Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][N:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10](=[O:17])[N:9]([C:18]2[CH:23]=[C:22]([O:24]C(C)C)[C:21]([Cl:28])=[CH:20][C:19]=2[F:29])[C:8]1=[O:30]>C(Cl)Cl.O>[NH2:6][N:7]1[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][C:10](=[O:17])[N:9]([C:18]2[CH:23]=[C:22]([OH:24])[C:21]([Cl:28])=[CH:20][C:19]=2[F:29])[C:8]1=[O:30]
Reactant: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)c(F)cc1Cl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: Nn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O

Procedure:
Conc. sulfuric acid (3 ml) was added to a solution of 1-amino-3-(4-chloro-2-fluoro-5-isopropyloxyphenyl)-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (4.5 g) in methylene chloride (50 ml) stirred at 0C . After 1 hour the mixture was diluted with water and processed. The oily product was chromatographed on silica gel eluting with ethyl acetate:hexane, 2:3, to give 1-amino-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione as a pale yellow amorphous solid (3.6 g,). 1H NMR (CDCl3,TMS): 7.27(1H, d, J=8.8 Hz), 6.88(1H, d, J=6.5 Hz), 6.28(1H, s), 5.86(1H, br. s), 4.61(2H, s)
Reaction SMILES: [CH:1]1([C@H:7]([OH:21])[CH2:8][NH:9][CH2:10][C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:11]12([CH2:10][N:9]3[CH2:8][C@H:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[O:21][C:30]3=[O:32])[CH2:12][CH:13]3[CH2:19][CH:17]([CH2:16][CH:15]([CH2:14]3)[CH2:20]1)[CH2:18]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O[C@H](CNCC12CC3CC(CC(C3)C1)C2)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1O[C@@H](C2CCCCC2)CN1CC12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
To a solution of (S)-1-cyclohexyl-2-((1-adamantylmethyl)amino)ethanol (22 mg, 0.077 mmol) and Et3N (15.6 mg, 0.154 mmol) in dry CH2Cl2(2 mL) at 0° C. was added triphosgene (9.2 mg, 0.031 mmol) in dry CH2Cl2(2 mL). The mixture was stirred for 30 min and then concentrated in vacuum to give the crude product, which was purified by preparative TLC to afford (S)-3-((1-adamantyl)methyl)-5-cyclohexyloxazolidin-2-one (5 mg, 21%). 1H NMR (MeOD, 400 MHZ): δ=1.18-1.97 (m, 25H), 2.75-2.95 (m, 2H), 3.42 (t, 1H), 3.72 (t, 1H), 4.83 (m, 1H); MS: m/z=318.
Reaction SMILES: [NH2:1][C@@:2]1([N:28]2[CH2:36][C:34](C(OC)C3C=CC=CC=3)([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[O:18][C@H:6]([CH:7](C(OC)C2C=CC=CC=2)[OH:8])[C@@:4](C(OC)C2C=CC=CC=2)([OH:5])[CH2:3]1>[Pd].C(O)C>[NH2:1][C@@:2]1([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[O:18][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1
Reactant: COC(c1ccccc1)C(O)[C@H]1O[C@@](N)(N2CC(C)(C(OC)c3ccccc3)C(=O)NC2=O)C[C@@]1(O)C(OC)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1cn([C@@]2(N)C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 24 h

Procedure:
A suspension of 1′-amino-3′, 5′, 5-tris(methoxybenzyl) thymidine and 10% palladium on charcoal in ethanol is shaken in a hydrogenation apparatus under hydrogen pressure of 50 psi for 24 h. The solid is filtered and the filtrate concentrated. The crude is purified by recrystallization.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][C:6]([NH2:8])=[O:7].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[N:43]1([C:48]2[CH:53]=[CH:52][C:51]([S:54]([O:57][C:58]3[CH:67]=[CH:66][C:61]4[NH:62][C:63](N)=[N:64][C:60]=4[CH:59]=3)(=[O:56])=[O:55])=[CH:50][CH:49]=2)[CH:47]=[CH:46][N:45]=[CH:44]1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][C:6]([NH:8][C:63]1[NH:62][C:61]2[CH:66]=[CH:67][C:58]([O:57][S:54]([C:51]3[CH:52]=[CH:53][C:48]([N:43]4[CH:47]=[CH:46][N:45]=[CH:44]4)=[CH:49][CH:50]=3)(=[O:56])=[O:55])=[CH:59][C:60]=2[N:64]=1)=[O:7]
Reactant: Nc1nc2cc(OS(=O)(=O)c3ccc(-n4ccnc4)cc3)ccc2[nH]1
