Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([C:16]1[O:17][C:18]2[CH:39]=[CH:38][CH:37]=[CH:36][C:19]=2[C:20]=1[CH:21]([OH:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:13][CH2:14][CH3:15].ClCCl>C(OCC)C>[CH2:12]([C:16]1[O:17][C:18]2[CH:39]=[CH:38][CH:37]=[CH:36][C:19]=2[C:20]=1[C:21]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)=[O:35])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1oc2ccccc2c1C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(-c2ccc(O)cc2)cc1
Reaction time: 1 h
Yield: 55.3 %

Procedure:
Pyridinium chlorochromate (1.74 g, 8.06 mmol), was added into a mixture of 4'-[(2-butyl-benzofuran-3-yl)-hydroxy-methyl]-biphenyl-4-ol (2.0 g, 5.37 mmol), and dichloromethane (20 mL). The reaction mixture was stirred for 1 hour, diluted with ethyl ether and filtered through a florisil pad. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexanes/EtOAc 3:1) gave a yellow solid(1.1 g): MS m/e 370 (M+);
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[CH3:11][O:12][CH2:13]Br.O>CN(C=O)C>[CH3:11][O:12][CH2:13][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[Br:3]
Reactant: Oc1ccccc1Br
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccccc1Br
Reaction time: 0.33 h
Yield: 53.1 %

Procedure:
To a stirring suspension of sodium hydride (1.2 g, 52.1 mmol, 60% dispersion in mineral oil) in DMF (75 mL) at 0° C. was added 2-bromophenol (6.0 g, 34.7 mmol) dropwise. After stirring for 20 min, bromomethyl methyl ether (4.3 g, 34.7 mmol) was added. After stirring for 16 h at room temperature, the mixture was poured into water (250 mL) and extracted with hexane. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel, hexane) to yield the title compound as a colorless oil (4.0 g, 53%). 1NHMR (400 MHz, CDCl3) δ 7.55 (d, 1H), 7.28 (t, 1H), 7.16 (d, 1H), 6.91 (t, 1H), 5.25 (s, 2H), 3.54 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](N2C=NC=N2)[CH:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)C(C(c1ccc(Cl)cc1)n1cncn1)n1cncn1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)C(=Cc1ccc(Cl)cc1)n1cncn1

Procedure:
1-(4-Chlorophenyl)-4,4-dimethyl-1,2-bis(1,2,4-triazol-1-yl)-pentan-3-one (0.5 g) was heated at 180° C. for 1 hour and at 200° C. for 3 hours on an oil bath. After cooling, the mixture was dissolved in chloroform (50 ml), washed with water (50 ml) and concentrated to give yellow oily substance (0.37 g). Triazole (0.095 g; 99%) was recovered from the aqueous layer by concentration. The oily substance was analyzed by the gas-chromatography under the following conditions:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[CH:4][C:3]=1[C:16]#[N:17].[N:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1.CC([O-])(C)C.[K+]>CS(C)=O>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:24][C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)=[C:3]([C:16]#[N:17])[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(-c2ccc(F)c(C#N)c2)c1
Reactant: Nc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cccc(-c2ccc(Nc3ccncc3)c(C#N)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.9 %

