Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:2].Cl[CH2:15][C:16]([O:18]C(C)(C)C)=[O:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([CH:1]=[O:2])[C:4]=1[O:13][CH2:15][C:16]([OH:18])=[O:17])=[O:7]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: COC(=O)c1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C=O)c1OCC(=O)O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
A mixture of 3.0 g of methyl 3-formyl-2-hydroxybenzoate, 3.31 g of t-butyl chloroacetate, 12.0 g of potassium carbonate and 40 ml of dimethylformamide is heated at 70° C. for 2.5 hours. After cooling, the reaction mixture is poured into water and the aqueous mixture is extracted with ethyl acetate. The extract is washed with an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is dissolved in trifluoroacetic acid and the solution is stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure and the residue is treated with ether to give 2.09 g of (2-methoxycarbonyl-6-formylphenoxy)acetic acid as pale yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][CH:8]([CH2:36][C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)[C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:27](=[O:35])[NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2].C(O)C.[H][H]>O1CCCC1.[Pd]>[C:1]([O:5][C:6](=[O:42])[NH:7][C@@H:8]([CH2:36][C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)[C:9]([N:11]1[CH2:12][CH2:13][C:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)([C:27](=[O:35])[NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:15][CH2:16]1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC(Cc1cccs1)C(=O)N1CCC(Cc2ccc([N+](=O)[O-])cc2)(C(=O)NC2CCCCC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCC(Cc2ccc(N)cc2)(C(=O)NC2CCCCC2)CC1

Procedure:
To a solution of {2-[4-Cyclohexylcarbamoyl-4-(4-nitro-benzyl)-piperidin-1-yl]-2-oxo-1-thiophen-2-ylmethyl-ethyl}-carbamic acid tert-butyl ester (9.77 mmol; 5.85 g) (prepared as in Example 1, substituting 4-nitrobenzylbromide for 4-biphenylmethyl bromide and cyclohexylamine for cyclohexylmethylamine), in tetrahydrofuran (20 mL) and ethanol (40 mL) was added 10% palladium on carbon (2 g), and the resulting mixture was hydrogenated under 50 psi of hydrogen pressure overnight at room temperature. The catalyst was removed via filtration, and the filtrate was evaporated to yield (S)-{2-[4-(4-aminobenzyl)-4-cyclohexylcarbamoyl-piperidin-1-yl]-2-oxo-1-thiophen-2-ylmethyl-ethyl}-carbamic acid tert-butyl ester. MS (ESI) m/z 569.40 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=1.O=S(Cl)[Cl:25]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([Cl:25])=[O:22])=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture of acid 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (2.0 g, 6.8 mmol) in SOCl2 (10 mL) was stirred at RT for 2 h under an inert atmosphere. The reaction was concentrated in vacuo to afford 2-(4-(quinolin-2-ylmethoxy)phenyl)acetyl chloride (2.0 g, 95%) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([I:9])[C:3]=1[OH:10].[CH2:11](Br)[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([I:9])[C:3]=1[O:10][CH2:11][CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(Br)c(O)c(I)c1
Reactant: BrCC=Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Br)c(OCC=Cc2ccccc2)c(I)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
2-Bromo-4-methyl-6-iodophenol (7.82 gm, 25 mmol) and cinnamyl bromide (4.93 g, 25 mmol) were added to DMF (20 ml). Diisopropylethylamine (5.3 ml, 30.4 mmol) was added and the mixture heated to 60° C. for 15 minutes and then allowed stir for 16 hours at room temperature. The DMF was removed under vacuum, and 1M HCl was added until the residue was acidic. The mixture was extracted with ethyl acetate, and the combined organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 1-bromo-3-iodo-5-methyl-2-(3-phenylallyloxy)-benzene (10.86 g, 100% yield).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([P:22](Cl)(Cl)=[O:23])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([P:22]2(=[O:23])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:18][CH:17]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: O=P(Cl)(Cl)c1ccc(F)cc1
Product: O=P1(c2ccc(F)cc2)c2ccccc2CN1c1ccccc1
Yield: 30 %

