Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16].[Br:22][CH2:23][CH2:24]Br.[Cl-].[NH4+]>C1COCC1>[CH3:13][O:14][C:15]([C:17]1([CH2:24][CH2:23][Br:22])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16]
Reactant: BrCCBr
Reactant: COC(=O)C1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(CCBr)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a solution of diisopropylamine (56 mL, 396 mmol) in TI-IF (85 mL) was added dropwise a solution of n-butyl lithium (240 mL, 393 mmol, 1.6M) in hexanes at −10° C. while maintaining the temperature below 0° C. After addition, the solution was stirred for 30 min at 0° C. To this, a solution of cyclopentanecarboxylic acid methyl ester (37.4 g, 263 mmol) in THF (50 mL) was added dropwise at −70° C. maintaining the internal temperature between −60 to −70° C. After addition, the reaction mixture was stirred for 1 h at −50 to −60° C. Then, a solution of 1,2-dibromoethane (47 mL, 545 mmol) in THF (50 mL) was added dropwise and the light brown suspension was stirred for 1 h at −70 to −60° C. Then, it was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride (200 mL) and the organic compound was extracted into ether (2×100 mL). The combined extracts were washed with a saturated solution of sodium chloride (150 mL) and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the resulting residue was distilled at 95-105° C./2.5 mm Hg to obtain 49.6 g (80% yield) of 1-[2-bromoethyl]cyclopentanecarboxylic acid methyl ester as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@@H:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:17])[C@@H:7]([N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:23]1=[O:24])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H](Nc1ccccc1N)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](C(=O)OC(C)(C)C)n1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of (S)-2-(2-Amino-phenylamino)-propionic acid tert-butyl ester (1.5 g, 6.3 mmol) in THF (10 mL) was added CDI (1.03 g, 6.3 mmol). The reaction mixture was stirred at room temperature for 1 h. When the reaction was completed, the reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4 and concentrated to afford 1.6 g of the desired product as an oily residue. The LCMS indicated only 40% purity; however, this product was used for the next reaction without further purification. LCMS (ESMS): m/z 263.38 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=2)=[CH:15][C:14](C(N2CCOCC2)=O)=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.NCCC1C2C(=CC=C([C:56]3[C:57]([CH3:65])([CH3:64])[C:58](=[O:63])[N:59]([CH2:61][CH3:62])[N:60]=3)C=2)NC=1C1C=C(C)C=C(C)C=1.[NH4+].[OH-]>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])=[CH:29][CH:30]=2)=[CH:15][C:14]([C:56]2[C:57]([CH3:65])([CH3:64])[C:58](=[O:63])[N:59]([CH2:61][CH3:62])[N:60]=2)=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCN1N=C(c2ccc3[nH]c(-c4cc(C)cc(C)c4)c(CCN)c3c2)C(C)(C)C1=O
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N4CCOCC4)cc3c2CCNCCCCc2ccc(NS(C)(=O)=O)cc2)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCN1N=C(c2ccc3[nH]c(-c4cc(C)cc(C)c4)c(CCNCCCCc4ccc(NS(C)(=O)=O)cc4)c3c2)C(C)(C)C1=O
Yield: 55 %

Procedure:
Reductive amination of 4-[4-(methanesulfonamido)phenyl] butyraldehyde (EXAMPLE 4) with 5-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-ethyl-4,4-dimethyl-2,4-dihydropyrazol-3-one was carried out according to the method of Example 6.2, Step F, except that 90:10 CH2Cl2-MeOH was used to develop the preparative TLC plates, while 90:10:1 CH2Cl2-MeOH-concd. NH4OH was used to extract the product. This gave a 55% yield of very pale golden-yellow glass; homogeneous by TLC in 92.5:7.5 CH2Cl2-MeOH. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e=628.5 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:15][CH2:14][CH2:13][CH2:12]1.[C:16]([O:20][C:21]([N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[O:11]=[C:6]1[C:5]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:24]3[N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH:27]=[CH:26][CH:25]=3)[CH:3]=2)[NH:7]1
Reactant: O=C1Nc2ccc(Br)cc2C12CCCC2
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C1(CCCC1)C(=O)N2
Temperature: 80 °C
Yield: 83.2 %

