Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=[O:9].C(N(CC)CC)C.[N:19]1([C:28](Cl)=O)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[N:20]1>C1(C)C=CC=CC=1>[N:19]1([C:28]2[O:9][C:8](=[O:10])[C:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=3[N:11]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[N:20]1
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: O=C(Cl)n1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cccc2nc(-n3nnc4ccccc43)oc(=O)c12
Reaction time: 12 h
Yield: 22.6 %

Procedure:
A solution of 960 mg of 6-methyl anthranilic acid in 30 ml of dry toluene containing 1.77 ml of dry triethylamine, which had been stirred for 30 minutes, was added to a solution of 2.1 gm of 1-benzotriazole carboxylic acid chloride in 30 ml toluene over a period of 30 minutes, and stirred for 12 hours. The resulting precipitate was filtered. The filtrate was reduced to one-half of its initial volume, and the resulting solids isolated by filtration. The combined residues were washed with water, dried under high vacuum and recrystallized from chloroform, giving 400 mg of 2-(1-benzotriazolyl)-5-methyl-4H-3,1-benzoxazin-4-one, m.p. 214°-215° C. (decomp.).
Reaction SMILES: [CH3:1][C@@:2]([S:22]([CH3:25])(=[O:24])=[O:23])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH3:21])=[N:11]1)[C:3]([O:5]CC)=[O:4].[OH-].[K+]>C1COCC1.CO.O>[CH3:1][C@@:2]([S:22]([CH3:25])(=[O:23])=[O:24])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH3:21])=[N:11]1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)[C@@](C)(CCn1cc(-c2ccccc2)c(C)n1)S(C)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nn(CC[C@](C)(C(=O)O)S(C)(=O)=O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of the ethyl (2R)-2-methyl-4-(3-methyl-4-phenyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)butanoate (178 mg, 0.488 mmol, 1 eq) in THF: Methanol:water (2:2:1, 5 mL) was added potassium hydroxide (170 mg, 3.03 mmol) and reaction was stirred at RT overnight. The reaction was concentrated, and the residue was dissolved in aqueous 1N sodium hydroxide (20 mL) and washed with ethyl acetate (3×20 mL). The aqueous layer was acidified using concentrated HCl, and extracted with ethyl acetate (3×50 mL). The combined organics extracts were dried (MgSO4), filtered, and concentrated to afford (2R)-2-methyl-4-(3-methyl-4-phenyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)butanoic acid (129 mg, 78.6%). LC-MS M+H+382.1.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[Cl:5][C:6]1[N:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.BrBr.O>C(O)(=O)C>[Cl:5][C:6]1[N:11]=[C:10]2[S:1][C:2]([NH2:3])=[N:12][C:9]2=[CH:8][CH:7]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2ccc(Cl)nc2s1
Reaction time: 2 h
Yield: 53.3 %

Procedure:
Potassium thiocyanate (16.0 g, 165 mmol) and 6-chloropyridin-3-amine (2.6 g, 20.2 mmol) were dissolved in acetic acid (52 mL). To this solution was added dropwise a solution of bromine (3.2 mL, 62.5 mmol) in acetic acid (12 mL) under cooling in a water bath, and the mixture was stirred for 2 hr. The mixture was warmed to, stirred for 10 hr, and water (30 mL) was added. This reaction mixture was filtered at 85° C., and the insoluble material was suspended in acetic acid (50 mL) and the suspension was filtered. The obtained filtrate was neutralized with aqueous ammonia solution, and the precipitated solid was collected by filtration and recrystallized from methanol to give the title compound (2.0 g, 54%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])[C:10]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[O:36][CH:37]([CH3:39])[CH3:38])=[N:9]2)=[CH:4][CH:3]=1.[CH2:40]1[O:42][CH:41]1[CH2:43][OH:44]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:23][CH2:24][N:25]([CH2:40][CH:41]([OH:42])[CH2:43][OH:44])[CH2:26][CH2:27]3)=[O:21])[C:10]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[O:36][CH:37]([CH3:39])[CH3:38])=[N:9]2)=[CH:4][CH:3]=1
Reactant: OCC1CO1
Reactant: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)N2CCNCC2)c(OC(C)C)c1
Solvent: CO
Product: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(O)CO)CC2)c(OC(C)C)c1
Temperature: 40 °C
Yield: 44.3 %

