Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:15]=2)[CH2:10]1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1COCC1>[OH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][C@@H:9]([NH:8][C:33](=[O:34])[O:35][CH2:36][CH3:37])[CH2:10]2)[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[N:17]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)C1
Temperature: -55 °C
Yield: 86.3 %

Procedure:
Under an N2 atmosphere at RT, triethylamine (174 μL, 1.25 mmol) was added to a solution of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (200 mg, 0.62 mmol) in THF (6.0 mL). After cooling the mixture to −55° C., ethyl chloroformate (59 μL in 600 μL THF, 0.62 mmol) was slowly added, and the reaction was warmed to RT over a period of 30 minutes. The mixture was quenched with H2O and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-20% EtOAc in a 1:1 mixture of CH2Cl2 and hexanes gave (R)-ethyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 2) (210 mg, 86%). 1H NMR (400 MHz, DMSO-d6) δ 8.42 (dd, J=7.8, 1.5 Hz, 1H), 8.18 (d, J=8.7 Hz, 1H), 7.59-7.58 (m, 2H), 7.38-7.33 (m, 2H), 6.94-6.90 (m, 2H), 4.27-4.12 (m, 3H), 4.04-3.98 (m, 3H), 3.87-3.86 (m, 1H), 2.50 (s, 3H), 2.26-2.18 (m, 1H), 2.05-1.99 (m, 1H), 1.16 (t, J=7.3 Hz, 3H) ppm. LC/MS: m/z 393.3 (M+H)+ at 2.31 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([C:11]1([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10].[N:29]1([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([C:11]1([CH2:24][CH2:25][CH2:26][CH2:27][N:32]2[CH2:33][CH2:34][N:29]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]=3)[CH2:30][CH2:31]2)[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(NCc1ccccn1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCc1ccccn1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(pyridin-2-ylmethyl)-amide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[CH:4]/[C:5](Cl)=[O:6].[NH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][C:13]([C:21]#[N:22])=[C:12]2[NH:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=1>>[Cl:31][C:26]1[CH:25]=[C:24]([NH:23][C:12]2[C:11]3[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([NH:8][C:5](=[O:6])[CH:4]=[CH:3][CH2:2][Br:1])[CH:10]=3)[N:15]=[CH:14][C:13]=2[C:21]#[N:22])[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Reactant: O=C(Cl)/C=C/CBr
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr

Procedure:
By using the method of Example 15, 4-bromo crotonyl chloride and 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinoline-3-carbonitrile was converted to the title compound which was obtained as a solid that could be purified with boiling methanol.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1.C(=O)([O-])O.[Na+].O>CN(C)C=O>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=3)[N:19]=2)[CH:18]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: Cc1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cn3cc(C)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
A solution of 2-bromo-1-(4-methylphenyl)ethanone (99.3 g, 0.47 mol) in dimethylformamide (250 mL) was added slowly to a solution of 5-methyl-2-pyridinamine (50.4 g, 0.47 mol) in dimethylformamide (250 mL). Sodium hydrogen carbonate (78.3 g, 0.93 mol) was added in portions and the mixture was stirred at room temperature for 15 min., then under reflux for 1.5 h. The mixture was cooled and poured into water (2500 mL). The solid was collected, washed with water (1000 mL) and recrystallised from dimethylformamide (400 mL). The solid was collected and dried in vacuo at 120° C. to give the title compound (89 g, 86%). 1H NMR (360 MHz, DMSO-d6) δ 8.30 (1H, d, J 1.5 Hz), 8.23 (1H, s), 7.84 (2H, d, J 8.0 Hz), 7.47 (1H, d, J 9.2 Hz), 7.25 (2H, d, J 8.0 Hz), 7.09 (1H, dd, J 9.2, 1.5 Hz), 2.33 (3H, s), and 2.28 (3H, s).
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]1[C:10]([F:11])=[CH:9][C:8](Br)=[CH:7][C:6]=1[F:13].[Li]CCCC.[CH3:19][C:20]([CH3:22])=[O:21].O>C(OC)(C)(C)C>[F:13][C:6]1[CH:7]=[C:8]([C:20]([OH:21])([CH3:22])[CH3:19])[CH:9]=[C:10]([F:11])[C:5]=1[CH:4]=[CH:3][O:2][CH3:1]
Reactant: COC=Cc1c(F)cc(Br)cc1F
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: O
Product: COC=Cc1c(F)cc(C(C)(C)O)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled (−78° C.) solution of 2-(4-bromo-2,6-difluorophenyl)vinyl methyl ether (45 g, 0.18 mol) in methyl tert-butyl ether (300 mL) was added n-BuLi (75 mL of 2.5M in hexanes, 0.19 mol), and the mixture was stirred at −78° C. for one hour. A solution of acetone (13.6 g, 0.24 mol) in methyl tert-butyl ether (100 mL) was added dropwise to the reaction mixture and the resulting solution was stirred at −78° C. for two hours. Water (90 ml) was added to quench the reaction. The resulting biphasic mixture was extracted with ethyl acetate (2×). The organic layers were dried and concentrated in vacuo. Purification via flash chromatography afforded the title compound.
Reaction SMILES: C(O[C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:40][CH2:39][CH2:38][O:37][CH3:36])=[O:35])=[N:13][C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:15][CH:16]=1
Reactant: COCCN
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Product: COCCNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-(2-methoxy-ethyl)-benzamide was prepared from 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester and 2-methoxyethylamine in an analogous manner to Example 1396. Product isolated as a yellow foam (19 mg, 33%). LCMS (m/e) 525 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.07 (s, 1H), 6.67 (d, 1H, J=8.4 Hz), 8.09 (s, 1H), 7.54 (d, 1H, J=7.8 Hz), 7.50-7.40 (m, 1H), 7.37 (s, 1H), 7.30-7.22 (m, 1H), 7.15-7.0 (m, 3H), 6.70-6.61 (m, 1H), 3.72-3.65 (m, 2H), 3.62-3.55 (m, 4H), 3.41 (s, 3H), 3.38 (s, 1H), 2.99-2.88 (m, 4H), 2.84-2.73 (m, 6H).
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]C(Cl)=O)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:1]2[O:13][C:5]([C:4]3[C:3]([CH:2]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:7])=[CH:18][CH:17]=1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Cc2cc3ccccc3c(=O)o2)cc1
Temperature: 200 °C
Yield: 6 %

