Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:9](=[O:10])[C:8]([O:11]C)=[CH:7][C:6]([CH:13]([CH3:15])[CH3:14])=[CH:5][CH:4]=1)=[O:2].Cl>[OH-].[Na+]>[CH:1]([C:3]1[C:9](=[O:10])[C:8]([OH:11])=[CH:7][C:6]([CH:13]([CH3:15])[CH3:14])=[CH:5][CH:4]=1)=[O:2]
Reactant: COc1cc(C(C)C)ccc(C=O)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc(C=O)c(=O)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-hydroxymethyl-4-isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one (20 g, 96 mmol) was dissolved in chloroform (300 ml), to which was added active manganese dioxide (80 g, 920 mmol) in several portions, and the resultant was stirred at room temperature for 4 hours. The insoluble matter was removed by filtration under reduced pressure, the filtrate was concentrated under reduced pressure and the resulting crude product was recrystallized from toluene to give 12.31 g of 7-formyl-4-isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one as yellow needle-like crystal (yield: 62%). Melting point of the product was 73°-75° C. 10% aqueous sodium hydroxide (50 ml) was added to the aldehyde (5 g, 24 mmol) and stirred overnight at room temperature. The reaction solution was acidified with 10% dilute hydrochloric acid, then extracted with methylene chloride, washed with water, dried, and solvent was distilled off to give a crude crystal (4.78 g). The crude crystal was recrystallized from ethyl acetate/hexane to give 7-formyl-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-1-one as a colorless needle-like crystal (yield: quantitative). This compound showed melting point of 76° C., which is identical to that described in the literature (Sci. Repts. Tohoku Univ., I, 37, 367 (1953)]. The compound (1.94 g, 10 mmol) was dissolved in tetrahydrofuran (20 ml), to which was added dropwise 2M phenyl lithium solution (5.2 ml, ca 10 mmol) in a nitrogen atmosphere while cooling to -78° C. The resultant was stirred for 10 minutes. An aqueous saturated sodium chloride was added to the reaction solution, and the resultant was extracted with methylene chloride, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography to give 1.95 g of 7-(α-hydroxybenzyl)-4-isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one as brown oil (yield: 71%). The compound (1 g, 3.7 mmol) and 1-(4-chlorobenzhydryl)piperazine (1.27 g, 4.4 mmol) were heated and refluxed in xylene (20 ml) for 2 hours, solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography [(ethyl acetate/hexane (1:2)] to give 1.71 g of 7-{1-[4-(4-chlorobenzhydryl)piperazinomethyl]-α-phenyl}-4-isopropyl-2-hydroxyl-2,4,6-cycloheptatrien-1-one (yield: 86%).
Reaction SMILES: [N:1]1([C:5]2[S:6][C@H:7]3[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C@H:10]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[C@H:8]3[N:9]=2)[CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:46]([N:48]([CH2:52][CH3:53])[C:49](Cl)=[O:50])[CH3:47]>C1COCC1>[CH2:46]([N:48]([CH2:52][CH3:53])[C:49](=[O:50])[O:15][CH2:14][C@H:12]1[O:13][C@H:7]2[C@H:8]([N:9]=[C:5]([N:1]3[CH2:4][CH2:3][CH2:2]3)[S:6]2)[C@@H:10]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[C@@H:11]1[O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH3:47]
Reactant: CCN(CC)C(=O)Cl
Reactant: COc1ccc(CO[C@@H]2[C@H]3N=C(N4CCC4)S[C@H]3O[C@H](CO)[C@H]2OCc2ccc(OC)cc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)OC[C@H]1O[C@@H]2SC(N3CCC3)=N[C@@H]2[C@@H](OCc2ccc(OC)cc2)[C@@H]1OCc1ccc(OC)cc1
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a solution of ((3aR,5R,6S,7R,7aR)-2-(azetidin-1-yl)-6,7-bis(4-methoxybenzyloxy)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methanol (300 mg, 0.60 mmol) in THF (10 mL) was added NaHMDS (1.1 g, 6.01 mmol), and followed by addition of diethylcarbamic chloride (1.22 g, 9.04 mmol) at room temperature. After stirring for 1 h, the reaction mixture was quenched with saturated aqueous NH4Cl (50 mL), extracted with dichloromethane (3×30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give a crude product 7 (320 mg), which was used in next step directly without further purification. [M+H]+ 600.1
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[NH:7].[Cl:14][C:15]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:16]=1[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20]>>[NH2:22][CH2:21][C:18]1[C:19]([NH2:20])=[N:7][C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=2)=[N:8][C:17]=1[C:16]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:15]=1[Cl:14]
Reactant: N=C(N)c1cccc(C(F)(F)F)c1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(-c2cccc(C(F)(F)F)c2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=412.9 (M+H+), was prepared from 3-trifluoromethyl-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[O:9]=[C:10]1[NH:19][CH:18]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[C:17]2[C:16](=[O:28])[CH2:15][CH2:14][CH2:13][C:12]=2[N:11]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1.CI.O>CN(C)C=O>[F:37][C:35]([F:38])([F:36])[C:31]1[CH:30]=[C:29]([N:11]2[C:12]3[CH2:13][CH2:14][CH2:15][C:16](=[O:28])[C:17]=3[CH:18]([C:20]3[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=3)[N:19]([CH3:1])[C:10]2=[O:9])[CH:34]=[CH:33][CH:32]=1
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Reaction time: 1 h

