Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH:4]2[CH2:3]1.[H-].[Na+].Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34].B>CN(C)C=O.CO>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH2:13][CH2:14][NH:15][CH2:16][CH:4]2[CH2:3][CH2:2]1
Reactant: Clc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3NC(=O)CC2C1
Agent: B
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Clc1ccccc1CN1CCC2CNCCN2c2ccccc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of Example 1C (50 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL) was added sodium hydride (65%, 6.98 mg, 0.19 mmol). The solution was allowed to stir at room temperature for 1 hour before addition of 1-(bromomethyl)-2-chlorobenzene (37.2 mg, 0.181 mmol). The reaction mixture was stirred overnight. The solution was concentrated. To the concentrate was added tetrahydrofuran (10 mL) followed by borane (1 M in tetrahydrofuran, 1 mL, 1 mmol). The solution was heated in an 80° C. oil bath for 4 hours. Methanol (20 mL) was added and heating of the resultant solution was continued in the 80° C. bath for 1 hour before concentration. To the concentrate was added dichloromethane (10 mL), methanol (1 mL) and HCl (4 M in dioxane, 2 mL) Once LC/MS analysis indicated the reaction was complete the solution was concentrated and purified by preparative HPLC to afford the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 7.46 (d, J=8.85 Hz, 1 H) 7.28-7.38 (m, 3 H) 6.95 (dd, J=7.93, 1.53 Hz, 1 H) 6.87-6.92 (m, 1 H) 6.82-6.87 (m, 1 H) 6.70 (dd, J=7.78, 1.37 Hz, 1 H) 4.56 (d, J=16.17 Hz, 1 H) 4.36 (d, J=16.48 Hz, 1 H) 3.46-3.56 (m, 1 H) 3.35-3.43 (m, 2 H) 3.06-3.28 (m, 4 H) 2.93-3.02 (m, 2 H) 1.89-1.99 (m, 1 H) 1.70-1.79 (m, 1 H) MS (ESI) m/z 328.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:16])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of 4-(1-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (18.24 g, 79.54 mmol) in dichloromethane (400 mL) and triethylamine (12.20 mL, 87.49 mmol) at 0° C. is added methanesulfonyl chloride (9.23 mL, 119.30 mmol). The reaction is allowed to warm to room temperature over 16 h. The mixture is washed with 0.1 M hydrochloric acid, saturated aqueous sodium bicarbonate, water, and brine. The material is dried over magnesium sulfate, filtered, and concentrated to dryness. The crude material is purified by flash chromatography over silica gel to afford 22.65 g of the title compound as a colourless oil. 1H NMR (CDCl3) δ (ppm): 1.19-1.30 (m, 2H), 1.39 (d, 3H), 1.44 (s, 9H), 1.6-1.8 (m, 3H), 2.66 (m, 2H), 2.99 (s, 3H), 4.16 (m, 2H), 4.62 (t, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[Na+].[Cl:6][C:7]1[CH:12]=[C:11](Cl)[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][N:8]=1.O>CN(C=O)C>[Cl:6][C:7]1[CH:12]=[C:11]([O:3][CH:2]([CH3:4])[CH3:1])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Reactant: CC(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(Cl)ncc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 61 %

