Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][CH:10]3[CH2:17][CH2:16][CH2:15][N:11]3[CH2:12][C:13]=2[CH:14]=1)([O-])=O>CO.[Pd]>[ClH:1].[CH2:17]1[CH:10]2[N:11]([CH2:12][C:13]3[CH:14]=[C:5]([NH2:2])[CH:6]=[CH:7][C:8]=3[CH2:9]2)[CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CN1CCCC1C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc2c(c1)CN1CCCC1C2
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a suspension of 7-nitro-1,2,3,5,10,10a-hexahydropyrrolo[1,2-b]isoquinoline hydrochloride (2.14 g, 8.40 mmol) in methanol (150 ml) was added 10% Pd/C (0.2 g) and the reaction mixture was hydrogenated at 50 psi for 2 h. The solution was filtered and the catalyst was washed with water to dissolve some precipitated product. The filtrate was concentrated and absolute ethanol was used to help evaporate the excess water. The resulting solid was dissolved in hot ethanol (50 ml) and ether was added to precipitate the product. This solid was collected to give the title compound (1.90 g, 100%) as an amorphous, off-white solid, MS 189 (M+H)+ ; NMR (DMSO-NaOD) 6.82 (d, 1H), 6.44 (d, 1H), 6.35 (s, 1H), 4.03 (d, 1H), 3.19 (broad s, 1H), 2.84 (d, 1H), 2.5-3.0 (m, 3H), 2.11 (broad s 1H), 2.7-2.9 (m, 2H), 1.52 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:17]=1
Reactant: CC(C)COc1cc(Cl)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CC(C)COc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-2-(2-methylpropoxy)phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.00 (6H, d, J=6.8 Hz), 2.06-2.12 (1H, m), 3.77 (2H, d, J=6.0 Hz), 5.24 (2H, s), 5.77 (1H, d, J=2.0 Hz), 6.89 (1H, d, J=1.6 Hz), 6.95 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.34 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=0.8 Hz, 4.8 Hz), 7.57 (1H, d, J=2.0 Hz), 8.03 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H19ClN4O2, 383. Found, 383.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([NH:12][CH2:13][C:14]([CH2:20][NH:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)([OH:19])[C:15]([F:18])([F:17])[F:16])[CH3:11]>>[CH2:10]([N:12]([CH2:13][C:14]([CH2:20][NH:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)([OH:19])[C:15]([F:17])([F:18])[F:16])[C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:11]
Reactant: O=C(O)c1ccccc1
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1

Procedure:
Prepared similarly to Example 1 from benzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [NH3:1].C([O:4][C:5]([C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:19][N:18]4[CH2:27][CH2:28][CH2:29][C:17]=34)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)=O)C.ClCCl.CO>CO>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]1[C:16]([C:13]2[CH:14]=[CH:15][C:10]3[N:11]([C:7]([C:5]([NH2:1])=[O:4])=[CH:8][N:9]=3)[CH:12]=2)=[C:17]2[CH2:29][CH2:28][CH2:27][N:18]2[N:19]=1
Reactant: N
Reactant: CCOC(=O)c1cnc2ccc(-c3c(-c4ccccn4)nn4c3CCC4)cn12
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1cnc2ccc(-c3c(-c4ccccn4)nn4c3CCC4)cn12
Temperature: 110 °C
Yield: 82 %

Procedure:
Add 7N ammonia in methanol (10 mL) to a sealed tube containing 6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (Example 35; 0.105 g, 0.28 mmol). Heat at 110° C. for 48 h. Flash chromatograph using dichloromethane/methanol mixtures to give the title compound (0.08 g, 82%) as a white solid. MS ES+ m/e 344.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.4-8.37 (m, 1H), 8.28 (s, 1H), 7.82-7.77 (m, 3H), 7.59 (d, J=9 Hz, 1H), 7.4 (dd, J=9.0, 2.0 Hz, 1H), 7.25 (m, 1H), 4.21 (t, J=7 Hz, 2H), 2.99 (t, J=7, 2H), 2.62 (quintet, 2H, 8 Hz).
Reaction SMILES: Cl.[CH2:2]([C:6]1[O:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]=1[CH2:11][NH2:12])[CH2:3][CH2:4][CH3:5].[CH2:17]([NH:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(N(CC)CC)C>[CH2:2]([C:6]1[O:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]=1[CH2:11][NH:12][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([C:30]([NH:29][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:39])=[CH:32][CH:33]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1oc2ccccc2c1CN
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(C=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCNC(=O)c1ccc(CNCc2c(CCCC)oc3ccccc23)cc1
Yield: 59 %

