Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Cl-].[O:7]([C:14]1[CH:15]=[C:16]([CH2:20][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([CH:51]2[CH2:53][CH2:52]2)=[CH:48][CH:49]=O)=[CH:43][CH:42]=1>O1CCCC1>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([CH:51]2[CH2:53][CH2:52]2)=[CH:48][CH:49]=[CH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:15]=2)=[CH:43][CH:42]=1
Reactant: c1ccc(Oc2cccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Reactant: O=CC=C(c1ccc(Cl)cc1)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1ccc(C(=CC=Cc2cccc(Oc3ccccc3)c2)C2CC2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
A stirred solution of 4.4 mL (0.011 mole) of n-butyllithium (2.5 molar in hexane) in 100 mL of dry tetrahydrofuran was cooled to -78° C., and 4.6 grams (0.01 mole) of 3-phenoxyphenylmethyltriphenylphosphonium chloride was quickly added. Upon completion of addition, the reaction mixture was stirred at -78° C. for one hour and then was allowed to warm to -20° C. where it stirred for one hour. The reaction mixture was cooled to -78° C., and 2.1 grams (0.01 mole) of 3-(4-chlorophenyl)-3-cyclopropylpropenal (prepared in Step B) in 10 mL of tetrahydrofuran was added during a 15 minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for two hours. The reaction was quenched with the addition of 15 mL of aqueous 10% hydrochloric acid solution. The mixture was extracted with diethyl ether. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 5% diethyl ether in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 3.2 grams of 1-(4-chlorophenyl)-1-cyclopropyl-4-(3-phenoxyphenyl)1,3-butadiene.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:25][CH2:26][CH2:27]Br)[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][C:19]([Br:24])=[CH:18][CH:17]=3>COCCOC>[Br:24][C:19]1[CH:18]=[CH:17][C:16]2[N:15]([CH2:25][CH2:26][CH2:27][O:8][CH2:7][CH:5]3[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]3)[C:14]3[C:22]([C:21]=2[CH:20]=1)=[CH:23][C:11]([Br:10])=[CH:12][CH:13]=3
Reactant: CC1(C)OCC(CO)O1
Reactant: BrCCCn1c2ccc(Br)cc2c2cc(Br)ccc21
Solvent: COCCOC
Product: CC1(C)OCC(COCCCn2c3ccc(Br)cc3c3cc(Br)ccc32)O1
Reaction time: 0.25 h
Yield: 70 %

Procedure:
Potassium terbutylate (0.8 g, 7.1 mmoles) are added, in an inert atmosphere, to a solution of solketal (0.9 g, 7.1 mmoles) in 10 ml of 1,2-dimethoxyethane. After 15 minutes, 3,6-dibromo-9-(3′-bromopropyl)carbazole (2.1 g, 4.7 mmoles) dissolved in 10 ml of 1,2-dimethoxyethane, are added dropwise. After hours, the 1,2-dimethoxyethane is removed by distillation at reduced pressure, the residue is recovered with water and extracted with ethyl acetate. After washing the organic phase with water until neutrality, said organic phase is anhydrified on sodium sulfate. The solvent is removed by distillation at reduced pressure. After purification by elution on an alumina column (heptane/ethyl acetate=9/1), 1.6 g of 3,6-dibromo-9-{(3-[(2,2-dimethyl-1,3-di-oxolan-4-yl)methoxy]propyl}-9H-carbazole are obtained (yield=70%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)[C:5]([NH2:7])=[O:6].[CH3:14][C:15]1[CH:19]=[C:18]([CH:20]([OH:22])[CH3:21])[O:17][N:16]=1>>[NH2:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([NH2:7])=[O:6])=[CH:3][C:2]=1[O:22][CH:20]([C:18]1[O:17][N:16]=[C:15]([CH3:14])[CH:19]=1)[CH3:21]
Reactant: Cc1cc(C(C)O)on1
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(F)c1
Product: Cc1cc(C(C)Oc2cc(C(N)=O)ccc2N)on1