Procedure:
3.38 g of sodium isopropoxide are added to a solution of 2.6 g of 2.4-dichloro-5-nitropyridine in 39 ml of DMF. The reaction medium is stirred at ambient temperature for 1 h 15 and 3.18 g of sodium isopropoxide are added. The reaction medium is stirred for a further 15 minutes and then the mixture is poured into 200 ml of water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification is carried out by flash chromatography on silica gel (40-63 microns), elution being carried out with a heptane/ethyl acetate mixture (90/10 to 80/20). 1.78 g of 2-chloro-5-nitro-4-(propan-2-yloxy)pyridine are obtained in the form of a pale yellow solid.
Reaction SMILES: P(Cl)(Cl)Cl.[ClH:5].Cl[C:7]([C:17]#[N:18])([CH2:13][CH2:14][CH:15]=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9]>CN(C=O)C>[Cl:5][C:17]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=[CH:15][N:18]=1
Reactant: Cl
Reactant: CCOC(=O)C(Cl)(C#N)CCC=O
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To 35 mL of DMF were added dropwise 6.85 g of PCl3 (50 mmol). Anhydrous HCl was introduced for 5 minutes while keeping the temperature around 70° C. Ethyl 2-chloro-2-cyano-5-oxopentanoate (7.83 g, 38.5 mmol) in 10 mL of DMF was added at 55° C. The resulting mixture was stirred for 2 h at 90° C., cooled to room temperature, quenched with water, extracted with CH2Cl2, dried over MgSO4, concentrated and distilled to give 4.4 g of the title compound (62%).
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:33]=[CH:32][C:13]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][C:20]([OH:31])([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H].CCOCC>CO.[OH-].[OH-].[Pd+2]>[ClH:1].[OH:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][C:20]([OH:31])([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[CH2:21][CH2:22]2)=[CH:32][CH:33]=1
Reactant: Cc1ccc(CC2(O)CCN(CCOc3ccc(OCc4ccccc4)cc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(CC2(O)CCN(CCOc3ccc(O)cc3)CC2)cc1
Reaction time: 8 h
Yield: 99.9 %

Procedure:
1-[2-(4-Hydroxyphenoxy)ethyl]-1-hydroxy-4-(4-methylbenzyl)piperidine hydrochloride. To a solution of 1-[2-(4-benzyloxyphenoxy)ethyl]-4-hydroxy-4-(4-methylbenzyl)piperidine hydrochloride (0.25 g, 0.53 mmol) in 30 mL of methanol was added 62.5 mg of 20% Pd(OH)2. The resulting mixture was hydrogenated at 20 psi of hydrogen for 3 h. The catalyst was removed through a short column of celite (5 g) and washed with methanol (3×15 mL). Methanol was evaporated in vacuo to give a residue, to which 50 mL of ether was added. The resulting mixture was stirred overnight. A white solid was collected by filtration and dried in vacuo, giving 200 mg (100%) of the title product: mp 133-135° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](O)(=O)[CH2:11][OH:12]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:10]([CH2:11][OH:12])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=C(O)CO
Product: OCc1nc2cc(Br)cnc2[nH]1

Procedure:
A procedure similar to that described in Preparation 43 was repeated, except that 7.00 g of 5-bromo-2,3-diaminopyridine (prepared as described in Preparation 57) and 8.50 g of glycolic acid were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 7.05 g of the title compound, melting at 230-233° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@:12]1([CH3:19])[C:16](O)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>ClCCl.CN(C)C=O>[Cl:23][C:16]([C@:12]1([CH3:19])[CH2:13][CH2:14][CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@@]1(C(=O)O)CCCN1C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@]1(C(=O)Cl)CCCN1C(=O)OCc1ccccc1

Procedure:
A solution of (S)-1-(benzyloxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (1.50 g) in dichloromethane (30 mL) was treated with oxalyl chloride (0.65 mL) and 3 drops of N,N-dimethylformamide at ambient temperature for 1.5 hours. The mixture was concentrated and the crude material used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1ccc(Br)c(I)c1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Br)c(-c2cccnc2)c1
Temperature: 120 °C
Yield: 69.8 %

Procedure:
A solution of Pd(Ph3P)4 (1.410 g, 1.220 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (3.94 ml, 24.41 mmol), pyridin-3-ylboronic acid (3.00 g, 24.41 mmol), and potassium carbonate (13.49 g, 98 mmol) in 32 mL dioxane and 16 mL water was heated to 120° C. overnight. LC/MS showed incomplete conversion, so an additional portion of pyridin-3-ylboronic acid (3.00 g, 24.41 mmol) and potassium carbonate (13.49 g, 98 mmol) were added and the reaction mixture was heated to 120° C. for 3 hours. LC/MS showed no further conversion, so the reaction mixture was poured into water and was extracted with DCM. The organics were then concentrated. Purification of the crude residue by column chromatography (0-100% EtOAc/heptane) gave 3-(2-bromo-5-(trifluoromethyl)phenyl)pyridine (5.150 g, 17.05 mmol, 69.8% yield) as a yellow solid. m/z (ESI) 303.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[Na].[C:8](OCC)(=[O:17])[CH2:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=O.C(O)(=O)C>O>[CH2:15]([O:14][C:12]([C:10]1[C:6]2[CH:5]=[N:4][NH:3][C:2]=2[N:1]=[C:8]([OH:17])[CH:9]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: Nc1cc[nH]n1
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(O)nc2[nH]ncc12
Temperature: 85 °C
Yield: 28.4 %

