Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH2:30][CH2:31][OH:32])[N:9]=2)[CH:7]=1.[N:34]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])([CH3:46])[C@H:35]([C:43](O)=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1COCC1.C(N=C=NC(C)C)(C)C>O>[C:50]([O:49][C:47](=[O:48])[N:34]([C@@H:35]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:43]([N:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]1[C:22](=[O:23])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]#[C:13][C:12]2[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[OH:33])=[N:9][N:10]([CH2:30][CH2:31][OH:32])[CH:11]=2)=[CH:20][CH:19]=1)=[O:44])[CH3:46])([CH3:53])([CH3:51])[CH3:52]
Reactant: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)[C@H]1CCCCN1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)N1CCCC[C@@H]1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a mixture of compound 5A (6.50 g, 13.98 mmol) and BOC-N-Me-Phe-OH (6A, 9.76 g, 34.94 mmol) was added anhydrous THF (350 mL) and the resultant mixture was stirred at rt for 10 min. Diisopropylcarbodiimide (DIPC, 5.41 mL, 34.94 mmol) was added slowly at rt. The reaction mixture was stirred at rt overnight. Water (˜10 mL) was added to the above mixture and the reaction mixture was stirred at rt for 3 hour. Solvent was removed and the residua were dissolved in ethyl acetate. It was filtered to remove solid (diisopropylurea). The filtrate was purified by silica column chromatography eluting with hexanes-ethyl acetate (v/v 1/1, 2/3, 1/2) to provide the title compound (7A, 4.3 g) as foam-like powder in 42.3% yield. 1H NMR (CDCl3, 500 MHz) δ 10.63 (s, 1H), 8.67 (s, 1H), 8.62 (s, 1H), 7.76 (s, 1H), 7.63 (m, 1H), 7.52 (d, 2H, J=7.5 Hz), 7.40-7.10 (m, 7H), 6.96 (d, 1H, J=8.0 Hz), 5.35 (br s, 1H), 5.13 (m, 1H), 4.29 (s, 2H), 4.05 (s, 2H), 3.81 (m, 1H), 3.20 (t, 1H, J=8.0 Hz), 3.09 (m, 2H), 2.94 (s, 3H), 2.87 (m, 1H), 2.35 (m, 1H), 1.75-1.10 (m, 12H), 0.74 (m, 1H). LCMS (ESI) m/z 748.26 (MNa+), 726.27 (MH+), 670.21, 626.20, 465.10, 373.18, 317.14 (100). HPLC: tR=5.70 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].N1C=CC=CC=1.Cl[C:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])=[O:21]>O1CCCC1>[F:12][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])=[O:21])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: -40 °C
Yield: 70.4 %

Procedure:
6-Amino-5-fluoro-1,3-dihydro-indol-2-one 3d (500 mg, 3.0 mmol) was dissolved in 10 ml of tetrahydrofuran under stirring, and added with 0.4 ml of pyridine to the solution at room temperature. After stirring to mix well, the mixture was cooled down to −40° C. in a dry ice-acetone bath. A solution of acetic acid chlorocarbonylmethyl ester (420 mg, 3.0 mmol) in 10 ml of tetrahydrofuran was added dropwise to the above reaction system. Upon completion of the addition, the dry ice-acetone bath was removed, and the reaction mixture was allowed to warm up to room temperature and stirred overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The resulting solid was washed with water for three times and dried to obtain the title compound acetic acid (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-methyl ester 27a (562 mg, yield 70.4%) as a gray solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]#[C:17][CH3:18])[C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]#[C:17][CH3:18])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCC(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC#CCC(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of the product from Step H (ca. 51.8 mmol) in THF (100 mL) and water (20 mL) was added at 0° C. a solution of lithium hydroxide monohydrate (6.5 g, 155 mmol). The solution was stirred for 1 hour at 0° C., then warmed to room temperature. After 48 hours, the solution was concentrated in vacuo. The aqueous mixture was extracted with EtOAc, acidified at 0° C. with 10% aq. HCl soln., then extracted with three portions of dichloromethane. The combined dichloromethane extracts were dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product as an orange oil (10.58 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[NH:10][C:9](=O)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:9]1[NH:10][C:11]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc2[nH]c(=O)[nH]c12
Product: COc1cccc2nc(Cl)[nH]c12

