Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([N:13]([C:15]2[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=2)[CH3:14])[N:3]=1.[CH3:29][O-:30].[Na+].C1(C)C=CC=CC=1>O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([N:13]([C:15]3[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([OH:23])=[O:22])=[CH:17][CH:16]=3)[CH3:14])[N:3]=[C:2]2[O:30][CH3:29])=[CH:7][CH:8]=1
Reactant: C[O-]
Reactant: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1nc(N(C)c2ccc(OC(C)C(=O)O)cc2)cc2ccc(Cl)cc12

Procedure:
A mixture of ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (1.25 g), sodium methoxide (0.63 g) and toluene was heated under reflux for 4 hrs. The mixture was cooled, poured into water and extracted with ethyl acetate. The organic fraction was dried (MgSO4) and evaporated to give 2-{4-[N-(7-chloro-1-methoxyisoquinolin-3-yl)-N-methylamino]phenoxy}propionic acid.
Reaction SMILES: C(Cl)CCl.[CH3:5][C:6]1[O:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1.C[O:15][C:16](=[O:67])[C@@H:17]([NH:34][C:35]([C@@H:37]1[CH2:46][C:45]2[CH:44]=[C:43]3[O:47][CH2:48][C@H:49]([C:51]4[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]5[CH:64]=[CH:63][C:62]([Cl:65])=[C:61]([Cl:66])[CH:60]=5)=[CH:53][CH:52]=4)[O:50][C:42]3=[CH:41][C:40]=2[CH2:39][NH:38]1)=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[C:27]=2[CH3:33])=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:66][C:61]1[CH:60]=[C:59]([CH:64]=[CH:63][C:62]=1[Cl:65])[CH2:58][O:57][C:54]1[CH:55]=[CH:56][C:51]([C@H:49]2[CH2:48][O:47][C:43]3=[CH:44][C:45]4[CH2:46][C@@H:37]([C:35]([NH:34][C@@H:17]([CH2:18][C:19]5[CH:24]=[CH:23][C:22]([O:25][C:26]6[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[C:27]=6[CH3:33])=[CH:21][CH:20]=5)[C:16]([OH:67])=[O:15])=[O:36])[N:38]([C:11]([C:9]5[N:10]=[C:6]([CH3:5])[O:7][CH:8]=5)=[O:13])[CH2:39][C:40]=4[CH:41]=[C:42]3[O:50]2)=[CH:52][CH:53]=1
Reactant: Cc1nc(C(=O)O)co1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(Oc3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)co1
Reaction time: 0.67 h

Procedure:
EDC (5 eq.) and 2-methyl-oxazole-4-carboxylic acid (10 equiv) were dissolved in DCM and stirred 40 min. To this solution was added (S)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester and stirred for 12 h. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (12 mg). LCMS (m/z): 866.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH2:4][N:3]1[C@@H:8]([C@@H:16]([CH3:19])[CH2:17][CH3:18])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[S:27][CH:28]=[C:29]([CH2:31]O)[N:30]=2)[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.O>[O:1]=[C:2]1[N:6]([CH2:31][C:29]2[N:30]=[C:26]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)[S:27][CH:28]=2)[C:5](=[O:7])[CH2:4][N:3]1[C@@H:8]([C@@H:16]([CH3:19])[CH2:17][CH3:18])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CC(=O)NC1=O
Reactant: OCc1csc(-c2cccnc2)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CC(=O)N(Cc2csc(-c3cccnc3)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 36C (0.081 g, 0.30 mmol) in dichloromethane (2 mL) at 0° C. was treated with the product from Example 57A (0.063 g, 0.33 mmol), triphenylphosphine (0.103 g, 0.39 mmol), followed by diethyl azodicarboxylate (0.061 mL, 0.39 mmol), stirred at 25° C. for 16 hours. Water (3 mL) was added and the reaction was stirred for 2 hours at 25° C. The reaction mixture was partitioned between dichloromethane and water, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated, to give the crude product, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH:13]1([C:16]2[C:17]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=2)[CH2:15][CH2:14]1>>[CH:13]1([C:16]2[C:17]([N:23]3[CH2:28][CH2:27][N:26]([C:4]([C:3]4[CH:7]=[CH:8][C:9]([I:11])=[CH:10][C:2]=4[F:1])=[O:6])[CH2:25][CH2:24]3)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=2)[CH2:14][CH2:15]1
Reactant: O=C(O)c1ccc(I)cc1F
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3F)CC2)c(C2CC2)c1
Yield: 89.8 %

