Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[NH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26]>>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Reactant: NCCOCCO
Product: OCCOCCNc1nc2nc(SCc3ccccc3)nc(Cl)c2s1

Procedure:
Prepared according to the method of Example 220 using the product of Example 219 (0.3 g) and 2-(2-aminoethoxy)ethanol.
Reaction SMILES: [CH:1](OC(=NC(C)C)NC(C)C)([CH3:3])[CH3:2].[CH3:14][C:15]1([CH3:30])[C@@H:17](/[CH:18]=[CH:19]\[C:20]([OH:22])=[O:21])[C@H:16]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>C(OCC)(=O)C>[CH3:14][C:15]1([CH3:30])[C@@H:17](/[CH:18]=[CH:19]\[C:20]([O:22][CH:1]([CH3:3])[CH3:2])=[O:21])[C@H:16]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C
Reactant: CC(C)N=C(NC(C)C)OC(C)C
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
2 g of O-isopropyl-N,N'-diisopropyl-isourea were added to a mixture of 2.7 g of the product of Step A and 10 ml of ethyl acetate and the mixture was stirred at room temperature for one hour, refluxed for 90 minutes and then cooled to 20° C. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The 3.5 g of oil residue were chromatographed over silica gel and eluted with a 7-3 benzene-cyclohexane mixture to obtain 1 g of tert.-butyl(1R,cis)2,2-dimethyl-3-[Z-2-(isopropoxycarbonyl)-ethenyl]-cyclopropane-carboxylate which was used as is for the next step.
Reaction SMILES: [Na].[CH2:2]([OH:6])[CH2:3][CH2:4][CH3:5].[CH2:7]([N:11]1[C:15]2=[N:16][C:17]([CH3:26])=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19](Cl)=[C:14]2[N:13]=[CH:12]1)[CH2:8][CH2:9][CH3:10]>C1C=CC=CC=1>[CH2:2]([O:6][C:19]1[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([CH3:26])[N:16]=[C:15]2[N:11]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:12]=[N:13][C:14]=12)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCn1cnc2c(Cl)c(C(=O)OCC)c(C)nc21
Reactant: CCCCO
Agent: [Na]
Solvent: c1ccccc1
Product: CCCCOc1c(C(=O)OCC)c(C)nc2c1ncn2CCCC

Procedure:
0.03 g. of sodium and 0.8 g. of n-butyl alcohol are refluxed for 5 hours in 50 ml. of dry benzene. After this time, 3 g. of 3-butyl-7-chloro-5-methyl-3H-imidazo[ 4,5-b]-pyridine-6-carboxylic acid, ethyl ester obtained in Example 3 c are added and the mixture is refluxed for 12 hours. After the inorganic precipitate has been filtered off, the solvent is removed in vacuo and the residue distilled to obtain 7-butoxy-3-butyl-5-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester, b.p. 210°-220° /0.01. Yield 2.1 g. (66%).
Reaction SMILES: CC(C)([O-])C.[K+].C(OC(=O)[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([O:21]CC)=O)[CH2:14]1)C>C1(C)C=CC=CC=1>[N:13]12[CH2:14][CH:15]([CH2:16][CH2:17][CH2:18]1)[C:19](=[O:21])[CH2:11][CH2:12]2
Reactant: CCOC(=O)CCN1CCCC(C(=O)OCC)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCN2CCCC1C2
Temperature: 25 °C

Procedure:
A suspension of potassium tert-butoxide (12.03 g, 107 mmol; Aldrich) in toluene (200 mL) was heated to reflux for 15 minutes, then a solution of ethyl 1-(3-ethoxy-3-oxopropyl)piperidine-3-carboxylate (10.70 g, 41.6 mmol; Example 35A) in toluene (50 mL) was added dropwise over 2 hour to the refluxing reaction mixture. After the addition was complete, the reaction was heated to reflux for an additional 2 hours, cooled to ambient temperature, and extracted with water (3×50 mL). The combined aqueous layers were acidified with concentrated hydrochloric acid (40 mL), then heated to reflux for 22 hours. The reaction was basified with 45 weight % potassium hydroxide (˜35 mL) and extracted with chloroform (3×100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.50-1.81 (m, 2 H), 1.90-1.96 (m, 2 H), 2.39-2.43 (m, 1 H), 2.49-2.54 (m, 2 H), 3.08-3.41 (m, 6 H); MS (DCI/NH3) m/z 140 (M+H)+.
Reaction SMILES: Cl.C[O:3][C:4](=O)[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[NH2:6][C@@H:5]([CH:7]([CH3:9])[CH3:8])[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:3]
Reactant: Br[Mg]c1ccccc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)[C@H](N)C(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 35.9 %

