Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([NH:19][CH:20]([CH3:25])[CH:21]=[C:22](Cl)Cl)=[O:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O-:27].[Na+]>CN1CCCC1=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:21]([CH2:22][O:27][CH3:26])=[C:20]([CH3:25])[N:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CC(C=C(Cl)Cl)NC(=O)c1nn(Cc2ccccc2)c2ccccc12
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COCc1oc(-c2nn(Cc3ccccc3)c3ccccc23)nc1C
Yield: 40.3 %

Procedure:
100 mg of 3-(1-benzylindazole-3-carboxamido)-1,1-dichloro-but-1-ene (0.267 mmol) and 29 mg of sodium methylate were stirred in 0.5 ml of N-methylpyrrolidone at 100° C. under argon overnight. The crude mixture was cooled and purified directly by column chromatography (SiO2, cyclohexane:ethyl acetate 3:1). 35.9 mg (40%) of 2-(1-benzylindazol-3-yl)-5-methoxymethyl-4-methyloxazole were isolated as a yellowish oil.
Reaction SMILES: OS(O)(=O)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:19][C@H:20]1[C@H:25]([OH:26])[CH2:24][C@@H:23]2[CH2:27][C@H:21]1[C:22]2([CH3:29])[CH3:28]>O.CC(C)=O>[CH3:19][C@H:20]1[C:25](=[O:26])[CH2:24][C@@H:23]2[CH2:27][C@H:21]1[C:22]2([CH3:28])[CH3:29]
Reactant: C[C@H]1[C@H](O)C[C@@H]2C[C@H]1C2(C)C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: C[C@H]1C(=O)C[C@@H]2C[C@H]1C2(C)C
Yield: 93.3 %

Procedure:
add a mixture of 9 ml of H2SO4 and 40 ml of H2O to a solution of Cr2O3 (15.0 g, 0.15 mol) in H2O (20 mL) at 0° C. Add dropwise the above Jones reagent to a solution of (1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ol (23.1 g, 0.15 mol) in acetone (100 mL) over a period for 2 hours at 0° C. Stir the resultant mixture for additional 1 hour. Dilute the mixture with 100 mL of water and then extract the aqueous mixture with ether (50 mL×3). The combined organic layers are washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give crude (1R,2R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-one as pale yellow oil (21.3 g, yield: 93.4%), MS (m/z): 151 (M−1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][NH:21]4)=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.Br[CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.O>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][CH2:35][N:21]1[C:22]2[C:18](=[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=4[O:26][CH3:27])=[CH:14][CH:13]=3)[CH:25]=[CH:24][CH:23]=2)[CH:19]=[N:20]1)[CH3:34]
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3[nH]ncc23)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ncc2c(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cccc21
Temperature: 90 °C
Yield: 85.7 %

Procedure:
4-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indazole (0.09 g, 0.245 mmol), ethyl bromopropionate (0.045 g, 0.245 mmol), cesium carbonate (81 mg, 0.294 mmol) in 6 mL DMF was stirred at RT overnight and then heated to 90° C. for 35 min. The reaction was cooled and distributed between EtOAc and H2O. The organic layer was separated and concentrated in vacuo. The crude product was purified by flash chromatography with a gradient from 0-30% ethyl acetate in hexanes to yield 3-[4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-propionic acid ethyl ester as a white solid (98 mg, 85.7%).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[S:20][C:18]=2[N:19]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 2,4-dichloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-trifluoromethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20]Br)[CH:9]=[CH:8][C:7]=1[C:22]([F:25])([F:24])[F:23])[CH3:2].[CH3:27][C@H:28]1[C@@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[NH:29]1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][N:29]2[C@@H:28]([CH3:27])[C@@H:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:31][C:30]2=[O:39])[CH:9]=[CH:8][C:7]=1[C:22]([F:23])([F:25])[F:24])[CH3:2]
Reactant: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CBr)ccc1C(F)(F)F
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Product: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)ccc1C(F)(F)F

