Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][O:9][CH2:8][C@H:7]([O:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C@@H:6]([O:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C@H:5]([CH3:23])[O:4][C:3]1=[O:24].[OH:25][C:26]1[C:27]([C:34](O)=[O:35])=[N:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:12]([O:11][C@@H:7]1[C@@H:6]([O:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C@H:5]([CH3:23])[O:4][C:3](=[O:24])[C@@H:2]([NH:1][C:34](=[O:35])[C:27]2[C:26]([OH:25])=[C:31]([O:32][CH3:33])[CH:30]=[CH:29][N:28]=2)[CH2:10][O:9][CH2:8]1)[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CCO[C@H]1[C@H](C)OC(=O)[C@@H](N)COC[C@@H]1OCCC(C)C
Reactant: COc1ccnc(C(=O)O)c1O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](OCCC(C)C)[C@@H](OCCC(C)C)[C@H](C)OC2=O)c1O
Temperature: 25 °C
Yield: 42.3 %

Procedure:
(3S,7S,8S,9S)-3-amino-7,8-bis(isopentyloxy)-9-methyl-1,5-dioxonan-2-one (130 mg, 0.376 mmol) and 3-hydroxy-4-methoxypicolinic acid (70.0 mg, 0.414 mmol) were diluted with DCM (3763 μl). PyBOP (215 mg, 0.414 mmol) was added, followed by N-ethyl-N-isopropylpropan-2-amine (216 μl, 1.242 mmol), and the mixture was stirred at room temperature until thin layer chromatography (TLC) indicated complete consumption of starting material. The reaction mixture was purified by column chromatography (SiO2; hexanes/EtOAc) to furnish the title compound (79.1 mg, 0.159 mmol, 42.3% yield) as a white solid: mp 61-70° C.; IR (thin film) 3530, 3371, 2955, 2873, 1750, 1649, 1529, 1262 cm−1; 1H NMR (400 MHz, CDCl3) δ 11.94 (s, 1H), 8.67 (d, J=8.1 Hz, 1H), 8.01-7.98 (m, 1H), 6.87 (d, J=5.2 Hz, 1H), 5.04 (ddd, J=8.2, 6.8, 5.0 Hz, 1H), 5.01-4.89 (m, 1H), 4.05 (dd, J=11.9, 6.8 Hz, 1H), 3.94 (s, 3H), 3.92-3.85 (m, 1H), 3.85-3.78 (m, 2H), 3.66-3.58 (m, 2H), 3.57-3.48 (m, 2H), 3.26-3.14 (m, 2H), 1.69 (dp, J=13.4, 6.7 Hz, 2H), 1.51-1.38 (m, 7H), 0.90 (dt, J=6.2, 2.7 Hz, 12H); 13C NMR (101 MHz, CDCl3) δ 170.30, 168.94, 155.32, 148.72, 140.66, 130.22, 109.56, 85.02, 83.63, 75.28, 73.94, 73.17, 72.48, 69.35, 56.09, 52.12, 39.23, 38.95, 24.96, 22.91, 22.67, 22.62, 22.50, 18.59; HRMS-ESI (m/z) [M+Na]+ calcd for C25H40N2NaO8, 519.2677, found 519.2687.
Reaction SMILES: [C:1]1([N:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]3([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](Cl)(=[O:24])[CH2:22][CH3:23].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:1]1([N:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]3([CH2:10][CH2:11][N:12]([C:21](=[O:24])[CH2:22][CH3:23])[CH2:13][CH2:14]3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(N2CC3(CCNCC3)c3ccccc32)cc1
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC(=O)N1CCC2(CC1)CN(c1ccccc1)c1ccccc12

Procedure:
A mixture of 1-phenylspiro[indoline-3,4'-piperidine] (Example 11), propionyl chloride and sodium bicarbonate in chloroform is stirred at reflux. The mixture is permitted to cool, filtered, and the filtrate concentrated, leaving 1-phenyl-1'-propionylspiro[indoline-3,4'-piperidine]. In a similar fashion, 1-phenylspiro[indoline-3,4'-piperidine] is treated with benzoylchloride to provide 1'-benzoyl-1-phenylspiro[indoline-3,4'-piperidine].
Reaction SMILES: [CH3:1][CH:2]([CH3:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:16][C:17]1[C:22]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:21][CH:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:8][CH:2]([CH3:1])/[CH:3]=[CH:4]/[C:5]([N:26]1[CH2:27][CH2:28][CH:23]([C:22]2[C:17]([CH3:16])=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:24][CH2:25]1)=[O:7]
Reactant: CC(C)/C=C/C(=O)O
Reactant: Cc1ncccc1C1CCNCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncccc1C1CCN(C(=O)/C=C/C(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28 %