Procedure:
Using 2-fluoro-4-iodobenzoic acid (399 mg) and 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine hydrochloride (381 mg) described in Preparation Example 85 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (627 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:20](=[O:41])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])=[O:30])=[C:24]([O:39][CH3:40])[CH:23]=1)[C:6]([O:8]CC)=[O:7].[OH-].[Na+].Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:20](=[O:41])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])=[O:30])=[C:24]([O:39][CH3:40])[CH:23]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(OCCNCCC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(CC(=O)CCNCCOc2ccc(C(=O)O)cc2OC)ccc1NC(=O)Nc1ccccc1C
Yield: 34.7 %

Procedure:
To a solution of ethyl 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoate (550 mg, 0.98 mmol) in THF (15 mL) was added 0.25 N NaOH (15 mL). The resulting mixture was then heated under reflux for 2 days. The mixture was poured into 1 N HCl and the solid was collected. The crude solid was recrystallized from EtOH—CHCl3 to give 182 mg (35%) 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoic acid 256 as a white crystalline powder. mp 115–118° C.; IR (KBr) 1707 cm−; 1H-NMR (DMSO-d6) δ 1.02–1.12 (m, 3 H), 2.25 (s, 3 H), 2.50 (s, 2 H), 3.35–3.89 (m, 10 H), 4.11–4.16 (m, 2H), 6.71–8.56 (series of m, total 12H), 12.65 (br s, 1H); MS (FAB) m/z 536 (M30 +1); Anal. Calcd for C29H33N3O7.3/4H2O: C, 63.43; H, 6.33; N, 7.65. Found: 63.34; H, 6.28; N, 7.28.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:3]=1N.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18].N(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:3]=1[C:16]1[CH:17]=[C:12]([Cl:11])[C:13]([Cl:18])=[CH:14][CH:15]=1
Reactant: Clc1ccccc1Cl
Reactant: Nc1cc(Cl)c(Cl)cc1Cl
Agent: CC(C)(C)ON=O
Product: Clc1ccc(-c2cc(Cl)c(Cl)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2',4,4',5,5'-pentachlorobiphenyl was prepared according to the standard procedure of Cadogan [J. I. G. Cadogan, J. Chem. Soc. (London), 1962, 4257-58]. Thus, 2,4,5-trichloroaniline (20 g, 0.1 mol) was dissolved in 1,2-dichlorobenzene (125 mL, 1.1 mol). t-Butyl nitrite (28.2 mL, 1.1 mol) was introduce to the stirred solution in three portions over 10 min. After 15 min the evolution of gas had subsided, and the reaction mixture was heated to reflux behind a safety shield for 90 min, and then stirred at ambient temperature for 12 h. The excess 1,2-dichlorobenzene was removed in vacuo and the residue containing the product was purified by filtration through silica gel following the method of E. K. Yau and J. K. Coward, Aldrichimica Acta, 1988, 21(4), 106-107, to give after crystallization from ethanol the title product (3 g, 9.3%). Mass spectrum: m/z at 324 for C12H5Cl5.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OC1[CH:23]([N:24]2[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]2)[C:22]2=[CH:31][CH:19]([O:20][C:21]2=[O:32])[CH:18]2[CH:14]([O:15][C:16](=[O:34])[CH:17]2[CH3:33])[CH2:13][C:12]2(C)[CH:10]1[O:11]2.O>N1C=CC=CC=1>[C:5]([O:4][CH:1]1[CH:23]([N:24]2[CH2:25][CH2:26][CH:27]([CH3:30])[CH2:28][CH2:29]2)[C:22]2=[CH:31][CH:19]([O:20][C:21]2=[O:32])[CH:18]2[CH:14]([O:15][C:16](=[O:34])[CH:17]2[CH3:33])[CH2:13][C:12]2([CH3:10])[CH:2]1[O:11]2)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CCN(C2C3=CC(OC3=O)C3C(CC4(C)OC4C2O)OC(=O)C3C)CC1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC1C(N2CCC(C)CC2)C2=CC(OC2=O)C2C(CC3(C)OC13)OC(=O)C2C
Reaction time: 20 h
Yield: 36.9 %