Procedure:
The procedure of Example 26 was employed utilizing N-benzylaniline and 4-fluorophenyl phosphonic dichloride to yield a pale yellow solid. The yellow solid was recrystallized from ethyl acetate to yield 1-(4-fluorophenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (5.9 g, 30% yield) as white needles having a melting point of 119°-120° C. and the following analysis:
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[Cl:7][C:8]1[CH:9]=[C:10]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1>ClC1C=CC=CC=1Cl>[Cl:7][C:8]1[CH:9]=[C:10]([S:14]([N:17]=[C:2]=[O:3])(=[O:15])=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: NS(=O)(=O)c1cccc(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Clc1ccccc1Cl
Product: O=C=NS(=O)(=O)c1cccc(Cl)c1
Yield: 40 %

Procedure:
5,7-Dichloro-4-[3-chlorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester ##STR30## Combine oxalyl chloride (25mL) and 3-chlorobenzenesulfonamide (4.3g, 23mmol) and reflux overnight. Remove oxalyl chloride in vacuo and combine the resulting residue with o-dichlorobenzene (25mL) and reflux. Evaporate the solvent in vacuo to distill to give [3-chlorobenzenesulfonyl]isocyanate (2g, 40%); bp 92°-5° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[CH2:15]([O:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][N:27]2[CH2:33][CH3:34])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.FC(F)(F)C(O)=O>C(O)(=O)C>[CH2:15]([O:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]2[C:24]=1[C:25]([C:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH:7]=1)=[CH:26][N:27]2[CH2:33][CH3:34])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCn1ccc2c(OCc3ccccc3)cc(F)cc21
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(C2=CCNCC2)c2c(OCc3ccccc3)cc(F)cc21
Temperature: 80 °C
Yield: 32.4 %

Procedure:
In pressure vessel, tert-butyl 4-oxopiperidine-1-carboxylate (370 mg, 1.86 mmol) was dissolved in acetic acid (3 mL) and then 4-(benzyloxy)-1-ethyl-6-fluoro-1H-indole (200 mg, 0.74 mmol) was added, followed by trifluoroacetic acid (1 mL). The reaction mixture was heated to 80° C. for 1 hour. Volatiles were evaporated and then water was added. The pH was adjusted to ˜12 with 15% aqueous NaOH and partitioned between EtOAc-water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give a crude product. The resulting residue was purified on alumina column chromatography eluting with DCM/methanol (0-6%) to afford 37-3 (84 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ (ppm) 8.78 (br. s, 2H), 7.51-7.41 (m, 5H), 7.27 (s, 1H), 6.99 (dd, J=9.9 Hz and 2.1 Hz, 1H), 6.63 (dd, J=11.8 Hz and 2.1 Hz, 1H), 5.84, (br. s, 1H), 5.16 (s, 2H), 4.11 (q, J=7.2 Hz, 2H), 3.46 (br. s, 2H), 2.93 (br.s, 2H), 2.61 (br. s, 2H), 1.31 (t, J=7.2 Hz, 3H). LCMS: calc 350.4 and found: 351.1 [MH]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCCC2)nc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (1.58 g, 10.00 mmol, 1.00 equiv), pyrrolidine (710 mg, 10.00 mmol, 1.00 equiv) and potassium carbonate (2.76 g, 20.00 mmol, 2.00 equiv) in CH3CN (20 mL) was stirred at 60° C. in an oil bath. After 2 h, the reaction mixture was allowed to reach ambient temperature. The solids were filtered off and the filtrate was concentrated under reduced pressure. The residue was triturated with 1×20 mL of petroleum ether to yield 1.8 g (93%) of the title compound as a yellow solid.
Reaction SMILES: ClC(Cl)C.C(OC([NH:12][C@@H:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH:14]([C:16]1[C:17](=[O:19])[CH:18]=1)[OH:15])=O)(C)(C)C.O.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[C:25]1([CH3:35])[CH:26]=[CH:27][C:28]([S:31]([OH:34])(=[O:32])=[O:33])=[CH:29][CH:30]=1.[NH2:12][C@@H:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH:14]([C:16]1[C:17](=[O:19])[CH:18]=1)[OH:15]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(O)c1cc1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)Cl
Solvent: O
Product: CCCC[C@H](N)C(O)c1cc1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 131.5 %

