Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CN(C=O)C>[I:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: Ic1ncnc2[nH]cnc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc2c(I)ncnc21

Procedure:
405 mg (1.65 mmol) of 6-iodo-9H-purine was dissolved in 2 mL DMF. 72 mg (1.81 mmol) of 60% sodium hydride was added followed by 320 μL (1.81 mmol) of trimethylsilylethoxymethyl chloride. Yield: 343 mg of an oily product.
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[N:14]=[CH:13][CH:12]=[C:11]([I:15])[C:7]=1[C:8](O)=[O:9].CO>ClCCl>[OH:5][C:6]1[N:14]=[CH:13][CH:12]=[C:11]([I:15])[C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: O=C(O)c1c(I)ccnc1O
Reactant: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(Cl)c1c(I)ccnc1O
Temperature: 75 °C

Procedure:
Thionyl chloride (3.81 ml, 52.2 mmol) was added to a suspension of 2-hydroxy-4-iodonicotinic acid (3.46 g, 13.1 mmol) in dichloromethane (12 mL) in a pressure vessel at room temperature. The reaction mixture was then heated at 75° C. for 3 h. An aliquot was taken and hydrolyzed with methanol. LCMS analysis showed the derived methyl ester seen as major compound. The reaction mixture was cooled to room temperature and was concentrated in vacuo to give 2-hydroxy-4-iodonicotinoyl chloride. 2-hydroxy-4-iodonicotinoyl chloride in MeOH (100 mL) was stirred at room temperature for 2 h. Concentration in vacuo of the reaction mixture afforded methyl 2-hydroxy-4-iodonicotinate (3.64 g, 13.1 mmol, quantitative yield). MS (ESI pos. ion) m/z: 280 (MH+). Calc'd exact mass for C7H61NO3: 279.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.Cl.[CH2:8]([N:15]1[CH2:20][CH2:19][O:18][CH:17]([C:21]([OH:23])=O)[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:24]([CH3:26])[CH3:25]>ClCCCl.CN(C)C=O>[CH2:8]([N:15]1[CH2:20][CH2:19][O:18][CH:17]([C:21]([N:24]([CH3:26])[CH3:25])=[O:23])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CNC
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(C)C(=O)C1CN(Cc2ccccc2)CCO1
Temperature: 65 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
Oxalyl chloride (372 μL, 4.27 mmol) was added to a mixture of 4-benzylmorpholine-2-carboxilic acid hydrochloride (1.00 g, 3.88 mmol) and N,N-dimethylformamide (15.0 μL, 0.194 mmol) in DCE (20 mL). The mixture was heated at 65° C. for 3 hours. After cooling to 0° C., Me2NH (2M solution in THF, 9.70 mL, 19.4 mmol) was added. The mixture was stirred at room temperature for 4 hours. The mixture was concentrated and the residue was diluted with water and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to afford desired product (803 mg, 83.4%) as brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][NH:11][CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[CH:4][CH:3]=1.[CH:29]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1)([CH3:31])[CH3:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:37](=[O:38])[C:36]3[CH:35]=[CH:34][C:33]([O:32][CH:29]([CH3:30])[CH3:31])=[CH:41][CH:40]=3)[CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)=[CH:6][CH:7]=1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1
Reactant: COc1ccc(C(=O)N(C)C2CNCC2c2ccc(Cl)cc2)cc1C(F)(F)F
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)c3ccc(OC(C)C)cc3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(4-isopropoxy-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 4-isopropoxybenzoic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light brown oil. MS m/e: 575.2 [M+H]+.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][C:27]([CH3:29])=[CH2:28])=[CH:7][CH:6]=1)(=O)C>[OH-].[Na+]>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][C:27]([CH3:29])=[CH2:28])=[CH:7][CH:6]=1
Reactant: C=C(C)CNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccc(NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: C=C(C)CNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccc(N)cc1

Procedure:
The mixture of 2 g of 4-(4-acetamidophenylmercapto)-3-(2-methylallylamino)-5-sulfamoylbenzoic acid and 20 ml of 2 N aqueous sodium hydroxide is refluxed for 1 hour under nitrogen. After cooling it is filtered and the filtrate acidified with acetic acid to a pH of 4-5. The precipitate formed is filtered off and recrystallized from aqueous ethanol, to yield the 4-(4-aminophenylmercapto)-3-(2-methylallylamino)-5-sulfamoylbenzoic acid melting at 237°-240°.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)[CH3:18].[Cl-].[Na+]>O1CCCC1>[C:20]1(/[C:17](/[CH3:18])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(=O)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)c1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 128.9 %

