Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:32]=[CH:31][C:22]([C:23]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:41][CH2:42][CH2:43][OH:44]>C(O)C>[OH:44][CH2:43][CH2:42][CH2:41][N:28]1[CH2:27][CH2:26][N:25]([C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:6]4[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=4)[CH2:12][CH2:13]3)=[O:18])=[CH:32][CH:31]=2)[CH2:30][CH2:29]1
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCNCC3)cc2)CC1
Reactant: OCCCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCN(CCCO)CC3)cc2)CC1
Reaction time: 1 h
Yield: 77.7 %

Procedure:
1-[4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoyl]piperazine (0.5 g) was dissolved in anhydrous ethanol (25 ml) and then, triethylamine (0.3 ml) and 3-bromo-1-propanol (0.5 g) were added. The solution was heated to reflux for 12 hours. The solvent was concentrated under reduced pressure and then, the residue was dissolved in chloroform (50 ml), and the solution was washed with water twice. Water (40 ml), methanol (5 ml) and aqueous 10% sodium hydroxide (10 ml) were added to chloroform solution and the mixture was stirred for 1 hour. The separated organic layers were washed with water and the solvent was concentrated under reduced pressure. The concentrated residue was crystallized by treatment with ether, and further recrystallized using ethyl acetate and ether, filtered and dried to give 0.44 g (yield: 78%) of the desired compound as white crystal.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH2:17][CH3:18])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([O:22]CC)=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.Cl.O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH2:17][CH3:18])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(CC)c2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 91.6 %

Procedure:
Employing ethyl 1-cyclopropyl-6,7,8-trifluoro-5-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (5 g), conc. hydrochloric acid (11 ml), water (4.4 ml) and acetic acid (44 ml), the procedure of Reference Example 23 is repeated to give 1-cyclopropyl-6,7,8-trifluoro-5-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (4.2 g), as white powder, m.p. 197°-198° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[C:19]4[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:18]=4[N:17]=[CH:16]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].C(Cl)Cl>O>[C:28]([NH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[C:19]4[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:18]=4[N:17]=[CH:16]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(-c2cccc(-n3cnc4cc(C(F)(F)F)ccc43)c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cccc(-c2cccc(-n3cnc4cc(C(F)(F)F)ccc43)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 8a (0.7 g, 1.79 mmol) was converted to the corresponding free base by partitioning between 0.1M aqueous NaOH (200 ml) and diethyl ether (200 ml). The phases were separated and the aqueous phase was extracted twice with ether. The combined ethereal phases were dried and evaporated. The residue was dissolved in dry methylene chloride (20 ml). Acetic anhydride (0.22 g, 2.15 mmol) was slowly added with ice cooling. After completed addition the mixture was stirred for one hour at room temperature. Methylene chloride (50 ml) and water (50 ml) was added and the aqueous phase was separated. The organic phase was dried and evaporated and the crude product purified by column chromatography, first with methylene chloride, then with methylene chloride/methanol (19:1 ), as eluent. Yield 400 mg, mp 118°-120° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH-].[Na+].[CH3:16]C(C)=O.O>CO>[CH3:16][O:12][C:11](=[O:13])[C:4]1[CH:3]=[C:2]([I:1])[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: O=C(O)c1cc(I)cc(C(=O)O)c1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(I)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
Dissolve 5-iodo-isophthalic acid (5 g, 15.6 mmol), NaOH (600 mg, 14.8 mmol) in a mixture of methanol (100 mL), acetone (20 mL) and water (2 mL). Stir at room temperature overnight. Concentrate and redissolve the residue in diethyl ether (100 mL) and water (100 mL). Separate the aqueous layer and wash with diethyl ether (50 mL). Acidify the washed solution with 5 N HCl to about pH=1. Stir for 30 min at room temperature and filter off solid. Wash the solid with water and dry to give the title compound (3.7 g, 77%).
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH:14]=O)=[CH:10][CH:9]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH:14]2[NH:6][C:1](=[O:5])[CH:2]([CH3:4])[O:3]2)=[CH:10][CH:9]=1
Reactant: O=CCOc1ccc(Cl)cc1
Reactant: CC(O)C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1OC(COc2ccc(Cl)cc2)NC1=O
Yield: 2.4 %