Procedure:
To a round bottomed flask was added 4-methoxy-1H-benzo[d]imidazol-2(3H)-one (1.8163 g, 11.06 mmol). POCl3 (1.031 mL, 11.06 mmol) was added and the reaction was brought to reflux. Upon completion, POCL3 was evaporated off. The residue was taken up in DCM. The reaction mixture was diluted with water and saturated sodium bicarbonate and extracted with DCM. The organic extract was washed with sat. sodium bicarbonate solution, water, brine, dried with magnesium sulfate, filtered, and concentrated to provide 2-Chloro-7-methoxy-1H-benzo[d]imidazole. MS (ESI, pos. ion) m/z: 182.9 (M+1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([N:13]2[CH2:17][CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH2:14]2)=[O:12])[CH2:3][CH2:2]1.Br[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[C:35]([F:38])([F:37])[F:36].C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([N:13]2[CH2:17][CH:16]=[C:15]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[C:35]([F:36])([F:38])[F:37])[CH2:14]2)=[O:12])[CH2:3][CH2:2]1
Reactant: CC1(C)OB(C2=CCN(C(=O)N3CCOc4ccccc43)C2)OC1(C)C
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(N1CC=C(c2ccc(F)cc2C(F)(F)F)C1)N1CCOc2ccccc21
Yield: 70.4 %

Procedure:
0.4 g of (2,3-dihydrobenzo[1,4]oxazin-4-yl)[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,5-dihydropyrrol-1-yl]methanone, 0.4 g of 1-bromo-4-fluoro-2-(trifluoromethyl)benzene, 1.4 ml of a 2N solution of sodium carbonate in water and 15 ml of ethylene glycol dimethyl ether are placed in a 100 ml three-necked flask equipped with a magnetic stirrer and placed under an inert atmosphere. The reaction mixture is degassed with nitrogen for 30 minutes and then the reaction mixture is heated at reflux for 14 h. After filtering and concentrating to dryness, the crude reaction product obtained is chromatographed on silica gel, elution being carried out with a gradient of ethyl acetate in dichloromethane varying from 0% to 10%. 0.31 g of (2,3-dihydrobenzo[1,4]oxazin-4-yl)[3-(4-fluoro-2-(trifluoromethyl)phenyl)-2,5-dihydropyrrol-1-yl]methanone is obtained.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)=[O:24])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)c2)c1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.17 min; [M+H]+=427.12.
Reaction SMILES: CO[C:3]1[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=1.[CH2:9]([Mg]Cl)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)(=O)C>[CH2:9]([C:3]1[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC1=CC(=O)CC1
Reactant: Cl[Mg]CCc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1C=C(CCc2ccccc2)CC1
Yield: 93.8 %

Procedure:
The general procedure for the preparation of substrates using 3-methoxycyclopentenone (1.29 g, 11.5 mmol) and phenethylmagnesium chloride (23 mmol, 1M in THF) gave, afler flash chromatography (4:1 hexanes:ethyl acetate), the title compound as a colorless liquid (2.01 g, 94%). Spectroscopic data were consistent with previously reported data for this compound.4
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]([NH2:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:5].Cl.C(N(CC)CC)C.[CH:24]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[S:35])=[CH:29][CH:28]=1)([CH3:26])[CH3:25]>CCOCC>[CH:24]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:15][CH:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[S:35])=[CH:29][CH:28]=1)([CH3:26])[CH3:25]
Reactant: CCOC(=O)C(N)Cc1ccc(Cl)cc1
Reactant: CC(C)c1ccc(N=C=S)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(Cl)cc1)NC(=S)Nc1ccc(C(C)C)cc1
Temperature: 0 °C
Yield: 80 %

Procedure:
DL-4-Chlorophenylalanine ethyl ester hydrochloride(5g, 18.9 mmol) was converted to the free base using triethylamine. A solution of the free base in 75 mL ether was added to a solution of 4isopropylphenylisothiocyanate in 150 mL ether, cooled on an ice-salt bath. The temperature was maintained at about 0° C. during addition. The reaction was stirred for four and one-half hours, at which time the reaction temperature was 12° C. The reaction mixture was filtered, the filtrate concentrated, and the resulting foamy residue triturated with petroleum ether while cooling on ice. This resulted in 6.1 g (15.1 mmol, 80%) N-(4-isopropylphenyl)-N'-[2-(4-chlorophenyl)-1-(ethoxycarbonyl)ethyl]thiourea, mp 73°-75° C.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Cs+].[Cs+].Cl[C:8]1[N:13]=[C:12]([N:14]2[C:18]3=[CH:19][N:20]=[C:21]([C:23]4[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:30])[CH:22]=[C:17]3[C:16]([CH:31]([OH:37])[CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:15]2)[CH:11]=[C:10]([CH2:38][CH3:39])[N:9]=1>CO>[CH3:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:23]=1[C:21]1[CH:22]=[C:17]2[C:16]([CH:31]([OH:37])[CH:32]([CH2:33][CH3:34])[CH2:35][CH3:36])=[CH:15][N:14]([C:12]3[CH:11]=[C:10]([CH2:38][CH3:39])[N:9]=[C:8]([O:4][CH3:1])[N:13]=3)[C:18]2=[CH:19][N:20]=1
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(-n2cc(C(O)C(CC)CC)c3cc(-c4c(C)cccc4C)ncc32)nc(Cl)n1
Agent: [Cs+]
Solvent: CO
Product: CCc1cc(-n2cc(C(O)C(CC)CC)c3cc(-c4c(C)cccc4C)ncc32)nc(OC)n1
Temperature: 60 °C

