Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3]>O1CCOCC1>[ClH:1].[N+:2]([C:5]1[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(c2ncccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4 N hydrochloric acid in dioxane (10 ml) was added to tert-butyl [1-(3-nitropyridin-2-yl)piperidin-4-yl]carbamate (Intermediate 38; 1.3 g, 4.2 mmol). The mixture was stirred at room temperature for 1 h under nitrogen gas. The solvent was removed in vacuo to give the title compound as a yellow powder (500 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:34]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:34]([C:38]1[CH:39]=[CH:40][C:41]([CH2:42][N:32]2[CH:31]=[CH:30][N:29]=[C:28]2[CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][C:10]2[CH:18]=[C:17]([CH3:19])[C:16]3[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=3)[CH:11]=2)=[CH:44][CH:45]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2ccc(C(C)(C)C)cc2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (40 mg, 0.085 mmol), 4-(tert-Butyl)-benzyl bromide (16.3 μL, 0.089 mmol, 1.05 equiv), and potassium carbonate (23.5 mg, 0.17 mmol) were combined in dimethylformamide (1.0 mL). After stirring at room temperature for 16 h, the solvents were removed and the residue purified by column chromatography to afford 36.0 mg (79%). Mass spec.: 618.6 (MH)+.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:7][SiH:8]([Cl:10])[Cl:9]>>[CH2:1]([Si:8]([CH3:7])([Cl:10])[Cl:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C[SiH](Cl)Cl
Reactant: C=CCCC=C
Product: C=CCCCC[Si](C)(Cl)Cl
Temperature: 40 °C
Yield: 87.6 %

Procedure:
5-Hexenylmethyldichlorosilane was prepared by combining 1,5-hexadiene (160 g, 1.95 m), 0.1 g of a platinum complex ##STR7## and methyldichlorosilane (5 g) in a flask equipped with a condenser and a thermometer. The mixture was heated to 40° C. to initiate the reaction. Additional methyldichlorosilane (120 g) was added dropwise to the mixture so that the temperature was kept below 55° C. The product was isolated in 87.6% yield by distillation under reduced pressure (bp 67°-9° C./2 mm Hg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1)[CH3:27]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=2)=[O:24])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCNCc1ccc2ccccc2n1
Product: CCN(Cc1ccc2ccccc2n1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-quinolin-2-ylmethyl-amine
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:27])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:10]2)[C:5](F)=[N:6][CH:7]=1.[CH3:28][O-:29].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:27])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:10]2)[C:5]([O:29][CH3:28])=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cnc2F)C[C@@H](C(F)(F)F)O1
Agent: [Na+]
Product: COc1ncc(Br)cc1[C@]1(C)C[C@@H](C(F)(F)F)OC(NC(=O)OC(C)(C)C)=N1
Temperature: 50 °C
Yield: 97 %

Procedure:
tert-Butyl ((4S,6S)-4-(5-bromo-2-fluoropyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate (5k, 0.500 g, 1.096 mmol, as described in Example 31, Method G, Step 9) was treated with sodium methanolate 25% MeOH (3 mL). The reaction was heated at 50° C. for 40 min. The reaction was quenched with water and methanol was removed by reduced pressure. The resulting mixture was extracted with EtOAc three times. The combined organic layers were dried on sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography using a gradient of 0-30% EtOAc/hexane to give tert-Butyl ((4S,6S)-4-(5-bromo-2-methoxypyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate (0.49 g, 97% yield). MS m/z=469.9 [M+H]+. Calculated for C17H21BrF3N3O4: 468.3
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][O:3]1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][N+:17]([O-:20])=[C:16]([CH3:21])[C:15]=1[CH3:22]>CS(C)=O>[CH3:1][C:2]1([CH3:10])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:14]2[CH:19]=[CH:18][N+:17]([O-:20])=[C:16]([CH3:21])[C:15]=2[CH3:22])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CO)CO1
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(OCC2COC(C)(C)OC2)cc[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
To a dimethyl sulfoxide (30 ml) solution of the (2,2-dimethyl-1,3-dioxan-5-yl)methanol (3.27 g, 22.4 mmol) separately obtained in the same manner as in the step (11a) in example 11, sodium hydride, in oil (837 mg, 20.9 mmol as the content was regarded as 60%) was added at room temperature. The mixture was stirred at room temperature for 15 minutes in a nitrogen atmosphere. To the mixture, 4-chloro-2,3-dimethylpyridine 1-oxide (3.03 g, 19.2 mmol) was added, and the mixture was stirred at 60° C. for 3 hours and 20 minutes. After cooled to room temperature, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 250 g, elution solvent: ethyl acetate, ethyl acetate/methanol=10/1) to obtain the title compound (3.84 g, yield: 74.8%) as a pale brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=2[F:22])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].[CH:26](I)([CH3:28])[CH3:27]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:14]2[C:15]([F:22])=[CH:16][C:17]([O:21][CH:26]([CH3:28])[CH3:27])=[CH:18][C:19]=2[F:20])[O:11][CH2:12][CH3:13])=[CH:24][CH:25]=1)#[N:2]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(O)cc1F
Reactant: CC(C)I
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(OC(C)C)cc1F