Procedure:
Is prepared in a similar manner as intermediate III.4 from 3-fluoro-4-nitro-benzamide and 1-(3-methylisoxazol-5-yl)ethanol.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CC1C=CC(S(O[CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][C:41]2=[O:46])(=O)=O)=CC=1>C(#N)C>[F:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][C:41]3=[O:46])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2N2CCCCC2=O)cc1
Reactant: Fc1cccc(C2CCCNC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CCCCN1c1ccccc1CCN1CCCC(c2cccc(F)c2)C1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
3-(3-Fluorophenyl)piperidine hydrochloride a2-4 (432 mg, 2 mmol, 1 eq) and K2CO3 (829 mg, 6 mmol, 3 eq) are added to a solution 2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl 4-methylbenzenesulfonate a2-3 (747 mg, 2 mmol, 1 eq) in acetonitrile (10 ml). The reaction mixture is stirred at 85° C. overnight, then filtered and the filtrate is condensed under reduced pressure. The residue is purified by basic reverse phase chromatography over silicagel (gradient CH3CN/H2O/NH4OH from 50/50/0.1 to 80/20/0.1) to afford 472 mg (1.24 mmol) of 1-(2-{2-[3-(3-fluorophenyl)piperidin-1-yl]ethyl}phenyl)piperidin-2-one as a free base. Oxalic acid (111 mg, 1.24 mmol, 1 eq) is added to the residue dissolved in diethylether. The precipitate obtained is filtered and dried under vacuum to afford 517 mg of 1-(2-{2-[3-(3-fluorophenyl)piperidin-1-yl]ethyl}phenyl)piperidin-2-one oxalate 24.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28][CH3:29])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[C:30]#[N:31])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.[CH3:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:40]=1[CH3:41].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O>[C:30]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][C:14]1[CH:32]=[CH:33][C:11]([C:9](=[O:10])[NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([C:37]4[CH:38]=[CH:39][C:40]([CH3:41])=[C:35]([CH3:34])[CH:36]=4)[N:7]=3)=[CH:12][CH:13]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:26]([O:28][CH3:29])=[O:27])#[N:31]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(Br)n4)cc3)c(C#N)cc21
Reactant: Cc1ccc(B(O)O)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(C)c(C)c5)n4)cc3)c(C#N)cc21
Temperature: 100 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
Methyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (51 mg, 0.1003 mmol), 3,4-dimethylphenylboronic acid (19.562 mg, 0.1304 mmol), sodium carbonate (31.901 mg, 0.301 mmol), toluene (1 mL), and water (0.1 mL) were placed in a vial with a Teflon lined screw cap. Argon was bubbled through the mixture for 10 minutes. Palladium (0) tetrakistriphenylphosphine (5.797 mg, 0.00501 mmol) was added and the vial was sealed. The vial was placed in a preheated sand bath (100° C.) and the mixture was stirred for 16 hours at that temperature. The mixture was cooled to ambient temperature and whole mixture was purified on silica gel (EtOAc-hexanes gradient) to provide 51.1 mg of the title compound as a thin film (95.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH:12]=2)([CH3:9])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(c1cccc(Cl)c1)C1CCC(=O)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C1=CCC(=O)CC1)c1cccc(Cl)c1

Procedure:
This compound is prepared in a manner analogous to that of Step C of Example 2, by the hydrogenation of 6.5 grams (0.026 mole) of 1-[2-(3-chlorophenyl)propan-2-yl]-1-cyclohexen-4-one in the presence of 0.4 gram (catalyst) of 10% palladium on charcoal in 50 mL of ethanol, yielding 4-[2-(3-chlorophenyl)propan-2-yl]cyclohexanone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:20](OCC1C=CC=CC=1)(=[O:22])[CH3:21]>C1COCC1>[CH3:9][S:8][C:4]1[N:3]=[C:2]([CH2:1][C:20](=[O:22])[CH3:21])[CH:7]=[CH:6][N:5]=1
Reactant: CC(=O)OCc1ccccc1
Reactant: CSc1nccc(C)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1nccc(CC(C)=O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.5 %

Procedure:
To a solution of 4-Methyl-2-(methylthio)pyrimidine (1) (3 g, 21.40 mmol) in THF (35.7 mL) at −10° C. was added LHMDS (32.1 mL, 32.1 mmol, 1M in THF). The resulting reaction was warmed to rt and stirred for 15 minutes, after which time the reaction was cooled back to −10° C. and Benzyl Acetate (3.21 mL, 23.54 mmol) was added. The reaction was then warmed to rt and stirred for 1 hour, after which time complete conversion to product was observed by LCMS. TLC after 1 hour still showed the presence of some starting material and the reaction was continued stirring for an additional hour. After this time there was no change in TLC and the reaction was worked up. The reaction was quenched by slow addition of saturated ammonium chloride and the volatile solvent evaporated. The mixture was then diluted with EtOAc and water. The organic layer was then washed with brine, dried with sodium sulfate, and concentrated. The crude residue was purified by flash chromatography with a gradient of 8-66% EtOAc in Heptane to give the desired product as a yellow liquid (1.93 g, 50%). MS (ES+): m/z=183.1 (100) [MH+]. HPLC: tR=0.91 minute over 3 minutes. Purity: 76% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6]>C1(N)CCCCC1>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[CH:2][CH:3]=4)[CH:9]=3)=[CH:20][CH:19]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Solvent: NC1CCCCC1
Product: Cc1ccc(NC(=O)c2ccncc2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reaction time: 48 h
Yield: 31.1 %

