Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH3:30][S:31]([N:34]1[CH2:39][CH2:38][NH:37][C:36]([CH3:41])([CH3:40])[CH2:35]1)(=[O:33])=[O:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:40][C:36]1([CH3:41])[CH2:35][N:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:39][CH2:38][N:37]1[CH2:18][C:13]1[N:14]([CH3:17])[C:15]2[C:11]([N:12]=1)=[C:10]([N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)[N:9]=[C:8]([N:7]1[C:6]3[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=3[N:4]=[C:3]1[CH2:1][CH3:2])[N:16]=2
Reactant: CC1(C)CN(S(C)(=O)=O)CCN1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(S(C)(=O)=O)CC3(C)C)n(C)c2n1
Reaction time: 17 h
Yield: 12.7 %

Procedure:
A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (167 mg, 0.43 mmol), 1-methanesulfonyl-3,3-dimethylpiperazine (100 mg, 0.52 mmol) and molecular sieves (4 Å, powdered, 830 mg) in DCE (10 mL) was stirred at ambient temperature for 5 h. Sodium triacetoxyborohydride (136 mg, 0.64 mmol) was added and the mixture stirred for 17 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH, 100:0 to 99:1 to 98:2 to 95:5) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 51:49 to 49:51) to afford 596 as a cream foam (31 mg, 13%). LCMS (method I): RT=3.42 min, M+H+=568. 1H NMR (CDCl3, 400 MHz) δ 8.01 (m, 1 H), 7.77 (m, 1 H), 7.26 (m, 2 H), 4.34 (m, 4 H), 3.87 (m, 9 H), 3.36 (q, J=7.5 Hz, 2 H), 3.16 (m, 2 H), 3.02 (s, 2 H), 2.77 (s, 3 H), 2.64 (m, 2 H), 1.46 (t, J=7.5 Hz, 3 H) and 1.29 (s, 6 H)
Reaction SMILES: C(O[C:5]([N:7]1[CH2:11][CH2:10][CH:9]([C:12]2[CH2:18][C@H:17]3[N:14]([C:15](=[O:22])[C@@H:16]3[C@H:19]([OH:21])[CH3:20])[C:13]=2[C:23]([O:25]CC=C)=[O:24])[CH2:8]1)=O)C=C.[C:29]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:30]=1.C(OCC)(=O)CCCCC.[Na]>O1CCCC1.C(O)C.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>[CH2:5]([N:7]1[CH2:11][CH2:10][CH:9]([C:12]2[CH2:18][C@H:17]3[N:14]([C:15](=[O:22])[C@@H:16]3[C@H:19]([OH:21])[CH3:20])[C:13]=2[C:23]([OH:25])=[O:24])[CH2:8]1)[CH:29]=[CH2:30]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C=CCOC(=O)C1=C(C2CCN(C(=O)OCC=C)C2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCCCCC(=O)OCC
Product: C=CCN1CCC(C2=C(C(=O)O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 267.5 %

Procedure:
To a solution of allyl (5R,6S)-3-(1-allyloxycarbonylpyrrolidin-3-yl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.24 g) in a mixture of tetrahydrofuran (20 ml) and ethanol (5 ml) were added triphenylphosphine (0.16 g), sodium 2-ethyl hexanoate (1.1 g), and tetrakis(triphenylphosphine)palladium(0) (0.37 g). After stirring at ambient temperature for 1 hour, the reaction mixture was washed with dichloromethane, and evaporated in vacuo. The residue was chromatographed on nonionic adsorption resin "Dialon HP-20" eluting with a mixture of water and acetonitrile (95:5, V/V). The fractions containing the desired compound were collected and lyophilized to give (5R,6S)-3-[1-allylpyrrolidin-3-yl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (500 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[C:7](=[NH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH2:18]([O:20][C:21](=[O:29])[CH:22](N)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:19]>N1C=CC=CC=1>[CH2:18]([O:20][C:21](=[O:29])[CH:22]([N:14]=[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]1[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:16])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:19]
Reactant: N=C(c1ccccc1)c1cc(Cl)ccc1O
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(N=C(c1ccccc1)c1cc(Cl)ccc1O)C(=O)OCC

