Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1([O:25][C@H:24]([CH2:26][O:27]CC2C=CC=CC=2)[C@@H:15]([O:16]CC2C=CC=CC=2)[C@@H:6]1[O:7]CC1C=CC=CC=1)[CH2:4][OH:5]>CO.C(O)(=O)C.[Pd]>[OH:1][CH2:2][C:3]1([O:25][C@H:24]([CH2:26][OH:27])[C@@H:15]([OH:16])[C@@H:6]1[OH:7])[CH2:4][OH:5]
Reactant: OCC1(CO)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: OC[C@H]1OC(CO)(CO)[C@@H](O)[C@@H]1O

Procedure:
In accordance with Flowchart G, 2,5-anhydro-2-C-(hydroxymethyl)-3,4,6-tris-O-(phenylmethyl)-D-glucitol 42 is hydrogenated in methanol/acetic acid over palladium on carbon, giving 2,5-anhydro-2-C-(hydroxymethyl)-D-glucitol 51, which is treated with copper sulfate and sulfuric acid in acetone, then neutralized, giving 2,5-anhydro-2-C-(hydroxymethyl)-21,3-O-(1-methylethylidene)-D-glucitol 52. Compound 52 is reacted with diphenyl phosphorochloridate in pyridine at reduced temperature, giving 2,5-anhydro-2-C-[[(diphenoxyphosphinyl)oxy]methyl]-1,3-O-(1-methylethylidene)-D-glucitol, 6-(diphenyl phosphate) 53, which is then treated with 80% aqueous acetic acid at 80° C., giving 2,5-anhydro-2-C-[[(diphenoxyphosphinyl)oxy]methyl]-D-glucitol, 6-(diphenyl phosphate) 54. Substitution of other esterifying agents as described in Flowchart A will result in the corresponding tetraesters. Compound 53 is hydrogenated in methanol over platinum oxide, giving directly the product 2,5-anhydro-2-C-[(phosphonooxy)methyl]-D-glucitol, 6-(dihydrogen phosphate) 55. Compound 54 may be hydrogenated under the same conditions, giving 55. ##STR20##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+]>C(O)C.O>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)O
Yield: 101.4 %

Procedure:
A solution of diethyl[4-(2,6-dichlorobenzyloxy)benzyl]malonate (3.02 g, 7.1 mmol) in ethanol (70 mL) with potassium hydroxide (0.48 g, 7.4 mmol) was stirred at room temperature for 18 h. The reaction mixture was diluted with water (100 mL) then concentrated to half the original volume in vacuo. The resulting aqueous solution was washed with ether then acidified with 3N HCl and the product extracted into ethyl acetate. The organic extract was washed with water then brine and dried (Na2SO4). Removal of solvent in vacuo afforded the title compound (2.86 g, 100%)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:24]([NH:26][C:27](=[O:33])[N:28]([CH2:30][CH2:31][CH3:32])[NH2:29])[CH3:25]>C1COCC1>[CH2:24]([NH:26][C:27](=[O:33])[N:28]([CH2:30][CH2:31][CH3:32])[NH:29][C:6](=[O:8])[C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[CH3:25]
Reactant: CCCN(N)C(=O)NCC
Reactant: O=C(O)c1ccsc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(NC(=O)c1ccsc1)C(=O)NCC
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 2.62 g (20.5 mmol) of thiophene-3-carboxylic acid and 2.8 mL (20.0 mmol) of triethylamine in 20 mL of THF was cooled to 5° C. and 2.6 mL (20.0 mmol) of isobutyl chloroformate was added dropwise over 5 minutes. The mixture was stirred at 5° C. for 5 minutes and added to a suspension of the 4-ethyl-2-propyl semicarbazide prepared above in 20 mL of THF at 5° C. This mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated to remove most of the solvent, taken up in 75 mL of water and extracted with two 100 mL portions of ethyl acetate. The combined ethyl acetate extracts were washed with 50 mL of 5% aqueous HCl and 50 mL of saturated aqueous sodium bicarbonate (NaHCO3), and dried over MgSO4. Removal of the solvent left 5.30 g of crude 4 -ethyl-2-propyl-1-(3-thenoyl) semicarbazide as an oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=2)=[O:16])=[CH:7][CH:6]=1.N>>[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([C:17]2[CH:22]=[C:21]([N+:1]([O-:4])=[O:2])[C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=2)=[O:16])=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)c2ccnc3ccccc23)ccc1O
Agent: N
Product: COc1cc(C(=O)c2ccnc3ccccc23)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
0.37 ml of 65 percent nitric acid is added dropwise at room temperature to 1.3 g of 4-hydroxy-3-methoxyphenyl 4-quinolyl ketone. After stirring for 3 hours the reaction mixture is poured into ice-water, adjusted to pH 6 with conc. ammonia and the precipitate formed is filtered. The thus-obtained residue is heated under reflux in 20 ml of acetonitrile, whereupon the crystals are filtered at 0°. There is obtained 4-hydroxy-3-methoxy-5-nitrophenyl 4-quinolyl ketone of m.p. 246°-248°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)#[N:2].C(N(CC)CC)C.ClC(OCC)=O.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([NH:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1)=[O:12])#[N:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: N#Cc1cccc(OCCCC(=O)O)c1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)CCCOc2cccc(C#N)c2)cc1
Reaction time: 0.03 h

