Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][C:15]2([CH:19]2[CH2:21][CH2:20]2)O)=[CH:11][CH:10]=1.[CH3:22][S:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[NH:32][CH:31]=[CH:30]2.[Cl-].[NH4+]>ClCCl>[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][C:15]2([C:30]2[C:29]3[C:33](=[C:25]([CH2:24][S:23][CH3:22])[CH:26]=[CH:27][CH:28]=3)[NH:32][CH:31]=2)[CH:19]2[CH2:21][CH2:20]2)=[CH:11][CH:10]=1
Reactant: OC1(C2CC2)CCc2ccc(Cl)cc21
Reactant: CSCc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C3(C4CC4)CCc4ccc(Cl)cc43)c[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
0.03 ml (0.40 mmol) of trifluoroacetic acid was added to 70.0 mg (0.34 mmol) of the compound from Example 119A and 65.4 mg (0.37 mmol) of the compound from Example 8A in 1.6 ml of dichloromethane at 0° C., and the mixture was stirred at 0° C. for 4 h. It was diluted with dichloromethane and added to saturated aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 52.4 mg (42% of theory) of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3]/[N:4]=[C:5](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1)\[C:6]([OH:8])=O.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[NH2:48][C@@H:49]1[C:77](=[O:78])[N:51]2[C:52]([C:65]([O:67][CH2:68][C:69]3[CH:74]=[CH:73][C:72]([O:75][CH3:76])=[CH:71][CH:70]=3)=[O:66])=[C:53]([C@H:56]3[C:60](=C=O)[CH2:59][C@@H:58](OC)[O:57]3)[CH2:54][S:55][C@H:50]12>CN(C)C=O.N1C=CC=CC=1>[CH3:68][O:67][C:65]([C@H:58]1[O:57][C@@H:56]([C:53]2[CH2:54][S:55][C@@H:50]3[C@H:49]([NH:48][C:6](=[O:8])/[C:5](=[N:4]\[O:3][CH3:2])/[C:9]4[N:10]=[C:11]([NH:14][C:15]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[S:12][CH:13]=4)[C:77](=[O:78])[N:51]3[C:52]=2[C:65]([O:67][CH2:68][C:69]2[CH:70]=[CH:71][C:72]([O:75][CH3:76])=[CH:73][CH:74]=2)=[O:66])[CH2:60][CH2:59]1)=[O:66]
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: COc1ccc(COC(=O)C2=C([C@@H]3O[C@H](OC)CC3=C=O)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@H]3CC[C@@H](C(=O)OC)O3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A stirred solution of 2-(Z)methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid hydrochloride (148mg) and N,N-diisopropylethylamine (0.107ml) in dimethylformamide (1ml) was cooled to -55 to -60° C. and methanesulphonyl chloride (0.024ml) was added. The mixture was stirred at the same temperature for 0.5h and then a solution of 4-methoxybenzyl (6R,7R)-7-amino-3-[(2R,5S)-5-methoxy-carbonyltetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (126mg) in dimethylformamide (1ml) was added followed by pyridine (0.023ml). The mixture was then stirred at 0° C. for 1h and then at room temperature for 0.5h. The mixture was partitioned between ethyl acetate and aqueous citric acid solution, and the organic phase was washed with water, then brine, dried over magnesium sulphate and evaporated. The title compound (100mg) was isolated by column chromatography of the residue (silica gel, 3:7 hexane:ethyl acetate as eluent); vmax (CHCl3) 3403, 1786, 1732 and 1681cm-1 ; δH (CDCl3) 1.66-2.36 (4H, m), 3.58 (1H, d, J 18.0Hz), 3.73 (3H, s), 3.81 (3H, s), 4.02 (1H, d, J 18.0Hz), 4.08 (3H, s), 4.53 (1H, dd, J 3.34, 8.91Hz), 5.02 (1H, d, J 4.8Hz), 5.18 (1H, d, J 11.8Hz), 5.24 (1H, d, J 12.0Hz), 5.30 (1H, dd, J 5.7, 9.9Hz), 5.86 (1H, dd, J 4.6, 8.6Hz), 6.72-6.83 (2H, m), 6.89 (2H, d, J 8.54Hz), 7.01 (1H, s) and 7.25-7.4 (17H, m).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([CH2:15][CH2:16][P:17]([CH:22]([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])(=[O:21])[O:18][CH2:19][CH3:20])#[N:14].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:29]([CH:15]([C:13]#[N:14])[CH2:16][P:17]([CH:22]([O:23][CH2:24][CH3:25])[O:26][CH2:27][CH3:28])(=[O:21])[O:18][CH2:19][CH3:20])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(OCC)P(=O)(CCC#N)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(OCC)P(=O)(CC(C#N)Cc1ccccc1)OCC
Reaction time: 0.17 h

