Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[CH:10][C:9]=2[CH:21]=1)=[O:4].Cl.N1C=CC=CC=1>O>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:12][C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:21][C:9]=3[CH:10]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc2oc(-c3ccc(OC)cc3)cc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1ccc2oc(-c3ccc(O)cc3)cc2c1
Temperature: 200 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
A mixture of 142 (0.45 g, 1.6 mmol) and Pyridine HCl (10 g) was heated to 200° C. After 1 hr, the reaction was cooled and diluted with water. The aqueous layer was extracted with EtOAc, dried, concentrated to give a solid which was triturated with CH2Cl2 and filtered to give 143 (0.23 g, 58%): Mp>300° C.; 1H NMR (DMSO-d6) δ 12.87 (br s, 1 H), 9.86 (br s, 1 H), 8.21 (d, 1 H, J=1.6 Hz), 7.86 (dd, 1 H, J=8.8 Hz, 1.5 Hz), 7.76 (d, 2H, J=8.8 Hz), 7.67 (d, 1 H, J=8.8 Hz), 7.29 (s, 1 H), 6.89 (dd, 2 H, J=7.7 Hz, 2.0 Hz); MS 253 (M−H)−
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4](=[O:19])[CH:3]=1.[N:20]([O-])=[O:21].[Na+].C(O)(=O)C>O>[CH2:8]([N:7]1[C:2]([NH2:1])=[C:3]([N:20]=[O:21])[C:4](=[O:19])[N:5]([CH2:16][CH2:17][CH3:18])[C:6]1=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCn1c(=O)cc(N)n(Cc2ccccc2)c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCn1c(=O)c(N=O)c(N)n(Cc2ccccc2)c1=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
2.0 g (7.7 mmol) of 6-amino-1-benzyl-3-propyluracil are heated to 80° C. in 15 ml of water and mixed with a solution of 0.55 g of sodium nitrite in 3 ml of water. After the addition of 1 ml of glacial acetic acid, a red solid is precipitated. The pH is adjusted to 4 and the suspension is stirred for a further 30 minutes at 80° C. After cooling, the crystals are filtered under suction and washed with water. 1.9 g of the title compound are obtained in the form of reddish-violet crystals (86% of theory), m.p. 208°-212° C./decomposition.
Reaction SMILES: [CH:1]1([C:6]([O:8]CC)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11](#[N:13])[CH3:12].[H-].[Na+]>C1COCC1>[CH:1]1([C:6](=[O:8])[CH2:12][C:11]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC#N
Reactant: CCOC(=O)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCCC1
Yield: 90 %

Procedure:
A solution of ethyl cyclopentanecarboxylate (prepared by esterification of commercially available cyclopentantecarboxylic acid, 30 g, 0.21 mol) and acetonitrile (10.1 g, 0.25 mol) in dry THF (80 mL) was added dropwise to a suspension of NaH (12.5 g, 0.31 mol) in dry THF (80 mL) and the resulting mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure and partitioned between water and EtOAc. The aqueous layer was separated, adjusted to pH 8 and extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4), and concentrated to give 3-cyclopentyl-3-oxopropanenitrile (26 g, 90% yield), which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ4.06 (s, 2 H), 2.92 (m, 1 H), 1.41-1.77 (m, 8 H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1)C1C=CC=CC=1>>[CH2:11]([O:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][NH:1][S:25]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[O:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1cc(=O)c(OCc2ccccc2)co1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1OCc1ccccc1
Product: O=c1cc(CNS(=O)(=O)c2ccc(Cl)cc2)occ1OCc1ccccc1
Yield: 56.9 %

Procedure:
N-(5-Benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-4-chloro-benzenesulfonamide (7-07) (20.0 g, 56.92%) was synthesized as a brown solid from 2-aminomethyl-5-benzyloxy-pyran-4-one (5) (20.0 g, 86.58 mmol) and 4-chloro-benzenesulfonyl chloride (6-07) (45.67 g, 216.45 mmol) following the procedure described for N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (7-01).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:25]1[O:29][N:28]=[CH:27][N:26]=1)[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:19][C:20]([O:22]CC)=[O:21])=[N:9]1.[OH-].[K+].C(O)(=O)C>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:25]1[O:29][N:28]=[CH:27][N:26]=1)[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:19][C:20]([OH:22])=[O:21])=[N:9]1
Reactant: CCOC(=O)Cc1nn(C(c2ccccn2)c2ncno2)c(=O)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=C(O)Cc1nn(C(c2ccccn2)c2ncno2)c(=O)c2ccccc12