Procedure:
A suspension of 9.2 g. of 5-chloro-2-hydroxy-benzophenone imine in 60 ml. of ehtanol is treated with 12.6 g. of aminomalonic acid diethyl ester hyrochloride and 5.0 ml. of pyridine and the mixture boiled at reflux for 1 hour while stirring. The mixture is then concentrated to dryness under reduced pressure and the residue partitioned between toluene and water. The organic phase is washed with water, briefly dried over sodium sulfate and evaporated to dryness. The residual oily residue crystallizes upon trituration with hexane. There is obtained [(5-chloro-2-hydroxy-α-phenylbenzyliden)amino] malonic acid diethyl ester, having a melting point of 55°-56° C. Recrystallization from ethanol yields gold-yellowish leaflets having the same melting point.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.[CH:17]1([C:20]2[CH:21]=[C:22]([CH3:41])[C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]([C:34]4[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=4)=[O:33])[CH2:28][CH2:27]3)=[N:24][CH:25]=2)[CH2:19][CH2:18]1>>[CH:17]1([C:20]2[CH:21]=[C:22]([CH3:41])[C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]([C:34]4[CH:39]=[CH:38][C:37]([N:11]5[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]5(=[O:15])=[O:16])=[CH:36][CH:35]=4)=[O:33])[CH2:28][CH2:27]3)=[N:24][CH:25]=2)[CH2:18][CH2:19]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3[C@H](CO)CCS3(=O)=O)cc2)CC1
Yield: 37.9 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (241 mg) described in Preparation Example 1 and [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (447 mg) described in Preparation Example 117 and by the reaction and treatment in the same manner as in Example 32, the title compound (178 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O>[Cl:27][CH2:28][C:29]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[CH:8]=[C:9]([CH2:12][O:13][CH3:14])[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:30]
Reactant: COCc1ccc(C)c(NCC=O)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COCc1ccc(C)c(N(CC=O)C(=O)CCl)c1
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-methyl-5-methoxymethylanilino)acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0° C. and α-chloroacetyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2-methyl-5-methoxymethylanilino)-acetaldehyde.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23](Cl)=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=[N:26]2)=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl>[Br:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([NH:17][CH2:16][C:13]3[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:11][CH:12]=3)=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=[N:26]2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(CNc2c([N+](=O)[O-])cnc3cc(Br)ccc23)cc1
Reaction time: 16 h
Yield: 93.4 %

Procedure:
1-(N-BOC-aminomethyl)-4-(aminomethyl)benzene (5.0 g, 21 mmol) in dichloromethane (50 mL) was added dropwise to a mixture of 7-bromo-4-chloro-3-nitroquinoline (5.81 g, 20 mmol) and triethylamine (5.63 mL) in dichloromethane (60 mL). The reaction was stirred for 16 hours and then washed sequentially with water and saturated aqueous sodium chloride. The organic fraction was dried over sodium sulfate, filtered and concentrated to provide a yellow crystalline solid. Recrystallization from 2-propanol yielded 9.1 g of tert-butyl {4-[(7-bromo-3-nitroquinolin-4-ylamino)methyl]benzyl}carbamate as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH2:17]([NH2:19])[CH3:18]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][CH2:17][CH3:18])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CCN
Product: CCNS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Reaction time: 16 h
Yield: 64.1 %

Procedure:
According to general procedure A, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and ethylamine (5 mL, 10.0 mmol, 2.0 M in THF) were stirred together for 16 hours. 4-bromo-N-ethyl-2-(trifluoromethoxy)benzenesulfonamide (0.23 g, 64%) was provided after purification. MS (ESI) m/z 348. HPLC purity 100.0% at 210-370 nm, 9.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH3:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][C@H:6]1[C:11]23[C:15](=[CH:16][C:17](=[O:18])[C@:9]([OH:20])([CH2:10]2)[CH2:8][C@H:7]1[CH2:21][C:22]([C@H:24]([OH:35])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:23])[NH:14][CH2:13][C@@H:12]3[OH:19].N1C=CC=CC=1.C(OC(=O)C)(=O)C>CS(C)=O>[CH3:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][C@H:6]1[C:11]23[C:15](=[CH:16][C:17](=[O:18])[C@:9]([OH:20])([CH2:10]2)[CH2:8][C@H:7]1[CH2:21][C:22]([C@@H:24]([OH:35])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:23])[NH:14][CH2:13][C@@H:12]3[OH:19]
Reactant: CC/C=C\C[C@@H]1[C@H](CC(=O)[C@H](O)CCCCCCCC(=O)O)C[C@@]2(O)CC13C(=CC2=O)NC[C@@H]3O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: CC/C=C\C[C@@H]1[C@H](CC(=O)[C@@H](O)CCCCCCCC(=O)O)C[C@@]2(O)CC13C(=CC2=O)NC[C@@H]3O
Yield: 88 %

