Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:18][OH:19])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28](=[O:38])[C:29]1[CH:34]=[C:33]([CH3:35])[C:32](O)=[C:31]([CH3:37])[CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:26][O:27][C:28](=[O:38])[C:29]1[CH:30]=[C:31]([CH3:37])[C:32]([O:19][CH2:18][CH:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:33]([CH3:35])[CH:34]=1
Reactant: COC(=O)c1cc(C)c(O)c(C)c1
Reactant: OCC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(OCC(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(C)c1
Temperature: 0 °C
Reaction time: 14 h
Yield: 27 %

Procedure:
To a solution of 2-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-2-cyclohexyl-ethanol (20 mg, 56 umol) in THF (1 ml) was added 4-hydroxy-3,5-dimethyl-benzoic acid methyl ester (11 mg, 62 umol; CAS Reg. No. 34137-14-9) and tri-phenylphosphine (18 mg, 68 umol) at ambient temperature under an argon atmosphere. The mixture was cooled to 0° C., di-tert-butyl azodicarboxylate (16 mg, 68 umol) was added and the suspension was stirred for 14 h at ambient temperature. The solvent was removed under reduced pressure to give a solid which was purified by column chromatography (silica gel, iPrOAc/heptane) to obtain the title compound (8 mg, 15 umol; 27%) as colorless oil. MS: m/e=517.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11](N)[CH:10]=[N:9]1.N([O-])=O.[Na+].[ClH:23]>[Cu]Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([Cl:23])[CH:10]=[N:9]1
Reactant: CC(C(=O)O)c1ccc(-n2cc(N)cn2)c(Cl)c1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: CC(C(=O)O)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Temperature: -3 °C
Reaction time: 1 h

Procedure:
2.65 g (10 mmoles) of 2-[3-chloro-4-(4-aminopyrazol-1-yl)phenyl]propionic acid are dissolved in 10 ml of 25% strength hydrochloric acid, the solution is cooled to -3° C., and 1.04 g (15 mmoles) of sodium nitrite (dissolved in 5 ml of water) are added. After 10 minutes the reaction mixture is stirred into a solution of 2 g (20 mmoles) of copper(I) chloride. Heating to 100° C. ist then effected for 1 hour, followed by cooling, extraction with chloroform and purification through chromatography on silica gel (benzene/cyclohexane/glacial acetic acid 2:1:1). 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid, m.p. 102°-103° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13].[Br:17]Br>C(O)(C)C>[Br:17][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:11](=[O:16])(=[O:15])[N:12]([CH3:13])[CH3:14])[CH:4]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Cl)c(S(=O)(=O)N(C)C)c1
Solvent: CC(C)O
Product: CN(C)S(=O)(=O)c1cc(C(=O)CBr)ccc1Cl

Procedure:
7.9 g of 4'-chloro-3'-dimethylsulfamoylacetophenone were reacted according to Example 1a) with 4.8 g of bromine and worked up. Colorless crystals from isopropanol, melting point: 98° C.
Reaction SMILES: C1C[O:4]CC1.C(O[C:14]1[CH:15]=[C:16]2[N:26]([C:27]([C:29]3[NH:30][C:31]4[C:36]([CH:37]=3)=[CH:35][C:34]([O:38][CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])=[CH:33][CH:32]=4)=[O:28])[CH2:25][CH:24]([CH2:44][Cl:45])[C:17]2=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)C1C=CC=CC=1>O.[Pd]>[Cl:45][CH2:44][CH:24]1[C:17]2=[C:18]3[C:23](=[CH:14][CH:15]=[C:16]2[N:26]([C:27]([C:29]2[N:30]=[C:31]4[C:36]([CH:37]=2)=[CH:35][C:34]([O:38][CH2:39][CH2:40][N:41]([CH3:42])[CH3:43])([OH:4])[CH:33]=[CH:32]4)=[O:28])[CH2:25]1)[N:22]=[CH:21][CH:20]=[CH:19]3
Reactant: CN(C)CCOc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc(OCc3ccccc3)c3ncccc43)cc2c1
Reactant: C1CCOC1
Agent: [Pd]
Solvent: O
Product: CN(C)CCOC1(O)C=CC2=NC(C(=O)N3CC(CCl)c4c3ccc3ncccc43)=CC2=C1
Temperature: 0 °C
Reaction time: 14 h
Yield: 93 %