Procedure:
A well-stirred mixture of homophthalic acid (10 g; 56 mmol) and 2-(4-methoxyphenyl)acetyl chloride (10 g, 230 mmol) was heated at 200° C. for 3 hours under nitrogen then cooled to 50° C. and dissolved in toluene (100 ml), The solvent was removed in vacuo and the residue was dissolved in methanol (100 ml). Silica (30 g) was added and the solvent was removed in vacuo. The crude product, thereby adsorbed onto silica, was applied to the top of a column of silica and purified by chromatography using 10-50% mixtures of ethyl acetate and hexane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 3-(4-methoxybenzyl)isocoumarin (0.9 g, 26%) as an oil; δH 3.75 (3H, s), 3.80 (2H, s), 6.50 (1H, s), 6.95 (2H, d, J=8.9 Hz), 7.30 (2H, d, J=8.9 Hz), 7.40-7.90 (3H, m), 8.10 (1H, d); m/z (M+H)+. 267.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][CH:27]([F:51])[O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][N:33]=[C:32]2[Sn](CCCC)(CCCC)CCCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:32]3[C:31]4[C:35](=[CH:36][CH:37]=[C:29]([O:28][CH:27]([F:26])[F:51])[CH:30]=4)[NH:34][N:33]=3)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2ccc(OC(F)F)cc12
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (200 mg, 0.47 mmol) and 5-difluoromethoxy-3-tributylstannyl-1H-indazole (crude from Step 1, 509 mg, 0.59 mmol) were dissolved in DMF (3.2 ml). The reaction mixture was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium (0) (27.0 mg, 0.023 mmol) and copper (I) iodide (18 mg, 0.095 mmol) were added. The reaction mixture was stirred at 90° C. for 2 h then cooled to room temperature, quenched with water and extracted with ethyl acetate/diethyl ether (2×). The combined organic layers were washed three times with water and once with brine then concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/dichloromethane (gradient: 0-30% EtOAc). The appropriate fractions were combined and concentrated and the residue was triturated with diethyl ether to afford 158 mg (64%) of 2-(5-difluoromethoxy-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as an off-white powder.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([C:33](O)=[O:34])[CH2:29][CH2:28]2)[CH2:16][C:15]1=[O:36].[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>C(Cl)Cl>[CH3:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][C@H:27]2[CH2:28][CH2:29][C@H:30]([C:33]([N:46]3[CH2:47][CH2:48][N:43]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=4)[CH2:44][CH2:45]3)=[O:34])[CH2:31][CH2:32]2)[CH2:16][C:15]1=[O:36]
Reactant: CN1C(=O)CN(C[C@H]2CC[C@H](C(=O)O)CC2)C(=O)c2ccccc21
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CN1C(=O)CN(C[C@H]2CC[C@H](C(=O)N3CCN(c4ccccn4)CC3)CC2)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Solid CDI (0.18 mmol, 0.03 g) was added to a solution of trans-4-(1-Methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-ylmethyl)-cyclo hexanecarboxylic acid (0.16 mmol, 0.05 g) in dry DCM (1 mL) under argon. After 1 h at room temperature, 1-Pyridin-2-yl-piperazine (0.22 mmol, 32 μL) was added and the reaction mixture was left stirring at room temperature under argon overnight. The solvent was removed under reduced pressure and the crude purified by column chromatography on silica gel using DCM/MeOH 95/5 as eluent to give 42 mg (yield 59%) of the titled compound
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[N:11]=[C:10](O)[CH:9]=[CH:8]2)(=[O:3])[CH3:2].O=P(Cl)(Cl)[Cl:19]>CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[N:11]=[C:10]([Cl:19])[CH:9]=[CH:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(F)c2nc(O)ccc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc(F)c2nc(Cl)ccc2c1
Temperature: 80 °C