Procedure:
To a solution of ethyl 3(2-pyridyl-1,2,4-oxadiazol5-ylmethyl)-4-oxo-3H-phthalazin-1-ylacetate (1.0 g) in methanol (10 ml) was added 20% aqueous KOH (0.5 ml) and the mixture refluxed for 30 minutes. Evaporation of excess methanol gave an orange residue. The residue was dissolved in water, acidified with acetic acid (1 ml) and the precipitated solid was collected and crystallized from isopropanol to yield the product (0.53 g; m.p. 196°-200° C.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2.C(N(CC)CC)C>C(COC)OC>[N:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=C(Cl)CCCCl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: O=C1CCCN1c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chlorobutryl chloride (388.0 g) was added at 40° to a solution of technical grade 8-aminoquinoline (3396.5 g) and triethylamine (278.3 g) in dimethoxyethane (2 l). After stirring overnight at ambient temperature the solids were filtered off. The filtrate was concentrated prior to additon of 13% potassium tert-butoxide in tert-butanol (2486 g) at 25°-30°. After two hours the mixture was neutralized with dilute hydrochloric acid. The slurry obtained by partial removal of the solvent was extracted three times with methylene chloride. The combined extracts were washed with water, dried over magnesium sulphate, filtered and concentrated. Ether (1 l) was added while cooling to 0°. Filtration, followed by vacuum-drying afforded 1-(8-quinolyl)-2-pyrrolidinone.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][C:11]([NH:13][NH:14]C(OC(C)(C)C)=O)=[O:12].[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>C(Cl)Cl.C(O)C.C1(C)C=CC=CC=1>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[CH2:8][CH2:9][CH2:10][C:11]([NH:13][NH2:14])=[O:12]
Reactant: CC(C)(C)OC(=O)NNC(=O)CCCN1C(=O)C=CC1=O
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: NNC(=O)CCCN1C(=O)C=CC1=O
Reaction time: 0.75 h
Yield: 90 %

Procedure:
To tert-Butyl 2-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanoyl)-hydrazinecarboxylate (245) (200 mg, 0.673 mmol) in 8 ml of DCM was added 2 ml of TFA. The mixture was stirred for 45 min, diluted with ethanol/toluene (8 ml, 1:1), evaporated and co-evaporated with ethanol/toluene (3×10 ml), crystallized with ethanol/EtAc/Hexane, filtered, and dried under vacuum to afford 188 mg (90%) of the title compound. 1H NMR (CD3OD) 6.72 (s, 2H), 5.39 (s, 0.6H), 3.47 (t, 2H, J=6.6 Hz), 2.20 (m, 2H), 1.85 (m, 2H); 13C NMR 172.72, 135.56, 54.93, 39.20, 37.99, 25.20; MS m/z+197.9 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][O:20][CH2:21][CH3:22])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:23])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Cl>CN(C=O)C>[CH2:21]([O:20][CH2:19][C:13]1[N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([O:23][CH2:30][C:31]4[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=4[CH3:33])=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:22]
Reactant: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)C
Reactant: Cc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4C)ccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Amino-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (750 mg, 2.39 mmol) was dissolved with heating in DMF (50 mL). Solid cesium carbonate (1.55 g, 4.77 mmol) was added. After 15 minutes, 2-methylbenzyl chloride (487 mg, 2.63 mmol) was added to the mixture. The reaction was stirred overnight at ambient temperature, then was poured onto water (500-750 mL) and a milky white precipitate formed immediately. The mixture was stirred for 1 hour, and then the precipitate was isolated by filtration. The solid was purified by flash chromatography (silica gel, gradient elution with 0.5-2% methanol in chloroform) followed by recrystallization from 2-propanol. The final product was isolated by filtration and dried overnight under vacuum at 60° C. to provide 780 mg of 2-(ethoxymethyl)-7-[(2-methylbenzyl)oxy]-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as an off white solid, mp 216.0-218.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)[CH2:10][C:11]([O:13]C)=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1>Cl>[NH2:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: COC(=O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2cc(N)ccc21
Agent: Cl
Product: Nc1ccc2c(c1)ncn2C(CC(=O)O)c1ccc(-c2ccccc2)cc1

