23][OH:24])=[N:20][N:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: CCOC(=O)c1nnc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)s1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1[nH]c(C(=O)NC2CCN(c3nnc(CO)s3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.7 %

Procedure:
A solution of ethyl 5-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3,4-thiadiazole-2-carboxylate (Example 219, 280 mg, 0.65 mmol) in THF (5 ml) was cooled to 0° C. and treated with diisobutylaluminium hydride (1.3 ml, 1.95 mmol) dropwise over 5 min. The reaction was kept in the ice bath and allowed to slowly warm to room temperature while stirring overnight. LC-MS indicated that the reaction was complete. The reaction was quenched with aqueous Rochelle salt, and the resultant mixture was diluted with EtOAc (10 ml) and stirred vigorously for 2 h. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried (Na2SO4), filtered, and concentrated to give a pale orange oil. The crude material was purified by preparatory HPLC (35-75% CH3CN/H2O, 0.1% TFA, 14 min.) to give 17 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH:4]=[C:5]1[NH:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])[C:6]1=[O:19].[C:24](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.O>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH:4]=[C:5]1[N:9]([CH3:24])[C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])[C:6]1=[O:19]
Reactant: O=C([O-])[O-]
Reactant: O=C1NC(=Cc2ccccc2F)C(=O)N1c1cc(F)ccc1F
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN1C(=O)N(c2cc(F)ccc2F)C(=O)C1=Cc1ccccc1F
Yield: 189.9 %

Procedure:
The 5-(2-fluorobenzylidene)-3-(2,5-difluorophenyl)imidazolidine-2,4-dione (1.25 g, 3.9 mmol), cesium carbonate (0.67 g, 2.06 mmol) and methyl iodide (0.84 g, 5.9 mmol) were allowed to stir overnight in DMF (15 mL), under a N2 atmosphere. The resulting solution was diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with brine (saturated), dried (over MgSO4), filtered and concentrated to give 1.3 grams of 5-(2-fluorobenzylidene)-3-(2,5-difluorophenyl)-1-methylimidazolidine-2,4-dione m.p. 94°-97° C. (compound 106 under Table B).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][O:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([CH2:36][C:37](O)=[O:38])[CH2:32][CH2:31]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH:27][C:37](=[O:38])[CH2:36][C@H:33]5[CH2:34][CH2:35][C@H:30]([O:29][CH3:28])[CH2:31][CH2:32]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: CO[C@H]1CC[C@H](CC(=O)O)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CO[C@H]1CC[C@H](CC(=O)NC2CCC(CCN3CCN(c4cccc5c4OCO5)CC3)CC2)CC1

Procedure:
The title compound, white solid (27.1 mg, 68.4%), MS (ISP) m/z=486.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and (trans-4-Methoxycyclohexyl)acetic acid (synthesized as described in W2009/013212 p. 73).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=2)=[N:5][CH:4]=1)=O.[NH2:18][C:19]1[C:20]([F:32])=[CH:21][C:22]([F:31])=[C:23]([CH:30]=1)[C:24]([NH:26][CH:27]1[CH2:29][CH2:28]1)=[O:25]>>[CH:27]1([NH:26][C:24]([C:23]2[C:22]([F:31])=[CH:21][C:20]([F:32])=[C:19]([NH:18][CH2:1][C:3]3[S:7][C:6]([NH:8][C:9]4[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=4)=[N:5][CH:4]=3)[CH:30]=2)=[O:25])[CH2:28][CH2:29]1
Reactant: O=Cc1cnc(Nc2ccc(C(=O)O)cn2)s1
Reactant: Nc1cc(C(=O)NC2CC2)c(F)cc1F
Product: O=C(O)c1ccc(Nc2ncc(CNc3cc(C(=O)NC4CC4)c(F)cc3F)s2)nc1
Yield: 95 %