Procedure:
To a solution of 0.97 g of diisopropylamine in 40 ml of tetrahydrofuran at -78° C. under an atmosphere of nitrogen are added 6.0 ml of a 1.6M solution of n-butyllithium in hexane. This solution is then stirred for a period of 10 minutes at this temperature, after which time a solution of 2.0 g of ethyl 2-cyanoethyl(diethoxymethyl)phosphinate in 10 ml of tetrahydrofuran is added. This mixture is then stirred for a period of 1 hour at -78° C. after which time a solution of 1.4 g of benzyl bromide in 10 ml of tetrahydrofuran is introduced. This mixture is then allowed to warm to room temperature when 40 ml of a saturated ammonium chloride solution is added. The aqueous layer is then extracted with 2×25 ml of diethyl ether and the organic extracts are combined and dried over magnesium sulphate. The solvent is then evaporated under reduced pressure and the crude product chromatographed on silica gel using ethyl acetate as an eluent to give ethyl 2-benzyl-2-cyanoethyl(diethoxymethyl)phosphinate as a viscous oil, 31P=+40.7 and +40.5 ppm (CDCl3).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[CH:14][C:15]=2[Br:17])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC.O.[OH-].[Na+]>CO.CCOCC>[Br:17][C:15]1[CH:14]=[C:13]([O:18][CH3:19])[CH:12]=[C:11]2[C:16]=1[NH:8][CH2:9][CH2:10]2
Reactant: COc1cc(Br)c2c(c1)CCN2C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: COc1cc(Br)c2c(c1)CCN2
Temperature: 55 °C
Yield: 85 %

Procedure:
Part D: To 1-(tert-butoxycarbonyl)-7-bromo-5-methoxyindoline (1.16 g) in methanol (28 mL) was added HCl/ether (1.0 M, 14.1 mL, 4 eq.). The reaction was heated at 55° C. for 4 hours and then cooled to room temperature. Water (25 mL) was added and the pH was adjusted to 9 with NaOH (1 N, aq.). The mixture was extrated with ether, which was washed with brine, dried over MgSO4, and concentrated to give 7-bromo-5-methoxyindoline (685 mg).
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[SH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[OH-].[Na+]>C(Cl)Cl>[C:1](=[O:7])([S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)Cl
Reactant: Sc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCC(=O)Sc1ccccn1
Reaction time: 1 h
Yield: 88.3 %

Procedure:
Following a general procedure (Rao et al., J. Org. Chem. 2000, 65: 1084), to a solution of n-hexanoyl chloride (6.73 g, 50.0 mmol) in CH2Cl2 (200 mL) was added 2-mercaptopyridine (5.55 g, 50.0 mmol) in portions as a solid during 5 min. The resulting mixture was stirred for 1 h, then 2 N NaOH (50 mL) was added. The organic phase was isolated, washed (water), dried (Na2SO4) and concentrated to afford a yellow oil. The oil was distilled bulb-to-bulb (110-120° C./0.03 mmHg) to afford a pale yellow oil (9.24 g, 88%): 1H NMR δ 0.89 (m, 3H), 1.35 (m, 4H), 1.73 (m, 2H), 2.69 (m, 2H), 7.29 (m, 1H), 7.60-7.76 (m, 2H), 8.62 (m, 1H); 13C NMR δ 13.7, 22.1, 24.9, 30.9, 44.0, 123.3, 129.9, 136.9, 150.2, 151.5, 196.4. Anal. Calcd for C11H15NOS: C, 63.12; H, 7.22; N, 6.69. Found: C, 63.02; H, 7.24; N, 6.74.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Br:14]Br.S([O-])([O-])=O.[Na+].[Na+].O>C(O)(=O)C>[Br:14][C:9]1[C:10]([O:12][CH3:13])=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(OC)c(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
2,4-Dimethoxybenzoic acid (30.0 g) was suspended in acetic acid (180 mL). A bromine (27.6 g)/acetic acid (60 mL) solution was slowly added dropwise to the suspension and, after completion of the dropwise addition, the mixture was stirred at 25° C. for 2 hrs, and the termination of the reaction was confirmed by HPLC. An aqueous solution of sodium sulfite (2.10 g) and water (360 mL) was added dropwise to the reaction mixture. After completion of the dropwise addition, the mixture was stirred at 25° C. for 1 hr. Precipitated crystals were filtered, washed 4 times with water (150 mL), and vacuum dried to give 5-bromo-2,4-dimethoxybenzoic acid as white crystals (41.2 g) (96%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4](I)[C:3]=1[F:13].C(O)CCC.C(=O)([O-])[O-].[Cs+].[Cs+].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[F:25])[C:3]=1[F:13]
Reactant: Fc1c(I)nc2ccccc2c1Cl
Reactant: OB(O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: Fc1ccccc1-c1nc2ccccc2c(Cl)c1F
Temperature: 50 °C
Yield: 64.5 %