Procedure:
To a solution of 8-fluoro-2-hydroxyquinolin-6-yl acetate (550 mg) in DMF (6 mL) was added POCl3 (0.6 mL). Then, the mixture was heated at 80° C. over a couple of hours. After aqueous work-up, the desired product, 2-chloro-8-fluoroquinolin-6-yl acetate (380 mg) was obtained by flash silica column chromatography.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:3][CH:2]=1.C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:11][C:1]1[CH:2]=[CH:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a suspension of 150 g of methyl p-toluate and 195.5 g of NBS in CCl4 (1.67 L) under N2 at 50° C. was added portion wise over 30 min, solid benzoyl peroxide (5.0 g). There was no exothermic reaction observed. After heating for 2 hours at 50° C., the yellow solution was heated at 65° C. for 6 hrs. There was still some unreacted starting material. The suspension was stirred overnight at 65° C. After cooling to room temperature (r.t), the precipitate formed was filtered off and washed with 150 mL of CCl4 and the filtrate was concentrated to afford a yellow oil that solidified on standing. The title compound, containing a small fraction of starting material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([C:12]([F:11])([F:20])[F:21])=[CH:14][CH:15]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 10 h
Yield: 62.1 %

Procedure:
6-Chloronicotinoyl chloride (0.83 g) was dissolved in toluene (15 mL), and the solution was cooled to 0° C. 4-(Trifluoromethyl)aniline (1.6 g) was added thereto at 0° C., and the mixture was stirred at room temperature for 10 hours. Ethyl acetate was added thereto, and the organic layer was washed with a 1 N aqueous sodium hydroxide solution and water and dried over sodium sulfate. After concentration under reduced pressure, the obtained solid was collected by filtration and washed with diethyl ether. The solid was dried under reduced pressure to obtain the title compound (0.88 g) as a white solid (yield: 29%).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[N:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([NH:12][C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:15]([CH3:16])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)=[O:31])=[CH:26][CH:25]=2)=[N:22][CH:23]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cn2)cc1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(Cl)cn4)cc3)cn12

Procedure:
Conducting the operations similar to those of Example 1 using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4-(5-chloro-2-pyridyl)benzenecarboxylic acid, the title compound was obtained as white solid.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].N1C=CN=C1.[CH3:10][C:11]([Si:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])[CH3:12]>O1CCCC1>[Si:14]([O:3][CH2:2][CH2:1][OH:4])([C:11]([CH3:13])([CH3:12])[CH3:10])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCO)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
Into a 2-L 3-necked round-bottom flask was placed tetrahydrofuran (800 mL), ethane-1,2-diol (40 g, 644.46 mmol, 1.00 equiv) and imidazole (61.4 g, 901.92 mmol, 1.40 equiv). This was followed by the addition of TBDPSCl (186.3 g) dropwise with stirring at 0° C. in 30 min. The resulting solution was stirred overnight at room temperature. The solids were filtered out, and the filtrate cake was washed with 200 mL of EA. The resulting mixture was washed with 200 mL of brine and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:25). Purification afforded 83 g (43%) of 2-[(tert-butyldiphenylsilyl)oxy]ethan-1-ol (85.2) as a colorless oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]([O:15][C:16]1[N:24]=[C:23]2[C:19]([N:20]=[CH:21][N:22]2[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[C:18]([NH2:31])[N:17]=1)[CH2:11][CH2:12][CH2:13][CH3:14].O>C(Cl)(Cl)Cl>[Br:1][C:21]1[N:22]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:23]2[C:19]([N:20]=1)=[C:18]([NH2:31])[N:17]=[C:16]([O:15][C@@H:10]([CH3:9])[CH2:11][CH2:12][CH2:13][CH3:14])[N:24]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCC[C@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCC[C@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reaction time: 3 h

