Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[NH:25][CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:40][N:41]([CH3:45])[C:42](Cl)=[O:43]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[N:25]([C:42](=[O:43])[N:41]([CH3:45])[CH3:40])[CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:16])([CH3:17])[CH3:15])[CH3:10])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(COc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2C(=O)N(C)C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 112.8 %

Procedure:
A solution of amine 84 (480 mg, 0.87 mmol) in DCM (10 mL) was cooled to 0° C. and treated with TEA (0.18 mL, 1.30 mmol) followed by dimethylcarbamyl chloride (0.10 mL, 1.04 mmol). The reaction mixture was allowed to warm to ambient temperature. After 6 h, the reaction mixture was diluted with DCM, washed successively with 1M HCl, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 88 (612 mg, 100%) as a white foam that was used without further purification. 1H NMR (CDCl3, 300 MHz): δ7.04 (q, J=9.0, 18.3 Hz, 1H), 6.88 (br s, 1H), 6.75-6.67 (m, 1H), 6.61-6.56 (m, 1H), 4.79-4.51 (m, 2H), 4.31 (d, J=5.7 Hz, 1H), 4.08-4.01 (m, 1H), 3.99-3.94 (m, 1H), 3.81-3.72 (m, 1H), 3.54-3.49 (m, 1H), 3.41-3.25 (m, 2H), 2.85-2.79 (m, 9H), 2.05-2.03 (m, 2H), 1.49-1.42 (m, 9H), 1.31 (d, J=6.9 Hz, 3H), 0.99 (s, 9H) ppm.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:33][C@H:34]1[CH2:38][CH2:37][CH2:36][C@H:35]1[C:39]([NH2:41])=[O:40].F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[C:39]([C@@H:35]1[CH2:36][CH2:37][CH2:38][C@@H:34]1[NH:33][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([NH:21][C:19]2[N:18]=[CH:17][C:8]3[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[C:7]=3[N:20]=2)=[C:23]([O:31][CH3:32])[CH:24]=1)(=[O:40])[NH2:41]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NC(=O)[C@@H]1CCC[C@@H]1N
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@H]2CCC[C@H]2C(N)=O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 18 h
Yield: 24.7 %

Procedure:
A mixture of 0.070 g (0.16 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.030 g (0.19 mmole) of (1R,2S)-2-amino-cyclopentanecarboxylic acid amide, 0.071 g (0.19 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.136 mL (0.78 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (gradient, 80:20-0:100) to give 0.022 g of N-[(1S,2R)-(2-carbamoyl-cyclopentyl)]-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-44) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH3:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]=1[C:3]1[N:17]=[C:18]2[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][N:19]2[CH:2]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: Nc1ncccc1O
Product: Cc1onc(-c2ccccc2)c1-c1cn2cccc(O)c2n1
Yield: 4 %

Procedure:
As described for Example 2, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using 2-amino-3-hydroxypyridine instead of 2-amino-3-methylpyridine, to the title compound (6 mg, 4%) which was obtained as a yellow foam. MS: m/e=292.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:21])=[C:7]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Cl.Cl[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([CH3:31])[CH2:26]1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:21][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][N:27]([CH3:31])[CH2:26]3)=[C:7]([C:13]3[CH:14]=[C:15]([CH3:20])[CH:16]=[C:17]([CH3:19])[CH:18]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C)cc(-c2c(O)c3ccc(Cl)cc3[nH]c2=O)c1
Reactant: CN1CCCC(CCl)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Product: Cc1cc(C)cc(-c2c(OCC3CCCN(C)C3)c3ccc(Cl)cc3[nH]c2=O)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 38.7 %

Procedure:
To a solution of 7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-1H-quinolin-2-one (100 mg in 3 mL dry N,N-dimethylformamide) was added 68 mg 3-chloromethyl-1-methylpiperidine hydrochloride followed by 55 mg sodium iodide and 97 mg potassium carbonate and the mixture heated to 80° C. on an oil bath. After 7 hours, an additional portion of potassium carbonate (48 mg) and 3-chloromethyl-1-methylpiperidine hydrochloride (68 mg) were added and the reaction allowed to proceed at 80° C. for another 14 hours. At this time the reaction was cooled to room temperature and quenched by pouring into 25 mL of ice/water. The precipitate was collected by filtration and washed with cold water. Purification of the crude by flash chromatography on silica gel (chloroform: 10% ammonium hydroxide in methanol, 95:5) provided the title compound (53 mg). MASS=411 (M+H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:21])[C:5]([Cl:20])=[C:6]([CH:19]=1)[CH2:7][N:8]([CH:16]1[CH2:18][CH2:17]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[F-].[Cs+].[CH2:24]([Sn](CCCC)(CCCC)CCCC)[CH:25]=[CH2:26]>C1COCC1>[CH2:26]([C:2]1[CH:3]=[C:4]([Cl:21])[C:5]([Cl:20])=[C:6]([CH:19]=1)[CH2:7][N:8]([CH:16]1[CH2:18][CH2:17]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:25]=[CH2:24]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(Br)cc(Cl)c1Cl)C1CC1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCc1cc(Cl)c(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1