Procedure:
To a solution of 4-chloro-3-fluoro-2-iodo-quinoline (from step D, 0.3 g, 0.9 mmol) in toluene (5 mL) was added n-butanol (2 mL), water (3 mL) and cesium carbonate (1.14 g, 3.5 mmol). The resulting mixture was degassed for 5 min. and tetrakis(triphenyl-phosphine)palladium(0) (5 mg, 5 mol %) and 2-fluorophenyl boronic acid (0.286 g, 2 mmol) were added. The reaction mixture was heated to 50° C. for 24 h., after which it was extracted with ethyl acetate. The organic layer was dried and concentrated in a rotary evaporator. The residue was purified by silica gel column chromatography using ethyl acetate/hexane gradient to yield the title compound (0.160 g, 48%). MS (ES) 336.1 (M+H)+.
Reaction SMILES: [C:1](OCC)(OCC)([O:4][CH2:5][CH3:6])[CH2:2][CH3:3].[C:13](#[N:17])[CH2:14][C:15]#[N:16]>>[CH2:5]([O:4][C:1](=[C:14]([C:13]#[N:17])[C:15]#[N:16])[CH2:2][CH3:3])[CH3:6]
Reactant: CCOC(CC)(OCC)OCC
Reactant: N#CCC#N
Product: CCOC(CC)=C(C#N)C#N
Temperature: 25 °C
Yield: 93 %

Procedure:
Triethyl orthopropionate (1000 g, 5.5 mole) and malononitrile (363 g, 5.5 mole) were combined and refluxed for 5 hours. The reaction mixture was cooled to room temperature and the residue was distilled at 125°-143° C. (3-7 mm Hg) to afford 768.1 g (93%) of (1-ethoxypropylidene)malononitrile as an orange liquid.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:21])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=2)[CH:9]([CH3:22])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:24][OH:25]>N1C=CC=CC=1.C(O)C>[CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:21])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[N:24][OH:25])[CH:14]=2)[CH:9]([CH3:22])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NO
Reactant: CCCCCCN1CCC(C)(c2cccc(C=O)c2)C(C)C1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCCCN1CCC(C)(c2cccc(C=NO)c2)C(C)C1
Yield: 21.1 %

Procedure:
A solution of 1-hexyl-3,4-dimethyl-4-(3-formylphenyl)piperidine (Example 28, 80 mg, 0.27 mmol) in a mixture of pyridine (1 mL) and ethanol (1 mL) was treated with hydroxylamine hydrochloride (22 mg, 0.32 mmol) and the resulting mixture was heated at reflux for 18 hours. The solvent was evaporated in vacuo and the residual orange oil was purified by column chromatography on silica gel (10 g) eluted with a gradient of dichloromethane:methanol:0.880 ammonia (98:1:1 to 94:5:1). This gave the title compound as an oil (18 mg).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.Cl[CH2:13][CH2:14][CH2:15][CH:16]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C=O>[O:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]1[O:22][CH:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14][CH2:13][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCCC(CCCCl)OC1CCCCO1
Solvent: CN(C)C=O
Product: CCCCCC(CCCN1C(=O)c2ccccc2C1=O)OC1CCCCO1
Temperature: 95 °C
Yield: 45 %