Procedure:
To 5 ml of a dichloroethane solution of 150 mg of 2-((2S)-2-tert-butoxycarbonylamino-1-hydroxyhexyl) cyclopropenone obtained in Example 22 was added 106 mg of p-toluene sulfonate monohydrate. After stirring at room temperature for 5 hours, the solvent was distilled off under reduced pressure to give 250 mg of the titled product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47]OS(C)(=O)=O)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:53]=[N+:54]=[N-:55].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][N:53]=[N+:54]=[N-:55])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCOS(C)(=O)=O)CCC3)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCN=[N+]=[N-])CCC3)cc1

Procedure:
In analogy to the procedure described in example 10(b), the (3R,4R)-3-[1-(2-methanesulfonyloxy-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 9(a)] was treated with sodium azide to yield the (3R,4R)-3-[1-(2-azido-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 686 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([CH3:27])=[CH:25][N:24]=[CH:23][C:22]=1[CH3:28].[CH3:31][NH:32][CH2:33][CH2:34][CH2:35][OH:36]>>[CH3:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH3:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]([CH2:33][CH2:34][CH2:35][OH:36])[CH3:31])[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: CNCCCO
Reactant: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCN(C)CCCO

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 6) and 3-(methylamino)propan-1-ol following the procedure outlined in Example 18, Step 2 (modifications: 22° C., 60 h). 1H NMR (300 MHz, DMSO-d6):):δ: 9.64 (s, 1H), 8.41 (s, 3H), 7.90 (d, J=9 Hz, 1H), 7.04 (d, J=9 Hz, 1H), 4.54 (s, 2H), 3.98 (t, J=6.9 Hz, 2H), 3.43 (t, J=6 Hz, 3H), 2.37-2.25 (4H, m), 2.14 (d, J=9.3 Hz, 8H), 1.76 (t, J=6.9 Hz, 2H), 1.37 (m, 6H). MS (ESI): 483.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Cl-].[CH2:13]([O:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:24])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCC(=O)O
Reactant: Fc1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)CCCCC(=O)c1ccc(F)c2ccccc12
Temperature: 0 °C
Yield: 69.8 %

Procedure:
To a mixture of 1-fluoronaphthalene (20.0 g) and adipic acid monoethyl ester chloride (27.5 g) was added gradually aluminum chloride (38.5 g) with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water (500 ml) and extracted with diethyl ether (200 ml×2). The organic layer was washed with a 10% aqueous solution of sodium hydrogen carbonate (200 ml), dried over anhydrous magnesium sulfate, and concentrated to give ethyl 6-(4-fluoro-1-naphthyl)-6-oxohexanoate as an oil (27.7 g, 67%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7]C(C2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)=O)=[CH:3][CH:2]=1.[F:28][C:29]1[C:40]([F:41])=[C:39]([O:42][CH2:43][C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]=2)[CH:38]=[CH:37][C:30]=1[C:31](N(OC)C)=[O:32]>>[F:28][C:29]1[C:40]([F:41])=[C:39]([O:42][CH2:43][C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]=2)[CH:38]=[CH:37][C:30]=1[C:31](=[O:32])[CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)c(F)c1F
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)c(F)c1F