Procedure:
(E)-4-Methylpent-2-enoic acid (26 mg, 0.23 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (20 μl, 0.23 mmol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 2-methyl-3-(4-piperidyl)pyridine hydrochloride (27 mg, 0.125 mmol) in DCM (2 ml). DIPEA (120 μl, 0.7 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 9.6 mg of a white solid (0.035 mmol, 15%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[Br-].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Zn+].CCOC(C)=O>C1COCC1.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[N:3]=[C:4]([Cl:20])[C:5]2[C:10]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Reactant: [Zn+]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(-c2ccccn2)c2c(Cl)nc(Cl)nc21
Temperature: 65 °C
Reaction time: 3 h
Yield: 42.5 %

Procedure:
To a solution of 2,4-dichloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 2.25 mmol), as prepared in Example 5, step 1, in THF (11 mL) was added tetrakis(triphenylphosphine)palladium(0) (131 mg, 0.113 mmol) and pyridin-2-ylzinc(II) bromide (9 mL, 4.5 mmol, 0.5 M solution in THF) which was then heated to 65° C. and stirred for 3 hrs. EtOAc (10 mL) was added and the resulting mixture was washed with water (20 mL). The aqueous layer was extracted with EtOAc (three×10 mL), and the combined organic layers were then washed with 1 M aqueous Na2SO3 (20 mL), sat. aqueous NaHCO3 (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was then purified via flash chromatography (20%-50% EtOAc/heptane) to give the title compound as a clear oil (378 mg, 43% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59-8.71 (m, 1H) 8.21 (s, 1H) 7.89 (td, J=7.77, 1.89 Hz, 1H) 7.70 (d, J=7.83 Hz, 1H) 7.39 (ddd, J=7.52, 4.86, 1.01 Hz, 1H) 5.67 (s, 2H) 3.50-3.67 (m, 2H) 0.79-0.95 (m, 2H) −0.17-0.00 (m, 9H). m/z (APCI+) for C17H20N4OCl2Si 395.00/397.00 (M+H)+.
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4]([CH:6]1[CH2:9][C:8]2([CH2:12][CH2:11][CH2:10]2)[CH2:7]1)=[O:5].[I-:13].[Na+]>CC(C)=O>[I:13]/[CH:2]=[CH:3]/[C:4]([CH:6]1[CH2:9][C:8]2([CH2:12][CH2:11][CH2:10]2)[CH2:7]1)=[O:5]
Reactant: O=C(/C=C/Cl)C1CC2(CCC2)C1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(/C=C/I)C1CC2(CCC2)C1
Reaction time: 8 h
Yield: 59.5 %

Procedure:
1-Chloro-3-(spiro[3.3]hept-2-yl)-1E-propen-3-one (7.3 g, 0.042 mole) was mixed with 25.2 g (0.168 mole) of sodium iodide and 45 ml of dry acetone (distilled from anhydrous potassium carbonate, b.p. 56° C). The mixture was refluxed with rapid stirring overnight. The mixture was cooled and the solvent was removed in vacuo. The solid residue was taken up in 75 ml of water and the products were extracted with 150 ml (3×50 ml) of ether. The organic material was washed with 50 ml of saturated sodium bicarbonate solution, 50 ml of aqueous sodium thiosulfate solution and 50 ml of saturated sodium chloride solution. The material was dried over anhydrous magnesium sulfate, filtered and the solvent was removed in vacuo to yield 6.9 g (62.2%) of crude 1-iodo-3-(spiro[3.3]hept-2-yl)-1E-propen-3-one.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=O)[O:5]CC)[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C1C=CC=CC=1>[CH2:1]([O:3][P:4]([Cl:20])([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOP(=O)(CCCCc1ccccc1)OCC
Solvent: c1ccccc1
Product: CCOP(=O)(Cl)CCCCc1ccccc1

