Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[S:17](Cl)(=[O:20])(=[O:19])[NH2:18]>C(#N)C>[N:1]1([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][S:17](=[O:20])(=[O:19])[NH2:18])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NS(=O)(=O)Cl
Reactant: OCCCOc1ccc(-n2ccnc2)cc1
Solvent: CC#N
Product: NS(=O)(=O)OCCCOc1ccc(-n2ccnc2)cc1
Reaction time: 20 h
Yield: 43 %

Procedure:
A solution of 9.0 g (0.041 mole) of 3-[4-(1H-imidazol-1-yl)phenoxy]propanol in 150 ml of acetonitrile was treated with a solution of one equivalent of sulfamoyl chloride in 13 ml of acetonitrile. The mixture was stirred for 20 hr. The reaction mixture was concentrated under vacuum and the residue was dissolved in water. The aqueous solution was filtered and the filtrate was basified to pH 8 with potassium carbonate. The mixture was extracted with ethyl acetate. The organic fraction was concentrated under a stream of nitrogen and the precipitate was collected and dried to give 5.2 g (43%) of tan powder, mp 105.0°-106.0° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[C:8]([F:10])[CH:9]=1)[CH3:2].[I-:14].[Na+].CC1C=CC(S(NCl)(=O)=O)=CC=1>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([I:14])[CH:7]=[C:8]([F:10])[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(F)cc(B(O)O)c1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(F)cc(I)c1
Reaction time: 20 h

Procedure:
(3-Ethoxy-5-fluorophenyl)boronic acid (2.5 g, 0.014 mol) was dissolved in THF (30 mL) and a solution of sodium iodide (4.1 g, 0.028 mol) in H2O (15 mL) was added followed by a solution of chloramine T (7.8 g, 0.1 mol) in H2O (15 mL). After 20 h stirring, the reaction mixture was extracted with diethylether (3×50 mL). The organic layers were combined and the solvent was evaporated. The resulting residue was triturated with hexanes (3×) and the hexanes layers were combined. The solvent was evaporated to yield 1-Ethoxy-3-fluoro-5-iodobenzene as an orange oil. The product was used in the next reaction step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[OH:15].[C:16]1([CH3:25])[C:17]([N:22]=[C:23]=S)=[CH:18][CH:19]=[CH:20][CH:21]=1>C(O)C>[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[O:15][C:3]2[CH:4]=[C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(=O)CCc1ccc(N)c(O)c1
Reactant: Cc1ccccc1N=C=S
Solvent: CCO
Product: CCOC(=O)CCc1ccc2nc(Nc3ccccc3C)oc2c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
A solution of ethyl 3-(4-amino-3-hydroxyphenyl)-propionate (1.94 g) in ethanol (50 ml) was treated with o-tolyl isothiocyanate (1.66 g) and then heated at 40° C. for 2 hours. The mixture was evaporated then treated with ethanol (50 ml), then with diisopropylcarbodiimide (3 mL) and then stirred at 40° C. for 1 hour. The mixture was evaporated and the residue was treated with diethyl ether (50 ml) then filtered. The filtrate was evaporated to dryness and the residue subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (2:3, v/v) to give the title compound (1.6 g) as a colourless oil.
Reaction SMILES: [CH3:1][N:2]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[C:25]([CH3:33])[CH:24]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH:4]1[C:9]([OH:11])=O.[NH2:34][OH:35]>>[OH:35][NH:34][C:9]([C@H:4]1[C@H:3]([N:2]([CH3:1])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7][O:6][CH2:5]1)=[O:11]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N(C)C3CCOCC3C(=O)O)cc2)c2ccccc2n1
Reactant: NO
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@@H]3CCOC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 40 %

