Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[CH2:25][CH2:26]Br>>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[CH2:25][CH2:26][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:6]1
Reactant: CC(=O)NCc1ccc2c(c1)N(C1CCNCC1)CC2
Reactant: Fc1cccc(CCBr)c1
Product: CC(=O)NCc1ccc2c(c1)N(C1CCN(CCc3cccc(F)c3)CC1)CC2
Yield: 58.1 %

Procedure:
1-(Piperidin-4-yl)-6-acetamidomethylindoline (250 mg) and 3-fluorophenethyl bromide (220 mg) were treated as in Example 2 to give the title compound (210 mg) as white needles (yield: 58%).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1)[CH2:10][C:11]#[CH:12]>>[F:8][C:7]1[C:2]([C:12]#[C:11][CH2:10][CH2:9][N:13]2[N:14]=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=[N:17]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#CCCn1nc2ccccc2n1
Reactant: Fc1cccnc1Cl
Product: Fc1cccnc1C#CCCn1nc2ccccc2n1

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-chloro-3-fluoropyridine (42 mg, 0.32 mmol) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (50 mg, 0.29 mmol, Example 109(D)). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 21 mg (80 μmol, 27%) of 2-(4-(3-fluoropyridin-2-yl)but-3-ynyl)-2H-1-benzo[d][1,2,3]triazol as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3](=[O:10])[NH:4][C:5](=[NH:9])[S:6][CH2:7][CH3:8].[CH3:12][N:13]=[C:14]=[O:15]>C(Cl)Cl>[CH3:11][N:2]([CH3:1])[C:3]([N:4]=[C:5]([S:6][CH2:7][CH3:8])[NH:9][C:14]([NH:13][CH3:12])=[O:15])=[O:10]
Reactant: CCSC(=N)NC(=O)N(C)C
Reactant: CN=C=O
Solvent: ClCCl
Product: CCSC(=NC(=O)N(C)C)NC(=O)NC

Procedure:
A solution of 5 parts of ethyl 4,4-dimethylthioallophanimidate and 1.8 parts of methylisocyanate in 70 parts of methylene chloride was refluxed for 2 hours. After evaporation of the solvent, the residue was recrystallized from ethylacetate to give ethyl N-dimethylcarbamoyl-4-methylthioallophanimidate (a compound of formula I), m.p. 109°-111.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][CH:9]([N:19]2C(=O)C3=CC=CC=C3C2=O)[C:8]1=[O:30])=[O:5])[CH3:2].O.NN>C(O)C>[NH2:19][CH:9]1[CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:8]1=[O:30]
Reactant: CCOC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CCCc2ccccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)CN1C(=O)C(N)CCCc2ccccc21

Procedure:
A solution of 1-ethoxycarbonylmethyl-3-phthalimido-3,4,5,6-tetrahydro-1-benzazocin-2(1H)-one (1.4 g) and hydrazine hydrate (0.19 g) in ethanol (400 ml) is refluxed for 4 hours. The solvent is removed under reduced pressure and the residue distributed between ethyl acetate (200 ml) and 2N hydrochloric acid (125 ml). The organic phase is washed with 2N hydrochloric acid (100 ml). The combined hydrochloric acid solutions are made strongly basic with 2N sodium hydroxide, extracted with ethyl acetate (2×200 ml), and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue recrystallized from ethanol/ether to give 3-amino-1-ethoxycarbonylmethyl-3,4,5,6-tetrahydro-1-benzazocin-2(1H)one as an oil, used without further purification in the next synthetic step.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[F:11][C:12]1[CH:17]=[C:16]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:15]=[CH:14][C:13]=1[CH2:26][C:27](Cl)=[N:28][OH:29].C(N(CC)CC)C>O1CCCC1>[F:11][C:12]1[CH:17]=[C:16]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:15]=[CH:14][C:13]=1[CH2:26][C:27]1[CH:2]=[C:1]([C:3]2[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=2)[O:29][N:28]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(COc2ccccn2)cc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(COc4ccccn4)cc3F)no2)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynyl-pyridine-2,6-diamine (43.2 mg, 0.325 mmol) described in Manufacturing Example 13-1-3 and (2-fluoro-4-(pyridin-2-yloxymethyl)-phenyl)acetohydroximoyl chloride (150 mg, 0.509 mmol) described in Manufacturing Example 204-1-8 was added triethylamine (97.2 μL, 0.697 mmol), which was stirred for 2 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1, then ethyl acetate) to obtain the title compound (73 mg, 37%).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[C:15]([CH:18]([CH3:23])[C:19]([O:21]C)=[O:20])[CH:16]=[CH:17][C:3]1=2.[Cl:24]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:24][C:17]1[C:3]2[N:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[C:5](=[O:13])[C:4]=2[CH:14]=[C:15]([CH:18]([CH3:23])[C:19]([OH:21])=[O:20])[CH:16]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)C(C)c1ccc2c(c1)C(=O)c1ccccc1CN2C
Solvent: ClC(Cl)Cl
Product: CC(C(=O)O)c1cc(Cl)c2c(c1)C(=O)c1ccccc1CN2C
Yield: 79.7 %