Procedure:
A mixture of diethyl(4-phenylbutyl)phosphonate (0.73 g., 2.6 mmole), benzene (10 ml.) and phosphorus pentachloride (1.0 eq.) is refluxed under argon for 30 minutes. The benzene and phosphorus oxychloride are removed in vacuo to give ethoxy(4-phenylbutyl)phosphinyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=2[Cl:17])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:17][C:10]1[CH:11]=[C:12]([CH:13]2[O:23][CH2:22][CH2:21][O:14]2)[CH:15]=[CH:16][C:9]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:18]([O-:20])=[O:19])[CH:4]=1
Reactant: OCCO
Reactant: Nc1ccc(Oc2ccc(C=O)cc2Cl)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Nc1ccc(Oc2ccc(C3OCCO3)cc2Cl)cc1[N+](=O)[O-]

Procedure:
4-[(4-Amino-3-nitrophenyl)oxy]-3-chlorobenzaldehyde (1.16 g, 5.3 mmol), ethylene glycol (5 ml) and p-toluenesulfonic acid (50 mg) in 150 mL of toluene was heated at 120 degrees centigrade with a Dean-Stark trap for 24 hours. The reaction mixture was diluted with ethyl acetate and washed twice with 1N NaOH. The organic layer was dried over MgSO4 and concentrated to give 4-{[2-chloro-4-(1,3-dioxolan-2-yl)phenyl]oxy}-2-nitroaniline. (M+1) 336.9, 2.60 min (LC/MS method B)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:18]=[C:19]([S:23]([C:26]2[CH:27]=[C:28]([C:33]([NH2:35])=[NH:34])[S:29][C:30]=2[S:31][CH3:32])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:43][CH3:44]>CC(C)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:43]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:18]=[C:19]([S:23]([C:26]2[CH:27]=[C:28]([C:33]([NH2:35])=[NH:34])[S:29][C:30]=2[S:31][CH3:32])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1)[CH3:44]
Reactant: CCI
Reactant: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2nc3ccccc3[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(-c2cccc(S(=O)(=O)c3cc(C(=N)N)sc3SC)c2)nc2ccccc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
A mixture containing ({4-[3-(1H-benzoimidazol-2-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester (prepared in Example 144) (25 mg, 0.05 mmol), K2CO3 (13 mg, 0.10 mmol), and iodoethane (12 mg, 0.08 mmol) in 0.5 mL acetone was heated to 60° C. for 2 hrs. The mixture was filtered then concentrated, and the residue dissolved in 0.5 ml of 50% TFA/DCM and stirred at 25° C. for 30 mins. The solvent was evaporated and the crude product purified by RP-HPLC, eluting with a linear gradient of 10% CH3CN in 0.1% TFA/H2O to 50% CH3CN over 30 mins, to give 26 mg (93%) of the title compound as yellow solid: 1H NMR (400 MHz, CD3OD) δ 8.58 (m, 1H), 8.44 (m, 1H), 8.41 (s, 1H), 8.20 (m, 1H), 8.02 (m, 2H), 7.90 (m, 1H), 7.71 (m, 2H), 4.55 (q, 2H), 2.75 (s, 3H), 1.59 (t, 3H). Mass spectrum (ESI, m/z) calcd. for C21H20N4O2S3 456.1, found 457.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:25](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH2:24])=[C:17]2[CH:16]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:25][C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH2:24])=[C:17]2[CH:16]=1
Reactant: COc1cc2c(-c3cc4c(CN)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CN)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 27.3 %

Procedure:
[2-(5,6-Dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-yl]methylamine is prepared as described in Example 179a starting with 0.080 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-yl]methylamine instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.80 cm3 of 5N potassium hydroxide. After purification by flash-pack chromatography (SiO2, dichloromethane/methanol 95/05 by volume as eluent), 0.015 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-yl]methylamine is obtained, the characteristics of which are as follows:
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][NH2:12]>C1C=CC=CC=1>[CH3:11][NH:12][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CN
Solvent: c1ccccc1
Product: CNC(=O)Cc1ccccc1