Procedure:
The same procedure as employed in the preparation of Example 1 (step a) but using (2-butyl-1-benzofuran-3-yl)methylamine hydrochloride, triethylamine and N-dodecyl-4-formylbenzamide gave the title compound as a colorless oil (59%). 1H NMR (CDCl3, 300 MHz) δ 7.76 (m, 2H), 7.58 (m, 1H), 7.42 (m, 3H), 7.29-7.18 (m, 2H), 6.23 (m, 1H), 3.87 (m, 4H), 3.46 (m, 2H), 2.75 (t, 2H, J=7.5 Hz), 1.77-1.56 (m, 5H), 1.45-1.23 (m, 20H), 0.98-0.86 (m, 6H). HPLC (Condition A), Rt: 5.49 min (HPLC purity: 97.4%).
Reaction SMILES: [C:1]([C:4]1[NH:9][C:8](=O)[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CS(Cl)(=O)=O.N1CCCCC1>ClCCl>[N:11]1([C:8]2[CH:7]=[CH:6][N:5]=[C:4]([C:1](=[O:3])[CH3:2])[N:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(=O)c1nccc(=O)[nH]1
Reactant: c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(=O)c1nccc(N2CCCCC2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26.9 %

Procedure:
To a stirred solution of 2-acetylpyrimidin-4(3H)-one (Intermediate 51, 500 mg, 3.62 mmol) in dichloromethane (10 mL) cooled to 0° C., pyridine (860 mg, 10.87 mmol) was added and stirred for 10 min at 0° C., followed by the addition of methane sulfonyl chloride (830 mg, 7.23 mmol) at 0° C. The above reaction mixture was stirred at room temperature for overnight. The reaction mixture was washed with water (50 mL), the aqueous layer was extracted with dichloromethane (50 mL). The combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude residue was dissolved in acetonitrile; piperidine (616 mg, 7.24 mmol) was added and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated under reduced pressure; water (50 mL) was added and extracted with ethyl acetate (2×30 mL). The combined organic layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield the crude product, which was purified by column chromatography over silica gel (10-50% ethyl acetate/pet ether) to obtain 1-[4-(piperidin-1-yl)pyrimidin-2-yl]ethanone 200 mg (46.8%).
Reaction SMILES: [Br:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.Cl.[NH2:9][CH2:10][C:11](=[O:15])[CH2:12][CH2:13][CH3:14].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1([C:5]([NH:9][CH2:10][C:11](=[O:15])[CH2:12][CH2:13][CH3:14])=[O:7])[CH2:4][CH2:3]1
Reactant: CCCC(=O)CN
Reactant: O=C(O)C1(Br)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)CNC(=O)C1(Br)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
A mixture of 2.57 g of 1-bromocyclopropanecarboxylic acid 4 [H. M. R. Hoffmann et al. J. Org. Chem. 54, 6096 (1989)], 2.22 g of 1-amino-2-pentanone hydrochloride 5 [M. Jackman et al. J. Am. Chem. Soc. 70, 2884 (1948)] and 3.36 g of N,N′-dicyclohexylcarbodiimide in 234 ml of methylene chloride in the presence of 2.46 ml of triethylamine is stirred overnight at room temperature. Then, it is filtered, the filtrate is concentrated by evaporation, and the residue is chromatographed on silica gel with ethyl acetate/hexane. 2.74 g of 1-bromo-N-(2-oxopentyl)-cyclopropane-1-carbamide 6 is obtained as a crystallizing oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][C:7]=1[NH2:8].[CH:22](=O)[CH3:23].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[C:10]1[CH:11]=[CH:12][C:6]2[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:22]([CH3:23])=[N:8][C:7]=2[CH:9]=1
Reactant: CC=O
Reactant: COCCNc1ccc(-c2nc3ccccc3o2)cc1N
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCn1c(C)nc2cc(-c3nc4ccccc4o3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.9 %