Procedure:
100 mg (0.49 mmol) of 4-(3-cyanophenoxy)butyric acid and 50 mg (0.49 mmol) of triethylamine were stirred in dimethylformamide under cooling with ice. 53 mg (0.49 mmol) of ethyl chloroformate was added to the resultant mixture. After stirring for 2 minutes, 58 mg (0.49 mmol) of p-aminobenzonitrile was added to the reaction mixture. The temperature was elevated to room temperature, and they were stirred overnight. 1 N hydrochloric acid was added to the reaction mixture. After the extraction with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate solution and then with saturated aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the crude title compound.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.Br[CH2:14][CH2:15][CH2:16][C:17]#[N:18]>C(#N)C>[O:10]1[CH2:11][CH2:12][N:7]([CH2:14][CH2:15][CH2:16][C:17]#[N:18])[CH2:8][CH2:9]1
Reactant: N#CCCCBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.2 %

Procedure:
To a suspension of K2CO3 (8.28 g, 60 mmol) and morpholine (4.35 g, 50 mmol) in acetonitrile (50 mL) was added 4-bromobutyronitrile (7.40 g, 50 mmol) dropwise at rt under N2. The mixture was stirred at rt for 6 h, filtered and concentrated in vacuo to give the title compound (7.26 g, 94.2%).
Reaction SMILES: [NH2:1][C@@H:2]([CH:34]([CH3:36])[CH3:35])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][C@H:6]1[C:21]([NH:23][C@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)=[O:22])=[O:4].[C:37]([N:44]([CH3:50])[C@H:45]([C:47](O)=[O:48])[CH3:46])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:40]([O:39][C:37]([N:44]([CH3:50])[C@@H:45]([CH3:46])[C:47]([NH:1][C@@H:2]([CH:34]([CH3:36])[CH3:35])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][C@H:6]1[C:21]([NH:23][C@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)=[O:22])=[O:4])=[O:48])=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)[C@H](N)C(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Yield: 88.5 %