Procedure:
[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (50 mg, 0.088 mmol, example 10 g) was dissolved in anhydrous methanol (10 mL). Glycidol (0.15 mL, 2.26 mmol) was added and the reaction was heated at 40° C. for 20 h. The mixture was cooled to room temperature and concentrated in vacuo. Chromatography of the residue over silica gel using 1-6% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2,3-dihydroxy-propyl)-piperazin-1-yl]-methanone (25 mg, 44%). HR-MS (ES, m/z) calculated for C33H39N4O5Cl2[(M+H)+]641.2292, observed 641.2300.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]1([CH2:21][OH:22])[CH2:20][O:19][CH2:18]1>C(#N)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:16][C:17]2([CH2:21][OH:22])[CH2:20][O:19][CH2:18]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: OCC1(CBr)COC1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnn(CC2(CO)COC2)c1
Temperature: 60 °C
Yield: 99.8 %

Procedure:
4-nitro-1H-pyrazole (0.5 g, 4.42 mmol) and K2CO3 (1.22 g, 8.84 mmol) were suspended in acetonitrile (30 mL) in a 2-necked flask under nitrogen and (3-(bromomethyl)oxetan-3-yl)methanol (1.36 g, 7.52 mmol) was added dropwise. The reaction was heated at 60° C. for 16 h and the solution was concentrated to about ⅓ of the volume under vacuum and then partitioned between DCM (50 mL) and water (50 mL). The organics were dried over Na2SO4, filtered and the solvent evaporated to give (3-((4-nitro-1H-pyrazol-1-yl)methyl)oxetan-3-yl)methanol as a transparent oil (0.94 g, quantitative yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[C:7]=1[CH:8]=[CH:9][C:10](O)=[O:11])#[N:2].S(Cl)([Cl:27])=O>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:21])[F:22])=[CH:15][C:14]=2[Cl:24])[C:7]=1[CH:8]=[CH:9][C:10]([Cl:27])=[O:11])#[N:2]
Reactant: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C=CC(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C=CC(=O)Cl

Procedure:
By the method of Example 7, Step A, 0.96 g (0.0026 mole) of 3-[4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazol-5-yl]acrylic acid and 1 mL of thionyl chloride were reacted in 20-30 mL of toluene, yielding 0.56 g of 3-[4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazol-5-yl]acrylic acid chloride as an oil. The nmr spectrum was consistent with the proposed structure and indicated the product to be primarily the trans acrylic acid derivative.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([C:14]([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=4[CH:26]=3)=[O:15])[C@@H:7]([CH2:10][C:11]([OH:13])=O)[CH2:8][O:9][C:4]=2[CH:3]=1.C1C[N:32]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH4+].[Cl-].CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([C:14]([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=4[CH:26]=3)=[O:15])[C@@H:7]([CH2:10][C:11]([NH2:32])=[O:13])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)C[C@H]1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)C[C@H]1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Yield: 28.7 %

Procedure:
{(3S)-7-Bromo-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetic acid (Intermediate 29a, 160 mg, 0.36 mmol) was dissolved in DCM (3 mL). PyBOP (223 mg, 0.43 mmol) and TEA (0.248 mL, 1.79 mmol) was added followed by NH4Cl (77 mg, 1.43 mmol). The mixture was stirred at rt over weekend. EtOAc (40 mL) was added. Washed with sat. aq. Na2CO3 (2×30 mL), HCl (0.5M, 20 mL) and brine (20 mL). Dried through a phase separator and evaporated under reduced pressure. The residue was purified using a SFC2-MS system and eluting with MeOH on a Waters Viridis 2-EP column 5μ30×250 mm. Pooling of homogenous fraction and removal of solvents in vacuo gave the title compound (46.1 mg, 28.9%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH:11]=1)=NON=2)=O.[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].N1CCCCC1.[C:26]([OH:29])(=O)[CH3:27]>C1C=CC=CC=1>[O:29]1[C:26]2[CH:27]=[CH:1][C:3]([CH:11]=[C:13]([C:14](=[O:15])[CH3:16])[C:12]([O:18][CH3:19])=[O:17])=[CH:4][C:5]=2[CH:6]=[CH:7]1
Reactant: CC(=O)O
Reactant: O=Cc1ccc2nonc2c1
Reactant: COC(=O)CC(C)=O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)C(=Cc1ccc2occc2c1)C(C)=O

