Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([N:14]3[CH2:15][CH2:16][N:17]([CH2:25][C:24]4[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=4)[CH2:18][CH2:19]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(CCl)c1
Reactant: Fc1ccc([C@H]2CC[C@H](N3CCNCC3)CC2)cc1
Product: COc1cccc(CN2CCN([C@H]3CC[C@H](c4ccc(F)cc4)CC3)CC2)c1

Procedure:
The title compound was prepared from trans 1-[4-(4-fluorophenyl)-1-cyclohexyl]piperazine (0.39 g, 1.5 mmole) and 3-methoxybenzyl chloride (0.22 g, 1.5 mmole) by the method described in example 45 to give the product (61%, mp: 84-85° C.). Calc'd for C24H31FN2O: C, 75.36%; H, 8.17%; N, 7.33%. Found: C, 75.53%; H, 8.23%; N, 7.30%.
Reaction SMILES: O[CH:2]([C:4]1[CH:8]=[N:7][N:6]([CH2:9][C@@H:10]2[C@H:13]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:25])[NH:11]2)[N:5]=1)[CH3:3].[C:26]([O:30][C:31](/[N:33]=[C:34](\[NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])/[N:35]1[CH:39]=[CH:38][CH:37]=[N:36]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:17]([O:16][C:15]([NH:14][C@@H:13]1[C:12](=[O:25])[NH:11][C@@H:10]1[CH2:9][N:6]1[N:5]=[C:4]([CH:2]([N:40](/[C:34](=[N:33]/[C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])/[N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)[C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH3:3])[CH:8]=[N:7]1)=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(O)c1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)/N=C(\NC(=O)OC(C)(C)C)n1cccn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1)N(C(=O)OC(C)(C)C)/C(=N/C(=O)OC(C)(C)C)n1cccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a solution of benzyl ((2R,3S)-2-((4-(1-hydroxyethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)carbamate (460 mg, 1.33 mmol), (E)-tert-butyl (((tert-butoxycarbonyl)imino)(1H-pyrazol-1-yl)methyl)carbamate (455 mg, 1.465 mmol), and triphenylphosphine (419 mg, 1.60 mmol) in THF (7 ml) at 0° C. was added DIAD (0.311 ml, 1.598 mmol) dropwise. The reaction was stirred at room temperature overnight and concentrated to dryness. Purification of the crude residue via silica gel chromatography (EtOAc-Heptane, 30-60%) afforded the title compound (190 mg, 22%) as a light yellow solid. LCMS: Rt=0.99 min, m/z=638.4 (M+1) Method 2m_acidic.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([Cl:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].Cl.[CH3:15][S:16]([CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:18])=[O:17].C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Cl:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:24]1[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][S:16]([CH3:15])(=[O:17])=[O:18])[CH2:26][CH2:25]1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: COc1cc(F)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 91.3 %

Procedure:
To 1-chloro-2-fluoro-4-(methyloxy)-5-nitrobenzene (Example 104, Step B) (0.822 g, 4.0 mmol), 4-[2-(methylsulfonyl)ethyl]piperazine hydrochloride (Example 148, Step B) (0.915 g, 4.0 mmol), and K2CO3 (1.7 g, 12 mmol) was added DMSO (8 mL). The reaction was heated to 100° C. for two days. The reaction was determined to be complete by TLC. The reaction mixture was diluted with H2O and extracted with DCM and EtOAc sequentially for two iterations. The organic was dried (MgSO4), filtered, and rotovapped down. Purification by flash chromatography provided the title compound of Step A (1.38 g, 91%). MS (M+H, ES+) 378.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH2:9][C:10](O)=[O:11])[N:7]=[N:8][C:4]=2[C:3]=1[O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[CH:17]=1.C(Cl)(=O)C(Cl)=O.[F:31][C:32]([F:41])([F:40])[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[NH2:39]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH2:9][C:10]([NH:39][C:38]3[CH:37]=[CH:36][N:35]=[CH:34][C:33]=3[C:32]([F:41])([F:31])[F:40])=[O:11])[N:7]=[N:8][C:4]=2[C:3]=1[O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[CH:17]=1
Reactant: Nc1ccncc1C(F)(F)F
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3CC(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3CC(=O)Nc2ccncc2C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
To a suspension of [5-chloro-4-(3-chloro-5-cyanophenoxy)-1H-1,2,3-benzotriazol-1-yl]acetic acid (15 mg, 0.041 mmol) (see step 2 in Example 16) in DCM (0.5 mL) was added oxalyl chloride (58 mg, 0.454 mmol), followed by addition of DMF (1 drop) and then, following bubbling cessation, by addition of 3-(trifluoromethyl)pyridin-4-amine (201 mg, 1.239 mmol). After 10 minutes, the reaction mixture was concentrated, taken up in MeOH/DMSO, and purified by reverse phase chromatography eluting with 30-95% MeCN/H2O+0.1% TFA. Product fractions were lyophilized to yield the title compound. 1H NMR (CDCl3) δ 8.1 (m, 3H), 8.50 (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.55 (m, 2H), 7.41 (m, 1H), 7.27 (m, 1H), 7.07 (s, 1H), 5.60 (s, 2H). HRMS (M+1)=507.0363
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1.[OH-].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].O>C(O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH:8]=2)[CH:3]=1
Reactant: CCCCCCCCCCCCBr
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCOc1ccc2cc(Br)ccc2c1