Procedure:
To a solution of 3-aminopyrazole (224 g, 2.7 mol) in water (1 L) were added a solution of diethyl oxalacetate sodium salt (567 g, 2.7 mol) in water (1.3 L) and then acetic acid in 4 portions (0.8 L). The reaction mixture was heated at 85° C. for 15 hours then cooled to room temperature and filtered. The precipitate was washed with water and then dried to afford the title compound as an orange solid (159 g, 28%). 1H NMR (250 MHz, DMSO): δ 1.35 (t, 3H), 4.36 (q, 2H), 6.69 (s, 1H), 8.16 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]([CH3:32])([CH3:31])[CH2:9][NH:10][CH:11]([C:14]1[N:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](=[O:27])[C:17]2=[CH:28][CH:29]=[CH:30][N:16]2[N:15]=1)[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1.CCN(CC)CC>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]([CH3:32])([CH3:31])[CH2:9][N:10]([CH:11]([C:14]1[N:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](=[O:27])[C:17]2=[CH:28][CH:29]=[CH:30][N:16]2[N:15]=1)[CH2:12][CH3:13])[C:39](=[O:40])[C:38]1[CH:42]=[CH:43][C:35]([Cl:34])=[CH:36][CH:37]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(NCC(C)(C)NC(=O)OC(C)(C)C)c1nn2cccc2c(=O)n1Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(CC(C)(C)NC(=O)OC(C)(C)C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.8 %

Procedure:
{2-[1-(3-Benzyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-propylamino]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (70 mg, 0.15 mmol) and 4-chlorobenzoylchloride (81.0 mg, 0.463 mmol) in CHCl3 (20 mL) was treated with Et3N (20.8 mg, 0.385 mmol). The reaction mixture was stirred at 25° C. for 18 h then concentrated under vacuum. The residue was and purified by preparative HPLC using a YMC S10 ODS 30×100 mm column to afford the desired material (52.2 mg, 57%) as a white powder: 1H NMR (CD3OD, 400 MHz) δ 7.55 (s, 1H), 7.45 (m, 5H), 7.08 (m, 1H), 6.67 (m, 1H), 5.87 (m, 1H), 3.93 (m, 1H), 3.72 (m, 1H), 3.48 (m, 1H), 3.30 (s, 1H), 1.81 (m, 1H), 1.38 (s, 9H), 1.17 (m, 3H), 0.90 (m, 3H), 0.54 (m, 3H); LC/MS (ESI+) 592 (M++H).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([CH2:8][CH3:9])=[CH:4][N:3]=1.[OH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(O)(C)C>[CH2:8]([C:5]1[N:6]=[CH:7][C:2]([N:14]2[CH2:15][CH2:16][CH:11]([OH:10])[CH2:12][CH2:13]2)=[N:3][CH:4]=1)[CH3:9]
Reactant: CCc1cnc(Br)cn1
Reactant: OC1CCNCC1
Solvent: CC(C)O
Product: CCc1cnc(N2CCC(O)CC2)cn1
Temperature: 150 °C

Procedure:
A mixture of 2-bromo-5-ethyl-pyrazine (1.66 g) and 4-hydroxy-piperidine (2.24 g) in isopropanol (15 mL) is heated to 150° C. overnight in an autoclave. After cooling to room temperature the solvent is evaporated in vacuo and water and dichloromethane are added. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound. LC (method 1): tR=0.66 min; Mass spectrum (ESI+): m/z=208 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH2:42]([NH:49][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 636.4 %

