Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[NH:25][C:24]5[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=5[N:22]=4)=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.C(O)(=O)C>C1COCC1.[Pd]>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:8]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[NH:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: C1=C(c2cccnc2Oc2ccc(Nc3nc4ccccc4[nH]3)cc2)CCOC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1cnc(Oc2ccc(Nc3nc4ccccc4[nH]3)cc2)c(C2CCOCC2)c1

Procedure:
To a round bottomed flask was added N-(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine (0.0784 g, 0.204 mmol), palladium, 10% wt. on activated carbon (0.043 g, 0.041 mmol), and acetic acid (0.023 mL, 0.408 mmol) in THF (a few drops of MeOH was added to help solubility). To remove oxygen from the round bottomed flask, the flask was flushed by nitrogen and the placed under vacuum repeatedly. Hydrogen gas was then introduced to the reaction and allowed to stir. Upon completion, the reaction was filtered through celite. The crude product was run through a SCX cartridge. Impurities were removed from column using DCM and MeOH. The product was flushed from the cartridge using 2.0 ammonia in MeOH to provide N-(4-(3-(Tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine. MS (ESI, pos. ion) m/z: 387.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH3:1][CH:2]([NH:6][C:7]1[CH:15]=[CH:14][C:10]2[N:11]=[CH:12][NH:13][C:9]=2[CH:8]=1)[CH2:3][CH2:4][CH3:5].[CH3:16][S:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:16][S:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:6]([CH:2]([CH2:3][CH2:4][CH3:5])[CH3:1])[C:7]2[CH:15]=[CH:14][C:10]3[NH:11][CH:12]=[N:13][C:9]=3[CH:8]=2)=[CH:20][CH:19]=1
Reactant: CSc1ccc(CBr)cc1
Reactant: CCCC(C)Nc1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCC(C)N(Cc1ccc(SC)cc1)c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from N-(pentan-2-yl)benzimidazol-5-amine (102 mg; 0.5 mmol; 1 eq.), 4-methylthiobenzylbromide (120 mg; 0.55 mmol; 1.1 eq.) and K2CO3 (76 mg; 0.55 mmol; 1.1 eq.) according to method 6; Yield: 0.038 g (22.4%); MS m/z: 340.3 [M+H]+; 1H-NMR (400 MHz, DMSO d6): δ 0.85-0.89 (m, 3H); 1.12 (d, 3H, 3J=6.6 Hz); 1.33-1.47 (m, 3H); 1.61-1.68 (m, 1H); 2.40 (s, 3H); 3.92-3.94 (m, 1H, CH3—N—CH—C3H7); 4.30 (s, 2H); 6.77-6.79 (m, 2H); 7.13-7.15 (m, 2H); 7.23-7.25 (m, 2H); 7.31-7.33 (m, 1H); 7.90 (s, 1H); 11.90 (br s, 1H); HPLC (METHOD [A]): rt 16.75 min (85.6%)
Reaction SMILES: C(Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[C:10]([O:13][C:14](=[O:16])[CH3:15])(=[O:12])[CH3:11]>>[C:10]([O:13][C:14](=[O:16])[C:15]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)(=[O:12])[C:11]1[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)OC(C)=O
Product: O=C(OC(=O)c1ccccc1)c1ccccc1

