Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]=[O:25])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[F:32][C:33]([Si](C)(C)C)([F:35])[F:34].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH:24]([OH:25])[C:33]([F:35])([F:34])[F:32])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Cn2c(C(O)C(F)(F)F)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
To a solution (5 ml) of 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde (500 mg) and (trifluoromethyl)trimethylsilane (170 mg) in THF was added a solution of tetra-N-butylammonium fluoride (1M, 0.03 ml) in THF at room temperature, and the mixture was stirred for 30 min. Then a solution (1M, 2 ml) of tetra-N-butylammonium fluoride in THF was added, and the mixture was stirred for 30 min. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (THF) and basic silica gel column chromatography (THF) and the crystals were washed with a mixture of ethyl acetate and diisopropyl ether, and recrystallized (MeOH-hexane) to give the title compound (290 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[Br:10]C1C(=O)C(Br)=CC(Br)(Br)C=1>ClCCl>[Br:10][C:7]1[CH:6]=[CH:5][C:4]([NH2:9])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1ccccc1N
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Solvent: ClCCl
Product: COc1cc(Br)ccc1N
Temperature: 25 °C
Yield: 90.5 %

Procedure:
A solution of o-Anisidine (5.46 g, 44.3 mmol) in dichloromethane (100 mL) was treated with 2,4,4,6-tetrabromo-2,5-cyclohexadiene-1-one (18.16 g, 44.3 mmol) portion-wise over 1 h at −5° C. Following the addition of the brominating agent, the dry ice/acetone bath was removed and the reaction mixture stirred over night at room temperature. Sodium hydroxide solution (1N) was added to the reaction mixture, and the layers were partitioned. The organic layer was washed with 1 N sodium hydroxide solution (1 L), washed with water (750 mL), dried over magnesium sulfate, filtered, and evaporated under reduced pressure, to give 8.096 g (89%) of 4-bromo-2-methoxyaniline. 1H NMR (DMSO-d6, 400 MHz) δ 6.90 (s, 1H), 6.83-6.76 (m, 1H), 6.57-6.55 (m, 1H), 4.86 (s, 2H), 3.76 (s, 3H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.635 min (89%).
Reaction SMILES: S([Cl:11])(C1C=CC(C)=CC=1)(=O)=O.[N+:12]([C:15]1[CH:16]=[C:17]([CH2:25]O)[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)([O-:14])=[O:13].C(N(CC)CC)C>ClCCl>[Cl:11][CH2:25][C:17]1[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(CO)cc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(CCl)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.8 %

Procedure:
Add slowly tosyl chloride (1.1 g, 6.02 mmol) to the mixture of (3-nitro-5-(trifluoromethyl)phenyl)methanol (1.1 g, 5.18 mmol) and triethylamine (1.62 mL) in dichloromethane (20 mL) at 0° C., stir the resulting mixture for 15 hrs at room temperature. Concentrate the mixture to obtain the crude product, purify by flash chromatography (silica gel, EtOAc:PE=1:15) to afford the title compound (655 mg, 55%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][O:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:7]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[CH:26]=3)=[N:6]2)[CH2:3][CH2:2]1.[Cl:27][C:28]1C=CC(CN2C(=O)C(CO)=CC(C3C=CC4OCCC=4C=3)=N2)=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:3]=[CH:2][C:1]([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][O:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:7]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[CH:26]=3)=[N:6]2)=[CH:30][CH:29]=1
Reactant: O=c1c(CO)cc(-c2ccc3c(c2)CCO3)nn1Cc1ccc(Cl)cc1
Reactant: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(CC2CC2)c1=O
Product: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccc(Cl)cc2)c1=O
Yield: 96.6 %

Procedure:
The general procedure of Example 1 (5) was carried out by use of 2-(4-chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-hydroxymethyl-2H-pyridazin-3-one, to thereby yield the title compound as a yellow powder (yield: 96.6%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Br-:18].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:18][CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:10][CH:11]=1)=[O:17]
Reactant: [Br-]
Reactant: CCCCCCCOc1ccc(C(C)=O)cc1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 137.7 %