Reactant: COC(=O)CCC(N)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(-n4ccnc4)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.9 mg of succinamic acid methyl ester, 25 mg of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and 12 μl diisopropyl-ethylamine were taken up in 0.4 ml dimethylformamide. Reaction mixture was stirred at room temperature for one hour and 5-(4-[1-imidazolyl]-phenylsulfonyloxy)-1H-benzimidazole-2-ylamine was added in 0.2 ml dimethylformamide. Reaction mixture was then stirred at room temperature for 24 hours. Solvent was evaporated in a Jouan model RC 10.10 centrifuge evaporator and title compound was solubilised in 0.5 ml dimethylsulfoxide for LCMS trigged purification yielding 3.9 mg of N-[5-(4-[1-imidazolyl]-phenylsulfonyloxy)-1H-benzimidazole-2-yl]-succinamic-acid-methyl ester. (LC/MS analysis: retention time=2.70 min., mass spectrum: 470.34, [M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.Cl.[O:15]([NH2:17])[CH3:16]>>[CH3:16][O:15][N:17]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=1[C:10]([F:13])([F:12])[F:11]
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: CON
Agent: Cl
Product: CON=Cc1ccc(F)cc1C(F)(F)F
Yield: 93 %

Procedure:
Reaction of 4-fluoro-2-trifluoromethyl-benzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil (93% yield). 1HNMR indicated a 92:8 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 4.00 (3H, s, OCH3), 7.25 (1H, m, aromatic), 7.37 (1H, m, aromatic), 8.08 (1H, m, aromatic), 8.36 (1H, broad s, CH).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:30](O)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:18][CH:17]([NH:29][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:16]2)=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Reactant: O=C(O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)c3ccccc3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
170 mg (0.41 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 8A) and 50 mg (0.41 mmol, 1.0 eq.) of benzoic acid were reacted according to General Method 1. Yield: 58 mg (35% of theory)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12]>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][S:11](=[O:13])(=[O:12])[NH2:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: N#Cc1ccc(OS(N)(=O)=O)cc1
Yield: 51 %

Procedure:
This compound was prepared by the procedure of Example 56 from a solution of 11.9 g (0.10 mole) of 4-cyanophenol (Aldrich Chemical Co.) and 9.1 ml (0.105 mole) of chlorosulfonyl isocyanate in 75 ml of toluene. The solid product was recrystallized from benzene-acetonitrile to give 10.1 g (51%) of white solid, mp 154°-156° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](N(OC)C)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][Mg]Br.CCOC(C)=O.[NH4+].[Cl-]>C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:15])[CH3:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)C1CCN(Cc2ccccc2)CC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 27.5 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-benzyl-N-methoxy-N-methylpiperidine-4-carboxamide (11.5 g, 44 mmol) in diethyl ether (150 mL) at 0° C. was added methyl magnesium bromide (15.7 g, 132 mmol), drop-wise over 10 min. The resulting mixture was stirred at 25-30° C. for 2 h. After completion of the reaction, the mixture was treated with EtOAc and saturated NH4Cl solution. The separated organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1-(1-benzylpiperidin-4-yl)ethanone product. [M+1]=218.1
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:14][CH2:15][CH2:16][CH3:17])=[N:8][C:9](SC)=[N:10][CH:11]=1)=[O:5])[CH3:2].C([N:21](CC)C(C)C)(C)C.N.O>CN1CCCC1=O.ClC1C=CC=C(C(OO)=O)C=1>[NH2:21][C:9]1[N:8]=[C:7]([NH:14][CH2:15][CH2:16][CH3:17])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][N:10]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCNc1nc(SC)ncc1C(=O)OCC