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [5-(4-Bromo-2-bromomethyl-phenoxy)-2-trifluoromethyl-phenyl]-acetic acid ethyl ester and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH3:16][C:17]1[O:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH2:28][CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:29][CH2:28][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:21][C:17]=2[CH3:16])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)COc1ccc(O)cc1C
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Product: CCOC(=O)COc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1C

Procedure:
(4-Hydroxy-2-methylphenoxy)acetic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester were coupled as described in Example 24, Step C.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:28])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:6][CH:5]=1.[CH3:29][CH:30]([CH3:34])[CH2:31][CH2:32]Br.C([O-])([O-])=O.[K+].[K+]>>[ClH:1].[CH3:2][N:3]([CH3:28])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][CH2:14][N:13]([CH2:32][CH2:31][CH:30]([CH3:34])[CH3:29])[CH2:12][C@H:11]2[CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)=[CH:6][CH:5]=1
Reactant: CC(C)CCBr
Reactant: CN(C)c1ccc([C@@H]2CCNC[C@H]2COc2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)CCN1CC[C@@H](c2ccc(N(C)C)cc2)[C@H](COc2ccc(C(F)(F)F)cc2)C1

Procedure:
Prepared from (41) (0.5 g), 3-methyl-1-bromobutane (0.4 g) and K2CO3 (0.5 g). Reflux for 8 h. Purification on silica gel. Yield of (69) 51%. M.p. 223.9°-225.1° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[N:5][C:4](=C(Cl)Cl)[N:3]=1.[CH:11]([NH:14][CH:15]=[O:16])([CH3:13])[CH3:12].O>>[CH:11]([NH:14][C:15]([C:4]1[NH:3][C:2]([Cl:1])=[C:6]([Cl:7])[N:5]=1)=[O:16])([CH3:13])[CH3:12]
Reactant: ClC1=NC(=C(Cl)Cl)N=C1Cl
Reactant: CC(C)NC=O
Solvent: O
Product: CC(C)NC(=O)c1nc(Cl)c(Cl)[nH]1
Yield: 85 %

Procedure:
654 g (3 mol) of 4,5-dichloro-2-dichloromethylene-imidazole in a finely powdered form were added incrementally in the course of about one hour, to a mixture, which had been initially introduced, of 783 g (9 mol) of isopropylformamide and 162 g (9 mol) of water, while stirring and cooling slightly, whereupon the internal temperature rose to about 75° C. The reaction mixture was then heated to about 90°-110° C. for a further half hour. After cooling, the product was precipitated in water, filtered off, washed with water and dried. In this way, 566 g (85% of theory) of 4,5-dichloro-imidazole-2-carboxylic acid isopropylamide with a melting point of 150° C. were obtained.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[O:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[CH3:20][C:21]1[O:27][C:24]([CH2:25][NH:26][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)c1cccnc1
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2cccc3nc(NC(=O)c4cccnc4)nn23)o1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg; 0.31 mmol; 1.0 eq.) and 5-methylfurfurylamine (1.0 mL) as an off-white solid (40 mg, 37%). HPLC, 2.38 min. Rt: (purity 98.6%). LC/MS, M−(ESI): 347.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][CH3:11])[N:3]=1.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>CCN(CC)CC>[C:12]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][CH3:11])[N:3]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCNc1nc(N)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCNc1nc(Cl)cc(NC(=O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the pyrimidine 18-2 (3.76 g, 21.8 mmol), pivaloyl chloride (10.7 mL, 87 mmol), Et3N (15.2 mL, 109 mmol) and TEF (80 mL) were stirred at room temperature for 24 hours. A further 3 mL of pivaloyl chloride and 4 mL of Et3N was added and the mixture stirred for another 24 hours. The solution was poured into saturated Na2CO3, extracted with EtOAc (2×), washed with brine, dried (MgSO4) and filtered through a pad of silica gel. Removal of the solvent afforded an orange solid. Trituration with ether/hexane ˜20:1 and filtration provided the title compound 18-4 as a white solid.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]1([O-:24])[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[N+:25]([O-])([OH:27])=[O:26]>C(O)(=O)C>[N+:25]([C:12]1[CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N+:8]([O-:24])[CH:13]=1)([O-:27])=[O:26]
Reactant: CCOC(=O)c1ccc[n+]([O-])c1C(=O)OCC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc([N+](=O)[O-])c[n+]([O-])c1C(=O)OCC
Temperature: 0 °C
Yield: 78 %