Procedure:
A solution of 5′-bromospiro[cyclopentane-1,3′-[3H] indol]-2′(1′H)-one (2.0 g, 7.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (430 mg, 0.3 mmol) in ethylene glycol dimethyl ether (50 mL) was stirred under a flow of nitrogen for 15 min. To the solution was added sequentially 1-t-butoxycarbonylpyrrole-2-boronic acid (2.1 g, 9.7 mmol) and potassium carbonate (2.4 g, 17 mmol) in water (10 mL). The mixture was heated to 80° C. for 3 h and allowed to cool. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine (30 mL) and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo. Crystallization from 20% ethyl acetate/hexane gave 2-(1′,2′-dihydro-2′-oxospiro[cyclopentane-1,3′-[3H]indol ]-5′yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (2.2 g, 83%) as a white powder, mp 179-180.5° C. 1H NMR (DMSO-d6, 400 MHz) δ 1.30 (s, 9H), 1.75-1.98 (m, 8 H), 6.16 (dd, 1H, J=1.8, 3.3 Hz), 6.22 (‘t’, 1 H, J=3.3, 3.3 Hz), 6.79 (d, 1 H, J=7.9 Hz), 7.08 (dd, 1 H, J=1.8, 7.9 Hz), 7.14 (‘d’, 1 H, J=1.5 Hz), 7.28 (dd, J=1.9, 3.3 Hz),10.30 (s, 1 H). MS (EI) m/z 352 [M+]. Anal. Calcd for C21H24N2O3: C, 71.57; H, 6.86; N, 7.95. Found: C, 71.08; H, 6.83; N, 7.74.
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:14]([CH:17]([CH2:29][CH2:30][CH3:31])[CH2:18][O:19][C:20]1[O:24][C:23]([C:25](OC)=[O:26])=[CH:22][CH:21]=1)[CH2:15][CH3:16]>C1COCC1>[O:26]=[C:25]([C:23]1[O:24][C:20]([O:19][CH2:18][CH:17]([CH2:29][CH2:30][CH3:31])[CH2:14][CH2:15][CH3:16])=[CH:21][CH:22]=1)[CH2:1][C:2]#[N:3]
Reactant: CC#N
Reactant: CCCC(CCC)COc1ccc(C(=O)OC)o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(CCC)COc1ccc(C(=O)CC#N)o1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Anhydrous CH3CN (0.15 mL, 2.87 mmol) was added to a solution of LiHMDS (1M/THF, 3.0 mL, 3.0 mmol) at −75° C. under inert atmosphere and the reaction mixture was stirred for 5 min. A solution of methyl 5-((2-propylpentyl)oxy)furan-2-carboxylate (1.337 mmol) in anhydrous THF (7 mL) was added to the reaction mixture and the reaction mixture was stirred under inert atmosphere while slowly warming to 0° C. for over 75 min. The reaction mixture was partitioned between aqueous NaHSO4 (10%) and EtOAc. Organic layer was washed with brine, concentrated under reduced pressure. Flash chromatography purification (10%-50% EtOAc—hexanes gradient) gave 3-oxo-3-(5-((2-propylpentyl)oxy)furan-2-yl)propanenitrile as an off-white solid. Yield (0.23 g, 66%); 1H NMR (400 MHz, DMSO-d6) δ 7.57 (d, J=3.8 Hz, 1H), 5.78 (d, J=3.8 Hz, 1H), 4.30 (s, 2H), 4.08 (d, J=5.6 Hz, 2H), 1.69-1.79 (m, 1H), 1.23-1.35 (m, 8H), 0.80-0.88 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:36]([OH:40])(=[O:39])[CH:37]=O>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([S:13]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)[CH:37]3[C:36]([OH:40])=[O:39])(=[O:15])=[O:14])=[CH:11][CH:12]=2)=[CH:34][CH:35]=1
Reactant: O=S(=O)(NCCc1ccccc1OCCN1CCCCC1)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1c2cccc(OCCN3CCCCC3)c2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 8 h
Yield: 52 %