Procedure:
L-Valine methyl ester hydrochloride (9.9 g, 59.06 mmol) was added portionwise to a 1.0 M solution of phenylmagnesium bromide (108.8 g, 0.6 mol) in THF at 0° C. and heated at reflux for 20 h. After quenching with crushed ice and NH4Cl salt, the organic layer was separated, washed with brine and concentrated under reduced pressure. The resulting solid was treated with HCl (2.0 M, 100 ml) and then evaporated to dryness under reduced pressure. Impurities precipitated out as a white solid, when the amine hydrochloride salt was dissolved in hot MeOH and allowed to cool to room temperature. After removing the impurities by filtration, the filtrate was made basic with KOH (1.0 M) and the organics were extracted into diethyl ether (4×100 ml). Combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to obtain a crude product as a light brown solid. Purification over silica gel, eluting with a 1:4 and 1:1 mixture of ethyl acetate and petrol gave the title compound (2) (5.42 g, 36%) as a white solid. m.p. 90–92° C. (liti 94–95° C.). [α]D25=−107.92° (c, 0.0424 in CHCl3) (litii: −127.7° (c, 0.639 in CHCl3). δH 0.81 (3H, d, 3J=6.90 Hz, CH3), 0.85 (3H, d, 3J=7.20 Hz), 1.67 (1H, ds, 3J=1.80 and 6.90 Hz, CH-Me2), 3.76 (1H, d, 3J=2.10 Hz, CH—NH2), 7.04–7.58 (10H, m, Ar). δC 16.3 and 23.2 (CH3), 28.1 (CH—Me2), 60.4 (CH—NH2), 79.9 (C—OH), 125.7, 126.1, 126.5, 126.8, 128.2 and 128.6 (o-, m- and p-Ar), 145.1 and 148.2 (α-Ar. Anal. Calcld. for C17H21NO: C 79.96; H 8.29; N 5.48. Found: C 79.80; H 8.15; N 5.39. ir 3338 (OH and NH2). m/e (CI—CH4) 256 (MH+, 14%), 72 (100%).
Reaction SMILES: [NH2-].[Na+].[C:3]1([CH2:13][C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[N:16]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CCOCC>[N:16]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:13]([C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][CH:4]=2)[C:14]#[N:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: N#CCc1cccc2ccccc12
Reactant: ClCCCCCCN1CCCCC1
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: N#CC(CCCCCCN1CCCCC1)c1cccc2ccccc12

Procedure:
3.9 g of sodium amide are added in small quantities to 16.7 g of 1-naphthyl-acetonitrile in solution in 200 ml of anhydrous ether. After 2 hours of heating to reflux, 20.5 g of 6-piperidino-1-chloro-hexane are added and heating is continued to reflux for another 5 hours. Then, using the conventional methods, 30 g of product are isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH:27]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:29][C@H:30]([C:32]([O:34][CH3:35])=[O:33])[CH3:31].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][NH:29][C@H:30]([C:32]([O:34][CH3:35])=[O:33])[CH3:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: COC(=O)[C@H](C)N
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)cn(C)c34)no2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)[C@H](C)NCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 35 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To a stirred solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carbaldehyde (D61) (395 mg), methyl L-alaninate (206 mg) and acetic acid (60 mg) in DCM (10 mL) was added NaBH(OAc)3 (424 mg). The mixture was stirred at 35° C. overnight. After cooled to room temperature, the reaction mixture was diluted with DCM (10 mL), washed with water and saturated sodium bicarbonate solution. The organic phase was separated and dried over anhydrous sodium sulphate. The solvent was evaporated and the residue was purified by Mass Directed Auto Prep to afford methyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}-L-alaninate (D81) as a white solid (160 mg). MS (ES): C26H27ClN4O4 requires 482; found 380.1 (M—C4H8NO2+).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:19](=[O:47])[CH2:20][CH2:21][N:22]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]2[O:38][N:37]=[C:36]([C:39]3[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:46])[CH:35]=2)[CH:29]=1)[C:23](=[O:27])[CH:24]([Cl:26])[Cl:25])[CH2:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=O)(C)(C)C.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>ClCCl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[NH2:8][C@@H:9]([C:19](=[O:47])[CH2:20][CH2:21][N:22]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]2[O:38][N:37]=[C:36]([C:39]3[C:40]([Cl:46])=[CH:41][CH:42]=[CH:43][C:44]=3[Cl:45])[CH:35]=2)[CH:29]=1)[C:23](=[O:27])[CH:24]([Cl:26])[Cl:25])[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(=O)CCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CCC(=O)O)C(=O)CCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1

