Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O.C(OCC)(=O)C.O>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[N:7]3[N:8]=2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: C1CNCCN1
Reactant: CC(C)(C)c1ccc(-c2nc3cccc(Br)n3n2)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)c1ccc(-c2nc3cccc(N4CCNCC4)n3n2)cc1

Procedure:
5-Bromo-2-(4-tert-butyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (20 mg, 60 μM) and piperazine (21 mg, 244 μM) in DMSO was heated at 80° C. for 8 h. The reaction was cooled and diluted with ethyl acetate (25 mL) and water (25 mL). After partitioning the ethyl acetate layer was washed with water (3×) and dried over magnesium sulfate. After filtering and concentration the title compound was obtained in 80% yield. LC/MS (Method A): r.t.=1.26 min. calculated mass=335 [M+H]+=336.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8](=[O:10])[CH3:9])[S:5][CH:6]=1.[Br:11]Br.O>C(O)(=O)C>[Br:11][C:6]1[S:5][C:4]([NH:7][C:8](=[O:10])[CH3:9])=[N:3][C:2]=1[CH3:1]
Reactant: CC(=O)Nc1nc(C)cs1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1nc(C)c(Br)s1
Reaction time: 2 h

Procedure:
To N-(4-methylthiazol-2-yl)acetamide (39.48 g) in acetic acid (200 ml) under a water-ice bath was added dropwise bromine (16 ml). After 2 h, water (500 ml) was added. Filtration, washing with water (3×) and drying gave N-(5-bromo-4-methylthiazol-2-yl) acetamide as off-white solid (52.13 g). H1-NMR (300 MHz, d6-DMSO) 12.27 (s, 1 H), 2.22 (s, 3 H), 2.13 (s, 3 H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15]CC)=[O:14])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)Cc1cccc(OCc2c(C)cccc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Cl)c1COc1cccc(CC(=O)O)c1
Reaction time: 3 h

Procedure:
To a stirred solution of Ethyl 2-(3-(2-chloro-6-methylbenzyloxy)phenyl)acetate (Step B, 4.94 g, 15.5 mmol) in absolute ethanol (80 ml) was added 1N NaOH (40 ml) at room temperature. The reaction mixture was stirred for 3 hours, acidified to pH 3.5-4.0 by adding 1N HCl and concentrated. The residue was taken into chloroform and washed with 0.1N HCl, brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to give the title compound.
Reaction SMILES: NC1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1>[OH-].[K+]>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=1[SH:3]
Reactant: COc1ccc2nc(N)sc2c1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(N)c(S)c1

Procedure:
To 2-amino-6-methoxy-1,3-benzthiazole (5 g, 0.027M) was added a solution of potassium hydroxide (25 g in 50 ml of water). The mixture was heated at 140° for 5 hours. The crude 2-amino-5-methoxybenzenethiol produced was diluted with water (150 ml) and to this was added copper powder (1.25 g, 1 equivalent) and iodobenzoic acid (5.8 g, 1 equivalent). The mixture was heated under reflux for 4 hours under nitrogen. On cooling the mixture was filtered to remove copper, and acidified with concentrated hydrochloric acid. The solution was filtered to give the product as a light green solid (5 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[I:13][C:14]1[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]([OH:24])=[CH:16][CH:15]=1>>[I:13][C:14]1[CH:15]=[CH:16][C:17]([O:24][CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: BrCc1ccc2ccccc2c1
Reactant: COC(=O)c1cc(I)ccc1O
Product: COC(=O)c1cc(I)ccc1OCc1ccc2ccccc2c1
Yield: 68 %

