Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:20](=O)([O-])[O-].[Cs+].[Cs+].C(I)C>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([N:13]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:20])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)c(C)c(NC2CCCC2)c1C
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCI
Product: COC(=O)c1cc(Br)c(C)c(N(C)C2CCCC2)c1C
Temperature: 80 °C
Yield: 82.4 %

Procedure:
To a stirred solution of methyl 5-bromo-3-(cyclopentylamino)-2,4-dimethylbenzoate (0.3 g, 1.07 mmol) in DMF (5 mL), cesium carbonate (0.697 g, 2.14 mmol) and ethyl iodide (0.3 mL, 5.38 mmol) were added; resulting reaction mass was heated at 80° C. for 12 h. On completion, reaction mass was cooled to room temperature and filtered, residue was washed with ethyl acetate and filtrate was concentrated and then purified by column chromatography to afford desired compound (0.3 g, 82%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:18])[CH:10]=[C:11]([S:15]([CH3:17])=O)[O:12]2)=[C:7]([O:19][CH3:20])[CH:6]=1)([CH3:3])[CH3:2].[OH:21][C:22]1[CH:27]=[CH:26]C(S)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[OH:21][C:22]1[CH:27]=[CH:26][C:17]([S:15][C:11]2[O:12][C:13]3[C:8]([C:9](=[O:18])[CH:10]=2)=[C:7]([O:19][CH3:20])[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=3)=[CH:24][CH:23]=1
Reactant: COc1cc(OC(C)C)cc2oc(S(C)=O)cc(=O)c12
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OC(C)C)cc2oc(Sc3ccc(O)cc3)cc(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
A mixture of 146 mg of 7-isopropoxy-5-methoxy-2-methylsulfinylchromone (0.493 mmol ) , 93 mg of 4-hydroxybenzenethiol(0.740 mmol), 102 mg of potassium carbonate (0.740 mmol) and 6 ml acetone was stirred for 2 hours at room temperature. The reaction solution was neutralized with dilute hydrochloric acid and extracted twice with ethyl acetate, and the organic layer was washed with saturated NaCl water and was then dried over sodium sulfate anhydride. The solvent was distilled off under reduced pressure, and the crude product was subjected to recrystallization from acetone-methanol, to give 102 mg of 2-(4-hydroxyphenylthio)-7-isopropoxy-5-methoxychromone (57% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][CH:20]([CH3:36])[C:21]([N:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>>[C:24]1([N:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:21]([CH:20]([NH:19][C:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:12])[CH3:36])=[O:22])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(N)C(=O)N(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: O=C(Cl)C(=O)Cl
Product: CC(NC(=O)c1cc2ccccc2[nH]1)C(=O)N(c1ccccc1)c1ccccc1
Yield: 83.6 %

Procedure:
Working in a manner similar to that described in Example 9, but starting with 2-indolcarboxylic acid (1.3 g), oxalyl dichloride (1 g) and (RS)-2-amino-N,N-diphenylpropionamide (1.2 g), and after recrystallization in acetonitrile, (RS)-N-(1-diphenylcarbamoylethyl)-2-indolcarboxamide (1.6 g), m.p. 242° C., is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]=2[O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:46][O:47][CH2:48][CH2:49]Br>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:49][CH2:48][O:47][CH3:46])=[CH:22][CH:23]=3)[N:18]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:17]=2[O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(O)cc2n1-c1ccccc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3ccccc3C)n(-c3ccccc3)c2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
The compound of example 8 (63.0 mg, 119 μmol) was dissolved in DMF, and cesium carbonate (116 mg, 358 μmol) and 2-bromoethyl methyl ether (13.5 μl, 143 μmol) were added. The reaction mixture was stirred at 50° C. for 3 h. The cooled mixture was diluted with water and extracted with EA. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (EA/HEP). 60.0 mg of the title compound were obtained.
Reaction SMILES: C[O:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4]>C(OCC)(=O)C>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([OH:5])(=[O:4])=[O:2])=[CH:7][CH:8]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
When the reaction ended, the mixture was allowed to cool and was left to stand overnight. The crystals that precipitated were filtered out, washed with dimethyl formamide, and dried under reduced pressure, yielding 3.0 g of intermediate B. To 2.0 g of intermediate B was then added 20 mL of p-toluenesulfonic acid methyl ester, and the mixture was stirred with heating for 6 hours at 120° C. The mixture was allowed to cool, after which 30 mL of ethyl acetate was added, and stirring was conducted for 30 minutes. The precipitating crystals were filtered out and dried, yielding 2.75 g of p-toluenesulfonate of V-1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[CH3:23][O:24][C:25](=[O:30])[CH2:26][C:27](Cl)=[O:28]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]([C:27](=[O:28])[CH2:26][C:25]([O:24][CH3:23])=[O:30])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)CC(=O)Cl
Reactant: COC(=O)c1cc(Cl)cn1NCc1ccc(C(F)(F)F)cc1
Product: COC(=O)CC(=O)N(Cc1ccc(C(F)(F)F)cc1)n1cc(Cl)cc1C(=O)OC

