Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[C:8]([CH2:12][CH2:13][CH3:14])O[C:10](=[O:11])[C:5]=2[S:4][N:3]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>Cl>[CH2:15]([N:22]1[C:10](=[O:11])[C:5]2[S:4][N:3]=[C:2]([CH3:1])[C:6]=2[N:7]=[C:8]1[CH2:12][CH2:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCc1nc2c(C)nsc2c(=O)o1
Reactant: NCc1ccccc1
Agent: Cl
Product: CCCc1nc2c(C)nsc2c(=O)n1Cc1ccccc1
Temperature: 200 °C

Procedure:
3-Methyl-5-propyl-isothiazolo[4,5-d][1,3]oxazin-7-one (method 58) (200 mg, 1.02 mmol) was taken in a 10 mL microwavable pyrex tube and benzyl amine (1 g, 9.34 mmol) was added to it. The resulting mixture was heated in a microwave synthesizer (CEM's Discoverer) at 200° C. for 20 min. The MS of the reaction mixture showed the complete disappearance of the starting material and the presence of the product peak at 286 (MH+). The reaction mixture was diluted with 1N HCl (10 mL) and extracted with EtOAc (2×30 mL). The combined EtOAc layers were washed with water, brine, dried and concentrated. The thus obtained crude product was purified by column chromatography to isolate the pure product as a white solid. Yield 208 mg (71%). 1H NMR (300 MHz) δ 0.98 (t, 3H), 1.76-1.88 (m, 2H), 2.68 (s, 3H), 2.74 (t, 2H), 5.42 (s, 2H), 7.10-7.19 (m, 2H), 7.28-7.39 (m, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1.Br[CH2:15][CH2:16][CH:17]1[O:21][CH2:20][CH2:19][O:18]1.O>CC(C)=O>[O:18]1[CH2:19][CH2:20][O:21][CH:17]1[CH2:16][CH2:15][S:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Sc1ncccn1
Reactant: BrCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: c1cnc(SCCC2OCCO2)nc1

Procedure:
Potassium carbonate (0.766 g) was added to a stirred solution of 2-mercaptopyrimidine (0.622 g) in acetone (10 cm3) at ambient temperature. 2-(2-Bromoethyl)-1,3-dioxolane (1 g) was added to the resulting mixture and the reaction heated under reflux for 3.5 hours. The reaction mixture was left to cool overnight, then poured into water and extracted with diethyl ether. The organic phase was dried with magnesium sulfate and evaporated under reduced pressure to give a yellow oil. This material was used in step 2 without further purification. M+ =212; 1H NMR (CDCl3): δ2.25 (2H,m); 3.25(2H,t); 3.90 (2H,m); 4.00 (2H,m); 5.05 (1H,t); 6.96 (1H,t); 8.52 (2H,d).
Reaction SMILES: Br[C:2]1SC2C=C(OC)C(C)=CC=2N=1.C1(C2SC3C=C(OC)C(C)=CC=3N=2)CC1.C1(B(O)O)CC1.COC1C(C)=CC2N=CSC=2C=1.[C:47]([O:51][C@@H:52]([C:56]1[C:64]([CH3:65])=[CH:63][C:59]2[N:60]=[CH:61][S:62][C:58]=2[C:57]=1[C:66]1[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=1)[C:53]([OH:55])=[O:54])([CH3:50])([CH3:49])[CH3:48]>>[C:47]([O:51][C@@H:52]([C:56]1[C:64]([CH3:65])=[CH:63][C:59]2[N:60]=[C:61]([CH3:2])[S:62][C:58]=2[C:57]=1[C:66]1[CH:67]=[CH:68][C:69]([Cl:72])=[CH:70][CH:71]=1)[C:53]([OH:55])=[O:54])([CH3:50])([CH3:48])[CH3:49]
Reactant: COc1cc2sc(Br)nc2cc1C
Reactant: Cc1cc2ncsc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: COc1cc2sc(C3CC3)nc2cc1C
Agent: COc1cc2scnc2cc1C
Agent: OB(O)C1CC1
Product: Cc1nc2cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(-c3ccc(Cl)cc3)c2s1

Procedure:
