Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]([CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)#[N:2].[C:12]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.Cl>>[C:12]1([NH:22][C:1]([N:3]([C:4]2[CH:5]=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=2)[CH3:11])=[NH:2])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(N(C)C#N)c1
Reactant: Nc1cccc2ccccc12
Agent: Cl
Product: Cc1cccc(N(C)C(=N)Nc2cccc3ccccc23)c1
Temperature: 25 °C

Procedure:
A mixture of N-cyano-N-methyl-3-toluidine (0.47 g, 3.22 mmol) and 1-naphthylamine.HCl (0.54 g, 3 mmol) in a 5 ml round bottom flask was heated in a preheated oil bath at 170-190° C. for 3 h under N2. The dark brown solution was allowed to cool to room temperature, and it became a rocky solid. The crude product was flash chromatographed on silica gel to yield N-(1-naphthyl)-N′-(m-tolyl)-N′-methylguanidine.HCl (40% yield) as a white powder. Elemental analysis: IR (CH2Cl2): 1625, 1600, 1560 cm−1. 1NMR (CDCl3): δ 2.135 (s, 3H), 3.536 (s, 3H), 6.847-7.972 (m, 11H). 13C-NMR (CDCl3): 20.9, 41.0, 122.6-141.6, 155.8. C19H20N3OCl.1/256 H2O. (Cacl.) C: 70.02%, H: 6.19%, N: 12.89%; (Found) C: 70.33%, H: 6.20%, N: 12.90%
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[F:26][P-:27]([F:32])([F:31])([F:30])([F:29])[F:28].N1CCOCC1.Cl.[Cl-].[NH2:41][CH2:42][CH2:43][N+:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46]([C:52](=[O:67])[C:53]([OH:66])([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:45]2>CN(C=O)C>[F:26][P-:27]([F:32])([F:31])([F:30])([F:29])[F:28].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:41][CH2:42][CH2:43][N+:44]12[CH2:49][CH2:48][CH:47]([CH2:50][CH2:51]1)[C@@H:46]([C:52](=[O:67])[C:53]([OH:66])([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH2:45]2)=[O:8]
Reactant: O=C(O)c1ccco1
Reactant: NCC[N+]12CCC(CC1)[C@@H](C(=O)C(O)(c1ccccc1)c1ccccc1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: O=C(NCC[N+]12CCC(CC1)[C@@H](C(=O)C(O)(c1ccccc1)c1ccccc1)C2)c1ccco1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-furoic acid (91.5 mg, 8.21 mmol) and HATU (284 mg, 7.52 mmol) in DMF (7.5 ml) is added polymer bound morpholine, 2.5 mmol/g (1.36 g, 34.2 mmol). The reaction mixture is left to stand at room temperature for 15 minutes after which time, a solution comprising of (R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetyl)-1-azonia-bicyclo[2.2.2]octane chloride hydrochloride [Example 180 i]] (310 mg, 6.84 mmol) in DMF (7.5 ml) is added. The reaction mixture is stirred at room temperature overnight. The reaction mixture is passed through a 2 g Isolute SPE (Al-B) cartridge. The filtrate is concentrated in vacuo and purification of the crude residue by chromatography on C18 silica, eluting with water:acetonitrile affords the title compound as a white solid.
Reaction SMILES: Cl.[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[CH2:12][NH:13][CH2:14][C:15]([C:17]1[CH:25]=[CH:24][C:20]2[O:21][CH2:22][O:23][C:19]=2[CH:18]=1)=[O:16].[OH-].[Na+].[BH4-].[Na+]>CO>[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[CH2:12][NH:13][CH2:14][CH:15]([C:17]1[CH:25]=[CH:24][C:20]2[O:21][CH2:22][O:23][C:19]=2[CH:18]=1)[OH:16]
Reactant: O=C(CNCC1COc2ccccc2O1)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CNCC1COc2ccccc2O1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.4 %