Procedure:
300 g of benzoyl chloride (2.13 mol) are mixed with 91 g of acetic anhydride (0.89 mol) and the mixture is heated to 100° to 120° C. The resultant acetyl chloride is removed by distillation under reduced pressure (400 mbar) and, upon completion of the reaction, excess benzoyl chloride is removed by distillation at about 7 mbar. The residue consists of pure benzoic anhydride. Yield: 200 g (=99% of theory) of benzoic anhydride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([C:18]([O:20]CC)=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([C:18]([OH:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ccccc1-c1ccc(C(=O)OC)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1-c1ccccc1C(=O)O
Temperature: 100 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A mixture of 2-ethyl 4′-methyl 2′-methyl-biphenyl-2,4′-dicarboxylate (2.404 g), ethanol (12 ml) and 4N aqueous sodium hydroxide solution (6 ml) was stirred at 100° C. overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and water (50 ml) was added to the obtained residue. This mixture was adjusted to pH 1 with 6N hydrochloric acid (5 ml), ethanol (10 ml) was added, and the mixture was stirred at room temperature for 10 min. This suspension was filtered, the obtained solid was washed with 20v/v % ethanol-water (10 ml), air-dried, and dried under reduced pressure at 80° C. to give the title compound (1.957 g, 95%).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:35])[NH:24][C:25]4[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=4)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.Cl>C1COCC1.O.[OH-].[Li+]>[F:34][C:31]([F:32])([F:33])[C:28]1[N:27]=[CH:26][C:25]([NH:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH:8]4[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:36])=[O:2])[CH2:10][CH2:9]4)=[CH:12][CH:13]=3)=[N:18][CH:19]=2)=[O:35])=[CH:30][CH:29]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(C(=O)Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1CCC(c2ccc(-c3ccc(C(=O)Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To 60 mg (0.1 mmol) (4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester in THF/H2O (10 mL; 4:1), 5 mL (4M) aqueous Lithium Hydroxide solution was added and the mixture stirred at 60° C. for 5 hours. Acidified with concentrated hydrochloric acid which precipitated the desired compound. Filtered and dried under vacuum to afford (4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid, which was subsequently dissolved in methanol (5 mL) one equivalent of potassium hydroxide and 2 mL of H2O were added and the resulting mixture was stirred at 40 C for 2 hours. Evaporated to dryness to afford (4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid as the potassium salt: M+1=484.1. HRMS=484.1822. 1H NMR (400 MHz, MeOD) ppm 0.79 (d, J=7.33 Hz, 1 H) 1.11 (td, J=12.44, 2.91 Hz, 3 H) 1.43-1.55(m, 2 H) 1.67-1.78 (m, J=7.14, 7.14, 6.95, 6.57 Hz, 2 H) 1.79-1.89 (m, 3 H) 2.02 (d, J=7.33 Hz, 2 H) 2.14(t, J=7.33 Hz, 1 H) 2.47 (s, 1 H) 7.29 (d, J=8.34 Hz, 2 H) 7.75 (d, J=8.59 Hz, 1 H) 7.88-7.95 (m, 2 H) 8.31(dd, J=8.46, 2.40 Hz, 1 H) 8.43 (dd, J=8.46, 2.15 Hz, 1 H) 8.97 (d, J=2.27 Hz, 1 H) 9.08 (d, J=1.52 Hz, 1H)
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:10]1[C:18]2[NH:17][C:16]3[CH2:19][CH2:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][C:15]=3[C:14]=2[CH:13]=[CH:12][CH:11]=1.[N:30]1([CH2:36][CH2:37][OH:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)Cl.[Cu]I>[N:30]1([CH2:36][CH2:37][O:38][C:10]2[C:18]3[NH:17][C:16]4[CH2:19][CH2:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][C:15]=4[C:14]=3[CH:13]=[CH:12][CH:11]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: OCCN1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(I)cccc3c2C1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3c(OCCN4CCCCC4)cccc3c2C1
Temperature: 150 °C
Yield: 25 %

Procedure:
Tri-potassium orthophosphate (1.92 g, 9.04 mmol), tert-butyl 6-iodo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (1.80 g, 4.52 mmol) and copper(I) iodide (0.430 g, 2.26 mmol) were suspended in 2-(piperidin-1-yl)ethanol (15 ml, large excess) and sealed into a microwave tube after bubbling argon through the solution for 5 minutes. The reaction was heated to 150° C. for 1.5 hours in the microwave reactor and cooled to RT. This reaction was repeat three times and the combined crude reaction mixture worked as follows. The mixture was diluted with DCM (50 mL) and washed with NaOH (3×30 mL), dried over sodium sulfate and the solvent removed under reduced pressure. The crude product was purified by preparative HPLC (0.1% HCOOH, CH3CN, H20). Fractions containing the desired compound were evaporated to dryness to afford tert-butyl 6-(2-(piperidin-1-yl)ethoxy)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (1.33 g, 25% yield) as a yellow gum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1.[Br:21][CH2:22][C:23](=O)[CH2:24][Cl:25]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([CH2:24][Cl:25])[CH2:22][Br:21])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Reactant: O=C(CCl)CBr
Solvent: C1CCOC1
Product: ClCC(CBr)=NNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1