Procedure:
Prepared according to the acylation condition used in Example 2 step f) from 4-chloro-1-(4-trifluoromethyl-benzylamino)-1H-pyrrole-2-carboxylic acid methyl ester and chlorocarbonylacetic acid methyl ester (1.5 eq.). 1H NMR (CDCl3, δ in ppm): 7.56 (d, 2H, J=8.0 Hz), 7.30 (d, 2H, J=8.0 Hz), 6.84 (d, 1H, J=2.2 Hz), 6.52 (d, 2H, J=2.2 Hz), 5.31 (d, 1H, J=14.6 Hz), 4.48 (d, 1H, J=15.0 Hz), 3.73 (s, 3H), 3.72 (s, 3H), 3.20 (dd, 3H, J=14.6 Hz, 16.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:19].Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:19][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:22][CH:23]=1
Reactant: COCCNC1CCc2ccc(N)c(OC)c2CC1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: COCCNC1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)c2CC1
Yield: 10.1 %

Procedure:
In an analogous manner to Experimental 691, part c, 1-methoxy-N*7*-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide were combined to yield N-((1R,2R)-2-{5-Chloro-2-[1-methoxy-7-(2-methoxy-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide (21.60 mg, 10.1% yield) as a beige foam. Purification again separated the compound into its corresponding enantiomers. 1H-NMR (CDCl3) δ 7.93 (s, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.29 (s, 1H), 6.87 (d, J=8.2 Hz, 1H), 5.42 (d, J=7.4 Hz, 1H), 3.92 (m, 1H), 3.71 (s, 3H), 3.51 (t, J=4.8 Hz, 2H), 3.36 (s, 3H), 3.24 (m, 2H), 2.85 (m, 8H), 2.69 (m, 1H), 2.48 (m, 1H), 2.22 (d, J=10.4 Hz, 2H), 2.10 (m, 2H), 1.38 (m, 7H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[C:26]([S:40]([NH:43]C(C)(C)C)(=[O:42])=[O:41])[C:27]([O:30]CC3C=CC(OC)=CC=3)=[N:28][CH:29]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[C:26]([S:40]([NH2:43])(=[O:42])=[O:41])[C:27]([OH:30])=[N:28][CH:29]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COc2ncc(-c3nc(NCc4ccccc4)c4c(-c5ccccc5)ccn4n3)cc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)cnc1O
Temperature: 60 °C
Reaction time: 6 h
Yield: 27.5 %

