Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.N.Cl.C[N:5](C)CCCN=C=NCC.[S:15]1[CH:19]=[CH:18][C:17]2[C:20]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:33][CH:34]4[CH2:39][CH2:38][CH:37]([C:40](O)=[O:41])[CH2:36][CH2:35]4)[CH2:26][CH2:25]3)=[CH:21][CH:22]=[CH:23][C:16]1=2>CN(C)C1C=CN=CC=1.ClCCl>[S:15]1[CH:19]=[CH:18][C:17]2[C:20]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:33][CH:34]4[CH2:39][CH2:38][CH:37]([C:40]([NH2:5])=[O:41])[CH2:36][CH2:35]4)[CH2:26][CH2:25]3)=[CH:21][CH:22]=[CH:23][C:16]1=2
Reactant: O=C(O)C1CCC(OCCCN2CCN(c3cccc4sccc34)CC2)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: O
Product: NC(=O)C1CCC(OCCCN2CCN(c3cccc4sccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 20.8 %

Procedure:
Ammonia water (28%, 0.5 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC)(0.36 g, 1.9 mmol) and 4-dimethylaminopyridine (DMAP) (0.05 g, 0.4 mmol) were added to a dichloromethane solution (10 ml) of 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-cyclohexanecarboxylic acid (0.5 g, 1.2 mmol) and the mixture was stirred at room temperature for 19 hours. To the reaction solution, dichloromethane was added and the mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=3:1→0:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from a solvent mixture of ethyl acetate-diisopropylether to obtain 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-propoxy]-cyclohexanecarboxylic acid amide (0.1 g, 22% yield), as white powder.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH2:28][O:29][CH3:30])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[O:31]1[C:35]2[CH:36]=[CH:37][C:38](B(O)O)=[CH:39][C:34]=2[CH2:33][CH2:32]1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH2:28][O:29][CH3:30])[N:8]([C:38]2[CH:37]=[CH:36][C:35]3[O:31][CH2:32][CH2:33][C:34]=3[CH:39]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: CCCCc1nc(CCOC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCc1nc(CCOC)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 71.1 %

Procedure:
A mixture of 4′-{[4-butyl-2-(2-methoxyethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2.5 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (2.0 g), copper(II) acetate (2.3 g), pyridine (2.5 mL), triethylamine (4.3 mL), molecular sieves 4 A (5.0 g) and dichloromethane (50 mL) was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (2.3 g, 72%) as a pale-yellow liquid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[C:7]([C:11]([O:13]CC)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.O.O.O.[OH-].[Li+]>O1CCCC1.O>[C:18]([CH2:17][CH2:16][C:6]1[C:5]2[C:9](=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)[NH:8][C:7]=1[C:11]([OH:13])=[O:12])([OH:20])=[O:19]
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(I)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1c(C(=O)O)[nH]c2cc(I)ccc12
Temperature: 25 °C
Yield: 95 %

Procedure:
Ethyl 6-iodo-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (4.15 g, 10 mmol) was dissolved in 25 ml tetrahydrofurane (THF) with stirring at rt. Then a solution of 1.26 g of lithium hydroxide trihydrate (3 equiv.) in 25 ml water was added and the resulting mixture was let to stir at rt for 24 h. After completion of the reaction THF was removed under reduced pressure and the pH was adjusted to 4-5, and the product was extracted with diethyl ether (3×30 ml). The organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to yield a light-beige-colored solid in 95-100% yield. mp. 230-232° C. 1H-NMR (DMSO-d6) δ 2.49 (m, 2H, 2′-H); 3.22 (m, 2H, 1′-H); 7.31 (dd, 1H, J=1.8 Hz, 5-H); 7.50 (d, 1H, J=8.5 Hz, 4-H); 7.74 (d, 1H, J=1.8 Hz, 7-H); 11.52 (s, 1H, NH); 12.53 (b, 2H, 2CO2H). 13C-NMR (DMSO-d6) δ 19.9 (C2′); 35.2 (C1′); 89.6 (C-6); 121.0 (C-7); 121.6 (C-3); 122.7 (C-4); 124.6 (C-2); 126.5 (C-3a); 127.9 (C-5); 137.3 (C-7a); 163.0 (2′-CO2H); 174.0 (2-CO2H). LC-MS (m/z): 377 [M-NH4+]+, 360 [M]+, 358 [M]−. Purity (LC-MS): 98%.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:19](=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[C:11]([NH:13][C:14](=[O:18])[CH:15](Br)[CH3:16])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[NH3:28]>ClC(Cl)C.C(OCC)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:19](=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[C:11]([NH:13][C:14](=[O:18])[CH:15]([NH2:28])[CH3:16])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)N1CCc2c(sc(NC(=O)C(C)Br)c2C(=O)c2ccccc2Cl)C1
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2c(sc(NC(=O)C(C)N)c2C(=O)c2ccccc2Cl)C1

