Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][N:6]1C(OC)=O.Br>>[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][NH:6]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)cc1F
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](Cc3ccc(F)cc3F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.3 %

Procedure:
Trans-methyl 2-(2,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.25 g, 0.71 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 6.21 mL, 35.48 mmol) and stirred at room temperature for 16 h. The solvents were evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(2,4-difluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (94.6 mg, 45%). 1H NMR (600 MHz, dmso) δ 1.43-1.51 (m, 1H), 1.63-1.78 (m, 3H), 2.52-2.60 (m, 1H), 2.65 (d, 2H), 2.76-2.87 (m, 2H), 3.08-3.13 (m, 1H), 5.67 (s, 1H), 6.98 (td, 1H), 7.12 (td, 1H), 7.27-7.34 (m, 1H). HRMS Calculated for [C15H16F2N2O2+H]+: 295.1258. Found: 295.1265
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[Br:10][C:11]1[CH:28]=[CH:27][C:14]([C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=2)=[O:16])=[CH:13][N:12]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][N:31]=1.CCN(C(C)C)C(C)C>C1COCC1>[Br:10][C:11]1[CH:28]=[CH:27][C:14]([C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](=[O:24])[NH:29][C:30]3[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][N:31]=3)=[CH:20][N:19]=2)=[O:16])=[CH:13][N:12]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(O)c1ccc(NC(=O)c2ccc(Br)nc2)nc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(=O)Nc2ccc(Br)cn2)cn1)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 13.5 %

Procedure:
2-chloro-1-methylpyridinium iodide (2.37 g, 18.6 mmol) was added to a suspension of 6-(6-bromonicotinamido)nicotinic acid 4 (2 g, 6.21 mmol) and 2-amino-5-bromopyridine 5 (1.07 g, 6.21 mmol) in THF (100 ml), followed by DIPEA (2.4 g, 18.6 mmol). The reaction mixture was stirred for 4 days at RT. The suspension was filtered off and washed with water (25 ml). The filtrate was concentrated, diluted in chloroform, washed with water and brine, and then dried over Na2SO4. The product precipitated during evaporation and was dried under vacuum to give 6-bromo-N-(5-(5-bromopyridin-2-ylcarbamoyl)pyridin-2-yl)nicotinamide 6 as a yellow solid (400 mg, 14%). Mp. 245-247° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:9]3[C:14]([N:15]=2)=[C:13]([NH:16][CH2:17][CH2:18][CH:19]=O)[N:12]=[CH:11][N:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Cl:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[N:36]1[CH2:41][CH2:40][N:39]([CH2:19][CH2:18][CH2:17][NH:16][C:13]2[N:12]=[CH:11][N:10]=[C:9]3[C:14]=2[N:15]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]3[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:38][CH2:37]1
Reactant: O=CCCNc1ncnc2c1nc(-c1ccccc1)n2-c1ccccc1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Clc1cccc(N2CCN(CCCNc3ncnc4c3nc(-c3ccccc3)n4-c3ccccc3)CC2)c1Cl
Temperature: 45 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
To the solution of 3-(8,9-diphenyl-9H-purin-6-ylamino)propanal obtained in step 2 (0.73 g, 2.13 mmol) and 1-(2,3-dichlorophenyl)piperazine hydrochloride (0.6 g, 2.13 mmol) in 1.2-dichloroethane was added Na(OAc)3BH (0.72 g, 3.40 mmol) and acetic acid (0.24 mL, 4.25 mmol) at room temperature and stirred for 18 hours at 45° C. The resulting reaction mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2, and washed with water. The organic layer thus separated was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained was purified by preparative HPLC (purification system, Gilson) to provide the title compound (460 mg) as a white solid.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].Cl.CN(C)CCCN=C=NCC.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][N:24]=[C:23]2[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Br:37])[CH:32]=1>CN(C=O)C>[Br:37][C:33]1[CH:32]=[C:31]([NH:30][C:23]2[C:22]3[C:27](=[CH:28][CH:29]=[C:20]([NH:19][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:21]=3)[N:26]=[CH:25][N:24]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CC#CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-butynoic acid (196 mg, 2.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (385 mg, 2.0 mmol) in DMF (5 mL) stirring at 25° C. for 20 minutes was added 6-amino-4-[(3-bromophenyl)amino]quinazoline (316 mg, 1.0 mmol). The resulting solution was stirred under N2 at 25° C. for 14 hours further 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (206 mg, 1.0 mmol) and 2-butynic acid (82 mg, 1.0 mmol) were. After another 8 hours further, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (197 mg, 1.0 mmol) and the acid (93 mg, 1.0 mmol) were added to the reaction. After stirring at 25° C. a further 12 hours, the reaction was quenched with water. The yellow precipitate was collected, sonicated with acetone, treated with triethyl amine and purified by preparative tlc on silica, eluting with 1:1 EtOAc/acetone. The desired product was isolated as a yellow solid (20 mg, 4.7%), mp 281-283° C.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.Cl.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH:36]1[CH2:41][NH:42][S:43]([CH3:46])(=[O:45])=[O:44].C(=O)([O-])[O-].[K+].[K+]>>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[S:13]([N:11]1[CH2:10][CH2:9][N:8]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=2)[C@@H:7]([CH2:6][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH:36]2[CH2:41][NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH2:12]1)(=[O:14])=[O:15]
Reactant: CS(=O)(=O)NCC1COCCN1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCOCC2CNS(C)(=O)=O)cc1)C(F)(F)F