Procedure:
A THF solution (0.12 M) of tert-butyl (5-bromo-2,3-dichlorobenzyl)cyclopropylcarbamate from the previous step (1 eq.), Pd(PCy3)2 (0.05 eq.) and cesium fluoride (2.0 eq.) was added allyl tributylstannane (1.2 eq.). The resulting brown solution was heated at reflux for 8 h and then filtered through a pad of SiO2. The insolubles were rinsed further with ether and the filtrate was concentrated in vacuo to afford a brown semisolid. Purification of the crude product thus obtained by way of column chromatography (SiO2, Hex→90:10 (v/v) Hex:Et2O) afforded the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[S:15](=[O:19])(=[O:18])([OH:17])[OH:16].[Cl-].[Ba+2:21].[Cl-]>>[CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[S:15]([O-:18])(=[O:17])=[O:16].[Ba+2:21].[CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[S:15]([O-:17])(=[O:19])=[O:16]
Reactant: O=S(=O)(O)O
Reactant: c1ccc2c(c1)ccc1ccccc12
Agent: [Ba+2]
Agent: [Cl-]
Product: O=S(=O)([O-])c1ccc2c(ccc3ccccc32)c1

Procedure:
Phenanthrene is sulfonated with concentrated sulfuric acid and then treated with barium chloride to obtain barium 2-phenanthrenesulfonate. The resulting barium salt is subjected to alkali fusion in an electric oven and then treated with hydrochloric acid to obtain 2-phenanthrol. 2-Phenanthrol is subjected to oxidative coupling in the presence of a copper-amine complex to synthesize racemic 1,1'-biphenanthryl-2,2'-diol (I). The resulting diol is reacted with optically active phenylethylamine and thiophosphoryl chloride to afford (±)-N((S)-1-phenylethyl)-1,1'-biphenanthryl-2,2'-diylthiophosphorylamide. Recrystallization of the racemate gives an optically active compound, which is then hydrogenolyzed with a reducing agent, such as lithium aluminum hydride, to give optically active 1,1'-biphenanthryl-2,2'-diol with an optical purity reaching nearly 100%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][C:14]#[N:15])[N:12]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:18][CH2:19][N:20]([CH2:22][CH2:23]Cl)[CH3:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]3([C:14]#[N:15])[CH2:23][CH2:22][N:20]([CH3:21])[CH2:19][CH2:18]3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CN(CCCl)CCCl
Reactant: N#CCc1coc(-c2ccc(F)cc2)n1
Agent: Cl
Product: CN1CCC(C#N)(c2coc(-c3ccc(F)cc3)n2)CC1
Yield: 30 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)acetonitrile and 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride as described in example 16 step 1b (430 mg, yield 30%). 1H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.05-8.00 (m, 2H), 7.41-7.35 (m, 2H), 2.83-2.79 (m, 2H), 2.26-2.18 (m, 7H), 2.04-1.94 (m, 2H). MS (ESI) m/z: Calculated for C16H16FN3O: 285.13. found: 286.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[CH2:16]([S:20][CH2:21][C:22](O)=[O:23])[CH2:17][CH2:18][CH3:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:22](=[O:23])[CH2:21][S:20][CH2:16][CH2:17][CH2:18][CH3:19])[CH:11]=1
Reactant: CCCCSCC(=O)O
Reactant: Fc1ccc(NCc2cccnc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCSCC(=O)N(Cc1cccnc1)c1ccc(F)cc1