Procedure:
To a solution of 4-fluoro-3′-methoxybiphenyl-3-carbonitrile (0.50 g, 2.20 mmol) in DMSO (4 mL) was added pyridine-4-amine (0.23 g, 2.42 mmol) and KOtBu (0.15 g, 1.38 mmol). The reaction stirred under nitrogen at room temperature for 12 h. The reaction mixture was partitioned between water and ethyl acetate, the layers were separated, the organics were washed with water, brine solution, dried over Na2SO4 and concentrated to give the crude product. The crude material was purified by silica gel column chromatography (DCM/(2M)NH4-MeOH=100/0−95/5) to afford 0.53 g of 3′-methoxy-4-(pyridine-4-ylamino)biphenyl-3-carbonitrile. MS (ESI) m/z 302.2 (M+H). 1H NMR MeOD) d ppm 8.24 (2H, d, J=6.41 Hz), 8.01 (1H, d, J=2.44 Hz), 7.93 (1H, dd, J=8.70, 2.29 Hz), 7.61 (1H, d, J=8.55 Hz), 7.40 (1H, t, J=7.93 Hz), 7.17-7.30 (2H, m), 6.92-7.05 (3H, m), 3.88 (3H, s).
Reaction SMILES: BrC1C=CC(O)=C(C2(O)C3C(=CC=CC=3)N(CCCCC)C2=O)C=1.[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][C:29]([C:33]2(O)[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]([CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:34]2=[O:47])=[C:28]([OH:49])[CH:27]=1>>[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][C:29]([CH:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]([CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:34]2=[O:47])=[C:28]([OH:49])[CH:27]=1
Reactant: CCCCCN1C(=O)C(O)(c2cc(Cl)c(Cl)cc2O)c2ccccc21
Agent: CCCCCN1C(=O)C(O)(c2cc(Br)ccc2O)c2ccccc21
Product: CCCCCN1C(=O)C(c2cc(Cl)c(Cl)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 15B, and making non-critical variations to replace 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(4,5-dichloro-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (86%): 1H NMR (300 MHz, CDCl3) δ 10.0-9.50 (br, 1H), 7.42 (t, 1H), 7.32 (d, 1H), 7.22 (td, 1H), 7.09 (s, 1H), 6.95 (d, 1H), 6.93 (s, 1H), 5.04 (s, 1H), 3.77-3.68 (m, 2H), 1.77-1.62 (m, 2H), 1.40-1.27 (m, 4H), 0.88 (t, 3H); MS (ES+) m/z 348 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([OH:28])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[CH3:35][C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1)=[O:37].N1C=CC=CC=1>C1COCC1.O.CN(C=O)C>[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:26](=[O:28])/[CH:25]=[CH:24]/[C:4]2[N:5]([C@@H:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16][CH2:15]3)[C:6]3=[N:7][C:8]([CH3:13])=[CH:9][C:10]([CH3:12])=[C:11]3[C:3]=2[C:1]#[N:2])=[CH:41][CH:40]=1)(=[O:37])[CH3:35]
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(NC(=O)/C=C/c2c(C#N)c3c(C)cc(C)nc3n2[C@H]2CCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 4-amino acetanilide (145 mg, 0.968 mmol), pyridine (0.262 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate.
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH2:17][O:18][CH2:19][C:20]#[CH:21])[CH2:6][NH:7][C:8]([NH:10][NH:11][C:12](OCC)=[O:13])=[O:9])[C:2]#[CH:3].C(=O)([O-])[O-].[K+].[K+]>CCO>[CH2:1]([O:4][CH:5]([CH2:17][O:18][CH2:19][C:20]#[CH:21])[CH2:6][N:7]1[C:8](=[O:9])[NH:10][NH:11][C:12]1=[O:13])[C:2]#[CH:3]
Reactant: C#CCOCC(CNC(=O)NNC(=O)OCC)OCC#C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#CCOCC(Cn1c(=O)[nH][nH]c1=O)OCC#C
Temperature: 65 °C
Reaction time: 16 h
Yield: 32.9 %