Procedure:
In 15 ml of methanol is dissolved 1.0 g of 5-[2-{(1,4-benzodioxan-2-ylmethyl)amino}acetyl]-1,3-benzodioxole hydrochloride prepared according to the procedure described in Example 3 and the solution is neutralized with 2N sodium hydroxide. Thereafter, 100 mg of sodium borohydride is added and the mixture is stirred for 6 hours at room temperature. After completion of the reaction, the solvent is distilled off and the residue is dissolved in ethyl acetate and washed twice with saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent is distilled off and the residue is crystallized from water-alcohol to give 800 mg (89%) of 5-[2-{(1,4-benzodioxan-2-ylmethyl)amino}-1-hydroxyethyl]-1,3-benzodioxole.
Reaction SMILES: C(N(CC)[C:4](=[O:8])[CH:5]([F:7])[F:6])C.Cl.[C:12]([O:15][CH2:16][CH3:17])(=[O:14])[CH3:13]>[O-]CC.[Na+]>[CH2:16]([O:15][C:12](=[O:14])[CH2:13][C:4](=[O:8])[CH:5]([F:6])[F:7])[CH3:17]
Reactant: CCN(CC)C(=O)C(F)F
Reactant: CCOC(C)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)CC(=O)C(F)F
Temperature: 60 °C
Reaction time: 6 h

Procedure:
In a sulfonation flask, N,N-diethyl-2,2-difluoroacetamide (1.51 g; 10 mmol) was dissolved in ethyl acetate (20 ml) before ethanolic sodium ethoxide (15 ml of a 21% solution; 40.2 mmol) was added dropwise. The resulting mixture was stirred at 60° C. for 6 hours. After cooling, the mixture was poured into ice-water (20 ml), acidified with hydrochloric acid (10%) and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated in a water jet vacuum. The residue was purified by distillation under reduced pressure to give the desired 4,4-difluoro-3-oxo-butanoic acid ethyl ester in the form of a colourless oil.
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:31]1([C:37]2[NH:41][N:40]=[C:39]([C:42]([NH:44][CH2:45][C:46]([OH:48])=O)=[O:43])[CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.[NH:50]1[CH2:53][CH:52]([O:54][C:55]2[CH:56]=[C:57]([CH:60]=[CH:61][C:62]=2[CH3:63])[C:58]#[N:59])[CH2:51]1>CN(C=O)C>[C:58]([C:57]1[CH:60]=[CH:61][C:62]([CH3:63])=[C:55]([CH:56]=1)[O:54][CH:52]1[CH2:51][N:50]([C:46](=[O:48])[CH2:45][NH:44][C:42]([C:39]2[CH:38]=[C:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:41][N:40]=2)=[O:43])[CH2:53]1)#[N:59]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Cc1ccc(C#N)cc1OC1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)cc1OC1CN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)C1
Yield: 22.5 %

Procedure:
DIPEA (193.9 mg, 1.5 mmol) followed by HOBt (53 mg, 0.29 mmol) and EDCI (75 mg, 0.39 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (92 g, 0.37 mmol) in DMF (3 mL) After 2 minutes of stirring, 3-(azetidin-3-yloxy)-4-methyl-benzonitrile hydrochloride (prepared by the method used for the synthesis of Intermediate 71) (84 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between cold water and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by preparative HPLC afforded 35 mg (22.5% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[3-(5-cyano-2-methyl-phenoxy)-azetidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 416, 92.49%. 1H NMR (300 MHz, DMSO-d6): δ 13.8 (s, 1H), 8.2 (t, 1H), 7.74 (t, 2H), 7.42 (m, 2H), 7.3 (m, 3H), 7.16 (s, 1H), 7.08 (s, 1H), 5.2 (m, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 4.2 (m, 1H), 3.8 (m, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>C(O)C>[Cl:28][C:26]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:27]=1
Reactant: Nc1cc(Cl)ccc1Oc1ccc(O)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: Cc1ccc2c(Nc3cc(Cl)ccc3Oc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 1d (80 mg, 4.5 mmol) was reacted with the product from Example 165c (106 mg, 4.5 mmol) in ethanol (15 mL) at 85° C. in a sealed tube for 18 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (40 mg, 18%).
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=4)[C:22]([O:24][CH3:25])=[O:23])[N:14]([CH3:29])[C:13]=3[CH:30]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:31](B(CC)CC)[CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH2:31]([C:2]1[C:3]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=4)[C:22]([O:24][CH3:25])=[O:23])[N:14]([CH3:29])[C:13]=3[CH:30]=2)=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:32]
Reactant: COC(=O)c1cccc(OCc2nc3ccc(Oc4ncccc4Br)cc3n2C)c1
Reactant: CCB(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1cccnc1Oc1ccc2nc(COc3cccc(C(=O)OC)c3)n(C)c2c1
Yield: 51.5 %