Procedure:
THF (8 mL) then HCO2N4 (0.23 g, 3.6 mmol) in H2O (1 mL) were added to cooled (0° C.) mixture of 17b (0.20 g 036 mmol) and 10% Pd/C (0.1 g) under N2. The mixture was stirred at 0° C. for 14 h, and was then filtered through Celite. The Celite was washed with CH2Cl2/H2O. The aqueous layer was extracted with CH2Cl2(×3). The CH2Cl2 extracts were dried (brine, Na2SO4) and passed through a short plug of silica gel to give 18b (0.16 g, 93%) as a yellow solid: mp 209–215° C.; 1H NMR [(CD3)2SO]δ 11.66 (s, 1 H), 10.02 (bs, 1 H), 8.76 (dd, J=4.1, 1.4, 1 H), 8.41 (dd, J=8.5, 1.3, 1 H), 8.07 (s, 1 H), 7.56 (dd, J=8.5, 4.1, 1 H), 7.40 (d, J=8.9, 1 H), 7.17 (d, J=2.2, 1 H), 7.11 (d, J=1.2, 1 H,) 6.93 (dd, J=8.9, 2.3, 1 H), 4.82 (dd, J=10.7, 9.6, 1 H), 4.57 (dd, J=11.0, 2.1, 1 H), 4.29 (m, 1 H), 4.06 (t, J=5.9, 2 H), 4.04 (m, 1 H), 3.91 (dd, J=11.1, 7.2, 1 H), 2.64 (t, J=5.8, 2 H), 2.28 (s, 6 H); 13C NMR [(CD3)2SO]δ 160.3, 153.9, 153.0, 146.4, 142.8, 136.1, 131.6, 130.7, 127.4, 124.8, 124.7, 122.5, 116.0, 114.6, 113.1, 105.5, 103.1, 103.0, 66.1, 57.8, 54.9, 47.7, 45.5, 40.7.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.O[N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN(C=O)C>[C:23]1(=[O:24])[N:19]([O:7][CH2:6][C@H:5]2[O:8][C@@H:1]([N:9]3[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]3=[O:11])[CH2:2][C@@H:3]2[OH:4])[C:20](=[O:29])[C:21]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]12
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CON3C(=O)c4ccccc4C3=O)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of thymidine (24.22 g, 0.1 mol), N-hydroxyphthalimide (21.75 g, 0.13 mol), triphenylphosphine (34 g, 0.13 mol) in dry DMF (400 ml) was added diisopropylazodicarboxylate (30 ml, 0.15 mol) over a period of 3 h at 0° C. After complete addition the reaction mixture was warmed up to room temperature and stirred for 12 h. The solution was concentrated under vacuum (0.1 mm, <40° C.) to furnish an orange-red residue. The residual gum was washed several times with Et2O and washing were discarded. The semi-solid residue was suspended in EtOH (500 ml) and heated (90° C.) to dissolve the product. On cooling 30.98 g (80%) of 5'-O-phthalimidothymidine was collected in 3-crops as white crystalline material, mp 233-235° C. (decomp.); 1H NMR (DMSO-d6) δ 11.29 (s, 1, NH), 7.85 (m, 4, ArH), 7.58 (s, 1, C6H), 6.20 (t, 1, H1', J1',2' =7.8 Hz, J1',2" =6.5 Hz), 5.48 (d, 1, OH3'), 4.36 (m, 3, H4',5',5"), 4.08 (m, 1, H3'), 2.09-2.13 (m, 2, H2',2"), and 1.79 (s, 3, CH3). Anal. Calcd. for C18H17O7N3 0.7 H2O: C, 54.05; H, 4.64; N, 10.51. Found: C, 53.81; H, 4.25; N, 10.39.
Reaction SMILES: [F:1][C:2]([F:18])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([O:16][CH3:17])=[CH:9]2)[C:3]([OH:5])=O.[Cl:19][C:20]1[CH:21]=[C:22]([F:28])[C:23]([NH:26][NH2:27])=[N:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([F:28])[C:23]([NH:26][NH:27][C:3](=[O:5])[C:2]([F:1])([F:18])[C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[N:12]=[CH:11][C:10]([O:16][CH3:17])=[CH:9]3)=[N:24][CH:25]=1
Reactant: COc1cnc2ccc(C(F)(F)C(=O)O)cc2c1
Reactant: NNc1ncc(Cl)cc1F
Product: COc1cnc2ccc(C(F)(F)C(=O)NNc3ncc(Cl)cc3F)cc2c1

