Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]1[O:15][CH2:14][CH2:13][O:12]1.CN([CH:19]=[O:20])C.O.O.C(O)(=O)C(O)=O>CCOCC.O.CCOC(C)=O>[O:12]1[CH2:13][CH2:14][O:15][CH:11]1[C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: Brc1c(C2OCCO2)oc2ccccc12
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=Cc1c(C2OCCO2)oc2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
3-Bromo-2-(1,3-dioxolan-2-yl)-1-benzofuran (6.6 g 24.5 mmol) is dissolved in Et2O (100 ml) in a 3-neck, flame-dried, round-bottom flask under nitrogen and cooled to −78° C. tert-butylithium (31.7 ml, 53.9 mmol) is added dropwise, and the chilled solution is stirred 1 h. DMF (2.18 ml, 28.2 mmol) is dissolved in Et2O (25 ml) and also added dropwise, and the mixture is stirred at −78° C. for another 7 h. The reaction is warmed to rt, whereby oxalic acid dihydrate (6.18 g, 49.0 mmol) and water (25 ml) are added. The reaction continued stirring at rt overnight and is then diluted with water (125 ml) and EtOAc (175 ml). The layers are allowed to separate, and the aqueous is extracted with EtOAc (1×100 ml). The organics are combined, dried over sodium sulfate, filtered, and concentrated to a brown oil. The crude material is chromatographed over 350 g slurry-packed silica, eluting with 30% ethyl acetate/hexane. The appropriate fractions are combined and concentrated to afford 3.84 g (72%) of 2-(1,3-dioxolan-2-yl)-1-benzofuran-3-carbaldehyde as a yellow/orange oil. MS (EI) m/z: 218 (M+).
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].[C:9]([N:13]=[N:14][C:15]1([N:21]=[C:22]=[S:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:12])([CH3:11])[CH3:10]>CO>[C:9]([N:13]=[N:14][C:15]1([NH:21][C:22]([NH:2][NH:3][C:4]([NH2:6])=[O:5])=[S:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: NNC(N)=O
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)N=NC1(NC(=S)NNC(N)=O)CCCCC1
Reaction time: 0.25 h

Procedure:
To a solution of 2.49 grams (0.0223 moles) of semicarbazide hydrochloride in 25 ml of methanol in a 50 ml erlenmeyer flask was added 1.75 grams (0.0223 moles) of 50% NaOH and the reaction stirred 15 minutes. To this solution was added 5.15 grams (0.0223 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane and the reaction mixture stirred for 6 days at room temperature. The methanol was evaporated under reduced pressure, the residue slurried in water and filtered. The filter cake weighed 5.0 grams (73% crude yield) after drying and was a pale yellow solid. The product did not melt but decomposed around 180° C. The infrared spectrum of the product contained amide carbonyls at 1620 and 1675 cm-1, a strong band at 1540 cm-1 [-N(H)CS], a strong NH band at 3200 cm-1 and weaker NH bands around 3400 cm-1. The isothiocyanate band at 2040 cm-1 was absent.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=1.[N:15]([O-])=O.[Na+]>CC(O)=O>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:4]2[CH:3]=[C:2]3[CH:1]=[N:15][NH:8][C:7]3=[CH:6][N:5]=2)[CH:10]=1
Reactant: O=N[O-]
Reactant: Cc1cc(-c2cccnc2)ncc1N
Agent: [Na+]
Solvent: CC(=O)O
Product: c1cncc(-c2cc3cn[nH]c3cn2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
To a solution of 4-methyl-2,3′-bipyridin-5-amine (185 g, 1 mol) in AcOH (27 L) was added aq. NaNO2 solution (82 g, 1.2 mol, 100 mL). The mixture was stirred for 16 h at room temperature. After reaction, the solvent was removed and the residue was purified by silica-gel column chromatography (mobile phase: EA:PE=1:1) to give 5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine as a yellow solid (98 g, 50%)
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:3]=1.[CH3:21][Zn]C.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1COCC1>[CH3:21][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:3]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)n3nccc3n2)cc1
Reactant: C[Zn]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2ccnn12
Yield: 84.4 %