Procedure:
6-(5-Formyl-thiazol-2-ylamino)-nicotinic acid (see Example 19) was treated with 5-amino-2,4-difluoro-N-cyclopropylbenzamide in manner similar to the preparation of Example 6 to afford the title compound in 95% yield. LC/MS; (M+H)+=446
Reaction SMILES: [S:1](=[O:30])(=[O:29])([O:3][CH2:4][C@H:5]1[CH2:9][C@@H:8]([NH:10][C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:19]=[C:15]3[N:14]=[C:13](Cl)[CH:12]=2)[C@H:7]([OH:27])[C@@H:6]1[OH:28])[NH2:2].CO>[Pd]>[S:1](=[O:30])(=[O:29])([O:3][CH2:4][C@H:5]1[CH2:9][C@@H:8]([NH:10][C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:19]=[C:15]3[N:14]=[CH:13][CH:12]=2)[C@H:7]([OH:27])[C@@H:6]1[OH:28])[NH2:2]
Reactant: NS(=O)(=O)OC[C@H]1C[C@@H](Nc2cc(Cl)nc3cc(-c4ccccn4)nn23)[C@H](O)[C@@H]1O
Agent: [Pd]
Solvent: CO
Product: NS(=O)(=O)OC[C@H]1C[C@@H](Nc2ccnc3cc(-c4ccccn4)nn23)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.6 %

Procedure:
(rac)-[(1R,2R,3S,4R)-4-{[5-chloro-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methyl rel-sulfamate (5.0 mg, 0.011 mmol; synthesized following Steps 1-4 of Method D starting from 5-pyridin-2-yl-2H-pyrazol-3-ylamine) is dissolved in methanol (1.00 mL, 0.0247 mol). Palladium on carbon (10%, 29.2 mg, 0.00275 mmol) is added and the suspension is purged with hydrogen gas and stirred for 3 days at room temperature under a balloon of hydrogen (1 atm). The reaction mixture is purged with nitrogen, filtered through celite and rinsed with methanol. The filtrate is concentrated in vacuo and purified by preparative HPLC to provide (rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl]methyl rel-sulfamate (1.0 mg, yield 22%). LCMS: (AA) M+1 421; 1H NMR (400 MHz, MeOD) δ 8.72-8.61 (m, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.18 (d, J=4.8 Hz, 1H), 7.99-7.88 (m, 1H), 7.47-7.37 (m, 1H), 7.01 (s, 1H), 6.41-6.32 (m, 1H), 4.30-4.18 (m, 2H), 4.16-3.92 (m, 3H), 2.61-2.49 (m, 1H), 2.48-2.35 (m, 1H), 1.68-1.56 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:39][C:40]1[O:44][C:43]([C:45]([F:48])([F:47])[F:46])=[C:42]([S:49](Cl)(=[O:51])=[O:50])[CH:41]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][CH:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([S:49]([C:42]2[CH:41]=[C:40]([CH3:39])[O:44][C:43]=2[C:45]([F:48])([F:46])[F:47])(=[O:51])=[O:50])[CH2:6][CH2:5]1
Reactant: CC(CN1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: Cc1cc(S(=O)(=O)Cl)c(C(F)(F)F)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1cc(S(=O)(=O)N2CCN(CC(C)n3cc(-c4ncnc5[nH]ccc45)cn3)CC2)c(C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
To a solution of 4-[1-(1-methyl-2-piperazin-1-ylethyl)-1H-pyrazol-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (16.0 mg, 0.036 mmol) in DCM (0.3 mL) was added triethylamine (7.6 μL, 0.054 mmol) followed by 5-methyl-2-(trifluoromethyl)furan-3-sulfonyl chloride (11 mg, 0.043 mmol). The reaction was stirred at room temperature for 1 h and trifluoroacetic acid (0.5 mL) was added to reaction vial. After stirring for 1 hour, the solvent was removed in vacuo. The residue was dissolved in methanol (1 mL) and treated with ethylenediamine (0.1 mL). The reaction solution was stirred for 1 hour and diluted with methanol and purified with preparative LCMS (C18 column eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to give the desired product as white solid (7.8 mg, 41%). 1H NMR (300 MHz, DMSO-D6): δ 12.17 (s, 1H); 8.73 (s, 2H); 8.34 (s, 1H); 7.64 (d, 1H); 7.59 (d, 1H); 7.03 (d, 1H); 4.76 (m, 1H); 3.02 (m, 5H); 2.78-2.50 (m, 5H); 1.53 (d, 3H); LCMS calculated for C22H25F3N7O3S(M+H)+: m/z=524.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)#[CH:2].[CH2:10]([O:12][C:13](=[O:17])/[CH:14]=[CH:15]\I)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:17])[CH:14]=[CH:15][C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)[CH3:11]
Reactant: CCOC(=O)/C=C\I
Reactant: C#Cc1ccc(C)cc1
Product: CCOC(=O)C=CC#Cc1ccc(C)cc1