Procedure:
22.29 g (0.1 mol) of 2-bromo-6-naphthol, 11.22 g (0.2 mol) of potassium hydroxide, and 32.36 g (0.13 mol) of 1-bromododecane were dissolved in ethanol (300 ml), and the solution was refluxed for 8 hr. Thereafter, water was added thereto, the mixture was cooled, and the resultant precipitate was collected by filtration and washed with a sodium hydroxide solution and then with water. The crude product thus obtained was recrystallized from ethyl acetate to give 2-bromo-6-dodecyloxynaphthalene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3[C:19]([O:38][CH2:39][CH2:40][OH:41])=[N:20][N:21]([CH3:37])[C:22]=3[NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[CH:17][C:12]=2[O:11][CH2:10]1>>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3[C:19]([O:38][CH2:39][CH2:40][O:41][C:5]4[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=4)=[N:20][N:21]([CH3:37])[C:22]=3[NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:34])[CH3:35])=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: Cn1nc(OCCO)c(-c2ccc3c(c2)OCO3)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: Clc1ncc(Br)cn1
Product: Cn1nc(OCCOc2ncc(Br)cn2)c(-c2ccc3c(c2)OCO3)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was made according to the procedure used for Example 13 except that (45 mg) of 5-bromo-2-chloropyrimidine was used and that N-[4-(1,3-benzodioxol-5-yl)-3-(2-hydroxyethoxy)-1-methyl-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 17) (70 mg) was used in place of 4-(tert-butyl)-N-{3-(2-hydroxyethoxy)-1-methyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}benzenesulfonamide (Example 12). The crude was purified by HPLC on a 5μ ODS Phenomenex Magellen™ column with a gradient elution of acetonitrile (5% to 95%) and 0.1M NH4OAc (95% to 5%) to yield the desired product as an off white solid (19.6 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].[C:20](=[O:25])=[N:21][C:22](Cl)=[O:23].N1C=CC=CC=1>C(Cl)Cl>[F:14][C:12]1[CH:11]=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[C:8]([N:7]2[C:22](=[O:23])[NH:21][C:20](=[O:25])[N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:19])[C:6]2=[O:18])[CH:13]=1
Reactant: O=C=NC(=O)Cl
Reactant: COC(=O)CNC(=O)Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(F)ccc2[N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of N-[(5-fluoro-2-nitrophenyl)carbamoyl]glycine methyl ester (20.47 g, 75.46 mmol) in methylene chloride is cooled in an ice-bath, treated with N-(chlorocarbonyl) isocyanate (7 mL, 86.94 mmol), treated dropwise with pyridine (7.5 mL, 92.92 mmol), warmed to and stirred at room temperature for 90 minutes, and filtered. The filtrate is poured into 0.11M hydrochloric acid (450 mL), the phases are separated and the aqueous phase is extracted with methylene chloride. The organic phase and extracts are combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain the title product as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=1
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc2c(Br)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(Br)nn(CCN3CCCC3)c2c1
Temperature: 50 °C
Yield: 64.7 %

Procedure:
A mixture of 3-bromo-6-nitro-1H-indazole (1.0 g, 4.1 mmol) and potassium carbonate (2.9 g 21 mmol) in DMF (20 mL) was stirred for 30 minutes after which 1-(2-chloro-ethyl)-pyrrolidine (1.8 g, 10 mmol) was added. The mixture was heated to 50° C. for 6 hours, cooled to room temperature and filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound (900 mg, 64%). 1H NMR (300 MHz, DMSO-d6) ppm 1.61 (m, 4H), 2.47 (m, 4H), 2.90 (t, 2H, J=6.44), 4.69 (t, J=6.44, 2H), 7.82 (m, 1H), 8.02 (m, 1H), 8.86 (m, 1H); MS (DCI/NH3) m/z 339 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][C:13]2[C:8]3=[C:9]([CH2:15][C:16](=O)[N:7]3[CH2:6]1)[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][C:13]2[C:8]3=[C:9]([CH2:15][CH2:16][N:7]3[CH2:6]1)[CH:10]=[CH:11][CH:12]=2)[CH2:19][CH3:20]
Reactant: CCCN(CCC)C1Cc2cccc3c2N(C1)C(=O)C3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCN(CCC)C1Cc2cccc3c2N(CC3)C1
Yield: 47.8 %

