Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][O:37][C:38]1[CH:44]=[C:43]([CH:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH3:53])[CH2:47][CH2:46]2)[CH:42]=[CH:41][C:39]=1[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[CH:42][C:43]([CH:45]4[CH2:46][CH2:47][N:48]([CH2:51][CH2:52][CH3:53])[CH2:49][CH2:50]4)=[CH:44][C:38]=3[O:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCCN1CCC(c2ccc(N)c(OC)c2)CC1
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCCN1CCC(c2ccc(Nc3nccc(-c4c(-c5ccc(OC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OC)c2)CC1
Temperature: 120 °C
Yield: 68.4 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), a different batch of 2-(methyloxy)-4-(1-propyl-4-piperidinyl)aniline (48 mg, 0.19 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 24 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (92 mg, 0.13 mmol, 68%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.37 (d, J=6.23 Hz, 1H), 8.50 (s, 1H), 8.24 (d, J=5.31 Hz, 1H), 8.10 (d, J=2.01 Hz, 1H), 7.76 (dd, J=8.61, 2.20 Hz, 1H), 7.66 (dd, J=18.77, 8.52 Hz, 2H), 7.34-7.45 (m, 2H), 7.27 (d, J=8.79 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.92-6.99 (m, 2H), 6.78 (dd, J=8.06, 1.65 Hz, 1H), 6.58 (d, J=5.13 Hz, 1H), 3.97 (s, 3H), 3.81 (s, 3H), 2.87-2.97 (m, J=10.80 Hz, 2H), 2.39-2.46 (m, 1H), 2.17-2.27 (m, 2H), 1.86-1.97 (m, 2H), 1.64-1.75 (m, 4H), 1.38-1.48 (m, 2H), 0.84 (t, J=7.23 Hz, 3H). MS (ESI): 704 [M+H]+.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].Cl.Cl.[CH2:8]([NH:15][NH2:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C1(C)C(C)=CC=CC=1>[CH2:8]([N:15]1[C:8]2[C:9](=[CH:10][CH:11]=[C:1]([OH:4])[CH:2]=2)[C:14]([CH2:13][CH3:12])=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NNCc1ccccc1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCc1nn(Cc2ccccc2)c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
1-(2-Fluoro-4-hydroxyphenyl)propan-1-one (5.37 g) that can be produced by the method described in Reference Example 9 or the like, sodium acetate (12.75 g; manufactured by Wako Pure Chemical Industries, Ltd.) and benzylhydrazine dihydrochioride (9.452 g; manufactured by Sigma-Aldrich Co.) were suspended in xylene (76 mL). The suspension was stirred overnight at reflux using a Dean-Stark apparatus. The reaction solution was cooled to room temperature, subsequently water was added thereto, and the mixture was extracted two times with ethyl acetate. The organic layer was washed two times with water and with brine, and was dried over anhydrous sodium sulfate. Subsequently, the solvent was evaporated under reduced pressure. Before completely evaporating the solvent, precipitates were filtered, and the solids were washed with n-hexane. Thus, the title compound (4.76 g) was obtained. Furthermore, the filtrate was concentrated under reduced pressure, and the solids precipitating in the middle of the concentrating process were also filtered. Thus, the title compound (3.44 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:21]([N:23]([CH2:33][CH3:34])[S:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Cl)(=[O:26])=[O:25])[CH3:22]>C(N(C(C)C)C(C)C)C>[CH2:33]([N:23]([CH2:21][CH3:22])[S:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:25])=[O:26])[CH3:34]
Reactant: CCN(CC)S(=O)(=O)CCCCCCl
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)S(=O)(=O)CCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 92 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and N,N-diethyl-5-chloropentanesulfonamide (531.9 mg, 2.20 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (50:1), to give N,N-diethyl-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]pentanesulfonamide (905.2 mg) as a yellow oil (yield based on 1-[(4-chlorophenyl)phenylmethyl]piperazine: 92.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:29]3[C:28]4[CH2:27][CH2:26][N:25]([C:30](=[O:36])[CH:31]=[CH:32][CH2:33][CH2:34][OH:35])[CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:29]3[C:28]4[CH2:27][CH2:26][N:25]([C:30](=[O:36])[CH:31]=[CH:32][CH2:33][CH2:34][O:35][S:45]([CH3:44])(=[O:47])=[O:46])[CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C(C=CCCO)N1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC=CC(=O)N1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