Procedure:
According to the procedure of Example 24, Step 3, 4-{methyl-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl]-amino}-tetrahydro-pyran-3-carboxylic acid (0.120 g, 0.255 mmol) and hydroxylamine provided (3S,4R)-4-{methyl-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl]-amino}-tetrahydro-pyran-3-carboxylic acid hydroxyamide as an amorphous white solid (0.050 g, 40%) after purification by Biotage Flash 40S chromatography, eluting with 4% methanol in ethyl acetate. MS: 486 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:30]=[CH:29][C:28]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=3)=[CH:27][CH:26]=2)[CH2:23][CH2:24]1)=[O:21])[CH3:18]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH2:26][O:27][CH2:28][CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][O:27][NH:26][C:22]([C:19]1[CH:20]=[CH:21][C:9]2[C:8](=[O:25])[C:7]3[C:6]4[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:16])([CH3:17])[C:10]=2[CH:18]=1)=[O:24]
Reactant: NOCCO
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(C(=O)NOCCO)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 2-aminooxy-ethanol.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.C(O[CH:21](OCC)[CH2:22][NH2:23])C>Cl.O1CCOCC1>[NH2:23][CH2:22][CH:21]1[C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:4][C:5]=2[CH2:9][CH2:10][O:11]1
Reactant: CCOC(CN)OCC
Reactant: CN(c1ccccc1)c1cccc(CCO)c1
Agent: Cl
Solvent: C1COCCO1
Product: CN(c1ccccc1)c1ccc2c(c1)CCOC2CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.7 %

Procedure:
2-{3-[Methyl(phenyl)amino]phenyl}ethan-1-ol (1.0 g, 4.4 mmol) was stirred in 4N HCl/dioxane (8 mL) at 0° C. Aminoacetaldehyde diethyl acetal (880 mg, 6.6 mmol) was added, and the reaction stirred for at r.t. for 1 h and then at 108° C. in the microwave for 1 h. The solution was concentrated and purified by silica gel chromatography (0% to 20% MeOH/DCM) to give 150 mg (13%) of the title compound as a yellow oil. [M+H] Calc'd for C17H20N2O, 269. Found, 269.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][C:5]=1[C:15](OCC)=[O:16])[CH3:2].[NH2-:22].[Li+].C(O)(=O)C.[ClH:28]>CCOCC>[ClH:28].[CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][C:5]=1[C:15]([NH2:22])=[O:16])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(OC)cc2c1N(CC)CC
Reactant: [NH2-]
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCN(CC)c1c(C(N)=O)[nH]c2ccc(OC)cc12
Yield: 36 %

Procedure:
Prepared from ethyl 3-(diethylamino)-5-methoxy-1H-indole-2-carboxylate (Unangst PC, et al., J. Heterocyclic Chem. 1987;24:817) and lithium amide by the procedure described in Example 18, with the exception that dilute acetic acid is substituted for 1.0N HCl during the wash of the ethyl acetate extracts. The crude product is purified by flash chromatography (silica gel, 30% ethyl acetate in dichloromethane elution) to give a foam. The foam is dissolved in ether and treated with gaseous HCl to provide the product salt in 36% yield after recrystallization from acetonitrile; mp 244° C.-dec.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[CH2:8][CH2:7][CH2:6]1)=[O:4].[F-].[K+].[F:19][C:20]([F:36])([F:35])[C:21]1[CH:34]=[CH:33][C:24]([O:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]2)=[CH:23][CH:22]=1>C(#N)C.C1COCC1>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:5]1([C:3](=[O:4])[CH2:2][N:29]2[CH2:30][CH2:31][CH2:32][CH:27]([CH2:26][O:25][C:24]3[CH:33]=[CH:34][C:21]([C:20]([F:19])([F:35])[F:36])=[CH:22][CH:23]=3)[CH2:28]2)[CH2:8][CH2:7][CH2:6]1
Reactant: COc1ccccc1C1(C(=O)CCl)CCC1
Reactant: FC(F)(F)c1ccc(OCC2CCCNC2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccccc1C1(C(=O)CN2CCCC(COc3ccc(C(F)(F)F)cc3)C2)CCC1
Reaction time: 8 h
Yield: 30.1 %

