Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:21]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH:22]([F:24])[F:23])=[C:17]([CH2:19]O)[CH:18]=1.C1C=CC(P([N:48]=[N+:49]=[N-:50])(C2C=CC=CC=2)=O)=CC=1>C1COCC1>[N:48]([CH2:19][C:17]1[CH:18]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=1[CH:21]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH:22]([F:24])[F:23])=[N+:49]=[N-:50]
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CO)C(F)F)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(NC(c2ccc(Cl)cc2CN=[N+]=[N-])C(F)F)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
DBU (0.20 mL, 1.34 mmol) was added to a stirred solution of (5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}phenyl)methanol (0.439 g, 1.34 mmol) and DPPA (0.29 mL, 1.34 mmol) in THF (1.7 mL) at 0° C. and the mixture was warmed to ambient temperature. After 3 h the solution was partitioned between EtOAc (20 mL) and water (10 mL). The EtOAc layer was washed with 1M NaOH (10 mL) and brine (10 mL), dried (Na2SO4) and reduced in vacuo to give N-{1-[2-(azidomethyl)-4-chlorophenyl]-2,2-difluoroethyl}-N-(4-methoxyphenyl)amine (0.463 g) as an oil: MS 353.5 (M+1).
Reaction SMILES: O.O.O.[Cl-:4].F[C:6]1[CH:15]=[CH:14][C:13]2[N+:12]3[CH:16]=[C:17]4[CH:26]=[CH:25][C:24]5[CH:23]=[C:22]([CH3:27])[CH:21]=[CH:20][C:19]=5[N:18]4[C:11]=3[CH:10]=[CH:9][C:8]=2[CH:7]=1.C[N:29]1[CH2:33][CH2:32][CH2:31][C:30]1=O.N1CCCC1>C(OCC)(=O)C>[Cl-:4].[CH3:27][C:22]1[CH:21]=[CH:20][C:19]2[N:18]3[C:11]4[CH:10]=[CH:9][C:8]5[CH:7]=[C:6]([N:29]6[CH2:33][CH2:32][CH2:31][CH2:30]6)[CH:15]=[CH:14][C:13]=5[N+:12]=4[CH:16]=[C:17]3[CH:26]=[CH:25][C:24]=2[CH:23]=1
Reactant: Cc1ccc2c(ccc3c[n+]4c5ccc(F)cc5ccc4n32)c1
Reactant: CN1CCCC1=O
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: Cc1ccc2c(ccc3c[n+]4c5ccc(N6CCCC6)cc5ccc4n32)c1
Reaction time: 3 h

Procedure:
A stirred mixture of 219.5 g. of 3-fluoro-10-methylimidazo[1,2-a:-3,4-a']diquinolin-15-ium chloride trihydrate and 580 ml. of N-methyl-2-pyrrolidinone is heated to 150° C. and 144 ml. of pyrrolidine is added over a 2 minute period. The mixture is heated and stirred at reflux (132°-140° C.) for 40 minutes, allowed to cool, and then is diluted with 2 l. of ethyl acetate. The precipitated solid is collected by filtration, washed with ethyl acetate, dried and dissolved in 1.6 l. of methanol. The methanol solution is treated with 20 g. of activated charcoal and filtered. The filtrate is passed over a column of 1 l. of IRA-410 anion exchange resin (Cl- form, suspended in methanol) over a period of 3 hours. The eluate is evaporated at reduced pressure to give a residue of 10-methyl-3-(1-pyrrolidinyl)-imidazo[1,2-a:3,4-a']diquinolin-15-ium chloride; m.p. 245°-320° C. (dec.) after crystallization from dimethylformamide and from 2-propanol/acetonitrile.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CN(C)P(=O)(N(C)C)N(C)C.C1OC1C>C(N(CC)CC)C>[CH2:18]([O:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCBr
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Agent: CC1CO1
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCOc1c(OC)cc([N+](=O)[O-])c2nccc(C)c12
Yield: 52 %

Procedure:
A stirred mixture of 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline [from Example 7B]--14.0 g, 0.06 mole - n-heptyl bromide (7.5 g, 0.045 mole) and hexamethylphosphoric triamide (12 ml) was heated at 120°, under N2, while a mixture of triethylamine (1 ml) and propylene oxide (6 ml) was added in small portions during 6 hr. Additional propylene oxide (4 ml) was added during 4 hr and the mixture was cooled and filtered and the dull red solid was washed with acetone to return 7.5 g of starting material. The combined filtrate and washings were diluted with water and the resulting solid was extracted with diethyl ether. The extract was washed with 5% sodium hydroxide and water, treated with carbon, dried (sodium sulfate) and evaporated to dryness. Trituration of the dark brown residual oil with petroleum ether (20°-40°) produced a tan solid which was extracted with additional petroleum ether (700 ml). Concentration of the extract to 300 ml and cooling in a Dry-Ice bath gave 7 g (52%) of 5-heptoxy-6-methoxy-4-methyl-8-nitroquinoline as a pale yellow solid, mp 52°-55°. Recrystallization from petroleum ether (20°-40°) provided the analytical sample as glistening pale yellow crystals, mp 56°-57°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C=O.[C:9](O)(=O)C.[NH:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:22]=[O:23])[C:16]=2[CH:15]=[CH:14]1>O>[O:4]1[CH2:5][CH2:6][N:1]([CH2:9][C:15]2[C:16]3[C:17]([CH:22]=[O:23])=[CH:18][CH:19]=[CH:20][C:21]=3[NH:13][CH:14]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CC(=O)O
Reactant: C1COCCN1
Agent: C=O
Solvent: O
Product: O=Cc1cccc2[nH]cc(CN3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Morpholine (0.24 ml, 2.7 mmol) and formaldehyde (37% aq; 0.21 ml, 2.7 mmol) were added to glacial acetic acid (3 ml) at 0° C. After stirring for 15 minutes 4-indolcarboxaldehyde (0.27 g, 1.9 mmol) was added. The mixture was stirred 5 minutes at 0° C. and then 3½h at room temperature, prior to the addition of water (6 ml) and washing with ether. The aqueous layer was made alkaline with 2N NaOH and then extracted with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated to afford 0.46 g of the entitled product as an oil which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([Mg]Br)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1[C:22]([Cl:23])=[N:21][C:19](Cl)=[N:18][C:16]=1[Cl:17]>C1C=CC=CC=1>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=[CH:11][C:10]([C:19]2[N:21]=[C:22]([Cl:23])[N:15]=[C:16]([Cl:17])[N:18]=2)=[CH:9][CH:8]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Br[Mg]c1ccc(-c2ccccc2)cc1
Solvent: c1ccccc1
Product: Clc1nc(Cl)nc(-c2ccc(-c3ccccc3)cc2)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 42.7 %

Procedure:
A mixture of 4-phenyl-phenyl magnesium bromide (prepared from 4-bromobiphenyl (7.75 g, 33 mmol) and magnesium turnings (0.83 g, 35 mmol) in 40 mL ether) and cyanuric chloride (4.00 g, 21.7 mmol) in benzene (90 mL) was stirred at 0° C. for 90 minutes. The reaction was evaporated to dryness, and the residue was flash chromatographed on silica gel with 50% hexanes/methylene chloride to provide the desired compound (2.80 g, 43%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:15]=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)=[CH:3][CH:2]=1.[Br:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CCOCC>[Br-:16].[CH2:21]([O:20][C:18]([CH2:17][N+:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:15]=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)=[CH:3][CH:2]=1)=[O:19])[CH3:22]
Reactant: c1ccn2nc(-c3ccncc3)nc2c1
Reactant: CCOC(=O)CBr
Solvent: CCOCC
Product: CCOC(=O)C[n+]1ccc(-c2nc3ccccn3n2)cc1
Product: [Br-]
Temperature: 100 °C

Procedure:
2-(4-Pyridyl)-s-triazolo[1,5-a]pyridine (10.0g), prepared as in Example I stage (a) was added to ethyl bromoacetate (25 ml). The mixture was heated to 100° C. for 1 hour, cooled and diluted with ether (80 ml). The solid which formed was filtered off, washed with ether and dried. Recrystallisation from methanol yielded 13.9g of 2-(1-ethoxycarbonylmethylpyridinium-4-yl)-s-triazolo[1,5-a]pyridine bromide, m.p. 174°-176° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:47][S:48]([NH2:51])(=[O:50])=[O:49].C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.O>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: CS(N)(=O)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Benzylamino-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.9 g, 1.9 mmol) obtained in step 5 was dissolved in DMF (15 mL), 1,1′-carbonyldiimidazole (1.2 g, 7.6 mmol) was added, and the mixture was stirred at room temperature for 2 hr. Methanesulfonamide (0.9 g, 9.5 mmol) and DBU (1.4 g, 9.5 mmol) were added to the reaction mixture, and the mixture was stirred at 60° C. for 1 hr. 10% Aqueous citric acid solution (5 mL) and water (60 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The precipitate was collected by filtration, washed with water (50 mL), and purified by silica gel column chromatography (chloroform/methanol=95/5) to give compound a-1 (0.8 g, 81%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][CH:10]=[N:9][CH:8]=1.[CH2:12]([O:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26](O)=[O:27])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([C:10]2[O:11][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][N:9]=2)=[O:27])=[CH:29][CH:30]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)COc1ccc(OCc2ccccc2)cc1
Reactant: c1ccc(-c2cnco2)nc1
Product: O=C(COc1ccc(OCc2ccccc2)cc1)c1ncc(-c2ccccn2)o1
Yield: 10 %

Procedure:
The title compound was prepared from 5-(2-pyridyl)oxazole and 2-(4-(benzyloxy)phenoxy)acetic acid (commercially available) using General Procedure B. Column chromatography (SiO2, 2.5×6 cm, 20-40% EtOAc-hexanes gradient) followed by PTLC (SiO2, 50% EtOAc-hexanes) afforded 11b (35 mg, 0.09 mmol, 10%) as a pale yellow solid: 1H NMR (CDCl3, 500 MHz) 8.70 (app d, 1H, J=4.0 Hz), 8.04 (d, 1H, J=8.1 Hz), 7.86 (td, 1H, J=7.7, 1.5 Hz), 7.55-7.52 (m, 1H), 7.44-7.33 (m, 6H), 6.94-6.89 (m, 4H), 5.45 (s, 2H), 5.03 (s, 2H); ESI-TOF m/z 387.1343 (C23H19N2O4+H+ requires 387.1345).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.Cl.[NH2:14][OH:15].[OH-].[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][CH2:10][C:9]2=[N:14][OH:15])=[CH:4][CH:3]=1
Reactant: O=C1CCC1c1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: ON=C1CCC1c1ccc(Cl)cc1

Procedure:
A solution of 2-(4-chlorophenyl)cyclobutanone (1.122 g, 6.09 mmol), hydroxylamine hydrochloride (3.541 g. 8.2 eq.) and 36 ml of 5% NaOH in 30 ml EtOH was heated at reflux for 2 h. The solution was cooled, adjusted to pH 6, and extracted with CHCl3. The organic extract was washed with brine and dried. Filtration and concentration yielded 2-(4-chlorophenyl)cyclobutanone oxime as an oil. 1 g (84%)
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[N:19]1([CH2:24][CH2:25][NH2:26])[CH2:23][CH2:22][CH2:21][CH2:20]1.Cl>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]1=[CH:17][C:2]([NH:26][CH2:25][CH2:24][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[N:3][C:4](=[O:18])[N:5]1[CH2:14][CH2:13]2
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: NCCN1CCCC1
Agent: Cl
Product: COc1ccc2c(c1)CCn1c-2cc(NCCN2CCCC2)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6, 1-a]isoquinolin-4-one (4) and 2-pyrrolidin-1-yl-ethylamine as in Example 1 d, followed by treatment with HCl. 1H-NMR (400 MHz, dB-DMSO) δ 7.64 (d, 1H), 7.59 (br, 1H), 7.00-6.92 (2H), 6.18 (s, 1H), 3.92 (t, 2H), 3.82 (s, 3H), 3.46 (m, 2H), 2.91 (t, 2H), 2.90-2.50 (6H) and 1.76 (4H); MS (ESI) (M+H)+ 341.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].O.[NH2:17][NH2:18].[BH4-].[Na+].O>CO>[CH:1]([C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][CH:12]([NH:17][NH2:18])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1noc(C2CCC(=O)CC2)n1