Procedure:
110 mg (0.221 mmol) of 4-(4-fluorophenoxy)-N-{2-[2-(2-piperidin-1-ylethoxy)phenyl]-ethyl}benzenesulfonamide are stirred together with 49.1 μl (0.441 mmol) of glyoxylic acid (50% strength in H2O) in 5 ml of trifluoroacetic acid at room temperature. After standing overnight, the mixture is concentrated in vacuo and the residue is chromatographed on silica gel, resulting in the desired carboxylic acid in a yield of 52%.
Reaction SMILES: Cl.[C:2]1([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:17]=[C:18]=[O:19].[K+]>O.C(O)C>[C:18]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)(=[O:19])[NH2:17]
Reactant: c1ccc(C2CNc3ccccc32)cc1
Reactant: [N-]=C=O
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(=O)N1CC(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture comprising 2.3 g of 3-phenyl indoline hydrochloride in 23 ml of water and 0.81 g of potassium isocyanate in 23 ml of ethanol was stirred for 15 minutes at room temperature. The precipitate which resulted was filtered off, washed with water and recrystallized from dilute ethanol. The yield of N-carbamoyl-3-phenylindoline was 0.9 g and the product had a melting point of 144°-145° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][O:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[Se](=O)=[O:13]>O1CCOCC1>[O:11]=[C:10]1[C:5]2[C:6](=[N:7][C:2]([CH:1]=[O:13])=[CH:3][CH:4]=2)[CH2:8][O:9]1
Reactant: Cc1ccc2c(n1)COC2=O
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1ccc2c(n1)COC2=O
Temperature: 100 °C
Yield: 79.7 %

Procedure:
A solution of 2-methyl-7H-furo[3,4-b]pyridin-5-one (1.41 g, 9.46 mmol) in dioxane (50 mL) is treated with selenium dioxide (1.2 g, 10.8 mmol) and the reaction mixture is heated at 100° C. for 3 h. Additional selenium dioxide (1.2 g, 10.8 mmol) is added at 3 and 6 hours and the reaction mixture is heated at 100° C. The reaction is heated at 100° C. for an additional 42 h. The reaction mixture is filtered through celite and washed with dioxane. The filtrate is concentrated under reduced pressure and subject to chromatography (silica gel, EtOAc/hexane). The high Rf product containing fractions are concentrated to give 5-Oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carbaldehyde (1.23 g, 80%). The low Rf containing fractions are concentrated to give 5-Oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carboxylic acid (159 mg, 9%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]=[C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:10][C:11]1[CH:15]=[N:14][N:13]2[CH2:16][CH2:17][NH:18][C:12]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1([C:33](Cl)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]=[C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:10][C:11]1[CH:15]=[N:14][N:13]2[CH2:16][CH2:17][N:18]([C:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:12]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1cnn2c1NCC2
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1cnn2c1N(C(c1ccccc1)(c1ccccc1)c1ccccc1)CC2
Temperature: 50 °C
Reaction time: 5 h
Yield: 51.6 %

Procedure:
To a solution of 7-[2,3-bis(tert-butoxycarbonyl)guanidino]-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (1.83 g) in pyridine (10 ml) was added triphenylmethyl chloride (1.67 g). The mixture was stirred at 50° C. for 5 hours. After cooling, chloroform (50 ml) was added to the reaction mixture, and the mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 2% methanol/chloroform to give 7-[-2,3-bis(tert-butoxycarbonyl)guanidino]-1-triphenylmethyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (1.57 g) as a solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[C:26]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])=[N:25][C:24]4[C:19](=[CH:20][C:21]([O:37][CH3:38])=[C:22]([C:33]([O:35][CH3:36])=[O:34])[CH:23]=4)[N:18]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[C:26]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])=[N:25][C:24]4[C:19](=[CH:20][C:21]([O:37][CH3:38])=[C:22]([C:33]([O:35][CH3:36])=[O:34])[CH:23]=4)[N:18]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: COC(=O)c1cc2nc(N3CCC[C@@H]3C)c(-c3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc2nc(N3CCC[C@@H]3C)c(-c3ccc4[nH]ncc4c3)nc2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of (S)-methyl 2-(1-(tert-butoxycarbonyl)-1H-indazol-5-yl)-7-methoxy-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (310 mg, crude) in dichloromethane (32 ml) was added trifluoroacetic acid (8 ml). After stirring overnight at room temperature, the pH value was adjusted to 7 with aqueous sodium bicarbonate and extracted with dichloromethane (2×25 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified via silica gel chromatography (10% ethyl acetate in petroleum ether) to give (S)-methyl 2-(1H-indazol-5-yl)-7-methoxy-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (240 mg) as yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([CH2:36][OH:37])[CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:3]=2)[CH:32]([CH2:36][OH:37])[CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(OCc1ccccc1)N1CCNC(CO)C1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(C(=O)OCc4ccccc4)CC3CO)nc(-c3ccccc3O)nc2c1
Temperature: 40 °C
Yield: 49 %