Procedure:
This compound was synthesized following the procedure outlined for Example 84. The reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) and N-(3-morpholinylmethyl)methanesulfonamide hydrochloride (published PCT patent application no. WO 2009/016410) (using an extra equivalent of potassium carbonate) followed by purification via column chromatography on silica gel (0 to 100% EtOAc in hexanes) delivered N-((4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)methyl)methanesulfonamide as a mixture of four isomers.
Reaction SMILES: O.NN.[C:4]([NH:7][C:8]1[C:12]([N+:13]([O-])=O)=[CH:11][N:10]([CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[O:18])[N:9]=1)(=[O:6])[CH3:5].C(OCC)C>CC(N(C)C)=O.CO.[Pd]>[C:4]([NH:7][C:8]1[C:12]([NH2:13])=[CH:11][N:10]([CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[O:18])[N:9]=1)(=[O:6])[CH3:5]
Reactant: CC(=O)Nc1nn(CC(=O)Nc2cccc(F)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CO
Product: CC(=O)Nc1nn(CC(=O)Nc2cccc(F)c2)cc1N
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
Hydrazine hydrate (43.6 μl, 0.9 mmol) was slowly added to a solution of 2-[3-(acetylamino)-4-nitro-1H-pyrazol-1-yl]-N-(3-fluorophenyl)acetamide (0.145 g, 0.45 mmol) in a mixture of dimethylacetamide (3 ml) and methanol (3 ml) in the presence of 10% palladium on carbon (0.030 g). The mixture was stirred at 75° C. for 20 minutes and then allowed to cool. The mixture was filtered through Celite and the residue washed with methanol. The filtrate was evaporated and the residue triturated with a 1:2 mixture of dichloromethane:diethyl ether to give 2-[3-(acetylamino)-4-amino-1H-pyrazol-1-yl]-N-(3-fluorophenyl)acetamide (0.125 g, 95% yield):
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18](Cl)=O)=[CH:16][C:3]1=2.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].N1C=CC=CC=1.Cl.[NH2:45][OH:46]>COCCOCCOC>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH:18]=[N:45][OH:46])=[CH:16][C:3]1=2
Reactant: NO
Reactant: O=C(Cl)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: COCCOCCOC
Solvent: c1ccncc1
Product: O=C1c2ccccc2COc2ccc(CC=NO)cc21
Temperature: -78 °C

Procedure:
A solution of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetyl chloride (15.00 g) in 150 ml of dry diglyme was stirred at -78° C. under nitrogen as lithium tri-tert-butoxyaluminohydride (104.6 ml of a 0.5M solution in diglyme) was added slowly dropwise over one hour. The reaction was stirred ten minutes at -78° C. and then quenched with 3 ml of glacial acetic acid added slowly dropwise. After warming the reaction to room temperature 50 ml of pyridine and 2 equiv. of hydroxylamine hydrochloride (7.27 g) was added and the slurry stirred at 50° C. for two hours. The solvent was evaporated using high vacuum and the residue taken up in chloroform and 1N HCl. The layers were separated and the aqueous phase extracted with chloroform. The combined organic phases were dried (MgSO4), filtered, and evaporated. The residue was purified by flash chromatography (silica; 5:2 hex-EtOAc) and recrystallized from ethyl acetate-hexane to give 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetaldoxime, as crystals, m.p. 132°-134° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: COc1ccccc1-c1cc(Cl)cc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cc(Cl)cc(-c3ccccc3OC)c2O1