Procedure:
To a stirring solution of 1-(4-(heptyloxy)phenyl)ethanone (500 mg, 2.13 mmol) in THF (8.5 mL) under nitrogen was added phenyltrimethylammonium tribromide (842 mg, 2.24 mmol). The reaction mixture was stirred at RT for 2 h, filtered under vacuum and the captured solid washed with THF. The combined liquors were concentrated to afford 919 mg (100%) of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone INT-4 as a yellow oil. LCMS-ESI (m/z) calculated for C15H21BrO2: 313.2. found 313.0 [M+H]+, tR=2.12 min. (Method 4).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18]C)=[O:17])=[CH:13][CH:14]=3)[CH:9]([CH2:20][CH2:21][C:22](=[O:35])[N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:33][CH2:32][CH2:31][C:30]4=[O:34])[CH2:25][CH2:24]3)[C:8]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Na+].Cl>C1COCC1>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]([CH2:20][CH2:21][C:22](=[O:35])[N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:33][CH2:32][CH2:31][C:30]4=[O:34])[CH2:27][CH2:28]3)[C:8]=2[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(c1)C(CCC(=O)N1CCC(N3CCCC3=O)CC1)C(c1ccccc1)=C2C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(c1)C(CCC(=O)N1CCC(N3CCCC3=O)CC1)C(c1ccccc1)=C2C1CCCCC1
Temperature: 70 °C

Procedure:
To a stirred solution of 1-cyclohexyl-3-(3-oxo-3-(4-(2-oxopyrrolidin-1-yl)piperidin-1-yl)propyl)-2-phenyl-3H-indene-5-carboxylic acid, methyl ester (460 mg, 0.1 mmol), in THF (1 mL) and MeOH (1 mL) was added 1M NaOH (0.16 mL, 0.16 mmol). The reaction mixture was heated in a sealed tube at 70° C. for 4 h. 1M NaOH (0.2 mL, 0.2 mmol) was added and heated for 5 h more. 1N HCl (0.5 mL) was added and the volatiles were removed in vacuo. A precipitate formed and it was collected by filtration and dried at open air to afford 1-cyclohexyl-3-(3-oxo-3-(4-(2-oxopyrrolidin-1-yl)piperidin-1-yl)propyl)-2-phenyl-3H-indene-5-carboxylic acid as a pale yellow solid. LCMS: m/e 552 (M+H)+, ret time 2.10 min, column A, 2 minute gradient.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([O:12][C:9]2[CH:10]=[CH:11][C:6]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[CH:7][CH:8]=2)=[CH:31][CH:32]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(I)cc1
Reactant: Oc1ccc(-c2ncco2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(-c3ncco3)cc2)cc1
Yield: 22.9 %

Procedure:
The title compound (60 mg, 30%) was prepared from product of step 2 (0.1 g, 0.6 mmol) and (R)-2-(4-Iodo-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.38 g, 0.9 mmol) using the procedure of Example 146, step 3; 1HNMR (400 MHz, CDCl3) δ 7.96 (d, J=8.8 Hz, 2H), 7.67 (s, 1H), 7.20 (s, 1H), 6.92 (m, 6H), 4.13 (m, 2H), 3.86 (m, 1H), 3.41 (m, 2H), 2.07-1.78 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([Br:20])=[CH:15][N:14]=1>C(#N)C>[Br:20][C:16]1[C:17]([CH3:19])=[CH:18][C:13]2[N:14]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[N:12]=2)[CH:15]=1
Reactant: Cc1cc(N)ncc1Br
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: CC#N
Product: Cc1cc2nc(-c3ccc(O)cc3)cn2cc1Br
Temperature: 110 °C
Yield: 94.9 %

Procedure:
2.00 g (corresponding to 9.28 mmol) of 2-bromo-4′-hydroxyacetophenone and 1.91 g (corresponding to 10.2 mmol) of 2-amino-5-bromo-4-methylpyridine were dissolved in 40 mL of acetonitrile. The resulting solution was heated under reflux in an oil bath at 110° C. for 3 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 10 mL of water and 10 mL of methanol. Then, about 50 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 10 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 2.67 g (corresponding to 8.81 mmol) of 6-bromo-2-[4′-hydroxyphenyl]-7-methylimidazo[1,2-a]pyridine (FIG. 9, Step 2).
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.[CH3:13]O>S(=O)(=O)(O)O>[OH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[C:4](=[O:5])[O:3][CH:2]2[O:1][CH3:13]
Reactant: CO
Reactant: O=C1OC(O)c2cccc(O)c21
Agent: O=S(=O)(O)O
Product: COC1OC(=O)c2c(O)cccc21
Reaction time: 16 h