Procedure:
In analogy to example 16.4 (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-4-hydroxy-phenyl)-2-ethoxy-acetamide was reacted with isopropyl iodide to give (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-4-isopropoxy-phenyl)-2-ethoxy-acetamide. Colorless oil. MS 387.1 ([M−H]−)
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[O:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH2:11]1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1
Reactant: C1=CCOC=C1
Reactant: Cc1cccc(O)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Product: Cc1cccc(OC2CCCCO2)c1C
Yield: 97.5 %

Procedure:
In a manner similar to Preparation 27 except use 2,3-Dimethylphenol (20 g, 0.164 mol), 1,2-dihyropyran (17.9 mL, 0.196 mol), p-toluenesulfonic acid (1.64 mmol), and triethylamine (1.80 mmol) to give 33.0 g (100%) of 2-(2,3-dimethylphenoxy)tetrahydro-2H-pyran as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.02 (t, J=7.8 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 6.79 (d, J=7.4 Hz, 1H), 5.38 (t, J=3.2 Hz, 1H), 3.95-3.81 (m, 1H), 3.58 (dtd, J=11.2, 4.1, 1.3 Hz, 1H), 2.26 (s, 3H), 2.18 (s, 3H), 2.08-1.97 (m, 1H), 1.91-1.85 (m, 2H), 1.74-1.57 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 155.00, 137.89, 125.92, 125.85, 123.15, 112.16, 96.46, 62.07, 30.75, 25.48, 20.23, 19.15, 11.90.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[O:11])[NH:5][C:6]=1[CH2:7][CH2:8][CH3:9].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[N:30]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[O:11])[N:5]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:6]=1[CH2:7][CH2:8][CH3:9]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1[nH]c(C=O)cc1Cl
Product: CCCc1c(Cl)cc(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 60 %

Procedure:
This compound was prepared using the same procedure as in Example 1. 5.2 g of 4-chloro-5-n-propyl-2-pyrrolaldehyde (0.030 moles) and 16.9 g of 4′-bromomethyl-2-(1-triphenylmethyltetrazol-5-yl)biphenyl (0.030 moles) yield 12 g of product which are used in the subsequent step. Formula: C41H34ClN5O (m.w. 648.21). Yield 60%.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[O:34][C:35]1[CH:40]=[C:39]([N:41]([CH3:43])[CH3:42])[N:38]=[CH:37][N:36]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:46]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][C:25]=1[O:34][C:35]1[CH:40]=[C:39]([N:41]([CH3:43])[CH3:42])[N:38]=[CH:37][N:36]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Oc2cc(N(C)C)ncn2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)c1cc(Oc2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)O)cn2)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-dimethylamino-pyrimidin-4-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (110 mg) is dissolved in ethanol (5 ml) and thereto is added 1N-aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-dimethylamino-pyrimidin-4-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (107 mg). MS (m/z): 719 [M+H]+
Reaction SMILES: [NH2:1][C@@H:2]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[CH2:3][N:4]([C:8]1[S:9][C:10]([C:16]2[S:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[N:24]=2)=[C:11]([CH2:13][O:14][CH3:15])[N:12]=1)C(=O)C.C1COCC1.Cl.[OH-].[Na+]>>[NH2:1][C@@H:2]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[CH2:3][NH:4][C:8]1[S:9][C:10]([C:16]2[S:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[N:24]=2)=[C:11]([CH2:13][O:14][CH3:15])[N:12]=1
Reactant: COCc1nc(N(C[C@@H](N)Cc2cccc(Cl)c2)C(C)=O)sc1-c1nc2ccncc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCc1nc(NC[C@@H](N)Cc2cccc(Cl)c2)sc1-c1nc2ccncc2s1
Temperature: 150 °C
Yield: 0.9 %