Procedure:
Lithium diisopropylamide (2.0 M in tetrahydrofuran, 265 μL, 0.53 mmol) is added at 0° C. to a solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 200 mg, 0.486 mmol) in N,N-dimethylformamide (10 mL). Methyl iodide (40 μL, 0.64 mmol) is added and the mixture is stirred for 1 h. Water is added and the mixture is extracted twice with dichloromethane. The combined organic layers are concentrated under reduced pressure, and the residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 50 mg; ESI mass spectrum [M+H]+=426; Retention time HPLC: 1.29 min (V001—006).
Reaction SMILES: BrC1N=C([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])C=CC=1.COC1C=C(C2OC3C=CC=CC=3N=2)C=CC=1B1OC(C)(C)C(C)(C)O1.Br[C:52]1[CH:53]=[CH:54][C:55]([F:58])=[N:56][CH:57]=1>>[F:58][C:55]1[N:56]=[CH:57][C:52]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])=[CH:53][CH:54]=1
Reactant: Fc1ccc(Br)cn1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(Br)n1
Agent: COc1cc(-c2nc3ccccc3o2)ccc1B1OC(C)(C)C(C)(C)O1
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1ccc(F)nc1

Procedure:
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole (200 mg, 0.57 mmol) was reacted with 5-bromo-2-fluoropyridine (59 μL, 0.57 mmol) to afford the desired 2-[4-(6-fluoropyridin-3-yl)-3-methoxyphenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.42 (s, 1H), 8.07–8.00 (m, 1H), 7.97–7.94 (m, 1H), 7.89 (s, 1H), 7.82–7.79 (m, 1H), 7.64–7.59(m, 1H), 7.48–7.45 (d, 1H), 7.41–7.38 (m, 1H), 7.03–6.99 (m, 1H), 3.98 (s, 3H). MS (ESI) 321 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.[CH:31](OCC)=[O:32]>>[CH:31]([NH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1)=[O:32]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N)c3ccccc32)cc1
Reactant: CCOC=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC=O)c3ccccc32)cc1

Procedure:
A mixture of 5-amino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) and ethyl formate (10 ml) is refluxed for 4 hours. The reaction solution is concentrated and the resulting residue is recrystallized from ethanol/petroleum ether to give 5-formylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.38 g) as colorless columnar crystal, m.p. 211°-213° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:15]([I:16])=[CH:14][NH:13][C:12](=[O:17])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[C:1]([NH:9][C:10]1[C:15]([I:16])=[CH:14][N:13]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12](=[O:17])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1nc(=O)[nH]cc1I)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(I)c(NC(=O)c2ccccc2)nc1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 8.3 g of N-benzoyl-5-iodocytosine dissolved in 60 ml DMF, was added at 0° C. 1.06 g of 55% NaH in mineral oil, and the solution was stirred at RT for 2 h. After 2.7 ml ethyl bromoacetate was added to the reaction mixture, the reaction solution was stirred for another 24 h at RT, which was followed by removal of the solvent under reduced pressure. The resulting residue was dissolved and the insoluble material was filtered off. The filtrate was washed two times with saturated aq ammonium chloride, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by column chromatography (1:1 hexane/EA) to yield 6.5 g of compd 2 (compd b in Scheme 1) as a yellow solid. mp 154-5° C. 1H NMR (400 MHz; CDCl3) δ 13.31 (br s, 1H), 8.37 (d, J=7.2 Hz, 2H), 7.69 (s, 1H), 7.55 (t, J=7.4 Hz, 1H), 7.46 (t, J=7.6 Hz, 2H), 4.49 (s, 2H), 4.27 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C:4]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:5]=1[C:6]#[N:7].C([O-])=O.[NH4+]>CO.O.[Zn]>[NH2:12][C:9]1[CH:10]=[CH:11][C:4]([CH2:3][CH:2]([CH3:15])[CH3:1])=[C:5]([CH:8]=1)[C:6]#[N:7]
Reactant: CC(C)Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CC(C)Cc1ccc(N)cc1C#N
Temperature: 80 °C
Reaction time: 4 h
Yield: 273.5 %