Procedure:
Acetic anhydride (150 μmol; 15 μl) is added to a solution of the compound of Example 9 (100 μmol; 40 mg) in pyridine (0.5 ml). The solution obtained is stirred for 20 hours then the reaction mass is poured into water. The aqueous phase is extracted twice with ethyl acetate and the organic phase obtained is washed with water then with a solution of sodium chloride. The organic phase is dried over magnesium sulphate, filtered then evaporated. The residue is eluted on silica with a mixture of isopropyl acetate and dichloromethane (20/80). 16 mg of product is obtained in the form of a white powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=2)[N:6]=1.[Cl:17][C:18]1[C:19]([CH3:28])=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[C:19]([CH3:28])=[C:20]([S:24]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=3)[N:6]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: CC(=O)Nc1ccc(-c2csc(N)n2)cc1
Product: CC(=O)Nc1ccc(-c2csc(NS(=O)(=O)c3cccc(Cl)c3C)n2)cc1

Procedure:
The title compound was prepared N-[4-(2-amino-1,3-thiazol-4-yl)penyl]acetamide and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (16.1 mg) with purity >90%: MS (pos) m/z 422.1, (neg) m/z 420.3. HRMS m/z 421.0327 (calc. of monoisotopic mass for C18H16ClN3O3S2 gives 421.0322).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:11]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:25][CH2:26]3)[CH:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])=[N:11]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccnc(N3CCNCC3)c2)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2cc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.4 %

Procedure:
1-(2,4-difluoro-phenyl)-5-[2-(piperazin-1-yl)-pyridin-4-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (30.0 mg, 0.06 mmol) prepared in Example 193, triethylamine (42.0 uL, 0.30 mmol) and methanesulfonyl chloride (7.0 uL, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11][N:10]=2)[CH2:5][CH2:4]1)#[N:2].[C-]#N.[K+].[CH3:21][OH:22]>>[CH3:21][O:22][C:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11][N:10]=2)[CH2:5][CH2:4]1)=[NH:2]
Reactant: CO
Reactant: N#CN1CCC(c2nsc3ccccc23)CC1
Agent: [C-]#N
Agent: [K+]
Product: COC(=N)N1CCC(c2nsc3ccccc23)CC1

Procedure:
A mixture of 3-(1-cyano-4-piperidinyl)-1,2-benzisothiazole (11.7 g, 0.048 mole), KCN (3.1 g) and MeOH (145 ml) was stirred and refluxed for 4 hours, and then stirred at ambient temperature for 14 hours. The MeOH was removed in vacuo and the residue diluted with water. The aqueous suspension was extracted with chloroform and the chloroform extract was washed with water and dried over MgSO4. Thereafter, the chloroform was evaporated in vacuo to yield 12.4 g of a solid. Recrystallization from EtOAc yielded 6.0 g (45.2%) of a solid. An analytical sample was obtained by a second recrystallization of a 3.5 g sample. The resultant solid (2.6 g) had a melting point of 144°-146° C.
Reaction SMILES: C([CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([CH2:21][NH:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32](=[O:46])[NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:27][CH2:26]3)=[O:20])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=O)N.[C:47](C1CCN(CC2C=CC(CCC(NCCN3CCC(OC(=O)NC4C=CC=CC=4C4C=CC=CC=4)CC3)=O)=CC=2)CC1)(=[O:49])[NH2:48]>>[C:47]([CH:5]1[CH2:4][CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([CH2:21][NH:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32](=[O:46])[NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:27][CH2:26]3)=[O:20])=[CH:13][CH:12]=2)[CH2:6]1)(=[O:49])[NH2:48]
Reactant: NC(=O)C1CCN(Cc2ccc(CCC(=O)NCCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)cc2)CC1
Reactant: NC(=O)C1CCN(Cc2ccc(CCC(=O)CNCCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)cc2)CC1
Product: NC(=O)C1CCCN(Cc2ccc(CCC(=O)CNCCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)cc2)C1