Procedure:
Following the procedure for the preparation of 2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone but substituting 2,3-Difluoro-N-methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide provided the title compound. MS: (M+H m/z=391.1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:16])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[C:4]([Cl:17])[N:3]=1.[H-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C=O)C>[CH2:22]([N:6]1[C:5]2[C:9](=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[Cl:17])[N:8]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[C:7]1=[O:16])[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: Nc1nc(Cl)c2[nH]c(=O)n(CCCCO)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)n(CCCCO)c2nc(N)nc(Cl)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of 2-amino-6-chloro-9-(4-hydroxybutyl)-8-oxo-7H-purine (0.8 g, 3.1 mM) in DMF (15 mL) was added NaH (0.12 g, 60% oil dispersion, 3 mM) all at once at zero degrees C. under nitrogen and stirred for 30 minutes. To this was added allyl bromide (0.37 g, 3.1 mM) and the resulting mixture was allowed to warm to room temperature and stirred overnight. Most of solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (120 g, CH2Cl2 /CH3OH/conc. NH4OH, 100/5/0.1) to give 7-allyl-2-amino-6-chloro-9-(4-hydroxybutyl)-8-oxo-7H-purine as an off-white powder (40 percent) mp 132°-133° C. IR (KBr) 3320, 1715, 1640, 1585, 1460 cm-1. 1H NMR (DMSO-d6) δ 6.70 (bs, 2H, exchangeable, NH2), 5.95 (m, 1H), 3.70 (t:, J=6.5 Hz, 2H, NCH2), 3.35 (m, 2H, CH2OH), 1.50 (m, 4H, CH2CH2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].S(=O)(=O)(O)O>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([O:18][CH3:19])=[CH:11][C:12]([C:15](=[O:17])[CH3:16])=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(C)=O)ccc1OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCc1ccccc1
Yield: 59.7 %

Procedure:
A stirred solution of 1-(4-benzyloxy-3-methoxyphenyl)ethanone (51.3 g, 200 mmol) in dichloromethane (750 mL) was cooled to 0° C. Nitric acid (90%, 14 mL, 300 mmol) was added dropwise to the cooled solution over 20 min. Sulfuric acid (96.2%, 16.3 mL, 300 mmol) was then added dropwise over 40 min at 0° C. Additional nitric acid (9.4 mL, 200 mmol) was added dropwise over 20 min. The reaction mixture was washed with water (3×200 mL), and saturated sodium bicarbonate (4×200 mL, or until neutral). The organic layer was dried over Na2SO4 and concentrated. The crude mixture was recrystallized from DMF to give 1-(4-benzyloxy-5-methoxy-2-nitrophenyl)ethanone (36 g, 60%). 1H NMR (400 MHz, CDCl3): δ 7.65 (s, 1H), 7.45-7.33 (m, 5H), 6.74 (s, 1H), 5.21 (s, 2H), 3.97 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:28]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](Cl)=[O:38])[CH2:33][CH2:32]1)(=[O:30])[CH3:29]>CC(C)=O>[C:28]([N:31]1[CH2:32][CH2:33][CH:34]([C:37]([O:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([C:11]3[S:15][C:14]([S:16](=[O:17])(=[O:18])[NH2:19])=[CH:13][CH:12]=3)(=[O:9])=[O:10])=[CH:4][CH:3]=2)=[O:38])[CH2:35][CH2:36]1)(=[O:30])[CH3:29]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(O)cc2)s1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(C(=O)Oc2ccc(S(=O)(=O)c3ccc(S(N)(=O)=O)s3)cc2)CC1
Reaction time: 0.25 h