Procedure:
A mixture of 10 g (0.25 mol) of sodium hydride and tetrahydrofuran is heated to 50° C., followed by dropwise addition over 30 minutes of a solution of 48 ml (0.19 mol) of ethyl diethylphosphonoacetate in 80 ml of tetrahydrofuran. A solution of 28.4 g (0.24 mol) of acetophenone in 60 ml of tetrahydrofuran is added dropwise at 0° C. and the mixture is stirred for 16 hours at 25° C. 250 ml of saturated sodium chloride solution are added at 0° C. and the resulting mixture is extracted with ether. The organic phase is dried (Na2SO4) and the solvents are evaporated off under reduced pressure. The 46.6 g of product obtained are purified by flash chromatography (90/10 cyclohexane/diisopropyl ether) (29 g; 63%).
Reaction SMILES: [Li][CH2:2]CCC.[C:6]1([CH:12]2[CH2:15][C:14](=O)[CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCCCCC>[CH2:2]=[C:14]1[CH2:15][CH:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:13]1
Reactant: O=C1CC(c2ccccc2)C1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C1CC(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a 2-3° C. suspension of methyltriphenylphosphonium bromide (0.36 g, 1 mmol) in THF (2.5 ml) was added dropwise n-BuLi (0.69 ml, 1.1 mmol, 1.6 M in hexan). After 1 hour stirring at 0° C., a solution of 3-phenyl-cyclobutanone (0.146 g, 1 mmol) in THF (1.5 ml) was added dropwise. The reaction mixture was stirred 24 hours at room temperature and then diluted with hexane. The so obtained precipitate was filtered and the filtrate was concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1) to provide (3-methylene-cyclobutyl)-benzene (57 mg, 40%) as a slightly yellow oil, MS: m/e=144.1 (M+).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>C(Cl)Cl>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([N:20]([C:41]([N:40]([CH3:44])[CH3:39])=[O:42])[CH3:21])[CH:16]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C)C(=O)Cl
Reactant: CNC1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N(C)C1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Yield: 85.4 %

Procedure:
To a solution of 25 mg of amine prepared in Example 11 and 0.05 mL of DIPEA in 0.5 mL of methylene chloride was added 15 mg of dimethylcarbamoyl chloride. After 2 h at 50° C. in a sealed vial, the volatiles were evaporated under a stream of nitrogen and the residue was purified on a 1 mm preparative silica gel plate eluted with ethyl acetate to afford 25 mg of title compound. Mass spec (NH3 /CI): 489 (M+1).
Reaction SMILES: CC([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1)=C.OO.[OH:16]S(O)(=O)=O.[O-]S([O-])=O.[Na+].[Na+]>CO>[OH:11][CH2:10][CH2:9][O:8][C:7]1[CH:12]=[CH:13][C:4]([OH:16])=[CH:5][CH:6]=1
Reactant: C=C(C)c1ccc(OCCO)cc1
Reactant: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: OCCOc1ccc(O)cc1

Procedure:
To a mixture of 2.50 g 2-(4-(1-methylethenyl)phenoxy)ethanol, 10 ml methanol, and 1.1 equivalents 50% aqueous H2O2 were added 0.1 equivalent 98% H2SO4. The reaction mixture warmed itself to reflux which subsided in a few minutes. After addition of 0.2 equivalent Na2SO3, methanol was removed under reduced pressure. The residue was taken up in ether, dried over Na2SO4 and NaHCO3, and filtered. Removal of solvent left 4-(2-(hydroxyethoxy)phenol in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[NH:4][N:3]=1.[C:13](/[CH:15]=[C:16](\[O-:18])/[CH3:17])#[N:14].[Na+]>>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[C:15](/[C:16](=[O:18])[CH3:17])\[C:13]#[N:14])[CH:9]=2)[NH:4][N:3]=1
Reactant: C/C([O-])=C/C#N
Reactant: O=Cc1ccc2[nH]nc(Br)c2c1
Agent: [Na+]
Product: CC(=O)/C(C#N)=C/c1ccc2[nH]nc(Br)c2c1

