Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][NH2:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]>C(O)(=O)C>[Br:1][C:8]1[CH:9]=[C:10]([O:11][CH3:12])[C:5]([O:4][CH3:3])=[CH:6][C:7]=1[CH2:13][CH2:14][NH2:15]
Reactant: COc1ccc(CCN)cc1OC
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cc(Br)c(CCN)cc1OC
Reaction time: 2 h
Yield: 79.2 %

Procedure:
Bromine (1.1 mL, 22 mmol) in acetic acid (10 mL) was slowly added into a vigorously stirred solution of 2-(3,4-dimethoxyphenyl)ethylamine (3.4 mL, 20 mmol) in 50 mL acetic acid. 2-bromo-4,5-dimethoxylbenzeneethanamine precipitated out after 15 minutes. The mixture was stirred for another two hours, filtered, and washed with dichloromethane 10 mL×3 and petroleum ether 10 mL×3. The resulting solid was taken up in water and the pH was brought to 10 with aqueous KOH solution. Extraction with dichloromethane followed by evaporation of the solvent yielded 4.12 g (78%) 2-Bromo-4,5-dimethoxylbenzeneethanamine. The crude product was dried under dynamic vacuum overnight and used without further purification.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:28]([C@@H:31]1[CH2:36][CH2:35][C@@H:34]([NH:37][C:38]([C:40]2[NH:41][C:42]3[C:47]([CH:48]=2)=[CH:46][C:45]([Cl:49])=[CH:44][CH:43]=3)=[O:39])[C@@H:33]([NH:50][C:51]([C:53]2[S:54][C:55]3[CH2:56][N:57]([CH3:62])[CH2:58][CH2:59][C:60]=3[N:61]=2)=[O:52])[CH2:32]1)(O)=[O:29]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[ClH:49].[Cl:49][C:45]1[CH:46]=[C:47]2[C:42](=[CH:43][CH:44]=1)[NH:41][C:40]([C:38]([NH:37][C@@H:34]1[CH2:35][CH2:36][C@@H:31]([C:28](=[O:29])[N:3]([CH3:4])[CH3:2])[CH2:32][C@@H:33]1[NH:50][C:51]([C:53]1[S:54][C:55]3[CH2:56][N:57]([CH3:62])[CH2:58][CH2:59][C:60]=3[N:61]=1)=[O:52])=[O:39])=[CH:48]2
Reactant: CN1CCc2nc(C(=O)N[C@H]3C[C@H](C(=O)O)CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1CCc2nc(C(=O)N[C@H]3C[C@H](C(=O)N(C)C)CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reaction time: 72 h
Yield: 118.7 %

Procedure:
Triethylamine (0.25 ml), dimethylamine hydrochloride (133 mg), 1-hydroxybenzotriazole monohydrate (53 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75 mg) were added to a chloroform suspension (10 ml) of (1R*,2S*,4R*)-4-carboxy-N1-[(5-chloroindol-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine (168 mg), and the mixture was stirred for 72 hours. The solvent was distilled off under reduced pressure, and water was added to the residue to conduct extraction with chloroform. The resultant organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by column chromatography on silica gel (dichloromethane:methanol=93:7). The thus-obtained colorless solid (135 mg) was suspended in ethanol (5 ml), to which 1N hydrochloric acid (0.5 ml) was added. The mixture was stirred for 2 hours, and the solvent was distilled off to obtain the title compound (112 mg) as colorless powder.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:12])[C:8]([CH3:19])=[C:7]2[C:3]=1[C:4]1[CH:23]=[C:22]([CH3:24])[CH:21]=[N:20][C:5]=1[NH:6]2.[CH:25]1([NH:28][C:29]([C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=2)=[O:30])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:29]([C:31]2[CH:36]=[C:35]([C:2]3[CH:10]=[C:9]([C:11]([NH:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:12])[C:8]([CH3:19])=[C:7]4[C:3]=3[C:4]3[CH:23]=[C:22]([CH3:24])[CH:21]=[N:20][C:5]=3[NH:6]4)[CH:34]=[CH:33][CH:32]=2)=[O:30])[CH2:26][CH2:27]1
Reactant: Cc1cnc2[nH]c3c(C)c(C(=O)NCCN(C)C)cc(Cl)c3c2c1
Reactant: O=C(NC1CC1)c1cccc(B(O)O)c1
Product: Cc1cnc2[nH]c3c(C)c(C(=O)NCCN(C)C)cc(-c4cccc(C(=O)NC5CC5)c4)c3c2c1

