Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(CC)C2C=CC=CC=2)C=CC=CC=1.[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][BH:19][O:18]1.[C:25]([NH:28][C:29]([CH:41]1[CH2:44][C:43]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)([NH:45][CH:46]=[O:47])[CH2:42]1)([CH2:37][CH2:38][CH:39]=[CH2:40])[C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:27])[CH3:26]>ClCCl>[C:25]([NH:28][C:29]([CH:41]1[CH2:42][C:43]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)([NH:45][CH:46]=[O:47])[CH2:44]1)([CH2:37][CH2:38][CH2:39][CH2:40][B:19]1[O:20][C:21]([CH3:23])([CH3:22])[C:17]([CH3:24])([CH3:16])[O:18]1)[C:30]([NH:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])(=[O:27])[CH3:26]
Reactant: CC1(C)OBOC1(C)C
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)C1CC(Cc2ccc(Cl)cc2)(NC=O)C1
Agent: CCP(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CC(Cc2ccc(Cl)cc2)(NC=O)C1
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
While under argon, bis(1,5-dicyclooctadiene)diiridium(I)dichloride (15 mg, 0.022 mmol) and diphenylphosphinoethan (18 mg, 0.044 mmol) in dichloromethane (3 mL) was cooled to 0° C. and treated with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.430 mL, 2.95 mmol). After 30 min, a solution of 2-acetamido-N-tert-butyl-2-(3-(4-chlorobenzyl)-3-formamidocyclobutyl)hex-5-enamide (330 mg, 0.738 mmol) in dichloromethane (10 mL) was added and the cooling bath was removed. After 16 h, the solution was diluted with dichloromethane (20 mL) and washed with water and saturated aqueous sodium chloride. The organic layer was dried over MgSO4, filtered and concentrated to give the crude product (420 mg, 99%), which was used in the next step without further purification. ESI MS found for C30H47BClN3O5 m/z [576.8 (M+1), 574.7 (M−1)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[CH:14]=3)=[CH:11][C:10]([NH2:27])=[N:9]2)=[CH:4][CH:3]=1.[O:28]=[C:29]1[NH:33][CH2:32][C@@H:31]([C:34](O)=[O:35])[CH2:30]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:24])([F:23])[F:25])[CH:14]=3)=[CH:11][C:10]([NH:27][C:34]([C@H:31]3[CH2:30][C:29](=[O:28])[NH:33][CH2:32]3)=[O:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1C[C@H](C(=O)O)CN1
Reactant: C[C@@H](OCc1cccc(-c2cc(N)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@@H](OCc1cccc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (52 mg) in N,N-dimethylacetamide (0.5 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (20 mg) prepared according to the same procedures as Preparation 5 and WSC.HCl (40 mg) at room temperature, and the mixture was stirred for 0.5 hours. To this reaction mixture was added water, and then the precipitated solid was collected by filtration. This solid was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected by filtration from this suspension, and dried under reduced pressure to give the titled compound (37 mg).
Reaction SMILES: [ClH:1].COC(=O)C(NC(=O)[C@H](C)N)C1CC1.C(OC([NH:23][CH:24]([CH2:34][CH3:35])[C:25]([NH:27][C@H:28]([C:30]([O:32][CH3:33])=[O:31])[CH3:29])=[O:26])=O)(C)(C)C>>[ClH:1].[NH2:23][CH:24]([CH2:34][CH3:35])[C:25]([NH:27][C@H:28]([C:30]([O:32][CH3:33])=[O:31])[CH3:29])=[O:26]
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)OC
Agent: COC(=O)C(NC(=O)[C@H](C)N)C1CC1
Agent: Cl
Product: CCC(N)C(=O)N[C@@H](C)C(=O)OC

Procedure:
Following the procedure for the preparation of methyl(L-alanylamino)(cyclopropyl)acetate hydrochloride but substituting methyl N-{2-[(tert-butoxycarbonyl)amino]butanoyl}alaninate and making non-critical variations provided the title compound asia solid: 1H NMR (DMSO-d6) δ 0.86–0.92, 1.39–1.41, 1.62–1.82, 3.64, 3.92, 4.18–4.23, 8.36, 8.92.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.Cl>CC(O)C>[ClH:11].[I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Ic1ccc2c(c1)NCC2
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4ccc(I)cc43)c2cc1OC
Yield: 78 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 78% yield from 6-iodo-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. The HCl salt was generated from the purified free base according to the procedure given in Example 2 (M.P. >230° C.; GC/MS: 433 (M+); anal. RP18-HPLC RT: 5.20 min.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[N:5]/[OH:6].[H-].[Na+].[CH3:24]OS(OC)(=O)=O.Cl>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:21])/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)=[N:5]/[O:6][CH3:24]
Reactant: COC(=O)/C(=N/O)c1ccccc1Oc1ccc(C)cc1
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO/N=C(/C(=O)OC)c1ccccc1Oc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.5 %