Procedure:
This compound was assembled from 2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetic acid and 1-(5-chloro-3-fluoropyridin-2-yl)hydrazine according to General Method I. LRMS (ESI) ml: calcd for C17H13ClF3N4O2S (M+H) 397.1. found 397.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:11])=[N:8][C:9]=1[CH3:10].[Cl:12][C:13]1[C:14]([CH3:23])=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[C:14]([CH3:23])=[C:15]([S:19]([NH:11][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][O:2][CH3:1])=[C:9]([CH3:10])[N:8]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: COCc1ccc(N)nc1C
Product: COCc1ccc(NS(=O)(=O)c2cccc(Cl)c2C)nc1C

Procedure:
This material was prepared in analogy to example 1 from 5-methoxymethyl-6-methyl-pyridin-2-ylamine (0.058 g) and 3-chloro-2-methyl-benzenesulfonyl chloride (0.094 g) as an off-white foam (0.093 g). MS (ESI−): 339.0 ([M−H]−)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:6]([OH:8])=[O:7].S(Cl)(Cl)=O.[CH2:19](O)[CH3:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:6]([O:8][CH2:19][CH3:20])=[O:7]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(OC)cc([N+](=O)[O-])c1
Yield: 85.6 %

Procedure:
The compound (5.33 g, 27.0 mmol) prepared in step 1 was dissolved in absolute ethanol (55.0 ml), added dropwise with thionyl chloride (2.96 ml, 40.55 mmol) at 0° C. The resulting mixture was refluxed for 6 hours. After completion, the reaction mixture was concentrated under reduced pressure and mixed with sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethan, dried over anhydrous magnesium sulfate, and concentrated to dryness. The residue was then purified by flash column chromatography (dichloromethane:hexane=4:1) to obtain the title compound (5.1 g, yield: 85.6%, ivory solid).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[CH:22]=[CH:23][C:24](O)=O>>[CH3:31][O:30][C:28]1[CH:27]=[C:21]([CH:20]=[C:19]([O:18][CH3:17])[CH:29]=1)/[CH:22]=[CH:23]/[C:24]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cc(OC)cc(OC)c3)nc2n(CCC)c1=O
Yield: 54.2 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.95 g (17.5 mmol) of 5,6-diamino-1,3-dipropyluracil and 4.0 g (19.2 mmol) of 3,5-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide/water to give 3.78 g (yield 54%) of Compound 32 as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Br.[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:12]([CH2:13][CH3:14])[CH2:10][CH3:11]
Reactant: BrCc1ccccc1Br
Reactant: CCNCC
Solvent: Cc1ccccc1
Product: CCN(CC)Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To 1-Bromo-2-bromomethyl-benzene (2.17 g, 0.008 mmol) in toluene (15 mL) was added diethylamine (3.05 mL) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered and concentrated to give Example 229A as an oil.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1>>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([C:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:25]
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)c1