Procedure:
Cs2CO3 (85 mg, 0.26 mmol) is added to a solution of 1-[1-(2-chloro-6-ethyl-pyrimidin-4-yl)-5-(2,6-dimethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-ol (100 mg, 0.22 mmol) in MeOH (4 mL). The mixture is heated at 60° C. for 30 min. The mixture is concentrated under reduced pressure, diluted with water (5 mL), and the product is extracted with DCM. The combined organic extracts are washed with brine, dried (Na2SO4), and concentrated under reduced pressure. Chromatography of the residue silica gel (hexane-EtOAc, 1:1) gives 1-[5-(2,6-dimethyl-phenyl)-1-(6-ethyl-2-methoxy-pyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-ol as colorless oil: 1H NMR (CDCl3) 10.18 (s, 1H), 8.39 (s, 1H), 7.54 (s, 1H), 7.27-7.12 (m, 3H), 6.41 (s, 1H), 5.00 (d, J=6 Hz, 1H), 4.12 (s, 3H), 2.78 (dd, J=7, 15 Hz, 2H), 2.075 (s, 6H), 1.39 (t, J=7 Hz, 2.05-1.26 (m, 5H), 0.92 (t, J=7 Hz, 6H); LCMS (1) m/z 459.33 (2.65 min).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:15])=[C:4]([CH2:9][C@@H:10]([N:12]=[N+]=[N-])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]>CCOC(C)=O.[Pd]>[F:1][C:2]1[C:3]([CH3:15])=[C:4]([CH2:9][C@@H:10]([NH2:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1c(C[C@H](C)N=[N+]=[N-])ccc(F)c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(C[C@H](C)N)ccc(F)c1F
Yield: 85.3 %

Procedure:
To a solution of (1S)-2-(3,4-difluoro-2-methylphenyl)-1-methylethyl azide (503 mg, 2.38 mmol) in 50 mL of EtOAc was added Pd/C (150 mg of 10% Pd) and the mixture was hydrogenated under hydrogen balloon for 1 h. The catalyst was removed by filtration through celite, then passed through silica gel plug eluting first with EtOAc (40 mL), then MeOH/EtOAc/NH4OH 20:75:5 (120 mL). The fraction with product was evaporated to give (1S)-2-(3,4-difluoro-2-methylphenyl)-1-methylethylamine (376 mg, 85%) as pale oil. ESI-MS: m/z (MH+) 186.4. 1H NMR (300 MHz, CDCl3): δ 6.82-6.97 (m, 2H), 3.12 (m, 1H), 2.48-2.73 (m, 2H), 2.25 (s, 3H), 1.34 (s, 2H), 1.12 (d, J=6.39 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[N:15]2)=[O:11].C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC#N>[CH2:29]([O:8][C:7]1[C:2]([F:1])=[C:3]([C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[N:15]3)=[O:11])[C:4]([F:9])=[CH:5][CH:6]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(c1ccc2nccnc2c1)c1c(F)ccc(O)c1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1ccc2nccnc2c1)c1c(F)ccc(OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of (2,6-difluoro-3-hydroxyphenyl)(quinoxalin-6-yl)methanone (57 mg, 0.2 mmol, 1.0 eq.) in CH3CN (10 mL) were added K2CO3 (56 mg, 0.4 mmol, 2 eq.) and (bromomethyl)benzene (38 mg, 0.22 mmol, 1.1 eq). The resulting mixture was stirred at rt overnight, then concentrated. The residue was purified via flash column chromatography (PE/EA=10/1, v/v) to afford (3-(benzyloxy)-2,6-difluorophenyl)(quinoxalin-6-yl)methanone as brown solid (38.4 mg, 51.2%). LRMS (M+H+) m/z calculated 377.1, found 377.1. 1H NMR (CDCl3, 400 MHz) δ 8.93-8.95 (d, 2 H), 8.48 (s, 1 H), 8.39-8.41 (d, 1 H), 8.23-8.26 (d, 1 H), 7.33-7.45 (m, 5 H), 7.10-7.16 (m, 1 H), 6.91-6.95 (t, 1 H), 5.17 (s, 2 H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][CH2:9][C:10](Cl)=[O:11]>ClCCl>[Cl:8][CH2:9][C:10]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:11]
Reactant: O=C(Cl)CCl
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(C(=O)CCl)CC1
Temperature: 0 °C