Procedure:
16.9 g (0.19 mole) of lactamide was added to a solution containing 32.3 g (0.19 mole) of (4-chlorophenoxy)acetaldehyde and 0.2 g of p-toluenesulfonic acid in 500 ml of toluene. The mixture was refluxed with stirring for 5 hours while water was removed azeotropically Toluene was removed under reduced pressure and the residue, which contained at least two major compounds, was purified by silica chromatography to give 1.1 g of 2-(4-chlorophenoxymethyl)-5-methyl-4-oxazolidinone, cis isomer, as a white crystalline solid melting at 84°-86°.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36](Cl)(=[O:38])=[O:37]>N.CO>[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:38])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccccc1S(=O)(=O)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29.2 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 2-Methylbenzenesulfonyl chloride (19 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (5.0 mg). MS m/z 343 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][CH2:14][CH3:15])[C:6]=2[N:7]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[N:16]1([C:4]2[C:5]3[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][CH2:14][CH3:15])[C:6]=3[N:7]=[C:2]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CNCCN1
Reactant: CCCSc1ncnc2c(N3CCCCC3)nc(Cl)nc12
Solvent: CS(C)=O
Product: CCCSc1ncnc2c(N3CCCCC3)nc(N3CCNCC3)nc12

Procedure:
Prepared analogously to Example 2 from 2-chloro-4-piperidino-8-n-propylthio-pyrimido[5,4-d]pyrimidine and piperazine in dimethylsulphoxide.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C@H:13]2[O:18][C@@:17]3([C:26]4[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][C:28]5[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=5)[CH:25]=4)[CH2:20][O:19]3)[C@H:16]([OH:37])[C@@H:15]([OH:38])[C@@H:14]2[OH:39])(=O)=O)=CC=1.[CH3:40][O-].[Na+]>>[Cl:36][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][C:24]=1[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][CH3:33])=[CH:30][CH:29]=1)[C@:17]1([C@H:16]([OH:37])[C@@H:15]([OH:38])[C@H:14]([OH:39])[C@@H:13]([CH2:12][O:11][CH3:40])[O:18]1)[O:19][CH2:20]2
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: C[O-]
Agent: [Na+]
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COC)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reaction time: 8 h

Procedure:
To ((1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-ethylbenzyl)-3′,4′,5′-trihydroxy-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-6′-yl)methyl 4-methylbenzenesulfonate (14 mg, 0.0243 mmol) was added 1 mL of freshly prepared sodium methoxide solution (3 M). After stirring overnight, the reaction was quenched with 2 mL of water. The organic solvent was distilled off and the water layer was extracted with ethyl acetate. The combined organic layers were washed with brine prior to drying over Na2SO4. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 7 mg of title compound. 1H NMR (CD3OD, 400 MHz) δ 7.36 (s, 1H), 7.23 (s, 1H), 7.10 (s, 4H), 5.13 (d, J=13.0 Hz, 1H), 5.07 (d, J=13.0 Hz, 1H), 4.09 (s, 2H), 3.91-3.86 (m, 1H), 3.76-3.67 (m, 2H), 3.62-3.55 (m, 2H), 3.43 (dd, J=10.4, 8.4 Hz, 1H), 3.31 (m, 3H), 2.60 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H); MS ESI (m/z) 435 (M+1)+, calc. 434.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=O)[O:11]C2=O)=[CH:4][CH:3]=1.[NH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([NH2:21])=[O:11])=[CH:4][CH:3]=1
Reactant: O=c1oc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Reactant: N
Product: NC(=O)c1ccccc1NCc1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
In 400 ml of concentrated aqueous ammonia, 14.4 g of 1-(4-chlorophenylmethyl)-2H-3,1-benzoxazine-2,4(1H)-dione were heated to 100° C. and stirred for 3 hours. After cooling, the crystals were collected by filtration, washed with water and dried. They were recrystallized from ethanol to obtain 8.6 g of title compound. m.p. 138°-139° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[CH:14]([C:17]1[N:18]=[C:19]([C:22](Cl)=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15].C(C1C=CC(OC)=CC=1NC(C1SC=C(C(C)C)N=1)=O)(=O)C>>[C:11]([C:3]1[C:2]([NH:1][C:22]([C:19]2[S:20][CH:21]=[C:17]([CH:14]([CH3:16])[CH3:15])[N:18]=2)=[O:23])=[C:7]([F:8])[C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)(=[O:13])[CH3:12]
Reactant: COc1ccc(C(C)=O)c(N)c1F
Reactant: CC(C)c1csc(C(=O)Cl)n1
Agent: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1F
Yield: 84 %