Procedure:
Dissolved 15 g(0.1 mol) of phenylacetyl chloride in 100 ml of benzene. While stirring on a magnetic stirrer, introduced methylamine into the benzene solution at 20°-30° C. Followed the procedure of compound 3-1 for the purification of the product to yield N-methyl phenylacetamide as light yellowish crystal. Yield, 12 g (80%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=[O:7])[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C(O)(=O)C.[N+:16]([O-])([OH:18])=[O:17]>C(OC(=O)C)(=O)C>[N+:16]([C:10]1[CH:9]=[CH:8][C:3]2[C:4]([CH:6]=[O:7])=[CH:5][S:1][C:2]=2[CH:11]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1csc2ccccc12
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=Cc1csc2cc([N+](=O)[O-])ccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 9 g of benzo[b]thiophene-3-carboxaldehyde in 50 ml of acetic anhydride was cooled to 0° C. by means of an external ethanol/ice bath. A solution of 40 ml of acetic acid and 20 ml of fuming nitric acid was added at such a rate to maintain the temperature of the reaction at 0°-5° C. Following the addition of the reagents, the reaction mixture was stirred for 1.5 hours. The reaction mixture was poured into 500 ml of ice and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The resulting oil was treated with ethanol. A solid formed, which was recovered by filtration providing 1.3 g of 6-nitrobenzo[b]thiophene-3-carboxaldehyde, m.p. 187°-192° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:3]=1.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[OH:34]>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[O:34][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:3]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)c(OC)c2)cc1
Reactant: Oc1ccc(F)cc1F
Product: COc1ccc(-c2cc(Oc3ccc(F)cc3F)nnc2-c2ccc(OC)c(OC)c2)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-3-(3,4-dimethoxyphenyl)-4-(4-methoxyphenyl)pyridazine (203 mg, 0.589 mmol) and 2,4-difluorophenol were reacted as starting materials at 150° C. for 20 hours and post-treatment was then conducted, whereby the title compound was obtained as a pale yellow amorphous solid (260 mg, quantitative).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][S:8]([C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[C:16]2[NH:21]C(=O)C)(=[O:10])=[O:9].[OH-].[Na+].[ClH:27]>C(O)CC>[ClH:27].[NH2:21][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH:18]=[CH:19][CH:20]=[C:11]2[S:8]([NH:7][CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)(=[O:10])=[O:9]
Reactant: CC(=O)Nc1cccc2c(S(=O)(=O)NCc3ccco3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Product: Nc1cccc2c(S(=O)(=O)NCc3ccco3)cccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.8 %

Procedure:
N-[5-[[(2-furanylmethyl)amino]sulfonyl]-1-naphthalenyl]acetamide (202 mg, 0.59 mmol) was suspended in a solution of sodium hydroxide (148 mg, 3.7 mmol) in 1-propanol (4 ml), and the mixture was refluxed for 5 hours. After the reaction mixture was concentrated, saturated brine was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and after the layer was dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (eluent: ethyl acetate) to give a brown oil. This oil was dissolved in 1-propanol (1 ml), 2N hydrochloric acid (0.4 ml) was added thereto, and the mixture was stirred at room temperature for 20 minutes. The precipitated crystal was filtered, washed with 1-propanol and diisopropyl ether, and dried under vacuum to give the title compound as an ash white crystal (135 mg, 67.8%).
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[P:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1([PH:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: NS(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(Pc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Commercially available benzenesulfonamide (21.630 mmole, 1 eq) was dissolved in tetrahydrofuran (75 mL). The resulting solution was cooled at 0° C. nBuLi (1.02 eq, commercial solution 2.5 M in hexanes) was added dropwise leading to a white suspension. The suspension was stirred at room temperature for 30 min. The suspension was cooled at 0° C. and commercial Ph2PCl (1.01 eq) was added dropwise. The clear solution obtained was stirred overnight at room temperature. The solvent was then evaporated. The crude product was dissolved in 40 mL of dichloromethane (DCM), and filtered over a plug of SiO2 under argon. The plug was washed 5 times with 20 mL of DCM, and once with 20 mL of ethyl acetate (EA). All organic layers were united and evaporated to a sticky oil. Co-evaporation in Et2O (twice 40 mL) lead to a white powder.
Reaction SMILES: N1CCCC1.CC1C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)CC(C)=O.[BH4-].[Na+].C([O:30][C:31](=O)[CH2:32][CH:33]([N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)[CH3:34])C>CO.CC(OC)(C)C.C1(C)C=CC=CC=1>[N:35]1([CH:33]([CH3:34])[CH2:32][CH2:31][OH:30])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CCOC(=O)CC(C)N1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCNC1
Solvent: CO
Solvent: COC(C)(C)C
Product: CC(CCO)N1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Pyrrolidine (28.159, 0.4 mol), toluene (200 ml), catalytic p-TsOH (200 mg) and ethyl acetoacetate (20 g, 0.15 mol) were refluxed together in a Dean-Stark apparatus under N2 for 3 hours. The reaction was cooled to room temperature and concentrated in vacuo. NaBH4 (3.1 g, 82 mmol) was dissolved in MeOH (50 ml) and cooled to 0-5° C. A portion of the previous crude reaction (5 g, 27 mmol) in MeOH (25 ml) was added to the reaction mixture and stirred for 72 hours. The reaction was quenched with an aqueous solution of NaOH (1% w/w, 50 ml) and concentrated in vacuo. The aqueous phase was extracted with TBME (3×50 ml). The combined organic extracts were dried over MgSO4, filtered, washed with TBME and concentrated in vacuo to give a mixture of the title compound, 3-pyrrolidin-1-yl-butanoic acid ethyl ester and residual TBME (3.5 g). The mixture (3.5 g) in THF (20 ml) was added to a solution of LiALH4 (1M in THF, 33.5 ml, 33.5 mmol) at 0-5° C. under N2. The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched with an aqueous solution of NaOH (1% w/w, 50 ml) at 0-5° C., filtered and washed with THF (3×20 ml). The combined organic layers were dried over MgSO4, filtered, washed with THF and concentrated in vacuo to give the title compound as a yellow oil (2 g, 73%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=2[O:16][CH2:17][CH:18]2[CH2:20][O:19]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][NH:26][CH3:27]>O1CCCC1>[CH3:25][N:26]([CH3:27])[CH2:20][CH:18]([OH:19])[CH2:17][O:16][C:15]1[CH:21]=[CH:22][CH:23]=[CH:24][C:14]=1[CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CNC
Reactant: CC(C)c1ccc(CCCCc2ccccc2OCC2CO2)cc1
Solvent: C1CCOC1
Product: CC(C)c1ccc(CCCCc2ccccc2OCC(O)CN(C)C)cc1
Yield: 95 %