Procedure:
A solution of 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (50 mg, 0.12 mmol) in cyclohexylamine (1 ml) was heated at 110° C. for 36 h and then at 160° C. for 48 h in a sealed tube. The reaction was concentrated under vacuum, the residue triturated with water and purified by preparative HPLC. The solvent was evaporated under vacuum to give 2-cyclohexylamino)-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (14.4 mg). NMR; δH [2H6]—DMSO 10.26,(1H, s), 8.62,(1H, t), 8.07,(1H, d), 7.92,(2H, d), 7.69-7.66,(2H, m), 7.43,(2H, d), 7.28,(1H, d), 6.84,(2H, m), 6.67,(1H, d), 3.72,(1H, m), 3.16,(2H, t), 2.19,(3H, s), 1.90,(2H, m), 1.70,(2H, m), 1.57,(1H, m), 1.31,(2H, m), 1.18,(3H, m), 1.04,(1H, m), 0.24,(2h, m). LCMS: retention time 3.14 min, MH+483.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:15]3=2)[CH:10]=[C:9]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1(C)C=CC=CC=1>[CH3:5][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:15]3=2)[CH:10]=[C:9]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)c1cc2ccc3sc4ccccc4c3c2[nH]1
Reactant: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2ccc3sc4ccccc4c3c2n1C

Procedure:
Using the procedure outlined in Example 34A except that dimethyl sulfate was used as the alkylating agent, ethyl 1H-[1]benzothieno[2,3-g]indole-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a quantitative yield of ethyl 1-methyl-1H-[1]benzothieno[2,3-g]indole-2-carboxylate, mp 85°-86°, (PhCH3), (C,H,N).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH:11]=[C:10]([CH3:14])[N:9]1[CH3:15].[N+:16]([O-])([OH:18])=[O:17].O.CC(OC)(C)C>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([N+:16]([O-:18])=[O:17])=[C:10]([CH3:14])[N:9]1[CH3:15]
Reactant: Cc1cc(=O)n(-c2ccccc2F)n1C
Reactant: O=[N+]([O-])O
Solvent: COC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1c([N+](=O)[O-])c(=O)n(-c2ccccc2F)n1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(2-Fluorophenyl)-1,5-dimethyl-1H-pyrazol-3(2H)-one (260 g, 1261 mmol) in TFA (1040 ml) was cooled to −10° C. and stirred for 30 mins. To the mixture was added fuming nitric acid (84 ml) dropwise and this was stirred for 15 mins under cooling then at RT for 1 hr. The resulting mixture was poured onto a mixture of ice (1500 ml), water (1000 ml) and TBME (2500 ml) and stirred until the ice melted, then at RT for 1 hr. The mixture was filtered, washed with water (200 ml) and TBME (1000 ml). The collected crystals were dried to give the title compound as red-brown crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=12.[Li+].[CH3:22]C([N-]C(C)C)C.IC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]([CH3:22])=[CH:10][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)ccnc32)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(C)cc3c(Br)ccnc32)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A mixture of 4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (D20) (6 g, 17.08 mmol) in THF (100 ml) was cooled to −78° C. LDA (2M in THF) (21.35 mL, 42.7 mmol) was added at −78° C. and stirred at this temperature for ca. 1 hour. Iodomethane (2.136 ml, 34.2 mmol) was then added. After stirred at −78° C. for further ca. 30 min, the mixture was quenched by addition of saturated NH4Cl solution (150 mL), extracted with ethyl acetate (100 mL×3). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified on normal phase chromatography eluting with a gradient of 0-30% ethyl acetate in cyclohexane to give the title compound containing impurities (5.4 g). LCMS (A): m/z (M+H)+ 365/367, C15H13BrN2O2S requires 364/366 (acidic).
Reaction SMILES: [I:1][C:2]1[C:19]([C:20]([O:22]CC)=[O:21])=[C:5]2[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]3([CH2:11][CH2:10]3)[CH2:9][N:4]2[N:3]=1.[OH-].[Na+]>C(O)C.O>[C:15]([O:14][C:12]([N:7]1[C:8]2([CH2:10][CH2:11]2)[CH2:9][N:4]2[N:3]=[C:2]([I:1])[C:19]([C:20]([OH:22])=[O:21])=[C:5]2[CH2:6]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1c(I)nn2c1CN(C(=O)OC(C)(C)C)C1(CC1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2c(C(=O)O)c(I)nn2CC12CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.7 %