Procedure:
To 20 g of FN-1 in 1 L of DMSO, was added 20 ml of dehydrated pyridine and 1 L of acetic anhydride. The solution was allowed to react for 12 hours. The solution was then allowed to settle and the supernatant fluid was removed by decantation. The residual solution containing a solid on the bottom of the beaker was added to a large amount of doubly distilled, deionized water. Next, the solid was filtered, washed with deionized water three times, and then dried to obtain 25 g of a solid of FN-2 (yield: 88%). 3 g of this FN-2 was dissolved in 100 ml of dimethyl sulfoxide, and the solution was poured in a tray and then dried at 60° C. After 12 hours, the polymer was removed to obtain a free standing film.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1.[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O>>[CH3:1][O:2][C:3]1[N:4]=[C:5]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1cccc(C)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1ccc([N+](=O)[O-])c(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.6 %

Procedure:
A mixture of 2-methoxy-6-methylpyridine (49.15 g, 0.292 mol) and nitric acid (76.0 mL, 0.292 mol) was added dropwise sulfuric acid (177.0 mL, 0.876 mol) at 0° C. The reaction mixture was stirred at room temperature for 1 hr. The mixture was poured into ice-water. The precipitate was collected by filtration and washed with water to give the title compound as a pale yellow solid (53.37 g, 0.317 mol, quant.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].Cl.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19]Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: ClCc1ccccn1
Reactant: Sc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Clc1ccc(SCc2ccccn2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 128.5 %

