Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](/[CH:13]=[CH:14]/[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:9](OC)[C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1.[NH2:26][NH2:27]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[C:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:27][NH:26][C:9]=3[C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1
Reactant: NN
Reactant: COc1c(/C=C/C(=O)OC(C)(C)C)c(=O)c2ccc(Cl)cc2[nH]c1=O
Solvent: CO
Product: CC(C)(C)OC(=O)Cc1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 25.1 %

Procedure:
To a slurry of t-butyl(E)-3-(8-chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepin-4-yl)acrylate (prepared as described in Example 44 of WO94/29275 published Dec. 22, 1994) (0.81 g, 2.2 mmol) in methanol (5 mL) was added anhydrous hydrazine (0.14 g, 4.5 mmol) dropwise via syringe. The resulting bright yellow mixture immediately darkened to an orange color. After 45 minutes of stirring at room temperature, the reaction mixture became a thick yellow-orange slurry which was allowed to stir for an additional 18 hours. The reaction mixture was filtered to give a solid which was recrystallized from ethanol. Very little product was recovered and the filtrate was concentrated and purified with a silica gel plug using ethyl acetate:hexanes (50:50) as the eluent to give an orange oil. This was allowed to crystallize in ethanol at −10° C. for 18 hours, filtered and dried at 100° C. to give the title compound (0.2 g, 25%, m.p. 226.5-228.6° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([CH3:18])[C@H:13]2[CH2:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)=[O:11])[CH:3]=1.[Si]([N:35]=[N+:36]=[N-:37])(C)(C)C>C1(C)C=CC=CC=1>[CH3:18][C@@H:14]1[CH2:15][CH2:16][CH2:17][N:12]([C:10]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:9]=[CH:8][C:5]=2[C:6]2[N:35]=[N:36][NH:37][N:7]=2)=[O:11])[C@@H:13]1[CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][N:22]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1ccc(C#N)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nn[nH]n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Temperature: 110 °C

Procedure:
A mixture of 4-methyl-2-((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidine-1-carbonyl)benzonitrile (obtained from Example A22, 0.098 g, 0.235 mmol), TMSN3 (0.06 mL, 0.47 mmol) and SnO(n-Bu)2 (0.006 g, 0.024 mmol) in toluene (2 mL) was heated at 110° C. overnight. The mixture was cooled to rt and filtered through a pad of diatomaceous earth, washing with methanol. The solvent was removed in vacuo and the resulting crude residue was purified by reverse-phase preparative HPLC to obtain the title compound. ESI-MS (m/z): 460 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](N(OC)C)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][Mg]Br>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:12])[CH3:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)CCc1ccc(Cl)c(Cl)c1
Solvent: CCOCC
Product: CC(=O)CCc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C. to a solution of 3-(3,4-dichlorophenyl)-N-methoxy-N-methylpropanamide (569 mg, 2.17 mmol) in ether (10 mL) was added drop wise methyl magnesium bromide (2.17 mL, 6.51 mmol) and the solution was stirred at 0° C. for 1 h. The reaction mixture was allowed to warm up to rt and stirred for 18 h.
Reaction SMILES: [C:1]12([PH:11][C:12]34[CH2:21][CH:16]5[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]5)[CH2:13]3)[CH2:19]4)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Li]CCCC.Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(OCCCC)CCC.C1(C)C=CC=CC=1>[C:1]12([P:11]([C:12]34[CH2:19][CH:18]5[CH2:20][CH:14]([CH2:15][CH:16]([CH2:17]5)[CH2:21]3)[CH2:13]4)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CCCCCCBr
Reactant: C1C2CC3CC1CC(PC14CC5CC(CC(C5)C1)C4)(C2)C3
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCOCCCC
Product: CCCCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2

Procedure:
5.5 g (18 mmol) of di(1-adamantyl)phosphine were placed in 60 ml of di-n-butyl ether, and 20 ml of a 2.5 M solution of n-BuLi (50 mmol) in toluene were added. The mixture was refluxed for 45 min and cooled and 3.0 g (18 mmol) of 1-bromohexane were added dropwise. The mixture was refluxed for 30 min, cooled and washed with saturated ammonium chloride solution (3×), the organic phase was separated off and dried over sodium sulfate and the solvent was distilled off under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CI.[C:18](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: CS(=O)(=O)c1cc(C(=O)O)c(Br)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1Br