Procedure:
biphenyl-2-yl-carbamic acid 1-[2-({3-[4(4-carbamoylpiperidin-1-ylmethyl)phenyl]propionyl}methylamino)ethyl]piperidin-4-yl ester, biphenyl-2-yl-carbamic acid 1-(2-{3-[4-(4-carbamoylpiperidin-1-ylmethyl)phenyl]propionylamino}ethyl)piperidin-4-yl ester;
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]([O:13][C:14]([N:16]([C:24]1[NH:25][CH:26]=[C:27]([CH:29]=[O:30])[N:28]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:15])([CH3:12])[CH3:11]>C(#N)C>[CH3:12][C:10]([O:13][C:14]([N:16]([C:24]1[NH:28][C:27]([CH:29]=[O:30])=[C:26]([Cl:1])[N:25]=1)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[O:15])([CH3:9])[CH3:11]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(C=O)c[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Cl)c(C=O)[nH]1
Temperature: 60 °C
Yield: 11.5 %

Procedure:
N-Chlorosuccinimide (0.346 g, 2.59 mmol) was added to a suspension of bis(1,1-dimethylethyl)(4-formyl-1H-imidazol-2-yl)imidodicarbonate (0.672 g, 2.158 mmol) in acetonitrile (10 mL). The mixture was heated at 60° C. for 2 hrs. The solvent was evaporated. Chromatography of the residue with ethyl acetate:hexane gave the title compound (0.086 g, 11%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 10.38-10.79 (m, 1H), 9.6 (s, 1H), 1.52 (s, 18H). ES MS: m/z 345
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>ClCCl>[CH3:24][C:23]([CH3:26])([CH3:25])[C:22]([NH:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][N:13]=1)=[O:27]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(C#Cc2ccccc2)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc(C#Cc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
(65 mg, 0.33 mmol) 5-Phenylethynyl-pyridin-2-ylamine (Example 1, step 1) was dissolved in dichloromethane (3 ml). Pyridine (52 mg, 53 μl, 0.67 mmol, 2 equiv.) and pivaloyl chloride (48 mg, 50 μl, 0.40 mmol, 1.2 equiv.) were added and the mixture was stirred for 2 hours at room temperature. The reaction mixture was extracted with 1N HCl solution and twice with dichloromethane. The organic extracts were combined, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with heptane:dichloromethane 50:50. The desired 2,2-dimethyl-N-(5-phenylethynyl-pyridin-2-yl)-propionamide (40 mg, 43% yield) was obtained as a light yellow solid, MS: m/e=279.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5].[Cl:19]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:17]([OH:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5]
Reactant: Nc1c(O)cccc1C(=O)Nc1ccc(Cl)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Nc1c(O)cc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: 50 °C
Reaction time: 4 h
Yield: 22.2 %

Procedure:
2-Amino-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide (3.06 g) and 1.80 g of N-chlorosuccinimide were dissolved in 60 ml of N,N-dimethylformamide, the solution was stirred at 50° C. for 8 hours and at room temperature for 4 hours and the insoluble matter was filtered off. The solvent was evaporated in vacuo, to the resulting residue was added a 1N aqueous solution of sodium hydroxide and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo and the resulting residue was purified by means of a silica gel column chromatography. Ethanol was added to the crudely purified product and the resulting precipitate was collected by filtration and dried in vacuo to give 767 mg of 2-amino-5-chloro-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide. The mother liquor was concentrated, then ethyl acetate-isopropyl ether was added thereto and the resulting precipitate was collected by filtration and dried in vacuo to give more 942 mg of the above-mentioned compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[NH:13][C:14](=[O:19])[O:15][C:16]([CH3:18])([CH3:17])[C:11]=3[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[S:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1>O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[NH:13][C:14](=[O:19])[O:15][C:16]([CH3:18])([CH3:17])[C:11]=3[CH:10]=2)[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][S:22][CH:23]=2)[CH:7]=1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(Br)c3)cc21
Reactant: OB(O)c1ccsc1
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(-c4ccsc4)c3)cc21