Procedure:
Sodium hydride (53%) (1.5 g. excess) is washed with benzene three times by decantation, then dimethyl formamide (100 ml.) is added. To this stirred suspension is added a solution of phthalimide (4.3 g., 0.03 mole) in dimethyl formamide (50 ml.) at such a rate as to keep the temperature below 35°C. A clear solution is obtained and to it is added 1-chloro-4-(2-tetrahydropyranyloxy)-nonane (7.8 g., 0.03 mole) and the resulting clear solution is stirred and heated at 95°C. for 20 hours. The reaction is then concentrated to one half its volume in vacuo, poured into ice water (200 ml.) and extracted with ether (2 × 150 ml.). The ether is washed with 5% sodium hydroxide (2 × 50 ml.), saturated sodium chloride solution (2 × 50 ml.) then dried over sodium sulfate. Evaporation of the ether affords 4.5 g. (45% yield) of N-[4-(2-tetrahydropyranyloxy)nonyl]phthalimide melting 59°- 61°C. After recrystallization from cyclohexane, the product melts at 62°-63°C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([C:10]2([F:25])[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[C:26]([N:30]=[C:31]=[O:32])([CH3:29])([CH3:28])[CH3:27].C(N(C(C)C)CC)(C)C>>[C:26]([NH:30][C:31]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2([F:25])[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:15]2)[CH:5]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: Nc1cccc(C2(F)CCN(CCOc3ccccc3)CC2)c1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)Nc1cccc(C2(F)CCN(CCOc3ccccc3)CC2)c1
Yield: 24 %

Procedure:
The title compound was prepared from the reaction of 4-(3-aminophenyl)-1-(2-phenoxyethyl) 4-fluoropiperidine dihydrochloride with tert-butylisocyanate in the presence of excess diisopropylethylamine as described in Example 19, with the exception that hydrochloride salt formation was not carried out. The desired material was obtained in 24% yield as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(N(CC)C(C)C)(C)C.[C:53](OC(=O)C)(=[O:55])[CH3:54].[OH-].[Na+]>O1CCCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:53]([N:40]1[CH2:41][CH2:42][N:37]([C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])[CH2:38][CH2:39]1)(=[O:55])[CH3:54]
Reactant: Clc1cnc2nc1Nc1ccc(N3CCNCC3)c(c1)CCc1cccc(c1)N2
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCN(c2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Temperature: 20 °C
Reaction time: 16 h
Yield: 46.2 %

Procedure:
A solution of 6-chloro-12-piperazin-1-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) (20 mg, 32 μmol) and N,N-diisopropylethylamine (27 μL, 0.16 mmol) in tetrahydrofuran (0.5 mL) was treated with acetic anhydride (15 μL, 0.16 mmol) and stirred at 20° C. for 16 h. The reaction mixture was treated with 2 M sodium hydroxide (0.16 mL, 0.32 mmol) and stirred at 20° C. for 16 h to remove the undesired acetamide. The reaction mixture was purified by preparative LCMS to give the desired product (10 mg, 47%) as a solid. LCMS for C24H26ClN6O (M+H)+: m/z=449.0.
Reaction SMILES: [CH2:1]([C:3]1([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=2)[C:4]1=[O:22])[CH3:2].Br[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][N:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][N:31]=3)[CH:9]=2)[C:4]1=[O:22])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CCOC(=O)CC1(CC)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC1(CC)CCc2cc(-c3ccc([N+](=O)[O-])cn3)ccc2C1=O
Temperature: 100 °C
Reaction time: 48 h
Yield: 66.3 %

