Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9]C2C(C)=CC=CC=2C)=[O:8])=[CH:5][CH:4]=1)#[N:2].[OH-:20].[K+].[Cl-].[Na+].[C:24](O)([CH3:27])([CH3:26])[CH3:25]>>[CH3:25][C:24]1[CH:27]=[CH:1][CH:3]=[C:4]([CH3:5])[C:26]=1[C:19]1[CH:18]=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=[CH:4][C:3]=1[C:1]([NH2:2])=[O:20]
Reactant: CC(C)(C)O
Reactant: [OH-]
Reactant: Cc1cccc(C)c1NC(=O)c1ccc(C#N)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Product: Cc1cccc(C)c1-c1cc(C(N)=O)ccc1C(N)=O
Yield: 43 %

Procedure:
Ten grams of 4-cyano-N-(2,6-dimethylphenyl)benzamide and 3 grams of finely powdered potassium hydroxide were slurried in t-butanol and heated at reflux for 50 minutes. The homogeneous mixture was poured into a saturated sodium chloride solution and extracted into chloroform. Material which was insoluable in both the organic and water phases was recovered by filtration, crystallized from methanol, and provided the title compound in 43% yield, m.p. 246-248° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](N)=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1([S:16](Cl)(=[O:18])=[O:17])C=CC=CN1.[N:20]([O-])=O.[Na+].S(Cl)(Cl)(=O)=O.C(NCC1C=CC=CC=1)C1C=CC=CC=1>>[Cl:1][C:2]1[C:7]([S:16]([NH2:20])(=[O:18])=[O:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccnc1Cl
Reactant: O=N[O-]
Reactant: O=S(=O)(Cl)C1(Cl)C=CC=CN1
Agent: [Na+]
Agent: c1ccc(CNCc2ccccc2)cc1
Solvent: O=S(=O)(Cl)Cl
Product: NS(=O)(=O)c1cccnc1Cl

Procedure:
The synthesis of a 2-halopyridine sulfonamide intermediate is illustrated in Reaction Scheme L. The 2-chloro-3-aminopyridine is converted to the 2-chloropyridinesulfonyl chloride by reaction with sodium nitrite/acid and sulfuryl chloride. This compound is then allowed to react with dibenzylamine to provide the desired 2-chloropyridine 3-sulfonamide intermediate. This compound may then be carried on to a final product using the methods described in Reaction Schemes A and D.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]1)=[N:8]2.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O)(=O)C>ClC(Cl)C>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][C:7]([NH:13][C@H:14]2[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]2)=[N:8]3)=[CH:26][CH:25]=1
Reactant: NCc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reactant: O=Cc1ccc(F)cc1
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Fc1ccc(CNCc2cccc3nc(N[C@@H]4CCc5ccccc54)ccc23)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.4 %

Procedure:
A solution of (5-aminomethyl-quinolin-2-yl)-(R)-indan-1-yl-amine (example 80, step B) (200 mg, 0.69 mmol), 4-fluorobenzaldehyde (94 mg, 0.76 mmol) and acetic acid (166 mg, 2.76 mmol) in 1,1-dichloroethane (10 ml) was stirred at room temperature for 30 minutes. Afterwards sodium triacetoxy-boron hydride (342 mg, 1.61 mmol) was added, the reaction mixture was allowed to stir for 17 hours at room temperature, poured into ice/saturated NaHCO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as light yellow oil (130 mg, 47%).
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]1)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:16]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17]1>>[CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:20]([CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:21])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C(=C/c1ccccc1)\CC1CCCCN1
Reactant: O=C(Cl)C1CCC1
Product: O=C(C1CCC1)N1CCCCC1C/C=C/c1ccccc1

Procedure:
Stage a) The method is the same as that of Example 1.1, Stage a), the initial reactants being (E)-2-(cinnamyl)piperidine and cyclobutanecarboxylic acid chloride, which furnish (E)-2-cinnamyl-1-(cyclobutanecarbonyl)piperidine (formula II; Ar=C6H5, m=1, n=2, R=cyclobutyl). Yield: 99%.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:10][C:11]([F:23])([F:22])[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.C1COCC1.[Ti](Cl)(Cl)(Cl)Cl>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[N:21]/[S:18]([C:15]1[CH:14]=[CH:13][C:12]([C:11]([F:10])([F:23])[F:22])=[CH:17][CH:16]=1)(=[O:19])=[O:20]
Reactant: O=Cc1ccccc1I
Reactant: NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(/N=C/c1ccccc1I)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 116 %

