Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6]2.[Br:17]Br>C(O)(=O)C>[Br:17][C:4]1[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:8]2
Reactant: BrBr
Reactant: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(Br)c(OC)ccc2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a suspension of ethyl 5-methoxy-1H-indole-2-carboxylate (5 g, 22.81 mmol) in acetic acid (100 mL) was added bromine (1.169 mL, 22.81 mmol) slowly at room temperature. The reaction mixture was stirred at room temperature for 2 days. The solid was filtered off, washed with acetic acid and hexanes, and dried to give the title compound as a white solid (6.8 g). LCMS m/z=298.6 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[C:20]1(C)C=CC=CC=1.COC(OC)OC>CO>[CH3:20][O:18][C:17](=[O:19])[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][Br:1]
Reactant: Cc1ccccc1
Reactant: O=C(O)CCCCCCCCCCCCCCCBr
Solvent: COC(OC)OC
Solvent: CO
Product: COC(=O)CCCCCCCCCCCCCCCBr
Temperature: 55 °C
Reaction time: 16 h

Procedure:
16-Bromo-hexadecanoic acid (6.0 g) was dissolved in MeOH (35 mL), toluene (100 mL) and trimethylorthoformate (20 mL), then Amberlyst 15 from Fluka (1.4 g) was added. The mixture was stirred at 55° C. for 16 h. The mixture was evaporated to dryness and dried under vacuum for 16 h to yield 7.7 g. The residue was suspended in MeOH (ca. 50 mL) and stirred for ca ½ h. The amberlyst 15 was filtered off after stirring with DCM (30 mL) for ½ h. The filtrate was concentrated to remove the DCM, and the clear solution was cooled and more MeOH (ca 20 mL, total ca 40 mL) was added. The flask was cooled and more crystals precipitated and after stirring for 30 min, the crystals were filtered off and washed with cold MeOH. The white crystals were dried under vacuum to yield 5.61 g.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[CH2:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][NH:20]1>CN(C=O)C>[CH2:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][N:20]1[C:10]1[CH:11]=[C:12]2[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14]
Reactant: c1ccc2c(c1)CNC2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3Cc4ccccc4C3)cc21
Yield: 44.7 %

Procedure:
177 mg of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 250 mg of isoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 110 mg of the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[N:5]=[C:4]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=2)[N:3]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=2)[N:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:33](=[O:36])[CH2:34][CH3:35])=[CH:14][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: CCC(=O)Cl
Reactant: Cc1cccc(CSc2nc(N)c(C#N)c(-c3ccc(N)cc3)n2)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(=O)Nc1ccc(-c2nc(SCc3cccc(C)n3)nc(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
The compound of Example 8 (170 mg) and triethylamine (0.2 mL) were added to 10 mL of acetonitrile, 0.12 g of propionyl chloride was added dropwise to the solution, and then the mixture was stirred at room temperature overnight. The resulting crystal was filtrated, washed with diethyl ether, and then dried under reduced pressure to give 85 mg of N-{4-[6-amino-5-cyano-2-(6-methylpyridin-2-ylmethylsulfanyl)-pyrimidin-4-yl]phenyl}propionamide as a white powder.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].Br[CH2:7][CH2:8][CH2:9][CH2:10]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1([C@@H:2]([CH3:5])[CH2:3][OH:4])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: BrCCCCBr
Reactant: C[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](CO)N1CCCC1
Temperature: 25 °C
Yield: 65 %