Procedure:
841 g of 6-acetyl-2-(2-bromopropionylamino)-3-(2-chlorobenzoyl)-4,5,6,7-tetrahydro-thieno[2,3 -C]pyridine was dissolved in a 0.72 liters of dichloroethane and 1.08 liters of ethyl acetate, into which ammonia gas was introduced at -10° C. The mixture was subjected to reaction in an autoclave at 100° C. for 1 hour. After completion of the reaction, excess ammonia gas was removed and the reaction solution was poured into 3N HCl under ice-cooling conditions. After extraction with ethyl acetate, the aqueous phase was neutralized with a saturated sodium carbonate aqueous solution, followed by repeating extraction with chloroform. The resultant organic phase was washed with a saturated saline solution, followed by drying with anhydrous magnesium sulfate and removal of the solvent by distillation under reduced pressure to obtain 636.8 g of the intended compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]([NH2:23])([CH3:22])[CH3:21]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][NH:23][CH:20]([CH3:22])[CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: BrCCCOc1ccc(OCc2ccccc2)cc1
Product: CC(C)NCCCOc1ccc(OCc2ccccc2)cc1

Procedure:
In a glass lined vessel, 1-benzyloxy-4-(3-bromopropoxy)benzene (33.4 g) in 300 ml of isopropylamine was heated at 100° for 10 hours under nitrogen at 1000 psi, then the excess isopropylamine was removed in vacuo and the residue was dissolved in 300 ml of water. The solution was made alkaline with 10% sodium hydroxide and the resulting oil extracted with dichloromethane. The dichloromethane extract, dried over potassium carbonate, was concentrated and distilled to yield 22.5 g of 1-benzyloxy-4-[3-(1-methylethyl)aminopropoxy]benzene, boiling range 180°-190° (0.5 mm) (97.8% pure by gas chromatography).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=O)(=[O:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:24]1[C:28]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][NH:26]/[C:25]/1=[N:34]\[C:35]([C:37]1[C:42]([NH2:43])=[N:41][C:40]([NH2:44])=[C:39]([Cl:45])[N:38]=1)=[O:36]>>[C:1]([O:5][C:6](=[O:7])[CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:22]=[CH:21][CH:20]=[C:16]([C:17]([N:31]2[CH2:32][CH2:33][C:28]3([NH:24]/[C:25](=[N:34]/[C:35]([C:37]4[C:42]([NH2:43])=[N:41][C:40]([NH2:44])=[C:39]([Cl:45])[N:38]=4)=[O:36])/[NH:26][CH2:27]3)[CH2:29][CH2:30]2)=[O:19])[CH:15]=1)(=[O:12])=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Reactant: CC(C)(C)OC(=O)CCNS(=O)(=O)c1cccc(C(=O)O)c1
Agent: Cl
Product: CC(C)(C)OC(=O)CCNS(=O)(=O)c1cccc(C(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)c1

Procedure:
The title compound was prepared from 3-(2-tert-butoxycarbonyl-ethylsulfamoyl)-benzoic acid (Int. AD) and 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide hydrochloride in an analogous method to Example 1; LC-MS Rt 0.93 mins; 636.3 [M+H]+, Method 2minLC_v003.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[C:16]1[C:20]([C:21](Cl)=[O:22])=[C:19]([CH3:24])[O:18][N:17]=1.[CH3:25][O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH2:35])[CH2:30]1)=[O:28]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:25][O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:21]([C:20]2[C:16]([C:10]3[C:11]([F:15])=[CH:12][CH:13]=[CH:14][C:9]=3[Cl:8])=[N:17][O:18][C:19]=2[CH3:24])=[O:22])[CH2:30]1)=[O:28]
Reactant: COC(=O)N1CCCC(N)C1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCCC(NC(=O)c2c(-c3c(F)cccc3Cl)noc2C)C1
Yield: 89.5 %