Procedure:
2-Chloro-1-[1-(2-methoxy-phenyl)-cyclobutyl]-ethanone (55 mg) in 2 mL acetonitrile was treated with freshly flamed-dried KF on Celite (200 mg) and 3-(4-trifluoromethyl-phenoxymethyl)-piperidine (66 mg, 1.1 equiv). The mixture was stirred overnight, diluted with THF (5 mL), filtered, concentrated in vacuo and purified on silica gel to give the desired 1-[1-(2-methoxy-phenyl)-cyclobutyl]-2-[3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-ethanone (32 mg, 30%). Data for this amino ketone: MS 462 (M+l); 1H NMR (300 MHz, CDCl3) partial: δ 6.8-7.6 (m, 8H), 3.85-3.95 (m, 2H, methylene adjacent to aryl ether), 3.09 (s, 2H, methylene adjacent to keto and amine moieties).
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[C:21]([CH:22]=O)=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>CO>[Cl:12][C:13]1[C:21]([CH:22]=[N:5][O:4][CH2:2][CH3:3])=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: CCON
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCON=Cc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.5 %

Procedure:
1.63 g (0.017 mol) of O-ethylhydroxylamine hydrochloride and 1.15 g (0.0085 mol) of finely powdered potassium carbonate were stirred for 1 hour in 60 ml of dry methanol. 4.00 g (0.015 mol) of 2-chloro-3-formyl-4-methylsulfonylbenzoic acid in 40 ml of methanol were then added. After stirring for 12 hours at room temperature, the solvent was removed, the residue was taken up in ethyl acetate and the organic phase was washed four times with water. After drying and removal of the solvent by distillation, 3.60 g of 2-chloro-3-ethoxyiminomethyl-4-methylsulfonylbenzoic acid (78% yield) were obtained.
Reaction SMILES: C[O:2][C:3]1[C:4]([C:21]#[C:22][C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)=[N:5][CH:6]=[C:7]([O:19][CH3:20])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.F[B-](F)(F)F.[IH2+:34].N1C=CC=CC=1.N1C=CC=CC=1>C1COCC1>[I:34][C:21]1[C:4]2=[N:5][CH:6]=[C:7]([O:19][CH3:20])[C:8]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:3]2[O:2][C:22]=1[C:23]1[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=1
Reactant: [IH2+]
Reactant: COc1ccc(COc2c(OC)cnc(C#Cc3cnn(C)c3)c2OC)cc1
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(COc2c(OC)cnc3c(I)c(-c4cnn(C)c4)oc23)cc1
Yield: 63 %

Procedure:
To a stirred solution of 3,5-dimethoxy-4-(4-methoxy-benzyloxy)-2-(1-methyl-1H-pyrazol-4-ylethynyl)pyridine (80 mg, 0.21 mmol) in dry THF (2 ml) was added bispyridine iodonium tetrafluoroborate (94 mg, 0.25 mmol) and the reaction was refluxed for 0.5 hours. After cooling, the reaction was quenched with 10% Na2S2O3 (aq) and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated onto silica-gel under reduced pressure. The solid residue was purified by flash chromatography (silica-gel, eluted with EtOAc:hexanes, 3:2) to give the product as a white solid (65 mg, 63%). 1H—NMR (300 MHz, CDCl3) δ 8.23 (s, 1H), 8.16 (s, 1H), 8.15 (s, 1H), 7.38 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.60 (s, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 3.77 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[O:18][CH3:19])[N:3]=1.COC1C=CC(OC)=CC=1CO.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+]>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=1[CH2:9][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[N:3]=1
Reactant: COc1ccc(OC)c(COc2cncc(Cl)n2)c1
Reactant: C1CNCCN1
Agent: COc1ccc(OC)c(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(OC)c(COc2cncc(N3CCNCC3)n2)c1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[(2,5-dimethoxybenzyl)oxy]pyrazine (1.02 g, 3.63 mmol; obtained according to the procedure of example 50, step 1, starting from 2,5-dimethoxybenzyl alcohol), piperazine (0.94 g, 10.9 mmol) and K2CO3 (0.50 g, 3.63 mmol). The yield of the title compound was 0.64 g (53%) which was obtained as a beige solid. Purity 100% (HPLC). MS m/z 331 (M+H)+. HRMS m/z calcd for C17H22N4O3 (M)+ 330.1692, found 330.1692.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1[NH:12][N:11]=[N:10][N:2]=1
Reactant: N#Cc1ccccc1O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Oc1ccccc1-c1nnn[nH]1
Reaction time: 5 h
Yield: 98 %