Procedure:
Amine 5 (12.57 g, 25.5 mmol) is then coupled with BOC-N-methyl-L-alanine (5.18 g, 25.5 mmol) using DIEA (22.3 mL, 0.13 mol), HBTU (10.64 g, 28.1 mmol) and HOBt (3.79 g, 28.1 mmol) in DMF (550 mL) under the same conditions as in step 1 above. Purification is carried out by flash chromatography on silica gel (CH2Cl2 as eluent initially, followed by 50% Et2O/CH2Cl2 to elute the desired product). The desired coupled product 6 is isolated as a white foam (15.30 g, 89% yield): 1H NMR δ (CDCl3) 7.28-7.38 (br m, 5H), 7.03-7.19 (br m, 4H), 6.73 (br s, 1H), 6.02-6.35 (br m, 1H), 5.05-5.26 (br m, 4H), 3.84-4.82 (br m, 5H), 2.68-3.56 (br m, 9H), 1.70-2.07 (br m, 5H), 1.47 (s, 9H), 0.60-1.33 (br m, 8H); LCMS (APCl+) 679.0 (MH+), 579.0 (MH+-BOC, 100%); HPLC(C18 column) 99.4%.
Reaction SMILES: [N+](C1C=CC([N:10]([C:14]2[C:19]([F:20])=[C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:17]=[C:16]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:15]=2)[C:11](=O)[O-:12])=CC=1)([O-])=O.[CH3:33][NH:34][C:35]1[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][CH:36]=1.C(O)(=O)C>C1COCC1>[F:20][C:19]1[C:14]([NH:10][C:11](=[O:12])[N:34]([CH3:33])[C:35]2[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][CH:36]=2)=[N:15][C:16]([O:27][CH2:28][C:29]([F:30])([F:32])[F:31])=[CH:17][C:18]=1[O:21][CH2:22][C:23]([F:25])([F:24])[F:26]
Reactant: O=C([O-])N(c1ccc([N+](=O)[O-])cc1)c1nc(OCC(F)(F)F)cc(OCC(F)(F)F)c1F
Reactant: CNc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C(=O)Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)c1F)c1ccc(Br)cc1
Reaction time: 288 h
Yield: 48.1 %

Procedure:
4-Nitrophenyl-3-fluoro-4,6-bis(2,2,2-trifluoroethoxy)pyridin-2-ylcarbamate (520 mg, 1.1 mmol) was dissolved in anhydrous THF (3 mL). To this solution was added N-methyl-4-bromoaniline (200 mg, 1.1 mmol). The reaction was allowed to stir for 12 d. The THF was evaporated and the crude material purified by reverse phase chromatography (HPLC grade CH3CN and H2O, both with 0.1% acetic acid) to afford the product as a tan solid (275 mg, 48% yield): mp 89-90° C.; 1H NMR (CDCl3) δ 8.78 (s, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.29 (d, J=8.8 Hz, 2H), 6.79 (d, J=4.7 Hz, 1H), 5.04-4.95 (q, J=8.8 Hz, 2H), 4.94-4.85 (q, J=9.1 Hz, 2H), 3.27 (s, 3H); ESI/MS 520, 522 (M+H), 518, 520 (M−H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OC(F)(F)F)[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1.[CH2:30]([Sn](CCCC)(CCCC)C#C)[CH2:31]CC>CN(C)C=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>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:30]#[CH:31])[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C#Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a degassed solution of 4-(6-bromo-4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (880 mg, 2 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) in N,N-dimethylformamide (50 mL), tributyl(ethynyl)tin (760 mg, 2.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (232 mg, 0.2 mmol) was added under argon. After being refluxed for 2 hours, the reaction mixture was concentrated in vacuo and the residue was portioned in a mixture of ethyl acetate (100 mL) and a saturated aqueous solution of potassium fluoride (100 mL). After the mixture being stirred vigorously for 1 hour, the separated aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 0.45 g of the crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28](=[CH2:31])[CH2:29][CH3:30])[C:5]2=[CH:4][CH:3]=1.[NH3:33]>>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH2:33])=[O:26])[CH:11]3[C:28](=[CH2:31])[CH2:29][CH3:30])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(CC)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: N
Product: C=C(CC)C1N(CC(N)=O)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 40 %

Procedure:
Racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.21 mmol) prepared in example 107a was stirred in a methanolic ammonia solution (7N, 10 mL) at room temperature for 18 h. The reaction mixture was concentrated, and the residue was purified by chromatography (EtOAc:MeOH=10:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-1′-[aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 41 mg, 40%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[N:6][C:7]([CH3:13])=[N:8]2.B(Br)(Br)Br.N>ClCCl>[OH:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[N:6][C:7]([CH3:13])=[N:8]2
Reactant: COc1cccc2nc(C)ncc12
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Cc1ncc2c(O)cccc2n1
Temperature: 20 °C
Reaction time: 0.01 h
Yield: 14.9 %