In a 250 ml rb flask were placed 1-[4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenyl amino]-5,8-dihydro-6H-9-thia-1,3,7-triaza-fluoren-7-yl}-5-hydroxy-pent-2-en-1-one (1.00 g, 1.91 mmol) in THF (80 ml) and to the solution was added triethylamine (0.58 g, 5.74 mmol) (0.80 ml) followed by methanesulfonyl chloride (0.54 g, 4.79 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight. THF was evaporated and to the residue was added water and small amount of methyl alcohol, sonicated. The precipitated off-white solid was filtered, washed with methyl alcohol and dried to provide 0.63 g of off-white solid. (55%) 1H-NMR (DMSO-d6) δ 8.601-8.585 (m, 1H), 8.394 (s, 1H), 8.196 (s, 1H), 7.906-7.864 (m, 1H), 7.769 (s, 1H), 7.584-7.564 (d, 1H), 7.523-7.501 (d, 1H), 7.388-7.357 (m, 1H), 7.239-7.216 (d, 1H), 6.765-6.703 (m, 2H), 5.280 (s, 2H), 4.957 (s, 1H), 4.843 (s, 1H), 4.366-4.337 (m, 2H), 3.940-3.860 (m, 2H), 3.255-3.189 (m, 6H), 2.655-2.626 (m, 2H). MS m/e 600.0 (M+H), RT=2.78 min
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12]O)=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O=S(Cl)Cl.[N-:19]=[N+:20]=[N-:21].[Na+]>C(Cl)(Cl)Cl>[N:19]([CH2:12][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:14])=[N+:20]=[N-:21]
Reactant: OCc1cc2cccc(Cl)c2nc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=NCc1cc2cccc(Cl)c2nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of (2,8-dichloroquinolin-3-yl)methanol (228 mg, 1 mmol) in CHCl3 (4 mL) was treated with SOCl2 (0.36 mL, 5 eq) dropwise, and the reaction was stirred at rt for 2 h before removal of solvents and the residue was partitioned between EtOAc and NaHCO3. The organic was separated and dried over Na2SO4. Solvents were removed under reduced pressure and the residue was dried under vacuum. The residue was dissolved in DMSO (2 mL) and treated with NaN3 (72 mg, 1.1 eq) at rt. LCMS showed completion after 4 h. The reaction mixture was partitioned between EtOAc (2 mL) and water (1 mL), and the water layer was extracted with EtOAc (5 mL) once and combined organics were washed with water, brine, dried over Na2SO4 and concentrated to give a pale yellow solid as 3-(azidomethyl)-2,8-dichloroquinoline (215 mg, 85%, 2 steps). This solid (50 mg, 0.2 mmol) in DCM (2 mL) was treated with piperidine (143 μL, 7.3 eq) in EtOH (2 mL) at reflux over night. The reaction was worked up and the residue was purified by column chromatography on silica gel (eluent: EtOAc/hexane, 1/5) to give a yellow solid (30 mg, 50%). 1H NMR (400 MHz, CDCl3) δ ppm 8.01 (1 H, s), 7.62 (1 H, t, J=8.0 Hz), 7.53 (1 H, d, J=8.0 Hz), 7.49 (1H, d, J=8.0 Hz), 4.02 (2H, s), 3.26-3.23 (m, 4H), 1.74-1.58 (m, 6H). Mass Spectrum (ESI) m/e=302 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]#N)[C:11]=3[CH:17]=2)=[N:4][N:3]=1.C(O)=[O:19]>[Ni].O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([CH:15]=[O:19])[C:11]=3[CH:17]=2)=[N:4][N:3]=1
Reactant: O=CO
Reactant: Cc1nnc(-c2ccc3occ(C#N)c3c2)o1
Agent: [Ni]
Solvent: O
Product: Cc1nnc(-c2ccc3occ(C=O)c3c2)o1
Yield: 55 %

Procedure:
A mixture of 5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-carbonitrile (1.00 g, 4.44 mmol), Raney-nickel (2.0 g), formic acid (16 mL) and water (4 mL) was heated under reflux for 30 min. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/tetrahydrofuran=1/1) and recrystallized from hexane/tetrahydrofuran to give the title compound (558 mg, yield 55%) as colorless crystals.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Cl[C:18]1[CH:19]=[C:20]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[N:30]=1)[C:21]([O:23]C(C)(C)C)=[O:22]>O1CCCC1>[C:13]([O:12][C:10]([N:7]1[CH2:6][CH2:5][CH:4]([O:3][C:18]2[CH:19]=[C:20]([CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[N:30]=2)[C:21]([OH:23])=[O:22])[CH2:9][CH2:8]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(=O)O)cc(C(F)(F)F)n2)CC1
Reaction time: 1 h

Procedure:
To sodium hydride (60% in mineral oil, 0.36 g, 8.9 mmol) in tetrahydrofuran (15 mL) at 0° C. was added tert-butyl 4-hydroxypiperidine-1-carboxylate (1.8 g, 8.9 mmol, Aldrich). The reaction mixture was allowed to reach room temperature and stir for 1 hour. A solution of tert-butyl 2-chloro-6-(trifluoromethyl)isonicotinate (1.0 g, 3.6 mmol, from Step 1) in tetrahydrofuran (4.9 mL, 60. mmol) was introduced and the mixture was stirred at room temperature over five nights. The mixture was quenched by the careful addition of 1N NaOH (15 mL) and allowed to stir overnight. The reaction was diluted with additional water and the aqueous layer was washed with Et2O. The aqueous layer was then acidified by the addition of c.HCl to achieve pH˜3. The product was extracted with three portions of ethyl acetate. The combined EtOAc extracts were dried over sodium sulfate, filtered and concentrated. The product was used without further purification. LCMS (M-tBu+H)+: 335.1.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([CH:19]=[C:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])[CH:14]=[CH:15][C:16]=2[OH:18])[CH2:11][CH2:10][C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[C].[Pd].CN(C=O)C>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])[CH:14]=[CH:15][C:16]=2[OH:18])[CH2:11][CH2:10][C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(O)c3c2CCC(=O)N3Cc2ccccc2)S1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(Cc2ccc(O)c3c2CCC(=O)N3Cc2ccccc2)S1
Reaction time: 2 h
Yield: 85.9 %

Procedure:
2.2 g of 10% palladium carbon was added to a DMF solution (20 ml) of 2.2 g of 5-(1-benzyl-8-hydroxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethylidene)thiazolidine-2,4-dione, and the mixture was subjected to catalytic reduction at room temperature for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride solution, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=50:1). The purified product was recrystallized from a dichloromethane-ether mixed solvent, giving 1.9 g (88% yield) of 5-(1-benzyl-8-hydroxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl)thiazolidine-2,4-dione as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:11]([CH3:10])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccc(Br)cc1
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a stirred solution of (4-bromophenyl)methanamine (500 mg, 2.687 mmol) in pyridine were added methanesulfonyl chloride (0.4 mL, 5.106 mmol) at 0° C. The reaction mixture was stirred for 1 h, then diluted with dichloromethane. The mixture was washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. N-(4-bromobenzyl)methane-sulfonamide (675 mg) was obtained in 95% yield.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:16][CH2:15][CH:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH2:13][CH2:12]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:26]1([NH:29][C:30](=[O:47])[C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[CH2:28][CH2:27]1>>[CH:26]1([NH:29][C:30](=[O:47])[C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([C:2]3[CH:10]=[C:9]4[C:5]([C:6]5([CH2:12][CH2:13][CH:14]([O:17][CH2:18][CH2:19][N:20]6[CH2:21][CH2:22][O:23][CH2:24][CH2:25]6)[CH2:15][CH2:16]5)[C:7](=[O:11])[NH:8]4)=[CH:4][CH:3]=3)[CH:32]=2)[CH2:27][CH2:28]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1Nc2cc(Br)ccc2C12CCC(OCCN1CCOCC1)CC2