Procedure:
The title compound was synthesized from 5-chloro-N-(2-(dimethylamino)ethyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxamide and 3-(cyclopropylcarbamoyl)phenyl boronic acid using an analogous procedure to that described in the preparation of compound 83. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.57 (dd, J=3.92, 2.40 Hz, 2 H) 0.71 (dd, J=6.95, 2.40 Hz, 2 H) 1.23 (s, 1 H) 2.26 (s, 3 H) 2.65 (s, 3 H) 2.87 (d, J=5.05 Hz, 6 H) 3.29 (q, J=5.98 Hz, 2 H) 3.61 (q, J=6.15 Hz, 2 H) 7.20 (s, 1 H) 7.50 (s, 1 H) 7.66 (t, J=7.83 Hz, 1 H) 7.77 (d, J=7.83 Hz, 1 H) 7.98 (d, J=7.83 Hz, 1 H) 8.08 (s, 1 H) 8.31 (d, J=1.77 Hz, 1 H) 8.57-8.61 (m, 1 H) 8.59 (d, J=4.55 Hz, 1 H) 12.05 (s, 1 H). [M+H] calc'd for C28H31N5O2 470; found, 470.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH2:30][CH:31]2[CH2:33][CH2:32]2)[C:25]([O:27]CC)=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH2:30][CH:31]2[CH2:32][CH2:33]2)[C:25]([OH:27])=[O:26])[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: CCOC(=O)C(CC1CC1)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C(CC1CC1)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.68 g, 0.4 mmol) and lithium hydroxide monohydrate (100 mg, 4.6 mmol) in a MeOH/THF/Water solvent mixture (15 ml/15 ml/15/ml) was stirred for 3 h at room temperature. After completion of reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid in 88% yield (0.4 g). 1H-NMR (CDCl3, 500 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.43 (s, 1H); 7.24 (s, 1H); 3.98 (q, 2H); 3.72 (t, 1H); 1.94 (m, 1H), 1.78 (m, 1H); 0.71 (m, 1H), 0.46 (m, 2H), 0.02-0.19 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17](Cl)=[O:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])(=[O:24])=[O:23].C(N(CC)CC)C>C(#N)C>[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([NH:28][C:17]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:12]=2[C:13]([F:16])([F:15])[F:14])=[O:18])[CH:29]=[CH:30][CH:31]=1)(=[O:23])=[O:24]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn(-c3ccc(Cl)cc3)c2C(F)(F)F)c1
Temperature: 60 °C