Procedure:
A mixture of 5 -(dipropylamino)-5,6-dihydro-4H-pyrrolo [3,2,1 -ij ]quinolin-2(1H)-one (0.75 g) and lithium aluminum hydride (0.21 g) was stirred in ether (20 mL) for 45 minutes. The reaction was quenched with methanol, evaporated and partitioned between ethyl acetate and water. Evaporation of the ethyl acetate gave an oil which was chromatographed on silica gel using ethyl acetate:hexane (1:20) as eluant to give, as the first compound eluted from the column 0.27 g of 5,6-dihydro-N,N-dipropyl-4H-pyrrolo[3,2,1-ij]quinolin-5-amine (compound 87). Continued elution of the column gave 0.34 g of 1,2,5,6-tetrahydro-N,N-dipropyl-4H-pyrrolo [3,2,1-ij]quinolin-5-amine (compound 92).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:15](O)[CH3:16]>OS(O)(=O)=O>[CH2:15]([O:13][C:12](=[O:14])[CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH2:1])[S:3][C:4]=2[CH:10]=1)[CH3:16]
Reactant: Nc1nc2ccc(CC(=O)O)cc2s1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc2nc(N)sc2c1

Procedure:
A solution of (2-amino-benzothiazol-6-yl)-acetic acid (0.61 mmol, as prepared by Meyer et al. in J. Med. Chem. 1997, 40, 1060) in absolute ethanol (10 mL) was treated with 3 drops of concentrated H2SO4 and ca. 1 g of dry 4A molecular sieves, and heated to reflux for 3 d. The reaction was concentrated to dryness in vacuo, partitioned between CH2Cl2 and saturated aqueous NaHCO3, filtered, and phases separated. The aqueous layer was extracted with CH2Cl2, and the combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and the filtrate concentrated in vacuo giving the title compound as a yellow solid. 1H NMR (CDCl3) δ 7.50 (1H, m), 7.41 (1H, d, J=8.3 Hz), 7.20 (1H, dd, J=8.2 Hz, 1.9 Hz), 4.15 (2H, q, J=7.2 Hz), 3.65 (2H, s), 3.42 (4H, s [NH2+H2O]), 1.26 (3H, t, J=7.1 Hz). ESI-MS (m/z): Calcd for C11H12N2O2S: 236.1; found 237.1 (M+H).
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[CH3:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26]I.[H-].[Na+]>C1COCC1.CCOCC>[CH3:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][O:1][CH:2]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccccc2)C1
Reactant: COCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCCCCOC(c1ccccc1)C1CCN(C(=O)OC(C)(C)C)C1
Yield: 17.5 %

Procedure:
To a stirred solution of tert-butyl 3-(hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate (205 mg, 0.74 mmol) and 4-methoxybutyl iodide (750 mg, 3.5 mmol) in dry THF (5 mL) under N2 was added 60& NaH in oil (0.14 g, 3.5 mmol). H2 evolution occurred. The mixture was heated at reflux for 8 h. The mixture was cooled, diluted with ether (90 mL), and washed with water (25 mL) and brine (25 mL), and dried over MgSO4. Removal of the solvent left an oil which was purified by flash chromatography on a 12-g silica cartridge eluted with a 0 to 100% EtOAc in hexanes gradient to afford tert-butyl 3-((4-methoxybutoxy)(phenyl)methyl)pyrrolidine-1-carboxylate (47 mg, 17%) as an oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f3) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[Br:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[Br:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(F)cc(Br)c2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2cc(F)cc(Br)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, ISP-MS: m/e=(M+H+), was prepared in accordance with the general method of example 12b) from 7-bromo-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (10.0 g, 0.035 mol) and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester 10 g, 0.042 mol). The product was isolated as a viscous yellow oil, (10.1 g, 65%); ISP MS: 445.3 (M+H)+
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12].[F:23][C:24]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:28][C:25]=1[C:26]#[N:27].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[F:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([F:12])[C:5]=1[C:4]1[N:27]=[C:26]([C:25]2[CH:28]=[C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:30]=[CH:31][C:24]=2[F:23])[N:2]([CH3:1])[N:3]=1
Reactant: CCCCCCCCCCCc1ccc(F)c(C#N)c1
Reactant: CN(N=C(Cl)c1c(F)cccc1F)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCc1ccc(F)c(-c2nc(-c3c(F)cccc3F)nn2C)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2,6-difluorobenzohydrazonoyl chloride (1.28 g), 2-fluoro-5-undecylbenzonitrile (1.09 g), anhydrous aluminum chloride (0.55 g) and o-dichlorobenzene (10 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (200 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.08 g of desired compound (melting point: 70.0°-73.0° C.).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12]SC)=[CH:7][CH:6]=1)[CH3:3].[N+:16]([CH:19]=[C:20]([NH:22][CH:23]([C:25]1[CH2:30][CH:29]=[CH:28][CH2:27][CH:26]=1)[CH3:24])[NH2:21])([O-:18])=[O:17]>>[CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12][NH:21][C:20]([NH:22][CH:23]([C:25]2[CH2:30][CH:29]=[CH:28][CH2:27][CH:26]=2)[CH3:24])=[CH:19][N+:16]([O-:18])=[O:17])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CC(NC(N)=C[N+](=O)[O-])C1=CCC=CC1
Reactant: CSCCSCc1ccc(CN(C)C)o1
Product: CC(NC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1)C1=CCC=CC1