Procedure:
The title compound was prepared from 2.85 g (70% purity, 8.87 mmol) 3-bromo-1H-indazole-5-carbaldehyde (Example 10A) and 1.03 g (9.75 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate in analogy to the procedure described in Example 9A yielding 1.12 g (43% of th.) of product which was used in subsequent steps without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7](C(C)C)[C:6]1=[O:17].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O.CC(C)CC(=O)C>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[NH:7][C:6]3=[O:17])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Reactant: CC(C)n1c(=O)n(CCCCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(O)(c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 5 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethyl)-2H-benzimidazol-2-one, 3.9 parts of 4-(4-fluorophenyl)-4-piperidinol, 5.3 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone is stirred and refluxed for 48 hours with water-separator. The reaction mixture is cooled to room temperature, water is added and the whole is alkalized with 15 parts of a sodium hydroxide solution 60%. The layers are separated and the organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaported. The oily residue is dissolved in 2-propanone. The solution is acidified with 2-propanol, previously saturated with gaseous hydrogen chloride, and the whole is stirred and refluxed for 15 minutes. The solvent is evaporated and the formed hydrochloride salt is dissolved in water. The free base is liberated in the conventional manner with a diluted sodium hydroxide solution. The product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is crystallized from methylbenzene. The product is filtered off and dried, yielding 2.5 parts of 1-{3-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 135.4° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[F:23][C:24]([F:34])([F:33])[C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26]>>[F:34][C:24]([F:23])([F:33])[C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:29][CH2:28]1)=[O:26]
Reactant: O=C(N1CCNCC1)C(F)(F)F
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCN(C(=O)C(F)(F)F)CC1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and 2,2,2-trifluoro-1-(piperazin-1-yl)ethanone to give 229. MS: (ESI+)=478.1
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[CH:4][CH:3]=2)=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: CC(C)OC(=O)N1CCC(CSc2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(CSc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 30.1 %

Procedure:
A mixture of 1-methylethyl 4-{[(4-bromophenyl)thio]methyl}-1-piperidinecarboxylate (292 mg, 0.78 mmol), [4-(methylsulfonyl)phenyl]boronic acid (157 mg, 0.78 mmol), 2M Na2CO3 (2 mL), and Pd(PPh3)2Cl2 (200 mg, 0.28 mmol) in DME (8 mL) stirred at 80° C. for 3 h, then at ambient temperature overnight. The mixture was poured onto a Varian Chem Elut column, flushed with EtOAc, and the organics concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 30% EtOAc/hexanes to give 105 mg (30%) of the title compound as a tan solid. 1H NMR (400 MHz, CDCl3): δ 7.98 (d, 2H, J=8.4 Hz), 7.73 (d, 2H, J=8.4 Hz), 7.51 (d, 2H, J=8.4 Hz), 7.38 (d, 2H, J=8.4 Hz), 4.89 (septet, 1H, J=6.2 Hz), 4.20-4.10 (m, 2H), 3.07 (s, 3H), 2.89 (d, 2H, J=6.8 Hz), 2.75-2.64 (m, 2H), 1.90-1.80 (m, 2H), 1.79-1.65 (m, 1H), 1.28-1.12 (m, 8H); LRMS (ESI), m/z 448 (M+H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[CH:9][N:8]([CH3:11])[C:6]=2[N:7]=1.[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>N1C=CC=CC=1.O>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13]([NH:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[CH:9][N:8]([CH3:11])[C:6]=2[N:7]=1)=[O:18]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cn1ccc2c(=O)[nH]c(N)nc21
Solvent: O
Solvent: c1ccncc1
Product: Cn1ccc2c(=O)[nH]c(NC(=O)C(C)(C)C)nc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To a suspension of 2-amino-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (4.82 g, 29.4 mmol) in pyridine (45 ml) was added pivaloyl chloride (11.6 ml, 94.0 mmol) at 0° C., and the mixture was stirred at 80° C. for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (×1). The organic layer was washed with water (×1) and brine (×1), dried over sodium sulfate and concentrated in vacuo. The residual solids were suspended in methanol (45 ml), and concentrated aqueous ammonia (10 ml) was added at 0° C. The suspension was stirred at the same temperature for 30 minutes, before addition of water. After stirring at 0° C. for 2 hours, the resulting crystals were collected by filtration and washed with water to give 5.46 g (75%) of the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2>C(Cl)Cl.N1C=CC=CC=1>[CH3:5][O:4][C:2]([NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:3]
Reactant: COC(=O)Cl
Reactant: Nc1cnc2ccccc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1cnc2ccccc2c1
Reaction time: 0.5 h

Procedure:
3.2 ml of methyl chloroformate am added dropwise to 5.0 g of 3-aminoquinoline in 30 ml of methylene chloride and 15 ml of pyridine at 0° C. in the course of 30 min. The mixture is subsequently stirred for a further 30 min and then worked up in the customary manner. The title compound is obtained as a crystalline solid: Rf (H)=0.41.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH2:15].[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH:15][CH2:21][C:17]1[O:16][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccco1
Reactant: NCCCc1ccc2ccccc2c1Cl
Product: Clc1c(CCCNCc2ccco2)ccc2ccccc12
Yield: 45 %