Procedure:
To a solution of N-methylpiperazine (0.096 mL, 0.86 mmol, d=0.902) stirring in dichloromethane (5 mL) at 0° C., was added chloro acetylchloride (0.034 mL, 0.43 mmol, d=1.419). After stirring at 0° C. for an hour, the reaction mixture was diluted with dichloromethane (25 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to obtain 2-chloro-1-(4-methylpiperazin-1-yl)ethanone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:22]2C(=O)C3=CC=CC=C3C2=O)=NN=[C:17]1[CH2:33][N:34]([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36].O.[NH2:43][NH2:44]>C(O)C>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[N:16]3[C:17]([CH2:33][N:34]([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])=[N:43][N:44]=[C:20]3[CH2:21][N:22]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1
Reactant: CC(C)N(Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl)C(C)C
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)N(Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2)C(C)C

Procedure:
In the manner given in Example 27, 2',5-dichloro-2-[3-[(diisopropylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-chloro-1-[(diisopropylamino)-methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([OH:10])[CH2:2]1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH:13]1[CH:18]=[O:19]>>[CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:8])[CH3:9])[CH:3]([O:10][CH:17]2[O:12][CH:13]([CH:18]=[O:19])[CH2:14][CH2:15][CH2:16]2)[CH2:2]1
Reactant: O=CC1CCC=CO1
Reactant: CC1CCC(C(C)C)C(O)C1
Product: CC1CCC(C(C)C)C(OC2CCCC(C=O)O2)C1

Procedure:
Menthol may be condensed with compound 16, 3,4-dihydro-2H-pyran-2-carboxaldeyde in the presence of acid to provide compound 17, 6-menthyloxy-tetrahydro-2H-pyran-2-carboxaldehyde. A Lewis acid or a protic acid may be employed, with protic acids being preferred. Aldehyde 17 may be reduced to an alcohol 19, 6-menthyloxy-tetrahydro-2H-pyran-2-methanol, by catalytic hydrogeneration for example, over Raney nickel or a nobel metal catalyst. Compound 17 may alternatively be reduced to compound 19 using a hydride reducing agent, such as sodium borohydride or lithium aluminum hydride.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.[H-].[Na+].P([O-])([O-])([O-])=O>CN(C=O)C.O>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:14]1[CH2:13][C@@H:12]([C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:18])([CH3:1])[O:3][CH2:4][C:5]=3[CH:11]=2)[O:16][C:15]1=[O:17]
Reactant: BrCCCCCCBr
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCBr)C(=O)O3)ccc2O1
Reaction time: 0.5 h