Procedure:
24.54 grams of 2-[[5-[(dimethylamino)methyl]furfuryl]thio]ethylmethylsulphide are reacted with 41 grams of 2-nitro-N'-(1,4-cyclohexadienyl-2-ethyl)-1,1-ethenediamine at 80° C. for 3 hours. The mixture is cooled and the procedure described in Example 1 is followed. Spectrophotometric analyses confirm the structure of the compound obtained.
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[N:7][CH:8]=1.Br[C:14]1C=CC(OC)=CN=1>>[CH3:14][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[N:7][CH:8]=1
Reactant: COc1ccc(CC(=O)O)nc1
Reactant: COc1ccc(Br)nc1
Product: Cc1ccc(CC(=O)O)nc1

Procedure:
(5-Methylpyridin-2-yl)acetic acid was prepared using analogous procedures to those used for the preparation of (5-methoxypyridin-2-yl)acetic acid (SM-1ab) substituting 2-bromo-5-methylpyridine for 2-bromo-5-methoxypyridine.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11]C(=O)C)[CH3:10])=[CH:4][CH:3]=1>Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([NH2:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)NC(C)Cc1ccc(I)cc1
Agent: Cl
Product: CC(N)Cc1ccc(I)cc1

Procedure:
9.00 g (29.69 mmol) N-[2-(4-iodo-phenyl)-1-methyl-ethyl]-acetamide (I52.1) are added to 150 mL HCl (4N) and the reaction mixture is stirred at reflux over night. Then the mixture is diluted with soda lye and extracted with EtOAc. The organic layer is dried with Na2SO4 and the solvent is removed in vacuo.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:14].O>CO>[O:14]=[C:5]1[N:4]([CH2:3][CH:2]=[O:1])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: O=C1COc2ccccc2N1CC(O)CO
Solvent: O
Solvent: CO
Product: O=CCN1C(=O)COc2ccccc21
Yield: 84.9 %

Procedure:
Compound 1-3 (1.69 g, 7.58 mmol) was dissolved in MeOH (126 mL) and H2O (25 mL) in a 300 mL round bottom flask at rt, and treated with NalO4 (4.86 g, 23.0 mmol). After 2 hrs the solid was filtered, washing with methanol. The filtrate was concentrated to a white solid, taken up in dichloromethane (50 mL), washed with water (3×) and brine, then dried over sodium sulfate, and concentrated to give Compound 1-4 as a white solid (1.23 g, 83%, mp=97.1-98.0° C.). 1H NMR (500 MHz, CDCl3) δ 9.68 (s, 1H), 7.04-7.00 (m, 3H), 6.68-6.65 (m, 1H), 4.73 (s, 2H), 4.70 (s, 2H); 13C NMR (125 MHz, CDCl3) 195, 165.2, 145.3, 128.7, 124.7, 123.2, 117.6, 114.7, 67.6, 51.2; Anal Calcd. for C10H9NO3: C, 62.82; H, 4.74; N, 7.33. Found: C, 62.85; H, 4.46; N, 7.22.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18](O)=[O:19].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(C(=O)O)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl piperazine-1-carboxylate (1.81 g, 9.7 mmol), 3-fluoro-4-methylbenzoic acid (1.50 g, 9.7 mmol), and triethylamine (6.8 mL, 49 mmol) in acetnitrile (30 mL), HBTU (4.06 g, 10.7 mmol) was added. After stirring at rt for 1 h, the mixture was poured onto water (150 mL), and the mixture was extracted with EtOAc (twice). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (4:1-2:1) to give 3.14 g (quant) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:10]1[CH2:11][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:12])[CH2:9]1)=[O:22])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)N1CC(NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 686 mg of Azetidin-3-yl-carbamic acid tert-butyl ester in 10 ml of DCM, 403 mg of triethylamine was added and the mixture was cooled to 0° C. Then, 598 mg of butyl chloroformate was slowly added. After the addition was completed the reaction mixture was allowed to warm to RT and to stir for 2 h. Then, 200 ml of DCM was added and the organic phase was washed two times with 0.1M aqueous hydrochloric acid and the with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 910 mg.