Procedure:
4 drops of concentrated sulfuric acid are added to a solution of 2.5 g of 3,7-dihydroxyphthalide (in the form of the crude product--see Examples 105 and 106) in 70 ml of methanol and, after the subsequent addition of 3 Å molecular sieve, the mixture is left to stand for approximately 16 hours. The mixture is then filtered and the filtrate is concentrated by evaporation. The crude product, 3 g of yellow oil, is purified by chromatography (flash-chromatography) on silica gel using ethyl acetate/n-hexane (3:7) to yield 1.9 g (70% of the theoretical yield) of 7-hydroxy-3-methoxy-phthalide in the form of reddish crystals, m.p. 77°-79° C. (after crystallisation from diethyl ether/n-hexane); IR spectrum (CHCl3): C=O 1745 cm-1.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]([NH:9][C:10]([C:12]1[CH:21]=[C:20]([Cl:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:23][CH2:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:11])([CH3:8])[CH2:6][CH3:7])C.CO.[OH-].[Na+]>C1COCC1>[Cl:22][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:23][CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[C:12]([C:10]([NH:9][C:5]([CH3:8])([CH2:6][CH3:7])[C:4]([OH:31])=[O:3])=[O:11])[CH:21]=1
Reactant: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(C)(NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCNCC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
A solution of 70 mg of 2-{[4-chloro-1-(piperidin-4-yl-methoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid ethyl ester (see example 160, step b)) in 4 mL THF and 1 mL MeOH was treated with 4 mL of 2 M aqueous sodium hydroxide. The reaction mixture was stirred at room temperature overnight. The organic solvent was removed in vacuo. The residue was taken up in 6 ml of water and it was treated with 2 M hydrochloric acid to adjust the pH to 6˜7, then extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulphate and concentrated to give 32 mg of 2-{[4-chloro-1-(piperidin-4-yl-methoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:1]1([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCCCC2)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
To a solution of piperidine (2.98 g) and methyl 6-chloronicotinate (5.00 g) in N,N-dimethylformamide (75 ml) was added potassium carbonate (12.08 g). The mixture was stirred at 100° C. for 3 hours. After cooling to ambient temperature, to the reaction mixture was added water (100 ml) and then the mixture was stirred for 15 minutes at ambient temperature. The resulting precipitates were filtered, washed with water, and dried to give methyl 6-(1-piperidyl)nicotinate (5.55 g), as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH:9]([C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:17][C:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccco1
Temperature: 0 °C
Yield: 85.5 %