Compound 7 was synthesized from compound 6A according to the procedure used to prepare compound 6B (except that trimethylboxine was used instead of cyclopropyl boronic acid) followed by the procedures to convert compound 5B to compound 5L as outlined in Example 1. 1H-NMR: 400 MHz, (CD3OD) δ: 7.69 (s, 1H), 7.65-7.51 (m, 4H), 5.22 (s, 1H), 2.76 (s, 3H), 2.57 (s, 3H), 0.94 (s, 9H). LCMS-ESI+: calc'd for C21H18ClNO3: 404.1 (M+H+). Found: 404.1 (M+H+).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[O:27]=[C:28]1[C:33](C(Cl)=O)=[CH:32][CH:31]=[C:30]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[O:29]1.[O:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[CH2:47][NH2:48]>>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[CH2:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([C:33]2[C:28](=[O:27])[O:29][C:30]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:31][CH:32]=2)=[O:7])[C@H:9]([C:24]([NH:48][CH2:47][C:43]2[O:42][CH:46]=[CH:45][CH:44]=2)=[O:26])[CH2:10]1
Reactant: NCc1ccco1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Product: CCCCCc1ccc(C(=O)N2CC(=NOCc3ccc(Cl)c(Cl)c3)C[C@H]2C(=O)NCc2ccco2)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 2-furylmethylamine the title compound was obtained in 92% purity by LC/MS. MS(ESI+): m/z=574.4.
Reaction SMILES: [BH4-].[Na+].[CH:3]1([CH:6]([NH:10][CH:11]2[CH2:13][CH2:12]2)[C:7](O)=[O:8])[CH2:5][CH2:4]1.II.[H][H]>C1COCC1>[CH:3]1([CH:6]([NH:10][CH:11]2[CH2:13][CH2:12]2)[CH2:7][OH:8])[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: O=C(O)C(NC1CC1)C1CC1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCC(NC1CC1)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (200 mg) was added to THF (10 mL), followed by cyclopropyl-cyclopropylamino-acetic acid (1 g of the material obtained in step B]). The mixture was cooled to 0° C. and a solution of iodine (558 mg) in THF (5 mL) was added carefully drop by drop over a period of 30 minutes. Vigorous hydrogen evolution was observed. The mixture was stirred at 0° C. for 30 minutes and then heated to reflux for 2 hours. The mixture was cooled and quenched with methanol until a clear solution was obtained. The solution was stirred for 30 minutes and then evaporated in vacuo. The residue was treated with 20% KOH (10 mL) and extracted with DCM. The combined organic extracts were dried over Na2SO4 and evaporated. The crude material was purified by flash chromatography using methanol/ethyl acetate 2:3 as an eluent to give 2-cyclopropyl-2-cyclopropylamino-ethanol (73 mg) as a colorless oil. MS (ESI): 142.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.N1C(Cl)=NC(Cl)=NC=1Cl.[CH3:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([N+:30]([O-:32])=[O:31])[CH:24]=1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:4]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([O:22][CH3:21])=[CH:24][C:25]=2[N+:30]([O-:32])=[O:31])=[O:6])=[CH:7][CH:8]=[C:9]([Cl:11])[N:10]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2Cl)c([N+](=O)[O-])c1
Yield: 22.5 %

Procedure:
To a solution of 2,6-dichloronicotinic acid (100 mg, 0.52 mmol) in CH2Cl2 (10 mL) was added cyanuric chloride (96 mg, 0.52 mmol). The mixture was stirred for half an hour, then 4-methoxy-2-nitroaniline (88 mg, 0.52 mmol) and triethylamine (0.1 mL, 0.72 mmol) were added. The resulting mixture was stirred at room temperature overnight and then diluted with ethyl acetate, washed with water. The organic phase was separated, dried over anhydrous Na2SO4, concentrated and purified by chromatography to give the title compound (40 mg, 22%) as a yellow solid. 1H NMR (DMSO-d6): 10.84 (bs, 1H), 8.09 (d, J=7.8, 1H), 7.75 (d, J=7.8, 1H), 7.57-7.52 (m, 2H), 7.37-7.33 (m, 1H), 3.86 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]2[N:8]([C@@H:11]3[O:33][C@H:32]([CH2:34][O:35]C(=O)C4C=CC=CC=4)[C@@H:22]([O:23]C(=O)C4C=CC=CC=4)[C@@:12]3([CH3:44])[O:13]C(=O)C3C=CC=CC=3)[CH:9]=[N:10][C:3]=12.[NH3:45]>CO>[NH2:45][C:2]1[N:7]=[N:6][CH:5]=[C:4]2[N:8]([C@@H:11]3[O:33][C@H:32]([CH2:34][OH:35])[C@@H:22]([OH:23])[C@@:12]3([CH3:44])[OH:13])[CH:9]=[N:10][C:3]=12
Reactant: N
Reactant: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nncc21
Solvent: CO
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nncc21

Procedure:
The compound from Step B (590 mg, 0.96 mmol) was added to a solution of ammonia in methanol and stirred in a steel bomb at 150° C. for 6 hours. The reaction mixture was evaporated to dryness to remove methanol. The crude product was purified on silica gel reverse-phase (C18) using water as eluant to give the title compound (35 mg) as a white powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:37]1([C:43]2[C:47]3[CH:48]=[CH:49][C:50](O)=[C:51]([CH2:52][CH2:53][CH3:54])[C:46]=3[O:45][CH:44]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:37]1([C:43]2[C:47]3[CH:48]=[CH:49][C:50]([O:1][CH2:2][CH2:3][C:4]4[NH:5][C:6]5[C:11]([CH:12]=4)=[CH:10][C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=5)=[C:51]([CH2:52][CH2:53][CH3:54])[C:46]=3[O:45][CH:44]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Reactant: CCCc1c(O)ccc2c(-c3ccccc3)coc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1c(OCCc2cc3cc(CC(=O)OC)ccc3[nH]2)ccc2c(-c3ccccc3)coc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
To a solution of the methyl 2-(2-hydroxyethyl)indole-5-acetate (37.6 mg; 0.16 mmol), Ph3P (47 mg; 1.1 eq), 3-phenyl-6-hydroxy-7-propylbenzofuran (45 mg; 1.1 eq) and THF (5 mL) was added diisopropyl azodicarboxylate (35 ,uL; 1.1 eq), and the mixture was stirred at room temperature overnight. The mixture was concentrated and chromatographed (silica gel, hexane:ethyl acetate::9:1 to 4:1) affording 18.6 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12](=O)[CH3:13])=[CH:8][CH:7]=1.[NH3:20].[H][H]>CO.[Ni]>[NH2:20][CH:12]([CH3:13])[CH2:11][O:10][C:9]1[CH:15]=[CH:16][C:6]([O:5][C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([Cl:1])[CH:3]=2)=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: N
Reactant: CC(=O)COc1ccc(Oc2cccc(Cl)c2)cc1
Agent: [Ni]
Solvent: CO
Product: CC(N)COc1ccc(Oc2cccc(Cl)c2)cc1
Reaction time: 2 h

Procedure:
51 g of 1-[4-(3-chlorophenoxy)-phenoxy]-2-propanone are dissolved in 510 ml of methanol in an autoclave, and 10 g of Raney nickel are added. 31 g of liquid ammonia are introduced, and then hydrogen gas is introduced under pressure. The reaction mixture is hydrogenated at 50 bar and +40° C.-45° C. for 2 hours. The reaction mixture is then filtered through diatomaceous earth and the solvent is distilled off completely in vacuo. The crude product is chromatographed over silica gel (eluant: diethyl ether/methanol, 9:1), yielding pure 2-amino-1-[4-(3-chlorophenoxy)-phenoxy]-propane in the form of a colourless, oily liquid, n20D : 1.5743.