Procedure:
To a solution of 7-chloro-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (1.49 g, 5.0 mmol) and tetrakis(triphenylphosphin)palladium (1.73 g, 1.5 mmol) in THF (50 mL) was added at 20° C. 2 M dimethylzinc/toluene solution (6.25 mL, 12.5 mmol) and the mixture was refluxed in an atmosphere of argon for 2 h. After the slow addition at 0° C. of sat. aqueous NH4Cl solution (12 mL), the mixture was partitioned between AcOEt and 10% sodium chloride solution. The organic layer was evaporated in vacuo and the residue was chromatographed on silica gel using AcOEt/hexane (1:3 v/v) as eluent to give the title compound (1.17 g, 84%). Pale yellow solid. MS (ISN) 276.1 [(M−H)−]; mp 89-90° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:15]=[C:14]([OH:16])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[OH:17])[CH3:2].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Br:26].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:15]=[C:14]([O:16][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Br:26])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[O:17][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Br:26])[CH3:2]
Reactant: BrCCCCCCBr
Reactant: CCOC(=O)c1cc(O)c(C(=O)OCC)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(OCCCCCCBr)c(C(=O)OCC)cc1OCCCCCCBr

Procedure:
25.4 g (0.1 mol) diethyl-2,5-dihydroxyterephthalate, 232 ml (1.5 mol) 1,6-dibromohexane, 130 g (0.94 mol) K2CO3 and 200 mg NaI in 200 ml acetone are heated under reflux for 12 hours. The initially yellow suspension decolorizes. After distilling off the solvent, 1200 ml diethyl ether are added to the reaction mixture and the whole is washed twice, each time with 200 ml water. The organic phase is then dried over Na2SO4 and the solvent is distilled off. The colourless product which crystallized out after adding 250 ml petroleum ether at -20° C. is recrystallized once from petroleum ether and twice from ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([N:14]=[C:15]=[S:16])[CH3:13].O>C(#N)C>[CH2:12]([NH:14][C:15](=[S:16])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH3:13]
Reactant: CCN=C=S
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CC#N
Solvent: O
Product: CCNC(=S)Nc1ccc(C(=O)OC)cc1
Temperature: 80 °C

Procedure:
To a solution of methyl 4-aminobenzoate (2-2) (30.2 mg, 0.20 mmol) in anhydrous acetonitrile (0.4 mL) is added ethyl isothiocyanate (2-1) (17.52 μL, 0.20 mmol) and the reaction mixture is heated at 80° C. overnight. After cooling to room temperature, the mixture is poured into water (50 mL) and extracted with ethyl acetate (EtOAc) (3×50 mL). The combined organic layers are washed with brine and dried using MgSO4. The drying agents are removed by filtration and the solvent is removed under vacuum. The resulting residue is then purified by flash column chromatography (silica gel, EtOAc/hexane, 0%-40%) to provide methyl 4-(3-ethylthioureido)benzoate (2-3).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[NH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33]([NH2:36])(=[O:35])=[O:34].CCN(C(C)C)C(C)C>C1COCC1>[Cl:32][C:30]1[CH:29]=[CH:28][C:27]([S:33]([NH2:36])(=[O:35])=[O:34])=[C:26]([CH2:25][CH2:24][NH:23][C:11]2[N:10]=[C:9]([NH:8][C@@H:5]3[CH2:6][CH2:7][C@H:2]([OH:1])[C:3]([CH3:21])([CH3:22])[CH2:4]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)[CH:31]=1
Reactant: NCCc1cc(Cl)ccc1S(N)(=O)=O
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C[C@H](Nc2nc(NCCc3cc(Cl)ccc3S(N)(=O)=O)ncc2C#N)CC[C@@H]1O
Temperature: 100 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
A mixture of 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (100 mg, 0.31 mmol), 2-(2-amino-ethyl)-4-chloro-benzenesulfonamide (150 mg, 0.64 mmol) and DIEA (80 mg, 0.62 mmol) in THF (4 mL) was stirred at 100° C. in a microwave reactor for 1 h. After cooling to room temperature, the reaction mixture was concentrated and the residue purified by standard methods to afford the title compound (53.3 mg, 0.060 mmol, 26% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.18-8.00 (m, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.50-7.34 (m, 2H), 4.41-4.23 (m, 1H), 3.89-3.51 (m, 2H), 3.41-3.33 (m, 2H), 3.29-3.22 (m, 1H), 2.04-1.80 (m, 1H), 1.80-1.68 (m, 2H), 1.67-1.38 (m, 3H), 1.05-0.93 (m, 6H). MS (ESI) m/z 479.1, 481.1 [M+H]+.
Reaction SMILES: C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:12][N:13]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:15]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:14]1=[O:36].Cl.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:39]=1.CN1CCOCC1>ClCCl>[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([S:44]([NH:12][N:13]2[CH2:17][CH:16]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[N:15]([CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[C:14]2=[O:36])(=[O:46])=[O:45])[CH:39]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COc1ccc(CCN2C(=O)N(N)CC2c2ccc(OC)cc2)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(CCN2C(=O)N(NS(=O)(=O)c3cccnc3)CC2c2ccc(OC)cc2)cc1
Temperature: 80 °C
Yield: 42.9 %