Procedure:
A solution of methyl 3-({6-[(3-bromopyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoate produced in Example (2a) (1.20 g, 2.56 mmol), triethylborane (1.0 M solution in THF, 5.12 mL, 5.12 mmol), a [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II)-dichloromethane mixture (0.21 g, 0.26 mmol) and potassium carbonate (0.71 g, 5.12 mmol) in DMF (10 mL) was stirred in a nitrogen atmosphere at 80° C. for two days. After leaving to cool, water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL). Then, the organic layer was washed with water (100 mL) twice and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by reverse phase column chromatography (acetonitrile/water, 2:1) to obtain the title compound (0.55 g, 51%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.Br.[C:19](SCC1C=CC2C(=CC=CC=2)C=1)(=[NH:22])[CH2:20][CH3:21]>C(O)C>[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:6][CH:7]=1)(=[NH:22])[CH2:20][CH3:21]
Reactant: CCC(=N)SCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Agent: Br
Solvent: CCO
Product: CCC(=N)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A mixture of tert-butyl 2-(4-aminophenyl)ethylcarbamate (709 mg, 3 mmol) and 2-naphthylmethyl propanimidothioate hydrobromide (930 mg, 3 mmol) in ethanol (10 mL) was stirred for overnight at ambient temperature. Then, the volatile components were removed by evaporation and the residue was partitioned between diethyl ether (10 mL) and water (10 mL). The aqueous phase was washed with diethyl ether (3×10 mL) and basified by NaOH to pH 10. The aqueous phase was extracted with chloroform (20×4) and the combined extract was dried (MgSO4). Concentration of the organic solvent afforded 831 mg (95%) of the title compound as a colorless powder. MS (ESI) m/z 292 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26](Br)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:33][O:34][C:35](=[O:72])[NH:36][CH:37]([C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH:44]1[C:48]1[NH:49][C:50]([C:53]2[CH:62]=[CH:61][C:60]3[C:55](=[CH:56][CH:57]=[C:58](B4OC(C)(C)C(C)(C)O4)[CH:59]=3)[CH:54]=2)=[CH:51][N:52]=1)=[O:42])[CH:38]([CH3:40])[CH3:39].C([O-])(O)=O.[Na+]>COCCOC.O>[CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([C:58]2[CH:57]=[CH:56][C:55]4[C:60](=[CH:61][CH:62]=[C:53]([C:50]5[NH:49][C:48]([CH:44]6[CH2:45][CH2:46][CH2:47][N:43]6[C:41](=[O:42])[CH:37]([NH:36][C:35]([O:34][CH3:33])=[O:72])[CH:38]([CH3:40])[CH3:39])=[N:52][CH:51]=5)[CH:54]=4)[CH:59]=2)[CH:25]=[CH:24]3)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)ccc5c4)ccc3c2)[nH]1)C(C)C
Temperature: 85 °C
Reaction time: 16 h
Yield: 17.1 %

Procedure:
(1-{2-[5-(6-Bromonaphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.174 g), [2-Methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (0.202 g), and NaHCO3 (0.108 g) were dissolved in a mixture of 1,2-dimethoxyethane (6 mL) and water (2 mL). The solution was degassed with nitrogen, and Pd(PPh3)4 (0.0176 g) was added. The reaction mixture was stirred at 85° C. for 16 hours and evaporated under vacuum. Solid was dissolved in ethyl acetate (10 mL) and extracted twice with water (10 mL) and once with brine (10 mL). Solution was evaporated, dissolved in DMF, purified by reverse phase HPLC (5-70% acetonitrile:water), and lyophilized, giving (1-{2-[5-(6′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-[2,2′]binaphthalenyl-6-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.050 g, 16%) as a white solid: 1H-NMR: 300 MHz, (MeOH-d4) δ: 8.3 (m, 4H), 8.1 (m, 6H), 8.0 (s, 2H), 7.8 (d, J=9.4, 2H), 5.3 (m, 2H), 4.3 (d, J=9.0, 2H), 4.1 (m, 2H), 3.9 (m, 2H), 3.7 (s, 6H), 2.6 (m, 2H), 2.2 (m, 6H), 0.9 (m, 12H); MS (ESI) m/z 839 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([OH:10])=[O:9])#[N:2].O[N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]([O:10][N:15]2[C:19](=[O:20])[CH2:18][CH2:17][C:16]2=[O:21])=[O:9])[CH:11]=[CH:12][CH:13]=1)#[N:2]
Reactant: N#Cc1cccc(C=CC(=O)O)c1
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: N#Cc1cccc(C=CC(=O)ON2C(=O)CCC2=O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.6 %