Procedure:
N-[(3-pyridyl)methyl]-N-(4-fluorophenyl)-α-(n-butylthio)acetamide was prepared by the method of Example 2 by reacting 10.1 g. of N-(4-fluorophenyl)-[(3-pyridyl)methyl]amine with 7.4 g. of α-(n-butylthio)acetic acid and 10.3 g. of N,N'-dicyclohexylcarbodiimide in 250 ml. of dichloromethane. Weight 6.5 g. as an oil.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH:11]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH3:26])[CH:17]=1)[CH2:12][C:13](O)=[O:14].C(N1C=CN=C1)([N:29]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH:11]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH3:26])[CH:17]=1)[CH2:12][C:13]([NH2:29])=[O:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(N)=O)N2Cc3ccccc3C2=O)ccc1OC
Reaction time: 0.33 h
Yield: 76.6 %

Procedure:
A mixture of 3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionic acid (12.6 g, 35.4 mmol) and 1,1'-carbonyldiimidazole (5.97 g, 36.8 mmol), in tetrahydrofuran (100 mL) was stirred for 1.5 hours at room temperature. To the solution was added ammonium hydroxide (7.5 mL, 112.5 mmol, 28-30%) and stirring was continued for 20 minutes. The tetrahydrofuran was removed in vacuo and the remaining residue was slurried in 100 mL of water for 30 minutes. The mixture was filtered and the white solid was washed with water (150 mL), air dried and dried in vacuo (60° C., <1 mm). The resulting solid was recrystallized form ethyl acetate (1.1 L) and was then dried in vacuo (60° C., <1 mm) to afford 9.61 g (77%) of 3-(1-oxoisoindolin2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionamide as a white solid: mp 169-171.5; 1H NMR (DMSO-d6) δ7.75-7.40 (m, 5H), 7.05-6.80 (m, 4H), 5.75 (m, 1H), 4.56 (d, J=17.6 Hz, 1H), 4.14 (d, J=17.6 Hz, 1H), 3.98 (m, 2H), 3.72 (s, 3H), 2.93 (m, 2H), 1.30 (t, J=6.9 Hz, 3H), 13C NMR (DMSO-d6) δ171.2, 166.8, 148.3, 147.8, 141.6, 132.2, 132.1, 131.2, 127.8, 123.4, 122.7, 119.1, 112.1, 111.7, 63.6, 55.4, 51.3, 46.2, 37.8, 14.6; Anal. Calcd. for C20 H22N2O5. Theoretical: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.89; H, 6.31; N, 7.83.
Reaction SMILES: [H-].[Na+].C(S)C.[CH2:6]([C:8]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([OH:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[C:21]([CH3:33])[CH:20]=1)([C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=1)[CH2:9][CH3:10])[CH3:7]>CN(C=O)C>[CH2:6]([C:8]([C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([OH:32])[C:28]([CH3:30])([CH3:31])[CH3:29])=[C:21]([CH3:33])[CH:20]=1)[CH2:9][CH3:10])[CH3:7]
Reactant: CCC(CC)(c1ccc(OC)cc1)c1ccc(CCC(O)C(C)(C)C)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(O)cc1)c1ccc(CCC(O)C(C)(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 37.6 %