Procedure:
Add 4-dimethylamino-pyridine (0.19 g, 1.5 mmol), triethylamine (3.2 mL, 23.2 mmol), and 3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl chloride (5.53 g, 20.1 mmol) to a solution of 3-amino-piperidine-1-carboxylic acid methyl ester (2.45 g, 15.5 mmol) in dichloromethane (100 mL). Stir the reaction at room temperature under nitrogen overnight. Wash the reaction with 1N HCl, saturated aqueous sodium bicarbonate solution, and brine; dry over magnesium sulfate; and concentrate. Purify by flash chromatography on silica gel (eluting with 0.75% methanol/chloroform) to give 5.49 g of the title compound as a yellow foam, 90% yield. 1H NMR: consistent with structure. MS (ion spray) 396 (M+).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[NH:3][CH:2]=1.[H-].[Na+].Cl[CH2:17][C:18]1[CH:28]=[CH:27][C:21]2[N:22]=[C:23]([S:25][CH3:26])[S:24][C:20]=2[CH:19]=1.O>CN(C=O)C>[CH3:26][S:25][C:23]1[S:24][C:20]2[CH:19]=[C:18]([CH2:17][N:3]3[C:4]4=[N:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=[C:9]4[N:1]=[CH:2]3)[CH:28]=[CH:27][C:21]=2[N:22]=1
Reactant: CSc1nc2ccc(CCl)cc2s1
Reactant: COC(=O)c1cnc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(SC)sc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a stirred solution of methyl 3H-imidazo[4,5-b]pyridine-6-carboxylate (1.34 g, 7.56 mmol) from Step 2 of this Example in anhydrous DMF (25 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 333 mg, 8.32 mmol) and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (1.3 g, 5.66 mmol) from Step 4 of Example 36 in DMF (5 mL). The mixture was allowed to warm to rt then stirred for a further 15 h. To the reaction mixture was added water (300 mL) and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and then brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM followed by 1% MeOH in DCM to afford methyl 3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (1.3 g, 46%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.95 (d, J=1.9 Hz, 1H), 8.81 (s, 1H), 8.56 (d, J=1.7 Hz, 1H), 8.00 (d, J=1.1 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.47 (dd, J=1.6, 8.4 Hz, 1H), 5.66 (s, 2H), 3.90 (s, 3H), 2.76 (s, 3H). LCMS (ESI) m/z 371 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:16]=2[C:17]([NH:19][CH2:20][C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N+:34]([C:31]1[CH:32]=[CH:33][C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:16]([CH:30]=1)[C:17]([NH:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]2[O:25][CH2:26][O:27][C:23]=2[CH:22]=1)=[O:18])([O-:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc3c(c2)OCO3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1NC1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.4 %

Procedure:
To a solution of 2-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(469 mg) in dichloromethane (6 mL) was added trifluoroacetic acid (1.07 g), and the mixture was stirred for 4 hours at ambient temperature. The reaction mixture was washed with 1N-sodium hydroxide solution, water and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 5-nitro-2-(4-piperidinylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (335 mg).
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:7]=1)=O.Cl.[NH4+:22].[OH-]>O>[C:3]([CH2:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:7]=1)(=[O:2])[NH2:22]
Reactant: COC(=O)Cc1nc(-c2ccccc2)ncc1C(=O)O
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: O
Product: NC(=O)Cc1nc(-c2ccccc2)ncc1C(=O)O
Yield: 63 %