Procedure:
5.8 g of 2-bromo-4-fluoro-5-methylsulphonylbenzoic acid are stirred, at room temperature for 12 h, in 20 ml of DMF together with 3.7 ml of methyl iodide and 8.3 g of potassium carbonate. The reaction mixture is then concentrated and 50 ml of water are added to it. The resulting precipitate is filtered off with suction and dried. Methyl 2-bromo-4-fluoro-5-methylsulphonylbenzoate is obtained, m.p. 126°.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=O)[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].[CH3:19][S:20]([CH2:23][C:24](=O)[CH3:25])(=[O:22])=[O:21]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:14])[N:15]([CH3:17])[N:16]=[C:24]([CH3:25])[C:23]=1[S:20]([CH3:19])(=[O:22])=[O:21])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Reactant: CC(=O)CS(C)(=O)=O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Temperature: 5 °C
Reaction time: 20 h
Yield: 90.3 %

Procedure:
To a 25 mL volume three-necked flask with Dean-Stark, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (1.01 g), 1-methylsulfonyl-2-propanone (7-2-1) (613 mg), and toluene (2.9 ml) were added under a nitrogen atmosphere. Water was removed by azeotropic distillation at 60° C. under 100 mmHg for 4 hours. The mixture was concentrated under reduced pressure. To the residue, toluene (1.73 g) and methanol (1.90 ml) were added, then lithium hydroxide monohydrate (80 mg) was added at 0° C. After the mixture was stirred at 0° C. for 4 hours and at 5° C. for 20 hours, 20 w/w % of sulfuric acid was added to adjust pH to less than 1. To the mixture was added toluene and water, and then the organic layer was removed. The aqueous layer was extracted with toluene 2 times. The organic layers were combined, and concentrated under reduced pressure to give 1.28 g of 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-34)-(1)-39).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[CH:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH:11]([N:14]1[CH2:19][CH2:18][N:17]([C:8]([C@H:5]2[CH2:4][CH2:3][C@@H:2]([OH:1])[CH2:7][CH2:6]2)=[O:10])[CH2:16][CH2:15]1)([CH3:13])[CH3:12]
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@@H](O)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 428 mg (3.0 mmol) of cis-4-hydroxycyclohexanecarboxylic acid (commercially available), 318 mg (1.5 mmol) of 1-(isopropyl)-piperazine (commercially available), 1.14 g (3.6 mmol) of TBTU and 900 mg (9 mmol) of triethylamine in 3 ml DMF was stirred for 12 h at room temperature. The mixture was purified by column chromatography on silica eluting with CH2Cl2 and methanol=9:1. Evaporation of the combined product fractions yielded 460 mg (61%) of the title compound as light brown oil. MS (m/e): 255.2 (MH+).
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[NH2:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][C:26](=[O:28])[NH2:27].[Cl:32][C:33]1[CH:34]=[C:35]([CH:49]=[CH:50][C:51]=1[Cl:52])[CH2:36][N:37]([CH3:48])[C:38]([C:40]1[CH2:41]N(C)[C:43](=[O:46])[C:44]=1[OH:45])=[O:39]>>[Cl:32][C:33]1[CH:34]=[C:35]([CH:49]=[CH:50][C:51]=1[Cl:52])[CH2:36][N:37]([CH3:48])[C:38]([C:40]1[CH2:41][N:23]([CH:24]([CH2:25][C:26]([NH2:27])=[O:28])[C:29]([OH:31])=[O:30])[C:43](=[O:46])[C:44]=1[OH:45])=[O:39]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: NC(=O)C[C@H](N)C(=O)O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(C(CC(N)=O)C(=O)O)C1
Yield: 6 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and asparagine as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (12 mg, 6% yield). 1H NMR (300 MHz, DMSO) δ: 13.1 (bs, 1H), 11.05 (bs, 1H), 7.62 (d, 1H, J=8.42), 7.53 (s, 1H), 7.51 (s, 1H), 7.25 (bs, 1H), 6.97 (s, 1H), 4.90 (m, 1H), 4.58 (s, 2H), 4.07 (s, 2H), 2.96 (s, 3H), 2.73 (m, 2H). HRMS (M−H) calcd for C17H16N3Cl2O6: 428.0416. found: 428.0415.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][C:14]#[N:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][C:24]([O:27][CH2:28][CH2:29]Cl)([CH3:26])[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]3([C:14]#[N:15])[CH2:29][CH2:28][O:27][C:24]([CH3:26])([CH3:25])[CH2:23]3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CCl)OCCCl
Reactant: N#CCc1nc(-c2ccc(F)cc2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CC(C#N)(c2nc(-c3ccc(F)cc3)cs2)CCO1
Yield: 48 %