Procedure:
A stirred suspension of NaH (60% dispersion in mineral oil, 80 mg, 2.0 mmol) in anhyd DMF (0.5 mL) was chilled to 0° C. and charged dropwise with ethanethiol (74 μL, 1.0 mmol). The reaction mixture was removed from the ice-bath and stirred at ambient temperature. After 10 min, additional DMF (0.5 mL) was added to facilitate stirring. To the resulting mixture was added dropwise a solution of 1-{4-[1-ethyl-1-(4-methoxyphenyl)-propyl]-2-methylphenyl}-4,4-dimethylpentan-3-ol (0.10 g, 0.26 mmol) in anhyd DMF (0.7 mL). The reaction mixture was transferred to an oil bath and heated at reflux. After 3 h the mixture was cooled, quenched with satd NH4Cl (50 mL), extracted with Et2O (2×50 mL). The combined extracts were washed with H2O (2×50 mL) and brine, then dried (Na2SO4), concentrated under reduced pressure and chromatographed (silica, EtOAC/Hex, 0:100 to 25:75) to give the title compound (36 mg, 37% non-optimized) as a tacky white solid: 1H-NMR (CD2Cl2) δ 7.00-7.06 (3H, m), 6.90-6.94 (2H, m), 6.71 (2H, d), 4.95 (1H, br s), 3.24 (1H, dd, J=1.8, 10.6), 2.85 (1H, ddd, J=5.1, 10.6, 13.9), 2.54 (1H, ddd, J=6.1, 10.4, 13.9), 2.24 (3H, s), 2.05 (4H, q, J=7.3), 1.72-1.84 (1H, m), 1.42-1.54 (1H, m), 0.88 (9H, s), 0.59 (6H, t, J=7.3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8]/[N:9]=[C:10]1/[C@H:11]2[S:16][CH2:15][C:14]([CH3:17])=[C:13]([C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19])[N:12]2[C:26]/1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][NH:9][C@@H:10]1[C:26](=[O:27])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]([Cl:23])([Cl:24])[Cl:25])=[O:19])=[C:14]([CH3:17])[CH2:15][S:16][C@H:11]12)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)/C(=N\NC(=O)OC(C)(C)C)[C@H]2SC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NNC(=O)OC(C)(C)C)[C@H]2SC1
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
In tetrahydrofuran (20 ml) is dissolved 2,2,2-trichloroethyl (E)-7-t-butoxycarbonylhydrazono-3-methyl-3-cephem-4-carboxylate (4.60 g), and under ice-cooling, a 1 M tetrahydrofuran solution of borane-tetrahydrofuran complex (23 ml) is added dropwise. The mixture is stirred at that temperature for 30 minutes. The reaction mixture is poured in a mixture of ethyl acetate (150 ml) and aqueous sodium chloride (200 ml). The organic layer is taken, dried over magnesium sulfate and concentrated. The residual oil is subjected to silica gel (50 g) column chromatography and elution is carried out with ethyl acetate-benzene. The above procedure gives crystals of 2,2,2-trichloroethyl 7β-t-butoxycarbonylhydrazino-3-methyl-3-cephem-4-carboxylate (2.49 g).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=O)[C:8]2[NH:13][N:12]=[C:11]([I:14])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[CH2:26][NH2:27].N1CCCN2CCCCCC=12.C1CN([P+](ON2N=NC3C2=CC=CC=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(#N)C>[CH2:1]([C:5]1[N:6]=[C:7]([NH:27][CH2:26][C:19]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=2[O:17][CH3:16])[C:8]2[NH:13][N:12]=[C:11]([I:14])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CCCCc1nc2c(I)n[nH]c2c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(I)c2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 51 %

Procedure:
A solution of 5-butyl-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (50 g, 157 mmol), (2,4-dimethoxyphenyl)methanamine (60 g, 359 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (47.9 g, 314 mmol) in acetonitrile (500 mL) was treated with ((1H-benzo[d][1,2,3]triazol-1-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (100 g, 192 mmol) and stirred for 6 hours at room temperature under nitrogen. The resulting suspension was filtered to remove precipitate and the filtrate was evaporated. The residue was purified on a silica cartridge (1500 g) (applied in minimum DCM) eluted with 0-80% cyclohexane-EtOAc (12 column volumes). Product-containing fractions were part evaporated to give a heavy suspension that was filtered and the solid air-dried to give the title compound (37.5 g, 80 mmol) as a white powder.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)(=[O:29])[CH3:28].N1C=CC=CC=1>C1COCC1>[CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:27](=[O:29])[CH3:28])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)NCc2ccccc2)c2c1oc1ccc(N)cc12
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)NCc2ccccc2)c2c1oc1ccc(NC(C)=O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-1-benzyl-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (80 mg, 0.23 mmol) (step 2) was treated with acetyl chloride (1.1 eq.) in THF (10 ml) containing pyridine (1.0 eq) at 0° C. and allowed to warm to room temperature. The reaction was stirred at room temperature for 2 h. The reaction mixture was filterd and the filterarte was concentrated. The residue was triturated with ethanol to obtain 63 mg of N1-benzyl-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as white solid; mp: 264-265° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F:13][C:14]([F:28])([F:27])[CH2:15][CH2:16][CH2:17][C:18]([C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[F:13][C:14]([F:27])([F:28])[CH2:15][CH2:16][CH2:17][C:18]([C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)=[O:19]
Reactant: O=C(CCCC(F)(F)F)c1cccc(O)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CCCC(F)(F)F)c1cccc(OCc2ccc3ccccc3n2)c1
Yield: 62 %