Procedure:
Acylation of 10.5 g. (0.054 mol.) of 2-phenylbenzofuran with 9.9 g. (0.058 mol.) of m-anisoyl chloride according to the procedure described in Example 1 gives 3-(3-methoxybenzoyl)-2-phenylbenzofuran.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C:18]3[C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:22][N:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[C:17]=3[C:16]2=[O:37])=[CH:11][CH:10]=1)=O.Cl.CN.C1COCC1.[C:46]([BH3-])#[N:47].[Na+]>CO.CCOC(C)=O.[Cl-].[Zn+2].[Cl-]>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([N:23]2[C:17]3[C:16](=[O:37])[N:15]([C:12]4[CH:13]=[CH:14][C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[CH2:1][NH:47][CH3:46])=[CH:10][CH:11]=4)[CH2:20][CH2:19][C:18]=3[C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:22]2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(-c3ccccc3C=O)cc1)C2=O
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(-c3ccccc3CNC)cc1)C2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.1 %

Procedure:
Ethyl 6-(2′-formyl-1,1′-biphenyl-4-yl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (485 mg, 0.98 mmol) and methylamine hydrochloride (135 mg, 2 mmol) were added together in 10 mL of 1:1 MeOH:THF and stirred at room temperature for 15 minutes. Zinc chloride (0.5 M in THF, 1 mL, 0.5 mmol) and Sodium cyanoborohydride (63 mg, 1 mmol) were then added and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with EtOAc and washed with H2O, brine, dried over MgSO4, and concentrated to afford 511 mg of desired product (100%). MS (ES+): 511.4, (M+H)+. 1HNMR (CDCl3) δ 7.50-7.41 (m, 3H), 7.39-7.22 (m, 7H), 6.92 (d, 2H), 4.47 (q, 2H), 4.20 (t, 2H), 3.86 (s, 2H), 3.80 (s, 3H) 3.37 (t, 2H), 1.44 (t, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:6]([N+:10]([O-:12])=[O:11])=[CH:7][C:8]=1[F:9])[NH2:5].[Br:13]Br>C(O)(=O)C>[Br:13][C:3]1[C:2]([Cl:1])=[C:8]([F:9])[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:4]=1[NH2:5]
Reactant: Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1c([N+](=O)[O-])cc(F)c(Cl)c1Br
Temperature: 0 °C