Procedure:
To the mixture of 2-iodobenzaldehyde (11) (12.3 g, 53 mmol) and 4-trifluoromethylbenzenesulfonamide (12) (12.15 g, 54 mmol) in CH2Cl2 (110 mL) and THF (27 mL) was added triethylamine (22.5 mL) and titanium(IV) chloride (3 mL) at 0° C. After stirring at 0° C. for 2 h, the solid was separated via Celite filtration. The filtrate was concentrated under reduced pressure to dryness, triturated with toluene to give 27 g of a yellow solid as the crude product (3) which was used without further purification.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:20]1[C:28]2[C:23](=[CH:24][C:25](Cl)=[CH:26][CH:27]=2)[NH:22][N:21]=1)=O)(C)(C)C.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][C:9]([C:20]2[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][N:21]=2)=[CH:10]3)=[O:18])[CH2:33][CH2:32]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2n[nH]c3cc(Cl)ccc23)cc2cc(C(=O)O)ccc21
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN1CCN(C(=O)c2ccc3[nH]c(-c4n[nH]c5ccccc45)cc3c2)CC1

Procedure:
A solution of 1-(tert-butoxycarbonyl)-2-(1H-indazol-3-yl)-1H-indole-5-carboxylic acid (4-5, 100 mg, 0.265 mmol), N-methyl piperazine (40 μL, 0.32 mmol), EDC (61 mg, 0.32 mmol), and HOAt (43.3 mg, 0.32 mmol)in 5 ml of DMF was treated with triethylamine (90 μL, 0.66 mmol) and mixed for 24 h. The solution was partitioned between ethyl acetate (3×50 mL) and water (75 mL). The combined organics were dried over Na2SO4, filtered and concentrated. The residual oil was dissolved in a 1:1 mixture of dichloromethane/trifluoroacetic acid and mixed for 45 min. The solvent was removed in vacuo and the residue was purified by reverse phase liquid chromatography (H2O/CH3CN gradient with 0.1% 1TFA present) to provide 3-{5-[(4-methylpiperazin-1-yl)carbonyl]-1H-indol-2-yl}-1H-indazole (4-6); 1H NMR (500 MHz, CD3OD) δ 11.36 (s, 1H), 8.14 (d, 1H, J=8.3 Hz), 7.83 (s, 1H), 7.58 (dd, 2H, J=8.5 Hz), 7.45 (t, 1H, J=8.3 Hz), 7.30 (dd, 2H, J=8.06 Hz), 7.17 (s, 1H), 4.55 (bs, 2H), 3.45 (bs, 2H), 3.25 (bs, 2H), 2.98 (s, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[N:13]=[CH:12][C:11]([O:14][C:15]2[C:16]([CH:30]3[CH2:34][CH2:33][CH2:32][N:31]3[C:35](=[O:37])[CH3:36])=[CH:17][C:18]3[NH:22][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[N:20][C:19]=3[CH:29]=2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH2:5]([O:4][C:2](=[O:3])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[C:16]([CH:30]3[CH2:34][CH2:33][CH2:32][N:31]3[C:35](=[O:37])[CH3:36])=[CH:17][C:18]3[NH:22][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[N:20][C:19]=3[CH:29]=2)=[CH:12][N:13]=1)[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(N)nc1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2C(C)=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.003 ml of ethyl chloroformate was added to a pyridine (1 ml) solution of 14.4 mg of 1-(2-(6-(6-amino-pyridin-3-yloxy)-2-pyridin-2-yl-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone obtained in Example 340 (step 1), and the reaction liquid was stirred at room temperature for 30 minutes. The reaction liquid was distilled under reduced pressure, and the resulting residue was dissolved in 1 ml of trifluoroacetic acid, and the reaction liquid was stirred at room temperature for 1 hour. The reaction liquid was distilled under reduced pressure, and the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid] and through silica gel column chromatography (developing solvent: chloroform/methanol=9/1) to obtain the entitled compound as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)=[CH:4][C:3]=1[NH2:19].[Br:20][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25].CCN(CC)CC>CCO>[BrH:20].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)=[CH:4][C:3]=1[NH:19][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25]
Reactant: Nc1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Reactant: CCN(CC)CCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: Br
Product: CCN(CC)CCNc1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Yield: 5 %