Procedure:
2-(4-(4-Fluorophenyl)thiazol-2-yl)acetonitrile (325 mg, 1.5 mmol), potassium carbonate (617 mg, 4.47 mmol), and 1-chloro-2-(2-chloroethoxy)-2-methylpropane (254 mg, 1.5 mmol) in DMF (5 mL) were microwaved at 160° C. for 5 min then 20 min. A second addition of potassium carbonate and 1-chloro-2-(2-chloroethoxy)-2-methylpropane was made and then the reaction was microwaved again for 30 min two times. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and purified on silica using a gradient of 0-30% ethyl acetate/hexanes to afford 4-(4-(4-Fluorophenyl)thiazol-2-yl)-2,2-dimethyltetrahydro-2H-pyran-4-carbonitrile (228 mg, 48% yield). MS (ESI) m/z: Calculated for C17H17FN2OS: 316.10. found: 317.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl>[C:18]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1c(C)cc(N)cc1C
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(C)cc(NC(=O)C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.1 %

Procedure:
Into an ice-cold solution of aniline 4 (15.1 g, 100 mmol) dissolved in methylene chloride (100 mL) were added sequentially pyridine (17.5 mL) and pivaloyl chloride (12.3 mL, 100 mmol) dropwise, and the resulting mixture was stirred at room temperature for 15 h. The mixture was diluted with methylene chloride and washed sequentially with 10% aq. hydrochloric acid, saturated aq. sodium bicarbonate and brine. Removal of solvents after drying (MgSO4) gave the pivalamide (19.8 g, 86% yield) as a pale brown solid, mp 126°-128° C. Spectral data: 1H NMR: δ 1.30 (s, 9H), 2.23 (s, 6H), 3.68 (s, 3H), 7.18 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)[N:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH2:14][N:13]([C:22]([C:21]4[C:20]([N:27]5[N:31]=[CH:30][CH:29]=[N:28]5)=[N:19][C:18]([CH3:17])=[CH:26][CH:25]=4)=[O:23])[CH2:12][CH:11]3[CH2:10]2)[N:3]=1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Reactant: Cc1ccc(C(=O)O)c(-n2nccn2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccc(C)nc4-n4nccn4)CC3C2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a pale yellow solution of 2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (Intermediate 23) (50 mg, 0.23 mmol) in 2 mL of DMF was added 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid (Intermediate 70) (51 mg, 0.25 mmol) followed by HATU (131 mg, 0.34 mmol) and DIPEA (0.118 mL, 0.69 mmol). The resulting solution was allowed to stir at room temp for 1 h and turned progressively more intense yellow as the reaction continued. The reaction was monitored via LCMS and quenched with H2O once starting materials we no longer observed. The resulting biphasic mixture was extracted with EtOAc three times. The combined organic layers were washed with brine, dried with Na2SO4 and conc. into a pale yellow oil under reduced pressure. The yellow residue was purified via FCC using 5-50% 2M NH3/MeOH in DCM. Minor impurities remained so the material was further purified via HPLC 0-99% CH3N to give the desired product. MS (ESI) mass calcd. for C21H24N8O, 404.47; m/z found 405.3 [M+H]+. 1H NMR (400 MHz, CDCl3) 7.80 (s, 2H), 7.72 (d, J=7.7 Hz, 1H), 7.29-7.24 (m, 1H), 6.30 (s, 1H), 3.90-3.80 (m, 2H), 3.73-3.63 (m, 2H), 3.59 (dd, J=11.6, 5.3 Hz, 1H), 3.47 (dd, J=11.6, 3.7 Hz, 1H), 3.33 (s, 1H), 3.00 (ddd, J=38.4, 21.7, 7.2 Hz, 3H), 2.68 (s, 3H), 2.30 (s, 6H).
Reaction SMILES: CC1C=C(C=CC=1OC)C=CC(OC)=O.[CH3:16][O:17][C:18]1[CH:29]=[CH:28][C:21]([CH:22]=[CH:23][C:24]([O:26]C)=[O:25])=[CH:20][C:19]=1[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38](=[O:40])[CH3:39])=[C:34]([OH:41])[C:33]=1[CH2:42][CH2:43][CH3:44]>>[CH3:16][O:17][C:18]1[CH:29]=[CH:28][C:21]([CH:22]=[CH:23][C:24]([OH:26])=[O:25])=[CH:20][C:19]=1[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38](=[O:40])[CH3:39])=[C:34]([OH:41])[C:33]=1[CH2:42][CH2:43][CH3:44]
Reactant: CCCc1c(OCc2cc(C=CC(=O)OC)ccc2OC)ccc(C(C)=O)c1O
Agent: COC(=O)C=Cc1ccc(OC)c(C)c1
Product: CCCc1c(OCc2cc(C=CC(=O)O)ccc2OC)ccc(C(C)=O)c1O