Procedure:
To a stirred solution of 5-methoxy-2-methylquinazoline (0.22 g, 1.26 mmol) in dichloromethane (20 mL) at 0° C. under argon was added a solution of boron tribromide in dichloromethane (1M, 3.8 mL), dropwise over 0.01 h. The resulting mixture was stirred at 20° C. for 48 h then poured into a mixture of ice (50 g) and 0.880 aqueous ammonia (50 mL) and stirred for 0.5 h. Organic phase was separated and aqueous phase washed with dichloromethane (3×30 mL). The aqueous phase was acidified (pH 6) with citric acid and the resulting mixture extracted with ethyl acetate (3×50 mL). The combined ethyl acetate extracts were dried (Na2SO4) and evaporated in vacuo to give the title compound (0.030 g, 15%) as an oil which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:31])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:25]1([CH:24]=[CH:23][C:22]([O:1][C:2]2[CH:14]=[CH:13][C:5]3[N:6]=[C:7]([S:9](=[O:11])(=[O:10])[NH2:12])[S:8][C:4]=3[CH:3]=2)=[O:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1nc2ccc(OC(=O)C=Cc3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (2.3 g., 0.01 mole), 4-dimethylaminopyridine (100 mg., catalyst) and triethylamine (1.4 ml., 0.01 mole) in dimethylformamide (20 ml.) is added cinnamoyl chloride (1.7 g., 0.01 mole). The reaction mixture is stirred at 25° C. for 2 hours and then poured into ice water and excess hydrochloric acid to give 3.5 g. of 2-sulfamoyl-6-benzothiazolyl 3-phenyl-2-propenoate which melts at 235°-235° C. after recrystallization from ethyl acetatehexane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][CH:9]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.CN([CH:21]=[O:22])C>C(Cl)Cl>[CH:21]([C:9]1[NH:10][CH:11]=[CH:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:22]
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2cc[nH]c2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(-c2cc[nH]c2C=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Following a standard procedure (Balasubramanian, T. et al, J. Org. Chem. 2000, 65, 7919-7929), a solution of 7 (472 mg, 3.00 mmol) in DMF (0.96 mL) and CH2Cl2 (30 mL) under argon was cooled to 0° C. and then POCl3 (340 μL, 3.60 mmol) was added dropwise. After 1 h, the flask was warmed to room temperature and stirred overnight (˜18 h). The reaction was quenched at 0° C. with 2.5 M NaOH (25 mL). The mixture was poured into water (50 mL), extracted with CH2Cl2, and the combined organic layers were washed with water, brine, dried (NaSO4), and concentrated. The residue was chromatographed [silica, CH2Cl2/ethyl acetate (9:1)] to give a brown solid. 1H NMR spectroscopy showed two regioisomers in ˜13:1 ratio. Cooling of the solution (ethyl acetate/hexanes) at ˜−16° C. resulted in precipitation of an orange solid, which proved to be a single regioisomer (354 mg, 64%): mp 149-150° C.; 1H NMR δ 2.41 (s, 3H), 6.42-6.44 (m, 1H), 7.10-7.13 (m, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 9.63-9.64 (m, 1H), 9.52-9.78 (br, 1H); 13C NMR δ 21.4, 111.6, 126.2, 128.9, 129.3, 129.7, 130.9, 137.7, 137.9, 180.2; FAB-MS obsd 186.0907, calcd 186.0919 (C12H11NO).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:22](Cl)(Cl)=[S:23]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]=[C:22]=[S:23])=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Nc1ccc(Oc2nccnc2Cl)cc1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: S=C=Nc1ccc(Oc2nccnc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(3-chloropyrazin-2-yloxy)benzenamine (620 mg, 2797 μmol) and sodium carbonate (652 mg, 6154 μmol) in chloroform (10 ml) was added thiophosgene (236 μl, 3077 μmol). The solution turned cloudy and was stirred overnight at room temperature. The solvent had evaporated so the residue was taken back up in chloroform and the solids were removed by filtration. The filtrate was collected and the solvent was removed by roto-vap to give the desired product as a brown solid which was used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[OH-:10].[Na+].O>CN1C(=O)CCC1>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:10][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([I:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(I)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Ic1ccc(COCc2ccc(I)cc2)cc1
Reaction time: 0.17 h