Procedure:
To ethyl 2-(2,3-bis(prop-2-ynyloxy)propylcarbamoyl)hydrazinecarboxylate (I-13c: 855 mg, 2.88 mmol) in EtOH (14.400 mL) was added potassium carbonate (1590 mg, 11.50 mmol). The mixture was stirred at 65° C. for 16 h. After cooling to room temperature, the mixture was concentrated. HCl 1N was added up to pH-3, and then extracted with AcOEt twice, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (30-100% AcOEt/heptane), and then repurified by silica gel chromatography (0-20% MeOH/CH2Cl2), giving 4-(2,3-bis(prop-2-ynyloxy)propyl)-1,2,4-triazolidine-3,5-dione (1-13d: 238 mg, 33%) as a colorless oil. LC-MS (M+1) 252.1, t=0.72 minute. 1H NMR (400 MHz, CD3CN) δ ppm 2.69 (t, J=2.27 Hz, 1 H) 2.76 (t, J=2.27 Hz, 1 H) 3.47-3.69 (m, 4 H) 3.93-4.04 (m, 1 H) 4.20 (d, J=2.27 Hz, 2 H) 4.22-4.28 (m, 2 H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:13](Cl)=[O:14])[S:12][CH:11]=[CH:10][CH:9]=1.[CH2:16]([NH2:25])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>ClCCCl.O>[CH2:16]([NH:25][C:13]([C:8]1[S:12][CH:11]=[CH:10][CH:9]=1)=[O:14])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC/C=C/c1ccccc1
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(NC/C=C/c1ccccc1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
(E)-N-Cinnamyl-2-thiophenecarboxamide may be obtained in the following manner: triethylamine (8 g) and then thenoyl chloride (6.5 g) are added to a solution, maintained under a nitrogen atmosphere and at a temperature in the region of 25° C., of (E)-cinnamylamine (5.3 g) in 1,2-dichloroethane (80 cc). The suspension obtained is stirred for 1 hour at a temperature in the region of 25° C. and then poured into water (80 cc). The aqueous phase is acidified to a pH in the region of 5 with 4 N aqueous hydrochloric acid solution and then extracted with 1,2-dichloroethane (2×50 cc). The combined organic phases are washed with water (2×40 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (4 kPa) at 40° C. The residue is stirred in isopropyl ether (40 cc). The solid is separated by filtration, washed with isopropyl ether (4×10 cc) and dried in the air. (E)-N-Cinnamyl-2-thiophenecarboxamide (5 g), m.p. 110° C., is thereby obtained.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:12]=1[C:13]#[N:14].Cl>CO>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[C:12]=1[C:13](=[N:2][OH:3])[NH2:14]
Reactant: N#Cc1c(F)cccc1C(F)(F)F
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=NO)c1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Yield: 56.6 %

Procedure:
In 540 ml of methanol was dissolved 58.8 g of hydroxylamine hydrochloride and to the solution was added 160 ml of aqueous solution of sodium carbonate containing 49.4 g thereof. 40 g of 2-fluoro-6-trifluoromethylbenzonitrile was added thereto at room temperature with stirring, and then further stirred 3 hours at 60° C. After removing the solvent methanol by distillation from the solution, the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and it was concentrated under reduced pressure, thereby obtaining crude crystals. The crystals were then added with 200 ml of 3N aqueous solution of hydrochloric acid and thoroughly stirred, then the insoluble substance resulted in the solution was removed by filtration. The filtrate was then neutralized with 10% aqueous solution of sodium hydroxide under cooling and then extracted again with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure to obtain 26.6 g of the objective compound. m.p. 155-157° C.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:12]=[C:11]([N:13]([CH3:15])[CH3:14])[C:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:9][N:8]=2)=[CH:4][CH:3]=1.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>N1C=CC=CC=1.ClCCl>[CH2:27]([O:26][C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:12]=[C:11]([N:13]([CH3:15])[CH3:14])[C:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:9][N:8]=2)=[CH:21][CH:22]=1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)Cc1cnc(Cc2ccc(N)cc2)nc1N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Cc1cnc(Cc2ccc(NC(=O)OCc3ccccc3)cc2)nc1N(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.8 %

Procedure:
To a mixture of methyl [2-(4-aminobenzyl)-4-(dimethylamino)pyrimidin-5-yl]acetate (1.50 g, 4.99 mmol) in pyridine (1.21 mL) and dichloromethane (20 mL) was added benzyl chloroformate (1.07 mL, 7.49 mmol). After stirring for 14 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The remaining residue was chromatographed on silica gel (NH silica gel, hexane/ethyl acetate 2:1) to give methyl [2-(4-{[(benzyloxy)carbonyl]amino}-benzyl)-4-(dimethylamino)pyrimidin-5-yl]acetate (1.99 g, 92%).
Reaction SMILES: [CH3:1][N:2]([CH3:48])[CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:18]([NH:20][C@H:21]([C:23]4[N:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:27](=[O:35])[C:26]5=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]5[N:24]=4)[CH3:22])=[N:17][CH:16]=[N:15][C:14]=3[N:13](COCC[Si](C)(C)C)[CH:12]=2)[CH:8]=[N:7]1.FC(F)(F)C(O)=O.N>>[CH3:48][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:18]([NH:20][C@H:21]([C:23]4[N:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:27](=[O:35])[C:26]5=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]5[N:24]=4)[CH3:22])=[N:17][CH:16]=[N:15][C:14]=3[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cnn(CCCN(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cnn(CCCN(C)C)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 44.7 %