Procedure:
3,4-Dichlorobenzenethiol (5 g) was added to a solution of sodium hydroxide (2.25 g) in ethanol (50 ml) and the resulting solution was treated with 2-picolyl chloride, hydrochloride (4.6 g) in ethanol (25 ml). After stirring for 4 hours at ambient temperature the mixture was filtered and the solvent removed by evaporation. The residue was converted into the hydrochloride with ethereal HCl and this was recrystallised from ethanol/ether to give 2-(((3,4-dichlorophenyl)thio)methyl)pyridine, hydrochloride (5.5 g) mp 213°-4° C. (Found: C,46.7; H,3.3; N,4.4 C12H9Cl2NS.HCl requires C,47.0; H,3.3; N,4.6%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]([OH:15])=[O:14])[C@H:10]([C:16]([OH:18])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.[Cl:48][C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([C:16](=[O:18])[NH:53][C:52]2[CH:54]=[CH:55][C:49]([Cl:48])=[CH:50][CH:51]=2)[C@H:11]([C:13]([OH:15])=[O:14])[CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](C(=O)O)C1
Reactant: Nc1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](C(=O)Nc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 1c (2.25 g; 9 mmol) is suspended in acetonitrile (30 ml) and N,N-diisopropyl ethyl amin (3.03 ml; 17 mmol) is added at 25° C. After 20 min a clear solution is obtained and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDCI (2.0 g; 10 mmol) and 1-hydroxybenzotriazole HOBt (1.41 g; 10 mmol) is added. After stirring for 30 min at 25° C. 4-chloroaniline (1.11 g; 9 mmol) is added to the reaction mixture. The mixture is stirred for 18 h at 25° C., evaporated to dryness and dissolved in ethyl acetate (100 ml). The organic phase is washed with 0.1 N HCl (2×100 ml), water and brine and dried over Na2SO4. The organic phase is filtered and the filtrate is evaporated to dryness. Yield: 1.08 g (33.7%), ESI-MS: m/z=368 [M−H]−, Cl-pattern
Reaction SMILES: F.F.F.C(N(CC)CC)C.[C:11]([O:14][C@H:15]1[C@@H:19]([NH:20][C:21]([CH2:23][C:24]2[C:36]3[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]=3[CH:27]=[CH:26][CH:25]=2)=[O:22])[C@H:18]([CH2:37][O:38][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[O:17][C@@H:16]1[N:56]1[CH:64]=[N:63][C:62]2[C:57]1=[N:58][CH:59]=[N:60][C:61]=2[Cl:65])(=[O:13])[CH3:12]>O1CCCC1>[C:11]([O:14][C@H:15]1[C@@H:19]([NH:20][C:21]([CH2:23][C:24]2[C:36]3[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]=3[CH:27]=[CH:26][CH:25]=2)=[O:22])[C@H:18]([CH2:37][OH:38])[O:17][C@@H:16]1[N:56]1[CH:64]=[N:63][C:62]2[C:57]1=[N:58][CH:59]=[N:60][C:61]=2[Cl:65])(=[O:13])[CH3:12]
Reactant: CC(=O)O[C@H]1[C@@H](NC(=O)Cc2cccc3c2Cc2ccccc2-3)[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@@H]1n1cnc2c(Cl)ncnc21
Agent: F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1[C@@H](NC(=O)Cc2cccc3c2Cc2ccccc2-3)[C@H](CO)O[C@@H]1n1cnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Triethylamine trihydrofluoride (1.6 mL, 9.82 mmol) was added to a stirring solution of 7 (1.54 g, 1.95 mmol) in anhydrous tetrahydrofuran (20 mL) at rt, and the resulting solution was stirred at rt for 24 h, then tlc-grade silica gel was added and volatiles were removed under reduced pressure. The residue was loaded on a tlc-grade silica gel column packed with dichloromethane and eluted with a gradient of dichloromethane to 1:19 methanol/dichloromethane to give 8 as a white solid, containing minor impurities (1.00 g, 93%). A small sample was purified by preparative silica gel tlc (1:19 methanol/dichloromethane) to give pure 8 as a white solid. Rf 0.16 (1:19 methanol/dichloromethane); mp 196-197° C.; [α]D22 +35.78 (c 0.34, CHCl3); UV (MeOH) λmax 264.0, 299.5, 288.5; 1H NMR (CDCl3, 400 MHz) δ 8.77 (s, 1H), 8.42 (s, 1H), 7.79-7.75 (m, 2H), 7.59-7.57 (m, 2H), 7.44-7.38 (m, 2H), 7.35-7.29 (m, 2H), 6.22 (d, J=2.2 Hz, 1H), 5.54-5.52 (m, 1H), 5.20 (d, J=8.0 Hz, 1H), 4.87-4.82 (m, 1H), 4.60-4.49 (m, 2H), 4.29-4.19 (m, 3H), 4.00 (d, J=12.0 Hz, 1H), 3.76 (d, J=12.0 Hz, 1H), 2.11 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 169.5, 156.1, 151.8, 151.3, 150.5, 144.5, 143.4, 141.2, 132.2, 127.7, 126.9, 124.6, 119.9, 88.7, 84.3, 75.5, 66.7, 61.1, 50.5, 47.0, 20.5; Mass ([M+H]+) 550, ([M+Na]+) 572. Anal. Calcd for C27H24ClN5O6: C, 58.97; H, 4.40; N, 12.73. Found: C, 59.05; H, 4.62; N, 12.33.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>COCCOC>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:13][CH2:12][CH2:11][O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: OCCOCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)OCCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
To a slurry of sodium hydride (0.4 g,17 mmol) in 20 ml ethylene glycol dimethyl ether cooled with an ice bath under an atmosphere of nitrogen, a solution of 2-benzyloxyethanol (2.1 ml,15 mmol) and p-toluene sulfonyl chloride (2.9 g,15 mmol) in ethylene glycol dimethyl ether was added dropwise. When the addition was complete, the ice bath was removed and the solution stirred at room temperature for 18 hours. After dilution with diethyl ether, the resulting slurry was filtered through anhydrous magnesium sulfate and concentrated under vacuum to yield 3.6 g of crude 2-benzyloxyethyl p-toluenesulfonate.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[NH:16]C2C=CC=CC=2)[N:3]=1.NCCCN1CC[O:30]CC1>CC(O)C.CO>[NH2:16][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2](=[O:30])[NH:3]2
Reactant: Clc1nc2nccc(Nc3ccccc3)c2c2ccccc12
Reactant: NCCCN1CCOCC1
Solvent: CO
Solvent: CC(C)O
Product: Nc1ccnc2[nH]c(=O)c3ccccc3c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
(6-Chloro-benzo[c][1,8]naphthyridin-1-yl)-phenyl-amine (25 mg, 0.08 mmol) and N-(3-aminopropyl)morpholine (18 mg, 0.12 mmol) were dissolved in iPrOH (2 mL), and stirred overnight at 100° C. The reaction mixture was diluted with MeOH, filtered through a membrane, and purified via prep-LC-MS. The purified product was converted to the HCl salt via dissolving in methanolic HCl, and concentration on the Genevac to provide 141 (5 mg, 12% yield) as a dark solid. LC-MS (M+H=414, obsd.=414). 1H NMR (400 MHz, d6-DMSO): δ 10.32 (s, 1H), 9.31 (t, 1H), 8.87 (d, 1H), 8.58 (d, 1H), 8.09 (t, 1H), 7.89 (t, 1H), 7.80 (t, 1H), 7.49 (m, 2H), 7.40 (d, 2H), 7.32 (t, 1H), 6.90 (d, 1H), 3.95 (d, 2H), 3.86 (d, 2H), 3.75 (m, 2H), 3.46 (m, 2H), 3.28 (m, 2H), 3.08 (m, 2H), 2.22 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([NH:21][O:22]C3CCCCO3)=[O:20])=[CH:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1>CO.O>[CH3:29][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([NH:21][OH:22])=[O:20])=[CH:13]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1
Solvent: O
Solvent: CO
Product: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NO)c2)cc1