Procedure:
(R)-tert-Butyl 4-(tert-butoxycarbonylamino)-7-(2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)acetamido)-5-oxoheptanoate (165 mg) was dissolved in anhydrous dichloromethane (2 mL) and cooled in an ice-bath under nitrogen. Then trifluoroacetic acid (2 mL) was added. After 4.5 h at 4° C. the mixture was concentrated under reduced pressure. The residue was dissolved and concentrated under reduced pressure again to give (R)-4-amino-7-(2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)acetamido)-5-oxoheptanoic acid trifluoroacetate salt as a tan solid. 1H NMR (CD3CN): 8.73 (m, 1H), 7.99 (m, 2H), 7.48 (m, 3H), 7.11 (s, 1H), 6.48 (s, 1H), 4.05 (m, 2H), 3.05-2.85 (m, 2H), 2.30 (m, 2H), 2.15 (m, 1H), 1.97 (m, 2H), 1.80 ppm (m, 1H). MW=594 confirmed by LC-MS, tr=10.07 min (Method Y) MH+=592-596.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11]C(=O)OC(C)(C)C)=[CH:8][CH:9]=2)[C:4]([C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[C:4]([C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:3]1
Reactant: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(NC(=O)OC(C)(C)C)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(N)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of [1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yl]-carbamic acid, tert-butyl ester [0.2 g, Reference Example 30] in dichloromethane was treated with trifluoroacetic acid (2 mL). After stirring at ambient temperature for 16 hours the reaction mixture was evaporated. The residue was suspended in saturated sodium bicarbonate solution (10 mL) and the resulting solid was filtered then dried to give the title compound as a yellow solid, m.p. 247-248° C. MS: 263 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12]2[NH:13][C:14](=[O:21])[C:15]3[C:20]([C:11]=2[C:10]2[CH:9]=[C:8]([Cl:22])[CH:7]=[CH:6][C:5]1=2)=[CH:19][CH:18]=[CH:17][CH:16]=3.[CH3:23]I>CN(C)C=O>[CH3:23][O:21][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]2[C:10]3[CH:9]=[C:8]([Cl:22])[CH:7]=[CH:6][C:5]=3[N:4]([CH3:3])[C:12]=2[N:13]=1
Reactant: Cn1c2ccc(Cl)cc2c2c3ccccc3c(=O)[nH]c21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc2c(c3ccccc13)c1cc(Cl)ccc1n2C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a stirred suspension of 0.08 g of 65% sodium hydride (in oil) in 5 ml of dimethylformamide, 0.5 g of 7-methyl-10-chloroindolo(2,3-c)isoquinolin-5(6H)-one is added at room temperature. The reaction mixture is stirred for 30 minutes and 2.5 g of methyl iodide in 30 ml of dimethylformamide is added dropwise thereto at room temperature. After addition, stirring is continued for further 16 hours at room temperature and then dimethylformamide is removed under reduced pressure. The residue is treated with water and extracted with dichloromethane. The organic layer is dried over magnesium sulfate and the solvent is evaporated in vacuo to give 404 mg of 5-methoxy-7-methyl-10-chloro-7H-indolo(2,3-c)isoquinoline, which is recrystallized from ethyl acetate, melting point 179°-180.5° C.
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][N:5]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:4]1.[NH:38]1[CH:42]=[N:41][N:40]=[CH:39]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:26][O:25][CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[N:17]=[C:16]1[C:14]([N:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[C@H:7]1[CH2:8][C@@H:3]([CH2:2][N:40]2[CH:39]=[N:38][CH:42]=[N:41]2)[CH2:4][N:5]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:6]1)=[O:15]
Reactant: c1nnc[nH]1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](CO)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](Cn3cncn3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Yield: 78.8 %