Procedure:
This material was synthesized by refluxing a mixture of 2-chloromethyl quinoline (2.6 g, 14.5 mmol), 3-(5,5,5-trifluoropentanoyl)phenol (3.7 g, 15.9 mmol), powdered potassium carbonate (6.0 g, 43.5 mmol) and a catalytic amount of potassium iodide (0.1 g) in dry acetone (50 ml) for 14 hours. After this period, the mixture was filtered, and the filtrate was concentrated. The residue was dissolved in ether, and the ethereal solution was washed with brine, dried over MgSO4, and then concentrated in vacuo. The pure desired ketone was isolated by chromatography on silica gel using 20% ethyl acetate in hexanes as eluent. The product was obtained in 62% yield (3.4 g), had a melting point 80°-82° C. and was a yellowish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH:11]=[CH:12][CH3:13])[CH:10]=1)[CH:6]=[O:7]>C(OCC)(=O)C.[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH2:11][CH2:12][CH3:13])[CH:10]=1)[CH:6]=[O:7]
Reactant: CC=Cc1cc(C=O)cc(OC)c1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCCc1cc(C=O)cc(OC)c1
Reaction time: 5 h

Procedure:
A mixture of 3-methoxy-5-(1-propenyl)benzaldehyde (1.6 g) and platinum oxide (150 mg) in ethyl acetate (150 ml) were hydrogenated at 16 psi in a Parr hydrogenator for 5 hours. The mixture was filtered through a celite/charcoal plug and evaporated. Purification of the residue by flash chromatography using 12% ethyl acetate in hexane afforded the title compound.
Reaction SMILES: Br.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([O:18]CC3C=CC=CC=3)=[C:14]([F:26])[CH:13]=2)=[C:5]([O:27]C)[CH:4]=1.[OH-].[Na+]>C(OCC)(=O)C.O>[Br:2][C:3]1[CH:4]=[C:5]([OH:27])[C:6]2[CH:7]=[N:8][N:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:26])[CH:13]=3)[C:10]=2[CH:11]=1
Reactant: COc1cc(Br)cc2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(-n2ncc3c(O)cc(Br)cc32)cc1F
Temperature: 130 °C
Yield: 19.4 %

Procedure:
48% Hydrobromic acid (10 mL) was added to 6-bromo-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-4-(methyloxy)-1H-indazole (D9) (1.16 g, 2.71 mmol) and the mixture heated at 130° C. for 3 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate and water. The pH was adjusted to 7 by the addition of 2M aqueous sodium hydroxide solution. After separation of the organic layer, the aqueous phase was re-extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with 5-100% ethyl acetate in hexane. The product was further purified by MDAP to yield the title compound (E5) (170 mg).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]2[C:18](=[O:19])[CH2:17][C:16]([CH3:21])([CH3:20])[CH2:15][C:14]2=[O:22])=[CH:5]1)(=O)C.CO.[OH-].[Na+].C>O>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]2[C:18](=[O:19])[CH2:17][C:16]([CH3:20])([CH3:21])[CH2:15][C:14]2=[O:22])=[CH:5]1
Reactant: CC(=O)n1cc(C2C(=O)CC(C)(C)CC2=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CC(=O)C(c2c[nH]c3ccccc23)C(=O)C1
Temperature: 60 °C
Yield: 60 %

Procedure:
To a mixture of 2-(1-acetyl-1H-indol-3-yl)-5,5-dimethylcyclohexane-1,3-dione of Example 1e (74.8 g, 0.25 mol) and methanol (30 mL), a solution of sodium hydroxide (30 g, 0.75 mol) in water (300 mL) was added at room temperature under stirring. The reaction mixture was heated at 60° C. for 2 h under stirring, and then activated charcoal (10 g) and water (300 mL) were added. The mixture was stirred for 10 min, charcoal was filtered off, and the filtrate was acidified with hydrochloric acid to pH 2. The solid product was filtered off, washed with water and dried to give 38.3 g (60%) of the colorless solid; m.p. 173° C.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].Cl.C(N=C=NCCCN(C)C)C.[F:18][C:19]1[CH:27]=[C:26]([N+]([O-])=O)[CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=O>N1C=CC=CC=1>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([N:4]([O:3][CH3:2])[CH3:5])=[O:23]
Reactant: CNOC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.79 g of N-methoxy-N-methylamine hydrochloride and 12.4 g of 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide hydrochloride were added to a pyridine (80 ml) suspension of 10 g of 2-fluoro-4-nitrobenzoic acid, and the reaction liquid was stirred overnight at room temperature. Pyridine was evaporated away under reduced pressure, and water was added to it. The resulting deposit was taken out through filtration, washed with water, and dried to obtain the entitled compound as a pale yellow solid.