Procedure:
To a stirred solution of Intermediate 350D (0.500 g, 1.118 mmol) in ethanol (10 mL) and water (1 mL) was added NaOH (0.369 g, 9.21 mmol) and the resulting solution was stirred at RT for 12 h. The volatiles were removed under reduced pressure and the residue was acidified with an aqueous solution of 1.5 N HCl. The solid product separated was filtered through a Buchner funnel and dried under vacuum to afford Intermediate 350E as a white solid (0.43 g, 90%). MS(ES): m/z=420 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 6.19 (br. s., 1H), 4.92 (br. s., 2H), 4.06 (br. s., 2H), 1.48 (s, 9H), 1.19 (br. s., 2H), 1.01-0.83 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][C:3]=1[CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1.Cl>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][C:3]=1[CH:19]1[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1C1CCNCC1
Reaction time: 1 h
Yield: 98.3 %

Procedure:
tert-Butyl 4-{2-methyl-5-[(phenylmethoxy)carbonylamino]phenyl}piperidine carboxylate (7.50 g, 17.6 mmol) was dissolved in CH2Cl2 (120 mL) and a HCl solution (4M in dioxane, 52.0 mL) was added and stirred for 1 h. The mixture was concentrated in vacuo and redissolved in CH2Cl2. Aqueous Na2CO3 solution (1 M) was added and the biphasic mixture was stirred for 20 min and separated. The organic layer was further washed with water, dried over Na2SO4 and concentrated in vacuo to afford N-(4-methyl-3-(4-piperidyl)phenyl)(phenylmethoxy)carboxamide (5.61 g, 98% yield) as a white solid. ESMS m/e: 326.0 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]([C:15]([F:18])([F:17])[F:16])[O:12]2)=[CH:7][C:6]=1[Cl:24])=[N+]=[N-]>CCO.[Pd]>[NH2:1][CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]([C:15]([F:17])([F:18])[F:16])[O:12]2)=[CH:7][C:6]=1[Cl:24]
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CN=[N+]=[N-])cc2OC1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1=Cc2cc(Cl)c(CN)cc2OC1C(F)(F)F
Reaction time: 8 h
Yield: 104.3 %

Procedure:
The ester from Step 4 (0.93 g, 2.57 mmole) was dissolved in EtOH (30 mL). 10% Pd-C (0.11 g, 11% weight) was added to the solution after flushing nitrogen. The mixture was stirred at hydrogen sphere for overnight. Pd was filtered off the filtrate was concentrated to give yellow oil (0.9 g, 100%): LCMS m/z 336.05 (M+H). This ester was of suitable purity to use without further purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[CH3:6][N:7]1[C:11](=[O:12])[C:10](=[O:13])[NH:9][C:8]1=[S:14]>>[Br:1][CH2:2][CH2:3][CH2:4][N:9]1[C:10](=[O:13])[C:11](=[O:12])[N:7]([CH3:6])[C:8]1=[S:14]
Reactant: BrCCCBr
Reactant: CN1C(=O)C(=O)NC1=S
Product: CN1C(=O)C(=O)N(CCCBr)C1=S