Procedure:
2-Bromomethylnaphthalene was reacted with methyl 5-iodosalicylate using the procedure described in Example 1 to give methyl 5-iodo-2-(naphth-2-ylmethoxy)benzoate in 68% yield. Using conventional procedures the ester was hydrolysed with base to give the corresponding acid, the acid chloride was prepared by reaction with thionyl chloride and the acid chloride was reacted with ethanolic ammonia to give 5-iodo-2-(naphth-2-ylmethoxy)benzamide in 84% yield from the ester, m.p. 163° C. The benzamide was converted to the corresponding benzonitrile in 72% yield, m.p. 108°-110° C., using the conditions described below in Example 27.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].Cl[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([C:37]([F:40])([F:39])[F:38])[CH:26]=[C:27]([C:28]3[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=3)[C:21]=2[N:20]=1>>[CH3:1][NH:2][S:3]([C:6]1[C:7]([N:12]2[CH2:17][CH2:16][N:15]([C:19]3[NH:20][C:21]4[C:27]([C:28]5[CH:29]=[C:30]([F:36])[C:31]([F:35])=[C:32]([F:34])[CH:33]=5)=[CH:26][C:25]([C:37]([F:40])([F:38])[F:39])=[CH:24][C:22]=4[N:23]=3)[CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1cccnc1N1CCNCC1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Product: CNS(=O)(=O)c1cccnc1N1CCN(c2nc3cc(C(F)(F)F)cc(-c4cc(F)c(F)c(F)c4)c3[nH]2)CC1

Procedure:
The piperazine from step (a) above (128 mg, 0.5 mmol) reacted with 2-chloro-6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzoimidazole (140 mg, 0.4 mmol, Example 51b) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 571 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.S(Cl)([Cl:12])=O>>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([Cl:12])=[O:9])[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(C(=O)O)cs1
Product: Cc1nc(C(=O)Cl)cs1
Temperature: 80 °C

Procedure:
To 2-methyl-1,3-thiazole-4-carboxylic acid (1 g) was added thionyl chloride (5 ml). The mixture was heated at 80° C. for 8 h. Thionyl chloride (5 ml) was added and the mixture heated for 2 h at 80° C. Further thionyl chloride (5 ml) was added and the mixture heated for 2 h. The mixture was concentrated in vacuo and azeotroped with toluene to give the title compound, 1.12 g.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][CH:25]([O:28][CH3:29])[O:26][CH3:27])[N:19]=[CH:18]3)[C:11](=[O:30])[CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:29][O:28][CH:25]([O:26][CH3:27])[CH2:24][N:20]1[C:21]2[C:17](=[CH:16][C:15]([N:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]3=[O:30])=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: COC(Cn1ncc2cc(-n3ccc(OCc4ccccc4)cc3=O)ccc21)OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(Cn1ncc2cc(-n3ccc(O)cc3=O)ccc21)OC
Temperature: 80 °C
Yield: 94.1 %

Procedure:
A solution of 4-(benzyloxy)-1-(1-(2,2-Dimethoxyethyl)-1H-indazol-5-yl)pyridin-2(1H)-one (4.96 g, 12.2 mmol) and ammonium formate (1.53 g, 24.4 mmol) in CH3OH was stirred for 10 min. Pd/C (5.5 g) was added under a nitrogen atmosphere. The reaction mixture was heated at 80° C. for 2 h and then allowed to cool. The mixture was filtered through a layer of Celite, and the filtrate was concentrated. The residue was triturated with MeOH, concentrated to dryness, triturated with EtOAc, sonicated for 20 min and then concentrated to give the title compound (3.62 g, 95%) as a yellow/white solid: 1H NMR (500 MHz, CDCl3) 8.06 (s, 1H), 7.68 (s, 1H), 7.58 (d, J=8.9 Hz, 1H), 7.39 (d, J=8.9 Hz, 1H), 7.27 (d, 1H, overlapping with solvent peak), 6.12 (s, 1H), 6.05 (d, J=7.3 Hz, 1H), 4.78 (t, J=5.2 Hz, 2H), 4.50 (d, J=5.2 Hz, 2H), 3.38 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8]O)=[CH:5][C:4]=1[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc(C=NO)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C#N)cc1C
Temperature: 25 °C

Procedure:
A solution of 20 (30.9 g, 0.187 mole) in of acetic anhydride (200 ml) heated at reflux for 1.5 hours, cooled to room temperature and poured with vigorous stirring into 2N aqueous Na2CO3 (2 L). Overnight refrigeration gave a solid which was collected, washed with water, and dried to give 25.6 grams (93%) of 21 m.p. 48°-50°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:16](I)[CH:17]=[CH2:18]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[N:10]2[CH2:18][CH:17]=[CH2:16])=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(=O)[nH]c2c1
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)ccc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 7-(methyloxy)-2(1H)-quinolinone (5 g, 0.029 mol) in DMF (70 ml) at 0° C. under N2 was added NaH (60% dispersion in oil; 2.5 g, 0.063 mol) stirred for 10 min, warmed to ambient temperature and stirred for a further 30 min. To this reaction mixture was added allyl iodide (3.13 ml, 0.034 mol) and stirred overnight. The reaction was quenched with water (20 ml) and concentrated. The product was obtained after column chromatography (gradient-5% MeOH in DCM) to yield 4.2 g (68%).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]3[CH:22]=[CH:23][C:24]([C:26]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:27])=[CH:25][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:33].[BH4-].[Na+]>>[CH2:13]([C:12]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:27])=[CH:25][C:19]=2[CH:18]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:34])[C:2]([CH3:35])([CH3:36])[CH3:1])=[C:7]([CH3:33])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)NCC(=O)O)ccc2s1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)NCC(=O)O)ccc2s1
Yield: 86.1 %