Procedure:
Compound 217c was synthesized from 1-(2-amino-3-fluoro-4-methoxyphenyl)ethanone and compound 214 as a beige solid in 84% yield, according to the procedure as described for compound 217a. MS (ESI, EI+): m/z=337 (MH+).
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28]C)[CH:23]=3)=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.[Na]>O>[CH3:36][C:33]1[CH:32]=[CH:31][C:30]([N:13]([C:10]2[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][CH:11]=2)[C:14]2[CH:15]=[CH:16][C:17]([CH:20]=[CH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)=[CH:18][CH:19]=2)=[CH:35][CH:34]=1
Reactant: COc1cccc(C=Cc2ccc(N(c3ccc(C)cc3)c3ccc(C)cc3)cc2)c1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3cccc(O)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
40 ml of N,N-dimethylformamide were added to a mixture of 4.06 g (10.0 mmol) of N,N-bis(4-methylphenyl)-4-amino-3'-methoxystilbene and 1.68 g (20.0 mmol) of sodium thioethylate. The thus prepared mixture was refluxed with stirring for 4 hours. The mixture was then cooled to room temperature, and poured into water. The ether component was extracted from the reaction mixture by a separating funnel. The thus obtained organic layer was washed with water, and dried over magnesium sulfate and further dried under reduced pressure, thereby producing a dark green oily material.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17]OS(C)(=O)=O)=[CH:11][CH:10]=2)[CH2:4][O:3]1.[Br-:24].[Li+]>CC(C)=O>[Br:24][CH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C@@H:5]2[CH2:4][O:3][C:2]([CH3:23])([CH3:1])[O:6]2)=[CH:10][CH:11]=1
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCOS(C)(=O)=O)cc2)O1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CC1(C)OC[C@@H](COc2ccc(CCCBr)cc2)O1
Temperature: 25 °C

Procedure:
Methanesulfonic acid 3-[4-((R)-2,2-dimethyl [1,3]dioxolan-4-ylmethoxy)-phenyl]-propylester (11.8 g, 34.2 mmol) in acetone (200 ml) is treated with lithium bromide (8.9 g, 100 mmol) and then heated at reflux for 5 h. After cooling to room temperature, the mixture is concentrated in vacuo. The resulting residue is dissolved in EtOAc (150 ml), washed with water (2×50 ml), brine, dried (MgSO4), filtered and concentrated in vacuo to give an oil. Purification by chromatography on silica eluting with 4:1 iso-hexane/EtOAc gives (R)-4-[4-(3-Bromo-propyl)-phenoxymethyl]-2,2-dimethyl-[1,3]dioxolane as a colourless oil which solidifies; 1H NMR (CDCl3): 1.39 (3H, s), 1.43 (3H, s), 2.02 (2H, pent, J=6.9 Hz), 2.63 (2H, tr, J=6.9 Hz), 3.38 (2H, tr, J=6.9 Hz), 3.90 (2H, m), 4.02 (1H, m), 4.15 (1H, m), 4.46 (1H, pent, J=6.9 Hz), 6.82 (2H, d, J=7.4 Hz), 7.10 (2H, d, J=7.4 Hz).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([O:19][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[O:18])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CN(C)CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Yield: 74.2 %