Procedure:
A solution of 2.65 g (9.56 mmol) of 4-Methoxycarbonylmethyl-2-phenyl-pyrimidine-5-carboxylic Acid in 11.6 mL of conc NH4OH is stirred at 25° C. for 3 h. The reaction is then diluted with H2O, chilled in ice and acidified with 6M HCl. The product is collected, washed with H2O (2×) and dried in vacuo (low heat) to give 1.55 g (63%) of orange solid: 1H NMR (DMSO-d6) δ 9.17 (s, 1H), 8.44 (m, 2H), 7.67 (s, 1H), 7.60 (m, 3H), 7.02 (s, 1H), 4.12 (s, 2H); MS (ESI)) m/z 256. (M−H). Analysis for C13H11N3O3. 0.5H2O: Calcd: C, 58.63; H, 4.55; N, 15.78. Found: C, 58.88; H, 4.53; N, 15.46.
Reaction SMILES: NC(N)=NC(=O)C1C=C(S(C)(=O)=O)C(S(C)(=O)=O)=CC=1C.Br[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[CH3:30].[C:31](=[O:33])=[O:32]>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:31]([OH:33])=[O:32])=[C:24]([CH3:30])[CH:25]=1
Reactant: O=C=O
Reactant: Cc1cc(Cl)ccc1Br
Agent: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Product: Cc1cc(Cl)ccc1C(=O)O

Procedure:
In a process for preparing N-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide, the step comprising reacting 2-bromo-5-chlorotoluene with a secondary or tertiary organolithium compound and CO2 to produce 4-chloro-2-methylbenzoic acid.
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[C:7]([C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[N:15]([C:19](=[O:21])[CH3:20])[C@@H:14]([CH3:22])[CH2:13][NH:12]4)[CH:6]=[N:5]2)[CH2:3][CH2:2]1.Br[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[N:25]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1.C(O)(C)(C)C>[CH:1]1([N:4]2[CH:8]=[C:7]([C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[N:15]([C:19](=[O:21])[CH3:20])[C@@H:14]([CH3:22])[CH2:13][N:12]4[C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)[N:25]=3)[CH:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2NC[C@@H]1C
Reactant: Brc1nn(C2CCCCO2)c2ccccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2N(c2nn(C3CCCCO3)c3ccccc23)C[C@@H]1C
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 57.2 %

Procedure:
A mixture of (S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.050 g, 0.169 mmol), 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.071 g, 0.253 mmol), tris(dibenzylideneacetone)dipalladium (0.015 g, 0.017 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.020 g, 0.034 mmol), cesium carbonate (0.165 g, 0.506 mmol), and t-butanol (2.0 mL) was heated in the microwave at 100° C. for 4 h. A second portion of 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.071 g, 0.253 mmol), tris(dibenzylideneacetone)dipalladium (0.015 g, 0.017 mmol), Xantphos (0.020 g, 0.034 mmol), cesium carbonate (0.165 g, 0.506 mmol) and dioxane (2.0 mL) was added, and the mixture stirred at 100° C. for 4.5 h. A third portion of 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.071 g, 0.253 mmol), tris(dibenzylideneacetone)dipalladium (0.015 g, 0.017 mmol), Xantphos (0.020 g, 0.034 mmol), and cesium carbonate (0.165 g, 0.506 mmol) was added, and the mixture stirred at 100° C. for 18 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford 1-((2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.048 g, 57%) as a tan solid. MS (ESI, pos. ion) m/z 497 [M+H]+.
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45](O)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1.Cl.[CH3:51][C:52]1[S:53][C:54]([CH2:57][NH2:58])=[CH:55][N:56]=1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45]([NH:58][CH2:57][C:54]4[S:53][C:52]([CH3:51])=[N:56][CH:55]=4)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:48][CH:49]=1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1ncc(CN)s1
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Agent: Cl
Product: Cc1ncc(CNC(=O)c2sc(-n3cnn(Cc4ccc(F)cc4)c3=O)nc2C)s1
Yield: 68 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with (2-methylthiazol-5-yl)methanamine hydrochloride, the title compound was obtained as a white solid in 68% yield: mp 176-177° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.25 (s, 1H), 7.41-7.31 (m, 2H), 7.07-6.97 (m, 3H), 6.49 (t, J=5.3 Hz, 1H), 4.97 (s, 2 H), 4.62 (d, J=5.3 Hz, 2H), 2.70 (s, 3H), 2.64 (s, 3H); MS (ES+) m/z 445.1 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:7]=[C:6]([CH3:19])[C:5]=1[C:20]([OH:22])=O.[N:23]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][CH2:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[N:7]=[C:6]([CH3:19])[C:5]=1[C:20]([N:31]1[CH2:32][CH2:33][CH:28]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:29][CH2:30]1)=[O:22]
Reactant: COCc1c(C(=O)O)c(C)nn1-c1cccc(C(F)(F)F)c1
Reactant: C1CCN(C2CCNCC2)C1
Product: COCc1c(C(=O)N2CCC(N3CCCC3)CC2)c(C)nn1-c1cccc(C(F)(F)F)c1
Yield: 95 %