Procedure:
To methylene chloride (300 mL) suspension of 3-cyanocinnamic acid (9.0 g) and N-hydroxysuccinic acid imide (9.0 g) was added WSC.HCl (15.0 g) at 0° C., and the mixture was stirred for 6 hours at room temperature. The reaction mixture was washed with water, and the organic layer was dried over anhydrous sodium sulfate. The crystals obtained by distilling off the solvent under a reduced pressure were filtered with diethyl ether, to give the captioned compound (13.0 g, 93%).
Reaction SMILES: CN(C=O)C.[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[S:32][CH:33]=[CH:34][N:35]=4)[CH2:28][CH2:27][C:26]([C:36](O)=[O:37])=[CH:25][C:24]=3[CH:39]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O.[CH3:44][N:45]([CH2:52][C:53]1[CH:59]=[CH:58][C:56]([NH2:57])=[CH:55][CH:54]=1)[CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>ClCCl.O.C(N(CC)CC)C>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[S:32][CH:33]=[CH:34][N:35]=4)[CH2:28][CH2:27][C:26]([C:36]([NH:57][C:56]4[CH:58]=[CH:59][C:53]([CH2:52][N:45]([CH3:44])[CH:46]5[CH2:51][CH2:50][O:49][CH2:48][CH2:47]5)=[CH:54][CH:55]=4)=[O:37])=[CH:25][C:24]=3[CH:39]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2nccs2)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2nccs2)cc1
Reaction time: 1 h
Yield: 66.3 %

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(thiazol-2-yl)methyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (70 mg) in dichloromethane (10 ml). Then, thionyl chloride (23 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. Then, this solution was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (42 mg) and triethylamine (385 mg) in dichloromethane (20 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:3) to give 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(thiazol-2-yl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 68) (66 mg) as yellow amorphous.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[CH:4][CH:3]=1.[NH2:19][C:20]1[C:33]2[C:32](=[O:34])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:35])[C:24]=2[CH:23]=[CH:22][CH:21]=1.[K].OS([O-])=O.[Na+]>OS(O)(=O)=O.O>[CH:10]1[CH:9]=[C:8]2[C:7]([C:6]3[C:15]([C:14](=[O:16])[C:13]2=[CH:12][CH:11]=1)=[C:2]([NH:1][C:23]1[CH:22]=[CH:21][C:20]([NH2:19])=[C:33]2[C:32]([C:31]4[C:26]([C:25](=[O:35])[C:24]=12)=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:34])[CH:3]=[CH:4][C:5]=3[NH2:18])=[O:17]
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reactant: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [K]
Solvent: O
Product: Nc1ccc(Nc2ccc(N)c3c2C(=O)c2ccccc2C3=O)c2c1C(=O)c1ccccc1C2=O
Temperature: 15 °C
Reaction time: 2.5 h
Yield: 100.7 %

