Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][N:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](OCC)=[O:19].Cl>C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][N:11]=1)[NH:8][C:7](=[O:12])[CH:6]2[C:18](=[O:19])[C:14]1[S:13][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1Cc2cc(Cl)ncc2N1
Reactant: CCOC(=O)c1cccs1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=C1Nc2cnc(Cl)cc2C1C(=O)c1cccs1
Temperature: 0 °C
Yield: 34.1 %

Procedure:
Pellets of sodium metal (232 mg, 10 mmol) were added to dry ethanol (10 mL) in a dry round-bottomed flask. When dissolution of the sodium was complete, solid 5-chloro-6-azaoxindole (340 mg, 2.0 mmol) was added followed by ethyl 2-thiophenecarboxylate (0.54 mL, 4.0 mmol). The mixture was heated under nitrogen at reflux overnight during which a precipitate formed. The mixture was cooled, poured into ice/water and acidified to pH 4 with 6N HCl solution. The solid product (475 mg) was collected by filtration, washed with water, and dried in the air. This material was recrystallized from methanol to afford the title compound (190 mg, 34%). 1H NMR (DMSO-d6): δ10.62 (br s, 1H), 8.79 (d, J=3.2 Hz, 1H), 7.92 (s, 1H), 7.77 (d, J=5 Hz, 1H), 7.65 (s, 1H), 7.17-7.14 (m, 1H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[N:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:18]4[N:23]=[N:22][C:21]([C:24]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[O:25])=[CH:20][CH:19]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(Cl)nn1)N1CCOCC1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nn1)N1CCOCC1
Temperature: 140 °C

Procedure:
A mixture of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-ol (E3) (84 mg, 0.385 mmol), 4-[(6-chloro-3-pyridazinyl)carbonyl]morpholine (E280, Step 1) (70 mg, 0.308 mmol) and potassium carbonate (85 mg, 0.616 mmol) in dry acetone (3 ml) was heated at 140° C. for 2×15 mins. (300 W) in a microwave reactor. The cooled reaction mixture was filtered, concentrated in vacuo. and Purified by column chromatography on silica gel, eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:190) to afford the title compound; MS (ES+) m/e 409 [M+H]+.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[CH3:29][C:27]1[N:26]=[CH:25][N:24]=[C:23]([N:20]2[CH2:21][CH2:22][CH:17]([C:15]([N:12]3[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]3)=[O:16])[CH2:18][CH2:19]2)[CH:28]=1
Reactant: Cc1cc(N2CCC(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC2)ncn1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCC(C(=O)N3CCNCC3)CC2)ncn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl acetate saturated with gaseous HCl was added to a solution of 1-(tert-butoxycarbonyl)-4-[1-(6-methylpyrimidin-4-yl)-4-piperidylcarbonyl] piperazine (14.07 g) in ethyl acetate (50 ml) and the resulting suspension stirred at ambient temperature for 3 hours. Solvent was evaporated to give 4-[1-(6-methylpyrimidin-4-yl)-4-piperidylcarbonyl] piperazine hydrochloride (11.79 g) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6][C:5]2=O.[OH-].[Na+].O=P(Cl)(Cl)[Cl:17]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][CH:6]=[C:5]2[Cl:17]
Reactant: O=c1cn[nH]c2ccc(Br)cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1cnnc2ccc(Br)cc12
Temperature: 0 °C
Yield: 43 %

Procedure:
A solution of Example 34C (0.4 g, 1.8 mmol) in POCl3 (2.5 mL) was heated to 100° C. for 2 hours, and poured slowly onto ice. The aqueous layer was cooled to 0° C. and adjusted to pH 5-7 with 50% NaOH. The aqueous layer was extracted with ethyl acetate (2×50 mL), and the combined organic layers were concentrated. The residue was purified by flash column chromatography on silica gel with 4:1 hexanes/ethyl acetate to provide the desired product (0.190 g, 43%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([N:18]3[C:22]4[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[N:20]=[C:19]3[CH3:28])[CH:14]([CH2:29][OH:30])[CH2:13]1)[CH2:5]2.C(N(C(C)C)CC)(C)C.[CH:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1>C(Cl)Cl>[CH3:28][C:19]1[N:18]([CH:15]2[CH2:16][CH2:17][N:12]([CH2:11][C@H:6]3[CH2:5][C:4]4[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:43](=[O:44])[CH:40]([CH3:42])[CH3:41])[CH:3]=4)[CH2:7]3)[CH2:13][CH:14]2[CH2:29][OH:30])[C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[N:20]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc2c(c1)nc(C)n2C1CCN(CC2Cc3ccc(N)cc3C2)CC1CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc2c(c1)nc(C)n2C1CCN(C[C@@H]2Cc3ccc(NC(=O)C(C)C)cc3C2)CC1CO
Reaction time: 1 h