Procedure:
1-Amino-3-[2-(4-methoxyphenyl)ethyl]-4-(4-methoxyphenyl)-2-imidazolidinone toluenesulfonic acid (0.3 g, 0.58 mmol) is stirred in dichloromethane (6 mL) and 3-pyridylsulfonylchloride HCl (135 mg, 0.63 mmol) is added followed by 4-methylmorpholine (0.2 mL). The mixture is heated in a microwave oven at 80° C. for 25 minutes. The mixture is evaporated and purified over silica (hexane/ethylacetate) to give the afford 0.12 g (41% yield) of the desired product as a white solid. 1H NMR (DMSO-d6) δ 10.3 (s, 1H), 9.0 (s, 1H), 8.9 (d, J=6 Hz, 1H), 8.2 (d, J=7.8 Hz, 1H), 7.65 (m, 1H), 7.2 (d, J=7.8 Hz, 2H), 7.05, (d, J=7.8 Hz, 2H), 6.95 (d, J=7.8 Hz, 2H), 6.8 (d, J=7.8 Hz, 2H), 4.5 (t, J=7 Hz, 1H), 3.8 (s, 3H), 3.75 (s, 3H), 3.3 (m, 1H), 3.2 (m, 1H), 2.75 (m, 2H), 2.4 (m, 2H). Anal. calcd. for C24H26N4O5S: C, 59.74; H, 5.43; N, 11.61; found C, 59.60; H, 5.47; N, 11.37. FAB-HRMS calcd. 483.1702; found 483.1720 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:24]=4[N:25]=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:34](OC(N1CCC2(CNC2)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:34][C:14]2([CH2:13][N:12]([CH2:16][C:17]3[S:18][C:19]4[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)[C:24]=4[N:25]=3)[CH2:11]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC2
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)CC2C1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1nc3c(N4CCOCC4)nc(Cl)nc3s1)C2

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester hydrochloride in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a white solid (70 mg, 71%).
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[CH:11](O)=[O:12]>>[O:10]1[C:9]2[CH:8]=[CH:7][C:5]([NH:6][CH:11]=[O:12])=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=CO
Product: O=CNc1ccc2c(c1)OCO2

Procedure:
Was prepared according to Example 2 from 3,4-(methylenedioxy)aniline and formic acid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:29][S:30]([O-:32])=[O:31].[Na+].CN(C)CCN>CS(C)=O>[CH3:29][S:30]([C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1)(=[O:32])=[O:31]
Reactant: CS(=O)[O-]
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Agent: CN(C)CCN
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2n1
Temperature: 125 °C
Reaction time: 5 h
Yield: 37.2 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (89 mg, 0.194 mmol) from Example 78, sodium methane sulfinate (80 mg, 0.777 mmol), and N,N-dimethylethylenediamine (7 mg, 0.078 mmol) in anhydrous DMSO (2 mL) at rt was purged for 15 min with a stream of argon. To the resulting mixture was added copper (I) trifluoromethane-sulfonate benzene complex (20 mg, 0.038 mmol). The reaction vessel was sealed and the mixture was stirred at 125° C. for 5 h. After cooling to rt, the reaction mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((5-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (33 mg, 37%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.39 (d, J=8.3 Hz, 1H), 7.90-8.02 (m, 2H), 7.78 (s, 1H), 7.25-7.36 (m, 2H), 5.54 (s, 2H), 4.74 (br s, 1H), 3.50 (br s, 1H), 3.33-3.34 (m, 4H), 2.02 (m, 1H), 1.87 (m, 1H), 1.55-1.65 (m, 2H), 1.15-1.30 (m, 4H); LCMS (ESI) m/z 458 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:14])[CH2:7][O:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4]1.[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH2:17]([O:1][CH2:2][C:3]1([CH3:14])[CH2:7][O:6][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:4]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: CC1(CO)COC(c2ccccc2)=N1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(COCc2ccccc2)COC(c2ccccc2)=N1
Reaction time: 16 h