Procedure:
The title compound was prepared (0.037 g, 29%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.39 g, 0.88 mmol) and methylamine (0.271 g, 8.8 mmol). mp 100-102° C.
Reaction SMILES: [OH-].[CH2:2]([N+:4]([CH2:9][CH3:10])([CH2:7][CH3:8])[CH2:5][CH3:6])[CH3:3].[C:11]([OH:14])(=[O:13])[CH3:12]>>[C:11]([O-:14])(=[O:13])[CH3:12].[CH2:2]([N+:4]([CH2:9][CH3:10])([CH2:7][CH3:8])[CH2:5][CH3:6])[CH3:3]
Reactant: CC(=O)O
Agent: CC[N+](CC)(CC)CC
Agent: [OH-]
Product: CC(=O)[O-]
Temperature: 25 °C

Procedure:
Into an eggplant-shaped flask, an aqueous tetraethylammonium hydroxide solution (1 mol) was charged, and while it was cooled to maintain room temperature, acetic acid (1 mol) was added to obtain tetraethylammonium acetate. Then, ethylene glycol was added as a solvent so that it became a predetermined concentration, and by means of an evaporator, water was distilled off to obtain a solution comprising 50% of tetraethylammonium acetate and 50% of ethylene glycol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)[N:5]=[C:4]([NH2:21])[CH:3]=1.[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][N:23]1[CH:27]=[C:26]([C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=3)[N:5]=[C:4]([NH2:21])[CH:3]=2)[CH:25]=[N:24]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1cc(-c2nc(N)cc(Cl)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cc(N)nc(-c3cnn(COCC[Si](C)(C)C)c3)n2)cn1
Temperature: 100 °C
Yield: 54.7 %

Procedure:
6-Chloro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (1.00 g, 3.07 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.958 g, 4.60 mmol), K3PO4 (1.95 g, 9.21 mmol), and Pd(PPh3)4 (0.355 g, 0.307 mmol) were suspended in dioxane (15.3 mL) and H2O (0.829 mL). After de-gassing with nitrogen, the reaction mixture was heated to 100° C. overnight. After cooling, the reaction mixture was diluted in EtOAc and washed with water and brine. The organics were dried with MgSO4, filtered and concentrated down to an orange oil. Purification of the resulting crude material by silica chromatography using a gradient of 0-10% MeOH/EtOAc afforded 6-(1-methyl-1H-pyrazol-4-yl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (0.623 g, 1.68 mmol, 54.7% yield) as a thick yellow oil. MS (apci) m/z=372.4 (M+H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=[O:4].[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1>>[F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13]([C:30]4[CH:31]=[CH:32][O:28][CH:29]=4)[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=[O:4]
Reactant: OB(O)c1ccoc1
Reactant: O=C(N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21)C(F)(F)F
Product: O=C(N1CCC[C@@H]2c3cc(-c4ccoc4)ccc3C[C@@H]21)C(F)(F)F
Yield: 61 %

Procedure:
The title compound is prepared from trifluoro-methanesulfonic acid cis-1-(2,2,2-trifluoro-acetyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester and furan-3-yl-boronic acid following a procedure analogous to that described in Step 2 of Intermediates 17 and 18. Yield: 61% of theory; LC (method 1): tR=4.60 min; Mass spectrum (ESI+): m/z=336 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[OH-:9].[Na+].Cl>>[CH3:1][NH:2][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:8])=[O:9]
Reactant: CN1CCCCC1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CNCCCCC(=O)O
Temperature: 25 °C