Procedure:
Into a solution of 3-chloro-4-fluoro-6-nitroaniline (200.3 g) in acetic acid (1.5 litter) was added bromine (339 g) during a period of 80 minutes at 50° C. under stirring and stirred for further 2 hours. The reaction mixture was poured into ice water (3 litter) and the resulting precipitate was collected by filtration, washed with water and added to a mixture of concentrated hydrochloric acid (300 ml) and ethanol (1.2 litter). The mixture was refluxed for 8.5 hrs. After cooling, the precipitate was collected by filtration and washed with water and dried. The title compound thus obtained weighed 235.6 g as yellow needles, mp 146°-147° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@:17]([CH3:21])([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:22][CH3:23])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C@@H:25]([CH:42]([CH3:44])[CH3:43])[CH2:26][N:27]1[CH2:32][CH2:31][C@:30]([C:34]2[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=2)([CH3:33])[C@@H:29]([CH3:41])[CH2:28]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C1COCC1>[OH:40][C:36]1[CH:35]=[C:34]([C@:30]2([CH3:33])[CH2:31][CH2:32][N:27]([CH2:26][C@@H:25]([NH:24][C:18]([C@@:17]3([CH3:21])[CH2:16][C:15]4[C:10](=[CH:11][C:12]([O:22][CH3:23])=[CH:13][CH:14]=4)[CH2:9][N:8]3[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[O:20])[CH:42]([CH3:43])[CH3:44])[CH2:28][C@@H:29]2[CH3:41])[CH:39]=[CH:38][CH:37]=1
Reactant: COc1ccc2c(c1)CN(C(=O)OC(C)(C)C)[C@@](C)(C(=O)O)C2
Reactant: CC(C)[C@H](N)CN1CC[C@@](C)(c2cccc(O)c2)[C@@H](C)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CN(C(=O)OC(C)(C)C)[C@@](C)(C(=O)N[C@H](CN1CC[C@@](C)(c3cccc(O)c3)[C@@H](C)C1)C(C)C)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
Compound 2.8 (200 mg, 0.623 mmol), 3-{(3R,4R)-1-[(2S)-2-amino-3-methylbutyl]-3,4-dimethylpiperidin-4-yl}phenol (J) (181 mg, 0.623 mmol) and BOP reagent (275 mg, 0.623 mmol) were dissolved in THF (20 mL). Triethylamine (1 mL) was added and the solution was stirred at room temperature for 3 h. The solution was extracted with CH2Cl2 and saturated NaHCO3 solution. The organic layer was dried and purified by column chromatography to afford 250 mg, (68%) of 2.9.
Reaction SMILES: O=C(C(=O)C)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>C(#N)C>[CH3:18][C:13]1[NH:14][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:12]=1
Reactant: NCc1ccccn1
Reactant: CCOC(=O)C(=O)C(C)=O
Solvent: CC#N
Product: CCOC(=O)N1C=C(C)NC1c1ccccn1
Reaction time: 8 h
Yield: 106.5 %

Procedure:
A mixture of 23.8 g of 2,3-dioxobutyric acid, ethyl ester, (Z)-2-oxime, 18 g of 2-aminomethyl pyridine and 250 ml of acetonitrile was refluxed for 7 hours and then stored at -10° C. overnight. The solid was collected, giving 20.68 g of 5-methyl-2-(2-pyridinyl)-1H-imidazole-3-carboxylic acid, ethyl ester.
Reaction SMILES: [Sn].[Cl:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][C:4]=1[N+:14]([O-])=O.[C:17](OC(=O)C)(=[O:19])[CH3:18].C(NC1C=CC=CC=1)(=O)C>Cl.C(O)(=O)C.O>[C:17]([NH:14][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=1[Cl:2])[CH:7]=[CH:8][C:9]([OH:11])=[O:10])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: CC(=O)Nc1ccccc1
Agent: Cl
Agent: [Sn]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cc(C=CC(=O)O)ccc1Cl
Temperature: 45 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Tin II chloride dihydrate (103 g, 0.46 mol) was dissolved in concentrated HCl (120 mL). Warming was necessary to obtain a clear solution. 4-Chloro-3-nitrocinnamic acid (25 g, 0.11 mol) was added portionwise with stirring. After about 20% of the starting material had been added, the mixture was warmed with a heat gun to 45° C. to initiate reaction. The rate of addition was controlled to maintain a temperature of 65-75° C. Cooling with a water bath was used to prevent the temperature exceeding 80° C. After the addition was complete and reaction started to subside, the mixture was transferred to an oil bath at 65° C. for 1 h. The mixture was cooled to room temperature. The solid was filtered, washed with 2 M HCl, (60 mL) and sucked dry. The filter cake was dried in a vacuum oven for 1 h, then in air overnight, to give about 34 g crude product. This material was suspended in acetic acid (100 mL) with stirring and acetic anhydride (100 mL, 1.1 mol) was added in one portion. The temperature rose to 35° C. After the initial exotherm subsided, the mixture was stirred in an oil bath at 110° C. for 2 h, but did not dissolve. LCMS showed complete conversion to the desired acetanilide. The solution was cooled and water (50 mL) was added cautiously. The mixture was concentrated to about 200 mL. More water (100 mL) and 2 M HCl (50 mL) were added. The precipitate was filtered, washed with water and dried to give 3-acetamido-4-chlorocinnamic acid (25.0 g, 95%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C@@H:64]1[C:67](=[O:68])[NH:66][C@@H:65]1[CH2:69][N:70]1[C:74]([CH2:75][NH:76][C:77](=[O:83])[O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[N:73][CH:72]=[N:71]1>C(Cl)Cl.CN(C=O)C>[C:79]([O:78][C:77]([NH:76][CH2:75][C:74]1[N:70]([CH2:69][C@@H:65]2[C@H:64]([NH:63][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:9])([CH3:8])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:29])/[C:16]3[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=3)[C:67](=[O:68])[NH:66]2)[N:71]=[CH:72][N:73]=1)=[O:83])([CH3:80])([CH3:82])[CH3:81]
Reactant: CC(C)(C)OC(=O)NCc1ncnn1C[C@H]1NC(=O)[C@H]1N
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1ncnn1C[C@H]1NC(=O)[C@H]1NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(=O)OC(C)(C)C)n1
Reaction time: 1 h
Yield: 58.1 %