Procedure:
A solution of tert-butyl (3R,5S)-3-(hydroxymethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (208 mg), 1,3,4-triazole (52 mg), triphenylphosphine (262 mg) and diisopropyl azodicarboxylate (40% toluene solution, 632 mg) in THF (5 ml) was stirred at 50° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, diluted with water and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:5-1:0) and ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9 to 3:1) was concentrated under reduced pressure to give the object product (180 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:18])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][N:24]=[C:25]=S>>[Cl:18][C:3]1[C:2]2[N:1]=[C:25]([NH:24][CH2:23][CH2:22][CH2:21][O:20][CH3:19])[N:12]([CH2:13][C:14]([CH3:15])([OH:16])[CH3:17])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: CC(C)(O)CNc1c(N)c(Cl)nc2ccccc12
Reactant: COCCCN=C=S
Product: COCCCNc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)O
Yield: 70.7 %

Procedure:
The method described in Part A of Example 7 was used to treat 1-[(3-amino-2-chloro-4-quinolinyl)amino]-2-methyl-2-propanol (3.00 g, 11.3 mmol) with 3-methoxypropylisothiocyanate (1.78 g, 13.6 mmol) to provide 2.9 g of 1-{4-chloro-2-[(3-methoxypropyl)amino]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol after chromatographic purification.
Reaction SMILES: Br.Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: Brc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(c3ccccn3)CC2)cc1
Yield: 74 %

Procedure:
A mixture of 10.6 parts of 1-(4-methoxyphenyl)piperazine dihydrobromide, 7.9 parts of 2-bromopyridine, 8.4 parts of potassium carbonate and 90 parts of N,N-dimethylformamide is stirred and refluxed overnight. The reaction mixture is diluted with water and the product is extracted twice with benzene. The combined extracts are dried, filtered and evaporated. The residue is crystallized from 1,1'-oxybisbutane. The product is filtered off and dried, yielding 8 parts (74%) of 1-(4-methoxyphenyl)-4-(2-pyridinyl)piperazine; mp. 125.6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10].N1C=CC=CC=1>C(Cl)Cl>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:9](=[O:10])[O:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccncc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-aminopyridine (1.97 g, 20.9 mmol) in DCM (75 mL) at 0° C. was added 4-nitrophenyl chloroformate (4.21 g, 20.9 mmol) and pyridine (1.7 mL, 20.9 mmol). Then, the mixture was stirred at RT overnight. The white precipitated was filtered off and washed with DCM (2×50 mL), and then dried in vacuo to give the title compound as a white solid, which was used in the next step without further purification. MS (ESI, positive ion) m/z: 260 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:11].[Br:13]Br>C(O)(=O)C>[Br:13][C:8]1[CH:9]=[CH:10][C:5]2[O:4][C:3](=[O:11])[C:2]([CH3:12])([CH3:1])[C:6]=2[CH:7]=1
Reactant: CC1(C)C(=O)Oc2ccccc21
Reactant: BrBr
Solvent: CC(=O)O
Product: CC1(C)C(=O)Oc2ccc(Br)cc21
Reaction time: 8 h