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(c1)NC(=O)C21CCC(OCCN2CCOCC2)CC1

Procedure:
Obtained as a white solid (81%) as a single isomer (exact isomeric form not determined) from 6′-bromo-4-(2-morpholinoethoxy)spiro[cyclohexane-1,3′-indolin]-2′-one (preparation 27) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (preparation 40) following the experimental procedure as described in preparation 38 followed by purification by flash chromatography (98:2 to 20:1 dichloromethane/methanol).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[C:5]([C:14](O)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].C1C=CC2N(O)N=[N:31]C=2C=1.CCN=C=NCCCN(C)C.N>C(Cl)Cl>[C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[C:5]([C:14]([NH2:31])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: ClCCl
Product: N#Cc1c(N2CCOCC2)sc(C(N)=O)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
4-Cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxylic acid (0.050 g, 0.13 mmol), HOBT (0.037 g, 0.274 mmol) and EDCI (50 mg, 0.261 mmol) were suspended in DCM (6.5 mL). After 30 min the reagents dissolved. To the resulting solution was added concentrated aqueous ammonia (0.26 mL, 6.5 mmol) and the solution was allowed to stir vigorously at rt overnight. The reaction mixture was concentrated and the residue was diluted with 1N HCl and extracted with EtOAc. The organic solutions were combined, washed with sat NaHCO3 and brine, dried over MgSO4 filtered and concentrated to give a brown solid. The solid was triturated with hexanes and cold EtOAc to give 4-cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxamide (48) (0.024 g, 49%). LCMS: (AA) ES+ 382, ES− 380. 1H NMR (400 MHz, d6-DMSO) δ: 7.78 (s, 1H), 7.54 (d, 2H), 7.43 (d, 2H), 3.77-3.79 (m, 4H) and 3.52-3.55 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][C:14]12[CH2:21][CH2:20][CH2:19][N:18]1[CH2:17][CH2:16][CH2:15]2>>[N:18]12[CH2:19][CH2:20][CH2:21][C:14]1([CH2:13][CH2:12][NH:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:15][CH2:16][CH2:17]2
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: NCCC12CCCN1CCC2
Product: O=[N+]([O-])c1ccc(NCCC23CCCN2CCC3)cc1

Procedure:
The procedures described in Example 12 were repeated except that 1-chloro-4-nitrobenzene (2 04 g, 12.9 mmol) and 5-(2-aminoethyl)-1 -azabicyclo[3.3.0]octane (4.00 g, 25.9 mmol) were employed. In this case, the desired compound was obtained as a yellow liquid (2.93 g, 8 2.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][CH:4]=1.C[Li].CN([CH:18]=[O:19])C>C1COCC1.C(NC(C)C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][C:4]=1[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: COCOc1ccc(OC)cc1
Agent: [Li]C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCOc1ccc(OC)c(C=O)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a mixture of 2-methoxy-5-(methoxymethoxy)benzene (30 g, 0.178 mol, 1 eq.) and diisopropylamine (507 uL, 3.6 mmol, 0.02 eq.) in THF (500 mL) was added methyl lithium (1.6 M/THF, 200 mL, 0.32 mol, 1.8 eq.) at −40° C. Upon the completion of addition, the mixture was warmed to 0° C., continued to stir at 0° C. for 3 h, cooled back down to −40° C. and added DMF (24.7 mL, 0.32 mol, 1.8 eq.) slowly. The mixture was then stirred at −40° C. for 1 h, quenched with a mixture of HCl (12 N, 120 mL) and THF (280 mL), warmed to rt, and added water (200 mL). The pH of the mixture was adjusted to pH 8-9 with solid K2CO3. The aqueous layer was extracted with EtOAc (300 mL) twice. The combined organic layers were dried over Na2SO4 and concentrated to give 2-methoxy-5-(methoxymethoxy)benzaldehyde (33.5 g, 95.7%) as a brown solid, which was used for next step without further purification. 1H NMR (400 MHz; CD3OD) 7.90 (s, 1H), 6.92 (s, 1H), 5.64 (s, 1H), 5.20 (s, 2H), 3.84 (s, 3H), 3.48 (s, 3H). LRMS (M+H+) m/z 198.1