Procedure:
255 ml of acetic anhydride were added to a mixture of 203.2 g (0.85 mol) of diethyl pyridine-2,3-dicarboxylate-N-oxide in 1.2 l of glacial acetic acid. 68.3 g (1.06 mol) of 98% strength nitric acid were then added in the course of 40 minutes at from 20° to 28° C. with gentle cooling and stirring and the mixture was stirred at 30° C. for 12 hours. The reaction solution was poured into 3.5 l of ice-water and extracted with methylene chloride. The organic phase was extracted in succession with water, saturated sodium hydrogencarbonate solution and sodium chloride solution, dried over magnesium sulfate and filtered off with suction through silica gel. After concentration, 177.6 g (78% of theory) of diethyl 5-nitropyridine-2,3-dicarboxylate-N-oxide were obtained of nD25 =1.5290. A sample crystallized after relatively long standing; m.p. 84°-86° C.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:18][CH2:17][C:16]=3[CH:27]=2)=[O:10])=[C:7]([F:30])[CH:6]=1.C(O)(=O)C>C(O)C.[OH-].[Na+]>[NH2:2][N:3]=[CH:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([OH:24])=[O:23])[CH2:18][CH2:17][C:16]=3[CH:27]=2)=[O:10])=[C:7]([F:30])[CH:6]=1
Reactant: CCOC(=O)CC1CCc2cc(NC(=O)c3ccc(C=NN)cc3F)ccc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: NN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)O)O3)c(F)c1

Procedure:
1.2 g (2.75 mmol) of the ester from Example 69 were stirred overnight at room temperature in a mixture of 20 ml ethanol and 5 ml 2 N aqueous sodium hydroxide solution. It was brought to pH 4 with 2 N acetic acid, and the precipitate of the title compound was filtered with suction, washed successively with water and with acetone, and dried in vacuo at 50° C. Yield: 0.84 g (82%) of a pale yellow powder, m.p. 250° C.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]=[N+]=[N-])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([Cl:12])=[C:9]([Cl:11])[CH:10]=[C:5]2[N:4]=1)[CH3:2]>CO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([Cl:12])=[C:9]([Cl:11])[CH:10]=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2cc(Cl)c(Cl)nc2n1-c1ccc(CCN=[N+]=[N-])cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: CCc1nc2cc(Cl)c(Cl)nc2n1-c1ccc(CCN)cc1
Reaction time: 6 h
Yield: 89.5 %

Procedure:
To a solution of 2-[4-(2-ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl azide (step 6, 69 mg, 0.2 mmol) in methanol (10 mL) was added Lindlar catalyst (5 mg). The resulting mixture was stirred for 6 h under hydrogen atmosphere. The mixture was filtered through a pad of Celite and the filtrate was concentrated. Purification by preparative TLC (dichloromethane/methanol=10:1) gave 60 mg (94%) of the title compound as colorless solids: MS (EI) m/z 334 (M+); 1H-NMR (CDCl3) δ 8.11 (1H, s), 7.43 (2H, d, J=8.3 Hz), 7.30 (2H, d, J=8.3 Hz), 3.11 (2H, t, J=6.6 Hz), 2.92 (2H, t, J=6.6 Hz), 2.81 (2H, q, J=7.5 Hz), 1.35 (3H, t, J=7.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[CH2:9]([O:12][C:13](OCCC)(OCCC)[O:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH3:11]>C(O)CC>[C:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[N:1]=[C:13]([O:14][CH2:15][CH2:16][CH3:17])[O:12][CH2:9][CH2:10][CH3:11])#[N:8]
Reactant: N#Cc1ccsc1N
Reactant: CCCOC(OCCC)(OCCC)OCCC
Solvent: CCCO
Product: CCCOC(=Nc1sccc1C#N)OCCC