Procedure:
3,3-Dimethyl-3H-benzofuran-2-one (2.81 g, 17.3 mmol) was added to a solution of Bromine (1.51 mL, 29.5 mmoL) and Acetic acid (35 mL) at room temperature, then stirred overnight. The resulting mixture was stripped of solvent, then distilled under high vacuum. The product fraction (2.08 g, 50%) was collected between 65° C. and 79° C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][S:18]2(=[O:23])=[O:22])=[CH:11][CH:10]=1.O.[BH4-].[Na+]>C(O)C>[CH2:1]([N:9]1[CH2:10][CH:11]=[C:12]([CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][S:18]2(=[O:23])=[O:22])[CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=S1(=O)CCCN1CCc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S1(=O)CCCN1CCC1=CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl bromide (3.1 cm3) was added at room temperature to a stirred solution of 2-[2-(4-pyridyl)ethyl]isothiazolidine-1,1-dioxide (4.9 g) in ethanol (30 cm3) and the mixture was heated under reflux for 3 hours. After cooling to room temperature, water (30 cm3) was added followed by sodium borohydride (1.2 g) and the mixture was stirred for 1 hour. Volatile material was removed in vacuo and the residue was treated with 2M hydrochloric acid to pH1, followed by neutralisation with sodium carbonate solution and subsequent extraction with chloroform (3×100 cm3). The dried (MgSO4) chloroform extract was evaporated to give an oil which was chromatographed on silica ("Merck" 60.9385) eluting with methanol:chloroform, 1:49, to give 2-[2-(1-benzyl-1,2,3,6-tetrahydropyrid-4-yl)ethyl]isothiazolidine-1,1-dioxide as an oil (4.5 g).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[Cl:10][S:11](O)(=[O:13])=[O:12].S(Cl)(Cl)(=O)=O>ClCCl>[F:1][C:2]([F:9])([F:8])[C:3]1[S:4][C:5]([S:11]([Cl:10])(=[O:13])=[O:12])=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)(F)c1cccs1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(C(F)(F)F)s1

Procedure:
5-trifluoromethyl-thiophene-2-sulfonylchloride was prepared from commercially available 2-trifluoromethyl-thiophene through reaction with chlorosulfonic acid in dichloromethane and subsequent silica gel chromatography (1H-NMR of the sulfonylchloride (CDCl3, 400 MHz): δ [ppm] 7.9 (1H, d), 7.5 (1H, d)).
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[CH3:37][N:38]([CH3:46])[C:39]1[CH:44]=[C:43]([NH2:45])[CH:42]=[CH:41][N:40]=1>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:45][C:43]1[CH:42]=[CH:41][N:40]=[C:39]([N:38]([CH3:46])[CH3:37])[CH:44]=1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)c1cc(N)ccn1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1cc(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)ccn1
Temperature: 50 °C

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (37.3 mg, 0.135 mmol) in dry dichloromethane (2.5 mL) was added triethylamine (0.047 mL, 0.338 mmol), 2-chloro-1-methylpyridinium iodide (38.3 mg, 0.15 mmol), and 2-dimethylamino-4-aminopyridine (21.7 mg, 0.158 mmol) sequentially at room temperature under nitrogen. The reaction was then heated to 50° C. for 1.5 hours. LC/MS showed reaction complete. The reaction mixture was concentrated and purified by HPLC on a 30×100 mm Waters Sunfire column to afford the title compound as an off-white solid after lyophilization.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=1)=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:3].[H][H]>[Pd].CO>[CH2:2]([N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:12][CH:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])=[CH:17][CH:16]=1)[OH:14])[CH3:3]
Reactant: [H][H]
Reactant: CCCCCCCN(CC)CC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCCCCN(CC)CC(O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
A solution of N-[4-[(ethylheptylamino)acetyl]phenyl]methanesulfonamide monohydrochloride as prepared in Preparation 6 (4.0 g, 0.0103 mol) and 150 ml of MeOH is reduced in a Parr hydrogenator using 10% palladium-on-carbon (0.3 g) at an initial hydrogen pressure of 50 PSI. After 18 hours the reaction mixture is filtered over Celite and the filtrate is concentrated in vacuo. The residue is mixed with NaHCO3 and extracted well with CH2Cl2. The combined organic extracts are washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue is then dissolved in Et2O, treated with Darco, and crystallized from Et2O:Pet ether to yield 3.1 g of N-[4-[2-(ethylheptylamino)-1-hydroxyethyl]phenyl]methanesulfonamide, m.p. 65°-67° C. The analytical sample has m.p. 71°-72° C.