Procedure:
A glass microwave reaction vessel was charged with N-((S)-2-amino-3-(3-chlorophenyl)propyl)-N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)acetamide (0.090 g, 0.1 8 mmol), THF (2.0 mL, 24 mmol), and 5 N HCl (2.0 mL, 10.0 mmol). The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 150° C. for 11 minutes. The solution was then made basic with 10 N NaOH and extracted with EtOAc. The solvent was removed, and the compound was purified by reverse phase HPLC to give the title compound (31 mg, 38%). LCMS (M+H) 445.7 calc. for C20H21ClN5OS2 446.09. 1H NMR (400 MHz, CD3OD): δ ppm 9.12 (s, 1H), 8.50 (d, J=5.7 Hz, 1H), 7.83 (d, J=5.7 Hz, 1H), 7.34 (s, 1H), 7.23 (m, 3H), 4.70 (dd, J=12.4, 17.4 Hz, 2H), 4.46 (m, 1H), 3.47 (s, 3H), 3.25 (dd, J=3.7, 13.2 Hz, 1H), 3.15 (dd, J=9.9, 13.2 Hz, 1H), 2.98 (m, 2H).
Reaction SMILES: [O:1]([C:8]1[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-])=O)=[C:10]([CH3:18])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.Cl>[O:1]([C:8]1[CH:9]=[C:10]([CH3:18])[C:11](=[CH:12][C:13]=1[CH3:14])[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Oc1ccccc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cc1cc(Oc2ccccc2)c(C)cc1N
Temperature: 25 °C
Reaction time: 10 h
Yield: 73.2 %

Procedure:
A solution of 12.3 g (50 mmol) of 4-phenoxy-2,5-dimethylnitrobenzene in 150 ml of dioxane and 150 ml of hydrochloric acid was admixed at room temperature with 34.1 g (151 mmol) of tin chloride. After 10 h of stirring at room temperature, the mixture was neutralized with aqueous NaHCO3 solution and extracted repeatedly with dichloromethane. Drying of the combined organic phases over Na2SO4 and evaporation of the solvent gave 7.9 g (99.5% purity, 73.2% yield) of the product; log P(HCOOH)=1.92.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@H:11]2[CH2:16][C@H:15]([CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:14]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:13]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@H:12]2[NH:42]C(OC(C)(C)C)=O)=O)=CC=1)([O-])=O.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[NH2:42][C@@H:12]1[C@@H:13]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C@H:14]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:15]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][C@H:11]1[OH:10]
Reactant: CC(C)(C)OC(=O)N[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)C[C@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)C[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
A suspension of (1R,2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-((tert-butoxycarbonyl)amino)cyclohexyl 4-nitrobenzoate (2.80 g, 4.02 mmol) and anhydrous K2CO3 (0.70 g, 0.51 mmol) in MeOH (100 mL) was stirred at room temperature for 2 h. The resulted clear solution was concentrated, and DCM (80 mL) was added. The mixture was washed with saturated aqueous NaHCO3 (60 mL), and the aqueous layer was further extracted with DCM (2×40 mL). The combined extract was dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:3 to 1:1), affording a white solid. The solid was dissolved in mixed MeOH and EtOAc (30 mL, 2:1). HCl (g) was bubbled into the solution for 30 sec, and the mixture was stirred at room temperature for 2 h. The solvent was then removed, water (30 mL) was added and the mixture was basified with diluted aqueous NaOH solution. Extraction with DCM (2×40 mL) was performed, and the combined extract was dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure, affording the title compound as an off-white solid (1.54 g, 94%). 1H NMR (400 MHz, CDCl3) δ 7.37-7.25 (m, 15H), 4.98 (d, J=11.3 Hz, 1H), 4.84 (d, J=10.8 Hz, 1H), 4.69 (d, J=11.3 Hz, 1H), 4.56 (d, J=10.8 Hz, 1H), 4.47 (s, 2H), 3.64 (dd, J=4.9, 8.9 Hz, 1H), 3.54-3.48 (m, 2H), 3.34-3.30 (m, 1H), 3.19 (t, J=9.4 Hz, 1H), 2.53-2.50 (m, 1H), 2.08-2.02 (m, 1H), 1.75-1.72 (m, 1H), 1.59-1.52 (m, 1H).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:25])[CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12)([CH3:3])[CH3:2].[CH2:26]1[O:28][CH2:27]1>C(O)C>[CH:1]([N:4]([CH:5]([CH3:25])[CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12)[CH2:26][CH2:27][OH:28])([CH3:2])[CH3:3]
Reactant: C1CO1
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)NC(C)C)=C21
Solvent: CCO
Product: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)N(CCO)C(C)C)=C21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The mixture of 5 g of slow moving 1-(2-isopropylaminopropyl)-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one and 14.75 ml of liquified ethylene oxide in 100 ml of absolute ethanol is stirred in a sealed pressure tube at room temperature for two days. The reaction mixture is recharged with an additional 14.75 ml portion of ethylene oxide and stirred for four additional days at room temperature. It is evaporated, the residue slurried in diethyl ether, collected by filtration and recrystallized from ethyl acetate to yield the 1-[2-(N-isopropyl-N-2-hydroxyethylamino)-propyl]-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one, RR racemate melting at 147°-149°.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:8](=[O:9])[C:7]([O:10][CH3:11])=[CH:6][C:5]([C:12]#[N:13])=[CH:4]1.C[O-].[Na+].CO.CS(O)(=O)=O.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C@@:31]([C:36]2[CH:37]=[N:38][C:39]([F:42])=[CH:40][CH:41]=2)(N)[C@@H:32]([NH2:34])[CH3:33])=[CH:27][CH:26]=1>CO>[CH2:2]([N:3]1[CH:4]=[C:5]([C:12]2[NH:34][C@@H:32]([CH3:33])[C@:31]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)([C:36]3[CH:37]=[N:38][C:39]([F:42])=[CH:40][CH:41]=3)[N:13]=2)[CH:6]=[C:7]([O:10][CH3:11])[C:8]1=[O:9])[CH3:1]
Reactant: C[C@H](N)[C@](N)(c1ccc(F)cc1)c1ccc(F)nc1
Reactant: CCn1cc(C#N)cc(OC)c1=O
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCn1cc(C2=N[C@@](c3ccc(F)cc3)(c3ccc(F)nc3)[C@H](C)N2)cc(OC)c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 2.5 %