Procedure:
A suspension of 4-hydroxymethyl-4-methyl-2-phenyloxazoline (19.1 grams, prepared by the method described in J. Amer, Chem. Soc. 1945, 67, 1069) in toluene (200 milliliters) was added slowly to a stirred suspension of sodium hydride (2.4 grams) in toluene (50 milliliters). Some warming was necessary to initiate the reaction. The mixture was then heated under reflux for 2 hours with stirring. Benzyl chloride (13.0 grams) was added to the mixture over a period of 10 minutes. The mixture was heated under reflux for a further 5 hours and then allowed to stand at room temperature for 16 hours. The mixture was washed with water (3 × 200 milliliters), dried (MgSO4) and evaporated under reduced pressure. The residue was distilled in vacuo to give the desired product, boiling point 147°-149°C at 0.3 Torr.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[CH3:41])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:49][C:50]1([F:54])[CH2:53][NH:52][CH2:51]1.CCN(C(C)C)C(C)C>C1COCC1>[F:1][C:2]([F:47])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[CH3:41])=[CH:24][N:23]=[C:22]([N:52]4[CH2:53][C:50]([F:54])([F:49])[CH2:51]4)[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1cc(C(=O)O)ccc1-c1nc(C)c(-c2cnc(S(C)(=O)=O)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Reactant: FC1(F)CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1-c1nc(C)c(-c2cnc(N3CC(F)(F)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-4-methyl-1,3-thiazol-2-yl}-3-methylbenzoic acid (INTERMEDIATE 54, 200 mg, 0.280 mmol) in THF (5 mL) was added 3,3-difluoroazetidine (129.5 mg, 0.840 mmol) and DIEA (0.244 mL, 1.399 mmol). The reaction mixture was stirred at 60° C. for 15 minutes to see complete conversion by LCMS. The solvent was evaporated, and the residue was purified on reverse phase HPLC, eluting with 10%-100% acetonitrile in water, to give title compound as a slightly yellow solid. LCMS (M+H)+: 728.1. 1H NMR (CDCl3, 500 MHz): δ 8.37 (s, 1H), 8.08 (s, 1H), 8.02 (d, J=8.5 Hz, 1H), 7.93 (s, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.78 (s, 2H), 5.79 (d, J=8.5 Hz, 1H), 4.78 (d, J=17.0 Hz, 1H), 4.58 (m, 4H), 4.42 (m, 3H), 4.08 (d, J=17.0 Hz, 1H), 2.72 (s, 3H), 2.43 (s, 3H), 0.80 (d, J=7.0 Hz, 3H). RTA IC50: 61 nM.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:15])[C:8]([C:12]([OH:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[H-].[Li+].C([Li])CCC.CN(C)[CH:25]=[O:26].Cl>O1CCCC1>[CH:25]([C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:15])[C:8]([C:12]([OH:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1)=[O:26]
Reactant: O=C(O)c1cc2cc(Br)ccc2cc1O
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1ccc2cc(O)c(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 7-bromo-3-hydroxynaphthalene-2-carboxylic acid (15.0 g, 56.2 mmol) (example 340) in tetrahydrofuran (100 mL) was added to a solution of lithium hydride (893 mg, 112 mmol) in tetrahydrofuran (350 mL). After 30 minutes stirring at room temperature, the resulting solution was heated to 50° C. for 2 minutes and then allowed to cool to ambient temperature over a period of 30 minutes. The mixture was cooled to −78° C., and butyllithium (1.6 M in hexanes, 53 mL, 85 mmol) was added over a period of 15 minutes. N,N-Dimethylformamide (8.7 mL, 8.2 g, 112 mmol) was added after 90 minutes additional stirring. The cooling was discontinued, and the reaction mixture was stirred at room temperature for 17 hours before it was poured into 1 N hydrochloric acid (aq.) (750 mL). The organic solvents were evaporated in vacuo, and the resulting precipitate was filtered off and rinsed with water (3×100 mL) to yield the crude product (16.2 g). Purification on silica gel (dichloromethane/methanol/acetic acid=90:9:1) furnished the title compound as a solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH2:15][C:16]([NH:18]C(CNC(C1CCN(C2C=CN=CC=2)CC1)=O)C(O)=O)=[O:17])(=[O:13])=[O:12].N1CCOCC1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH2:15][C:16]([NH2:18])=[O:17])(=[O:12])=[O:13]
Reactant: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)O
Solvent: C1COCCN1
Product: NC(=O)CNS(=O)(=O)c1ccc2ccccc2c1
Yield: 36 %