Procedure:
A solution of methyl 3-(5-amino-1H-benzimidazol-1-yl)-3-(1,1′-biphenyl)-4-ylpropanoate (10 mg, 27 μmol) in hydrochloric acid (10 mL of a 5N solution) was stirred at room temperature for 48 hours. The solution was then evaporated in vacuo to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=4.11 min, MH+ 358].
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[C:5]([N:9]2[C:33](=[O:34])[C:12]3=[CH:13][N:14]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH:32]=[CH:31][CH:30]=[N:29]5)=[CH:24][CH:23]=4)[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10]2)[N:4]=[CH:3]1.C([BH3-])#N.[Na+]>O1CCCC1.ClCCl>[OH:8][CH2:7][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][C:5]=1[N:9]1[C:33](=[O:34])[C:12]2=[CH:13][N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:24][CH:23]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]2=[N:10]1
Reactant: Cn1cnc(-n2nc3c4ccccc4n(Cc4ccc(-n5cccn5)cc4)cc-3c2=O)c1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1cnc(-n2nc3c4ccccc4n(Cc4ccc(-n5cccn5)cc4)cc-3c2=O)c1CO
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1-Methyl-4-(3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)-1H-imidazole-5-carbaldehyde (Example 555, 50 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2 mL) and dichloromethane (15 mL), cooled to 0° C. and treated with sodium cyanoborohydride (0.033 mL, 1 M tetrahydrofuran solution, 0.033 mmol, 0.3 equiv). After stirring for 5 minutes at 0° C., the mixture was warmed to ambient temperature and stirred for 1 hour. Additional sodium cyanoborohydride (0.033 mL, 1 M tetrahydrofuran solution, 0.033 mmol, 0.3 equiv) was added and after 1 hour, the mixture was concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (85:15 to 40:60; water containing 0.5% trifluoroacetic acid:acetonitrile containing 0.5% trifluoroacetic acid). The appropriate fractions were concentrated in vacuo, providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.04 (1H, br s), 8.37 (1H, br d, J=4.7 Hz), 8.20 (1H, m), 7.85 (1H, d, J=8.8 Hz), 7.77 (2H, d, J=8.3 Hz), 7.74-7.65 (4H, m), 7.61 (1H, br t, J=6.7 Hz), 7.44 (2H, d, J=7.6 Hz), 6.51 (1H, m), 5.82 (2H, s), 4.00 (2H, s) 2.65 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 452.1842 [(M+H)+; calculated for C25H22N7O2: 452.1829].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9]C)[C:3]=1[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]1=[O:23].B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([OH:9])[C:3]=1[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[N:13]([CH3:22])[C:12]1=[O:23]
Reactant: COc1cc(F)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(O)cc(F)cc2F)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
13.6 g (40 mmol) of 3-(2,4-difluoro-6-methoxyphenyl)-1-methyl-6-trifluoromethyluracil was dissolved in 150 ml of dichloromethane, and 66.7 ml (200 mmol) of boron tribromide (3.0M dichloromethane solution) was dropwise added thereto at 0° C. After stirring at room temperature for 3 hours, the reaction solution was poured into ice water and neutralized with sodium hydrogencarbonate. It was extracted with dichloromethane. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained crude crystals were washed with isopropyl ether to obtain 9.8 g (yield: 75.4%) of the desired product as white crystals. Melting point: 195-196° C.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CC[O:9]CC.C=CCCC=CCC.[CH3:20][C:21]([C@H:23]1[N:26]([CH:27]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:25](=[O:46])[C@@H:24]1[C@H:47]([O:49][C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH3:48])=[CH2:22]>O1CCCC1>[OH:9][CH2:22][C@H:21]([C@H:23]1[N:26]([CH:27]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:25](=[O:46])[C@@H:24]1[C@H:47]([O:49][C:50]([O:52][CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)=[O:51])[CH3:48])[CH3:20]
Reactant: CCOCC
Reactant: C=C(C)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Agent: C=CCCC=CCC
Agent: FB(F)F
Agent: [BH4-]
Solvent: C1CCOC1
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)OC(=O)OCc3ccccc3)[C@H]2[C@H](C)CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a solution of sodium borohydride (0.32 g) in dry tetrahydrofuran (40 ml) was added dropwise boron trifluoride-etherate (1.81 g) at 10°-20° C. under nitrogen gas, and the resultant mixture was stirred for 1 hour. After addition of 1,5-octadiene (1.21 g) and stirring for 1 hour, a solution of (3S,4S)-4-(1-methylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (2.63 g) in dry tetrahydrofuran (10 ml) was dropwise added thereto at 20°-25° C. over a period of 1 hour, followed by stirring for 3 hours. The reaction mixture was quenched with water (7 ml) at 10°-30° C. for 1 hour. After addition of 4% sodium bicarbonate solution (5.3 ml), the mixture was heated at 40°-45° C., treated with 35% hydrogen peroxide solution (5.3 ml) at 40°-45° C. and cooled down to room temperature. Sodium sulfite (0.2 g) and toluene (6 ml) were added to the mixture, followed by stirring. The organic layer was separated and the aqueous layer was extracted with toluene (12 ml). The combined extracts were washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave an oily residue, which was purified by silica gel chromatography to yield (3S,4R) 4-(1-(S)-hydroxymethylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (1.88 g) and the corresponding 4-(1-(R)-hydroxymethylethyl) compound (0.51 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.O1CCCC1.[CH:23]1([Mg]Cl)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CCOCC>[CH:23]1([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: Cl[Mg]C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Nc1cc2ccc(C3CCCCC3)cc2cn1)C1CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 19 %