Procedure:
E-α-hydroxyimino-2-(4-methylphenoxy)phenylacetic acid methyl ester (0.71 g, 0.0025 mole) was dissolved in dried tetrahydrofuran (10 ml), followed by the addition of 60% sodium hydride (0.13 g, 0.033 mole). Then, the mixture was stirred at room temperature for 20 minutes and to this was added dropwise a solution of dimethylsulfate (0.44 g, 0.0035 mole) dissolved in dried THF (2.5 ml) under ice cooling, followed by stirring for 1.75 hours under ice cooling. After completion of the reaction, water was added to the reaction mixture which was adjusted to pH 1 with conc. hydrochloric acid. The mixture was extracted twice with methylene chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain E-α-methoxyimino-2-(4-methylphenoxy)phenylacetic acid methyl ester (0.61 g, yield: 81.3%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:33]=[CH:32][C:11]3[N:12]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:13]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=4[N:23]4[CH:27]=[N:26][CH:25]=[N:24]4)[C:18]#[N:19])=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1.[N:34]([Si](C)(C)C)=[N+:35]=[N-:36].C([Sn](=O)CCCC)CCC>CN(C=O)C>[C:28]([N:12]1[C:11]2[CH:32]=[CH:33][C:8]([C:5]3[CH:6]=[N:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[CH:9][C:10]=2[N:14]=[C:13]1[C:15]1[CH:16]=[C:17]([C:18]2[N:34]=[N:35][NH:36][N:19]=2)[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[N:26][CH:25]=[N:24]1)([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(C)(C)n1c(-c2cc(C#N)ccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CN(C)C=O
Product: CC(C)(C)n1c(-c2cc(-c3nn[nH]n3)ccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 100 °C
Yield: 9.1 %

Procedure:
To a solution of 3-[5-(2-Amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-4-1,2,4-triazol-1-yl-benzonitrile (example 7) (100 mg, 0.23 mmol) in DMF (5 mL) are added azidotrimethylsilane (0.06 mL, 0.46 mmol) and dibutyltin oxide (175 mg, 0.69 mmol) at room temperature. The solution is heated up to 100° C. for 5 hours in a microwave reactor. The solution is cooled down and is extracted with Sat. NH4Cl (10 mL) and EtOAc (3×10 mL). The combined organic layer is dried with MgSO4 (500 mg) and is filtered. The filtrate is concentrated and the residue is purified by preparative HPLC to afford the title compound (10 mg, 9%) LCMS (ESMS): m/z: 479.40 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[Cl:49][C:50]1[CH:60]=[CH:59][C:53]([O:54][CH2:55][CH2:56]CO)=[CH:52][CH:51]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:42][CH2:43][CH2:56][CH2:55][O:54][C:53]2[CH:59]=[CH:60][C:50]([Cl:49])=[CH:51][CH:52]=2)=[CH:18][CH:17]=1
Reactant: OCCCOc1ccc(Cl)cc1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCCOc4ccc(Cl)cc4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 44.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (78 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (120 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(4-chlorophenoxy)-1-propanol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (60 mg, yield 37%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][N:14](CC3C=CC(OC)=CC=3)[C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.C1(S)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][NH:14][C:15](=[O:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(Cc2ccc(-c3ccnc(Cl)n3)s2)C(=O)c2ccccc2)cc1
Agent: Sc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(-c2ccnc(Cl)n2)s1)c1ccccc1