Procedure:
A stirred solution of 1-methyl-2-piperidinone (4.40 mL, 40.0 mmol) in aqueous sodium hydroxide (4 M, 11.0 mL, 44.0 mmol) was heated at 100° C. for 15 h. The reaction mixture was cooled to room temperature and then acidified to pH 2 with concentrated hydrochloric acid. The mixture was then concentrated under reduced pressure to give crude 5-methylaminopentanoic acid as a pinkish white solid. To the crude 5-methylaminopentanoic acid was added MeOH (40.0 mL, 987 mmol) and concentrated hydrochloric acid (0.33 mL, 4.0 mmol). The resulting cloudy solution was heated at 60° C. for 39 h at which time LC-MS showed remaining starting material. Additional concentrated hydrochloric acid (0.33 mL, 4.0 mmol) was added and the resulting mixture was heated at 60° C. for 33 h and then at 65° C. for an additional 24 h. LC-MS showed remaining starting material. The reaction mixture was concentrated under reduced pressure and a solution of hydrogen chloride in MeOH (1.25 M) was added to the residue. The resulting mixture was heated at 60° C. for 72 h at which time no remaining starting material was observed by LC-MS. The reaction mixture was partially concentrated under reduced pressure and the solid material that formed was removed by filtration, washing with MeOH. The filtrate was then concentrated under reduced pressure to provide methyl 5-methylaminopentanoate hydrochloride (7.57 g, 100% yield) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH3:8])[CH:7]=1.[H][H]>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[C:6]([CH3:8])[CH:7]=1
Reactant: [H][H]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(F)ccc1N
Yield: 85 %

Procedure:
A mixture of 125 g of 5-fluoro-2-nitrotoluene, 3.0 g of 5% palladium on carbon, and 200 ml of ethanol was reduced in a Parr hydrogenator under 46 p.s.i. hydrogen pressure. After hydrogen uptake had ceased, the catalyst was removed by filtration, and the ethanolic filtrate was evaporated under reduced pressure to give a colorless liquid. Purification by vacuum distillation yielded 85.7 g of 4-fluoro-2-methylaniline, b.p. 67°-71°/4.2 mm.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:6]=1[C:7]([CH3:25])=[C:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]([CH3:16])=[N:10]2.[OH-].[Li+]>CO>[Cl:15][C:12]1[CH:13]=[CH:14][C:5]([CH2:4][C:3]([OH:26])=[O:2])=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:16])[C:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[C:7]2[CH3:25]
Reactant: COC(=O)Cc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2c(Cl)ccc(CC(=O)O)c2c(C)c1Cc1ccc(Cl)cc1

Procedure:
A solution of [8-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-yl]acetic acid methyl ester (0.11 g), methanol (5.0 mL) and 1.0 M aqueous lithium hydroxide solution (0.84 mL) was stirred at room temperature for 17 hours. The solvent was removed under reduced pressure and the residue diluted with water. The pH of the mixture was adjusted to 3-4 by the addition of 1.0 M aqueous hydrochloric acid and the resulting precipitate collected by filtration and washed with water. Crystallisation from industrial methylated spirits gave title compound as a white solid, 0.056 g.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:12][CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Na+].[Cl:42][C:43]1[CH:48]=[CH:47][C:46](F)=[CH:45][CH:44]=1>CN(C)C=O>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([O:1][CH2:2][C:3]2[N:4]([CH2:12][CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:16]3)[C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:45][CH:44]=1
Reactant: Fc1ccc(Cl)cc1
Reactant: OCc1cc2ccccc2n1CCCC1CCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2cc3ccccc3n2CCCC2CCCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere 2-hydroxymethyl-1-[3-(1-tritylpiperidin-3-yl)propyl]-1H-indole (2.89 g, 5,61 mmol) was dissolved in about 11.2 ml of N,N-dimethylformamide. The resulting solution was then placed in an ice bath and sodium hydride (0.247 g of a 60% suspension in mineral oil, 6.18 mmol) was added and the resulting mixture was stirred at room temperature for about 60 minutes. To the reaction mixture 1-chloro-4-fluorobenzene (0.658 ml, 0.807 g, 6.18 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then heated to 80° C. and maintained at this temperature for about eight hours. The reaction mixture was then cooled to room temperature and stirred at this temperature overnight. Another half equivalence of sodium hydride was added and the reaction mixture was stirred at room temperature overnight again. Another half equivalence of 1-chloro-4-fluorobenzene was added and the reaction mixture was heated to 80° C.
Reaction SMILES: [CH2:1]([CH2:6][CH2:7][NH2:8])[CH2:2][CH2:3][CH2:4][NH2:5].[C:9](=[O:20])([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])N.N>>[CH2:12]([O:11][C:9]([NH:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:20])=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH2:1]([CH2:6][CH2:7][NH2:8])[CH2:2][CH2:3][CH2:4][NH2:5]
Reactant: CCCCCCCCOC(N)=O
Agent: N
Agent: NCCCCCCN
Product: CCCCCCCCOC(=O)NCCCCCCNC(=O)OCCCCCCCC
Temperature: 25 °C