Procedure:
37 g of ethyl 3-(4-chlorobenzoylamino)-3-(2-furylcarbonyl)propionate are dissolved in 150 ml of chloroform. 64.9 g of phosphorus oxychloride are added dropwise to the solution at room temperature, and the mixture is refluxed at 60° to 70° C. for 8 hours under stirring. After the reaction is completed, the mixture is poured into ice-water. The aqueous mixture is neutrallized with sodium bicarbonate and then extracted with ethyl acetate. The extract is washed with water, dried, treated with activated charcoal and then evaporated under reduced pressure to remove solvent. The residue is crystallized with diisopropyl ether, and then recrystallized from ethanol. 30 g of ethyl 2-[2-(4-chlorophenyl)-5-(2-furyl)-4-oxazolyl]acetate are thereby obtained. Yield: 85.5%
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.OC1C2N=NNC=2C=CC=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([S:47][CH:48]2[N:51]([CH2:52][C:53](O)=[O:54])[C:50](=[O:56])[CH2:49]2)=[CH:43][CH:42]=1>CN(C=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:53](=[O:54])[CH2:52][N:51]2[CH:48]([S:47][C:44]3[CH:45]=[CH:46][C:41]([O:40][CH3:39])=[CH:42][CH:43]=3)[CH2:49][C:50]2=[O:56])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(SC2CC(=O)N2CC(=O)O)cc1
Reactant: NCCCCCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(SC2CC(=O)N2CC(=O)NCCCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A solution of 6-phenylhexylamine (Morse M. A. et al., Cancer Research, 1991, 1846), (1.4 g, 8 mmol) in DMF (50 ml) was added to DCC (1.6 g, 8 mmol), hydroxybenzotriazole (1.0 g, 8 mmol) and (4-(4-methoxyphenylthio)-2-oxoazetidin-1-yl)acetic acid (2.1 g, 8 mmol) and the mixture stirred for 2 hours at room temperature. Ethyl acetate (250 ml) was added, the precipitate filtered, the filtrate washed with dil NaHCO3, water (x2), dried (MgSO4) and evaporated to an oil which was purified by flash chromatography on silica gel using hexane/ethyl acetate (1:3). Evaporation of the appropriate fractions gave the product as a colourless oil, 77% yield. 1H NMR δ (CDCl3) 1.34-1.47 (10H, m, (CH2)5), 2.59 (2H, t, J=7.7 Hz, CH2), 2.83 (1H, dd, J=2.2, 15 Hz, H3a), 3.18-3.36 (3H, m, CH2H3b), 3.78 (3H, s, OCH3), 3.80, 3.99 (each 1H, d, J=15 Hz, NCH2), 4.95 (1H, m, H4), 6.23 (1H, bt, NH), 6.87 (2H, d, J=6.8 Hz, 2, 6 Ph--H), 7.14-7.39 (7H, m, 3, 5 Ph--H, Ph--H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:12](Br)[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:12]([O:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CBr
Reactant: COC(=O)c1cncc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cncc(OCC(C)C)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, to a solution of methyl 5-hydroxynicotinate (5.00 g) in DMF (50 mL) were added isobutyl bromide (5.33 mL) and potassium carbonate (9.04 g), and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give a crude product of the title compound (5.13 g) as a pale-brown oil. The obtained crude product was directly used for the next step.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH2:14][N:15]2[C:20](=[O:21])[CH2:19][CH2:18][CH2:17][C:16]2=O)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Mg]I>>[NH:1]([C:8]1[N:13]=[C:12]([CH2:14][N:15]2[CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][C:20]2=[O:21])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]I
Reactant: O=C1CCCC(=O)N1Cc1ccnc(Nc2ccccc2)n1
Product: CC1CCCC(=O)N1Cc1ccnc(Nc2ccccc2)n1