Procedure:
N-Bromosuccinimide (1.504 g, 8.45 mmol) was added portionwise to a stirred solution of 2-{[(1S)-1-methylpentyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2.453 g, 7.68 mmol) in chloroform (40 ml) under at atmosphere of nitrogen cooled in an ice-bath. After 3 hours LCMS indicated the reaction to be 80% complete and more N-bromosuccinimide (0.68 g) was added and stirring continued for a further 2 hours. Water (40 ml) was added and the phases separated using a hydrophobic frit. The organic phase was evaporated and the residue dissolved in dichloromethane and purified on an aminopropyl (NH2) cartridge (100 g) using a 0-100% ethyl acetate in cyclohexane gradient followed by a 0-20% methanol (+1% triethylamine) gradient over 60 mins. The appropriate fractions were combined and evaporated in vacuo to the title compound as a white foam (2.38 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:29])[CH2:9][C:10]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(C(OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12].[OH-].[Na+].C(O)C>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:30]2[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:29])[CH2:9][CH:10]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(CCc1ccccc1)(CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C
Temperature: 50 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
Step 5 A mixture of diethyl 2-[2-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]-2-(2-phenylethyl)malonate (4.87 g, 9.41 mmol), 1 N aqueous sodium hydroxide (10.4 mL, 10.40 mmol), ethanol (10 mL), and acetone (10 mL) was stirred at 50° C. overnight. The mixture was concentrated and the residue was dissolved in dimethoxyethane (20 mL), and stirred at 80° C. overnight. The mixture was concentrated, and the residue was dissolved in ethyl acetate (30 mL). The solution was washed with water (2×5 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The material obtained was purified by flash chromatography (10:90 ethyl acetate/hexane) to give ethyl 4-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate as a light yellow oil (3.53 g, 99% yield). LC-MS ret. time 4.18 min, m/z 446.0 (MH+); 1H NMR (CDCl3) δ: 1.33 (t, 3H), 1.83-2.17 (m, 2H), 2.58 (s, 3H), 2.67-2.78 (m, 2H), 3.00 (dd, 1H), 3.14 (m, 1H), 3.49 (dd, 1H), 4.09 (q, 2H), 7.14-7.36 (m, 5H), 7.47-7.55 (m, 2H), 7.72-7.83 (m, 3H), 8.33 (d, 2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li:10]CCCC>>[CH:1]1([Li:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1=Cc2ccccc2C1
Reactant: [Li]CCCC
Product: [Li]C1C=Cc2ccccc21

Procedure:
Indene was reacted with BuLi to form indenyl lithium, which compound was reacted with methyl iodide to form 1-methylindene. Use was made of: 18.2 grams of indene, 100 ml of n-BuLi solution, 22.0 grams of methyl iodide.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].[C:27]([N:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1)(=[O:29])[CH3:28]>>[C:27]([N:30]1[CH2:35][CH2:34][CH:33]([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[NH:8][C:9](=[O:26])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=2[O:24][CH3:25])[CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1NC1CCN(C(C)=O)CC1

Procedure:
The title compound, light yellow solid, MS: m/e=510.4 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and 1-acetyl-4-piperidone.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Si:7]([O:14][CH2:15][C@H:16]([OH:24])[CH2:17][C:18]#[C:19][Si](C)(C)C)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>CO>[Si:7]([O:14][CH2:15][C@@H:16]([OH:24])[CH2:17][C:18]#[CH:19])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)CC#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC[C@H](O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (1.5 eq) is added to a solution of (R)-1-(tert-butyldimethylsilyloxy)-5-(trimethylsilyl)pent-4-yn-2-ol (1 eq) in methanol and the mixture stirred at room temperature for 8 hours. The solvent is removed under reduced pressure and aqueous ammonium chloride solution added. The mixture is extracted with ethyl acetate (3×) and the combined organic layers washed with brine, dried (MgSO4), concentrated under reduced pressure and purified by flash chromatography (biotage) using a gradient of EtOAc in hexane.