Agent: N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCNc1nc(N)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-(methylthio)-4-(propylamino)pyrimidine-5-carboxylic acid ethyl ester (A1, 11.7 g) in N-methylpyrrolidone (90 mL), meta-chloroperbenzoic acid (70 to 75% wt, 20.8 g) was added under ice cooling, and the mixture was stirred at room temperature for 40 minutes. To the reaction mixture, N,N-diisopropylethylamine (23.9 mL) and 10% aqueous ammonia (60.0 mL) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into water (400 mL). The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain ethyl 2-amino-4-(propylamino)pyrimidine-5-carboxylate (C3, 8.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:15][CH2:14][CH2:13][CH2:12]1)[C:7](=[O:16])[C:6]([C:17](OCC)=[O:18])=[C:5]2[OH:22].Cl.[C:24]([O:28][C:29](=[O:32])[CH2:30][NH2:31])([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:12][CH2:13][CH2:14][CH2:15]1)[C:7](=[O:16])[C:6]([C:17]([NH:31][CH2:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:32])=[O:18])=[C:5]2[OH:22]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCC2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCC2)C1=O
Temperature: 85 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
A mixture of ethyl 6′-chloro-4′-hydroxy-2′-oxo-spiro[cyclopentane-1,1′-naphthalen]-3′-carboxylate (0.66 g, 2 mmol) and glycine tert-butyl ester hydrochloride (0.5 g, 3 mmol) in 10 mL dioxane was treated with DIPEA (1 mL, 6 mmol). The mixture was warmed to 85° C. and stirred for 4 hours, M+1=406. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc hexane to give the title compound (0.8 g) as a pale yellow solid. MS (m/z)=406 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1C=C[C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:34][CH2:33]2)[CH:17]=[CH:18][CH:19]=1)(=[O:11])=[O:10].ClC1C=CC(Cl)=CC=1[S:51](Cl)(=O)=O>>[Cl:1][C:2]1[S:51][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:33][CH2:34][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:36][CH2:37]2)[CH:17]=[CH:18][CH:19]=1)(=[O:11])=[O:10]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5cc(Cl)ccc5Cl)c4)cc23)CC1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5cc(Cl)sc5Cl)c4)cc23)CC1
Yield: 27 %

Procedure:
The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide substituting 2,5-dichloro-3-thiophenesulfonyl chloride (86 mg, 0.352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 16.7 mg the title compound (27%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].C1C(=O)N([Br:20])C(=O)C1>C(Cl)Cl>[Br:20][C:8]1[C:7]([C:9]([F:10])([F:11])[F:12])=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(N)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: Cc1cc(N)cc(C(F)(F)F)c1Br
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-methyl-5-(trifluoromethyl)aniline (4.84 g, 0.011 mol) was dissolved in CH2Cl2 and cooled to 0° C. NBS (4.92 g, 1 eq) was added and the mixture stirred overnight. The reaction mixture was loaded onto silica gel and eluted with 0-20% EtOAc in hexane to give 2.3 g of M21-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[C:15]=2[N+:21]([O-])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N#N.[C:26]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>[Pd].CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[N:21]=[C:34]([C:33]4[CH:36]=[CH:37][C:30]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:31][CH:32]=4)[O:20][C:16]=3[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(O)c2[N+](=O)[O-])CC1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [Pd]
Agent: N#N
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3oc(-c4ccc(C(C)(C)C)cc4)nc23)CC1
Temperature: 80 °C
Yield: 81 %

Procedure:
4-(3-hydroxy-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.00 g, 3.09 mmol) was charged to a 250 mL round bottom flask containing 10% Pd/C, stir bar and septum. Under a positive stream of N2, 2-propanol (80 mL) was added via syringe. The flask was evacuated and fitted with a balloon containing H2 and stirred, under H2, at room temperature for 18 h. LC-MS indicated only aniline present. 4-tert-Butyl-benzaldehyde (800 μL, 4.64 mmol) was added, the balloon was replaced with an air condenser and the stirring solution was heated to 80° C. for 48 h. The reaction was cooled to room temperature and filtered through celite to remove the catalyst and the solvent removed in vacuo to give a brown oil. This oil was adsorbed onto silica and purified by column chromatography, eluting with 11% ethyl acetate in hexane to afford the product as a clear waxy material (1.09 g, 81%). Mass Spectrum (+ESI): 436 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([C:10]#N)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C(O)=[O:15]>[Ni]>[N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: N#Cc1ccc(-n2cccn2)cc1
Reactant: O=CO
Agent: [Ni]
Product: O=Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-pyrazol-1-yl-benzonitrile (1.6 g, 9.47 mmol), prepared in Step A of Preparation 42, in 75% aqueous formic acid (36 mL) was added Raney nickel alloy (1.6 g). The reaction was heated at reflux for 1.25 h and was cooled to room temperature. The solids were removed by filtration through Celite with the aid of hot EtOH. The solution was diluted with water and CHCl3. The aqueous layer was washed with CHCl3 (3×). To the organic solution was carefully added aqueous NaHCO3 until a pH of about 8 was achieved. The organic layer was dried (MgSO4), filtered, and concentrated. Purification by medium pressure chromatography (2:1 hexanes:EtOAc) provided the title compound (1.44 g) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.01 (d, 1H), 7.96 (d, 2H), 7.87 (d, 2H), 7.76 (d, 1H), 6.51 (m, 1H); MS 173 (M+1).
Reaction SMILES: [CH:1]([C@@H:4]1[N:8]([C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[N:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:25]=5)=[CH:20][CH:19]=4)=[C:11]3[N:10]=2)[C:7](=[O:37])[NH:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:41][CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]>>[Si:44]([O:43][CH2:42][CH2:41][N:6]1[CH2:5][C@H:4]([CH:1]([CH3:3])[CH3:2])[N:8]([C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[N:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])[N:25]=5)=[CH:20][CH:19]=4)=[C:11]3[N:10]=2)[C:7]1=[O:37])([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]
Reactant: CC(C)[C@H]1CNC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)[C@H]1CN(CCO[Si](C)(C)C(C)(C)C)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a solution of (S)-5-isopropyl-1-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (0.23 g, 0.443 mmol) at 0° C. was added sodium hydride (0.0355 g, 0.887 mmol) and the reaction stirred 10 minutes. (2-Bromoethoxy)(tert-butyl)dimethylsilane (0.212 g, 0.887 mmol) was added and the reaction stirred for 2 hours while warming to ambient temperature. The reaction was poured onto water and extracted into EtOAc. The combined organic layers were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The crude material was chromatographed using 20% EtOAc/dichloromethane as eluent to yield (S)-1-(2-(tert-butyldimethylsilyloxy)ethyl)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (0.18 g, 60%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]>C(Cl)Cl.CS(C)=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([N:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: COc1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