Procedure:
By an analogous process to Method 17, 2-anilino-4-(2,6-dioxopiperidin-1-ylmethyl)pyrimidine (Method 16; 2.21 g, 7.47 mmol) was treated with methyl magnesium iodide to prepare the intermediate animal which was taken on without chromatographic purification to give the final product which was purified, after aqueous work-up, by chromatography eluting with DCM/MeOH (98:2) to give the title compound (375 mg, 17%) as a glassy solid. NMR: 1.2 (d, 3H), 1.65 (m, 2H), 1.93 (m, 2H), 2.33 (t, 2H), 3.6 (q, 1H), 4.25 (d, 1H), 4.7 (d, 1H), 6.65 (d, 1H), 6.93 (t, 1H), 7.25 (t, 2H), 7.76 (d, 2H), 8.4 (d, 1H), 9.53 (s, 1H); m/z 297.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([N:23]2[CH2:37][C:26]3=[C:27]4[N:32]([N:33]=[C:25]3[CH2:24]2)[C:31]([CH3:34])=[C:30]([Cl:35])[C:29]([CH3:36])=[N:28]4)=[O:22])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:35][C:30]1[C:29]([CH3:36])=[N:28][C:27]2[N:32]([N:33]=[C:25]3[CH2:24][N:23]([C:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[O:14][C@H:10]4[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)=[O:22])[CH2:37][C:26]3=2)[C:31]=1[CH3:34]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1O[C@H]1CCCN(C(=O)OC(C)(C)C)C1)C3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1O[C@H]1CCCNC1)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A mixture of (S)-3-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (270 mg; 0.51 mmol; 1 eq.) and TFA (2 mL) in DCM (2 mL) was stirred at room temperature for 1 hour then concentrated in vacuo. The residue was taken up in water, the pH made basic with 5M NaOH and extracted with DCM (2×). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the title compound (176 mg, 81%) as white foam. 1H NMR (CDCl3) δ 7.41-7.33 (m, 2H), 7.08-6.98 (m, 2H), 5.02-5.01 (m, 2H), 4.67 (br s, 2H), 4.33 (br s, 1H), 3.11-3.06 (m, 1H), 2.91 (s, 2H), 2.85 (s, 1H), 2.84-2.72 (m, 3H), 2.69 (s, 1H), 2.62 (s, 2H), 1.98-1.91 (m, 1H), 1.80-1.69 (m, 3H), 1.50-1.40 (m, 1H). HPLC (max plot) 98.9%, Rt 2.85 min. UPLC/MS: (MS+) 426.4 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([NH2:11])[C:6](=[CH:9][CH:10]=1)[C:7]#[N:8].[S:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Zn+2].[Cl-]>[NH2:8][C:7]1[C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:4][C:5]=2[N:11]=[C:17]2[CH2:18][CH2:19][S:14][CH2:15][C:16]=12
Reactant: O=C1CCSCC1
Reactant: N#Cc1ccc(C(F)(F)F)cc1N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=[N+]([O-])c1ccccc1
Product: Nc1c2c(nc3cc(C(F)(F)F)ccc13)CCSC2
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 54.7 %

Procedure:
To a solution of 4-trifluoromethyl anthranilonitrile (12.2 g) in 50 ml of nitrobenzene was added freshly fused and pulverized zinc chloride (13.4 g). This was stirred at 50° C. for 1.5 hours after which was added tetrahydrothiopyran-4-one (9.9 g). The reaction mixture was stirred at 130° C. for 2 hours and allowed to cool, and the resulting complex was filtered and rinsed with ethyl ether. The solid was partitioned between 2-butanone (MEK) and NH4OH and the aqueous phase was extracted with MEK (2x). The organics were washed with water, dried (saturated NaCl, MgSO4) and concentrated to give 10.2 g of a yellow powder m.p. 253°-259° C. d. A 3.7 g portion was recrystallized from methanol/water to give 3.0 g of an off-white powder, m.p. 258°-262° C. d.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]3[N:15]=[C:16](Br)[S:17][C:13]=3[CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CCN(C(C)C)C(C)C.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[OH:37]>CC(N(C)C)=O>[N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]3[N:15]=[C:16]([NH:30][C@@H:31]4[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]4[OH:37])[S:17][C:13]=3[CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: Brc1nc2ccc(Cn3cnc4ccccc43)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4ccccc43)cc2s1
Temperature: 120 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
To a suspension of 6-((1H-benzo[d]imidazol-1-yl)methyl)-2-bromobenzo[d]thiazole from Step 1 of Example 1 (34.4 mg, 0.1 mmol) in DMA (3 mL) were added DIEA (15 mg, 0.12 mmol) and (1R,2R)-2-aminocyclohexanol (13.8 mg, 0.12 mmol) at rt. The reaction mixture was stirred in a sealed tube at 120° C. overnight. After cooling to rt, the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using a mixture of water (containing 5% CH3CN, 0.05% HCOOH) and CH3CN (containing 0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)-2-((6-((1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (22 mg, 58%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.99 (d, J=7.3 Hz, 1H), 7.60-7.72 (m, 2H), 7.55 (dd, J=2.6, 6.0 Hz, 1H), 7.26-7.34 (m, 1H), 7.12-7.25 (m, 3H), 5.47 (s, 2H), 4.76 (br s, 1H), 3.26-3.39 (m, 2H), 2.03 (d, J=10.0 Hz, 1H), 1.87 (d, J=9.4 Hz, 1H), 1.62 (d, J=4.7 Hz, 2H), 1.03-1.39 (m, 4H). LCMS (ESI) m/z 379 (M+H)+.