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.Br[CH:26]([CH3:33])[CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>C1COCC1>[O:31]=[C:30]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:33][N:1]1[CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(Br)CCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(N2CCCCCC2=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
To a solution of benzyl 4-aminopiperidin-1-carboxylate (1.7 g) and triethylamine (1.1 mL) in THF (40 mL) was added dropwise 5-bromohexanoyl chloride (1.1 mL), and the mixture was stirred at 0° C. for 2 hours. The solvent was distilled off under reduced pressure and the residue was diluted with water, and extracted with ethyl acetate. The extract was washed with an aqueous 5% citric acid solution and a saturated saline solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in DMF (40 mL), and cooled at 0° C., sodium hydride (60% in oil; 0.60 g) was added thereto, and the mixture was stirred at 0° C. for one hour, at room temperature for one hour and at 80° C. for 15hours. The solvent was distilled-off under reduced pressure, the residue was diluted with water, and the solution was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and saturated saline solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1 to 5/1) to obtain the title compound (0.25 g, 10%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:9]2([OH:17])[O:14][CH2:13][C@@H:12]([CH3:15])[NH:11][C@H:10]2[CH3:16])[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[NH2:25][S:26]([C:29]1[C:30]([Cl:47])=[CH:31][C:32]([NH:40][CH2:41][C:42]2[O:43][CH:44]=[CH:45][CH:46]=2)=[C:33]([CH:39]=1)[C:34]([O:36][CH2:37]Cl)=[O:35])(=[O:28])=[O:27]>C(#N)C>[NH2:25][S:26]([C:29]1[C:30]([Cl:47])=[CH:31][C:32]([NH:40][CH2:41][C:42]2[O:43][CH:44]=[CH:45][CH:46]=2)=[C:33]([CH:39]=1)[C:34]([O:36][CH2:37][N:11]1[C@H:12]([CH3:15])[CH2:13][O:14][C@:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)([OH:17])[C@@H:10]1[CH3:16])=[O:35])(=[O:27])=[O:28]
Reactant: NS(=O)(=O)c1cc(C(=O)OCCl)c(NCc2ccco2)cc1Cl
Reactant: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1COC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1

Procedure:
A solution of free base of (2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (20a) (0.023 mole) (U.S. Pat. No. 5,104,870), triethylamine (0.055 mole) and acetonitrile (30 mL) is stirred with cooling on an ice bath. A solution of chloromethyl 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoate (15) (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles removed by spin evaporation, and the residue partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give (2S,3S,5R)-4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethyl)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (520). See eg., U.S. Pat. No. 5,104,870) and Sandler, et al., Organic Functional Group Preparations, p. 324 (1968).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C[O-].[Na+].[C:9]([O:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C)C=O>[C:9]([O:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCCCCCBr
Reactant: c1c[nH]cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCCCn1ccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Imidazole (70 mg) and 1.4 M sodium methoxide (1 ml) were added to N,N-dimethylformamide (3 ml) and the mixture was stirred at room temperature for 30 minutes. A solution of N-(tert-butoxycarbonyl)-6-bromo-hexylamine (280 mg) in N,N-dimethylformamide (1 ml) was added and after heating at 80-90° C. for 30 minutes stirring was continued overnight at room temperature. Evaporation in vacuo followed by stirring with acetone and fitration gave a filtrate which after evaporation was purified by chromatography on silica gel with ethyl acetate/methanol (4:1) as eluent to yield the title compound as a colourless oil.