Procedure:
A mixture of 5-Formylbenzofurazan (0.6 g, 4.1 mmol), methyl acetoacetate (0.52 g, 4.5 mmol), piperidine (0.019 g, 0.225 mmol), and acetic acid (0.014 g, 0.225 mmol) in benzene (30 mL) was stirred and refluxed with a Dean-Stark trap for 8 h. Benzene was evaporated, the residue was dissolved in ethyl acetate (80 mL) and washed with brine (50 mL), saturated potassium bisulfate solution (50 mL), and saturated sodium bicarbonate solution in sequence. The ethyl acetate solution was dried (magnesium sulfate), solvent removed under reduced pressure and the residue was purified by column chromatography (SiO2, EtOAc/hexane, 10%-15%). The product, methyl 2-{(benzofuran-5-yl)methylene}-3-oxobutyrate, was obtained as an oil (0.98 g, 98.3%) and was used in the next step without any further characterization.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:15]#[N:16])=[C:10]([CH3:14])[NH:11]2)=[CH:7][CH:6]=1.[CH2:17](I)[CH3:18]>CN(C=O)C>[CH2:17]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([O:4][CH3:3])[CH:13]=2)[C:9]([C:15]#[N:16])=[C:10]1[CH3:14])[CH3:18]
Reactant: COc1ccc2c(C#N)c(C)[nH]c2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(C)c(C#N)c2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a suspension of NaH (0.6 g, 2 eq.) in DMF (7 mL) is added a solution of 6-methoxy-2-methyl-1H-indole-3-carbonitrile (1.3 g, 7.0 mmol) in DMF (8 mL) followed by ethyl iodide (1.2 mL, 2 eq.) at 0° C. After stirring for 1 h, the mixture is poured into ice water and then extracted with CH2Cl2. The organic layer is washed with brine and dried with Na2SO4. The solvent is evaporated under vacuum and purified with flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 92% of 1-ethyl-6-methoxy-2-methyl-1H-indole-3-carbonitrile.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:21].[P:22]([O-:34])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[K+].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[O:21]=[C:4]1[NH:5][C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7](=[O:8])[N:3]1[CH2:2][O:34][P:22](=[O:23])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OP(=O)(OCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O)OC(C)(C)C
Temperature: 0 °C
Yield: 38.6 %

Procedure:
35.5 Grams of 3-(chloromethyl)-5,5-diphenyl-2,4-imidazolidinedione from Step (A), 30.7 g of potassium di(t-butyl) phosphate, 0.6 g of potassium carbonate, and 0.15 g of potassium iodide were slurried into 200 mL acetonitrile. The reaction mixture was heated at reflux for 2.5 hours. The solution was filtered to remove potassium chloride precipitate. The filtrate was cooled to 0° C. and filtered to give 22.3 g of the title compound (38.6% yield); mp 108.5° C. (d). 1H NMR (DMSO-d6): 1.3 ppm (s, 18H), 5.2 (d, 2H), 7.3-7.5 (m, 10H), 9.9 (s, 1H); doublet from long range phosphorus coupling.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[C:18]([NH:19][C:20](=[O:29])[C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=4[F:28])=[CH:17][NH:16][N:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[F:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:21]=1[C:20]([NH:19][C:18]1[C:14]([C:11]2[NH:10][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=2)=[N:15][NH:16][CH:17]=1)=[O:29]
Reactant: COC(=O)c1cccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1c[nH]nc1-c1nc2c(C(=O)O)cccc2[nH]1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
A solution of 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazole-4-carboxylic acid methyl ester (220 mg, 0.55 mmol) in THF/water (1:1, 10 ml) was treated with lithium hydroxide hydrate (70 mg, 1.66 mmol) and the mixture stirred at ambient temperature for 18 h. The volatiles were removed in vacuo, the mixture acidified to pH5 by the addition of 2M aqueous hydrochloric acid and the solid formed collected by filtration, washed with water then dried under vacuum to give 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazole-4-carboxylic acid (165 mg) as a brown solid. (LC/MS: Rt 3.28, [M+H]+ 384).
Reaction SMILES: N[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH3:13])=[N:4][CH:3]=1.N([O-])=O.[Na+].C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].[FH:27]>N1C=CC=CC=1>[F:27][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH3:13])=[N:4][CH:3]=1
Reactant: F
Reactant: COC(=O)c1nc(N)cnc1OC
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1nc(F)cnc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 140 mL of 70% solution of hydrogen fluoride in pyridine was dissolved 17.3 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxylate at an ice-cooled temperature. Then, 7.8 g of sodium nitrite was added at −50° C. in three portions. After the foaming had ceased, the temperature was slowly elevated, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a mixture of 300 mL of ice and 200 mL of chloroform, the deposited insoluble matter was filtered off, and then the organic layer was separated. The remaining aqueous layer was extracted with ten portions of chloroform, provided that the total quantity of liquid came to 500 mL. The organic layers thus obtained were united, pH was adjusted to 7 with a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. The organic layer thus obtained was washed with saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel chromatography [eluent: n-hexane:ethyl acetate=4:1] to obtain 14.3 g of methyl 6-fluoro-3-methoxy-2-pyrazinecarboxylate as a solid product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[S:14][C:13]=3[CH2:12][CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1.C([OH:28])(C)(C)C.CC(C)=O.C[N+]1([O-])CCOCC1.[OH2:41]>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:17]3[CH:16]=[C:15]([C:18]4[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=4)[S:14][C:13]=3[CH2:12][CH2:11][CH2:10][CH:9]2[OH:41])=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2=CCCCc3sc(-c4ccncc4)cc32)cc1
Reactant: CC(C)(C)O
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: OC1CCCc2sc(-c3ccncc3)cc2C1(O)c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 72 %