Procedure:
The reductive ammination of 3-(1-chloronaphthalen-2-yl)propan-1-amine and furan-2-carbaldehyde was performed as described for compound I to obtain the compound as a pale yellow oil (45% yield).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:22])[F:23])=[CH:16][CH:17]=2)(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S(=O)(=O)c2ccc(NC(=O)C(C)(O)C(F)(F)F)cc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2cccc(O)c2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a stirred suspension of N-[4-(3-methoxyphenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (1.25 g, 3.1 mmol) in dry methylene chloride (30 mL) was added boron tribromide (9.3 mL of a 1.0M solution of boron tribromide in methylene chloride, 9.3 mmol). The resulting solution was stirred at room temperature for 2 hours, diluted with methylene chloride (50 mL) and washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting tan solid was triturated with methylene chloride to yield the title propanamide as a white solid (0.98 g, 78%); mp 164°-167° C. 1H-NMR (300 MHz, 66-DMSO): 1.57 (s, 3H, CH3) 7.00-7.04 (m, 1H, aromatic) 7.24 (t, 1H, J=1.6 Hz, aromatic) 7.31-7.40 (m, 2H, aromatic) 7.55 (s, 1H, OH) 7.89 (d, 2H, J=8.9 Hz, aromatic) 8.00 (d, 2H, J=9.0 Hz, aromatic) 10.22 (s, 1H, NH), 10.41 (s, 1H, ArOH). MS (CI, CH4): 390 (M+1). Analysis for C16H14F3NO5S.0.50 H2O: Calculated: C, 48.20; H, 3.51; N, 3.51. Found: C, 47.98; H, 3.71; N, 3.44.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N+](C1C=C(S(O[CH2:23][C@@H:24]2[O:26][CH2:25]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[O:26]1[CH2:25][C@@H:24]1[CH2:23][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=Cc1ccc(OC[C@H]2CO2)cc1
Yield: 89.1 %

Procedure:
In 800 ml of anhydrous methyl ethyl ketone was dissolved 23.54 g of 4-hydroxybenzaldehyde and 50 g of (R)-(-)-glycidyl m-nitrobenzenesulfonate. To the solution was added 34.6 g of anhydrous potassium carbonate, and the mixture was refluxed with heating for 2.5 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was extracted with ethyl acetate. The extract was washed with water, dried with magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and purified with chloroform to give 30.6 g of the title compound (yield 89%).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:11])[C@H:4]([O:6][Si](C)(C)C)[CH3:5].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[Mg]Br.[Cl-].[NH4+].O>C1COCC1>[Cl:1][CH2:2][C:3]([C:16]1[CH:15]=[CH:14][C:13]([F:12])=[CH:18][C:17]=1[F:19])([OH:11])[CH:4]([OH:6])[CH3:5]
Reactant: Fc1ccc([Mg]Br)c(F)c1
Reactant: C[C@@H](O[Si](C)(C)C)C(=O)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 0.17 h

Procedure:
A solution of 0.7 g (3.6 mmol) of (R)-1-chloro-3-(trimethylsilyloxy)butan-2-one in 5 mL of THF was cooled to −20° C., and 5.4 mL (3.8 mmol) of a 0.7 M solution of 2,4-difluorophenylmagnesium bromide prepared by a method as that in Example 3 was added dropwise thereto over a period of 10 minutes. After the completion of the dropwise addition, stirring was continued for another 5 hours, and 10 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added, and extraction was performed with ethyl acetate (20 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain 1-chloro-2-(2,4-difluorophenyl)butane-2,3-diol as a colorless oil. A quantitative analysis was performed by HPLC (under the same HPLC measurement conditions as those in Example 6). As a result, the yield was determined to be 79% ((2S,3R)/(2R,3R)=43/57).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:11]([NH2:13])[CH3:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C@@H:11]([NH:13][C:43]([C:39]2[CH:38]=[C:37]3[C:42](=[CH:41][CH:40]=2)[N:34]([CH2:33][C:30]2[CH:29]=[CH:28][C:27]([C:22]4[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:32][CH:31]=2)[C:35]([CH3:47])=[C:36]3[CH3:46])=[O:44])[CH3:12])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: COc1cc(OC)cc([C@H](C)N)c1
Product: COc1cc(OC)cc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3,5-dimethoxyphenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 563 [M+H]+.