Procedure:
52.0 g of 1,4-diaminoanthraquinone (92% pure) and 47.0 g of 1-aminoanthraquinone (98% pure) are dissolved in 512 g of 96% strength H2SO4 and this solution is added dropwise, with efficient stirring, to 460 g of water within 30 minutes. After cooling to about 15° C., 110.0 g of potassium peroxodisulphate are added, with efficient stirring, within about 3 hours and the mixture is allowed to warm slowly to 20° C. The melt is stirred at about 20° C. for 2-3 hours and then added to a mixture of 600 ml of water and 150 ml of 40% strength NaHSO3 solution and, after addition of a defoamer, the mixture is heated to 80°-90° C. in 30 minutes. After 30 minutes at 80°-90° C., the solid is filtered off hot with suction, washed with water to neutrality and dried at 100° C. 97.4 g of 4,4'-diamino-1,1'-dianthrimide (81% pure), corresponding to 86% of theory, were obtained.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([O:46][CH3:47])([CH3:45])[CH2:10][C@@H:9]([CH3:48])[C:7](=[O:8])[C@H:6]([CH3:49])[C@@H:5]([OH:50])[C@@:4]1([OH:52])[CH3:51].Cl[Sn]Cl.[N+](=[CH2:58])=[N-].C(OCC)C>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([O:46][CH3:47])([CH3:45])[CH2:10][C@@H:9]([CH3:48])[C:7](=[O:8])[C@H:6]([CH3:49])[C@@H:5]([O:50][CH3:58])[C@:4]1([OH:52])[CH3:51]
Reactant: C=[N+]=[N-]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@@H](OC)[C@@]1(C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Clarithromycin (J. Antibiot. 43 (1990) 544-549) (1.00 g, 1.34 mmol) and SnCl2 2H2O (0.307 g, 1.36 mmol) were dissolved in DMF (10 mL) and stirred at RT for 1 hour. A solution of diazomethane in diethylether prepared by Method B (cca 6 mmol) was added and the resulting mixture was stirred at RT for 4 hours. The mixture was diluted with aq. NaHCO3 (50 mL) and extracted with ethyl-acetate (3×30 mL). The organic layer was dried over Na2SO4, and concentrated to afford a mixture of the title and starting compounds (24%:73% LC-MS).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH:11]=[O:12])[CH2:8]2.C12CC3CC(CC(C3)[C:14]1=[O:23])C2.ClCC([O-])=O.C=O.[OH-].[Na+]>CO.O1CCCC1>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1([CH2:14][OH:23])[CH2:11][OH:12])[CH2:8]2
Reactant: O=CC1C2CC3CC(C2)CC1C3
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: C=O
Agent: O=C([O-])CCl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCC1(CO)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 283 g of 2-adamantane carbaldehyde (which had been synthesized by Darzen reaction of adamantanone with chloroacetate, hydrolysis of the resulting glycidyl ester, and subsequent heating for decarbonation), 300 g of tetrahydrofuran, and 500 ml of methanol under ice cooling, 380 g of a 37% formaldehyde aqueous solution was added and then 350 g of a 25% sodium hydroxide aqueous solution was added dropwise over 30 minutes. After the completion of dropwise addition, the ice bath was removed, and the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into a saturated sodium chloride aqueous solution, which was extracted with a 1:1 tetrahydrofuran/ethyl acetate mixture. The crude product obtained by concentrating the organic layer was recrystallized from n-hexane/diethyl ether, collecting 288 g (yield 85%) of the target compound.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[CH:23][CH:24]=2)[C:19]([CH2:29][C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]=2[O:39][CH3:40])=[CH:18]1.[Cl:41][C:42]1[CH:47]=[C:46]([Cl:48])[C:45]([Cl:49])=[CH:44][C:43]=1O>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:41][C:42]1[CH:47]=[C:46]([Cl:48])[C:45]([Cl:49])=[CH:44][C:43]=1[O:35][C:34](=[O:36])[C:33]1[CH:37]=[CH:38][C:30]([CH2:29][C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[N:17]([CH3:16])[CH:18]=2)=[C:31]([O:39][CH3:40])[CH:32]=1
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc([N+](=O)[O-])cc12
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)Oc2cc(Cl)c(Cl)cc2Cl)ccc1Cc1cn(C)c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 67 %

Procedure:
1.66 g of dicyclohexylcarbodiimide are added at room temperature, with stirring and in a nitrogen atmosphere, to a mixture of 2.38 g of 4-(1-methyl-5-nitroindol-3-ylmethyl)-3-methoxybenzoic acid [Example 1, Process Step a1)], 1.48 g of 2,4,5-trichlorophenol and 1.0 g of 4-dimethylaminopyridine in 140 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for 15 hours and filtered. The filtrate is concentrated by evaporation in vacuo at 50° and the residue is dissolved in 400 ml of chloroform, with heating. The organic phase is washed at room temperature with 50 ml of 2N hydrochloric acid and 50 ml of water and dried over magnesium sulfate, and the solution is concentrated to dryness at 40° under 11 torr. The residue is chromatographed on 350 g of silica gel (eluant: dichloromethane). The 3-methoxy-4-(1-methyl-5-nitroindol-3-ylmethyl)-benzoic acid 2,4,5-trichlorophenyl ester obtained in that manner is suspended in 50 ml of ether and isolated by filtration. Yield 67%. Yellow crystals of m.p. 235°-236°.