Procedure:
Prepared from 6-(3-bromo-5-fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 3-thiophene boronic acid according to procedure B. A brownish-orange solid: mp 200-203° C.; 1H-NMR (CDCl3) δ 8.62 (s, 1H), 7.53 (q, 1H, J=1.4 Hz), 7.50 (d, 1H, J=1.5 Hz), 7.49 (d, 1H, J=2.0 Hz), 7.45-7.40 (m, 1H), 7.35 (d, 1H, J=1.8 Hz), 7.27-7.24 (m, 2 H), 7.15 (dt, 1H, J=5.8, 2.0 Hz), 6.94 (d, 1H, J=8.2 Hz), 1.80 (s, 6H); MS ((−)APCI) [M−H]−@m/z 352. Anal. Calc. For C20H16FNO2S.0.50 H2O: C, 66.28; H, 4.73; N, 3.87. Found: C, 66.54; H, 5.03; N, 3.52.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])[CH3:2].C(N(CC)CC)C.[Cl:20][C:21]([SH:24])([Cl:23])[Cl:22]>CCOCC>[Cl:20][C:21]([Cl:23])([Cl:22])[S:24][N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:7](=[NH:12])[C:8]([Cl:9])([Cl:11])[Cl:10]
Reactant: SC(Cl)(Cl)Cl
Reactant: CCOCCNC(=N)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOCCN(SC(Cl)(Cl)Cl)C(=N)C(Cl)(Cl)Cl
Reaction time: 4 h
Yield: 83.6 %

Procedure:
To 4.7 g (0.02 mole) N-(2-ethoxyethyl)trichloroacetamidine, 2.1 g (0.02 mole) triethylamine, and 50 ml ether, cooled in an ice bath, was added 3.8 g (0.02 mole) perchloromethylmercaptan over 15 minutes. The temperature rose from 1.5° C. to 8.5° C. The solution was stirred 11/4 hours longer, filtered and rotary evaporated to give 6.4 g solid. Recrystallization from petroleum ether (cooling in dry ice) gave 4.0 g (54% yield; mp 65°-66° C.). The structure was confirmed via IR and elemental analysis.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>>[OH:25][CH2:24][CH2:26][NH:27][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: NCCO
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCO)cn1
Yield: 81 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using ethanolamine instead of methylamine, to the title compound (92 mg, 81%) which was obtained as a white solid. MS: m/e=354.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C>[Br:1][C:2]1[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=Cc1cccc(O)c1Br
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(C=O)c1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-bromo-3-hydroxybenzaldehyde (1 eq.) in DMF (0.4 M) was added cesium carbonate (1.2 eq.) and ethyl bromoacetate (1 eq.). The resulting suspension was stirred at RT for 16 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic extracts were washed with water and brine. Drying over MgSO4, filtration and concentration of the filtrate in vacuo afforded the crude product as a red oil. Purification by way of column chromatography (SiO2, 5:1 (v/v) Hex:EtOAc→1:1 (v/v) Hex:EtOAc) afforded the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([OH:11])([C:7]([F:10])([F:9])[F:8])[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27]1[CH:41]=[CH:40][C:30]([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)=[O:32])=[CH:29][CH:28]=1>O1CCCC1>[F:39][C:35]1[CH:34]=[C:33]([C:31]([C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:4](=[O:6])[C:3]([OH:11])([C:2]([F:1])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8])=[CH:41][CH:40]=2)=[O:32])[CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(C(=O)c2cccc(F)c2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(c1ccc(NC(=O)C(O)(C(F)(F)F)C(F)(F)F)cc1)c1cccc(F)c1
Temperature: 25 °C
Yield: 55.2 %

Procedure:
To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanoic acid (1.17 g, 5.5 mmol) in dry tetrahydrofuran (35 mL) was added 1,1'-carbonyldiimidazole (0.89 g, 5.5 mmol). The mixture was heated at reflux for 45 minutes, then cooled to room temperature. 4-Amino-3'-fluorobenzophenone (1.08 g, 5.0 mmol) was added in one portion and the reaction mixture heated at reflux for 48 hours. Tetrahydrofuran was removed from the reaction mixture in vacuo, and the residue dissolved in ethyl ether and filtered. The filtrate was washed with 3N HCl (50 mL) and water. The ether extract was dried (MgSO4) and concentrated in vacuo to an off-white solid. Purification by flash column chromatography (5% v/v ethyl ether/methylene chloride) yielded the title propanamide as a tan solid (1.13 g, 55%); mp 169°-171° C. 1H-NMR (300 MHz, d6 -DMSO): 7.50-7.64 (m, 4H, aromatic) 7.77-7.82 (m, 2 H, aromatic) 7.94-7.98 (m, 2H, aromatic) 9.84 (s, 1H, NH) 10.85 (bs, 1H, OH). MS (CI, CH4): 410 (M+1).