Procedure:
Methyl 2-(5,6-dihydro-5-methyl-11-oxodibenz[b,e]azepin-2-yl)propionate (2.0 g), chloroform (50 ml) and N-chlorosuccinimide (1.4 g) were treated in the same manner as described in Example 9 to obtain the desired compound (1.7 g) as a yellow oily material.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9](=[O:14])[C:10]([O:12][CH3:13])=[O:11]>>[CH3:13][O:12][C:10](=[O:11])[C:9](=[O:14])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1ccncc1
Product: COC(=O)C(=O)Nc1ccncc1

Procedure:
In a manner similar to that employed in Referential Example 242, the title compound was prepared from 4-aminopyridine and methyl chlorooxoacetate.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10](B3OC(C)(C)C(C)(C)O3)[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.Br[C:25]1[C:30](=[O:31])[N:29]([CH3:32])[C:28]2[N:33]([C:36]3[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=3[F:43])[N:34]=[CH:35][C:27]=2[CH:26]=1>>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([C:25]3[C:30](=[O:31])[N:29]([CH3:32])[C:28]4[N:33]([C:36]5[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=5[F:43])[N:34]=[CH:35][C:27]=4[CH:26]=3)[CH:9]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: Cn1c(=O)c(Br)cc2cnn(-c3c(F)cccc3F)c21
Reactant: Cc1ccc(NC(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(NC(=O)NC2CC2)cc1-c1cc2cnn(-c3c(F)cccc3F)c2n(C)c1=O

Procedure:
The title compound was prepared by a method similar to that described in Example 1, step 5 (Method A), starting from the 1-cyclopropyl-3-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea and 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one. MS (ESI, pos.ion) m/z: 317.2 (M+1).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH2:15])[CH2:6][C@@H:5]1[CH3:16])(=[O:3])[CH3:2].[CH3:17][O:18][CH2:19][CH2:20][N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:15][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:24]3[CH:23]=[N:22][N:21]([CH2:20][CH2:19][O:18][CH3:17])[CH:25]=3)[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:16])[CH2:6]1
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COCCn1cc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cn1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
(2S,4R)-1-Acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 7) (900 mg, 2.82 mmol), 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (852 mg, 3.38 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (309 mg, 0.422 mmol) and K2CO3 (895 mg, 6.48 mmol) were combined in 1,4-dioxane (12 ml) and water (4.0 ml) and heated at 110° C. for 60 min (microwave). The reaction was heated for a further 10 min and then, for a further 30 min under the same conditions. PdCl2(dppf) (309 mg, 0.422 mmol), K2CO3 (895 mg, 6.48 mmol) and water (1.5 ml) were added and the mixture heated at 110° C. for 30 min (microwave). The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate (150 ml) and DCM (3×150 ml). The organics were combined, dried (hydrophobic frit) and evaporated under vacuum. The residue was dissolved in DCM, the solution applied to a silica cartridge (100 g) and purified the cartridge eluted with an ethyl acetate/cyclohexane gradient (0-100% over 10 CV followed by 100% ethyl acetate for 5 CV). The cartridge was washed using a methanol/DCM gradient (0-20% over 10 CV, followed by holding at 20% methanol/DCM for 5 CV). The cartridge was further washed using a gradient 2M ammonia in methanol/DCM (0-20% over 10 CV, followed by 2M ammonia in methanol/DCM 20% for 5 CV). The appropriate fractions were combined and evaporated under vacuum to leave 1-((2S,4R)-4-amino-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (631 mg, 1.921 mmol, 68% yield) as a brown glass. LCMS (HpH), Rt 0.68 min, MH+ 329
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:3]=1[CH2:4][CH2:5][N:6]=[C:7]2[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1
Reactant: O=C(NCCc1ccccc1Br)c1ccc(C(F)(F)F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(C2=NCCc3c(Br)cccc32)cc1
Temperature: 0 °C