Procedure:
A mixture of (S)-2-aminopropan-1-ol (566 mg, 7.54 mmol), 1,4-dibromobutane, and potassium carbonate (2.09 g, 15.1 mmol) in acetonitrile (70 mL) was heated at reflux overnight and allowed to cool to room temperature. The insoluble solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was diluted with DCM (75 mL) and washed (25 mL sat'd K2CO3). The aqueous phase was extracted with DCM (2×25 mL) and the combined organic extracts were dried over Na2SO4. The solvent was removed under reduced pressure and purified on a silica gel column to yield (S)-2-(pyrrolidin-1-yl)propan-1-ol (630 mg, 65%) as a clear oil. 1H NMR (CDCl3): δ 3.63 (m, 1H), 3.38 (m, 1H), 2.97 (br s, 1H), 2.69 (m, 1H), 2.60 (br s, 4H), 1.72 (br s, 4H), 1.06 (d, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]([NH:42][C:43]([C:45]2([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[CH2:50][CH2:49][N:48]([C:51]3[C:52]4[CH:59]=[CH:58][NH:57][C:53]=4[N:54]=[CH:55][N:56]=3)[CH2:47][CH2:46]2)=[O:44])[CH2:39][CH2:40]O)=[CH:34][CH:33]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([CH:38]([NH:42][C:43]([C:45]2([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[CH2:46][CH2:47][N:48]([C:51]3[C:52]4[CH:59]=[CH:58][NH:57][C:53]=4[N:54]=[CH:55][N:56]=3)[CH2:49][CH2:50]2)=[O:44])[CH2:39][CH2:40][N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])=[CH:36][CH:37]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CCN2C(=O)c3ccccc3C2=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
Triphenylphosphine (158 mg) and phthalimide (22.11 mg) were added in one portion to a stirred solution of tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 36) (53 mg) dissolved in THF (10 mL) and cooled to 0° C. under argon. The resulting solution was stirred at 0° C. for 30 minutes. Diethyl azodicarboxylate (0.093 mL) was added dropwise at 0° C. under argon. The resulting suspension was stirred at 0° C. for 60 minutes and overnight at room temperature. The suspension was quenched with water. The THF was removed in vacuo and the aqueous phase extracted with DCM. The organic phase was dried and concentrated to provide crude product. The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% methanol in DCM. The solvent was evaporated to dryness to afford tert-butyl 4-(1-(4-chlorophenyl)-3-(1,3-dioxoisoindolin-2-yl)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate as a white solid (14.00 mg, 21.23%).
Reaction SMILES: [C:1]1([C:7]([CH:9](Br)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[N:26]/[NH:27][C:28](=[NH:30])[NH2:29])=[CH:21][CH:20]=1>C(O)C>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[N:26]/[N:27]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:29]=[C:28]2[NH2:30])=[CH:21][CH:20]=1
Reactant: COc1ccc(/C=N/NC(=N)N)cc1
Reactant: O=C(c1ccccc1)C(Br)c1ccccc1
Solvent: CCO
Product: COc1ccc(/C=N/n2c(N)nc(-c3ccccc3)c2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
A solution of desyl bromide (1.72 g, 6.26 mmol), and 2-[(E)-1-(4-methoxyphenyl) methylidene]-1-hydrazinecarboximidamide (2.4 g, 12.5 mmol) was heated at reflux in ethanol (10 mL) for 2 h. The mixture was cooled at room temperature for additional 10 h, and a yellow precipitate formed. The yellow precipitate was filtered, washed with hot water and recrystallized from ethanol to give N1-[(E)-1-(4-methoxyphenyl)methylidene]-4,5-diphenyl -1H-1,2-imidazolediamine 3 (1.57 g, 68%) as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[C:20](Cl)(=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(Cl)(=O)OCC>C(Cl)Cl>[CH2:36]([C:37]1[O:12][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:9]=2[N:8]=1)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: COc1cccc(C(=O)O)c1N
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCc1nc2c(OC)cccc2c(=O)o1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50 %

Procedure:
Triethylamine (5.30 ml) was added to a suspension of 2-amino-3-methoxybenzoic acid (3.00 g) in methylene chloride (30 ml). The mixture was cooled with ice and stearoyl chloride (5.44 g) was dropwise added thereto. The reaction mixture was stirred for 2.5 hours at room temperature and then cooled with ice. Then, triethylamine (2.80 ml) and ethyl chlorocarbonate (1.88 ml) were added to the reaction mixture successively. The reaction mixture was stirred for 1 hour at 0° C. and for 3 hours at room temperature successively, and then concentrated. The residue, with chloroform added thereto, was washed with water and saturated brine successively. The organic layer was dried over sodium sulfate anhydride and then concentrated. The residue was purified by silica gel column chromatography (silica gel 150 g, chloroform-hexane), thereby yielding 3.73 g of the aimed compound as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:18](=[O:33])([O:30][CH2:31][CH3:32])[O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1>CC(C)CC(=O)C>[C:18](=[O:33])([O:30][CH2:31][CH3:32])[O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]([N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:10]2)=[O:28])=[CH:24][CH:25]=1
Reactant: CCOC(=O)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)N1CCC(Nc2ccc(Cl)cc2)CC1
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)Oc1ccc(CC(=O)N(c2ccc(Cl)cc2)C2CCN(C(C)C)CC2)cc1
Reaction time: 1 h