Procedure:
5-(4-(Benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)-N-(tert-butyl)-2-((4-methoxybenzyl)oxy)pyridine-3-sulfonamide (0.100 g, 0.154 mmol) was dissolved in TFA (25 mL) and stirred for 6 h at 60° C. TFA was removed under reduced pressure and reaction mixture was diluted with saturated sodium bicarbonate (100 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure to give a residue which was purified by preparative HPLC (Condition B-70 as described in general methods) to get 5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)-2-hydroxypyridine-3-sulfonamide (20.0 mg, 27.5%). LCMS Condition B-38: retention time 2.48 min, [M−1]=471.0. HPLC Condition B-6: retention time 15.64 min, Purity 99.67%. 1H NMR (400 MHz, DMSO-d6) δ 4.75 (d, J=8.0 Hz, 2H), 6.61 (t, J=8.0 Hz, 1H), 6.74 (d, J=4.0 Hz, 1H), 7.03 (s, 2H), 7.24-7.28 (m, 1H), 7.32-7.39 (m, 5H), 7.44-7.52 (m, 4H), 7.87 (d, J=2.8 Hz, 1H), 8.42 (d, J=4.0 Hz, 1H), 8.77 (d, J=4.0 Hz, 1H), 12.70 (s, 1H).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14](=[O:23])[CH2:15][C@@H:16]([CH2:20][CH2:21][CH3:22])[C:17](O)=[O:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:24]([O:28][C:29](=[O:37])[CH2:30][CH:31]([NH2:36])[CH:32]([OH:35])[CH2:33][F:34])([CH3:27])([CH3:26])[CH3:25].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:24]([O:28][C:29](=[O:37])[CH2:30][CH:31]([NH:36][C:17](=[O:18])[CH:16]([CH2:15][C:14]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:23])[CH2:20][CH2:21][CH3:22])[CH:32]([OH:35])[CH2:33][F:34])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Reactant: CCC[C@H](CC(=O)n1c2ccccc2c2ccccc21)C(=O)O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Temperature: 25 °C
Yield: 53 %

Procedure:
A stirred mixture of (2R)-2-(2-carbazol-9-yl-2-oxo-ethyl)-pentanoic acid (2.94 g, 9.50 mmol), 3-amino-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester (2.07 g, 9.99 mmol), HOBT (1.41 g, 10.43 mmol), DMAP (1.34 g, 10.97 mmol) and anhydrous THF (40 ml) was cooled to 0° C. before EDC (2.00 g, 10.43 mmol) was added. The mixture was allowed to warm to room temperature during 16 h then concentrated under reduced pressure. The residue purified by flash chromatography (33% EtOAc in 40/60 hexanes) to give the sub-title compound (2.51 g, 53%) as a foam: 1H NMR (400 MHz, CDCl3) δ 0.90-1.03 (3H, m), 1.20-1.90 (13H, m), 2.50-3.00 (3H, m), 3.12-3.26 (1H, m), 3.59-3.80 (2H, m), 4.00-4.68 (3H, m), 6.53-6.89 (1H, m), 7.30-7.52 (4H, m), 7.95-8.05 (2H, m), 8.15-8.26 (2H, m); 19F NMR (376 MHz, CDCl3) −229.10, −229.34, −230.95, −231.09.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].Cl.[CH2:18](N=C=NCCCN(C)C)[CH3:19].C(O)C>C(OCC)C.CN(C)C1C=CN=CC=1>[CH2:18]([O:15][C:14](=[O:16])[CH2:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)[CH3:19]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CC(=O)O)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 40 h
Yield: 95 %