Procedure:
To a 100 mL round-bottomed flask was added N-(2-bromophenethyl)-4-(tri-fluoromethyl)benzamide (1.6 g, 4299 μmol, from step 1), toluene (50 mL), phosphorus pentaoxide (1061 μL, 17196 μmol, Aldrich). The reaction mixture was stirred at reflux for 5 h. The mixture was cooled down and then poured into ice (ca 50 g), and extracted with EtOAc (2×50 mL). The organic extract was washed with water (30 mL), saturated NaCl (30 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 10% EtOAc/hexanes to give 5-bromo-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline. MS (ESI pos. ion) m/z: 354 (M+1).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8])=[N+:2]=[N-:3].[CH:12]([N-]C(C)C)(C)C.[Li+].C1CCCCC1.IC.O>O1CCCC1>[N:1]([CH2:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8])=[N+:2]=[N-:3]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C(C)CCN=[N+]=[N-]
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CCN=[N+]=[N-]
Reaction time: 0.5 h

Procedure:
To a solution of 1.3 g of methyl 4-azido-2-methylbutyrate (which was prepared by the method as described in Tetrahedron, 1987, 43, 1811–1822) in 13 ml of tetrahydrofuran, 16.7 ml of 1.5N lithium diisopropylamide-cyclohexane solution was added at −78° C. in nitrogen atmosphere, followed by 30 minutes' stirring at the same temperature. To the solution 1.6 ml of iodomethane was added at −78° C., followed by 30 minutes' stirring at the same temperature. Water was added to the reaction liquid, followed by extraction with diethyl ether. The diethyl ether layer was washed with saturated brine, dried on anhydrous magnesium sulfate and the solvent was distilled off. The residue was separated and purified on silica gel column chromatography (ethyl acetate/hexane=1/30) to provide 406 mg of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:16][C:15]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:17]([F:20])([F:19])[F:18])[O:14][N:13]=2)=[CH:8][C:7]=1[CH3:29])(=[S:3])[NH2:2].[C:31](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[NH2:2][C:1]([S:3][CH3:31])=[N:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:16][C:15]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:17]([F:20])([F:18])[F:19])[O:14][N:13]=2)=[CH:8][C:7]=1[CH3:29]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC(N)=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CSC(N)=NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C

Procedure:
To a solution of 0.30 g of N-thiocarbamoyl-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl benzoic acid amide and 0.26 g of potassium carbonate in 10 mL of N,N-dimethylformamide, 0.107 g of methyl iodide was added and the resultant mixture was stirred at room temperature for 15 hours. After the completion of the reaction, the reaction mixture was diluted with 20 mL of water and the diluted reaction mixture was extracted with ethyl acetate (30 mL×1). The organic phase was dehydrated and dried with saturated brine and over anhydrous sodium sulfate, respectively, in this order, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (1:3) to obtain 0.28 g of the objective substance as a colorless resin-state substance.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[CH3:15])[CH:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O.C1COCC1.O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:16])[CH3:15])[CH:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under an inert atmosphere a 100 mL four necked flask (flame dried) with a magnetic stirrer was charged with 835 mg (2.54 mmol) 1-[(3SR,4SR)-1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanone in 25 mL THF. The yellow solution was cooled to 0° C. and 34 mg (0.89 mmol) LiAlH4 was added. The mixture was stirred for 30 min at 0° C. and 30 min from 0° C. to 15° C. At 0° C. 10 mL ethyl acetate was added drop-wise, followed by 5 mL THF:water 9:1 and 1 mL 4 N aqueous NaOH and 1 mL water. The mixture was stirred for 30 min at 40-50° C. and Na2SO4 was added. The mixture was filtered off and concentrated under vacuum. The residue was purified by chromatography on silica eluting with a gradient formed from DCM, methanol, NH3aq. to yield after evaporation of the product containing fractions 466 mg (55%) of the title compound as off-white foam. MS (m/e): 330.1 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:16]([CH2:17][C:18]([OH:20])=O)[C:15](=[S:21])[NH:14][C:13](=[O:22])[CH:12]=1.[NH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].N1C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:16]([CH2:17][C:18]([NH:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:20])[C:15](=[S:21])[NH:14][C:13](=[O:22])[CH:12]=1
Reactant: COc1ccc(-c2cc(=O)[nH]c(=S)n2CC(=O)O)c(OC)c1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(=O)[nH]c(=S)n2CC(=O)NCCNC(=O)OC(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.1 %