Reaction SMILES: [F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][NH:5][C:6](=[O:31])[N:7]([C@H:9]([CH2:16][O:17][C:18](=[O:30])[NH:19][C:20]1[N:21]=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:10][CH2:11][CH2:12][C:13](O)=[O:14])[CH3:8].C(N(CC)CC)C.ClC(OC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[CH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[C:20]([NH:19][C:18](=[O:30])[O:17][CH2:16][C@@H:9]([N:7]([CH3:8])[C:6]([NH:5][CH2:4][C:3]2[CH:32]=[CH:33][CH:34]=[C:35]([F:36])[C:2]=2[F:1])=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[N:21]=1
Reactant: CN(C(=O)NCc1cccc(F)c1F)[C@@H](CCCC(=O)O)COC(=O)Nc1cc2ccccc2cn1
Agent: CC(C)OC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)NCc1cccc(F)c1F)[C@@H](CCCCO)COC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.4 %

Procedure:
To a solution of (S)-5-(3-(2,3-difluorobenzyl)-1-methylureido)-6-(isoquinolin-3-ylcarbamoyloxy)hexanoic acid (˜2.04 mmol, 1.0 equiv.) and triethylamine (0.38 mL, 2.78 mmol, 1.2 equiv.) in anhydrous THF (7 mL) was added isopropyl chloroformate (2.80 mL, 2.80 mmol, 1.2 equiv.) dropwise at 0° C. After stirred at RT for 20 min, the mixture was filtered and transferred to a solution of NaBH4 (0.18 g, 4.76 mmol, 2.0 equiv.) in water (2.0 mL). The resulting mixture was stirred at RT for 1 h, and quenched with saturated NH4Cl. The solution was extracted with EtOAC twice. The organic layers were washed with brine, dried over Na2SO4, and concentrated. The resulting residue was purified on silica gel column (50-100% EtOAc in hexanes followed by 10% MeOH in dichloromethane) to give (S)-2-(3-(2,3-difluorobenzyl)-1-methylureido)-6-hydroxyhexyl isoquinolin-3-ylcarbamate (0.58 g, 52% for two steps). LRMS (M+H+) m/z 487.3.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[Si:7](Cl)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].N1C=CN=C1.CN(C)C=[O:23]>CCCCCC>[Si:7]([O:6][CH:5]([OH:23])[CH2:4][CH2:3][CH2:2][Cl:1])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCl
Reactant: CN(C)C=O
Agent: c1c[nH]cn1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OC(O)CCCCl
Temperature: 25 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
4-Chloro-1-butanol (5.43 g, 50 mmol) was dissolved in dimethylformamide (50 mL) and tert-butyldimethylsilylchloride (7.54 g, 50 mmol) was added, followed by imidazole (3.4 g, 50 mmol). After 24 hours of stirring at room temperature, the reaction mixture was diluted with hexane, washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give colorless liquid which was purified by chromatography on silica gel eluting with hexane/ethyl acetate (30:1) to give the product (7.26 g, 56%). 1H NMR (CDCl3) δ: 0.05 (s, 6H), 0.89 (s, 9H), 1.64-1.68 (m, 2H), 1.82-1.86 (m, 2H), 3.57 (t, 2H), 3.64 (t, 2H).
Reaction SMILES: C(O[C:6](=[O:23])[NH:7][C:8]1[CH:9]=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.[Cl:34][C:35]1[CH:40]=[CH:39][N:38]2[N:41]=[CH:42][C:43](C(Cl)=O)=[C:37]2[N:36]=1>O1CCOCC1.ClCCl>[F:22][C:19]([F:20])([F:21])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[O:11][N:10]=[CH:9][C:8]=1[NH:7][C:6]([C:43]1[CH:42]=[N:41][N:38]2[CH:39]=[CH:40][C:35]([Cl:34])=[N:36][C:37]=12)=[O:23]
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Reactant: CC(C)(C)OC(=O)Nc1cnoc1-c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(Nc1cnoc1-c1ccccc1C(F)(F)F)c1cnn2ccc(Cl)nc12
Temperature: 40 °C
Yield: 85.7 %

Procedure:
A mixture of [5-(2-trifluoromethyl-phenyl)-isoxazol-4-yl]-carbamic acid tert-butyl ester (345 mg, 1.05 mmol, 1.0 equiv), 4M HCl in dioxane (2 mL) in 1,4-dioxane (3 mL) was heated to 40° C. for 20 hours. The mixture was concentrated under vacuum affording a residue which was dissolved in dichloromethane (12 mL) and treated with diisopropylethylamine (271 mg, 2.10 mmol, 2.0 equiv). The mixture was cooled with an ice-bath, and a solution of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (1.05 mmol, 1.0 equiv) in dichloromethane (6 mL) was added dropwise. The resultant mixture was stirred at ambient temperature for 18 hours. The solution was washed sequentially with 1M HCl aqueous solution, saturated aqueous sodium bicarbonate solution and water. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated (methanol), and the isolated solid was washed with methanol and diethyl ether before drying under vacuum to give 367 mg (86%) of 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(2-trifluoromethyl-phenyl)-isoxazol-4-yl]-amide. LCMS (ESI) m+H=408.0 (mono Cl); 1H NMR (400 MHz, DMSO-d6) δ: 9.50 (s, 1H), 9.35 (d, 1H), 9.22 (s, 1H), 8.71 (s, 1H), 8.03 (d, 1H), 7.97-7.82 (m, 3H), 7.38 (d, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:19]([NH2:21])=[O:20])=[CH:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:15][CH2:16][NH2:17])[C:7]=2[N:18]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:22]([NH:17][CH2:16][CH2:15][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:5]=[C:4]([C:19]([NH2:21])=[O:20])[C:3]([NH2:2])=[N:18][C:7]1=2)(=[O:24])[CH3:23]
Reactant: NCCn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NCCn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a solution of 2-amino-9-(2-aminoethyl)-9H-pyrido[2,3-b]indole-3-carboxamide (16, 50.0 mg, 0.186 mmol) in pyridine (2 mL) was added DMAP (23.0 mg, 0.188 mmol) and acetic anhydride (23 μL, 0.243 mmol). The reaction was stirred at RT under an atmosphere of argon. After 1 h, the reaction was concentrated and the crude product was purified by HPLC (Phenomenex Luna 15 μm C18, aqueous NH4OAc/CH3CN) to yield 9-[2-(acetylamino)ethyl]-2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (22, 11 mg, 19%). NH4OAc standard conditions. DAD Retention time =5.18 min. M+H=312. 1H NMR (300 MHz, DMSO-d6): δ 8.73 (s, 1H), 8.01 (t, J=5.7 Hz, 1H), 7.80 (d, J=7.5 Hz, 1H), 7.58 (br s, 2H), 7.46 (d, J=8.1 Hz, 1H), 7.33 (t, J=8.1 Hz, 1H), 7.18 (t, J=7.5 Hz, 1H), 4.31 (t, J=6.0 Hz, 2H), 3.41 (q, J=6.0 Hz, 2H), 1.71 (s, 3H).
Reaction SMILES: [NH:1]1[C@:9]2([CH2:11][OH:12])[O:10][C@:2]1([C@H:5]([C@@H:7]2[OH:8])[OH:6])[CH2:3][OH:4].[F:13][C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20]Br)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].C(OCC)C>CN(C)C=O>[F:13][C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][N:1]2[C@:9]3([CH2:11][OH:12])[O:10][C@:2]2([C@H:5]([C@@H:7]3[OH:8])[OH:6])[CH2:3][OH:4])=[CH:16][CH:15]=1
Reactant: OC[C@]12N[C@](CO)(O1)[C@@H](O)[C@@H]2O
Reactant: Fc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: OC[C@]12O[C@](CO)([C@@H](O)[C@@H]1O)N2CCOc1ccc(F)cc1

Procedure:
A solution of a compound Formula XIV (2.60 g, 0.0159 mol), 2-(4-fluorophenoxy)ethyl bromide (3.70 g, 0.0169 mol), and Na2CO3 (1.86 g, 0.0175 mol) in 11 mL of dimethylformamide was heated at 85° C. for 8 h. The solution was cooled, then treated with 250 mL of ethyl ether portion wise, and the solvent was removed. The resultant residue was diluted with chloroform, filtered, and concentrated. This crude material was chromatographed on a Waters Prep-500 HPLC (88:11:1, CHCl3 /MEOH/NH4OH) to give the product, which was recrystallized from EtOAc/hexane (3.49 g, 73%), mp 96°-98° C. (corrected). 1H NMR supported the assigned structure.