Procedure:
To a slurry of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (160 mg, 0.373 mmol) in DCM:DMF (30:1, 3.1 mL) at 0° C. was added DIPEA (163 μL, 0.933 mmol) followed by HATU (142 mg, 0.373 mmol). To the resulting solution was added a solution of tert-butyl ((1-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-1H-1,2,4-triazol-5-yl)methyl)carbamate (92 mg, 0.311 mmol) in DCM:DMF (30:1, 3.1 mL). After 1 h of stirring it was concentrated in vacuo and taken up in EtOAc/brine. The layers separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine (3×), dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM, 70%) to afford the title compound (128 mg, 58%). LCMS: Rt=0.97 min, m/z=708.2 (M+1) Method 2m_acidic.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[CH:7]=1.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:44])=[C:22]([S:24]([N:27]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH3:43])[C:28]2[S:32][N:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])[CH:23]=1.[Cl-].[Na+]>>[Cl:17][C:18]1[C:19]([O:16][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=2[C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:20][C:21]([F:44])=[C:22]([S:24]([N:27]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH3:43])[C:28]2[S:32][N:31]=[CH:30][N:29]=2)(=[O:25])=[O:26])[CH:23]=1
Reactant: N#Cc1cc(-c2cc(Cl)ccc2O)ccn1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: [Cl-]
Agent: [Na+]
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(Cl)cc3-c3ccnc(C#N)c3)cc2F)c(OC)c1
Yield: 100 %

Procedure:
Prepared according to Preparation 255 using 4-(5-chloro-2-hydroxyphenyl)pyridine-2-carbonitrile (Preparation 339, 0.23 g, 0.001 mol) and 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 333, 461 mg, 0.998 mmol). Saturated aqueous sodium chloride solution (20.0 mL) was added to the reaction resulting in the formation of a white precipitate. This was filtered and washed with water (20.0 mL) and heptane (20.0 mL) before being dried in vacuo for 2 hours to afford the title compound as a white solid, 0.67 g, 100% yield.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:27]3[CH:28]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]=3[Cl:29])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Reactant: OB(O)c1cc(Cl)ccc1Cl
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Clc1ccc(Cl)c(-c2ccc(CN3CCNC(Cc4ccccc4)C3)cc2)c1
Temperature: 85 °C
Yield: 59 %

Procedure:
0.1 g of 3-(S)-benzyl-1-(4-bromo-benzyl)-piperazine were combined with 1.5 equiv. of 2,5-dichlorophenyl boronic acid, 0.05 equiv. of tetrakis(triphenylphosphine)palladium(0), 6 equiv. of 2M aqueous sodium carbonate solution, toluene and ethanol. The reaction mixture was heated at 85° C. under nitrogen overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography to afford 0.07 g of the title compound. Yield 59% ES MS (+) m/z 411.