Procedure:
(S)-2-(1-((5-(1-(3-(Dimethylamino)propyl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.05 mmol) was treated with trifluroacetic acid (2 ml, 26 mmol) and a solution of ammonia (7N in methanol, 5 ml, 35 mmol) according to the method decried in Example 27 to give 12 mg (42% yield) of the title compound. Purity 97%.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.[C:20]([O:24][C:25]([N:27]([CH:40]([CH3:42])[CH3:41])[CH2:28][C@H:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:30](O)=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:29]([C:30]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:31])[CH2:28][N:27]([CH:40]([CH3:41])[CH3:42])[C:25](=[O:26])[O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:34][CH:35]=1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (2.92 g, 9.51 mmol) and (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (3.25 g, 9.51 mmol) in DCM (40 mL) and DIEA (5.0 mL, 28.7 mmol) was stirred at room temperature for 10 minutes. HBTU (3.61 g, 9.51 mmol) was added to the mixture. The mixture was stirred at room temperature for 1 hour. The solvent was removed, and the residue was dissolved in ethyl acetate (500 mL) and washed with water (6×100 mL). The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by EtOAc-DCM/MeOH (20:1) to give tert-butyl (S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (3.68 g, 69%.) LC/MS (APCI+) m/z 558.2 [M+H]+.
Reaction SMILES: [C:1]([O:7][CH:8]([CH2:10][CH3:11])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13].N1CCCCC1.O>C1C=CC=CC=1.C(O)(=O)C>[N+:12]([C:15]1[CH:16]=[C:17]([CH:18]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH:8]([CH3:9])[CH2:10][CH3:11])=[O:6])[CH:20]=[CH:21][CH:22]=1)([O-:14])=[O:13]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCC(C)OC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: O
Product: CCC(C)OC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O

Procedure:
A solution of sec-butyl acetoacetate (5.0 g, 0.031 moles), 3-nitrobenzaldehyde (4.7 g, 0.031 moles), 0.5 ml of piperidine and 0.5 ml of acetic acid in 50 ml of benzene was heated at reflux for one hour collecting 1 eq. of water. The cooled solution, in ethyl acetate, was washed with sodium hydrogen carbonate, potassium hydrogen sulfate and brine, dried and evaporated to give 9.2 g of the title A compound as a dark oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH2:13].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[S:22]([NH:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[F:3])(=[O:24])=[O:23]
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To NaH (60% dispersion in mineral oil) (0.734, 18.3 mmol) in THF (100 mL) at 0° C. was added dropwise a solution of 2-fluoro-4-nitrobenzenamine (2.20 g, 14.1 mmol) in THF (25 mL). The solution turned deep red in color and was stirred at 0° C. for 1 hour. A solution of 2,3-dichlorobenzene-1-sulfonyl chloride (3.80 g, 15.5 mmol) in THF (25 mL) was then added dropwise, at which point the reaction turned orange/yellow in color. The mixture was allowed to warm to room temperature and then was stirred for and additional 30 minutes. The reaction was quenched by addition of NH4Cl (aq., sat.), and then concentrated. The mixture was partitioned between water and ethyl acetate. The organics were dried with MgSO4, filtered, and concentrated to afford 2,3-dichloro-N-(2-fluoro-4-nitrophenyl)benzenesulfonamide.
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C@H:21]([CH2:25][C:26]3[CH:38]=[CH:37][C:29]4[NH:30][C:31]([C:33]([F:36])([F:35])[F:34])=[N:32][C:28]=4[CH:27]=3)[C:22]([OH:24])=O)=[O:19])[CH2:14][CH2:13]2)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[N:81]1([CH:87]2[CH2:92][CH2:91][NH:90][CH2:89][CH2:88]2)[CH2:86][CH2:85][CH2:84][CH2:83][CH2:82]1>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]1[NH:30][C:29]2[CH:37]=[CH:38][C:26]([CH2:25][C@@H:21]([NH:20][C:18]([N:15]3[CH2:16][CH2:17][CH:12]([N:11]4[CH2:10][C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[NH:3][C:2]4=[O:1])[CH2:13][CH2:14]3)=[O:19])[C:22](=[O:24])[N:90]3[CH2:91][CH2:92][CH:87]([N:81]4[CH2:86][CH2:85][CH2:84][CH2:83][CH2:82]4)[CH2:88][CH2:89]3)=[CH:27][C:28]=2[N:32]=1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: O=C(O)[C@@H](Cc1ccc2[nH]c(C(F)(F)F)nc2c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@H](Cc1ccc2[nH]c(C(F)(F)F)nc2c1)C(=O)N1CCC(N2CCCCC2)CC1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.3 %