Procedure:
[(2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-5-carbonyl)-amino]-acetic acid (150 mg, 0.295 mmol) is reduced using NaBH4 (22 mg, 0.589 mmol) analogous to Example 2 to afford the title compound (130 mg, 86%).
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2>C1C=CC=CC=1.O.FC(F)(F)S([O-])(=O)=O.[Ag+]>[C:2]1([C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]4)[CH2:3]2)[CH2:9]3)[CH:11]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC12CC3CC(CC(C3)C1)C2
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: c1ccccc1
Product: c1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Silver trifluoromethanesulfonate (5 g) and 50 ml of benzene were mixed, 4.2 g of 1-bromoadamantane dissolved in 50 ml of benzene was added thereto over 30 minutes, and the resulting mixture was stirred for 12 hours in a dark place. The obtained reaction solution was poured in 300 ml of water and extracted with hexane, and the organic phase was washed with water and saturated saline, dried and concentrated to obtain a crude product. This crude product was purified by column chromatography, as a result, 1.7 g of 1-phenyladamantane was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[C:16]([C:18]1[C:23]2[N:24]=[C:25]([NH:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[O:26][C:22]=2[C:21](F)=[C:20]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:19]=1[CH3:43])#[N:17]>CS(C)=O>[C:16]([C:18]1[C:23]2[N:24]=[C:25]([NH:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[O:26][C:22]=2[C:21]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:20]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:19]=1[CH3:43])#[N:17]
Reactant: CCOC(=O)CCCNc1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)CCCNc1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Temperature: 150 °C
Reaction time: 5 h
Yield: 48.8 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (139 μl, 1.10 mmol) and triethylamine (153 μl, 1.10 mmol) were added to a dimethyl sulfoxide (5 ml) solution of ethyl 4-[(4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)amino]butanoate (I-280) (279 mg, 0.732 mmol), followed by stirring in an oil bath at 150° C. for 5 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform and washed with saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was purified by silica gel column chromatography (eluent, chloroform:methanol=10:1, v/v) to obtain the entitled compound (170 mg, 49%) as a brown oily substance.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:31]5[CH:32]=[C:33]([NH:37][C:38](=[O:45])[C:39]6[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=6)[CH:34]=[CH:35][CH:36]=5)=[N:24][N:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=45)[CH:19]=[CH:18][N:17]=3)=[CH:10][CH:11]=2)[CH2:6]1)=O.O[Li].O>C1COCC1.O>[CH2:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:31]5[CH:32]=[C:33]([NH:37][C:38](=[O:45])[C:39]6[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=6)[CH:34]=[CH:35][CH:36]=5)=[N:24][N:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=45)[CH:19]=[CH:18][N:17]=3)[CH:8]=2)[CH2:13][CH2:14][NH:5]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CN(C(=O)C(F)(F)F)CC4)n2)c1)c1ccccc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
To a solution of N-{3-[3-(2-{[2-(2,2,2-Trifluoroacetyl)-1,2,3,4-tetrahydro-7-isoquinolinyl]amino}-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}benzamide (191 mg, 0.30 mmol) in THF (4.0 mL) was added a solution of LiOH.H2O (19.8 mg, 0.47 mmol) in H2O (1.5 mL). The mixture was stirred at rt for 30 min. The mixture was partitioned between saturated aq. NaHCO3 and 5:1 CHCl3/isopropanol. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give 191 mg of crude product. Purification by silica gel chromatography (0 to 40% sat. ammonia/MeOH in EtOAc) afforded 163.2 mg of the title compound as a white powder. LCMS ((ES)+ 538.3. 1H NMR (400, DMSO-d6) δ 2.63 (t, 2H, J=5.6), 2.96 (t, 2H, J=5.6), 3.80 (s, 2H), 6.46 (d, 1H, J=5.2), 6.95 (d, 1H, J-=8.4), 7.11 (t, 1H, J=6.4), 7.29 (d, 1H, J=8.0), 7.36 (d, 1H, J=9.2), 7.43-7.57 (m, 5H), 7.93 (d, 2H, J=7.2), 8.09 (s, 1H), 8.21 (d, 1H, J=5.6), 8.49 (d, 1H, J=8.8), 8.82 (d, 1H, J=6.8), 9.41 (s, 1H), 10.37 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][O:7][C:8]=1[CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])([OH:3])=[O:2].N1C=CC=CC=1.[C:28](O)([CH3:31])([CH3:30])[CH3:29].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[C:28]([O:2][C:1]([C:4]1[N:5]=[CH:6][O:7][C:8]=1[CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:3])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)O
Reactant: O=C(NCCc1ocnc1C(=O)O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ncoc1CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2.9 g of 4-carboxy-5-{2-(benzyloxycarbonylamino)ethyl}oxazole, 4.9 g of pyridine, 6 ml of tert-butyl alcohol and 50 ml of chloroform was added dropwise 1.84 g of phosphoryl chloride at -10° C., and the mixture was stirred at the same temperature for 1 hour and further at room temperature overnight. The mixture was washed and dried, and then the solvent was removed. The residue was purified by silica gel chromatography to obtain 2.85 g of 4-tert-butoxycarbonyl-5-{2-(benzyloxycarbonylamino)ethyl}oxazole as a colorless oily product.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]1[C:23]2[CH2:22][C@@H:21]3[C:12](=[C:13]([OH:33])[C@@:14]4([OH:32])[C@@H:19]([CH2:20]3)[C@H:18]([N:24]([CH3:26])[CH3:25])[C:17]([OH:27])=[C:16]([C:28]([NH2:30])=[O:29])[C:15]4=[O:31])[C:11](=[O:34])[C:10]=2[C:9]2[O:8][C:7](=[S:35])[NH:6][C:5]=2[CH:4]=1.C(N(C(C)C)CC)(C)C.[CH2:46]([O:53][C:54](=[O:57])[CH2:55]Br)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C)C=O>[NH2:30][C:28]([C:16]1[C:15](=[O:31])[C@:14]2([OH:32])[C@@H:19]([CH2:20][C@H:21]3[C:12](=[C:13]2[OH:33])[C:11](=[O:34])[C:10]2[C:9]4[O:8][C:7]([S:35][CH2:55][C:54]([O:53][CH2:46][C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)=[O:57])=[N:6][C:5]=4[CH:4]=[C:3]([N:2]([CH3:36])[CH3:1])[C:23]=2[CH2:22]3)[C@H:18]([N:24]([CH3:25])[CH3:26])[C:17]=1[OH:27])=[O:29]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CN(C)c1cc2[nH]c(=S)oc2c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1cc2nc(SCC(=O)OCc3ccccc3)oc2c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Reaction time: 0.08 h