Procedure:
To a solution of 4-[4-(4-chlorophenyl)-7,8-dihydro-6H-cyclohepta[b]thien-2-yl]pyridine (304.0 mg, 0.899 mmol) in tert-butyl alcohol (2.06 mL, 21.5 mmol) were added water (3.43 mL) and acetone (20.56 mL). N-methylmorpholine N-oxide (210.8 mg, 1.79 mmol) and 4% osmium tetroxide in water (0.164 mL, 0.0269 mmol) were added and the resulting pinkish suspension was heated at 50° C. for 3 hr. The reaction mixture was allowed to cool to rt and then diluted with ethyl acetate (15 mL) and water (10 mL), the organic layer was separated and the aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with brine (10 mL) then dried over anhydrous MgSO4, Insoluble materials were removed by filtration and then the filtrate was concentrated and the obtained residue was purified by column chromatography (SiO2, elution with 0-20% MeOH/DCM) to give the title compound as a yellow foam (241.8 mg, 72% yield). LCMS: (FA) ES+ , 372/374. 1H NMR (400 MHz, DMSO) δ 8.50 (dd, J=4.6, 1.6 Hz, 2H), 7.49 (d, J=13.4 Hz, 1H), 7.44 (dd, J=4.6, 1.6 Hz, 2H), 7.38 (d, J=8.6 Hz, 2H), 7.25 (d, J=8.6 Hz, 2H), 5.75 (s, 1H), 5.71 (s, 1H), 4.83 (d, J=4.8 Hz, 1H), 4.14 (t, J=5.1 Hz, 1H), 2.93 (dd, J=15.7, 3.9 Hz, 1H), 2.75-2.55 (m, 1H), 2.05-1.73 (m, 2H), 1.52 (d, J=3.7 Hz, 1H), 1.38 (t, J=12.9 Hz, 1H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[O:21][CH3:22].[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[O:28].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Br:13][C:14]1[C:15]([O:21][CH3:22])=[C:16]([CH:27]([C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([F:23])[CH:25]=2)[OH:28])[C:17]([F:20])=[CH:18][CH:19]=1
Reactant: O=Cc1cccc(F)c1
Reactant: COc1cc(F)ccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1c(Br)ccc(F)c1C(O)c1cccc(F)c1
Temperature: -60 °C

Procedure:
A total of 1.64 ml of diisopropylamine was dissolved in 27 ml of tetrahydrofuran, 6.8 ml of a 1.57 M solution of n-butyllithium in hexane was added at −50° C. under stirring, and the mixture was stirred at −30° C. for 30 minutes. After cooling to −60° C., 2 g of 1-bromo-4-fluoro-2-methoxy-benzene obtained in Production Example II-1-a was added and the mixture was stirred at −60° C. for 1 hour. Then, 1.55 ml of 3-fluoro-benzaldehyde was added, followed by stirring for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated, to give 2.4 g of the title compound as a yellow-brown oil.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[OH:18])[CH:14]([C:19]([OH:21])=[O:20])[CH2:13][CH2:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][C:22](=[O:24])[CH3:23])[CH:14]([C:19]([OH:21])=[O:20])[CH2:13][CH2:12]2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cc2c(cc1O)C(C(=O)O)CC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc2c(cc1C(=O)c1ccccc1)CCC2C(=O)O