Reactant: NN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)c1noc(C2CCC(NN)CC2)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
A mixture of 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexanone (Intermediate 11; 600 mg, 2.9 mmol) and hydrazine hydrate (160 mg, 3.2 mmol) in methanol (2 mL) was heated at reflux for 3 h. The reaction mixture was cooled to 0° C. and sodium borohydride (220 mg, 5.8 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 4 h and then at room temperature overnight. Water was added and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried (sodium sulfate), filtered, and evaporated to give [4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-hydrazine (280 mg, 43%) which was used directly in the next step without further purification. Mass spectrum M+=224.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][C:6](=O)[CH2:5][CH2:4][C@@H:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[NH:15][NH2:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[CH2:12]([O:11][C:9]([C@H:3]1[CH2:4][CH2:5][C@@H:6]([NH:16][NH:15][C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C@H:2]1[CH3:1])=[O:10])[CH3:13]
Reactant: CCOC(=O)[C@H]1CCC(=O)C[C@H]1C
Reactant: CC(C)(C)OC(=O)NN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H]1CC[C@@H](NNC(=O)OC(C)(C)C)C[C@H]1C
Reaction time: 0.17 h
Yield: 52.1 %

Procedure:
To a 500-mL 3-neck round-bottomed flask was added (1S,2R)-ethyl 2-methyl-4-oxocyclohexanecarboxylate (10.00 g, 54.3 mmol) in chloroform (201 ml). Then AcOH, glacial (3.13 ml, 54.3 mmol), and tert-butyl carbazate (7.89 g, 59.7 mmol) was added into the reaction mixture. The flask was placed into a pre-heated bath (30° C.) and allowed to stir 10 min. Then NaBH(OAc)3 (34.5 g, 163 mmol) was slowly added into the reaction mixture in small portions. The bath was removed after the addition and the overall mixture was allowed to stir under inert atmosphere 16 h. The progress of the reaction was monitored by LC/MS and TLC (30% EtOAc/DCM; Ninhydrin stain) which suggested reaction completion. The mixture was neutralized with the slow addition of sat. aq. NaHCO3 into the reaction mixture. After the material was neutralized, the layers were separated and the aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in-vacuo. The crude sample was analyzed by TLC (30% EtOAc/hexane; ninhydrin stain; Peak 1: Rf=0.46 & Peak 2: Rf=0.38) The crude material was divided into two portions and purified by chromatography through an Interchim (25 micron) silica-gel column (300 g)*(Two 300 Gram Columns were used), eluting with a gradient of 0-30% EtOAc in hexane, to provide tert-butyl 2-((1R,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)hydrazinecarboxylate (8.512 g, 28.3 mmol, 52.2% yield) (Peak 1; Cis)1H NMR (400 MHz, CDCl3) δ 6.03-6.28 (m, 1H), 4.07-4.16 (m, 2H), 3.59-3.90 (m, 1H), 2.76-2.97 (m, 1H), 2.55 (d, J=2.74 Hz, 1H), 2.01 (dd, J=3.03, 13.40 Hz, 1H), 1.59-1.77 (m, 3H), 1.49-1.56 (m, 2H), 1.46 (s, 10H), 1.19-1.31 (m, 3H), 1.02 (d, J=7.04 Hz, 3H); LCMS (ESI) m/z 301.1 (M+H)+ and tert-butyl 2-((1S,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)hydrazinecarboxylate (5.089 g, 16.94 mmol, 31.2% yield) (Peak 2; trans)1H NMR (400 MHz, DMSO-d6) δ 7.89-8.27 (m, 1H), 5.75 (s, 1H), 4.08-4.19 (m, 1H), 2.74-2.93 (m, 1H), 2.21-2.46 (m, 2H), 1.99 (s, 1H), 1.66 (d, J=3.91 Hz, 3H), 1.38 (s, 9H), 1.14-1.26 (m, 5H), 0.79 (d, J=7.04 Hz, 3H); LCMS (ESI) m/z 301.1 (M+H)+.