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (5.00 g) and 1,6-dibromohexane (9.26 ml) in DMF (50 ml) at 0° under nitrogen was treated in three equal portions with sodium hydride (60% dispersion in mineral oil, 963 mg). The mixture was stirred at 0° for 30 min and then at 20° for a further 2.5 h. Phosphate buffer solution (pH 6.5, 50 ml) and water (150 ml) were added and the mixture was extracted with diethyl ether (2×150 ml). The combined extracts were washed with water (2×150 ml) and were dried (Na2SO4). The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel. Elution with MeOH-dichloromethane (1:4) gave the title compound (7.10 g). LCMS RT=3.52 min, ES+ve 412 (MH)+, 414 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](C2ON=C3C=CC(C(C4N(C)C=NC=4)O)=CC=23)=[CH:4][CH:3]=1.[C:25]([O-:28])([O-])=O.[K+].[K+]>O.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[O:28])[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cncc1C(O)c1ccc2noc(-c3ccc(Cl)cc3)c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
TiCl3/15% in H2O (200 ml) was added at room temperature to a solution of intermediate (6-c) (38 g) in THF (300 ml). The mixture was stirred at room temperature for 90 minutes. The mixture was poured out on ice, basified with K2CO3, filtered over celite, washed with ethyl acetate and decanted. The organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1 and 95/5/0.1), yielding 18.7 g (49%) of (±)-[2-amino-5-[4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl](3-chlorophenyl)methanone (interm. 6-d).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[N:11]1[CH2:22][CH2:21][C:14]2([C:19](=[O:20])[NH:18][CH2:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1.[H-].[Na+].Cl[CH2:26][C:27]1[CH:28]=[C:29]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:30]=[CH:31][CH:32]=1>C1COCC1>[N:35]1[CH:36]=[CH:37][CH:38]=[C:33]([C:29]2[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=2)[CH2:26][N:18]2[CH2:17][CH2:16][CH2:15][C:14]3([CH2:21][CH2:22][N:11]([C:2]4[CH:3]=[N:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)[CH2:12][CH2:13]3)[C:19]2=[O:20])[CH:34]=1
Reactant: O=C1NCCCC12CCN(c1cnc3ccccc3n1)CC2
Reactant: ClCc1cccc(-c2cccnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1N(Cc2cccc(-c3cccnc3)c2)CCCC12CCN(c1cnc3ccccc3n1)CC2
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
To a stirred solution of 9-(quinoxalin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one (0.035 g, 0.12 mmol) in dry THF (4.0 mL), NaH (0.014 g, 0.36 mmol) was added at rt and the mixture was stirred for 10 min. 3-(3-Chloromethyl-phenyl)-pyridine (0.05 g, 0.24 mmol) was then added and the reaction mixture was heated to 60° C. for 6 h. The mixture was quenched with 1 ml saturated aqueous NH4Cl solution, diluted with 50 ml water and the resulting mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to obtain the crude product. Preparative HPLC purification furnished the title compound as a pale yellow sticky solid (0.025 g, 46%). [1H-NMR (CDCl3, 300 MHz): δ 8.84-8.81 (m, 1H), 8.66-8.58 (m, 2H), 7.92-7.81 (m, 2H), 7.72-7.65 (m, 1H), 7.35-7.61 (m, 6H), 4.68 (s, 2H), 4.31-4.20 (m, 2H), 3.70-3.55 (m, 2H), 3.31 (t, 2H), 2.43-2.29 (m, 2H), 1.96-1.82 (m, 4H), 1.75-1.63 (dt, 2H); HPLC RtA=4.635 min (96%); LCMS RtC=0.395, [M+H]+=464.0].
Reaction SMILES: [CH2:1]([C:13]1C=C[C:16]([OH:19])=[CH:15][CH:14]=1)CCCCCCCCCCC.[NH2:20][CH2:21][CH2:22][CH2:23][Si](OCC)(OCC)OCC.C=O>C1(C)C=CC=CC=1>[O:19]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:1][C:23]=2[CH:22]=[CH:21][NH:20]1
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: CCCCCCCCCCCCc1ccc(O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1

Procedure:
This benzoxazine was prepared from 4-dodecylphenol (26.2 g, 100 mmol), 3-aminopropyltriethoxysilane (22.1 g, 100 mmol), paraformaldehyde (6.3 g, 210 mmol), and toluene (150 mL). The method to prepare this compound was the same as that used to make the previous benzoxazines. The final product was a clear, faint yellow liquid. The yield was 92%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]#[N:17])[CH:5]=[CH:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]#[N:17])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: CC1=C(C#N)C(c2cccc(Br)c2)NC(=O)N1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)N1C(=O)NC(C)=C(C#N)C1c1cccc(Br)c1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-(3-bromophenyl)-5-cyano-3,6-dihydro-4-methyl-2-oxo-(2H)-pyrimidine (0.29 g, 1 mmol) in THF (5 mL) chilled to −78° C. was added LDA (0.55 mL, 1.1 mmol, 2.0 M in THF). The resulting yellow suspension was stirred for 0.5 h, warmed to −20° C. for 0.5 h and recooled to −78° C.; then ethyl chloroformate (0.14 mL, 1.5 mmol) was added via syringe. The reaction mixture was stirred for 20 min, warmed to room temperature and quenched with EtOAc. This mixture was washed with aqueous NaHCO3 solution and with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash column chromatography (10% to 30% EtOAc/hexanes) to give, after evaporation of solvent, 6-(3-bromophenyl)-5-cyano-3,6-dihydro-4-methyl-2-oxo-1-(2H)-pyrimidinecarboxylic acid, 1-ethyl ester as a colorless solid (0.29 g; 80%): 1H NMR (CDCl3, 400 MHz) δ 7.48 (m, 2H), 7.28 (m, 2H), 5.87 (s, 1H), 4.33 (m, 2H), 2.22 (s, 3H), 1.33 (t, 3H, J=7.0 Hz); LC/MS (ES+) 364 (M+H+).