Procedure:
Into the same device as used in Example 1 were placed 5.96 g (0.050 mole) of orthocyanophenol, 9.76 g (0.150 mole) of sodium azide, 20.65 g (0.150 mole) of triethylamine hydrochloride and 60 ml of toluene. The mixture wasreacted for 5 hours in the same manner as in Example 1, giving 7.95 g (0.049 mole) of 5-(2-hydroxyphenyl)-1H-tetrazole (yield 98.0% based on orthocyanophenol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:18]=[C:19]([N:23]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][C:24]2=[O:32])[CH:20]=[CH:21][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:16][C:17]1[CH:18]=[C:19]([N:23]2[CH:28]=[CH:27][C:26]([C:29]([NH:15][CH2:14][C:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[N:9][CH:10]=3)=[O:30])=[CH:25][C:24]2=[O:32])[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(-c2ccc(CN)cn2)ccn1
Reactant: O=C(O)c1ccn(-c2cccc(F)c2)c(=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(CNC(=O)c3ccn(-c4cccc(F)c4)c(=O)c3)cn2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2′-methyl-[2,4′-bipyridin]-5-yl)methanamine 18-2 (14 mg, 0.07 mmol), 1-(3-fluorophenyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid 89-3 (16 mg, 0.07 mmol), and HATU (29 mg, 0.076 mmol) were added N,N-diisopropylethylamine (DIEA, 17 μL, 0.098 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and subjected to reverse phase preparative HPLC separation to yield 1-(3-fluorophenyl)-N-((2′-methyl-[2,4′-bipyridin]-5-yl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxamide 89. MS m/z 415.2 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[CH2:30][C:20]3([C:28]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:29])[CH2:19][C:16]2=[N:17][CH:18]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[O:29]=[C:21]1[NH:22][C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:28]2[C:20]21[CH2:19][C:16]1=[N:17][CH:18]=[C:13]([NH:12][C:9](=[O:11])[CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:14]=[C:15]1[CH2:30]2
Reactant: Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: O=C(O)CCc1ccccc1
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-phenylpropionic acid (35 mg, 0.23 mmol), (±)-3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 4), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: CON(C)[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1.[CH:17]1([Mg]Br)[CH2:21][CH2:20][CH2:19][CH2:18]1.N#N.Cl>C1COCC1>[CH:17]1([C:4]([C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=2)=[O:15])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)cc1
Reactant: Br[Mg]C1CCCC1
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Product: O=C(c1ccc(C(F)(F)F)cc1)C1CCCC1
Temperature: 25 °C
Yield: 84 %

Procedure:
To a cold (0° C.) solution of N-methoxy-N-methyl-4-(trifluoromethyl)benzamide (3.44 g, 14.75 mmol) in anhydrous THF (70 mL) was added dropwise over a period of 30 minutes a solution of cyclopentylmagnesium bromide (2 M in diethyl ether, 29.5 mmol, 14.75 mL) under inert atmosphere of N2. The reaction mixture was slowly allowed to warm to rt overnight. An aqueous solution of HCl (1N, 50 mL) was added and the resulting mixture was extracted with diethyl ether (3×50 mL). The combined organic layers were washed with brine (1×50 mL), dried over MgSO4, filtered and evaporated under vacuum to give a brown oil (3.0 g). Purification by chromatography (SiO2, DCM/c-Hex 1/3) gave the title compound as a colorless oil (610 mg, 17%). 1H NMR (CDCl3, 300 MHz) δ 8.24 (d, J=8.1 Hz, 2H), 7.90 (d, J=8.1 Hz, 2H), 3.96-3.79 (m, 1H), 2.21-2.00 (m, 4H), 2.01-1.71 (m, 4H). HPLC (Condition A), Rt: 5.22 min (HPLC purity: 98.6%).
Reaction SMILES: [CH2:1]([N:5](C(OC(C)(C)C)=O)[CH2:6][CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH2:20][CH2:21][N:22]([CH2:30][CH:31]=[C:32]=[CH2:33])C(OC(C)(C)C)=O)[CH:2]=[C:3]=[CH2:4].Cl>CCO.CCOCC>[CH2:30]([NH:22][CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:1][CH:2]=[C:3]=[CH2:4])[CH:31]=[C:32]=[CH2:33]
Reactant: C=C=CCN(CCCN(CCCCCCCCN(CCCN(CC=C=C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: C=C=CCNCCCNCCCCCCCCNCCCNCC=C=C
Yield: 92.6 %