Reaction SMILES: C([O:3][P:4]([CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)([CH2:6][CH2:7][CH2:8][CH3:9])=[O:5])C>Cl>[ClH:21].[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][CH2:12][CH2:11][CH2:10][P:4]([CH2:6][CH2:7][CH2:8][CH3:9])(=[O:3])[OH:5])=[CH:20][CH:19]=1
Reactant: CCCCP(=O)(CCCNCc1ccc(Cl)cc1)OCC
Agent: Cl
Product: CCCCP(=O)(O)CCCNCc1ccc(Cl)cc1

Procedure:
A solution of 1.86 g of 3-(p-chlorobenzylamino)propyl(n-butyl)phosphinic acid ethyl ester in 30 ml of semi-concentrated hydrochloric acid is heated under reflux overnight, a clear solution forming after only 10 minutes. The solution is then cooled to 0°, whereupon a white precipitate forms. The precipitate is filtered off, washed with water and dried under reduced pressure at 60°. Recrystallisation from water and drying yield 3-(p-chlorobenzylamino)propyl(n-butyl)phosphinic acid hydrochloride having a melting pint of 212°-214°.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]([CH3:12])([CH3:11])[CH2:8][CH2:9][OH:10].CC=C(C)C.C(N(CC)CC)C.[S:25](Cl)([CH3:28])(=[O:27])=[O:26]>C(Cl)(Cl)Cl.CCOCC>[S:25]([O:10][CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)(=[O:27])(=[O:26])[CH3:28]
Reactant: CC(C)(CCO)CC1OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CC=C(C)C
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(CCOS(C)(=O)=O)CC1OCCO1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
81.9 g of 4-(dioxolan-2-yl)-3,3-dimethylbutanol, prepared above, are dissolved in 600 ml of chloroform, stabilized with amylene, in the presence of 62 ml of triethylamine. The mixture is cooled to 5° C. and 81 ml of mesyl chloride are added dropwise. The mixture is subsequently stirred for 4 hours at 5° C. and then left overnight at this temperature, washed with cold water and evaporated at 30° C. under vacuum. The residue obtained is taken up with ether and washed with sodium bicarbonate. The ether phase is dried over magnesium sulfate and then evaporated at 30° C. under vacuum to give 93.5 g of 4-(dioxolan-2-yl)-3,3-dimethylbutanol mesylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH2:26][NH2:27])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[CH3:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>ClCCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH2:26][NH:27][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(CN)c3ccccc23)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(CNC(=O)c3ccccc3C)c3ccccc23)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-aminomethyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester (32) (60 mg, 0.153 mmol) in DCE (5 mL), was added pyridine (62 ul, 0.765 mmol), 2-methyl-benzoyl chloride (22 ul, 0.168 mmol) and dimethyl-pyridin-4-yl-amine (4 mg, 0.031 mmol). After stirring at 70° C. overnight, the resultant solution was concentrated in vacuo to give the crude product. Purification using reverse phase HPLC provided the title compound (G-1). LCMS showed m/z: 510 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:47])[N:7]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[CH:41]=3)[C:8]([CH:12]([N:18]([C:30](=[O:38])[C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)[CH2:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[N:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:22][CH2:21][CH2:20][CH2:19][N:18]([CH:12]([C:8]1[N:7]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[CH:41]=2)[C:6](=[O:47])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)[C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[C:30](=[O:38])[C:31]1[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=1
Reactant: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(C(=O)N(C)C)c2nc3cc(Cl)ccc3c(=O)n2Cc2cccc(C)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(CCCN)C(C(=O)N(C)C)c2nc3cc(Cl)ccc3c(=O)n2Cc2cccc(C)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-[[1-[7-chloro-3-(3-methylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl](4-methylbenzoyl)amino]propylcarbamate, was added 20% solution of trifluoroacetic acid in methylene chloride at room temperature. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC to give N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-methylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide (9 mg) as TFA salt.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[I:13]Cl>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([I:13])[CH:6]=1)[CH3:2]
Reactant: ClI
Reactant: CCOC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(O)c(I)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
Charge a 10 L double jacketed reactor with a mechanical stirrer and a reflux condenser with 4-hydroxy benzoic acid ethyl ester (967 g, 8.81 mol) and acetic acid (5.8 L). Heat the mixture to 65° C. and add a solution of ICl (1010 g) in acetic acid (1 L) in ½ h. Stir the resulting mixture at 60-62° C. for 16 h. Cool the black solution to 20° C. and transfer on water (5 L) and ice (7.5 kg). Stir the resulting suspension over 1 h at 20° C., filter and wash the cake with water (2 L) and cyclohexane (6 L). Dry the solid under vacuum at 55° C. till constant weight to give 4-hydroxy-3-iodo-benzoic acid ethyl ester (1372.8 g, 4.70 mol). 11H NMR (250 MHz, CDCl3): 1.38 (t, J=7.1 Hz, 3H), 4.35 (quartet, J=7.1 Hz, 2H), 5.8 (s, 1 H), 7.01 (d, J=8.5 Hz, 1H), 7.95 (dd, J=8.5 Hz, 2.0 Hz, 1H), 8.37 (d, J=2 Hz, 1 H).