Procedure:
1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (300 mg, 1.13 mmol), 2-chloro-N,N-dimethylethylamine hydrochloride (196 mg, 1.36 mmol), and cesium carbonate (1.11 g, 3.39 mmol) were reacted in accordance with the method of First Step of Example 3 to obtain 282 mg of the heading compound as a colorless powdery crystal (yield 74%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([C:10]2[NH:14][CH:13]=[C:12]([S:15](Cl)(=[O:17])=[O:16])[CH:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C(Cl)Cl>[N:22]1([CH2:21][CH2:20][NH:19][S:15]([C:12]2[CH:11]=[C:10]([C:8]([C:7]3[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[O:9])[NH:14][CH:13]=2)(=[O:17])=[O:16])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: NCCN1CCOCC1
Reactant: O=C(c1cc(S(=O)(=O)Cl)c[nH]1)c1cccnc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cc(S(=O)(=O)NCCN2CCOCC2)c[nH]1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
To a solution of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-sulfonyl chloride (500 mg, 1.64 mmol) in DCM (5 mL) was added 4-(2-aminoethyl)morpholine (427 mg, 3.28 mmol) and triethylamine (0.5 mL). The mixture was stirred at room temperature for 4 hours. The reaction was extracted with DCM, the combined DCM was washed with water and brine, dried and concentrated. The residue was purified on a silica gel column to give 450 mg (69%) of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-sulfonic acid (2-morpholin-4-yl-ethyl)-amide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[NH:5][CH2:6][CH:7]([OH:14])[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[Br:19][C:20]1[CH:27]=[C:26]([Br:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Cl>>[Br:19][C:20]1[CH:27]=[C:26]([Br:28])[CH:25]=[CH:24][C:21]=1[CH2:22][O:14][CH:7]([CH2:6][NH:5][C:4]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:2]([Cl:1])[CH:3]=1)[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: ClCc1ccc(Br)cc1Br
Reactant: OC(CNc1ccc(Cl)c(Cl)c1)Cn1ccnc1
Product: Clc1ccc(NCC(Cn2ccnc2)OCc2ccc(Br)cc2Br)cc1Cl

Procedure:
Reaction of 1-[3-(3,4-dichloroanilino)-2-hydroxypropyl]-imidazole with 2,4-dibromobenzyl chloride yields 1-[2-(2,4-dibromobenzyloxy)-3-(3,4-dichloroanilino)-propyl]-imidazole.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][CH2:15][CH:16]([C:24]1([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]1=[O:37])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:61]1(=[O:71])[NH:65][C:64](=[O:66])[C:63]2=[CH:67][CH:68]=[CH:69][CH:70]=[C:62]12>C1COCC1>[O:66]=[C:64]1[C:63]2[C:62](=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:61](=[O:71])[N:65]1[CH2:14][CH2:15][CH:16]([C:24]1([CH2:38][CH:39]([CH3:40])[CH3:41])[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]1=[O:37])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)CC1(C(CCO)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reaction time: 8 h
Yield: 52.9 %

Procedure:
Diethyl azodicarboxylate (182 uL, 1.16 mmol) is added to a mixture of tert-butyl α-(2-hydroxyethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (468 mg, 1.16 mmol), triphenylphosphine (304 mg, 1.16 mmol), phthalimide (171 mg, 1.16 mmol) and THF (10 mL) at room temperature. The mixture is allowed to stir overnight and is concentrated. Purification by column chromatography (2 columns, 5% acetone/CH2Cl2 and 10% EtOAc/hexane) provided 327 mg (51%) of the title compound as a colorless oil.
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH2:13])C.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([N:13]2[C:7]3[C:6](=[CH:11][C:10]([Cl:12])=[CH:9][CH:8]=3)[CH2:5][C:4]2=[O:14])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)Cc1cc(Cl)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)Cc3cc(Cl)ccc32)CC1
Yield: 138.8 %