Procedure:
1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.250 g, 0.808 mmol) was added to a solution of 3-methylsulfonylaniline hydrochloride (0.184 g, 0.889 mmol) and triethylamine (0.563 mL, 4.04 mmol) in acetonitrile (20 mL). The reaction mixture heated at 60° C. for 12 h, concentrated and crude product purified by column chromatography on silica gel to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-methane sulfonyl-phenyl)-amide. 1H-NMR (CD3OD, 300 MHz) δ 8.37 (s, 1H), 8.17 (s, 1H), 7.97 (d, 1H, J=8.5 Hz), 7.73 (d, 1H, J=8.0 Hz), 7.59–7.66 (m, 3H), 7.51 (d, 2H, J=8.8 Hz), 3.15 (s, 3H); LCMS m/z=443.9 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O:13][C:14]([C:16]1[S:26][C:19]2[N:20]=[C:21]([NH2:25])[N:22]=[C:23](Cl)[C:18]=2[CH:17]=1)=[O:15])C>C1COCC1>[NH2:25][C:21]1[N:22]=[C:23]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:18]2[CH:17]=[C:16]([C:14]([OH:15])=[O:13])[S:26][C:19]=2[N:20]=1
Reactant: CCOC(=O)c1cc2c(Cl)nc(N)nc2s1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(OCc2ccccc2)c2cc(C(=O)O)sc2n1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a nitrogen filled flask containing sodium hydride (0.5 mmol, 60% in mineral oil) in anhydrous THF (5 ml) was added benzyl alcohol (0.5 mmol). The suspension was stirred vigorously for 10 minutes until no more gas was evolved before being transferred to a microwave reaction tube containing 2-amino-4-chloro-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.129 g, 0.5 mmol). The sealed tube was heated to 90° C. for 5 mins using 300 W in a CEM microwave apparatus (CARE!). The reaction mixture was partitioned between DCM and water, the water layer neutralised and evaporated to dryness in vacuo to leave the pure product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1Cl)=[O:11].[OH-].[Na+]>O>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]2[NH:9][C:10](=[O:11])[C:12]3[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=3[O:1][C:2]=2[CH:7]=1
Reactant: Cc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2Cl)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(c1)Oc1ccc([N+](=O)[O-])cc1C(=O)N2
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A solution of N-(2-Hydroxy-4-methylphenyl)-2-chloro-5-nitrobenzene carboxamide (530 mg, 1.7 mmol) and 2 N NaOH (0.95 ml, 1.9 mol) in water (5 ml) was heated under reflux for 10 h. The resultant slurry was allowed to stand overnight at room temperature and a copious amount of water was added. The resulting mixture was filtered and solid was collected to obtain the compound (380 mg, 83%). Mp: 274-277° C.
Reaction SMILES: COC1C=CC(C2[CH:15](OC(=O)C)[C:14](=[O:20])[N:13](C(=O)C)[C:12]3[CH:24]=[CH:25][CH:26]=[CH:27][C:11]=3S2)=CC=1.NC1C=CC=CC=1>C(Cl)(Cl)Cl>[C:14]([NH:13][C:12]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:11]=1)(=[O:20])[CH3:15]
Reactant: COc1ccc(C2Sc3ccccc3N(C(C)=O)C(=O)C2OC(C)=O)cc1
Solvent: Nc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
7-(3). The compound (VII) (200 mg) and aniline (63 mg) are added to chloroform (10 ml), and the mixture is stirred at room temperature for 2 hours. The chloroform solution is concentrated and subjected to thin layer chromatography using silica gel (developer, benzene:ethyl acetate=1:1) to give acetanilide (62 mg, 88.3%) and the title compound (II) (159 mg, 89.2%), m.p. 196°-198° C.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2].[CH2:35]([NH2:37])[CH3:36].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20]([NH:37][CH2:35][CH3:36])(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(S(=O)(=O)Cl)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNS(=O)(=O)c1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, abs. THF (3 ml) was stirred with molecular sieve (4 Å, 30 mg) for 30 min (7R)-6-Cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl chloride (63%, 50 mg, 62 μmol), ethylamine (2 M solution in THF; 94 μl, 0.19 mmol, 3 eq.) and triethylamine (9 μl, 62 μmol, 1 eq.) were added, and the mixture was stirred at RT for 12 h. The reaction solution was then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (29.9 mg, 93% of theory).
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>C1COCC1>[I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(C(=O)O)c1I
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)Cl)c1I
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2-iodo-3-methyl benzoic acid (1310 mg, 5 mmol) and thionyl chloride (730 μL, 10 mmol) were dissolved into THF (10 mL) and stirred at RT for 4 days. The solvents were removed in vacuo and the resulting residue was dissolved into EtOAc, washed with brine. The combined organic layers were dried (MgSO4) and the solvents were removed in vacuo resulting in an oil that was used without further purification or characterization.
Reaction SMILES: [NH2:1][CH:2]1[CH2:17][O:16][C:5]2=[C:6]([F:15])[CH:7]=[C:8]3[C:13]([C:12](=[O:14])[NH:11][CH2:10][CH2:9]3)=[C:4]2[CH2:3]1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][CH:30]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[F:15][C:6]1[CH:7]=[C:8]2[C:13](=[C:4]3[CH2:3][CH:2]([NH:1][CH2:30][CH2:29][CH2:28][C:22]4[C:21]5[C:25](=[CH:26][CH:27]=[C:19]([F:18])[CH:20]=5)[NH:24][CH:23]=4)[CH2:17][O:16][C:5]=13)[C:12](=[O:14])[NH:11][CH2:10][CH2:9]2
Reactant: O=CCCc1c[nH]c2ccc(F)cc12
Reactant: NC1COc2c(F)cc3c(c2C1)C(=O)NCC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NCCc2cc(F)c3c(c21)CC(NCCCc1c[nH]c2ccc(F)cc12)CO3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 9-amino-6-fluoro-3,4,9,10-tetrahydro-2H-pyrano[2,3-h]isoquinolin-1(8H)-one (49) (110 mg, 0.47 mmol) in anhydrous methanol (7 ml) was added 3-(5-fluoro-1H-indol-3-yl) propanal (2) (89 mg, 0.47 mmol), acetic acid (0.060 ml), and NaBH3CN (59 mg, 0.930 mmol). Resulting reaction mixture was stirred at room temperature for 3 hr. The solvent was removed in vacuo and the residue was re-dissolved in CH2Cl2 (120 ml). The solution was washed with 1 N NaOH and H2O, saturated. NaCl. The organic solution was separated, dried over Na2SO4, then concentrated in vacuo. The crude compound was purified on silica gel eluting with 80% EtOAc/Hexane to yield the title compound. MS (ES) m/z 410.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][O:13][C:12](=[O:15])[NH:11]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[H-].[Na+].Cl[C:19]1[CH:24]=[CH:23][N:22]2[N:25]=[CH:26][C:27]([C:28]([NH:30][CH2:31][CH2:32][Cl:33])=[O:29])=[C:21]2[N:20]=1.[NH4+].[Cl-]>CN(C=O)C.O>[Cl:33][CH2:32][CH2:31][NH:30][C:28]([C:27]1[CH:26]=[N:25][N:22]2[CH:23]=[CH:24][C:19]([N:11]3[C@@H:10]([C:4]4[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)[CH2:14][O:13][C:12]3=[O:15])=[N:20][C:21]=12)=[O:29]
Reactant: COc1ncc(F)cc1[C@H]1COC(=O)N1
Reactant: O=C(NCCCl)c1cnn2ccc(Cl)nc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(F)cc1[C@H]1COC(=O)N1c1ccn2ncc(C(=O)NCCCl)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.9 %