Procedure:
To 2-(4-chloro-7-methyl-quinazolin-2-yl)-phenol (245 mg, 0.91 mmol) in 3.0 mL of CH2Cl2 was added sequentially 3-hydroxymethyl-piperazine-1-carboxylic acid benzyl ester (336.3 mg, 1.34 mmol) and triethylamine (190 mL, 1.37 mmol), and the reaction mixture was heated at 40° C. for 6 h. The reaction mixture was cooled and extracted with water (2×10 mL) and the organic layer was separated and dried over Na2SO4. The solvent was removed under reduced pressure to give an oil. The residue was purified by normal phase LC (20-85% EtOAc-hexanes) to give 3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylic acid benzyl ester (216 mg, 64% yield). LC/MS: m/z 485.4 (M+H)+ at 3.02 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:31])[CH2:17][C:16]2[NH:15][C:14]3[CH2:13][C:12]([CH3:19])([CH3:18])[CH2:11][C:10](=[O:20])[C:9]=3[CH:8]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[C:7]=2[C:6](=[O:30])[CH2:5]1.Cl[C:33]([O:35][CH3:36])=[O:34]>O1CCCC1.CN(C)C=O>[CH3:19][C:12]1([CH3:18])[CH2:13][C:14]2[N:15]([C:33]([O:35][CH3:36])=[O:34])[C:16]3[CH2:17][C:4]([CH3:31])([CH3:3])[CH2:5][C:6](=[O:30])[C:7]=3[CH:8]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[C:9]=2[C:10](=[O:20])[CH2:11]1
Reactant: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)N1C2=C(C(=O)CC(C)(C)C2)C(c2ccc([N+](=O)[O-])cc2)C2=C1CC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A slurry of 17 mg of sodium hydride (80% dispersion in mineral oil) in 10 ml of anhydrous tetrahydrofuran was stirred at room temperature under an atmosphere of dry nitrogen and treated dropwise with a solution of 200 mg of 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-(4-nitrophenyl)-1,8(2H,5H)-acridinedione in 5 ml of dimethylformamide. The mixture was then heated at reflux for 15 minutes, cooled to room temperature, treated with 44 ml of methyl chloroformate and stirred at room temperature under an atmosphere of dry nitrogen for 18 hours. The solvents were removed under reduced pressure and the resulting waxy residue was taken up in diethyl ether and the insoluble material was filtered off. The filtrate was then purified by column chromatography on silica gel using hexane/ethyl acetate (gradient: 80:20 to 50:50) as the eluent to give methyl 2,3,4,5,6,7,8,9-octahydro-3,3,6,6-tetramethyl-9-(4-nitrophenyl)-1,8-dioxo-1H-acridine-10-carboxylate as a white crystalline solid of melting point 189-190° C.
Reaction SMILES: C(C1C=CC(C2C=CC(C(C)(C)C)=CC=2)=CC=1)(C)(C)C.[Li].Cl[CH2:23][CH:24]1[CH2:29][CH2:28][CH:27]([CH:30]2[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:31]2)[CH2:26][CH2:25]1.[F:39][C:40]([F:44])=[C:41](F)[F:42].Cl>C1(C)C=CC=CC=1.C1COCC1>[CH2:36]([CH:33]1[CH2:34][CH2:35][CH:30]([CH:27]2[CH2:26][CH2:25][CH:24]([CH2:23][C:41]([F:42])=[C:40]([F:44])[F:39])[CH2:29][CH2:28]2)[CH2:31][CH2:32]1)[CH2:37][CH3:38]
Reactant: CCCC1CCC(C2CCC(CCl)CC2)CC1
Reactant: FC(F)=C(F)F
Agent: CC(C)(C)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCC1CCC(C2CCC(CC(F)=C(F)F)CC2)CC1
Reaction time: 3 h
Yield: 93 %