Procedure:
(2-Amino-5-chloro-phenyl)-acetic acid ethyl ester (3.3 g, 15.4 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.6 g, 23 mmol) were set stirring in CH2Cl2 (50 mL) and sodium triacetoxyborohydride (4.9 g, 23.1 mmol) was added followed by acetic acid (3 mL). After 5 days saturated NaHCO3 was added and the organics separated. The organics were dried (MgSO4) and evaporated to give 7.5 g of a clear golden oil. The oil was purified (silica, 50% EtOAc/hexanes) to give 3.4 g (63%) of a white solid. TLC (silica, 25% EtOAc/hexanes): Rf=0.18. MS (electrospray): exact mass calculated for C18H23ClN2O3, 350.14. m/z found, 373.1 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.40-7.30 (m, 2H), 7.00 (d, J=8.4 Hz, 1H), 4.55-4.45 (m, 1H), 4.40 (m, 2H), 3.63 (s, 2H), 2.94 (m, 2H), 2.45-2.30 (m, 2H), 1.82 (m, 2H), 1.62 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[OH:24].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O1CCOCC1>[F:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[O:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: COc1ccc2c(Cl)ccnc2c1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2c1
Temperature: 110 °C
Yield: 50 %

Procedure:
To 4-chloro-7-methoxyquinoline (0.900 g, 4.6 mmol), 2-fluoro-4-nitrophenol (2.3 g, 14 mmol), and N,N-dimethylpyridin-4-amine (0.068 g, 0.56 mmol) was added dioxane (10 mL) and pyridine (6.4 ml, 79 mmol). The resulting mixture was heated at 110° C. in an argon-purged sealed tube for 16 hours. An aliquot was analyzed by LCMS and indicated the presence of desired product. The reaction mixture was concentrated in vacuo and diluted with 2 N NaOH. The resulting solid was filtered, and the filtrate was extracted with CH2Cl2. The organic layers were dried over sodium sulfate and filtered through a pad of silica gel along with the solids using 10% MeOH/CH2Cl2 as eluent. The collected fractions were concentrated in vacuo to yield 4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinoline (0.900 g, 2.3 mmol, 49% yield) as a brownish solid. Calcd for C16H11FN2O4: [M]+=314. Found: [M+H]+=315.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:16]([N:2]([CH3:1])[CH:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:7][CH2:8]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(Cc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
tert-Butyl 4-(methylamino)piperidine-1-carboxylate (3.0 g, 14.019 mmol, 1.0 eq.) was dissolved in DCM (30 ml); benzaldehyde (1.7 ml, 16.823 mmol, 1.2 eq.) was added and the mixture was stirred for 1 hour at RT. NaBH(OAc)3 (4.81 g, 28.038 mmol, 3.0 eq.) was then added at 0° C. and the reaction mixture was stirred for 14 hours at RT. After monitoring by TLC, DCM (300 ml) was added to the reaction and washing was carried out in succession with sodium hydrogen carbonate solution (100 ml), water (100 ml) and sat. NaCl solution (100 ml). The organic phase was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 1% MeOH in DCM). Yield: 28% (1.2 g, 3.947 mmol)
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:8][C:7]=1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[Cl:36][C:37]([Cl:47])([O:39][C:40](=O)[O:41]C(Cl)(Cl)Cl)[Cl:38]>ClCCl>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][NH:2][C:40](=[O:41])[O:39][C:37]([Cl:47])([Cl:38])[Cl:36])=[C:7]([C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[CH:8]=1)=[O:22]
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)OC(Cl)(Cl)Cl)c(-c3ccnn3C)c2)c1

Procedure:
N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide hydrochloride (80.0 mg, 194 μmol), triethylamine (277 μl, 10 eq) and triphosgene (64.8 mg, 1.1 eq) were dissolved in 5 mL of dichloromethane and stirred under reflux for 5 mins. The solvent was removed under vacuum and 4 mL of ethyl acetate was added. It was divided in two and used immediately in the preparation of compound 5 and 7 without purification. LCMS m/z (%)=528 (M+H, 100).