Procedure:
The method used for preparation of this compound is analogous to the method described for compound 2. Starting materials: (E)-3-[1-(4-dimethylamino-benzene sulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (compound A4) (0200 g), methanol/water 3/2 (50 ml), amberlyst IR15 (0.402 g).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[N+:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1)([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([C:1]([OH:7])([C:15](=[O:16])[C:14]2[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:19][CH:18]=2)[CH2:2][O:3][CH2:4][CH2:5][OH:6])=[O:16])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: OCCOCCO
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: O=C(c1ccc([N+](=O)[O-])cc1)C(O)(COCCO)C(=O)c1ccc([N+](=O)[O-])cc1
Yield: 83.3 %

Procedure:
Diethylene glycol (31.8 g, 0.3 mole) and p-nitrobenzoyl chloride (116 g, 0.62 mole) were reacted under the conditions described in Example 1, Part A. The product was crystallized from ethyl acetate to give bis-(4-nitrobenzoyl)-diethylene glycol (101 g) as a pale yellow solid, m.p. 100°-102° C. The product was homogeneous by TLC.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[OH:8][C@@H:9]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:25]2[C:24](=[O:30])[CH2:23][C@@:22]2([CH3:31])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:19](=[O:21])[CH3:20])[CH2:10]1.N1C=CC=CC=1>O1CCCC1>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([O:8][C@@H:9]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:25]2[C:24](=[O:30])[CH2:23][C@@:22]2([CH3:31])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:19](=[O:21])[CH3:20])[CH2:10]1)=[O:4]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(=O)C(Cl)(Cl)Cl)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
A solution of trichloroacetyl chloride (0.5 ml.) in dry tetrahydrofuran (8 ml.) was added dropwise to a cooled (-80°) and stirred solution of 3α-hydroxy-5α-pregnane-11,20-dione (0.75 g.) and pyridine (0.35 ml.) in dry tetrahydrofuran (15 ml.). After 30 min. the mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with 2N-hydrochloric acid, aqueous sodium hydrogen carbonate, then water. The solution was dried and concentrated to leave a residue which was crystallised from benzene then benzene-petrol to afford the title compound (0.21 g.), m.p. 126°-127°, [α]D + 86°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].C(Cl)(Cl)Cl>[N:23]1([NH:22][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: NN1CCOCC1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccccc2c1NN1CCOCC1
Reaction time: 15 h

Procedure:
A solution of 4-chloro-3-nitroquinoline (5.00 g, 24.0 mmol) in 100 mL of CH2Cl2 was treated with triethylamine (6.37 mL, 48.0 mmol) and 4-aminomorpholine (3.47 mL, 36.0 mL) under an atmosphere of nitrogen. After 15 h, the reaction mixture was diluted with 5% Na2CO3 solution and CHCl3, and the phases were separated. The organic portion was washed with another portion of 5% Na2CO3 solution, water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield a bright yellow solid. Recrystallization from acetonitrile gave N-(morpholin4-yl)(3-nitroquinolin-4-yl)amine (4.54 g) as bright yellow needle-like crystals.