Procedure:
The general procedure was used to convert 1-Ethynyl-4-methyl-benzene and (Z)-ethyl-3-iodoacrylate to the title product. Purification by flash chromatography (10% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow oil (350 mg, 85% yield). 1H NMR (400 MHz, CDCl3) δ 7.43-7.41 (d, J=8.1, 2H), 7.16-7.14 (d, J=7.9, 2H), 6.37-6.34 (d, J=11.4, 1H), 6.12-6.09 (d, J=11.4, 1H), 4.29-4.23 (q, J=7.1, 2H), 2.36 (s, 3H), 1.35-1.31 (t, J=7.1, 3H). 13C NMR (100 MHz, CDCl3) δ 164.92, 139.62, 132.12, 129.28, 127.83, 123.14, 119.76, 101.77, 86.19, 60.44, 21.66, 14.42. Anal. Calcd. for C14H14O2: C, 78.48; H, 6.59; Found C, 78.22; H, 6.78.
Reaction SMILES: Br[C:2]1[C:3]([CH2:11][CH3:12])=[N:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.[Cl:13][C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][C:2]2[C:3]([CH2:11][CH3:12])=[N:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: CCc1nc([N+](=O)[O-])ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Temperature: 105 °C
Yield: 28.7 %

Procedure:
A mixture of 3-bromo-2-ethyl-6-nitropyridine (3.168 g, 13.71 mmol), 2-chloro-4-hydroxypyridine (3.55 g, 27.4 mmol) and K2CO3 (5.69 g, 41.1 mmol) in DMA (25 mL) was sparged with Ar and heated at 105° C. overnight. The mixture was cooled to RT, treated with EtOAc, washed successively with 10% K2CO3, 5% LiCl, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 3-((2-chloropyridin-4-yl)oxy)-2-ethyl-6-nitropyridine (1.102 g, 28%). MS (ESI) m/z: 280.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[NH3:28]>>[C:24]([CH2:25][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:22]([OH:23])=[O:27])(=[O:26])[NH2:28]
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Reactant: N
Product: NC(=O)Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from example 34.1.) was ring opened with ammonia at 22° C. to give the title compound as a white solid. MS: 375.1 ([M−H]−).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21]C=CC=4)N=3)=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.C(OC1C=CC(C(N(OC)C)=O)=CC=1)C1C=CC=CC=1>>[CH2:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8](=[O:9])[CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:15][CH:14]=1)[C:18]1[CH:27]=[CH:26][CH:25]=[CH:20][CH:21]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: CON(C)C(=O)c1ccc(OCc2ccccc2)cc1
Product: O=C(Cc1ccncc1)c1ccc(OCc2ccccc2)cc1

Procedure:
Following the procedure for the preparation of 2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone but substituting 4-benzyloxy-N-methoxy-N-methyl-benzamide provided the title compound. MS: (M+H m/z=304.2).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=[O:10])=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1.[CH3:17][Sn](C)(C)C>CN(C=O)C.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>[NH2:1][C:2]1[N:7]=[C:6]([CH3:17])[C:5]([CH:9]=[O:10])=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1
Reactant: C[Sn](C)(C)C
Reactant: CCCCCNc1nc(N)nc(Cl)c1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCCNc1nc(N)nc(C)c1C=O
Temperature: 100 °C

Procedure:
A mixture of the product from step (i) (20 g), tetramethyltin (20 ml) and tetrakis(triphenylphosphine)palladium (0) (2 g) in DMF (200 ml) was heated at 100° C. for 16 h then evaporated under reduced pressure. The residue was partitioned between EtOAc/brine, the organics separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 50-60% EtOAc/isohexane to afford the subtitle compound, 14.4 g.