Procedure:
In the manner given in Example 1, 7-bromo-2-hydrazino-5-(2-pyridyl)-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1 -bromo-3-chloro-propanone under nitrogen to give 7-bromo-2-[[2-bromo-1-(chloromethyl)ethylidene]hydrazino]-5-(2-pyridyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH2:10][CH3:11])[C:3]=1[CH:12]=O.[OH-].[Na+].[C:16]1([CH2:22][C:23]#[N:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[NH2:24][C:23]1[C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:3]2[C:2](=[CH:7][C:6]([CH2:8][CH3:9])=[N:5][C:4]=2[CH2:10][CH3:11])[N:1]=1
Reactant: N#CCc1ccccc1
Reactant: CCc1cc(N)c(C=O)c(CC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc2nc(N)c(-c3ccccc3)cc2c(CC)n1

Procedure:
A mixture of 4-amino-2,6-diethylpyridine-3-carbaldehyde (2.2 g), ethanol (26 ml), aqueous sodium hydroxide solution (10% w/v; 2.2 ml) and phenylacetonitrile (3.8 ml) was heated at reflux for 2 hours. Volatile material was removed by evaporation and the residue was partitioned between ethyl acetate and 2M hydrochloric acid. The organic phase was separated and discarded. The aqueous phase was adjusted to pH 6 with solid sodium carbonate and then extracted twice with dichloromethane. The combined extracts were dried (MgSO4) and solvent was removed by evaporation to give 2-amino-5,7-diethyl-3-phenyl-1,6-naphthyridine (B) as a pale yellow solid (3.2 g); m.p. 109.5°-112° C.; NMR (d6 -DMSO): 1.27(t, 3H), 1.28(t, 3H), 2.77(q, 2H), 3.09(q, 2H), 6.41(broad, 2H), 7.05(s, 1H), 7.4-7.6(m, 5H), 7.96(s, 1H); mass spectrum (+ve FAB, methanol/NBA): 278 (M+H)+ ; microanalysis, found: C, 68.1; H, 6.5; N, 13.1%; C18H19N3.HCl.0.25H2O requires: C, 68.0; H, 6.5; N, 13.2%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Ca+2].O.[C:20](Cl)(Cl)=[S:21]>CCOCC>[C:8]1([C:7]2[C:2]([N:1]=[C:20]=[S:21])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1ncccc1-c1ccccc1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CCOCC
Product: S=C=Nc1ncccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6 G. of 2-amino-3-phenylpyridine and 7.4 g. of calcium carbonate in 500 ml. of water is added to a solution of 2.9 ml. thiophosgene in 105 ml. of ether. The reaction mixture is stirred at room temperature for 3 hours and the ether layer is separated. The water layer is extracted with ether and the combined ether extracts dried and evaporated to dryness affording 3-phenyl-2-pyridylisothiocyanate. The residue from the evaporation is allowed to stand at room temperature for 3 days. The reaction mixture is then triturated with ether and filtered affording 9-phenyl-3-(3-phenyl-2-pyridyl) pyrido (1,2-a) 1,3,5-triazine-2,4-dithione m.p. 90°-92° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[C:9]([N+:14]([O-])=O)=[N:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)[CH3:2].C.O.NN>CO>[CH2:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Oc2cccnc2[N+](=O)[O-])c(OC)c1
Agent: NN
Solvent: O
Solvent: CO
Product: CCc1ccc(Oc2cccnc2N)c(OC)c1
Yield: 96.7 %

Procedure:
To a stirred solution of 3-(4-ethyl-2-methoxyphenoxy)-2-nitropyridine (1.3 g, 4.7 mmol) in methanol (30 ml) were added anhydrous Ferric chloride (66 mg) and activated charcoal (66 mg). The resulting mixture was heated to reflux and Hydrazine hydrate (80%) (2 mL, 39 mmol) was added dropwise. The reaction was allowed to stir under reflux condition for 5 hours, then filtered through celite. The filtrate was concentrated under reduced pressure, taken in ethyl acetate (150 ml). The organic phase was washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.11 g of the title compound, 100% yield.
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.Cl[CH2:12][C:13]([N:15]([C:17]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)[CH3:16])=[O:14].N>CO>[Cl:31][C:28]1[CH:29]=[CH:30][C:17]2[N:15]([CH3:16])[C:13](=[O:14])[CH2:12][N:2]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]=2[CH:27]=1
Reactant: CN(C(=O)CCl)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: N
Solvent: CO
Product: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Yield: 96.09 %