Procedure:
Combined 6-chloronicotinic acid (20 g, 12.74 mmol) and HATU (72.6 g, 19.1 mmol) in DMF (200 mL) and added triethylamine (38.6 g, 38.2 mmol) drop wise, followed by benzylamine (16.36 g, 15.28 mmol) and stirred at room temperature overnight. Then the reaction mixture was poured into ice-water and stirred for 20 minutes to give a solid. The solid was collected by filtration, washed with water (30 mL×2), and dried under reduced pressure to give the title compound (20 g, 64%) as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([S:6]([NH2:9])(=[O:8])=[O:7])[C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:9][S:6]([C:4]2[C:3]3[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=3[S:1][CH:5]=2)(=[O:7])=[O:8])=[O:23])=[CH:17][CH:16]=1
Reactant: NS(=O)(=O)c1csc2ccccc12
Reactant: O=C=Nc1ccc(Cl)cc1
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1csc2ccccc12
Yield: 46.9 %

Procedure:
3-Benzo[B]thiophenesulfonamide (6.4 mmol) was reacted with 4-chlorophenylisocyanate (6.4 mmol) as described in Method A to obtain 1.1 g of the title product as a solid. 1H NMR (CD3SOCD3): δ10.94 (bs, 1 H), 8.99 (s, 1 H), 8.75 (s, 1 H), 8.27 (d, J =8 Hz, 1 H), 8.16 (d, J =8 Hz, 1 H), 7.60 (dd, J =8, 8 Hz, 1 H), 7.53 (dd, J =8, 8 Hz, 1 H), 7.38 (d, J =9 Hz, 2 H), 7.31 (d, J =9 Hz, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)(=[O:7])=[O:6].Cl.CCN(CC)CC.[C:27](Cl)(=[O:29])[CH3:28]>C(Cl)Cl>[Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:27](=[O:29])[CH3:28])[CH2:10][CH2:9]1)(=[O:6])=[O:7]
Reactant: CC(=O)Cl
Reactant: NC1CCN(S(=O)(=O)Cc2ccccc2Br)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1CCN(S(=O)(=O)Cc2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a mixture of 1-(2-bromobenzylsulfonyl)piperidin-4-amine.HCl (200 mg, 0.54 mmol) and Et3N (164 mg, 1.62 mmol) in dry DCM (20 mL) was added acetyl chloride (85 mg, 1.1 mmol) drop-wise at rt. The reaction mixture was stirred at rt for 2 hours before concentrating to dryness and purifying the residue by HPLC to give the title compound (180 mg, 89%). MS (ESI): mass calcd. for C14H19BrN2O3S, 374.03; m/z found, 374.8 [M+H]+.
Reaction SMILES: [N:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[CH2:14][CH2:15][N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]3=[N:11][C:4]=1[CH:5]=[N:6]2.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:36].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[NH2:36][C:5]1[C:4]2[N:11]=[C:12]3[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:14][N:13]3[C:3]=2[C:2]2[C:7](=[CH:8][CH:9]=[CH:10][N:1]=2)[N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c1nc1cnc3cccnc3c12
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCn2c1nc1c(N)nc3cccnc3c12
Reaction time: 2 h

Procedure:
A solution of tert-butyl 9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c][1,5]naphthyridine-8-carboxylate (1 g, 3 mmol) in dichloromethane (100 mL) was treated with MCPBA (1 g, 77% purity), and the reaction was stirred for two hours. Analysis by LC/MS indicated the presence of starting material, and additional MCPBA (1 g) was added. The next day, the reaction cooled in an ice bath and was treated with 100 mL of concentrated ammonium hydroxide. The reaction was stirred for several minutes, and then p-toluenesulfonyl chloride (730 mg, 3.8 mmol) was added. The reaction was stirred for several minutes, removed from the ice bath, and stirred for three hours at room temperature. Water was added, and the mixture was extracted with dichloromethane. The combined organic fractions were purified by automated flash chromatography on silica gel (eluting with a gradient of 2% ammonium hydroxide methanol as the polar component in dichloromethane). The resulting oil was triturated in diethyl ether to provide a yellow solid, which was isolated by filtration to provide 0.64 g of tert-butyl 6-amino-9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c][1,5]naphthyridine-8-carboxylate.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:15]CC2C=CC(OC)=CC=2OC)[C:5]([NH:8][CH2:9][C:10](OCC)=[O:11])=[N:6][CH:7]=1.CO.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[Br:1][C:2]1[N:3]=[C:4]2[NH:15][C:10](=[O:11])[CH2:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1NCc1ccc(OC)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C1CNc2ncc(Br)nc2N1
Temperature: 75 °C
Yield: 96 %