Procedure:
825 mg of PVA 13 kDa was dissolved in 55 ml of dry NMP under a nitrogen flow at 130° C. Then the temperature was decreased to 50° C. and 5 g of 4-monoiodobenzyl bromide was added. After 10 minutes, 1.35 g of dried sodium hydroxide was added. After 5 hours of reaction time, cold water was added and a paste material has appeared. The sticky paste could not be filtrated. Water was easily removed because the material was struck to the walls of the flask. After water was poured out, the pasty residue was washed with methanol and dried. After conventional steps of purification, MIB-PVA 13 kDa including residual NMP was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[C:3]1[C:11](OCC)=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:12][CH2:11][C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][N:9]=2
Reactant: CCOC(=O)c1cc2cccnc2n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(CO)cc2cccnc21
Yield: 106.5 %

Procedure:
A procedure similar to that described in Preparation 2 was repeated, except that 130 mg of ethyl 1-methyl-7-azaindole-2-carboxylate (prepared as described in Preparation 80), 23 mg of lithium aluminum hydride and 2 ml of tetrahydrofuran were used, to give 110 mg of the title compound having Rf=0.47 (on silica gel thin layer chromatography using a 3:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH3:29])[N:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:11]([CH3:30])[CH:10]=1)=[O:7])=O.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH:38][CH2:1][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH3:29])[N:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:11]([CH3:30])[CH:10]=1)=[O:7]
Reactant: CN(C)CCN
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccc(C=O)c3)cc2C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccc(CNCCN(C)C)c3)cc2C)n1
Reaction time: 16 h

Procedure:
To 3-formyl-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)benzamide (0.100 g, 0.23 mmol) in MeOH (6 mL) was added N1,N1-dimethylethane-1,2-diamine (0.13 mL, 1.1 mmol) and AcOH (0.010 mL, 0.23 mmol). The reaction was allowed to stir for 2.5 h, at which point sodium triacetoxyborohydride (0.096 g, 0.46 mmol) was added. After approximately 16 h, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate. The aqueous layer was extracted four times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a solid. Purification by reverse-phase HPLC using acetonitrile/water/TFA as eluent gave 3-((2-(dimethylamino)ethylamino)methyl)-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)benzamide as a white solid. MS m/z=512 [M+1]+. Calc'd for C29H33N7O2: 511.63.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH2:9]([NH2:12])[CH2:10][NH2:11].BrN1C(=O)CCC1=O.[OH-].[Na+]>C(Cl)Cl>[NH:11]1[CH2:10][CH2:9][N:12]=[C:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: NCCN
Reactant: O=Cc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: c1ccc(C2=NCCN2)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
Pyridinecarboxaldehyde (0.95 ml, 10 mmol) is added into a reaction flask containing 20 ml of methylene chloride and ethylene diamine (0.78 ml, 10.5 mmol) is added. After the reaction is carried out at 0° C. for 20 minutes, N-bromosuccinimide (1.87 g, 10.5 mmol) is added. The reaction temperature is slowly raised from 0° C. to the room temperature and the reaction is further carried out for 24 hrs at the room temperature. 10% sodium hydroxide solution is added to have the solution become alkaline. After extraction with a small amount of methylene chloride is carried out for 2 times, the organic layer is collected and concentrated to obtain white solids. After purified by silicone chromatographic column, the product pyil is obtained. The yield is about 90%. 1H NMR (400 MHz, CDCl3): δ 8.55-8.54 (m, 1 H), 8.11 (d, 1 H, J=7.6 Hz), 7.76-7.71 (m, 1 H), 7.34-7.21 (m, 1 H), 3.82 (s, 4 H).