Procedure:
A solution of N-[5-(2-Chloro-pyrimidin-4-yl)-thiophen-2-ylmethyl]-N-(4-methoxybenzyl)-benzamide (25 mg, 0.055 mmol) in 0.25 mL CH2Cl2 was treated with trifluoroacetic acid (0.25 mL) as co-solvent and PS-thiophenol resin (3 eq.) at 40° C. for 15 h. The material was filtered and concentrated to a yellow solid (16 mg, 88%). The crude material was used in the next step.
Reaction SMILES: Cl.[NH2:2][OH:3].[H-].[Na+].[CH2:6]([N:13]1[C:17](=[O:18])[CH:16]2[C:19]([CH3:33])([CH3:32])[N:20]([CH3:31])[CH:21]([CH2:22][C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[CH:15]2[C:14]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[NH2:28][C:27](=[N:2][OH:3])[C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH:21]2[N:20]([CH3:31])[C:19]([CH3:32])([CH3:33])[CH:16]3[C:17](=[O:18])[N:13]([CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:14](=[O:34])[CH:15]23)=[CH:30][CH:29]=1
Reactant: CN1C(Cc2ccc(C#N)cc2)C2C(=O)N(Cc3ccccc3)C(=O)C2C1(C)C
Reactant: NO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(Cc2ccc(C(N)=NO)cc2)C2C(=O)N(Cc3ccccc3)C(=O)C2C1(C)C
Temperature: 0 °C
Reaction time: 48 h
Yield: 97.7 %

Procedure:
2.19 g (31.56 mmol) of hydroxylamine hydrochloride were suspended in 8 ml of DMF and cooled to 0° C. 0.79 g (26.3 mmol) of 80% sodium hydride was added slowly. 1.02 g (2.63 mmol) of (1RS, 3aSR,6aRS)-4-(5-benzyl-2,3,3-trimethyl-4,6-dioxo-octahydro-pyrrolo[3,4-c]pyrrol-1-ylmethyl)-benzonitrile were dissolved in DMF and added to the reaction mixture. The cooling was then no longer applied. The mixture was stirred at room temperature for 2 days. Thereafter, it was filtered and the DMF was removed in a high vacuum. The mixture was purified chromatographically (RP18, gradient from water to methanol). 1.08 g (97%) of (3aRS,4RS,6aSR)-4-[4-(amino-hydroxyimino-methyl)-benzyl]-2-benzyl-5,6,6-trimethyl-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione were isolated as a colourless powder. M.p.: 189°-192° C. ISP-MS: 421.5 ([M+H]+, 100).
Reaction SMILES: [OH:1][C:2]1[C:3]([Br:13])=[C:4]([C:8]([Br:12])=[CH:9][C:10]=1[Br:11])[C:5]([NH2:7])=[O:6].[Na].Br[CH2:16][C:17]([O:19][CH2:20]C)=[O:18]>CO>[CH3:20][O:19][C:17](=[O:18])[CH2:16][O:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([Br:12])=[C:4]([C:5](=[O:6])[NH2:7])[C:3]=1[Br:13]
Reactant: NC(=O)c1c(Br)cc(Br)c(O)c1Br
Reactant: CCOC(=O)CBr
Agent: [Na]
Solvent: CO
Product: COC(=O)COc1c(Br)cc(Br)c(C(N)=O)c1Br
Yield: 87.8 %