Procedure:
From 2-chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenylamine (0.100 g, 0.320 mmol), anhydrous EtOH (1.3 mL), 2-bromo-N,N-diethylethylamine.HBr (0.334 g, 1.28 mmol) and Et3N (0.230 mL, 1.60 mmol) was obtained 0.006 g (5%) of the title compound as a white solid. 1H NMR (acetone-d6): 8.08 (d, 1H, J=5.5 Hz), 7.48–7.37 (m, 3H), 7.34 (d, 1H, J=5.2 Hz), 2.82–2.80 (m, 4H), 2.62–2.58 (m, 4H), 1.07 (t, 6H, J=7.0 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH3:26])([CH3:25])[CH2:17][CH2:18][N:19]3[CH:22]([CH3:24])[CH3:23])=[CH:14][C:13]=2[CH3:27])=[CH:7][CH:6]=1)[CH3:2].C=O.[C:31]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH3:25])([CH3:26])[CH2:17][CH2:18][N:19]3[CH:22]([CH3:23])[CH3:24])=[CH:14][C:13]=2[CH3:27])[CH3:31])=[CH:9][CH:10]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CCN3C(C)C)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N(C)c2cc3c(cc2C)C(C)(C)CCN3C(C)C)cc1
Yield: 30.6 %

Procedure:
A solution of 4-(1-isopropyl-4,4,6-trimethyl-1,2,3,4-tetrahydroquinolin-7-ylamino)-benzoic acid ethyl ester (Compound 46, 30 mg, 0.0788 mmol), formaldehyde (23.66 mg, 0.788 mmol), sodium cyanoborohydride (3.9 mg, 0.788 mmol), acetic acid (0.125 mL), and acetonitrile (1 mL) was stirred at room temperature overnight. The solvent was removed and the residue was purified by silica gel chromatography (5% ethyl acetate in hexane, Rf=0.27) to give the title compound(9.5 mg, 31%) as a white solid:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10][N:11]=2)[N:8]=1)=C.O.I([O-])(=O)(=O)=[O:23].[Na+]>C1COCC1.[Os](=O)(=O)(=O)=O>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10][N:11]=2)[N:8]=1)=[O:23]
Reactant: C=Cc1ccc2nnc(CNC(=O)OC(C)(C)C)n2n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1nnc2ccc(C=O)nn12
Reaction time: 0.08 h
Yield: 72 %

Procedure:
Tert-butyl (6-vinyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (485 mg, 1.76 mmol) was dissolved in 5 mL of THF and 5 mL of water then osmium tetroxide (0.687 mL (4% water solution), 0.0176 mmol) was added and stirred for 5 min. Sodium periodate was added (141, 3.53 mmol) and the reaction was stirred for 2 h. The reaction was then extracted with dichloromethane (3×10 mL), dried over Na2SO4 and concentrated. Purification via MPLC (DCM/MeOH+1% NH4OH) afforded title compound as a tan solid (350 mg, 72% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([N+:12]([O-])=O)=[CH:5][C:4]=1[O:15][CH3:16].[Br:17][CH2:18][C:19](=O)[C:20](=O)[CH3:21]>C(O)(=O)C.[Pd]>[Br:17][CH2:18][C:19]1[C:20]([CH3:21])=[N:9][C:7]2[C:6](=[CH:5][C:4]([O:15][CH3:16])=[C:3]([O:2][CH3:1])[CH:8]=2)[N:12]=1
Reactant: CC(=O)C(=O)CBr
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2nc(C)c(CBr)nc2cc1OC

Procedure:
11.4 g (50 mmols) of 1,2-dimethoxy-4,5-dinitrobenzene are dissolved in 100 ml of glacial acetic acid and, after adding 0.6 g of 10% strength palladium-on-characoal, hydrogenated under normal pressure; the temperature can rise to 60° C. during the hydrogenation. Consumption of hydrogen: 7,300 ml (100% of theory). The catalyst is filtered off and the filtrate is cooled, under nitrogen, to 5° to 10° C. Whilst stirring well, 9 g (55 mmols) of 1-bromo-2,3-butanedione are added dropwise at 10° C. The solution is stirred for 60 minutes, during which time the desired product starts to precipitate out. The reaction mixture is discharged into 300 ml of cold water and the mixture is stirred for 10 minutes. The product which has precipitated is filtered off, washed with water and dried in vacuo at 60° C.
Reaction SMILES: [CH2:1]([NH2:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[S:16](N)([NH2:19])(=[O:18])=[O:17]>>[CH2:1]([NH:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NS(N)(=O)=O
Reactant: CCCCCCCCCCCCCCN
Product: CCCCCCCCCCCCCCNS(N)(=O)=O
Yield: 63 %