Procedure:
To a solution of (6aR,7aS,8S,11aS)-5,8-bis(dimethylamino)-9,11a,12-trihydroxy-11,13-dioxo-2-thioxo-2,3,6,6a,7,7a,8,11,11a,13-decahydrotetraceno[2,1-d][1,3]oxazole-10-carboxamide (Example 42) in N,N-dimethylformamide (DMF) is added 2 equivalents of diisopropylethylamine, after stirring for 5 min. 1.2 equivalent of benzyl-2-bromoacetate is added. The reaction mixture is stirred for 1 hr and mixture triturated with diethyl ether and solid is collected. It is purified by extraction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:33])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[N:19][N:18]=[C:17]1[CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].[Br:34]N1C(=O)CCC1=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:33])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:17]([CH2:21][N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])=[N:18][N:19]=[C:20]1[Br:34]
Reactant: O=C(c1ccccc1Cl)c1cc(Cl)ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Reactant: O=C1CCC(=O)N1Br
Product: O=C(c1ccccc1Cl)c1cc(Cl)ccc1-n1c(Br)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
Following the procedure of Example 1, 2',5-dichloro-2-[3-phthalimidomethyl-4H-1,2,4-triazol-4-yl]benzophenone is reacted with N-bromosuccinimide to form the 2',5-dichloro-2-[3-bromo-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].O[CH2:14][C:15]1[CH:16]=[CH:17][C:18](=[O:21])[NH:19][CH:20]=1>>[O:21]=[C:18]1[NH:19][CH:20]=[C:15]([CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=3[C:2](=[O:3])[O:4][C:5]2=[O:12])[CH:16]=[CH:17]1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: O=c1ccc(CO)c[nH]1
Product: O=c1ccc(Cn2c(=O)oc(=O)c3ccccc32)c[nH]1