Procedure:
35.5 g (95 mmol) of 3-hydroxy-2,4,6-tribromobenzamide is suspended in 150 ml of methanol and dissolved by adding 2.18 g (95 mmol) of sodium. The mixture is combined with 17.5 g (104 mmol) of ethyl bromoacetate and maintained under reflux for three hours. After several hours of agitation, the crystallized product is vacuum-filtered, washed with a small amount of ice-cold methanol, and dried at 60° C., thus obtaining 37.2 g (88% of theory) of 3-carbamoyl-2,4,6-tribromophenoxyacetic acid methyl ester, mp 231°-233° C.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[C:12]([O:16][C:17]([NH:19][C@H:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:21][OH:22])=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:12]([O:16][C:17]([NH:19][C@H:20]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:21][O:22][S:8]([CH3:7])(=[O:10])=[O:9])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](COS(C)(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
11 ml of pyridine and then 6.6 ml of methanesulfonyl chloride were added dropwise, at room temperature, to a solution containing 9.9 g of 2(R)-t-butoxycarbonylamino-2-phenylethanol [prepared as described in step (a) above] dissolved in 120 ml of methylene chloride. This mixture was stirred for 15 hours at room temperature, after which the solvent was removed by distillation. The residue was dissolved in ethyl acetate and water and the ethyl acetate layer was separated. This layer was washed with an aqueous solution of potassium hydrogen sulfate and an aqueous solution of sodium bicarbonate and then dried over anhydrous magnesium sulfate, after which the solvent was distilled off. The crystalline residue was collected by filtration and washed with a small amount of diisopropyl ether and cyclohexane to give 12.2 g of the title compound, melting at 108°-109° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:21]=[C:22]([C:23]([NH2:25])=O)[C:4]=2[N:3]=1.COC(OC)[N:35]([CH3:37])C.O.[NH2:41]N>C(O)(=O)C>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:21]=[C:22]([C:23]3[N:35]=[CH:37][NH:41][N:25]=3)[C:4]=2[N:3]=1
Reactant: NN
Reactant: COC(OC)N(C)C
Reactant: Cc1c(Cn2c(C)nc3c(C(N)=O)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Cn2c(C)nc3c(-c4nc[nH]n4)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Temperature: 105 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
A mixture of 2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole-4-carboxamide (0.52 g, 1.202 mmol) in N,N-dimethylformamide dimethyl acetal (30 mL, 224 mmol) was stirred at 105° C. for 2 hours and the reaction is complete. The reaction was concentrated under reduced pressure. To the crude material was added Acetic Acid (30 mL) and hydrazine monohydrate (0.264 mL, 8.42 mmol). The reaction mixture was stirred at 100° C. for 1 h and concentrated. The crude was purified using silica gel (0˜2% MeOH/DCM) to give the product(0.245 g, 42%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.48 (s, 3H), 2.56 (s, 3H), 3.10-3.15 (m, 4H), 3.67-3.79 (m, 4H), 5.62 (s, 2H), 6.37 (d, J=7.83 Hz, 1H), 7.19 (d, J=2.02 Hz, 1H), 7.26 (t, J=7.83 Hz, 1H), 7.55 (d, J=1.77 Hz, 1H), 7.62 (d, J=7.58 Hz, 1H), 8.09 (s, 1H), 13.83 (s, 1H). MS(ES+) m/e 457.1[M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[S:12][CH:13]=[C:14]([C:16]([N:18]2[CH2:23][C:22]3([CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]4[CH:48]=[CH:47][C:34]([CH2:35][CH2:36][O:37][CH2:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])=[CH:33][CH:32]=4)[CH2:25][CH2:24]3)[O:21][CH2:20][CH2:19]2)=[O:17])[N:15]=1)([CH3:10])[CH3:9].C1(C)C=CC=CC=1>C(Cl)Cl>[CH:8]([C:11]1[S:12][CH:13]=[C:14]([C:16]([N:18]2[CH2:23][C:22]3([CH2:24][CH2:25][N:26]([CH2:29][CH2:30][C:31]4[CH:32]=[CH:33][C:34]([CH2:35][CH2:36][O:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:47][CH:48]=4)[CH2:27][CH2:28]3)[O:21][CH2:20][CH2:19]2)=[O:17])[N:15]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCOCCC(=O)OC(C)(C)C)cc4)CC3)C2)cs1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCOCCC(=O)O)cc4)CC3)C2)cs1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (10 mL) was added to a solution of tert-butyl 3-(4-(2-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenethoxy)propanoate [Example 1, step d] (0.55 g) in DCM (20 mL) and the resultant solution allowed to stand at 20° C. for 1 hour. Toluene (30 mL) was added and the solvents were evaporated under reduced pressure. The residue was azeotroped with acetonitrile (×2) to yield the subtitled compound. Yield 0.60 g.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:20]1[S:21][C:22]([CH:26]=[O:27])=[C:23]([Cl:25])[N:24]=1.O>O1CCCC1>[Cl:25][C:23]1[N:24]=[C:20]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:21][C:22]=1[CH:26]=[O:27]
Reactant: O=Cc1sc(Cl)nc1Cl
Reactant: NCc1ccc(Cl)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=Cc1sc(NCc2ccc(Cl)cc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of p-chlorobenzylamine (61, 283 mg, 2.00 mmol) and N,N-Diisopropylethylamine (0.697 mL) in tetrahydrofuran (20 mL) was slowly added 2,4-Dichloro-thiazole-5-carbaldehyde (93, 364 mg, 2.00 mmol) in tetrahydrofuran (10 mL) at room temperature. The reaction was stirred at room temperature overnight. The reaction mixture was poured into iced water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a yellow solid (94, 0.3 g, 50%). MS (ESI) [M−H+]=286.97.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[OH2:13].O[NH2:15]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:15][OH:13])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O
Reactant: NO
Reactant: O=Cc1ccc(Br)c([N+](=O)[O-])c1
Solvent: CO
Product: O=[N+]([O-])c1cc(C=NO)ccc1Br
Temperature: 25 °C