Procedure:
To a solution of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (131.8 mg, 0.4527 mmol) in tetrahydrofuran (6.0 mL, 74 mmol) in an oven-dried flask at 0° C. was added DPPPNiCl2 (18.2 mg, 0.0336 mmol) followed by 2.0 M of cyclohexylmagnesium chloride in ether (0.60 mL). The reaction was stirred at 0° C. for 1.5 hours and then heated at 40° C. overnight. DPPPNiCl2 (21 mg) and 2.0 M of cyclohexylmagnesium chloride in ether (0.60 mL) were added. The reaction was heated at 50° C. for an additional 3.5 hours. The mixture was then partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 24.8 mg (19%) of N-(7-cyclohexylisoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=5.228, M+H=295.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.06 (s, 1H), 8.40 (s, 1H), 7.82 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.61 (dd, J=8.6, 1.7 Hz, 1H), 2.67 (t, J=11.7 Hz, 1H), 2.10-1.99 (m, 1H), 1.93-1.79 (m, 4H), 1.74 (d, J=12.3 Hz, 1H), 1.58-1.20 (m, 5H), 0.82 (dq, J=4.9, 2.9 Hz, 4H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH:21]([C:23]1[N:27]([CH3:28])[C:26](C2SC=CC=2)=[N:25][CH:24]=1)[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Ni]>[CH2:1]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH:21]([C:23]1[N:27]([CH3:28])[CH:26]=[N:25][CH:24]=1)[OH:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(C(O)[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2Cc2ccccc2)cnc1-c1cccs1
Agent: [Ni]
Solvent: CCO
Product: Cn1cncc1C(O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1Cc1ccccc1
Yield: 72.4 %

Procedure:
To a Raney-Nickel (NDT-90, 1400 ml) was added 1-{(2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy) pyrrolidin-2-yl}-1-(1-methyl-2-thiophenylimidazol-5-yl)methanol (222 g) in ethanol (4.4 l) under an atmosphere of nitrogen. The mixture was stirred and heated under reflux for 2.5 hours. After cooling, the Raney-Nickel was removed by filtration and washed with ethanol (1 l×5). The filtrate and the washings were combined, dried over magnesium sulfate, evaporated in vacuo to give 1-{(2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy) pyrrolidin-2-yl}-1-(1-methylimidazol-5-yl)methanol (133.4 g) as an amorphous solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:25]=[CH:24][C:7]([CH2:8][CH2:9][C:10]([NH:12][CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[CH2:26](Br)[CH:27]=[CH2:28].N12CCCC1=NCCC2>O1CCCC1>[CH2:28]([CH2:2][CH2:1][NH:3][C:4]1[CH:25]=[CH:24][C:7]([CH2:8][CH2:9][C:10]([NH:12][CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11])=[CH:6][CH:5]=1)[CH:27]=[CH2:26]
Reactant: C=CCBr
Reactant: CCNc1ccc(CCC(=O)NC(C(=O)OCC)C(=O)OCC)cc1
Agent: C1CN=C2CCCN2C1
Solvent: C1CCOC1
Product: C=CCCCNc1ccc(CCC(=O)NC(C(=O)OCC)C(=O)OCC)cc1