Procedure:
To a solution of (S)-4-(5-fluoro-2-methoxypyridin-3-yl)oxazolidin-2-one (prepared according to Example 30; 50 mg, 0.236 mmol) in DMF (1 mL) was added sodium hydride (11 mg, 0.28 mmol, 60% in mineral oil). The mixture was stirred at ambient temperature for 20 minutes, then treated with 5-chloro-N-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (61 mg, 0.236 mmol). The mixture was stirred at 16 hours, and then treated with saturated NH4Cl solution (10 mL) and water (20 mL). The resulting precipitate was collected by filtration, washed with water and Et2O, then dried under reduced pressure to afford (S)-N-(2-chloroethyl)-5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (83 mg, 81% yield) as a beige solid. MS (apci) m/z=434.9 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C(=O)C)=[CH:11][C:10]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[K+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)Nc1cc(O)ccc1OCc1ccccc1
Yield: 53.6 %

Procedure:
A solution of acetic acid 4-benzyloxy-3-methanesulfonylaminophenyl ester (1.6 g) and potassium hydride (2.67 g) in methanol (10 ml) was stirred for 18 hours at room temperature. The reaction mixture was acidified with 1N hydrochloric acid to pH 5-7 and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford N-(2-benzyloxy-5-hydroxyphenyl)methanesulfonamide (750 mg).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][C@@H:5]([C:7](O)=[O:8])[C@H:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:8][CH2:7][C@@H:5]1[CH2:6][C:2](=[CH2:1])[CH2:3][C@H:4]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=C1C[C@@H](C(=O)O)[C@H](c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1C[C@@H](CO)[C@H](c2ccccc2)C1
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of (+−)-trans-4-methylene-2-phenylcyclopentanoic acid (26 g, 129 mmol) from Step B1 in THF (600 mL) under nitrogen at −10° C. was added dropwise over 15 min 1M lithium aluminum hydride (LAH) in THF (193 mL, 193 mmol). After 16 h at rt, the excess LAH was quenched by dropwise addition of acetone and the reaction was then poured into dilute aq. HCl. The mixture was extracted twice with ether and the organic layers were washed with brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC (20% ethyl acetate in hexanes) to afford the title product (23.8 g) which was the same as in Method A.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15]C#N)=[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=2)=[O:5])[CH3:2].S.[Na].[BH4-].[Na+].CO>CC(O)=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([SH:15])=[C:10]([C:18]([CH3:19])([CH3:21])[CH3:20])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(SC#N)c(C(C)(C)C)cc2[nH]1
Agent: S
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1cc2cc(S)c(C(C)(C)C)cc2[nH]1