Procedure:
In a solution of 5.0 g of 4-bromo-3-nitrobenzaldehyde in 50 ml of methanol, 3.6 ml of 50% hydroxyamine aqueous solution was added with stirring at room temperature, and continued to stir at the same temperature for 18 hours. After the completion of the reaction, 60 ml of water was added in the reaction mixture, and precipitated solid was filtered off, washed with water and then dried to obtain 5.0 g of the aimed product as yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[O:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])[CH2:18][CH2:17]1.O>O1CCCC1.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([N:19]3[CH2:20][CH2:21][O:16][CH2:17][CH2:18]3)[CH:23]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Nc1cccc(N2CCOCC2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Clc1ncc(Cl)c(Nc2cccc(N3CCOCC3)c2)n1
Reaction time: 8 h

Procedure:
2,4,5-Trichloropyrimidine (0.960 g, 5.2 mmol) was dissolved in tetrahydrofuran (20 mL). Potassium carbonate (1.20 g, 8.70 mmol) was added, followed by 3-morpholinoaniline (0.875 g, 4.90 mmol). After stirring overnight, water (30 mL) and dichloromethane (30 mL) were added, the phases separated and the aqueous layer extracted once with dichloromethane (30 mL). The combined organic fractions were dried over sodium sulfate, concentrated onto silica gel and chromatographed (120 g SiO2, 0-50% EA:Hex). (2,5-Dichloro-pyrimidin-4-yl)-(3-morpholin-4-yl-phenyl)-amine was isolated as an off-white solid (1.16 g, 73%). m.p.=142-145° C.; LCMS (m/e) 325 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.20 (s, 1H), 7.38 (s, 1H), 7.28 (m, 1H), 7.21 (s, 1H), 7.01 (d, 1H, J=7.8 Hz), 6.75 (d, 1H, J=8.4 Hz), 3.88 (t, 4H, J=4.8 Hz), 3.21 (t, 4H, J=4.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21]O)[C:9]2=[O:23])[CH:7]=1.C(Cl)[Cl:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:19])([F:20])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][Cl:28])[C:9]2=[O:23])[CH:7]=1
Reactant: ClCCl
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(CO)c2cc(C(F)(F)F)ccc21
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(CCl)c2cc(C(F)(F)F)ccc21
Reaction time: 0.5 h

Procedure:
To a solution of (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-1-hydroxymethyl-6-trifluoromethyl-1,3-dihydro-indol-2-one ((S)-IV) (64.5 g, 0.166 mol) in CH2Cl2 (700 mL) was added PCI3 (2.0 M in CH2Cl2, 255.0 mL, 0.510 mol) dropwise at 0° C. under N2 over a period of 50 minutes. The resultant mixture was warmed to room temperature and the stirring continued overnight (16 h). The mixture was quenched with ice at 0° C. and the resultant mixture was stirred vigorously for 30 minutes. The organic layer was separated and the aqueous layer was washed with CH2Cl2. The combined organic layer was washed with brine and dried over Na2SO4. Chromatography (silica gel, EtOAc/Hexanes) provided the title compound as a white dry foam (42.0 g, 62% yield). 1H NMR (CDCl3): δ 3.55 (s, 3H), 5.39 (d, J=10.5 Hz, 1H), 5.95 (d, J=11.0 Hz, 1H), 6.76 (dd, J=1.5, 9.0 Hz, 1H), 7.28 (m, 2H), 7.35 (dd, J=1.5, 9.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.78 (dd, J=1.0, 2.5 Hz, 1H).
Reaction SMILES: Br[O:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=[O:6].B([O-])([O-])O[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.C(OCC)(=O)C>[C:14]1([C:9]2[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]([OH:2])=[CH:11][CH:10]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1OBr
Reactant: [O-]B([O-])Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 87 %

Procedure:
In 400 ml of water, 21.7 g of bromosalicylic acid, 13.41 g of phenyl borate and 15.28 g of potassium carbonate were dissolved. The solution was stirred at room temperature for 40 minutes. The completion of the reaction was confirmed by TLC, and the reaction solution was poured into a mixture of diluted hydrochloric acid and ethyl acetate. The organic phase was extracted, separated, and washed with a saturated aqueous sodium chloride solution. The organic phase was dried with magnesium sulfate, and concentrated. The concentrate was recrystallized with acetonitrile to obtain 5-phenylsalicyclic acid as colorless crystals. The amount was 18.58 g (yield: 87%). The molecular structure was confirmed with a mass spectrum. Synthesis of ethyl 5-phenylsalicylate