Procedure:
To a stirred mixture of 7.5 parts of N-(4-chlorophenyl)-1-(1-methylethyl)-4-piperidinamine and 80 parts of 4-methyl-2-pentanone are added dropwise 9 parts of [4-(2-chloro-2-oxoethyl)-phenyl] ethyl carbonate. Upon completion, the whole is heated to reflux and stirring is continued for one hour at reflux temperature. After cooling, the precipitated product is filtered off and stirred for 30 minutes in a mixture of alkaline water and trichloromethane. The layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated yielding 5.5 parts of {4-[2-{(4-chlorophenyl)-[1-(1-methylethyl)-4-piperidinyl]amino}-2-oxoethyl]phenyl} ethyl carbonate as an oily residue.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:5]=[CH:6][C:7](OS(C2C=CC=CC=2S(N(C)C2CCN(C)CC2)(=O)=O)(=O)=O)=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15](=[NH:17])[NH2:16].CC1C=CC([O:64][S:65]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=2[S:74]([N:77]([CH3:85])[CH:78]2[CH2:83][CH2:82][N:81]([CH3:84])[CH2:80][CH2:79]2)(=[O:76])=[O:75])(=[O:67])=[O:66])=C(C=1)OCCCOC1C=CC=C2C(NC(=O)C=12)=O.C(C(=CC1C=CC(O)=CC=1)C(O)=O)#N>>[CH3:3][C:4]1[CH:5]=[C:6]([O:64][S:65]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=2[S:74]([N:77]([CH3:85])[CH:78]2[CH2:83][CH2:82][N:81]([CH3:84])[CH2:80][CH2:79]2)(=[O:75])=[O:76])(=[O:67])=[O:66])[CH:7]=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15]([NH2:17])=[NH:16]
Reactant: Cc1ccc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C2CCN(C)CC2)c(OCCCONC(=N)N)c1
Reactant: Cc1ccc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C2CCN(C)CC2)c(OCCCOc2cccc3c2C(=O)NC3=O)c1
Agent: Cl
Agent: N#CC(=Cc1ccc(O)cc1)C(=O)O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C2CCN(C)CC2)c1
Yield: 76 %

Procedure:
N-{3-[5-Methyl-3-[(2-(N-methyl-N-(1-methyl-4-piperidinyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}guanidine dihydrochloride: The title compound was prepared in 76% yield from N-{3-[5-methyl-3-[(2-(N-methyl-N-(1-methyl-4-piperidinyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide, as prepared in the preceding step, in a manner analogous to step f of Example 1. 1H-NMR (300 MHz, DMSO-d6) δ 8.25 (d, J=7.9 Hz, 1H), 8.15 (d, J=7.9 Hz, 1H), 8.02 (t, J=7.6 Hz, 1H), 7.89 (t, J=7.7 Hz, 1H), 7.37 (br s, 4H), 6.75 (s, 1H), 6.53 (s, 1H), 6.47 (s, 1H), 4.07 (m, 1H), 3.97 (t, J=6.3 Hz, 2H), 3.87 (t, J=6.3 Hz, 2H), 3.22 (m, 2H), 3.17 (s, 3H), 2.79 (s, 3H), 2.72 (t, J=12.0 Hz, 2H), 2.22 (s, 3H), 1.99 (pentet, J=6.3 Hz, 4H), 1.60 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C24H35N5O7S2: 570.2 (M+H), 592.2 (M+Na). Found: 570.1, 592.1.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]12([C:18]3[CH:19]=[C:20]([C:44]4[CH:49]=[CH:48][C:47](/[CH:50]=[CH:51]/[C:52]([O:54]C(C)(C)C)=[O:53])=[CH:46][CH:45]=4)[CH:21]=[CH:22][C:23]=3[O:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2>C(Cl)Cl>[C:8]12([C:18]3[CH:19]=[C:20]([C:44]4[CH:45]=[CH:46][C:47]([CH:50]=[CH:51][C:52]([OH:54])=[O:53])=[CH:48][CH:49]=4)[CH:21]=[CH:22][C:23]=3[O:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]/[CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][CH:14]([CH2:16]3)[CH2:15]1)[CH2:17]2
Reactant: CCCCCC=CCC=CCCCCCCCC(=O)Oc1ccc(-c2ccc(/C=C/C(=O)OC(C)(C)C)cc2)cc1C12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCC=CC/C=C/CCCCCCCC(=O)Oc1ccc(-c2ccc(C=CC(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
TFA (1.6 ml) was dropped into an ice-cooled solution of octadeca-9,12-dienoic acid (E)-3-adamantan-1-yl-4′-(2-tert-butoxycarbonylvinyl)biphenyl-4-yl ester (110 mg, 0.159 mmol) in DCM (1.6 ml) and the resulting solution was stirred for 30 min at 0° C. The solvent was removed under reduced pressure to obtain the title compound as a white solid (100 mg, 99%).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.[NH2:16][NH2:17]>>[CH:10]1([NH:9][C:8]([NH:16][NH:17][C:8](=[N:7][CH:4]2[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]2)[NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:7][CH:4]2[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: NN
Product: C1CCC(N=C(NNC(=NC2CCCCC2)NC2CCCCC2)NC2CCCCC2)CC1