Procedure:
In an oven-dried 2 L round bottom flask under nitrogen, ((3S)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-pyrrolidinyl)acetic acid (60 g, 262 mmol) dissolved in diethyl ether (600 mL) was treated with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (55.2 g, 288 mmol), 4-(dimethylamino)pyridine (3.20 g, 26.2 mmol), and ethanol (33.6 ml, 576 mmol) at room temperature and the mixture was stirred for 40 h. The reaction mixture began as a white suspension, but then became a pale yellow solution with gummy yellow material at the bottom of the flask after 1 h, which was difficult to stir. Another stir bar was added in order to get the mixture stirring; however, a vortex was not obtained so the reaction was stirred longer than overnight to ensure the reaction went to completion. The reaction mixture was diluted with ether (400 mL) and washed with 1M aqueous sodium hydrogen sulfate solution (800 mL) and saturated aqueous sodium bicarbonate solution (800 mL). The organic phase was isolated, dried over magnesium sulfate, and concentrated to dryness to give the title compound as a clear pale yellow liquid (64.1 g, 249 mmol, 95%). MS(ES)+m/e 258.2 [M+H]+, 280.2 [M+Na]+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[OH:28][C@@:29]([CH3:41])([C:33]([NH:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[O:34])[C:30](O)=[O:31]>>[CH2:13]([O:12][CH2:11][CH2:10][N:7]1[C:8](=[O:9])[C@@H:2]([NH:1][C:30](=[O:31])[C@:29]([OH:28])([CH3:41])[C:33]([NH:35][CH2:36][C:37]([F:38])([F:39])[F:40])=[O:34])[C:3]2[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=2[C:5]2[CH:23]=[CH:22][CH:21]=[CH:20][C:6]1=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@](O)(C(=O)O)C(=O)NCC(F)(F)F
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: C[C@](O)(C(=O)NCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and (S)-2-hydroxy-2-methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid, the title compound was prepared in the same manner as described for example 1c. Colorless, amorphous solid (91%). MS: m/e=556(M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([CH2:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#N)=[CH:15]C=3)=[N:9][C:8]=2[CH:21]=1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].O.[N:31]1C=CC=C[CH:32]=1>>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([C:12]3[CH:13]=[CH:20][C:19]([C:32]#[N:31])=[C:16]([CH3:15])[CH:17]=3)=[N:9][C:8]=2[CH:21]=1
Reactant: N#Cc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3s2)cc1
Reactant: c1ccncc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(-c2nc3cc(N)ccc3s2)ccc1C#N
Temperature: 95 °C

Procedure:
8.8 g (29.8 mmol) of 4-(5-nitro-benzothiazol-2-ylmethyl)-benzonitrile are dissolved in 300 ml pyridine, combined with 15.4 g sodium dithionite and 60 ml water at 50° C. and heated to 95° C. for 1 hour. The pyridine is distilled off, the residue is combined with ice water, the precipitated product is suction filtered and dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14].[C:18]([OH:21])(=[S:20])[CH3:19].CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][S:20][C:18](=[O:21])[CH3:19]
Reactant: C=Cc1cccc(CC(=O)OC)c1C(=O)OC
Reactant: CC(O)=S
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COC(=O)Cc1cccc(CCSC(C)=O)c1C(=O)OC
Temperature: 25 °C
Yield: 31.9 %

Procedure:
Nitrogen was bubbled through a solution of 2-methoxycarbonylmethyl-6-vinyl-benzoic acid methyl ester (1.31 g, 5.60 mmol), thioacetic acid (4.00 mL, 56.0 mmol), and AIBN (0.184 g, 1.10 mmol) in benzene (30 mL) for 3 h at rt to remove oxygen. The mixture was heated at reflux for 3 h. The solution was allowed to cool to rt and saturated aqueous NaHCO3 (100 mL) was added. The mixture was extracted with EtOAc (100 mL) and the organic layer was washed with H2O (100 mL) and brine (100 mL), then dried over MgSO4 and concentrated in vacuo. Flash chromatography on SiO2 (10% EtOAc/hexanes) provided 2-(2-acetylsulfanyl-ethyl)-6-methoxycarbonylmethyl-benzoic acid methyl ester as a yellow solid (0.555 g, 33%): 1H NMR (CDCl3): δ 2.40 (s, 3H), 2.94–2.99 (m, 2H), 3.13–3.18 (m, 2H), 3.75 (s, 3H), 3.78 (s, 2H), 3.99 (s, 3H), 7.25 (d, J=7.6 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][N:32]=3)[C:28]#[N:29])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[C:27]([C:28]4[S:4][C:3]5[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=5[C:1](=[O:10])[N:29]=4)[CH:30]=[CH:31][N:32]=3)[CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: N#Cc1ccnc(N2CCN(c3ccc(F)cc3)CC2)c1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2ccnc(N3CCN(c4ccc(F)cc4)CC3)c2)sc2ccccc12
Yield: 17.9 %