Procedure:
To a solution of 2-(2-(2-methoxyethyl)aminoanilin-5-yl)benzoxazole (see Working Example 51-1) (98 mg, 0.346 mmol) in dimethylformamide (2 mL) was added an aqueous solution of acetaldehyde (approx. 90%, 65.1 μL, 1.66 mmol) and oxone (213 mg, 0.346 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (41.4 mg, 39% yield) as light brown crystals.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:9][C:10]1[CH:15]=[CH:14]C=[CH:12][CH:11]=1.Cl.[OH-].[Na+]>C(OCC)(=O)C.C(O)C>[CH:2]1([CH:1]2[CH2:14][CH2:15][CH:10]([NH2:9])[CH2:11][CH2:12]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Nc1ccccc1
Reactant: CC1CCCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC1CCC(C2CCCCC2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-methyl-cyclohexanone (112 g, 1.0 mol), aniline (186 g, 2 mol) and ethanol (26 mL) was stirred at room temperature and 12 M hydrochloric acid (167 mL) was added during 30 min. The dark yellow solution was refluxed at 85° C. for seven days. The solution was cooled and diluted with ethyl acetate. The mixture was stirred in an ice bath and made alkaline (pH=9) with a 27% sodium hydroxide solution, keeping the temperature below 30° C.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[NH2:18][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1.I([O-])(=O)(=O)=O.[Na+].CO>O>[OH:3][CH:2]1[C@H:1]([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[CH:4]([OH:5])[N:18]1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: Nc1ncccn1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: Nc1ccn([C@@H]2O[C@H](CO)C(O)N(c3ncccn3)C2O)c(=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
To a solution of cytidine (2.43 g) and 2-aminopyrimidine (0.95 g) in water (15 ml) was added sodium metaperiodate (2.13 g) at 15° C. The solution was stirred at ambient temperature for four hours. To the reaction mixture was added methanol (20 ml). A precipitate was filtered off and the filtrate was condenced in vacuo. The condenced solution was lyophilized to give white powder of 1-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]cytosine (3.20 g).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([Cl:16])[CH:8]=2)[N:3]=1.[CH3:18][S:19]([OH:21])=[O:20].[Na]>CN(C=O)C>[Cl:16][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:17])[N:3]=[C:2]([S:19]([CH3:18])(=[O:21])=[O:20])[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10]2
Reactant: FC(F)(F)c1nc2cc(Cl)c(Cl)cc2nc1Cl
Reactant: CS(=O)O
Agent: [Na]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1nc2cc(Cl)c(Cl)cc2nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6,7-trichloro-3-trifluoromethylquinoxaline (64 mg, 0.2 mmol) in DMF (1 ml) was added methanesulfinic acid, sodium salt (43 mg, 0.4 mmol). The reaction mixture was stirred at room temperature overnight, then it was partitioned between ethyl acetate and water. The organic layer was separated and concentrated to an oil. This oil was further purified by column chromatography (ethyl acetate:hexanes 1:3) to yield the title compound as a white solid.
Reaction SMILES: [CH:1]1[C:2]2[N:3]([CH:8]=[N:9][CH:10]=2)[C:4](=[S:7])[NH:5][N:6]=1.[Na].[CH2:12](Br)[CH:13]=[CH2:14]>CO>[CH2:14]([S:7][C:4]1[N:3]2[CH:8]=[N:9][CH:10]=[C:2]2[CH:1]=[N:6][N:5]=1)[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: S=c1[nH]ncc2cncn12
Agent: [Na]
Solvent: CO
Product: C=CCSc1nncc2cncn12
Reaction time: 0.08 h

Procedure:
A 15.2 gm. portion of imidazo[1,5-d]-as-triazine-4(3H)-thione in 75 ml. of methanol is treated with 2.3 gm. of sodium in 75 ml. of methanol. After 5 minutes, a 12.0 gm. portion of allyl bromide is added and the reaction is continued as described in Example 29 giving the desired product, m.p. 68°-69.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2.B(Br)(Br)Br.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][C:8]=2[C:9]([OH:12])=[CH:10][CH:11]=1
Reactant: COc1ccc(OC)c2c1CCC2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: COc1ccc(O)c2c1CCC2
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To the clear solution of 4,7-Dimethoxyindane (22.5 gm, 0.126 mole) in Methylene chloride (400 ml), added Boron tribromide (12.27 ml, 0.13 mole) at 0° C. After 2 hours stirring at 0-10° C., water (100 ml) was added and then the reaction mixture was extracted with Methylene chloride. The Methylene chloride layer was dried over Sodium sulphate and distilled off to give a crude mass which was purified by column chromatography using 7% Ethyl acetate in Hexane (9.0 gm).
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[OH:8][CH:9]([CH3:16])[CH2:10][C:11]([O:14][OH:15])([CH3:13])[CH3:12].S(=O)(=O)(O)O>>[CH3:6][C:5]([O:15][O:14][C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]([OH:8])[CH3:16])([CH2:4][C:2](=[O:1])[CH3:3])[CH3:7]
Reactant: CC(=O)C=C(C)C
Reactant: CC(O)CC(C)(C)OO
Agent: O=S(=O)(O)O
Product: CC(=O)CC(C)(C)OOC(C)(C)CC(C)O