Procedure:
Pd(PPh3)4 (0.479 g, 0.414 mmol) was added to a solution of 4E (3.2 g, 8.28 mmol), 2-bromo-5-nitropyridine (1.84 g, 9.11 mmol) and cesium carbonate (8.1 g, 24.85 mmol) in a mixture of ethanol (4 mL), water (4 mL) and toluene (80 mL) under argon atmosphere. The resulting mixture was degassed for further 10 min and stirred at 100° C. for 48 h. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The separated organic layer was treated with saturated NaCl solution, dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was triturated in ethanol to afford the title compound (2.1 g, 66%) as a solid. 1H NMR (300 MHz, CDCl3): δ 9.52 (d, J=2.7 Hz, 1H), 8.56 (dd, J1=2.1 Hz, J2=8.4 Hz, 1H), 8.21 (d, J=8.4 Hz, 1H), 7.97 (m, 3H), 4.11 (q, J=7.5 Hz, 2H), 3.23-3.12 (m, 1H), 3.06-2.93 (m, 2H), 2.56-2.46 (m, 2H), 2.14-2.07 (m, 1H), 1.85-1.61 (m, 2H), 1.22 (t, J=6.9 Hz, 3H), 0.94 (t, J=7.8 Hz, 3H). ESI-MS m/z=383 (M+H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:10]=1.C(N(CC)CC)C>C(O)C>[Cl:8][C:9]1[N:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:12]=[C:13]([NH:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:14]=1
Reactant: Clc1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Reactant: CC(=O)NCCN
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)NCCNc1cc(Cl)nc(-c2ccc(Cl)cc2)n1
Temperature: 85 °C
Reaction time: 48 h
Yield: 41.2 %

Procedure:
N-Acetylethylenediamine (1.02 g) was dissolved in ethanol (250 ml) and 4,6-dichloro-2-(4-chlorophenyl)pyrimidine (2.5 g) then triethylamine (1.35 ml) added. The mixture was heated to 85° C. with stirring for 48 hrs. The solvent was then removed in vacuo and purified by column chromatography on silica gel eluting first with ethyl acetate then a mixture of ethyl acetate and methanol (9:1 v/v) to furnish the title compound (1.29 g).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH:37]=O)=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.[CH3:51][O:52][NH2:53]>C(O)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH:37]=[N:53][O:52][CH3:51])=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CO[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCC=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: CON=CCOc1ccc(Cc2cc([C@@H]3O[C@H](OC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Yield: 66.4 %

Procedure:
To a solution of (2S,3S,4R,5S,6S)-2-(4-chloro-3-(4-(2-oxoethoxy)benzyl)phenyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (200 mg, 0.365 mmol), in ethanol (10 mL) under nitrogen atmosphere, were added pyridine (0.147 mL, 1.82 mmol), sodium acetate (299 mg, 3.65 mmol) and O-methylhydroxylamine hydrochloride (152 mg, 1.82 mmol). The reaction mixture was refluxed for 5 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was extracted with ethyl acetate (3×25 mL). The organic layer was separated, washed with water (3×10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1.5:8.5 Acetone:Pet. Ether) to afford the title compound (140 mg, 64.5%).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15].[CH2:17](O)[CH3:18]>>[CH2:17]([O:15][C:5]1[CH:6]=[CH:7][C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])=[CH:9][C:4]=1[C:3]([OH:2])=[O:16])[CH3:18]
Reactant: CCO
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Product: CCOc1ccc(S(=O)(=O)NC)cc1C(=O)O

Procedure:
Prepared in analogy to Example B13(d-e) from 2-Hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and ethanol. MS (m/e): 257.9 ([M−H]−, 100%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[F:22][C:23]1[CH:44]=[CH:43][C:26]([CH2:27][CH2:28][N:29]2[CH:33]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:31]=[N:30]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:32]3[CH:31]=[N:30][N:29]([CH2:28][CH2:27][C:26]4[CH:43]=[CH:44][C:23]([F:22])=[CH:24][CH:25]=4)[CH:33]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(CCc3ccc(F)cc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccc(F)cc4)c3)c3cc(Br)cnc32)cc1
Yield: 30.97 %

Procedure:
Using similar reaction conditions as described in step-i of example-1,5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 1) (200 mg, 0.41 mmol) was coupled with 1-(4-fluorophenethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Intermediate 64C) (172 mg, 0.54 mmol) using sodium carbonate (130 mg, 1.23 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.020 mmol) in toluene/ethanol/water (20/10/5 ml) to afford 70 mg (30.97% yield) of the pure product after column purification using 30% ethyl acetate in hexane as eluent. MS: m/z=540.9 (M+1).