Procedure:
1-ethyl-3-methoxy-2-pyridone-5-carbonitrile (30 mg) was dissolved in methanol (1 mL), and 25% sodium methoxide-methanol solution(6.6 mL) was added thereto. The mixture was stirred at room temperature for 17 hours, and methanesulfonic acid (11 μL) and a solution of (1S,2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine (44.5 mg) in methanol (1 mL) were successively added. The mixture was stirred at room temperature for two days and concentrated in vacuo. The residue was dissolved in ethyl acetate, and the solution was washed with brine, and dried over anhydrous sodium sulfate. After removal of the sodium sulfate by filtration, the organic solvent was evaporated in vacuo to give a residue, which was purified by column chromatography on silica gel (chloroform:methanol=10:1) to give the title compound (1.8 mg) as a brown solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([CH3:18])=[C:7]([CH:11]=[CH:12][C:13]=2[S:14]([CH3:17])(=[O:16])=[O:15])[C:8]([OH:10])=O)[CH2:3][CH2:2]1.[CH3:19][N:20]1[C:24]([OH:25])=[CH:23][C:22]([CH3:26])=[N:21]1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC.[Si](C#N)(C)(C)C.[C-]#N.[K+]>C(#N)C>[CH3:19][N:20]1[C:24]([OH:25])=[C:23]([C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:13]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)[C:6]=2[CH3:18])[C:22]([CH3:26])=[N:21]1
Reactant: Cc1cc(O)n(C)n1
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: C[Si](C)(C)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nn(C)c(O)c1C(=O)c1ccc(S(C)(=O)=O)c(NC2CC2)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under nitrogen, 0.50 g (1.9 mmol) of 3-cyclopropylamino-2-methyl-4-(methyl-sulfonyl)benzoic acid, 0.27 g (2.4 mmol) of 1,3-dimethyl-5-hydroxypyrazole and 0.43 g (2.2 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were dissolved in dry acetonitrile. The mixture was stirred at RT for 1 day and allowed to stand for 2 days. 0.52 ml (3.7 mmol) of NEt3, 0.10 ml (0.7 mmol) of Me3SiCN and a spatula tip of KCN were added, and the mixture was stirred at RT for 2 days. The solvent was removed under reduced pressure, and the residue was taken up in CH2Cl2 and 10% strength H2SO4. The organic phase was separated off, the aqueous phase was extracted once with CH2Cl2, the combined organic phases were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC. This gave 0.16 g of a white-beige amorphous solid in a purity of 93%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]2[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:22])[C:12]=12.C(N(CC)CC)C>ClCCl>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]2[CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:12]=12
Reactant: OC1CCCCc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CCCCc2cccnc21
Reaction time: 0.17 h

Procedure:
To a solution of oxalyl chloride (1 mL) in dichloromethane, cooled to −78° C. was added dropwise a solution of dimethyl sulfoxide (1.5 mL) in dichloromethane. The mixture was stirred for 10 minutes and a solution of 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (Chem. Pharm. Bull. 43, 3, 1995), (1.42 g, 8.7 mmol) in dichloromethane was added to it. After 30 minutes, triethylamine (6 mL) was added to the reaction mixture and it was stirred at ambient temperature for 1 hour and partitioned in dichloromethane/water. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel, eluting with ethyl acetate to yield the title compound: 1H NMR (300 MHz, CDCl3) δ 8.64 (dd, J=4.58, 1.53 Hz, 1 H), 7.58 (dd, J=7.63, 1.53 Hz, 1 H), 7.33 (dd, J=7.80, 4.75 Hz, 1 H), 2.92 (m, 2 H), 2.80 (m, 2 H), 1.90 (s, 4 H); MS (DCI/NH3) m/z 162 (M+H)+.