Procedure:
A mixture of 19.60 g. (0.20 mole) of mesityl oxide, 36.90 g. (0.25 mole) of 3-hydroxy-1,1-dimethylbutyl hydroperoxide (90%) and 10 g. of Amberlyst 15® sulfuric acid type ion exchange resin was stirred for 16 hours at 30° C. The resin was separated by filtration and the filtrate subjected to steam distillation at 20 torr in the presence of sodium bicarbonate to maintain a slightly alkaline pH during the distillation. The distillation was ended when the removal of unreacted mesityl oxide was complete.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[CH3:36][N:28]([CH2:27][CH2:26][O:25][CH2:24][CH2:23][NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:32])[CH3:33]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CN(CCOCCN)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCOCCNc1c([N+](=O)[O-])cnc2ccccc12)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A stirred solution of 4-chloro-3-nitroquinoline (32.3 g, 155 mmol) in 400 mL of anhydrous CH2Cl2, under N2, was treated with triethylamine (43.1 mL, 310 mmol) and tert-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate (37.2 g, 171 mmol). After stirring overnight, the reaction mixture was washed with H2O (2×300 mL) and brine (300 mL). The organic portion was dried over Na2SO4 and concentrated to give a brown oil. Column chromatography (SiO2, 33% ethyl acetate/hexanes-67% ethyl acetate/hexanes) gave 46.7 g of tert-butyl methyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethyl)carbamate as a yellow solid.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1>CCOCC>[Br:1][CH2:2][C:3]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: C1COCCN1
Solvent: CCOCC
Product: O=C(CBr)N1CCOCC1
Reaction time: 8 h

Procedure:
Bromoacetylbromide (20.1 g) was added dropwise to a rapidly stirred solution of morpholine (17.4 g) in ether (200 ml). After stirring overnight, the mixture was washed with water (2×50 ml), dried (MgSO4) and evaporated to afford a colourless oil. 1H NMR (360 MHz, CDCl3) δ3.46 (2H, m, 2×CHHN), 3.63 (2H, m, 2×CHHN), 3.69 (4H, m, 2×CH2O), 3.75 (2H, s, CH2Br).
Reaction SMILES: [Cl-:1].[CH3:2][N+:3]1([CH3:14])[CH2:13][CH2:12][C:6]2([O:10][C:9](=[O:11])[NH:8][CH2:7]2)[CH2:5][CH2:4]1.C(O[Cl:20])(C)(C)C>CO>[Cl-:20].[Cl:1][N:8]1[CH2:7][C:6]2([CH2:12][CH2:13][N+:3]([CH3:2])([CH3:14])[CH2:4][CH2:5]2)[O:10][C:9]1=[O:11]
Reactant: CC(C)(C)OCl
Reactant: C[N+]1(C)CCC2(CC1)CNC(=O)O2
Agent: [Cl-]
Solvent: CO
Product: C[N+]1(C)CCC2(CC1)CN(Cl)C(=O)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8,8-Dimethyl-2-oxo-1-oxa-3-aza-8-azoniaspiro[4.5]decane chloride (1.60 g, 7.25 mmol) was dissolved in methanol (80 ml). t-Butylhypochlorite (1.18 g, 10.87 mmol) was added to the solution, and the combined mixture was stirred for 1 hour at room temperature. The reaction mixture was monitored by HPLC-MS. The reaction mixture was concentrated in vacuo. The crude material was purified by Prep-HPLC to give 243 mg (13%). 1H NMR (CDCl3) δ 3.84 (s, 2H), 3.52-3.69 (m, 4H), 3.25 (s, 3H), 3.18 (s, 3H), 2.32-2.46 (m, 4H); MS(ESI+) calculated for C9H16ClN2O2: 219.09, Found: 219 (M+).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([C:20]=2Cl)=[CH:18][CH:17]=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=3)=[O:10])[CH2:4][CH2:3]1>[Pd].O1CCCC1.ClCCl>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[C:16]([C:22]([F:25])([F:23])[F:24])[CH:15]=3)=[O:10])[CH2:6][CH2:7]1
Reactant: C[C@H]1CC[C@H](NC(=O)c2cnc3cc(C(F)(F)F)ccc3c2Cl)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H]1CC[C@H](NC(=O)c2cnc3cc(C(F)(F)F)ccc3c2)CC1
Reaction time: 0.17 h