Procedure:
Prepared by a similar procedure as described for preparation 7B, starting from isatoic anhydride and 5-hydroxymethyl-1H-pyridin-2-one (prepared as described in WO 01/77078 A1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[C:10]([CH3:26])[CH:9]=2)=[CH:4][C:3]=1[C:27]1[N:31]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([F:40])[C:33]=2[F:41])[N:30]=[N:29][N:28]=1.Cl>O1CCOCC1>[F:41][C:33]1[C:34]([F:40])=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:32]=1[N:31]1[C:27]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]3[S:12][C:11]([CH:13]4[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]4)=[C:10]([CH3:26])[CH:9]=3)[CH:4]=2)=[N:28][N:29]=[N:30]1
Reactant: COc1ccc(-n2nnnc2-c2cc(-c3cc(C)c(C4CCN(C(=O)OC(C)(C)C)CC4)s3)cnc2N)c(F)c1F
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-n2nnnc2-c2cc(-c3cc(C)c(C4CCNCC4)s3)cnc2N)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To Compound 1107 (100 mg, 0.17 mmol) was added 4 mL of 4.0 N HCl in dioxane. The reaction was stirred at room temperature for 2 hours and concentrated under reduced pressure. The resulting yellow residue was dissolved in a minimum of MeOH and precipitated with cold Et2O. The yellow solids were filtered and dried to provide 3-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)-5-(4-methyl-5-(piperidin-4-yl)thiophen-2-yl)pyridin-2-amine (Compound 22, 80 mg, 98%) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[S:12])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18](=[O:25])[CH2:19][C:20](=O)[CH:21](Br)[CH3:22].C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:16][O:17][C:18](=[O:25])[CH2:19][C:20]1[N:13]=[C:11]([C:10]2[CH:9]=[N:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:15][CH:14]=2)[S:12][C:21]=1[CH3:22]
Reactant: NC(=S)c1ccc(-c2ccccc2)nc1
Reactant: COC(=O)CC(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)Cc1nc(-c2ccc(-c3ccccc3)nc2)sc1C
Yield: 56.6 %

Procedure:
A mixture of 6-phenyl-thionicotinamide (7.0 g) and 4-bromo-3-oxo-pentanoic acid methyl ester (9.15 g, 35 mmol) in 1,4-dioxane (30 mL) was heated at reflux for 4 h. The reaction mixture was cooled, poured into aqueous saturated NaHCO3, and extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (hexanes/EtOAc, 2/1) to afford the title compound (6.0 g, 56%). MS (ESI) m/z 325 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=[C:4]2[CH:3]=1.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[F:29])[C:22]([O:24][CH3:25])=[O:23].N1C=CC=CC=1>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:18][C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=3[F:29])[C:22]([O:24][CH3:25])=[O:23])=[O:13])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: O=C(O)c1cnc2cc(Br)ccn12
Reactant: COC(=O)c1ccc(F)c(N)c1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture comprising 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (step 3) (1.8 g, approximately 7.47 mmol) and thionyl chloride (10 ml, 137 mmol) under N2 was heated at reflux for 1.5 hrs. The reaction mixture was concentrated in vacuo and azeotroped with toluene. Methyl 3-amino-4-fluorobenzoate (1.263 g, 7.47 mmol) (pre-dried at 45° C.) was added followed by pyridine and the mixture was stirred at room temperature under N2 overnight. The reaction mixture was diluted with EtOAc and washed with H2O. The resulting solid was collected by filtration. The filtrate was dried (MgSO4) and concentrated in vacuo and triturated with ether to afford cream solid. The solids were combined and dried at 45° C. to afford the title compound;