Procedure:
To a solution of 2-isobutyl-5-nitrobenzonitrile (D56) (7.5 g) in methanol (80 mL) and water (80 mL) was added ammonium formate (51.9 g) and zinc (26.9 g). The reaction mixture was stirred at 80° C. for 4 h. After cooling the reaction, the solid was filtered, the filtrate was concentrated under reduced pressure, the residue was extracted with EtOAc (300 mL*2), the combined organic layers were washed with water (30 mL*2), dried and concentrated to give 5-amino-2-(2-methylpropyl)benzonitrile (D57) (17.5 g) as a colorless solid. MS (ES): C11H14N2 requires 174. found 175.1 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C@@H:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([OH:30])[CH2:25]1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+].[H][H]>[Pd]>[CH3:23][C:15]([C:13]1[CH:12]=[CH:11][C:10]([C@@H:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([OH:30])[CH2:25]2)=[C:9]([OH:8])[CH:14]=1)([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCC(C)(C)c1ccc([C@@H]2CCC[C@H](O)C2)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCCCC(C)(C)c1ccc([C@@H]2CCC[C@H](O)C2)c(O)c1
Yield: 77 %

Procedure:
A mixture of 22.0 g. (0.0539 mol.) of cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]cyclohexanol, 12.0 g. of sodium bicarbonate and 2.0 g. of 10% palladium on carbon was stirred under one atmosphere of hydrogen for 2 hours. The reaction mixture was filtered through diatomaceous earth with ethyl acetate and the filtrate evaporated to a solid. The solid was recrystallized from hexane to yield 13.2 g. (77%) of the title product, m.p. 109°-110° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([NH:44][C:45](=[O:47])[CH3:46])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:43][CH2:42][CH:41]([NH:44][C:45](=[O:47])[CH3:46])[CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)NC1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(C)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with N-piperidin-4-yl-acetamide (TCI) to give the title compound. HR-MS (ES, m/z) calculated for C36H44Cl2N5O3 [(M+H)+] 664.2816, observed 664.2813.
Reaction SMILES: C[C:2]([CH3:4])=[O:3].C(C(O)=O)C[C:7](F)(F)[C:8]([F:29])([F:28])[C:9]([F:27])([F:26])[C:10]([F:25])([F:24])[C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15].C1(C)C=CC(S(O)(=O)=[O:42])=CC=1>C1(C)C=CC=CC=1>[CH2:4]([C:2]([OH:42])=[O:3])[CH2:7][C:8]([F:28])([F:29])[C:9]([F:26])([F:27])[C:10]([F:24])([F:25])[C:11]([F:22])([F:23])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15]
Reactant: O=C(O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
A suspension with the desired amount of nanocrystalline cellulose (2 grams in 100 grains methanol; 2 wt %) was solvent exchanged to acetone and then to dry toluene by several successive centrifugations and redispersions. Sonication was performed after each solvent exchange step. The suspension was transferred to a 3-neck round bottom flask and an excess of 2H,2H,3H,3H-perfluoroundecanoic acid (available from SynQuest Laboratories) was added to the stirring suspension followed by a catalytic amount of p-toluenesulfonic acid. The surface modification of the cellulose nanostructures were conducted at 105° C. for up to 24 hours. Following surface treatment, the material was purified and dried as in Example 1.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:44][O:45][C:46](=[O:52])[C@H:47]([C@@H:49]([CH3:51])[OH:50])[NH2:48]>CN(C=O)C>[N:1]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:48][C@H:47]([C:46]([O:45][CH3:44])=[O:52])[C@@H:49]([CH3:51])[OH:50])=[O:17])=[CH:18][CH:19]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: O=C(O)c1ccc(Cn2cnc3ccccc32)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)c1ccc(Cn2cnc3ccccc32)cc1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A solution of 4-[(1H-benzoimidazol-1-yl)methyl]benzoic acid (0.37 g, 1.47 mmol) in dry DMF was treated sequentially with EDC (0.34 g, 1.76 mmol) and HOBt (0.25 g, 1.62 mmol), stirred at room temperature for 30 min, treated sequentially with DIPEA (0.62 mL, 3.6 mmol) and a solution of threonine methyl ester hydrochloride (0.27 g, 1.62 mmol), stirred for 3 h and concentrated under reduced pressure. The resultant residue was partitioned between CH2Cl2 and water. The layers were separated and the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica, CH2Cl2:CH3OH 95:5) to afford the title product in 64% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 368 (MH+).
Reaction SMILES: F[C:2]([F:17])(S(F)(=O)=O)[C:3](F)(F)[C:4](F)(F)[C:5](F)(F)F.O[C@@H]1C[C@@]2(C)[C@@H:30]([CH2:31][CH2:32][C:33]2=[O:37])[C@H:29]2[C@H:20]1[C@@H:21]1[C:26]([CH2:27][CH2:28]2)=[CH:25][C:24](=[O:38])[CH2:23][CH2:22]1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:17][C@H:2]1[CH2:3][C@@:4]2([CH3:5])[C@@H:30]([CH2:31][CH2:32][C:33]2=[O:37])[C@H:29]2[C@H:20]1[C@@H:21]1[C:26]([CH2:27][CH2:28]2)=[CH:25][C:24](=[O:38])[CH2:23][CH2:22]1
Reactant: C[C@]12C[C@@H](O)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: C[C@]12C[C@H](F)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reaction time: 0.5 h