Procedure:
To a stirred solution of the acid (R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propanoic acid (33 mg, 0.06 mmol) and diisopropylethylamine (33 mg, 0.25 mmol) in methylene chloride (2 mL) was added a solution of PyBOP (33 mg, 0.06 mmol) and 4-piperidinopiperidine (12 mg, 0.07 mmol) in methylene chloride (1 mL). The reaction mixture was stirred at room temperature for 16 h and was subjected to preparative thin layer chromatography for purification (1:10 2M ammonia in methanol/methylene chloride) to give the title compound (4.6 mg, 12% yield). 1H-NMR (CD3OD, 500 MHz) δ 7.73-7.71 (m, 1H), 7.62 (bs, 1H), 7.39-7.36 (m, 1H), 7.19-7.11 (m, 2H), 6.96 (t, J=7.2 Hz, 1H), 6.81 (d, J=7.9 Hz, 1H), 5.06-5.02 (m, 1H), 4.67-4.58 (m, 1H), 4.49-4.40 (m, 1H), 4.38 (s, 1H), 4.33 (bs, 1H), 4.25-4.16 (m, 2H), 4.10-4.03 (m, 1H), 3.22-3.14 (m, 3H), 3.04-2.87 (m, 4H), 2.79-2.71 (m, 1H), 2.58-2.48 (m, 1H), 2.44-2.33 (m, 1H), 2.31-2.22 (m, 1H), 2.04-1.92 (m, 1H), 1.86-1.43 (m, 11H), 1.33-1.29 (m, 1H), 0.94-0.84 (m, 1H), −0.04-−0.12 (m, 1H). LC/MS: tR=1.97 min, 681 (MH)+.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH2:10][C@@H:11]([NH:16]C(=O)OC(C)(C)C)[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][C:6]2[O:24][CH:25]([CH3:32])[C:26]3[C:31]([C:5]=2[CH:4]=1)=[CH:30][CH:29]=[N:28][CH:27]=3)#[N:2].Cl.O1CCOCC1>ClCCl>[NH2:16][C@@H:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10][O:9][C:8]1[C:3]([C:1]#[N:2])=[CH:4][C:5]2[C:31]3[C:26](=[CH:27][N:28]=[CH:29][CH:30]=3)[CH:25]([CH3:32])[O:24][C:6]=2[CH:7]=1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1C#N)-c1ccncc1C(C)O2)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)COc1cc2c(cc1C#N)-c1ccncc1C(C)O2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73.5 %

Procedure:
To a solution of tert-butyl ((2S)-1-((9-cyano-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (15 mg, 0.034 mmol) in dichloromethane (2 mL) cooled to 0° C. was added HCl, 4M in dioxane (1.0 mL, 4.00 mmol) slowly over a period of 1 min. The reaction mixture was stirred at 0° C. for 5 min and then warmed to room temperature and allowed to stir for 2 h. The solvents were removed under reduced pressure and the crude material was washed with 5% methanol in ethyl acetate to afford 8-(((S)-2-amino-4-methylpentyl)oxy)-5-methyl-5H-chromeno[3,4-c]pyridine-9-carbonitrile (9 mg, 0.025 mmol, 73% yield) as a yellow solid. 1H NMR (400 MHz, MeOD) δ 8.74 (bs, 2H), 8.58 (s, 1H), 8.34 (d, J=6 Hz, 1H), 7.01 (s, 1H), 5.74 (t, J=6.4 Hz, 1H), 4.48 (m, 1H), 4.33 (m, 1H), 3.78 (m, 1H), 1.82-1.68 (m, 6H), 1.06 (m, 6H). LCMS (ESI) m/e 338.2 [(M+H)+, calcd for C20H24N3O2 338.2] LC/MS retention time (method D): tR=1.17 min. HPLC retention time (method A): tR=7.97 min and 8.03 min (diastereomeric mixture); HPLC retention time (method B): tR=8.77 min (peaks overlapped).