Procedure:
In a small distillation apparatus a mixture of 12.4 g(0.1 mol) 2-amino-3-cyanothiophene and 37.2 g (0.15 mol) tetra-n-propylorthocarbonate is heated for 3 hours at 155° C. n-PrOH, which arises during the reaction is directly distilled out of the reaction flask. After completion of the reaction, excess tetra-n-propylorthocarbonate is distilled off under reduced pressure and the resulting raw material purified by column chromatography over silica gel (eluant: hexane/tert.butylmethyl ether 6:1). Yield: 10.6 g of 3-cyano-2-(1,1-dipropoxymethyleneamino)thiophene in the form of slightly brownish crystals; m.p. 65-67° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C@H:27]([NH:30][C:31]([C@@H:33]4[CH2:38][CH2:37][CH2:36][CH2:35][N:34]4C(OC(C)(C)C)=O)=[O:32])[C:28]#[N:29])=[CH:22][CH:21]=3)=[CH:19][C:14]=2[S:13][C:12]1=[O:46])(C(C)(C)C)(C)C.C(OCC)C>C(O)=O>[C:28]([C@@H:27]([NH:30][C:31]([C@@H:33]1[CH2:38][CH2:37][CH2:36][CH2:35][NH:34]1)=[O:32])[CH2:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[CH:17]=[CH:16][C:15]3[N:11]([CH2:10][CH2:9][OH:8])[C:12](=[O:46])[S:13][C:14]=3[CH:19]=2)=[CH:25][CH:24]=1)#[N:29]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@H](C#N)Cc1ccc(-c2ccc3c(c2)sc(=O)n3CCO[Si](C)(C)C(C)(C)C)cc1
Solvent: O=CO
Solvent: CCOCC
Product: N#C[C@H](Cc1ccc(-c2ccc3c(c2)sc(=O)n3CCO)cc1)NC(=O)[C@@H]1CCCCN1
Yield: 86 %

Procedure:
A solution of (S)-tert-butyl 2-((S)-2-(4-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)phenyl)-1-cyanoethylcarbamoyl)piperidine-1-carboxylate (103 mg) in formic acid (1 ml) was stirred at 50° C. for 10 min. The solvent was removed in vacuo and the residue was purified by flash silica chromatography eluting with 1:14 2M ammonia in methanol/DCM to give, after trituration with diethyl ether, the title compound (60 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26]CC)=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:35][C:36]1[CH:37]=[CH:38][C:39]([O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])=[C:40]([CH2:42][OH:43])[CH:41]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:43][CH2:42][C:40]4[CH:41]=[C:36]([CH3:35])[CH:37]=[CH:38][C:39]=4[O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:24]([OH:26])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CC[C@H](C)Oc1ccc(C)cc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(COCc4cc(C)ccc4O[C@@H](C)CC=C)nn23)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 15.2 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.20 g, 0.342 mmol) and (S)-(5-methyl-2-(pent-4-en-2-yloxy)phenyl)methanol (0.085 g, 0.411 mmol) in DMF (4 ml) was added sodium hydride (0.021 g, 0.513 mmol) and the mixture was stirred at rt. After 5 h, the reaction was diluted with EtOAc and washed with 1N HCl, water then brine. The organic phase was dried (Na2SO4), filtered and concentrated. The yellow residue was purified by flash chromatography (Biotage; 10% MeOH/DCM; 10 CV) to give (S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methyl-2-(((5-methyl-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (32.7 mg, 0.052 mmol, 15.05% yield) as a pale yellow oil. LCMS (M+H) calcd for C36H51N4O6: 635.38. found: 635.5.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=O)[C:5](=[O:12])[N:6]2[CH3:11].O.NN>ClCCl.O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:12])[N:6]2[CH3:11]
Reactant: CN1C(=O)C(=O)c2c(Cl)cccc21
Agent: NN
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)Cc2c(Cl)cccc21
Temperature: 130 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-chloroisatin (CAS#6344-05-4, 3.64 g, 20.0 mmol) in acetonitrile (150 mL) was added potassium carbonate (11.1 g, 80 mmol) followed by iodomethane (2.75 mL, 44.0 mmol). The reaction was then placed at 60° C. and stirred for 40 minutes. The reaction was then cooled to room temperature, filtered and concentrated to 10% of the original volume. The reaction was then diluted with dichloromethane, water, and brine. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate filtered, and concentrated to provide 4-chloro-1-methyl-1H-indole-2,3-dione as an orange solid without the need for further purification. The 4-chloro-1-methyl-1H-indole-2,3-dione (1.55 g, 7.92 mmol) was then treated with hydrazine hydrate (14.8 ml, 475 mmol). The reaction was then placed at 70° C. and heated to 130° C. over 20 minutes. The reaction was stirred at 130° C. for 45 minutes, at which time the reaction was placed at room temperature and cooled by the addition of ice. Once the reaction was cooled to room temperature it was diluted with dichloromethane and water and the layers were then separated. The aqueous layer was extracted an additional two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane 0 to 2%) to afford 4-chloro-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 182.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([C@@H:19]([CH2:35][NH:36][CH3:37])[CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]3=[O:34])[CH2:24][CH2:23]2)[CH:15]=[CH:16][C:17]=1[Cl:18]>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]([C@H:19]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]3=[O:34])[CH2:26][CH2:27]2)[CH2:35][N:36]([CH3:37])[C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CNC[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Product: CN(C[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccc(F)cc1