Procedure:
The title compound was prepared following the procedure previously described in Example 1, using 0.43 g (2.0 mmol) of N-tetradecylamine and 0.2 g (2.0 mmol) of sulfamide as starting reagent. 0.37 g of a white solid were obtained. Yield 63%; m.p. 99-101° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.C1CN[S:26](=[O:28])(=[O:27])[CH2:25][CH2:24]1.OC1C=CC=C2C=1[N:40]=[CH:39][CH:38]=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:40]4[CH2:24][CH2:25][S:26](=[O:27])(=[O:28])[CH2:38][CH2:39]4)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Reactant: Oc1cccc2cccnc12
Reactant: O=S1(=O)CCCCN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(N3CCS(=O)(=O)CC3)cc2)cn1)c1ccc(Cl)s1
Temperature: 130 °C
Yield: 55.4 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 (56 mg, 0.10 mmol), 1,4-butanesultam (52 mg, 0.38 mmol), 8-hydroxyquinoline (6 mg, 0.040 mmol) and K2CO3 (50 mg, 0.36 mmol) in DMSO (1 mL) was degassed before being charged with CuI (10 mg, 0.052 mmol). The mixture in a sealed tube was heated at 130° C. overnight. The mixture was then purified by HPLC to give the titled compound (10 mg). MS 451.1 and 453.1 (M+H, Cl pattern).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CO.[OH-].[Na+].Cl>O.C1COCC1>[CH3:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)ccc1C(=O)O
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To two batches of methyl 2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoate (0.452 g, 1.198 mmol) in a 250 mL round-bottomed flask equipped with a stir bar was added MeOH (12 ml), THF (12 ml) and 2N sodium hydroxide (5.99 ml, 11.98 mmol). The reaction was stirred overnight. The reaction mixture was diluted with water and acidified with 1N HCl. The solid was extracted with EtOAc (3×). The organic layer was dried over MgSO4, filtered and concentrated providing the title compound as a yellow solid (0.412 g, 1.134 mmol, 95%): 1H NMR (300 MHz, DMSO-d6) δ 12.94 (s, 1H), 9.43 (s, 1H), 8.14-8.03 (m, 2H), 8.03-7.89 (m, 3H), 7.61 (d, J=8.7 Hz, 2H), 2.60 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.95; ESIMS m/z 364 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:15][CH2:14][CH2:13][C:12]3[CH:11]=[C:10]([C:16]([OH:18])=O)[S:9][C:8]=3[C:7]=2[CH:19]=1)#[N:2].C(Cl)(=O)C(Cl)=O.[Cl:26][C:27]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:28]=1[NH:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C=O)C.C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:15][CH2:14][CH2:13][C:12]3[CH:11]=[C:10]([C:16]([N:29]([C:28]4[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:27]=4[Cl:26])[CH3:30])=[O:18])[S:9][C:8]=3[C:7]=2[CH:19]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)-c1sc(C(=O)O)cc1CCO2
Reactant: CNc1ccc(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN(C(=O)c1cc2c(s1)-c1cc(C#N)ccc1OCC2)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 9-cyano-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-2-carboxylic acid (300 mg) in dichloromethane (10 mL) was added DMF (1 drop) and oxalyl chloride (0.165 mL) and the reaction stirred at room temperature for 30 min. The solvent was then reduced in vacuo and the residue redissolved in acetonitrile (10 mL). To this solution was added 2,4-dichloro-N-methylaniline (0.16 mL) and potassium carbonate (308 mg) and the reaction stirred at room temperature for 16 h. The mixture was partitioned between water (40 mL) and ethyl acetate (30 mL). The organic layer was dried (Na2SO4), reduced in vacuo and purified on silica to give 336. (CDCl3): 3.11 (2H, t), 3.39 (3H, s), 4.32 (2H, t), 6.91 (1H, s), 7.07 (1H, d), 7.32 (1H, d), 7.37-7.44 (2H, m), 7.58 (1H, s), 7.79 (1H, s). MH+ 429:431:433 (3:2:1)
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[C:12]([F:15])([F:14])[F:13])=[C:7](F)[CH:6]=1>C(O)CCC.O>[Br:4][C:5]1[CH:6]=[C:7]2[C:8]([C:11]([C:12]([F:15])([F:14])[F:13])=[N:2][NH:3]2)=[CH:9][CH:10]=1
Reactant: NN
Reactant: O=C(c1ccc(Br)cc1F)C(F)(F)F
Solvent: CCCCO
Solvent: O
Product: FC(F)(F)c1n[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
Hydrazine hydrate (3.5 mL, 45 mmol) was added to a solution of 1-(4-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (1.00 g, 3.69 mmol) in 1-butanol (15 mL). The reaction was heated to reflux for 5 hours, then cooled to room temperature and left stirring overnight. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-50% ethyl acetate/heptanes) gave the title compound (310 mg, 32%) as an off-white solid. 1H NMR (400 MHz, CDCl3, δ): 7.42 (dd, J=8.58, 1.56 Hz, 1H), 7.72 (d, J=8.58 Hz, 1H), 7.75 (dd, J=1.56, 0.78 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].[NH2:10][C@H:11]([C:14]([OH:16])=[O:15])[CH2:12][SH:13].O>C(O)C>[CH3:2][C:1]1([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:10][CH:11]([C:14]([OH:16])=[O:15])[CH2:12][S:13]1
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC(=O)c1cccnc1
Solvent: O
Solvent: CCO
Product: CC1(c2cccnc2)NC(C(=O)O)CS1
Yield: 37.8 %