Procedure:
[1-(5-Amino-indan-2-ylmethyl)-4-(2,5-dimethyl-benzoimidazol-1-yl)-piperidin-3-yl]-methanol (65 mg; 0.165 mmol) was dissolved in CH2Cl2 (1 mL). Diisopropylethylamine (70 μL; 0.4 mmol) and cyclopropanecarbonyl chloride (18 μL; 0.2 mmol) were added and the reaction mixture was stirred for one hour. All volatiles were removed and N-{(R)-2-[4-(2,5-Dimethyl-benzoimidazol-1-yl)-3-hydroxymethyl-piperidin-1-ylmethyl]-indan-5-yl}-isobutyramide was isolated by flash chromatography (1-10% CH3OH in EtOAc) as a waxy oil (68 mg; 90%).
Reaction SMILES: [C:1]([C@@:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].[CH:18](Cl)(Cl)Cl>>[C:1]([C@@:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([O:15][CH3:18])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2]
Reactant: ClC(Cl)Cl
Reactant: C#C[C@@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Product: C#C[C@@]1(C)CCc2c(C)c(OC)c(C)c(C)c2O1

Procedure:
By the same procedure as described in Example 28 (R)-2-ethynyl-3,4-dihydro-6-methoxy-,5,7,8-tetramethyl-H-1-benzopyran was prepared from (R)-(-)2-ethynyl-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol. This product was produced as white prisms=93°-95° C. [α]D25 -57.14°, (C 0.28, CHCl3).
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[CH:5][C:4]([C:8]([F:11])([F:10])[F:9])=[N:3]1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:19]=[O:20].[OH-].[Na+]>O.CO>[OH:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:5]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: Cn1nc(C(F)(F)F)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: Cn1nc(C(F)(F)F)c(C=O)c1O
Temperature: 50 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol (9.8 g, 0.059 mole) was added in portions to a mixture of phosphorus oxychloride (9.2 g, 0.060 mole) and N,N-dimethylformamide (10 mL, 0.12 mole) with cooling to control the reaction temperature near 40° C. The mixture was then heated and held at 90°-100° C. for one hour and poured while still warm (50° C.) into a mixture of methanol and water. The pH was adjusted to basic with 10% sodium hydroxide. The aqueous solution was washed with ether, then adjusted to acidic pH with 37% hydrochloric acid, and extracted with a mixture of ether and ethyl acetate. The extracts were dried with magnesium sulfate, filtered and concentrated in vacuo to give 5-hydroxy-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxaldehyde (9.4 g, 82% yield) which was recrystallized from ethyl acetate/cyclohexane to give a white solid, mp=116°-118° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:25](O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:11]
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Yield: 84.6 %

Procedure:
10.32 g of 2-indolecarboxylic acid in 70 ml of THF are placed in a three-necked flask at RT, 10.38 g of carbonyldiimidazole are added and, after the evolution of gas has ceased, 7.62 g of benzyl alcohol are then added. After refluxing for 5 hours, the mixture is poured into water and extracted with DCM, and the extracts are dried and evaporated. The crystals formed are washed with iPrOH to give 13.62 g of the expected compound: m.p.=136° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:24][CH2:25][CH:26]=[CH2:27].O>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]([CH2:6][CH2:5][CH:4]=[CH2:3])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[CH2:24][CH2:25][CH:26]=[CH2:27]
Reactant: C=CCCBr
Reactant: COC(=O)Cc1cccc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(CCC=C)(C(=O)OC)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(3-Fluoro-phenyl)-acetic acid methyl ester (4.30 g) was dissolved in tetrahydrofuran (20 mL) and cooled to −78° C. Lithium bis(trimethylsilyl)amide (25.6 mL, 1M THF solution) was added and the solution was stirred for 30 minutes. 4-Bromo-but-1-ene (2.60 mL) was added and the reaction contents were allowed to warm to room temperature and stir for an hour. The reaction mixture was again cooled to −78° C. Lithium bis(trimethylsilyl)amide (25.6 mL, 1M THF solution) was added and the solution was stirred for 30 minutes. 4-Bromo-1-butene (2.60 mL) was added and the reaction mixture was allowed to warm to room temperature and stir for an hour. The contents were again cooled to −78° C. and further aliquots of Lithium bis(trimethylsilyl)amide (25.6 mL, 1M THF solution) and 4-bromo-1-butene (2.60 mL) were added following the procedure outlined above. After stirring overnight, water (20 mL) was added and the reaction mixture extracted with diethyl ether (2×60 mL). The combined organic extracts were dried with magnesium sulfate and evaporated. The resulting liquid was purified by column chromatography on silica eluting with ethyl acetate/isohexane (1/99) to afford the sub-titled compound (5.0 g).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[C:11]([O:12][CH2:13][C:14]2[C:15]([C:20]3[N:24]([CH:25]([CH3:27])[CH3:26])[N:23]=[CH:22][C:21]=3[CH3:28])=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][N:9]=[C:8]([O:29][CH3:30])[CH:7]=1.Cl>>[CH:25]([N:24]1[C:20]([C:15]2[C:14]([CH2:13][O:12][C:11]3[C:6]([CH:2]=[O:1])=[CH:7][C:8]([O:29][CH3:30])=[N:9][CH:10]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:21]([CH3:28])[CH:22]=[N:23]1)([CH3:27])[CH3:26]
Reactant: COc1cc(C2OCCO2)c(OCc2cccnc2-c2c(C)cnn2C(C)C)cn1
Agent: Cl
Product: COc1cc(C=O)c(OCc2cccnc2-c2c(C)cnn2C(C)C)cn1
Temperature: 40 °C
Yield: 90.9 %