Reaction SMILES: CCCCCC.[C:7]([O:11][C:12](=[O:25])[NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1Br)([CH3:10])([CH3:9])[CH3:8].[CH:26](=[O:28])[CH3:27].[Cl-].[NH4+]>C1COCC1.O>[C:7]([O:11][C:12](=[O:25])[NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[CH:26]([OH:28])[CH3:27])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)ccc1Br
Reactant: CC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccc(C(F)(F)F)cc1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
At −78° C. under nitrogen 1.6 M butyllithium solution in hexane (13.8 ml, 20 mmol) were added dropwise to (2-Bromo-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (3.4 g, 10 mmol) in THF (60 ml). The reaction was stirred for 15 minutes at −78° C. and acetaldehyde (881 mg, 20 mmol) was added dropwise. After stirring for 15 minutes at −78° C. saturated aqueous ammonium chloride solution was added and the reaction was allowed to warm to room temperature. The reaction was diluted with water and extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated to yield the crude product which was purified by column chromatography (heptane:ethyl acetate=7:3). The product was isolated as a yellow viscous oil (1.78 g, 58%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][CH2:5][CH2:6][CH2:7]Cl.[OH:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][CH2:5][CH2:6][CH2:7][N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][OH:11])[CH2:14][CH2:15]1
Reactant: COC(CCCCCl)OC
Reactant: OCC1CCNCC1
Product: COC(CCCCN1CCC(CO)CC1)OC

Procedure:
To a cooled (0° C.) and stirred suspension of isonipecotic acid (25.83 g, 200 mmol), in anhydrous THF (100 ml) was added lithium aluminium hydride (1M in THF; 200 ml), under a nitrogen atmosphere. The reaction was allowed to attain room temperature and it was stirred for 18 h, then refluxed for a further 4 h. The reaction was quenched by sequential addition of water (7.5 ml), 15% sodium hydroxide solution (7.5 ml) and water (15 ml). The reaction was filtered to remove a granular precipitate and the filtrate was concentrated under vacuum to give 11.24 g of 4-(hydroxymethyl)piperidine as a colourless oil. The title compound was prepared from 5-chloropentanal dimethyl acetal (20.4 g, 122 mmol) and 4-(hydroxymethyl)piperidine (15.7 g) using a similar method to that described for Example 8 (step 2). δ (360 MHz, DMSO-d6) 1.10 (2H, m), 1.28 (2H, m), 1.39 (2H, m), 1.48 (2H, m), 1.60 (2H, br d), 1.77 (2H, t), 2.20 (2H, t), 2.80 (2H, br d), 3.21 (8H, m), 4.31 (1H, t), 4.37 (1H, t).
Reaction SMILES: [CH3:1][C:2]([CH3:46])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:45])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:44])=[CH:11]/[CH2:12][CH2:13]/[C:14](/[CH3:43])=[CH:15]/[CH2:16][CH2:17]/[C:18](/[CH3:42])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:41])=[CH:23]/[CH2:24][CH2:25]/[C:26](/[CH3:40])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:39])=[CH:31]/[CH2:32][CH2:33]/[C:34](/[CH3:38])=[CH:35]/[CH2:36][OH:37].[CH:47]1([C:53](Cl)=[O:54])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>N1C=CC=CC=1.CCCCCC>[CH:47]1([C:53]([O:37][CH2:36][CH:35]=[C:34]([CH3:38])[CH2:33][CH2:32][CH:31]=[C:30]([CH3:39])[CH2:29][CH2:28][CH:27]=[C:26]([CH3:40])[CH2:25][CH2:24][CH:23]=[C:22]([CH3:41])[CH2:21][CH2:20][CH:19]=[C:18]([CH3:42])[CH2:17][CH2:16][CH:15]=[C:14]([CH3:43])[CH2:13][CH2:12][CH:11]=[C:10]([CH3:44])[CH2:9][CH2:8][CH:7]=[C:6]([CH3:45])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:46])[CH2:1][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[O:54])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCCCCCCCCCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCOC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 Grams of solanesol were dissolved in 50 ml of pyridine and the solution was added dropwise with of 15% solution of 4.6 g of cyclohexylcarboxylic acid chloride in pyridine over 30 minutes. After completion of the addition, the mixture was stirred at room temperature for two hours to complete the reaction. Then, the reaction product was diluted with n-hexane, washed with water and concentrated. The concentrate was purified by chromatography with 80 g of silica gel in n-hexane/benzene solvent mixture as elution solvent to obtain the final product as a white solid (m.p. 34.0°-35.0° C.). Yield: 6.2 g.