Procedure:
Methyl 3-methyl-4-methoxycinnamate was carried through steps analogous to those described in Example 16, steps b., c. and d. Methyl 4-methoxy-3-(4-acetyl-3-hydroxy-2-propylphenoxy)methylcinnamate melted at 141°-143° C. The title compound was recrystallized from ethanol to give flocculent needles, mp 245°-246° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10](=[O:31])[CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29]Br)([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C>[C:5]([O:9][C:10](=[O:31])[CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][N:1]=[N+:2]=[N-:3])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOCCN=[N+]=[N-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
Sodium azide (1.5 g, 23 mmol) was added to a solution of compound 3 (1.9 g, 4.1 mmol) in dry DMF (50 mL) and the resulting mixture was stirred at 80° C. overnight. The reaction mixture was concentrated in vacuo and then triturated with CH2Cl2 (20 mL) and filtered to remove sodium azide. The filtrate was concentrated in vacuo and the residue was loaded onto a silica gel gravity column (200 g) and eluted with CH2Cl2:MeOH 100:0 to 20:1 (v/v) to afford compound 4 as a colorless oil (1.0 g, 57%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:8]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][N:22]=2)(=[O:20])=[O:19])[N:7]([CH3:30])[N:6]=1.[H-].[Na+].Cl[C:34]1[N:39]=[CH:38][C:37](S(C)(=O)=O)=[CH:36][N:35]=1>C1COCC1.CC(N(C)C)=O>[CH:27]([C:24]1[CH:25]=[CH:26][C:21]([S:18]([NH:17][C:8]2[N:7]([CH3:30])[N:6]=[C:5]([O:4][CH2:3][CH2:2][O:1][C:34]3[N:35]=[C:36]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:37]=[CH:38][N:39]=3)[C:9]=2[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:19])=[O:20])=[N:22][CH:23]=1)([CH3:28])[CH3:29]
Reactant: CS(=O)(=O)c1cnc(Cl)nc1
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(OCCOc3nccc(S(C)(=O)=O)n3)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reaction time: 0.08 h
Yield: 40.6 %

Procedure:
To a solution of N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-5-isopropyl-2-pyridinesulfonamide (Example 40) (112 mg) in anhydrous THF (5 ml) at 0° C. and under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 21.8 mg) and the mixture was stirred for 5 minutes. To the mixture was added 2-chloro-5-(methylsulfonyl)pyrimidine (50 mg) in dimethylacetamide (1 ml). After stirring for 150 min. the reaction mixture was partitioned between ethyl acetate (50 ml) and saturated ammonium chloride solution (50 ml). The ethyl acetate layer was washed with brine (50 ml), dried (MgSO4), filtered and evaporated to dryness. Purification of the residue on a Phenomenex Magellen™ column using a 0.1M NH4OAc:MeCN gradient (95:5 to 60:40) over 5min. and then an isocratic flow (60:40) for 15 minutes gave the title compound as a white solid (31 mg).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:25])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[C:10]([Cl:20])=[CH:9][C:8]=2[C:21]([F:24])([F:23])[F:22])(=[O:3])[CH3:2].[CH3:26][S:27][CH2:28][CH2:29][NH2:30]>>[C:1]([C:4]1[C:5](=[O:25])[NH:6][C:7]2[C:12]([C:13]=1[NH:30][CH2:29][CH2:28][S:27][CH3:26])=[CH:11][C:10]([Cl:20])=[CH:9][C:8]=2[C:21]([F:22])([F:23])[F:24])(=[O:3])[CH3:2]
Reactant: CSCCN
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)c(Cl)cc(C(F)(F)F)c2[nH]c1=O
Product: CSCCNc1c(C(C)=O)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)cc12
Yield: 75.8 %