Procedure:
Dissolve 0.5 gm of the product of Step H in 2 ml of EtOH and while stirring treat the mixture with 10 ml of 2N HCl in Et2O. Stir the resulting mixture overnight, filter and dry the solids (in vacuo) to obtain 0.22 gm of the desired product, mp 283°-284° C. dec. Using the abbreviated form for naming the compounds embraced by formula I, it is to be noted that the following specific compounds are readily prepared by applying the foregoing described techniques and procedures and by applying known prior art principles to achieve the necessary modifications:
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[NH:4][CH:5]([CH3:29])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][C:19]=1[O:27][CH3:28].[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH2:42])(=[O:41])=[O:40]>>[CH3:31][N:2]([CH3:1])[C:3](=[O:30])[NH:4][CH:5]([CH3:29])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:42][S:39]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[Cl:32])(=[O:41])=[O:40])=[O:23])=[CH:20][C:19]=1[O:27][CH3:28]
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc(CC(C)NC(=O)N(C)C)cc12
Reactant: NS(=O)(=O)c1ccccc1Cl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2Cl)ccc1Cc1cn(C)c2ccc(CC(C)NC(=O)N(C)C)cc12

Procedure:
Using a similar procedure to that described in Example 2, part c, except starting from 4-[5-[2-(N',N'-dimethylureido)propyl]-1-methylindol-3-ylmethyl]- 3-methoxybenzoic acid, and using 2-chlorophenylsulfonamide instead of 2-methylphenylsulfonamide, the title compound was obtained (88%) as a white solid; mp 131°-136° C.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]2[CH2:25][C:24]([CH3:27])([CH3:26])[C:23]3[N:22]=[C:21]([C:28](O)=[O:29])[CH:20]=[CH:19][C:18]=3[NH:17]2)[CH:12]=[CH:13][C:14]=1[F:15].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]2[CH2:25][C:24]([CH3:26])([CH3:27])[C:23]3[N:22]=[C:21]([C:28]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:29])[CH:20]=[CH:19][C:18]=3[NH:17]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)O)nc21
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)NS(C)(=O)=O)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To a suspension of 60% sodium hydride (267.5 mg, 6.9 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (0.66 g, 6.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A81. A solution of 6-(3-chloro-4-fluoro-phenyl)-8,8-dimethyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid (233.8 mg, 0.7 mmol) and 1,1′-carbonyldiimidazole (221.0 mg, 1.4 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B81. Solution B81 was added to Solution A81 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[6-(3-chloro-4-fluoro-phenyl)-8,8-dimethyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carbonyl]-methanesulfonamide (115.1 mg, 40%) as a white solid: MS (ESI) M+1=412.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:12][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(Cl)ccc1C(=O)OC
Yield: 99.3 %

Procedure:
A mixture of methyl 4-chloro-2-hydroxybenzoate (2f) (96.3 g, 0.52 mol), allyl bromide (134 ml, 1.55 mol) and ground potassium carbonate (107 g, 0.77 mol) in 1500 ml of dry acetone was heated under reflux for 20 hours. The inorganic salt was removed by filtration, and the solvent and excess allyl bromide evaporated to dryness to give 3f (117 g, 99.6% yield) as a yellow solid, mp 47°-55° C. NMR (CDCl3) δ7.73 (d, 1H, J=8 Hz, aromatic proton meta to Cl), 6.97 (m, 2H, aromatic protons alpha to Cl), 6.40-5.17 (m, 3H, olefinic orotons), 4.57 (m, 2H, CH2) and 3.90 (s, 3H, CH3).