Procedure:
To a solution of 2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid (40 g, 124 mmol) in DMF (300 mL) was added tert-butyl (2-aminoethyl)carbamate (40 g, 250 mmol) and pyridine (30 mL), and the mixture was stirred at room temperature for 15 minutes. The solution was cooled to 0° C. and it was purged with nitrogen gas for 3 times. After 10 minutes, a 50% solution of T3P in DMF (109 mL) was added drop-wise at 0° C., and stirring was continued for 1 hour, whereupon the water/ice bath was removed and stirring was continued for 4 hours. The reaction solution was slowly poured into a stirring solution of aqueous HCl solution (2500 mL, 0.5 M), and the suspension was stirred at room temperature for 1 hour. The formed solid was filtered, and the filter cake was washed with 0.5M HCl solution (500 mL) followed by water (500 mL). The solid was dried in the vacuum oven at 50° C. for 20 hours to give 54.6 g of light beige powder. This solid was suspended in EtOAc (500 mL), heated to 70° C. under a stream of nitrogen gas with stirring for 1 hour, and then at room temperature for 18 h. The suspension was cooled down to 0° C., and the solid was filtered, the filter cake washed with cold (0° C.) EtOAc (100 mL) and dried in the vacuum oven at 50° C. for 9 hours to give 49.0 g of off-white solid. This solid was suspended in acetonitrile (300 mL), and stirred at 70° C. under a stream of nitrogen for 18 h. The mixture was cooled to 0° C., and the resultant solid was filtered, washed with cold acetonitrile (50 mL) and dried in the vacuum oven at 50° C. for 8 hours to give 46.5 g of off-white solid. This solid was suspended in EtOAc (350 mL), heated to 70° C. under a stream of nitrogen gas with stirring for 1 hour, and then at room temperature for 18 h. The suspension was cooled down to 0° C., and the solid was filtered, the filter cake washed with cold (0° C.) EtOAc (50 mL) and dried in the vacuum oven at 50° C. for 9 hours to give the title compound (45.4 g, 78.8%) as an off-white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:21])[N:11]([C:18](Cl)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[N:22]1([CH2:27][CH:28]([OH:31])[CH2:29][OH:30])[CH2:26][CH2:25][CH2:24][CH2:23]1.N1C=CC=CC=1>C1COCC1>[OH:31][CH:28]([CH2:27][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:29][O:30][C:18]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:21])=[O:19]
Reactant: OCC(O)CN1CCCC1
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Cl)c3ccccc32)[nH]1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC(O)CN3CCCC3)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride (150 mg, 0.5 mmol) and 3-pyrrolidin-1-yl-propane-1,2-diol (88 mg, 0.6 mmol) in 3.0 mL of THF was added 80 μl of pyridine dropwise at room temperature. Upon addition, the reaction mixture was stirred at room temperature for 20 min., and filtered. The orange solid was then washed with ethyl acetate and hexane sequentially and dried in a vacuum oven overnight to give 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-3-pyrrolidin-1-yl-propyl ester as an orange solid. 1HNMR (400 MHz, CDCl3 and 2 drops of DMSO-d6) δ 12.63 (s, br, 1H, NH-1′), 11.77 (s, br, 1H, OH), 7.86–7.88 (m, 1H), 7.51–7.53 (m, 1H), 7.42 (s, 1H, H-vinyl), 7.18–7.25 (m, 2H), 6.06 (d, J=2.3 Hz, 1H, H-4′), 4.65–4.73 (m, 2H), 4.44–4.56 (m, 2H), 3.91–3.93 (m, 1H), 3.33–3.52 (m, 2H), 2.88–3.15 (m, 2H), 2.40 (s, 3H, CH3), 2.36 (s, 3H, CH3), and 2.01–2.32 (m, 4H).