Procedure:
A solution of 5-[(4-hydroxyphenyl)sulfonyl]thiophene-2-sulfonamide (3.19 g; 0.01 mole) in acetone (60 ml) at -15° was treated with triethylamine (1.11 g; 0.011 mole). Then 1-acetylpiperidine-4-carbonyl chloride hydrochloride (2.41 g; 0.011 mole) was added, portionwise, during 15 minutes at -15°. The cooling bath was removed and stirring was continued. After 20 hours at room temperature, the reaction mixture was treated with triethylamine (1.11 g; 0.011 mole). Then after stirring one hour longer, the reaction mixture was treated with 1-acetylpiperidine-4-carbonyl chloride hydrochloride (2.41 g; 0.011 mole) and triethylamine (2.22 g; 0.022 mole) and stirred at room temperature.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:26]=2[NH:25][CH:24]=[C:23]3[Cl:27])(=[O:16])=[O:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>CN(C)C=O>[Cl:27][C:23]1[C:22]2[C:26](=[C:18]([NH:17][S:14]([C:11]3[CH:12]=[CH:13][C:8]([S:5](=[O:7])(=[O:6])[NH:4][CH2:3][CH2:2][N:28]4[CH:32]=[CH:31][N:30]=[CH:29]4)=[CH:9][CH:10]=3)(=[O:16])=[O:15])[CH:19]=[CH:20][CH:21]=2)[NH:25][CH:24]=1
Reactant: O=S(=O)(NCCBr)c1ccc(S(=O)(=O)Nc2cccc3c(Cl)c[nH]c23)cc1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: O=S(=O)(NCCn1ccnc1)c1ccc(S(=O)(=O)Nc2cccc3c(Cl)c[nH]c23)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 59.7 %

Procedure:
557 mg (1.13 mmol) of 4-[N-(2-bromoethyl)sulfamoyl]-N-(3-chloro-1H-indole-7-yl)benzenesulfonamide and 820 mg (12.0 mmol) of imidazole were added to 10 ml of dimethylformamide and the mixture was stirred at 80° C. for 2 days. After concentrating, the residue was dissolved in ethyl acetate. The mixture was washed with water, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography, to give 324 mg of the title compound.
Reaction SMILES: Cl.CO[CH:4](OC)[CH2:5][N:6]([CH3:18])[C:7](=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1>CC(O)=O.ClCCl>[CH3:16][O:15][C:11]1[CH:12]=[CH:13][C:14]2[CH:4]=[CH:5][N:6]([CH3:18])[C:7](=[O:17])[CH2:8][C:9]=2[CH:10]=1
Reactant: COc1cccc(CC(=O)N(C)CC(OC)OC)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc2c(c1)CC(=O)N(C)C=C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
Add concentrated HCl (3.5 L) to a solution of N-(2,2-dimethoxyethyl)-2-(3-methoxyphenyl)-N-methylacetamide (790 g, 2.709 mol, 1.0 eq) dissolved in HOAc (3.5 L). Stir the mixture for 16 hours at room temperature. Dilute the reaction mixture with 4 L of dichloromethane and then quench slowly with 50% NaOH (4.0 L) over 2 hours. Separate the two layers. Collect the organic layer, dry over sodium sulfate and concentrate under vacuum to yield an off-white solid. The solid is put through a silica plug (1/1 hexanes/ethyl acetate) to obtain the product (Cmpd N, 460 g, 84% yield).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.Cl.[CH3:44][NH:45][CH2:46][CH3:47]>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([N:45]([CH2:46][CH3:47])[CH3:44])=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([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
Reactant: CCNC
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Agent: Cl
Product: CCN(C)C(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and N-methylethanamine hydrochloride
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=O)[NH:10][C:5]2=[CH:4][CH:3]=1.[O:14]([CH2:21][CH2:22][NH2:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:14]([CH2:21][CH2:22][NH:23][C:11]([C:9]1[NH:10][C:5]2[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:8]=1)=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCOc1ccccc1
Reactant: O=C(O)c1cc2nc(Cl)ccc2[nH]1
Product: O=C(NCCOc1ccccc1)c1cc2nc(Cl)ccc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (Preparation 6) and 2-phenoxyethylamine. On completion of the reaction, the mixture was partitioned between water and dichloromethane on a hydrophobic frit, washing with dichloromethane. The organic filtrate was concentrated in vacuo then triturated with dichloromethane/methanol/ethyl acetate to give the title compound as a white solid. δH (d6 DMSO): 3.68 (2H, m), 4.13 (2H, m), 6.94 (3H, m), 7.25 (4H, m), 7.83 (1H, d), 8.95 (1H, t), 12.09 (1H, s). m/z (ES+)=316 [M+H]+; RT=3.45 min.