Procedure:
To 4-(1,3-dioxolan-2-yl)-5-((2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxypyridine (41 mg, 0.1 mmol, 1 eq.) in a RB flask was added HCl (6 N, 2.0 mL). The mixture was warmed to 40° C., O/N, cooled to rt, neutralized to pH 7-8 with NaHCO3(sat) solution, and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (33.3 mg, 99%) as an pale-yellow oil. 1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H), 8.71 (dd, J=4.7, 1.6 Hz, 1H), 7.99 (dd, J=7.9, 1.5 Hz, 1H), 7.76 (s, 1H), 7.40 (dd, J=7.1, 4.7 Hz, 1H), 7.39 (s, 1H), 7.01 (s, 1H), 4.86-4.99 (m, 2H), 4.12 (sep, J=6.7, 1H), 3.82 (s, 3H), 1.86 (s, 3H), 1.40 (d, J=767 Hz, 3H), 1.29 (d, J=6.7 Hz, 3H). LRMS (M+H+) m/z 367.1.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([C@@H:11]1[C@:19]2([CH3:20])[C@H:14]([C@@H:15]([OH:21])[CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12]1)[CH3:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[C:1]([O:7][CH2:8][C@@H:9]([C@@H:11]1[C@:19]2([CH3:20])[C@H:14]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12]1)[CH3:10])(=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4]
Reactant: C[C@@H](COC(=O)C(C)(C)C)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H](COC(=O)C(C)(C)C)[C@H]1CC[C@H]2C(=O)CCC[C@]12C
Temperature: 0 °C

Procedure:
The crude compound of Example 3E (0.96 g) was dissolved in 19 mL of dichloromethane and cooled to 0° C.; 3.1 g of pyridinium dichromate was added, followed by 22 mg of pyridinium p-toluenesulfonate. The resultant mixture was stirred for 1.5 hours at 0° C.; an additional 1.3 g of pyridinium dichromate and 20 mg of pyridinium p-toluenesulfonate were added, and the mixture was allowed to warm to ambient temperature overnight. The mixture was diluted with ether and filtered through a pad of diatomaceous earth with an ether wash. The filtrate was washed with 1 N aqueous HCl, and then filtered through a plug of silica gel. The crude product was purified by chromatography on an Analogix IntelliFlash 280™, eluting with a gradient of 8% to 15% ethyl acetate in hexanes. Fractions containing the titled compound were combined and concentrated in vacuo (0.77 g, 96%, 2 steps).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].Cl[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([CH3:22])[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Na+].[I-]>CS(C)=O>[CH3:22][C:14]1[CH:13]=[C:12]([CH2:11][O:9][C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: C=Cc1ccc(O)cc1
Reactant: Cc1cc(CCl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CS(C)=O
Product: C=Cc1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
A mixture of 4-vinylphenol (10% wt. solution in propylene glycol) (1.25 g, 1.04 mmol), 4-Chloromethyl-2-methylquinoline (0.24 g, 1.2 eq), Cs2CO3 (0.85 g, 2.5 eq) and NaI (0.20 g, 1.2 eq) in DMSO (1 ml) was stirred at rt overnight. After work up, the residue was purified by flash column chromatography (40% ethyl acetate-hexanes) to give 2-methyl-4-(4-vinyl-phenoxymethyl)-quinoline (0.134 g, 46.8%) as a white solid. MS Found: (M+H)+=276.
Reaction SMILES: [C:1]([NH:20][S:21](=[O:46])(=[O:45])[O:22][CH2:23][C@@H:24]1[C@@H:31]2[C@@H:27]([O:28][C:29]([CH3:33])([CH3:32])[O:30]2)[C@H:26]([N:34]2[CH:42]=[N:41][C:40]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[CH2:43][NH2:44])[O:25]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:47][O:48][C:49]1[CH:57]=[CH:56][CH:55]=[CH:54][C:50]=1[C:51](Cl)=[O:52]>>[C:1]([NH:20][S:21](=[O:45])(=[O:46])[O:22][CH2:23][C@@H:24]1[C@@H:31]2[C@@H:27]([O:28][C:29]([CH3:33])([CH3:32])[O:30]2)[C@H:26]([N:34]2[CH:42]=[N:41][C:40]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[CH2:43][NH:44][C:51](=[O:52])[C:50]2[CH:54]=[CH:55][CH:56]=[CH:57][C:49]=2[O:48][CH3:47])[O:25]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(=O)(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)O[C@H]2n1cnc2c(CN)ncnc21
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)NCc1ncnc2c1ncn2[C@@H]1O[C@H](COS(=O)(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]2OC(C)(C)O[C@H]21