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:35])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]1([CH3:35])[CH2:6][CH2:7][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([OH:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c(C(=O)C(=O)OCC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCOC1(C)CCN(c2c([C@H](O)C(=O)OCC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
To a stirred yellow solution of ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (22 g, 40.6 mmol) in anhydrous toluene (800 mL) was added 1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (16.25 mL, 16.25 mmol). The mixture was cooled to −35° C. and catechoborane (7.11 mL, 56.9 mmol) was added over 5 min. After 30 min, the reaction mixture was slowly warmed to −15° C. and stirred for additional 2 h. A this point LCMS indicated approx 60% conversion, so mixture was cooled to −35° C. and 3.5 mL of catechoborane was added and stirred at −15° C. for 2 h. At his point LCMS indicates completion of reaction. Mixture was then dluted with EtOAc (1 L) and sat. Na2CO3 (300 mL). The mixture was stirred vigorously for 30 min, and the organic phase washed with sat Na2CO3 (2×200 mL) each time vigorously stirring for 30 min, dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel chromatography (5-70% EtOAc/hexane) to afford desired (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (17 g, 31.3 mmol, 77% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.19-8.10 (m, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.58-7.52 (m, 1H), 7.33 (t, J=7.8 Hz, 1H), 6.86-6.82 (m, 1H), 6.10 (dd, J=10.8, 5.1 Hz, 1H), 5.57 (d, J=5.2 Hz, 1H), 5.48 (d, J=16.9 Hz, 1H), 5.27 (d, J=10.2 Hz, 1H), 4.35 (dq, J=10.8, 7.2 Hz, 1H), 4.23 (dq, J=10.7, 7.1 Hz, 1H), 4.03 (dt, J=5.2, 1.5 Hz, 2H), 2.65 (s, 3H), 2.00 (d, J=14.5 Hz, 2H), 1.84 (br. s., 2H), 1.36 (s, 3H), 1.29-1.24 (m, 3H). LCMS (M+H)=543.4.
Reaction SMILES: CS(C)=O.FC(F)(F)C(O)=O.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[OH:20])=[CH:15][CH:14]=1.CCN(CC)CC>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)=[O:20])=[CH:17][CH:18]=1
Reactant: COc1cccc(C(O)c2ccc(Br)cc2)c1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)c2ccc(Br)cc2)c1
Reaction time: 0.33 h

Procedure:
To a solution of DMSO (8.13 mL, 114.7 mmol) in CH2Cl2 (80 mL) at −78 was added solution of trifluoroacetic acid (TFAA) (12.12 mL, 86.0 mmol) in CH2Cl2 (50 mL) over 5 min. The mixture was stirred for 20 min and a solution of (4-bromo-phenyl)-(3-methoxy-phenyl)-methanol (16.8 g, 57.4 mmol) in CH2Cl2 (50 mL) was added dropwise over 5 min. The reaction mixture was stirred at −78° C. for 30 min and Et3N (24.0 mL, 172 mmo) was added. The mixture was stirred at −78° C. for an additional 30 min and at room temperature for 1 h. The CH2Cl2 layer was washed with brine (3×30 mL), dried over Na2SO4 and concentrated. Purification with hexanes/EtOAc (10:1) afforded 16.0 9 of (4-Bromo-phenyl)-(3-methoxy-phenyl)-methanone. 1HNMR (400 MHz, CDCl3) δ 7.67-7.66 (comp, 2H), 7.64-7.60 (comp, 2H), 7.37 (m, 1H), 7.34-7.27 (comp, 2H), 7.14-7.11 (m, 1H), 3.84 (s, 3H).