Procedure:
The title compound was prepared according to the general Method 14b using (6-tert-butyl-5-thiocyanato-1H-indole-2-carboxylic acid ethyl ester (prepared in Example ZZ; 0.25 g, 0.83 mmol), sodium hydrogen sulfide (0.13 g, 2.48 mmol), sodium borohydride (0.188 g, 4.98 mmol), MeOH (5 mL), and AcOH (1 mL). MS(APCI): 278 (M+H).
Reaction SMILES: [CH:1](OCC)=[O:2].[H-].[Na+].[CH3:8][O:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][CH2:15][C:16]2=[O:19])=[CH:12][CH:11]=1.O>C1C=CC=CC=1>[OH:2][CH:1]=[C:15]1[CH2:14][C:13]2[C:17](=[CH:18][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)[C:16]1=[O:19]
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc2c(c1)C(=O)C(=CO)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a mixture of ethyl formate (15.75 mL, 0.195 mol) and NaH (60%, 7.80 g, 0.195 mol) in benzene (550 mL) was added a suspension of 6-methoxy-indan-1-one (15.81 g, 0.0974 mol) in benzene (150 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature overnight and treated with water. The solid was filtered, washed with water, and oven dried to give the desired product (16.86 g, 91%). The product may exist in sodium salt form, however, it was carried into the next reaction without further characterization. MS (DCI/NH3) m/z: 191.1 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 3.50 (s, 2H) 3.80 (s, 3H) 7.13-7.20 (m, 2H) 7.47 (d, J=8.14 Hz, 1H) 7.74 (s, brd, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:9]=2[O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[C:5]2[CH:26]=[CH:27][NH:28][C:4]=2[C:3]1=[O:29].CN1C=C(C2C=C([N+]([O-])=O)C=CC=2OC2C=CC=CC=2)C2C=CNC=2C1=O>>[NH2:23][C:21]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=2)=[C:8]([C:6]2[C:5]3[CH:26]=[CH:27][NH:28][C:4]=3[C:3](=[O:29])[N:2]([CH3:1])[CH:7]=2)[CH:22]=1
Reactant: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccc(C#N)cc2)c2cc[nH]c2c1=O
Agent: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Product: Cn1cc(-c2cc(N)ccc2Oc2ccc(C#N)cc2)c2cc[nH]c2c1=O

Procedure:
Example 33b was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 33a for the product of Example 2b, to provide the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3[N:11]=[C:12]4[C:18]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:17][NH:16][C:13]4=[N:14][CH:15]=3)[CH:8]=2)[CH:3]=[CH:2]1.N1C2C(=CC(C3N=C4C(C(=O)C(C)(C)C)=CNC4=NC=3)=CC=2)C=C1>>[NH:1]1[C:9]2[C:8](=[C:7]([C:10]3[N:11]=[C:12]4[C:18]([C:19](=[O:24])[C:20]([CH3:23])([CH3:21])[CH3:22])=[CH:17][NH:16][C:13]4=[N:14][CH:15]=3)[CH:6]=[CH:5][CH:4]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccc4cc[nH]c4c3)nc12
Agent: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccc4[nH]ccc4c3)nc12
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc4[nH]ccc34)nc12

Procedure:
Substituting indole 4-boronic acid for 3-(1-pyrrolidino)phenyl boronic acid. MP=257-258 C, (M+H)+=319. 1-[2-(1H-Indol-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one. Substituting indole 6-boronic acid for 3-(1-pyrrolidino)phenyl boronic acid. MP=>300 C, (M+H)+=319. 1-[2-(1H-Indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one. Substituting 5-indoleboronic acid for 3-(1-pyrrolidino)phenyl boronic acid. MP=296-297 C, (M+H)=319.
Reaction SMILES: C1COCC1.[C:6]([C:10]1[C:15]([F:16])=[CH:14][C:13]([CH:17]2[CH2:19][CH:18]2[C:20]([O:22]CC)=[O:21])=[CH:12][C:11]=1[F:25])([CH3:9])([CH3:8])[CH3:7].[OH-].[Na+]>CO>[C:6]([C:10]1[C:11]([F:25])=[CH:12][C:13]([CH:17]2[CH2:19][CH:18]2[C:20]([OH:22])=[O:21])=[CH:14][C:15]=1[F:16])([CH3:9])([CH3:7])[CH3:8]
Reactant: CCOC(=O)C1CC1c1cc(F)c(C(C)(C)C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1c(F)cc(C2CC2C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a toluene (50 ml) solution of the compound of Example 38C (4.0 g, 20.4 mmol), Co(TPP) (411 mg, 0.61 mmol) and 1-methyl-1H-imidazole (5.0 g, 61.2 mmol), ethyl diazoacetate (3.5 g, 30.6 mmol) was added and the mixture was stirred for 5 minutes at room temperature followed by additional stirring for 2 hours at 80° C. Then, evaporation and purification by silica gel column chromatography, eluting with gradually from hexane to hexane/EtOAc (20:1), gave ethyl 2-(4-tert-butyl-3,5-difluorophenyl)cyclopropanecarboxylate (4.4 g, 76%, trans). To a THF (5 ml) solution of ethyl 2-(4-tert-butyl-3,5-difluorophenyl)cyclopropanecarboxylate (4.4 g, 15.5 mmol), 2M sodium hydroxide aqueous solution (30 ml) and MeOH (30 ml) were added and the mixture was stirred for 1 hour at room temperature. After the reaction was completed, the aqueous layer was extracted, and then acidified with 2M HCl aqueous solution and the whole was extracted with EtOAc, followed by evaporation, to give the title compound (3.48 g, 88%) as white solids.