Procedure:
The title compound was prepared following the procedure described in Example 127, step a using {(3aR,4R,6R,6aR)-6-[6-(aminomethyl)-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methyl tritylsulfamate and 2-methoxybenzoyl chloride.
Reaction SMILES: C([O:9][CH:10]([C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)[C:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:12])(=O)C1C=CC=CC=1.Br>CS(C)=O>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]([C:10]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:9])=[O:12])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=C(OC(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Agent: Br
Solvent: CS(C)=O
Product: O=C(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Yield: 91 %

Procedure:
Into a 500 mL three-necked, round-bottomed flask equipped with a magnetic stirrer, dropping funnel and nitrogen inlet, 2-benzoyloxy-1,2-bis(4-nitrophenyl)ethanone (15.0 g, 36.9 mmol) was dissolved in DMSO (dimethyl sulfoxide) (150 mL) and stirred until the solution become homogeneous. Then, hydrobromic acid (48%, 50 mL) was added through dropping funnel and stirred at 60° C. During this process, light yellow crystals were separated from the reaction mixture. After the reaction mixture had been allowed to cool down on its own, the crystals were collected by suction filtration, 10.1 g (91% yield), mp 211-212° C. Anal. Calcd. for C21H12N4O6: C, 56.01%; H, 2.69%; N, 9.33%; O, 31.97%. Found: C, 55.75%; H, 2.50%; N, 9.30%; O, 33.98%: FT-IR (KBr, cm−1): 1347, 1527, 1682. Mass spectrum (m/e): 282 (M+, 100% relative abundance). 1H-NMR (DMSO-d6, δ in ppm): 8.27-8.30 (dd, 4H, Ar), 8.41-8.44 (dd, 4H, Ar). 13C-NMR (DMSO-d6, δ in ppm) 123.94, 131.66, 136.81, 150.75, 190.06.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1.[CH3:22][NH:23][CH2:24][CH2:25][OH:26]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:23]([CH3:22])[CH2:24][CH2:25][OH:26])=[CH:21][C:10]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: CNCCO
Reactant: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1
Product: CN(CCO)CCCOc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and 2-(methylamino)ethanol were converted to yield 2-({3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-methyl-amino)-ethanol as colorless oil, MS: 360 (MH+).
Reaction SMILES: [CH2:1]([CH:3]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([N+:15]([O-])=O)=[CH:8][C:7]=1[O:18][CH2:19][CH:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][CH3:24])[CH3:2].O.NN>[Pd].C(O)C>[CH2:25]([CH:20]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:19][O:18][C:7]1[CH:8]=[C:9]([NH2:15])[C:10]([NH2:12])=[CH:11][C:6]=1[O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:27][CH2:28][CH2:29][CH3:30])[CH3:26]
Reactant: CCCCC(CC)COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OCC(CC)CCCC
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCCC(CC)COc1cc(N)c(N)cc1OCC(CC)CCCC