Procedure:
A mixture of 3.63 g of 3-acetylpyridine, 3.63 g of L-cysteine, 25 ml of water and 25 ml of ethanol was refluxed for 24 hours. The reaction mixture was concentrated under reduced pressure, isopropanol was added to the residue, and the resultant powder was collected by filtration. Ethanol was added to the powder, the insoluble matter was filtered off, and the filtrate was concentrated to dryness. The residue was dissolved in water and adjusted to pH 6 by addition of diluted hydrochloric acid under ice cooling and stirring, and the resultant powder was collected by filtration, washed with ethanol and dried to give 2.54 g of 2-methyl-2-(3-pyridyl)thiazolidine-4- carboxylic acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:12])=[C:7]([CH2:9][CH2:10][OH:11])[CH:8]=1.FC(F)(F)C(O)=O.[CH:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([N:30]2[CH2:35][C:34]3([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[O:33][CH2:32][CH2:31]2)=[O:29])[N:27]=1)([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:12][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][N:38]2[CH2:39][CH2:40][C:34]3([O:33][CH2:32][CH2:31][N:30]([C:28]([C:26]4[N:27]=[C:23]([CH:20]([CH3:21])[CH3:22])[S:24][CH:25]=4)=[O:29])[CH2:35]3)[CH2:36][CH2:37]2)=[CH:8][C:7]=1[CH2:9][CH2:10][OH:11]
Reactant: OCCc1cc(CBr)ccc1F
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(F)c(CCO)c4)CC3)C2)cs1
Reaction time: 8 h

Procedure:
A solution of 2-(5-(bromomethyl)-2-fluorophenyl)ethanol [Aromatic Intermediate 2] (5.17 g) in ethanol (20 mL) was added dropwise to a suspension of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate [Example 1, step b] (9.4 g) and potassium carbonate (6.75 g) in ethanol (75 mL) and the resulting mixture stirred overnight. The mixture was filtered, the filter cake was washed with ethanol (50 mL), and the filtrate and washings combined and evaporated. The residue was partitioned between water (100 mL) and ethyl acetate (250 mL). The phases were separated and the organic phase washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by flash silica chromatography using 95:5 ethyl acetate:triethylamine as solvent to give the subtitled compound as a clear oil. Yield 7.9 g.
Reaction SMILES: Cl.[F:2][C:3]([F:15])([F:14])[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([NH:9][NH2:10])=[O:8].[CH3:16][O:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1)=[O:19].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[O:28]=[C:27]([NH:10][NH:9][C:7]([C:6]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([F:14])([F:15])[F:2])[CH:5]=1)=[O:8])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([O:17][CH3:16])=[O:19])=[CH:21][CH:22]=1
Reactant: NNC(=O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CC(=O)NNC(=O)c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
To a solution of 3-(trifluoromethyl)benzohydrazide hydrochloride (2.3 g) in N,N-dimethylformamide (20 mL) were added the compound (1.8 g) obtained in Example 206a, N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (3.50 g), 1-hydroxybenzotriazole (1.25 g) and triethylamine (4.68 g). The reaction mixture was stirred at room temperature overnight, poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.0 g) as a colorless solid.