Procedure:
A mixture of hexamethylenetetramine (17.5 g., 0.125 mol), methanol (135.5 ml) and 2(2-chloro-N-methylacetamido)-5-chlorobenzophenone (80.5 g., 0.25 mol) was saturated with ammonia. Heat the stirred mixture slowly to reflux with a steady stream of ammonia flowing through the mixture. During the course of the reaction ##STR5## was prepared. The product was not isolated. Hold at reflux for 6 hours. Stop the flow of ammonia and remove the solvent under vacuum. Take up the residue in a mixture of toluene (500 ml.) and hot water (500 ml). Separate the toluene phase and add to it, with stirring, 3N nitric acid (169 ml). The crystals which separate are filtered, wash with toluene (50 mls) and resuspended in a mixture of toluene (250 ml) and water (250 ml). Concentrated ammonia (30 ml) is added to pH 8. The toluene phase is separated, washed with water (250 ml) and then distilled to dryness in vacuo yielding 96.09% of 7-chloro-1-methyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, melting point 125° to 127° C.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:18])[N:4](C)[C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:19][O:20]C1C=C2C(=CC=1)NC(=O)C2=O>>[OH:1][C:2]1[C:3](=[O:18])[NH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:8]([O:20][CH3:19])=[CH:7][CH:6]=2
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Reactant: CCOC(=O)c1c(O)c(=O)n(C)c2ccccc12
Product: CCOC(=O)c1c(O)c(=O)[nH]c2ccc(OC)cc12

Procedure:
Intermediate 27 was prepared as a white powder following the procedure described for Intermediate 16 by replacing indoline-2,3-dione with 5-methoxyindoline-2,3-dione. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.20 (1 H, s), 10.22 (1 H, br. s.), 7.27 (1H, d, J=8.8 Hz), 7.04 (1H, dd, J=9.1, 2.5 Hz), 6.82 (1 H, d, J=2.5 Hz), 4.41 (2 H, q, J=7.1 Hz), 3.32 (3 H, s), 1.35 (3 H, t, J=7.1 Hz). LC-MS (ESI) m/z 264.0 (M+H), RT=1.64 min (Method B).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)#[CH:2].Br[C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1.CCN(C(C)C)C(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:17]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[C:3]([C:1]#[C:2][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: Brc1ccc2ccccc2n1
Reactant: C#Cc1nc2c(N3CCOCC3)ccnn2c1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of compound 41d (1.4 g, 3.4 mmol) in DMF (5 mL) was treated with 2-bromoquinoline (2.0 g, 9.6 mol), Pd(PPh3)2Cl2 (240 mg, 0.34 mmol), Cut (30 mg, 0.16 mmol) and DIPEA (4.4 g, 34.11 mmol) under N2. The reaction mixture was stirred at rt overnight, and concentrated in vacuo. The residue obtained was purified by flash column chromatography on silica gel (EtOAc:petroleum ether (1:2)) to obtain compound 41e as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C31H34N6O3: 539.3 (M+H). found: 539.4.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[N:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)([CH3:38])[CH3:37]>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:42]4[CH2:43][CH2:44][N:39]([CH:36]([CH3:38])[CH3:37])[CH2:40][CH2:41]4)[N:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Reactant: CC(C)N1CCNCC1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(C)C)CC4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (250 mg, 0.471 mmol) in 1,4-dioxane (5 mL) was added 1-isopropylpiperazine (302 mg, 2.36 mmol). The reaction mixture was stirred at room temperature for 2.5 h and concentrated to give the product which was used without further purification. LCMS-ESI+ calc'd for C33H41ClN5O3S (M+H+): 622.3; Found: 622.2 (M+H+).
Reaction SMILES: O[C:2]1([OH:20])[C:10](=[O:11])[C:9]2[C:4](=[C:5]([N+:16]([O-:18])=[O:17])[CH:6]=[CH:7][C:8]=2[NH:12][C:13](=[O:15])[CH3:14])[C:3]1=[O:19].[CH3:21][C:22]1[CH:23]=[C:24]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:25]=[CH:26][C:27]=1[CH3:28]>S(=O)(=O)(O)O>[C:13]([NH:12][C:8]1[CH:7]=[CH:6][C:5]([N+:16]([O-:18])=[O:17])=[C:4]2[C:9]=1[C:10](=[O:11])[C:2]([C:25]1[CH:26]=[C:27]([CH3:28])[C:22]([CH3:21])=[CH:23][C:24]=1[NH:29][C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])([OH:20])[C:3]2=[O:19])(=[O:15])[CH3:14]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c2c1C(=O)C(O)(O)C2=O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1ccc([N+](=O)[O-])c2c1C(=O)C(O)(c1cc(C)c(C)cc1NC(=O)C(C)C)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.3 %