Procedure:
Agitated in a reaction vessel are 116 parts of 1,6-hexamethylenediamine with 346 parts of O-octyl carbamate and 2000 parts of n-octanol-(1) at a reflux temperature of 185° C.-195° C. for 16 hours while the ammonia is removed by distillation. The precipitate formed in the reaction mixture, cooled to 100° C.-110° C., is removed by filtration. The reaction product is allowed to crystallize by cooling to room temperature. By means of filtration, washing with n-octanol-(1) and drying, 236 parts of 1,6-bis(octoxycarbonylamino)hexane, C24H48N2O4 (molecular weight 428), are obtained corresponding with 55 percent of theory relative to 1,6-hexamethylenediamine and O-octylcarbamate. The melting point is 106° C.-108° C. (from ethyl acetate).
Reaction SMILES: C([O:8][NH:9][C:10]([CH2:12][N:13]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:14](=[O:26])[CH2:15][CH:16]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[O:11])C1C=CC=CC=1.C>C(O)C.[Pd]>[OH:8][NH:9][C:10]([CH2:12][N:13]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:14](=[O:26])[CH2:15][CH:16]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[O:11]
Reactant: CC(C)CC(CC(=O)N(CC(=O)NOCc1ccccc1)CC(C)C)C(=O)N(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)CC(CC(=O)N(CC(=O)NO)CC(C)C)C(=O)N(C)C
Yield: 93.8 %

Procedure:
N4 -(Benzyloxycarbamoyl-methyl)-2,N4 -diisobutyl-N1,N1 -dimethyl-succinamide (0.45 g, 0.0011 mol) was dissolved in ethanol (5.0 ml) and 10% palladium on charcoal (100 mg) was added. Hydrogen was bubbled through the mixture for 1 hour at room temperature. The catalyst was removed by filtration and the solvent was removed under reduced pressure to give a crude solid contaminated with charcoal. The solid was then purified by column chromatography (acid-washed silica gel, 5% methanol in dichloromethane) to give the title compound as a white foamy solid (340 mg, 96%). 1H-NMR; δ (CDCl3, 3:1 mixture of rotamers), 11.65 (0.25H, s), 10.15 (0.75H, s), 7.89 (1H, br s), 4.59 (0.75H, d, J=16.4 Hz), 4.33 (0.25H, d, J=17.8 Hz), 3.90 (0.25H, d, J=17.8 Hz), 3.66 (1H, m), 3.56 (0.75H, d, J=16.5 Hz), 3.40 (1.5H, m), 3.13 (0.75H, s), 3.11 (2.25H, s), 2.95 (2.25H, s), 2.93 (0.75H, s), 2.92 (0.5H, m), 2.79 (0.75H, m), 2.67 (0.25H, m), 2.35 (0.25H, m), 2.23 (0.75H, dd, J=4.6 Hz, 14.6 Hz), 1.92 (1H, m), 1.62 (1H, m), 1.39 (2H, m), 1.02-0.78 (12H, br m); 13C-NMR; δ (CDCl3), 176.6, 176.5, 173.9, 172.5, 165.8, 56.7, 54.0, 50.0, 48.6, 40.9, 37.4, 37.3, 36.5, 35.9, 35.8, 35.0, 34.3, 31.4, 28.1, 26.6, 25.3, 23.4, 23.3, 22.4, 21.5, 21.3, 19.8 and 13.8. Found C 56.95, H 9.35, N 12.34%; C16H31N3O4.0.5H2O requires C 56.78%, H 9.53%, N 12.42%.