Procedure:
DCC (1.03 g, 4.97 mmol) was dissolved in tetrahydrofuran (15 mL). Hydrazine (135 mg, 4.22 mmol) was added via syringe. Stirring 30 hours at room temperature produced a clear yellow mixture which was evaporated to a white powder (922 mg). Solution of this powder in diethyl ether, filtration and acidification with HCl (60 mL of saturated Et2O) gave a yellow white precipitate (856 mg). Two recrystallizations (EtOH in an Et2O chamber) gave white prisms (133 mg, 18%, M.P. 288°-290° C.). The low percentage of nitrogen in the elemental analysis of this compound indicates that two equivalents of DCC have reacted to hydrazine, forming the title compound. 1H NMR ([2H]--CH3OH) δ 3.21 (s, 4, N-bearing cyclohexyl), 2.0-1.5 (m, 44, cyclohexyls). 13C NMR ([2H]--CH3OH) δ 154.1 (guanidine), 51.7 (N-bearing cyclohexyl), 32.4 and 24.8 (cyclohexyls). IR shows peaks at 1639 and 1589 cm-1. Elem. Analysis (C26N6H50Cl2 :1/2 H2O). Theor. C 59.30, H 9.76, N 15.96, Found C 58.94, H 9.76, N 16.01.
Reaction SMILES: [OH-].[NH4+:2].[CH2:3]([O:5][CH2:6][C:7]1[N:8]([CH2:32][CH2:33][CH3:34])[C:9]2[C:18]3[CH:17]=[C:16]([O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:15]=[CH:14][C:13]=3[N+:12]([O-])=[CH:11][C:10]=2[N:31]=1)[CH3:4].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[C:25]([O:24][C:23](=[O:29])[NH:22][CH2:21][CH2:20][O:19][C:16]1[CH:15]=[CH:14][C:13]2[N:12]=[C:11]([NH2:2])[C:10]3[N:31]=[C:7]([CH2:6][O:5][CH2:3][CH3:4])[N:8]([CH2:32][CH2:33][CH3:34])[C:9]=3[C:18]=2[CH:17]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CCCn1c(COCC)nc2c[n+]([O-])c3ccc(OCCNC(=O)OC(C)(C)C)cc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCCNC(=O)OC(C)(C)C)cc3c21
Reaction time: 16 h

Procedure:
Ammonium hydroxide (50 mL) was added to a solution of tert-butyl 2-[(2-ethoxymethyl-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]ethylcarbamate (9.7 g, 22 mmol) in dichloromethane (120 mL), and the mixture was cooled to 10° C. p-Toluenesulfonyl chloride (4.16 g, 21.8 mmol) was added in small portions, while maintaining the reaction temperature below 15° C. The reaction was stirred for 16 hours; a tan precipitate formed. Dichloromethane (500 mL) was added, and the precipitate was isolated by filtration and washed with diethyl ether to provide 3.98 g of tert-butyl[2-(4-amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]carbamate as a fine powder. The organic layer was washed sequentially with ammonium hydroxide, water, and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was recrystallized from acetonitrile to provide 4.4 g of tert-butyl 2-[(4-amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]ethylcarbamate as a peach-colored powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][NH:19]C(OC(C)(C)C)=O)[CH:14]=2)[N:9]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])[CH2:29][CH2:28]2)[C:8]1=[O:43].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:19][CH2:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[O:34])[CH2:29][CH2:28]1)[C:8](=[O:43])[N:7]([CH2:6][C:5]1[CH:44]=[CH:45][C:46]([O:47][CH3:48])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:16]2=[O:17]
Reactant: COc1ccc(Cn2c(=O)c3cc(CNC(=O)OC(C)(C)C)ccc3n(C3CCN(C(=O)OCc4ccccc4)CC3)c2=O)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2c(=O)c3cc(CN)ccc3n(C3CCN(C(=O)OCc4ccccc4)CC3)c2=O)cc1OC
Yield: 104 %