Procedure:
Methyl thiosalicylate (0.70 g, 4.2 mmol) and 2-[4-(4-fluorophenyl)-1-piperazinyl]isonicotinonitrile (0.69 g, 2.4 mmol) were dissolved in toluene (2.0 ml), and triethylamine (0.71 ml, 5.1 mmol) was added thereto. The reaction mixture was refluxed for 17 hrs and the precipitated crystals were collected by filtration. The filtrate was concentrated, subjected to a silica gel (50 g) column chromatography, eluted with hexane-ethyl acetate (2:1, v/v) to give crystals, which were combined with the previously obtained crystals and recrystallized from acetone-ethanol to give the titled compound (0.18 g, 17%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[H-].[Na+].F[C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:32]=1[F:40]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([N:17]([C:31]4[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:32]=4[F:40])[CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[C:11]=3[CH:10]=[N:9]2)=[CH:26][CH:27]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: COc1ccc(Cn2ncc3c(NCCN4CCOCC4)ccnc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ncc3c(N(CCN4CCOCC4)c4ccc([N+](=O)[O-])cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.2 %

Procedure:
1-(4-Methoxybenzyl)-N-(2-morpholinoethyl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.025 g, 0.06804 mmol) was charged to a pressure tube in DMF (1 mL). NaH (0.004082 g, 0.1021 mmol) was added, and the reaction was allowed to stir at room temperature for 15 minutes. 1,2-difluoro-4-nitrobenzene (0.009389 ml, 0.08505 mmol) was added, and the reaction was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (25 mL) and washed with water (15 mL). The organics were then dried with brine, dried over Na2SO4, filtered and concentrated. Purification via flash Si 5 g eluting with 1-5% MeOH/DCM to afford 28 mg (80%) of product as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.32 (d, 1H), 8.14 (m, 2H), 7.61 (t, 1H), 7.30 (m, 2H), 6.82 (d, 3H), 6.43 (d, 1H), 5.54 (s, 2H), 4.05 (t, 2H), 3.75 (s, 3H), 3.59 (t, 4H), 2.76 (t, 2H), 2.44 (m, 4H); 19F NMR (376 MHz, CDCl3) −113.92 (s, 1F); LRMS (apci pos): 307.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21](C#N)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[C:26](=[O:29])([O-])[O-:27].[Na+].[Na+]>S(=O)(=O)(O)O.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:26]([OH:27])=[O:29])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2c(OCc3nnc4ccc(C#N)cn34)ccnc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(OCc3nnc4ccc(C(=O)O)cn34)ccnc2c1
Temperature: 100 °C
Yield: 89 %

Procedure:
3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile (0.050 g, 0.15 mmol) was dissolved in concentrated sulfuric acid (0.375 mL) and water (0.125 mL). The reaction mixture was heated at 100° C. for 3.5 hours then slowly poured in to ice. The mixture was adjusted to approx. pH 7 with saturated aqueous sodium carbonate. A precipitate formed which was collected on a glass frit, washing with water. The solid was dried under high vacuum to afford 3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (0.047 g, 89% yield) as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=[O:8].C1COCC1.[CH:14]1([CH2:20][Mg]Br)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CCOCC>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]([OH:8])[CH2:20][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1ncsc1C=O
Reactant: Br[Mg]CC1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ncsc1C(O)CC1CCCCC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A 3-neck, 100 mL round-bottom flask was charged with the product from Example 22D (412.6 mg, 3.5 mmol) and anhydrous THF (15 mL) under N2 atmosphere. The reaction was cooled to −10° C. Cyclohexylmethylmagnesium bromide (7 mL, of a 1.0M solution in ether, 7 mmol) was added dropwise. The reaction was stirred for 1 hour, warmed to room temperature, and stirred for an additional 3 hours. The reaction was quenched with 10 mL THF/1M HCl (1:1). The aqueous and organic layers were separated. The pH ofthe aqueous layer was adjusted to 3 with 1M HCl. The aqueous layer was extracted with EtOAc (3×10 mL). All organic layers were combined and washed with brine, dried (MgSO4), and concentrated under vacuum. The residue was purified by silica gel column (1:1 EtOAc/hexanes) to provide 425.2 mg (58%) of the title compound as an orange oil.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.FC(F)(F)C(O)=O>>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCOCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
A mixture of tert-butyl 3-[2-(6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl)ethoxy]propionate (0.41 g, 1.0 mmol) and trifluoroacetic acid (5 ml) was stirred at 0° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the titled compound (0.30 g, 85%).