Procedure:
By the procedure of Example 1(i), 1,3-dibromopropane was reacted with 1-methyl-2-thioxo-4,5-imidazolidinedione to yield 1-(3-bromopropyl)-3-methyl-2-thioxo-4,5-imidazolidinedione which, on reaction with thiourea by the procedure of Example 1(ii) gave S-[6-(1-(3-methyl-4,5-dioxo-2-thioxoimidazolidinyl))propyl]isothiourea hydrobromide. Hydrolysis of the latter compound by the procedure of Example 1(iii) and recrystallisation of the product from water gave the title compound, m.p. 141°-143°.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:46])[CH2:10][C:11]1[CH:45]=[CH:44][CH:43]=[CH:42][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)=[N:27][CH:28]=2)[N:16]=1>C(Cl)Cl>[CH3:21][C:20]1[C:15]([CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[CH2:10][C:9]([NH2:8])=[O:46])=[N:16][C:17]([NH:22][C:23]2[CH:28]=[N:27][C:26]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[N:18][CH:19]=1
Reactant: Cc1cnc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)nc1CCc1ccccc1CC(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2ccc(C3CCNCC3)nc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
TFA (0.5 mL) was added to a solution of tert-butyl 4-(5-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (A20) (70 mg, 0.13 mmol) in DCM (5 mL) and the resulting mixture stirred for 18 hours at room temperature. The volatiles were removed in vacuo and the residue partitioned between 2 M aqueous NaOH (10 mL) and EtOAc (25 mL). The organic layer was separated then washed with water (25 mL), brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound 4 as an off white solid (45 mg, 79%); 1H NMR (400 MHz, d4-MeOH) δ 8.79 (dd, J=2.6, 0.5 Hz, 1H), 8.15 (dd, J=8.6, 2.7 Hz, 1H), 8.13 (d, J=0.6 Hz, 1H), 7.28-7.22 (m, 2H), 7.21-7.14 (m, 3H), 3.64 (s, 2H), 3.20-3.10 (m, 4H), 3.02-2.95 (m, 2H), 2.88-2.68 (m, 3H), 2.11 (s, 3H), 1.95-1.84 (m, 2H), 1.71 (qd, J=12.7, 4.0 Hz, 2H). LCMS-A: rt 4.241 min; m/z 431 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:11][C@H:12]([C:20]([NH2:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2([NH:22][C:20](=[O:21])[C@H:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(=O)N1CCC(=O)CC1
Solvent: CCO
Product: CC(=O)N1CCC2(CC1)NC(=O)[C@H](Cc1ccccc1)N2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-acetylpiperidin-4-one (1.5 g, 10.8 mmol) and (S)-phenylalaninamide (1.8 g, 10.8 mmol) in EtOH (30 ml) was heated under reflux for 2.5 h and stirred at RT for a further 16 h. After removal of the solvent and drying in vacuo, the product 8-acetyl-3-(S)-benzyl-1,4,8-triazaspiro[4,5]decan-2-one was obtained in a yield of 3.0 g (99%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2C=O)=[O:5].[CH3:24][O:25][CH2:26][CH2:27][NH:28][CH3:29].[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[Cl:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[CH2:29][N:28]([CH2:27][CH2:26][O:25][CH3:24])[CH3:30])=[O:5]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=Cc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reactant: CNCCOC
Agent: [Na+]
Solvent: CC(=O)O
Product: COCCN(C)Cc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reaction time: 4 h
Yield: 63.5 %

Procedure:
To a stirred suspension of 8-(2,6-dichlorobenzoylamino)-4-formylquinoline (100 mg), N-(2-methoxyethyl)methylamine (28 mg) and acetic acid (17 mg) was added sodium triacetoxyborohydride (91.6 mg) portionwise over a period of 5 minutes at ambient temperature, and the resulting mixture was stirred at the same temperature for four hours. The crude product was partitioned in dichloromethane and aqueous saturated sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure. The residue was purified by a preparative thin layer chromatography (5%0 methanoldichloromethane) and recrystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-4-[N-(2-methoxyethyl)-N-methylaminomethyl]quinoline (77 mg) as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21](OC)=[O:22])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:22][CH2:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:13][CH2:14]2
Reactant: COC(=O)c1ccc2c(c1)CCC2NC(=O)OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NC1CCc2cc(CO)ccc21)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 48.1 %

Procedure:
To a solution of methyl 1-(benzyloxycarbonylamino)-2,3-dihydro-1H-indene-5-carboxylate (5.59 mmol, 1.82 g) in THF (30 mL) at 0° C. was added lithium aluminium hydride (5.59 mmol, 5.59 mL) in a dropwise fashion. Stirring at 0° C. was continued for 1.5 h after which time the reaction mixture was quenched with water and sat Rochelle's salt added followed by DCM & the organics separated/dried (1PS paper) before being concentrated to dryness. The residue was purified by flash chromatography (50 g, 1:1 EtOAc/heptane) to give an off-white solid (800 mg, 2.69 mmol, 48.1%). MS (ESI): m/z [M+H]+ 298.2