Procedure:
Dry ammonia is passed into a solution of 27 g of crude 5-benzoyl-6-acetoxy-indane-1-carboxylic acid chloride in 200 ml of anhydrous benzene at a temperature of 15°-20° C., with exclusion of moisture, until saturation is reached. The reaction solution is then evaporated to dryness in vacuo and the evaporation residue is partitioned between 200 ml of water and 3 times 200 ml of methylene chloride. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo. Fractional crystallisation of the evaporation residue from hot dimethylformamide-water gives 5-benzoyl-6-hydroxy-indane-1-carboxylic acid amide of melting point 205°-207° C. The starting material can be obtained as follows. A solution of 20 g of 5-benzoyl-6-hydroxy-indane-1-carboxylic acid in 200 ml of acetic anhydride is heated to the reflux temperature for 4 hours. It is then evaporated to dryness in vacuo, 50 ml of toluene are added to the evaporation residue and the mixture is evaporated to dryness. This procedure is repeated twice more. The crude 5-benzoyl-6-acetoxy-indane-1-carboxylic acid thus obtained is used directly for further conversion.
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][C:13]([N:15]1[CH2:23][C@H:22]2[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:16]1)=[O:14])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](O)[CH2:25][CH3:26]>>[CH2:1]([CH:8]([CH2:12][C:13]([N:15]1[CH2:16][C@H:17]2[C@H:22]([CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:23]1)=[O:14])[C:9]([O:11][CH2:24][CH2:25][CH3:26])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCO
Reactant: O=C(O)C(CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccccc1
Product: CCCOC(=O)C(CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccccc1

Procedure:
To 2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid (100 mg) were added propanol (2 ml) and boron trifluoride diethyl ether complex (12 μl) with stirring. After the mixture was stirred at room temperature for 24 hours, the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, washed succecively with saturated sodium bicarbonate solution and brine, and dried over MgSO4. The solvent was evaporated under reduced pressure to give 106 mg of propyl 2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate as a colorless viscous oil.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[N:25]=[CH:24][C:23]3[CH:26]=[C:27]([C:33]4[CH:34]=[N:35][N:36](C(OC(C)(C)C)=O)[CH:37]=4)[N:28](S(C)(=O)=O)[C:22]=3[CH:21]=2)=[N:17][CH:18]=1>CN(C=O)C.O>[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[N:25]=[CH:24][C:23]3[CH:26]=[C:27]([C:33]4[CH:37]=[N:36][NH:35][CH:34]=4)[NH:28][C:22]=3[CH:21]=2)=[N:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Nc4ccc(F)cn4)cc3n2S(C)(=O)=O)cn1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Fc1ccc(Nc2cc3[nH]c(-c4cn[nH]c4)cc3cn2)nc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
DBU (10.8 μL, 0.072 mmol) was added to a solution of tert-butyl 4-(6-(5-fluoropyridin-2-ylamino)-1-(methylsulfonyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)-1H-pyrazole-1-carboxylate (Preparation 54, 17 mg, 0.036 mmol) in DMF (240 μL). The reaction mixture was stirred for 1 hour at 50° C. and for 1 hour at 100° C. The reaction mixture was diluted with water and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was then purified using preparative TLC eluting with 5% MeOH/aq NH3 10/1 in DCM to afford the title compound as a white solid (7 mg, 24%). 1H NMR (500 MHz, CD3OD): δ 6.66 (d, J=0.9 Hz, 1H), 7.18-7.21 (m, 1H), 7.46-7.50 (m, 1H), 7.71 (s, 1H), 8.03 (br s, 2H), 8.07-8.09 (m, 1H), 8.42 (d, J=0.9 Hz, 1H). ESI-HRMS Found 295.1103, calculated for C15H12FN6 [M+H]+: 295.1102. MPS1 IC50 (uM): 0.1586