Procedure:
The amide (253 mg, 0.68 mmol) in 3:1 tetrahydrofuran-dichloromethane (75 mL) containing 10% Pd on carbon (150 mg) was hydrogenated at 40 p.s.i. H2 for 10 min (ambient temperature). Filtration of the reaction mixture and chromatography through a Biotage silica cartridge (8×4 cm i.d.) using a gradient of hexane to 20% ethyl acetate (in hexane) afforded 40 mg (12%) of 431:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:27]2
Reactant: Clc1cccc2c1CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1c(F)c(N2Cc3cccc(Cl)c3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 24 %

Procedure:
268 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 154 mg of 4-chloroisoindoline, 274 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 93 mg of the target compound.
Reaction SMILES: [Br:1][C:2]1[C:45]([N+:46]([O-])=O)=[CH:44][CH:43]=[CH:42][C:3]=1[CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:7]1.[CH:49]([Mg]Br)([CH3:51])[CH3:50]>>[Br:1][C:2]1[C:3]([CH2:4][O:5][CH:6]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:14][CH:13]=3)[CH2:10][CH2:9][N:8]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:7]2)=[CH:42][CH:43]=[C:44]2[C:45]=1[NH:46][C:49]([CH3:51])=[CH:50]2
Reactant: CC(C)[Mg]Br
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cccc([N+](=O)[O-])c2Br)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3cc(C)[nH]c3c2Br)cc1

Procedure:
Analogously to Example 21b, 0.350 g of benzyl 3-(2-bromo-3-nitrobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 21c) and 2.84 ml of isopropylmagnesium bromide (0.5M in tetrahydrofuran) are reacted. The title compound is obtained as a white foam. Rf=0.23 (1:2 EtOAc-heptane); Rt=6.13.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[CH2:21]O)[CH:6]=1.P(Br)(Br)[Br:25]>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[CH2:21][Br:25])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2cc(Br)ccc2CO)c1
Reactant: BrP(Br)Br
Product: COC(=O)Cc1ccc(OC)c(Oc2cc(Br)ccc2CBr)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 4, using the following starting materials: [3-(5-bromo-2-hydroxymethyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and phosphorus tribromide.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[C:7]=1[Cl:13].[OH-].[Na+].[ClH:16]>>[Cl:13][C:7]1[C:8]([CH3:12])=[N:9][CH:10]=[CH:11][C:6]=1[Cl:16]
Reactant: Cc1nccc(N)c1Cl
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Product: Cc1nccc(Cl)c1Cl
Reaction time: 1 h

Procedure:
Sodium nitrite (36 g) was added in portions to a stirred solution of 4 -amino-3 -chloro-2 -picoline (24.85 g) in conc. hydrochloric acid (750 ml) cooled to 0°-5°. After 1 hour at 0°-5 ° and a further 2 hours at room temperature the mixture was basified (NaOH), allowing the temperature to rise to ca. 50°, and extracted with ether. After drying (K2CO3 ), the extract was evaporated to dryness to give 3,4 -dichloro-2 -picoline (26.5 g) as a low melting solid.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:13][CH2:14][C@H:15]1[O:21][CH:19](O)[C@H:18]([N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])[C@@H:17]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@H:16]1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:12])[CH3:11]>ClCCCl.C(OCC)(=O)C>[C:10]([O:13][CH2:14][C@H:15]1[O:21][C@@H:19]([F:7])[C@H:18]([N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])[C@@H:17]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@H:16]1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:12])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(=O)OC[C@H]1OC(O)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(=O)OC[C@H]1O[C@@H](F)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 2 h
Yield: 98.7 %

Procedure:
Under nitrogen gas atmosphere, diethylaminosulfur trifluoride (5.8 ml, 43.9 mmol) was added to a solution of Compound 23 (5.95 g, 11.2 mmol) in 1,2-dichloroethane (50 ml) under ice cooling, and the mixture was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, and dried over magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:ethyl acetate=4:1) to obtain Compound 24 (5.9 g, 99%).