Procedure:
N-(2,2-dihydroxy-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (0.20 g, 0.71 mmol) and N-(3,4-dimethylphenyl)isobutyramide (136 mg, 0.71 mmol) were dissolved in conc. sulfuric acid (5 mL) and stirred at room temperature for 3 hrs. The reaction mixture was extracted with ethylacetate and ice-water, washed with brine. The washed organic layer dried over sodium sulfate, concentrated in a vacuum, and purified through silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (30 mg, 10%).
Reaction SMILES: I[CH3:2].[OH-].[Na+].[C:5]([O:9][C:10]([N:12]1[CH2:23][CH2:22][C:15]2([NH:19][C:18](=[S:20])[NH:17][C:16]2=[O:21])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O>CO>[C:5]([O:9][C:10]([N:12]1[CH2:13][CH2:14][C:15]2([N:19]=[C:18]([S:20][CH3:2])[NH:17][C:16]2=[O:21])[CH2:22][CH2:23]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=S)NC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSC1=NC2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1
Reaction time: 8 h
Yield: 77.1 %

Procedure:
Iodomethane (0.329 ml, 5.28 mmol) and a 1 N aqueous NaOH solution (3.3 ml, 3.3 mmol) were sequentially added to a solution of 4-oxo-2-thioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (944 mg, 3.3 mmol) in methanol (33 ml) at room temperature, and the mixture was stirred at the same temperature overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers were combined and dried over magnesium sulfate, and the solvent was then distilled off. The residue was purified by silica gel column chromatography to give 2-methylsulfanyl-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (762 mg, 77%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:25][CH3:26])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]([CH3:23])([CH3:22])[CH2:20][O:21][C:17]=3[C:16]([CH3:24])=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)=[O:4].C(N(CC)CC)C.Cl[C:35](Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH2:25]([C@H:2]1[NH:1][C:35](=[O:37])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[C:18]4[C:19]([CH3:22])([CH3:23])[CH2:20][O:21][C:17]=4[C:16]([CH3:24])=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:26]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc(C)c3c2C(C)(C)CO3)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3ccc(C)c4c3C(C)(C)CO4)nc2)C1=O
Temperature: 0 °C
Yield: 128 %

Procedure:
(2R)-2-amino-N-{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}butanamide (Intermediate 188, 300 mg, 0.84 mmol) was dissolved in ethyl acetate (6 mL). Triethylamine (0.47 ml, 3.36 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (100 mg, 0.34 mmol) in ethyl acetate (6 mL) was slowly added. At the end of addition the mixture was treated with an aqueous saturated solution of NaHCO3 and two phases were separated. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to obtain a waxy solid. The residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate 70:30 to cyclohexane/ethyl acetate 50:50 as eluents affording the title compound (166 mg) as a white foam.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:13]([C:16]1[CH:17]=[C:18]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[Cl:12][C:11]1[C:2]([NH:25][S:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)(=[O:24])=[O:23])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: Clc1nc2ccccc2nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Temperature: 150 °C

Procedure:
2,3-Dichloroquinoxaline (26.1 g, 131.1 mmol), m-Nitrobenzene sulfonamide (26.5 g, 131.1 mmol) and potassium carbonate (18.1 g, 131.1) were dissolved in anhydrous DMSO (500 mL). The reaction was heated to 150° C. for 2 h. The reaction mixture was poured into water (400 mL), followed by addition of 2M HCl (60 mL). The product was extracted with EtOAc (3×500 mL). The organic layers were combined and washed water (2×500 mL) and brine (2×500 mL). The product was then dried with sodium sulfate to give N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide. MS (EI) for C14H9ClN4O4S: 364.94, 366.97 (MH+)