Procedure:
Working as in Example F, but starting with 8 g of diethyl 4-ethylaminobenzylacetamidomalonate, 4 ml of allyl bromide and 5.82 ml of 1,5-diazabicyclo-[4.3.0] non-5-ene in 50 ml of tetrahydrofuran, and after purification by flash chromatography (eluent: 90/10 CH2Cl2/EtOAc by volume), 5.6 g of a solid are obtained, which solid is recrystallized from 35 ml of cyclohexane. 5.43 g of diethyl 4-(allylethylamino)benzylacetamidomalonate are thus obtained in the form of a white solid melting at 86° C.
Reaction SMILES: CN(C)C=O.[C:6]([O:17][CH3:18])(=[O:16])[C:7]1[CH:15]=[C:13]([OH:14])[C:11]([OH:12])=[C:9]([OH:10])[CH:8]=1.Br[CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>O>[OH:14][C:13]1[C:11]2[O:12][CH2:20][CH2:21][O:10][C:9]=2[CH:8]=[C:7]([C:6]([O:17][CH3:18])=[O:16])[CH:15]=1
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(O)c2c(c1)OCCO2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To 20 mL of an N,N-dimethylformamide solution containing 2.25 g of methyl gallate, 1.3 mL of 1,2-dibromoethane and 4.05 g of potassium carbonate were added, and the mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, then fed into water, and the resultant solution was extracted with a mixed solvent of ethyl acetate:toluene of 5:1. The organic layer was washed with water and an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 1.66 g of a brown oily substance, methyl 8-hydroxy-2,3-dihydro-1,4-benzodioxin-6-carboxylate.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:18][CH3:19])=[C:7]([O:12][CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:8]=2)[N:3]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1>CC#N>[CH:13]1([O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][C:6]=2[O:18][CH3:19])[N:3]=[C:2]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[N:11]=[CH:10]3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1cc2nc(Cl)ncc2cc1OC1CCCC1
Solvent: CC#N
Product: COc1cc2nc(N[C@H]3CC[C@H](O)CC3)ncc2cc1OC1CCCC1
Temperature: 60 °C

Procedure:
To a suspension of 2-chloro-6-(cyclopentyloxy)-7-methoxyquinazoline (100.0 mg, 0.36 mmol) (obtained from the company compound collection) in 20 ml of CH3CN at room temperature was added the trans-4-aminocyclohexanol (207.0 mg, 1.79 mmol). The resulting mixture was heated to 60° C. for 5 hours. The reaction was cooled and partitioned with EA and water. The organics layer was washed with water (2×20 mL) and brine (20 mL), combined and dried over MgSO4, Removal of the solvent provided a yellow solid. The crude material was purified using silica gel eluting with 95/5 EA/MeOH to afford 45.9 mg of the desired product with 35.9% yield. 1H NMR (400 MHz, DMSO-d6) ppm 1.14-1.40 (m, 4H), 1.51-2.06 (m, 12H), 3.36-3.52 (m, 1H), 3.66-3.80 (m, 1H), 3.82-3.95 (m, 3H), 4.54 (s, 1H), 4.75-4.88 (m, 1H), 6.74 (d, J=8.06 Hz, 1H), 6.83 (s, 1H), 7.12 (s, 1H), 8.80 (s, 1H). HRMS: m/z 358.21218 [M+H]+), calc. 358.21252. MS m/z, (APCI); 358.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]([CH2:19][CH2:20][CH3:21])[C:15]([O:17]C)=[O:16])=[C:12]([CH3:22])[N:11]=[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH:14]([CH2:19][CH2:20][CH3:21])[C:15]([OH:17])=[O:16])=[C:12]([CH3:22])[N:11]=[C:10]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1
Yield: 48.1 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-(4-chlorophenyl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.056 g; 0.142 mmol), sodium hydroxide 10N (0.142 mL; 1.42 mmol) in methanol (1.4 mL). Purification by flash-chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane followed by a purification by preparative HPLC (HPLC method 1) furnished 0.026 g (48%) of the title compound as a white solid.