Procedure:
4-Fluorobenzoyl chloride (0.093 mL) was reacted with (S)-1′-[3-(3,4-dichloro-phenyl)-4-methylamino-butyl]-[1,4′]bipiperidinyl-2-one (0.325 g) in dichloromethane (8 mL) overnight. The reaction was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic extracts were dried, evaporated, and purified by chromatography, with dichloromethane:methanol (gradient 97:3, 94:6) as eluent to give the title compound (0.33 g). Rf=0.41 in methylene chloride:methanol (95:5). MS: m/z=534 (M+). The product was dissolved in methanol (2 mL) and citric acid was added. The solution was concentrated and the residue was triturated with ether. The product was obtained as a white foam(0.11 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([N:12]1[CH2:15][CH:14]([OH:16])[CH2:13]1)=[S:11].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]=[C:10]([N:12]3[CH2:15][CH:14]([OH:16])[CH2:13]3)[S:11][C:2]=2[CH:7]=1
Reactant: OC1CN(C(=S)Nc2ccc(Br)cc2Br)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: OC1CN(c2nc3ccc(Br)cc3s2)C1
Temperature: 150 °C

Procedure:
N-(2,4-Dibromophenyl)-3-hydroxyazetidine-1-carbothioamide (0.366 g, 1.0 mmol) and Cs2CO3 (0.489 g, 1.5 mmol) were suspended in acetonitrile (10 mL), and the stirred reaction mixture was heated under microwave irradiation at 150° C. for 12 minutes. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (2:1 to 1:2 hexane/ethyl acetate) to provide 1-(6-bromobenzo[d]thiazol-2-yl)azetidin-3-ol. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.85-3.91 (m, 2H), 4.29-4.36 (m, 2H), 4.61-4.72 (m, 1H), 5.90 (d, J=8 Hz, 1H), 7.36-7.44 (m, 2H), 8.02-8.03 (m, 1H); MS (DCI/NH3) m/z 285 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH2:12][OH:13])=[N:8][C:9]=2[O:10][CH3:11])[CH2:3][CH2:2]1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:12]=[O:13])=[N:8][C:9]=2[O:10][CH3:11])[CH2:3][CH2:2]1
Reactant: COc1nc(CO)ccc1C1CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1nc(C=O)ccc1C1CC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
Manganese dioxide (67 g) was added to a solution of (5-cyclopropyl-6-methoxypyridin-2-yl)methanol (14.1 g) in chloroform (200 mL), and the mixture was stirred at 65° C. for one hour. The reaction solution was filtered through celite and the filtrate was concentrated to give 5-cyclopropyl-6-methoxypyridine-2-carbaldehyde (11 g, 85%).