Procedure:
3-Acetyl-6-chloro-4-methylsulfoxy-8-trifluoromethyl-2-quinolinone (351 mg, 1 mmol) and methylthioethylamine (91 mg, 1 mmol) were used and the reaction was carried out as in the above process of example 1 to obtain the desired product (287 mg, yield: 76%).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[C:13]([O:17][C:18](=[O:50])[C@H:19]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[C:43]([O:44][CH3:45])=[CH:42][C:41]([CH2:46]O)=[CH:40][C:39]=2[O:48][CH3:49])=[CH:34][CH:33]=1)[NH:20][C:21](=[O:30])[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:70]1(=[O:76])[NH:74][C:73](=[O:75])[CH2:72][CH2:71]1>C1COCC1>[C:13]([O:17][C:18](=[O:50])[C@H:19]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[C:39]([O:48][CH3:49])=[CH:40][C:41]([CH2:46][N:74]3[C:73](=[O:75])[CH2:72][CH2:71][C:70]3=[O:76])=[CH:42][C:43]=2[O:44][CH3:45])=[CH:34][CH:33]=1)[NH:20][C:21](=[O:30])[C:22]1[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=1[Cl:28])([CH3:15])([CH3:16])[CH3:14]
Reactant: COc1cc(CO)cc(OC)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(CN2C(=O)CCC2=O)cc(OC)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
DEAD (0.13 mL) was added to an ice-cooled solution of N-(2,6-dichlorobenzoyl)-4-[2,6-dimethoxy-4-(hydroxymethyl)phenyl]-L-phenylalanine tert-butyl ester (250 mg), triphenylphosphine (175 mg) and succinimide (90 mg) in THF (3 mL) under N2. The mixture was stirred at 0° C. for 30 min, and warmed to room temperature and stirred for 2 h. The mixture was partitioned between H2O and EtOAc, and the aqueous layer was extracted with EtOAC. The combined organic layer was dried (MgSO4), and concentrated in vacuo. The residue was purified by preparative TLC (silica gel; eluent: EtOAc/hexane 1:1) to give N-(2,6-dichlorobenzoyl)4-[2,6-dimethoxy-4-(succinimidomethyl)phenyl]-L-phenylalanine tert-butyl ester (138 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7](S(C)=O)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>ClC1C=C(C)C=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: Nc1ccccn1
Reactant: CS(=O)C1=NS(=O)(=O)c2cc(Cl)ccc2N1
Solvent: Cc1cccc(Cl)c1
Product: O=S1(=O)N=C(Nc2ccccn2)Nc2ccc(Cl)cc21

Procedure:
7-Chloro-3-methylsulfinyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (0.25 g) and 2-aminopyridine (0.25 g) in 3-chlorotoluene (5 mL) was heated at 150° C. for 1 h. After cooling, the white precipitate was collected by filtration and washed with diethylether. The insoluble material was dissolved in 1M NaOH (20 mL), treated with charcoal, filtered, and the filtrate was adjusted to pH 3 with 6N HCl. The precipitate was collected by filtration, washed with water, dissolved in hot DMF (15 mL), mixed with an equal volume of distilled water and cooled. The white precipitate was collected by filtration, washed with water and dried (yield: 0.12 g); m.p. >310° C.
Reaction SMILES: Cl.[CH:2]([NH:5][OH:6])([CH3:4])[CH3:3].[OH-].[Na+].[Br:9][CH:10]([CH2:14][CH2:15]Br)[C:11](Cl)=[O:12]>C(Cl)Cl.O>[Br:9][CH:10]1[CH2:14][CH2:15][O:6][N:5]([CH:2]([CH3:4])[CH3:3])[C:11]1=[O:12]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: CC(C)NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)N1OCCC(Br)C1=O
Temperature: 5 °C
Yield: 10.5 %

Procedure:
To a stirred mixture of 5.3 g (47 mmol) of N-isopropylhydroxylamine hydrochloride in 100 ml of methylene chloride cooled to 5° C. was added 3.8 g (47 mmol) of 50% sodium hydroxide solution in 20 ml of water. To this mixture was added with stirring 12.4 g (47 mmol) of 2,4-dibromobutyrylchloride and twenty minutes later an additional 7.6 g (94 mmol) of 50% sodium hydroxide solution was added. After twenty hours the organic phase was separated, dried over anhydrous magnesium sulfate and concentrated to an oil. This oil was chromatographed on silica gel with 40% ethyl acetate-hexane to afford 1.1 g of oily dihydro-4-bromo-2-isopropyl-2H-1,2-oxazin-3(4H)-one.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:30]1[CH:31]=[C:32]([O:36][CH3:37])[CH:33]=[CH:34][CH:35]=1>>[CH3:37][O:36][C:32]1[CH:31]=[C:30]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][C:24]([F:27])([F:25])[F:26])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])[CH:35]=[CH:34][CH:33]=1
Reactant: COc1cccc(Br)c1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Product: COc1cccc(C(=O)c2cn(-c3cccc(-c4ccccc4OC(F)(F)F)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12f and 3-bromoanisole