Procedure:
In analogy to the procedure described in Example 18], 5-methoxymethyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave the title compound in 95% yield as light brown viscous oil. MS: 451.2 (MH+).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([N:20]([CH3:35])[C@H:21]([CH2:33][OH:34])[CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[SH:36][C:37]1[S:38][C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[S:38]1[C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=[C:37]1[S:36][C:33](=[O:34])[C@H:21]([CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:20]([C:18](=[O:19])[C@H:9]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[CH3:35]
Reactant: Sc1nc2ccccc2s1
Reactant: CN(C(=O)[C@H](CCc1ccccc1)NC(=O)OC(C)(C)C)[C@H](CO)CCCNC(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C(=O)[C@H](CCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Sc1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 51.8 %

Procedure:
This was prepared in a two step sequence. A solution of Boc-homophenylalanyl-Nδ-Boc-Nα-methylornithinol (D) (392 mg) and 2-mercaptobenzothiazole (267 mg) in dry tetrahydrofuran (9 ml) was cooled to 0° C. under nitrogen atmosphere. Then, a solution of triphenylphosphine (1.04 g), anhydrous tetrahydrofuran (1 ml), and diethyl azodicarboxylate (620 μl) was added. The reaction mixture was stirred for 1.5 h at 0° C., concentrated in vacuo, and purified by flash chromatography (30% ethyl acetate/hexane) to give Boc-homophenylalanyl-Nδ-Boc-Nα-methylornithinyl 2-benzo-thiazolyl thioether (270 mg). This intermediate was deprotected by Procedure E to afford titled product (75 mg): HPLC [20 to 40% gradient (acetonitrile/0.1% TFA) over 60 min, retention time=42.96 min]; 1H NMR (400 MHz, D2O) δ1.49 (m, 2H), 1.83 (m, 2H), 1.98 (m, 1H), 2.18 (m, 1H), 2.79 (m, 2H), 2.82 (s, 3H), 3.09 (m, 2H), 3.57 (dd, J=14.8; 11.2 Hz, 1H), 3.70 (dd, J=14.8; 4.0 Hz, 1H), 4.46 (m, 1H), 5.01 (m, 1H), 7.17 (m, 2H), 7.38 (m, 3H), 7.49 (t, J=8.0 Hz, 1H), 7.61 (t, J=7.2 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), and 7.94 (d, J=8.4 Hz, 1H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[F:27])[C:21](O)=[O:22]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:21]([C:20]2[CH:24]=[CH:25][C:26]([F:27])=[C:18]([F:17])[CH:19]=2)[OH:22])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc(F)c(F)c1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 3,4-difluorobenzoic acid
Reaction SMILES: [CH2:1]([N:17]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[N:42])[CH:36]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[O:43]1CCO[CH2:45][CH2:44]1.[ClH:49]>C(O)C.C1C=CC=CC=1>[ClH:49].[ClH:49].[CH2:44]([O:43][C:41](=[NH:42])[C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([CH2:34][N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:36]=1)[CH3:45]
Reactant: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C#N)c1
Reactant: C1COCCO1
Agent: Cl
Solvent: CCO
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)OCC)c1
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of α-[N,N-di(n-hexadecyl)amino]-m-toluonitrile (29.0 g., 0.05 mole), ethanol (40 ml., 0.67 mole) and dioxane (100 ml.) was saturated with dry hydrogen chloride gas for 40 minutes at 15°-25° C. It was then stoppered and held overnight at room temperature. Thin layer chromatography analysis (4:1, benzene:ethanol on silica gel) indicated complete reaction of the nitrile. The mixture was evaporated in vacuo yielding the named product quantitatively as a foam [35.0 g., ~ 100% yield, Rf .87 (4:1, benzene: ethanol on silica gel)].