Procedure:
Using an analogous procedure to that described in Example 20, 2-[2-(2-naphthalenesulphonamido)acetamido]-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]propionic acid was reacted with morpholine to give yl-morpholinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]-ethyl}-2-(2-naphthalenesulphonamido)acetamide in 36% yield.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[N:24][C:25]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:26][CH:27]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:14]=2)[CH:9]=[N:8]1.[CH3:47][C@H:48]1[CH2:50][O:49]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH2:47][C@@H:48]([OH:49])[CH3:50])[CH2:30][CH2:29]5)=[N:24][CH:23]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:36])=[O:35])[CH:14]=2)[CH:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (270 mg. 0.41 mmol) was alkylated using (S)-2-methyloxirane (48 mg, 0.82 mmol), DIPEA (159 mg, 1.23 mmol) and ethanol (10 mL) to get 350 mg (crude) of the titled compound. MS: m/z=680.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([OH:21])=[O:20])([O-:3])=[O:2].CO[CH2:24][CH2:25]OC.C(N(CC)CC)C.C(OC(Cl)=O)C>[Cl-].[Na+].O.C(OCC)C.C(O)C>[N+:1]([C:4]1[CH:9]=[C:8]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([O:21][CH2:24][CH3:25])=[O:20])([O-:3])=[O:2]
Reactant: COCCOC
Reactant: O=C(O)Cc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)Cc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
To a solution of 13.8 g. (48.4 mmoles) of 2-nitro-4-benzoylphenylacetic acid in 150 ml. of 1,2-dimethoxyethane at 15° C. was added 5.87 g. (58.1 mmole) of triethylamine. After 5 minutes 5.75 g. (53.2 mmoles) of ethylchloroformate was added and the reaction mixture allowed to stir at 10° C. for 15 minutes. Ethanol (15 ml.) was added and the reaction subsequently was added to a mixture of diethyl ether and a saturated brine solution. The organic phase was separated, dried over magnesium sulfate and concentrated to an oil, which was induced to crystallize, 14.3 g. (94% yield), m.p. 61°-62° C.
Reaction SMILES: FC1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=3)[C:15]([O:17]C)=O)[C:8]2=[O:22])=CC=1.C1(CN2CCN(C3C=C(C=CN=3)C(OC)=O)C2=O)CC1.[F:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][C:53]=1[F:54])[CH2:49][NH2:50]>>[CH:5]1([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=3)[C:15]([NH:50][CH2:49][C:48]3[CH:51]=[CH:52][C:53]([F:54])=[C:46]([F:45])[CH:47]=3)=[O:17])[C:8]2=[O:22])[CH2:23][CH2:24]1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: NCc1ccc(F)c(F)c1
Agent: COC(=O)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Product: O=C(NCc1ccc(F)c(F)c1)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Yield: 49 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate with methyl 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)isonicotinate to react with 3,4-difluorobenzylamine, 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-N-(3,4-difluorobenzyl)isonicotinamide was obtained as a colorless solid in 49% yield: mp 134-136° C.; 1H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 8.36 (d, J=5.1 Hz, 1H), 7.41-7.39 (m, 1H), 7.17-7.00 (m, 4H), 4.54 (d, J=6.0 Hz, 2H), 4.07 (t, J=8.1 Hz, 2H), 3.60 (t, J=8.1 Hz, 2H), 3.14 (d, J=7.2 Hz, 2H), 1.00-0.87 (m, 1H), 0.58-0.52 (m, 2H), 0.24-0.19 (m, 2H); MS (ES+) m/z 387.3 (M+1).