Procedure:
A 250 mL 3-neck round bottom flask fitted with a condenser is charged with 1,2-bis((2-ethylhexyl)oxy)-4,5-dinitrobenzene (8.9 g, 0.021 mol), hydrazine monohydrate (11.6 g, 0.231 mol), Pd/C (0.27 g), and ethanol (100 mL). The mixture is warmed to reflux under nitrogen overnight. The mixture is filtered while hot under a nitrogen blanket. A solid is precipitated out upon cooling, washed with methanol and dried overnight under vacuum to yield the product as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1([C:13]#N)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.[NH4+].[Cl-].O.C1[CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:23][O:22][CH2:21][CH2:20][CH2:13][C:3]1([N:2]([CH3:15])[CH3:1])[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1
Reactant: C1CCOC1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COCCCC1(N(C)C)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (9.68 g, 46 mmole) in absolute THF (30 ml) was added dropwise while cooling with ice. A viscous precipitate thereby formed, and 100 ml of absolute THF was therefore added to achieve a better mixing. The mixture was stirred for 24 hours at room temperature. 20% NH4Cl solution (100 ml) and water (120 ml) were added while cooling with ice to the reaction mixture, and the organic phase was separated and the aqueous phase was extracted with ether (3×120 ml).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#N.CC(C[AlH]CC(C)C)C.Cl.[OH-:28].[Na+]>C1COCC1.CCOC(C)=O.CCOCC>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH:1]=[O:28])[CH2:4][CH2:5]2)=[CH:12][CH:13]=1
Reactant: [OH-]
Reactant: N#CC1CCN(CCc2ccc(F)cc2)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=CC1CCN(CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-cyano-1-[2-(4-fluorophenyl)-ethyl]piperidine (1.00 g, 4.3 mmol) in THF (20 mL) under argon at 0° C. was added DIBAL-H (4.6 mL of a 1.0 M solution in THF, 4.6 mmol) via syringe. After stirring overnight at room temperature, 10% aqueous HCl (25 mL) was added and the solution was stirred for 3 hours. The entire mixture was then poured into 10% aqueous NaOH (50 mL), then extractd 2× with ether. The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to afford a pale yellow oil. The oil was chromatograohed on silica gel eluting with EtOAc. The appropriate fractions were combined and evaporated to afford an oil. This oil was distilled (b.p. 166° C., 0.05 mm Hg) to afford 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxaldehyde, obtained as a colorless oil. Anal. Calcd for C14H18FNO: C, 71.46; H, 7.71; N, 5.95. Found: C, 71.08, H, 7.81; N, 5.86.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[C@@H:12]2[CH2:17][CH2:18][C@H:9]1[C@@H:10]([OH:20])[C@H:11]2[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O[N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=C[C:26]=2[N:25]=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.Cl.N1CCC[C@H]1C#N>CN(C)C=O>[C:26]([C@@H:27]1[CH2:28][CH2:29][CH2:30][N:23]1[C:14]([C@@H:13]1[C@@H:12]2[CH2:17][CH2:18][C@@H:9]([C@@H:10]([OH:20])[C@H:11]2[OH:19])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:16])#[N:25]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)O)[C@@H]2CC[C@H]1[C@@H](O)[C@H]2O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#C[C@@H]1CCCN1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H](C(=O)N2CCC[C@H]2C#N)[C@@H]2CC[C@H]1[C@@H](O)[C@H]2O
Reaction time: 3 h

Procedure:
To a solution of (1S,3S,4S,5S,6R)-2-(tert-butoxycarbonyl)-5,6-dihydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid obtained in Example 1-3 (500 mg) 1-hydroxybenzotriazole hydrate (415 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (493 mg) in dimethylformamide (10 mL), were added diisopropylethylamine and (2S)-2-pyrrolidinecarbonitrile hydrochloride with cooling on an ice bath. The reaction mixture was stirred at that temperature for 3 hrs.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:16])[C:9]3[S:15][CH:14]=[CH:13][C:10]=3[CH2:11][O:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:17][C:18]([F:26])([F:25])[C@:19]([OH:24])([CH3:23])[C:20](O)=[O:21]>>[F:17][C:18]([F:26])([F:25])[C@:19]([OH:24])([CH3:23])[C:20]([NH:1][C:2]1[C:7]2[C:8](=[O:16])[C:9]3[S:15][CH:14]=[CH:13][C:10]=3[CH2:11][O:12][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: C[C@](O)(C(=O)O)C(F)(F)F
Reactant: Nc1cccc2c1C(=O)c1sccc1CO2
Product: C[C@](O)(C(=O)Nc1cccc2c1C(=O)c1sccc1CO2)C(F)(F)F
Yield: 35 %

Procedure:
Substantially the same procedure as in Example 1 was repeated using 9-amino-4,10-dihydrothieno[3,2-c][1]benzoxepin-10-one obtained in Reference Example 11 (0.840 g, 3.63 mmol) and (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid obtained in Reference Example 27 (1.14 g, 7.26 mmol) to give Compound 33 (0.47 g, 35%).