Procedure:
To a reaction vessel under an argon atmosphere, 41.5 g of 4,4′-di-t-butyl-biphenyl and 500 ml of THF were added, and the resultant solution was cooled to 0° C. Thereto, 2.16 g of metal lithium was added a little at a time, and stirring was carried out for 3 hours. Next, a THF 100 ml solution of 20.0 g of 4-chloromethyl-4′-propylbicyclohexane was slowly added dropwise, and stirring was carried out for another 3 hours. Then 9.00 g of tetrafluoroethylene was added to allow reaction for 30 minutes while returning to room temperature. The resultant reaction mixture was poured into 500 ml of 1N hydrochloric acid, and mixing was carried out. Then, 500 ml of toluene was added to separate layers to an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was sequentially washed with 1N hydrochloric acid and water, and the resultant solution was dried over anhydrous magnesium sulfate. The resultant solution was concentrated under reduced pressure, a residue was purified by fractionation by means of column chromatography (silica gel; heptane), and thus 21.9 g of 4-propyl-4′-(2,3,3-trifluoroallyl)-1,1′-bicyclohexane (T-2) was obtained. Yield from compound (T-1) was 93%.
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:14]([OH:16])=O)=[N:6]2)[CH2:4][CH2:3][CH2:2]1.[NH2:17][C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:21]([CH2:31][C:32]2([OH:38])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:20][CH2:19]1.C(P(=O)(OCC)OCC)#N.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:14]([NH:17][C@H:18]3[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@@H:21]([CH2:31][C:32]4([OH:38])[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[CH2:20][CH2:19]3)=[O:16])=[N:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)CC[C@@H]1CC1(O)CCOCC1
Reactant: O=C(O)c1nn(C2CCC2)c2ccccc12
Agent: CCOP(=O)(C#N)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2nn(C3CCC3)c3ccccc23)CC[C@@H]1CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.7 %

Procedure:
The mixture of 1-cyclobutyl-1H-indazole-3-carboxylic acid (135 mg, 0.63 mmol, step 2 of Example 4), tert-butyl cis-5-amino-2-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidine-1-carboxylate (197 mg, 6.27 mmol, step 5 of Example 2), diethyl cyanophosphonate (0.13 mL, 0.75 mmol), and N,N-diisopropylethylamine (0.16 mL, 0.94 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 12 h. Then the mixture was poured onto aqueous saturated sodium hydrogencarbonate (100 mL), and the aqueous layer was extracted with ethyl acetate/toluene (3:1, 100 mL×3). The combined organic layer was concentrated under reduced pressure. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/n-hexane (1:2) to give 112 mg (35%) of the title compound as a pale yellow amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[F:19][C:20]([F:33])([F:32])[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29](Cl)=[O:30])[CH2:25][CH2:24]1)=[O:22]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:29]([CH:26]2[CH2:25][CH2:24][N:23]([C:21](=[O:22])[C:20]([F:33])([F:19])[F:32])[CH2:28][CH2:27]2)=[O:30])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=C(Cl)C1CCN(C(=O)C(F)(F)F)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CCNC(=O)C2CCN(C(=O)C(F)(F)F)CC2)c1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a stirred solution of 3-methoxy phenylethylamine (9.3 g, 61.6 mmol) and triethylamine (8.1 g, 11.2 ml, 80.1 mmol) in CH2Cl2 (50 ml) at 0° C. under an atmosphere of N2 was added 1-trifluoroacetyl-piperidine-4-carbonyl chloride (15.0 g, 61.6 mmol) as a solution in CH2Cl2 (50 ml) in a dropwise manner. The reaction was allowed to warm to RT overnight. The reaction was quenched with water (50 ml), the layers were separated, and the organic layer was washed with water (1×50 ml). The combined aqueous layers were back extracted with CH2Cl2 (1×75 ml). The combined organic layers were washed with brine (1×75 ml). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid was triturated with Et2O and filtered to give the desired product (18.8 g, 52.3 mmol, 85% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH3:16])=[O:14].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH3:16])=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1c(C)nc2ccccc2c1N
Reactant: BrCc1ccccc1
Product: COC(=O)c1c(C)nc2ccccc2c1NCc1ccccc1

Procedure:
Methyl 4-benzylamino-2-methylquinoline-3-carboxylate was synthesized by the same method as described for 1-(4-(4-bromobenzylamino-2-methylquinolin-3-yl)ethanone (Example 1, Intermediate 2c) starting from methyl 4-amino-2-methylquinoline-3-carboxylate and benzyl bromide. MS(ES+): M++H=307.