Oxalyl chloride (11.9 mL, 23.78 mmol) was dissolved in DCM (200 mL) and cooled to −78° C. DMSO (3.4 mL, 47.58 mmol) in DCM (15 mL) was added to the solution dropwise via an addition funnel. Upon completion of addition, the reaction was allowed to stir 10 min. 1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinol (4.04 g, 15.86 mmol) in DMSO (6 mL) and DCM (15 mL) was added dropwise via addition funnel. Upon completion of addition, the reaction was allowed to stir 15 minutes. TEA (11.0 mL, 79.3 mmol) was then added dropwise via addition funnel. Upon completion of addition, the bath was removed and the reaction was allowed to warm to rt. The reaction was stirred until alcohol was consumed as indicated by TLC. The solvent was removed in vacuo and the residue was taken up in EtOAc. The suspension was washed twice with H2O, followed by brine. The organic layer was dried with MgSO4, filtered and concentrated to provide the title compound of step B (3.91 g, 15.59 mmol, 97%) as a bright yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.47-2.51 (m, 4H), 3.82 (t, J=6.2 Hz, 4H), 3.91 (s, 3H), 6.52 (d, J=2.6 Hz, 1H), 6.61 (dd, J=9.5, 2.6 Hz, 1H), 7.91 (d, J=9.5 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](=[O:7])[CH2:3][CH:2]=1.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([O:12][C:10]([CH2:9][N:1]1[CH:2]=[CH:3][C:4](=[O:7])[CH:5]=[CH:6]1)=[O:11])[CH3:14]
Reactant: CCOC(=O)CBr
Reactant: O=C1C=CN=CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc(=O)cc1

Procedure:
14.25 g of 4-pyridone was dissolved in 250 ml of DMF, and 25 ml of ethyl bromoacetate and 31.1 g of potassium carbonate were added thereto and reacted for 2.5 hours at 60° C. After the reaction, the insoluble part was filtrated out, and the remaining filtrate solution was concentrated. The formed residue was purified with silicagel-column chromatography (chloroform/methanol=10/1-5/1), to obtain 22.8 g of 1-ethoxycarbonylmethyl-4-pyridone. This was dissolved in 400 ml of dimethoxyethane and 30 g of Lawesson's reagent was added thereto and reacted for 30 minutes, while heated under reflux. After the reaction, the reaction solution was concentrated, and the residue formed was purified with silicagel-column chromatography (chloroform/methanol=20/1) and then crystallized with dichloromethane/ether, to obtain 13.6 g of 1-ethoxycarbonylmethyl-4-thiopyridone.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14])[C:3]([NH:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH:22]1([N:25]2[CH2:30][C:29]3([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[O:28][CH2:27][C:26]2=[O:36])[CH2:24][CH2:23]1>CN(C)C=O.O>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([CH:2]([N:33]2[CH2:34][CH2:35][C:29]3([O:28][CH2:27][C:26](=[O:36])[N:25]([CH:22]4[CH2:23][CH2:24]4)[CH2:30]3)[CH2:31][CH2:32]2)[C:3]([NH:5][CH3:6])=[O:4])=[C:8]([F:14])[CH:9]=1
Reactant: CNC(=O)C(Br)c1ccc(Br)cc1F
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
A solution of 2-bromo-2-(4-bromo-2-fluorophenyl)-N-methylacetamide (0.579 mmol) in N,N-dimethylformamide (3 mL) was treated with potassium carbonate (1.715 mmol) and 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (0.632 mmol). The reaction was allowed to stir at room temperature overnight. The reaction solution was then diluted with water (50 mL) and was extracted three times with dichloromethane. The organic layers were combined and were washed with water three times, twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-6% methanol/dichloromethane) afforded the title compound as a yellow oil (185 mg, 63% yield). MS(ES)+ m/e 454.0/455.9 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br:19][CH2:20][CH2:21]Br>CN(C)C=O.O>[Br:1][C:2]1[C:3]([O:12][CH2:21][CH2:20][Br:19])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)cc(Br)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc(Cl)cc(Br)c1OCCBr
Temperature: 50 °C
Reaction time: 8 h
Yield: 123.4 %

Procedure:
A suspension of 3′-bromo-5′-chloro-2′-hydroxyacetophenone (2.4 g, 10 mmol), potassium carbonate (2.8 g, 20 mmol) and 1,2-dibromoethane (3.5 mL, 41 mmol) in anhydrous N,N-dimethylformamide (30 mL) was stirred at 50° C. overnight. After cooling, the reaction mixture was diluted with water (100 mL), and the whole was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated aqueous ammonium chloride solution (50 mL, twice) and brine (50 mL) and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the title reference compound (4.4 g) as orange oil (Quantitative).