Procedure:
A solution of 0.102 g of benzyl 4-[3-(3,4-dimethoxybenzyl)-6-({[(1,1-dimethylethoxy)carbonyl]amino}methyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carboxylate obtained in stage 5.4 and 0.5 ml of TFA in 9.5 ml of DCM is stirred at AT for 2 h 00. A saturated NaHCO3 solution is added. The organic phase is dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure to give 0.09 g of the expected product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]2[N:16]([C:31]3[C:32]4[C@H:39]([CH3:40])[CH2:38][C@@H:37]([O:41][C:42](=[O:52])[C:43]5[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][CH:44]=5)[C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:17][C:18]3([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:11]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:53]N1C(=O)CCC1=O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:15]([Cl:53])=[CH:14][CH:13]=[C:12]2[N:16]([C:31]3[C:32]4[C@H:39]([CH3:40])[CH2:38][C@@H:37]([O:41][C:42](=[O:52])[C:43]5[CH:44]=[CH:45][C:46]([N+:49]([O-:51])=[O:50])=[CH:47][CH:48]=5)[C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:17][C:18]3([CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:22][CH2:23]3)[C:11]=12)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c(CNC(=O)OC(C)(C)C)cccc43)c21
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c3ccc(Cl)c4CNC(=O)OC(C)(C)C)c21
Reaction time: 48 h
Yield: 27.8 %

Procedure:
To a stirred solution of tert-butyl 4-((tert-butoxycarbonylamino)methyl)-1-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (17 mg, 0.024 mmol) in DCM (0.5 mL) was added 1-chloropyrrolidine-2,5-dione (NCS) (5.7 mg, 0.043 mmol). The reaction mixture was stirred at about room temperature for 48 hours. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution and brine, dried and concentrated. The residue was purified by column chromatography (hexanes:EtOAc, 1:1) to give tert-butyl 4-((tert-butoxycarbonylamino)methyl)-5-chloro-1-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (5 mg, 28%). LCMS (APCI+) m/z 749, 751 [M+H]+; Rt=4.66 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([CH2:21][C:22]2([C:25]([F:28])([F:27])[F:26])[CH2:24][CH2:23]2)[CH2:19][NH2:20])=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[N:17][C:12]([CH3:11])=[N:13][CH:14]=1)[CH2:21][C:22]1([C:25]([F:26])([F:27])[F:28])[CH2:24][CH2:23]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: Cc1ncc(C(CN)CC2(C(F)(F)F)CC2)cn1
Product: Cc1ncc(C(CNC(=O)c2ccccc2Cl)CC2(C(F)(F)F)CC2)cn1

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 2-(2-methyl-pyrimidin-5-yl)-3-(1-trifluoromethyl-cycl opropyl)-propylamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=398.1, tR (minutes, Method F)=2.55. [α]D20=−25.5 (c=5.1 mg/mL,CHCl3)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:11])[CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13][CH3:12])[CH:10]=1)[C:5]([NH2:7])=[O:6])=[O:17]
Reactant: COc1ccccc1C(=O)Cl
Reactant: NC(=O)c1cc(N)cc(N)c1
Product: COc1ccccc1C(=O)Nc1cc(NC(=O)c2ccccc2OC)cc(C(N)=O)c1

Procedure:
By the procedure similar to that described in Example 12, 3,5-diaminobenzamide was condensed with 2-methoxybenzoylchloride to obtain 3,5-bis(2'-methoxybenzamido)-benzamide having a melting point between 226° - 227°C.