Procedure:
Following a procedure similar to that described in Example 1(b), a solution of 648 mg of 2-{2-[4-(4-isopropylphenyl)butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] in 13 ml of tetrahydrofuran was treated with 2.6 ml of 50% by volume aqueous dimethylamine. The reaction mixture was worked up and purified as described in Example 1(b), to give 703 mg (yield 95%) the title compound as a colorless oil.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[S:9][CH2:8][CH:7]([S:10]C(=O)C)[CH2:6]1)=[N+:2]=[N-:3].C[O-].[Na+]>CO>[N:1]([CH2:4][CH:5]1[S:9][CH2:8][CH:7]([SH:10])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CC(=O)SC1CSC(CN=[N+]=[N-])C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NCC1CC(S)CS1
Reaction time: 2 h
Yield: 20.7 %

Procedure:
A 0° C. solution, under argon, of 0.279 g of product from Example 141 in 3 ml of dry methyl alcohol is treated with 0.35 ml of 4.35M sodium methoxide. After 2 hours, the reaction mixture is concentrated in vacuo and the residue purified by chromatography (silica gel: 0-5% diethyl ether/hexane) to give 0.0465 g of the desired product.
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH2:11][CH2:10][CH2:9][CH:5]([C:6]([OH:8])=[O:7])[CH2:4]1.[CH2:12]([S:16](Cl)(=[O:18])=[O:17])[CH2:13][CH2:14][CH3:15]>>[CH2:12]([S:16]([N:3]1[CH2:11][CH2:10][CH2:9][CH:5]([C:6]([OH:8])=[O:7])[CH2:4]1)(=[O:18])=[O:17])[CH2:13][CH2:14][CH3:15]
Reactant: O=C(O)C1CCCNC1
Reactant: CCCCS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCS(=O)(=O)N1CCCC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1N-sodium hydroxide aqueous solution (4.1 mL) was added to nipecotic acid (500 mg, 3.87 mmol), and, under ice-cooling, butanesulfonylchloride (0.98 mL, 7.74 mmol) was added dropwise. The mixture was raised to room temperature, and stirred for 15 hours. The reaction mixture was then extracted with chloroform. The organic layer was collected, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified using silica gel column chromatography to obtain the target (354 mg, 37%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@H:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.I[CH3:37]>>[CH3:37][N:23]([S:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)=[CH:19][CH:18]=1)(=[O:22])=[O:21])[C@H:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CCC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Reactant: CI
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@H]3CCC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Yield: 93 %

Procedure:
According to the procedure of Example 15, Step 2, the reaction of 250.0 mg (0.5 mmol) of tert-butyl cis-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate with iodomethane provided 238.0 mg of tert-butyl cis-2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate in 93% yield. MS: 511.2 (M+H)+