Procedure:
Ethyl 2-(5-bromo-3-(2,4-dimethoxybenzylamino)pyrazin-2-ylamino)acetate (0.484 g, 1.138 mmol), methanol (0.461 mL, 11.38 mmol) and TFA (7 mL) were combined in a sealable vessel with a stirbar. The system was purged with nitrogen. The resulting mixture was sealed, stirred vigorously and heated at 75° C. in an oil bath for 25 min. The resulting mixture was diluted with water (14 mL) and stirred at room temperature for 5 min. Solids were collected by vacuum filtration, washed with water and diethyl ether and dried under high vacuum to give the desired product (0.375 g, 1.093 mmol, 96% yield) as a pink solid. MS (ESI) m/z 229.0 [M]+, 231.3 [M+2]+.
Reaction SMILES: [SiH3:1][SiH2:2][SiH2:3][SiH2:4][SiH2:5][SiH2:6][SiH2:7][SiH2:8][SiH2:9][SiH2:10][SiH2:11][SiH2:12][SiH2:13][SiH2:14][SiH2:15][SiH3:16].[F:17][C:18]([F:24])([F:23])[S:19]([OH:22])(=[O:21])=[O:20]>ClCCl>[F:17][C:18]([F:24])([F:23])[S:19]([O:22][SiH2:16][SiH2:15][SiH2:14][SiH2:13][SiH2:12][SiH2:11][SiH2:10][SiH2:9][SiH2:8][SiH2:7][SiH2:6][SiH2:5][SiH2:4][SiH2:3][SiH2:2][SiH2:1][O:22][S:19]([C:18]([F:24])([F:23])[F:17])(=[O:21])=[O:20])(=[O:21])=[O:20]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: [SiH3][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH3]
Solvent: ClCCl
Product: O=S(=O)(O[SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2]OS(=O)(=O)C(F)(F)F)C(F)(F)F

Procedure:
In an argon atmosphere, to a tetrahydrofuran solution (1 ml) of 68 mg (0.20 mmol) of octaethylcyclotetrasilane was added 0.72 ml (0.20 mmol) of a tetrahydrofuran solution (0.26M) of phenyldimethylsilyllithium, and stirred at 0° C. for 15 minutes. Then, tetrahydrofuran was distilled out under vacuum, and hexane (1 ml) was added to give a hexane solution (Solution 1). A dichloromethane solution (1 ml) of 71 mg (0.05 mmol) of hexadecasilane (6) obtained in Example 6 was treated with 15 mg (0.10 mmol) of trifluoromethanesulfonic acid at room temperature for 30 minutes to give 1,16-bis(trifluoromethanesulfonyloxy)hexadecasilane. Then, dichloromethane was distilled out under vacuum, and hexane (1 ml) was added to afford a hexane solution (Solution 2). The Solution 1 was added to the Solution 2 at -78° C., and stirred for 15 minutes. Methanol (0.1 ml) and triethylamine (0.1 ml) were added, then saturated aqueous sodium bicarbonate solution (2 ml) was added, stirred, the hexane layer was separated, and dried with magnesium sulfate. The resulting crude product was purified by a silica gel column (hexane) chromatography to give 46 mg (36% yield) of hexacosasilane (7) as a colorless crystal.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.[C:34](O)(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[N:38]1[CH:39]=[CH:40][C:35]([C:34]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][CH:10]3[O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[CH:5][CH:4]=2)=[O:41])=[CH:36][CH:37]=1
Reactant: O=C(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(=O)c3ccncc3)cc2)C(OCc2ccc3ccccc3c2)C1
Yield: 20.9 %

Procedure:
A solution of 60 mg (0.13 mmol) of tert-butyl (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine--carboxylate, 16 mg (0.13 mmol) of isonicotinic acid, 34 mg (0.26 mmol) of ethyidiisopropylamine and 58 mg (0.13 mmol) of benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP) in 5 ml of acetonitrile was stirred at room temperature for 2 hours. Subsequently, the reaction mixture was evaporated under reduced pressure and the residue, without further working-up, was chromatographed on silica gel using a 3:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 15 mg (21% of theory) of (3RS,4RS)-4-(1-tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-benzyl pyridine-4-carboxylate as a colourless solid; MS: 552 (M)+.