Procedure:
4.6 ml of perfluorobutane-1-sulfonic acid fluoride is added in drops to 5.0 g of 11α-hydroxy-estr-4-ene-3,17-dione in 100 ml of toluene and 7.3 mnl of 1,8-diazabicyclo[5,4,0]undec-7-ene at 20° C. After 30 minutes, the solution is diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, 3.8 g of 11β-fluoro-estr-4-ene-3,17-dione with a melting point of 173-174° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([C:22](OCC)=[O:23])=[N:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH:22]=[O:23])=[N:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(C)cc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2nc(C=O)cc2-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
A solution of ethyl 1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrazole-3-carboxylate (700 mg) in tetrahydrofuran (10 mL) was cooled to −78° C., and a 1.5 mol/L solution (3.8 mL) of diisobutylaluminum hydride in toluene was added dropwise. After the completion of the dropwise addition, the mixture was stirred at −78° C. for 30 min. 1 mol/L Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a solution of the residue in acetonitrile (15 mL) were added tetra-n-propylammonium perruthenate (66 mg), N-methylmorpholine N-oxide (442 mg) and molecular sieves 4 A powder (1.0 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→2:1) to give the title compound as a pale-yellow solid (yield 224 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14]CC)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1.[OH-].[Li+]>CO.O1CCCC1.O>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([OH:14])=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=1
Reactant: CCOC(=O)c1cnc2ccc(Cl)nc2c1Nc1cccc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc2ccc(Cl)nc2c1Nc1cccc(C(F)(F)F)c1
Yield: 97.9 %

Procedure:
ethyl 6-chloro-4-((3-(trifluoromethyl)phenyl)amino)-1,5-naphthyridine-3-carboxylate (3.95 g, 10 mmol) was dissolved in 50 mL methanol and 50 mL tetrahydrofuran. To the resulting mixture was added dropwise a solution of lithium hydroxide (1.26 g, 30 mmol) in water (50 mL). After the completion of the dropwise addition, the resulting mixture is reacted at room temperature for 4 hrs. The reaction was concentrated, and 200 mL water was added. The resulting mixture was adjusted with hydrochloric acid to pH=3. The solid was separated, and dried in vacuum to obtain a yellow solid (3.6 g).
Reaction SMILES: Cl.[CH2:2]1[N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[N:13]=[CH:14][C:8]3=[C:9]2[C:4](=[CH:5][CH:6]=[CH:7]3)[CH2:3]1.C(O)C.[BH4-].[Na+]>O>[CH2:2]1[N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[NH:13][CH2:14][C:8]3=[C:9]2[C:4](=[CH:5][CH:6]=[CH:7]3)[CH2:3]1
Reactant: C1=Nc2ccccc2N2CCc3cccc1c32
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1cc2c3c(c1)CNc1ccccc1N3CC2
Reaction time: 1 h

Procedure:
A stirred mixture, under N2, of 18.0 g of 1,2-dihydroindolo[1,7-ab][1,5]benzodiazepine hydrochloride and 100 ml of absolute ethanol is cooled to 0° C., and sodium borohydride is added in small portions and at such a rate as to minimize frothing and to keep the reaction temperature below 5° C. The addition takes about 1 hour and 3 g of NaBH4 is required to discharge the initial maroon color, and another 0.5 g is added to insure complete reduction. An hour later, water is added in portions to decompose excess reagent and maximize precipitation of product. The crystalline solid is filtered, washed well with water and dried to yield 1,2,6,7-tetrahydroindolo[1,7-ab][1,5]benzodiazepine, m.p. 175°-177° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH:26]=[CH:25][C:23]([OH:24])=[CH:22][CH:21]=1)[OH:20]>>[NH2:16][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:13][C:12]=1[O:20][C:19]1[CH:26]=[CH:25][C:23]([OH:24])=[CH:22][CH:21]=1
Reactant: Oc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Product: Nc1cc(OCc2ccccc2)ccc1Oc1ccc(O)cc1

Procedure:
4-Benzyloxy-1-chloro-2-nitro-benzene (from Example 27A) was reacted with hydroquinone according to the procedure from Example 39A and reduced according to the procedure from Example 39B to provide the title product.