Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:10][NH2:11])[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=1)[C:18]([C:35](O)=[O:36])=[CH:17]2)#[N:13].OCC1(CNC(C2N(CC3C=CC=C(OC(F)(F)F)C=3)C3C(C=2)=CC(C#N)=CC=3)=O)CCCC1>>[CH2:1]([O:3][C:4]([C:6]1([CH2:10][NH:11][C:35]([C:18]2[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:32])[F:33])[CH:25]=3)[C:20]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:12]#[N:13])=[CH:22][CH:21]=3)=[O:36])[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)C1(CN)CCC1
Agent: N#Cc1ccc2c(c1)cc(C(=O)NCC1(CO)CCCC1)n2Cc1cccc(OC(F)(F)F)c1
Product: CCOC(=O)C1(CNC(=O)c2cc3cc(C#N)ccc3n2Cc2cccc(OC(F)(F)F)c2)CCC1
Yield: 52.2 %

Procedure:
1-({[5-Cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carbonyl]amino}methyl)-cyclobutanecarboxylic acid ethyl ester was prepared from 1-aminomethyl-cyclobutanecarboxylic acid ethyl ester (262 mg, 1.65 mmol) and 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (400 mg, 1.10 mmol) in the same manner as 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (1-hydroxymethyl-cyclopentylmethyl)amide giving 1-({[5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carbonyl]amino}methyl)cyclobutanecarboxylic acid ethyl ester as a colourless gum (287 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH:12]([C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:13].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH:12]([C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:13]
Reactant: Oc1cccc(Cl)c1
Reactant: COC(=O)c1ccccc1C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccccc1C(C)Oc1cccc(Cl)c1
Yield: 88 %

Procedure:
A solution of 3-chlorophenol (8.2 g) in DMF (30 ml) was added dropwise to a stirred suspension of sodium hydride (1.3 g) in DMF (30 ml). An hour later, a solution of crude methyl 2-(1-bromoethyl)benzoate described above (12 g) in DMF was added with stirring. After stirring at room temperature for 2 hours, the resulting mixture was poured into water and extracted with ether. The ether extracts were washed successively with water (×2), aqueous sodium hydroxide (×2), and brine, then dried and concentrated to give methyl 2-[1-(3-chlorophenoxy)ethyl]-benzoate (14.84 g, 88% pure by GC), as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][NH:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[C:38]([O-:41])(O)=O.[Na+].C(Cl)(Cl)=O.C1(C)C=CC=CC=1.[CH3:54][O:55][C:56]1[CH:65]=[CH:64][CH:63]=[CH:62][C:57]=1[O:58][CH2:59][CH2:60][NH2:61]>C1COCC1>[CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=3)[CH2:16][N:15]2[C:38](=[O:41])[NH:61][CH2:60][CH2:59][O:58][C:57]2[CH:62]=[CH:63][CH:64]=[CH:65][C:56]=2[O:55][CH3:54])=[O:13])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: O=C([O-])O
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1)C(=O)OCC
Reactant: COc1ccccc1OCCN
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NCCOc1ccccc1OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 30 h

Procedure:
To a solution of 12 (0.06 mmol) in THF (2 mL), was added a large excess of NaHCO3 (s) and a solution of phosgene in toluene (0.078 mmol). After 10 min of agitation the slurry was filtered and concentrated to dryness. The solid was redissolved in dichloromethane and a large excess of NaHCO3 (s) and 2-(2-methoxy-phenoxy)-ethylamine (15 mg, 0.09 mmol) was added. The slurry was agitated for 30 hrs at RT. The slurry was filtered, concentrated to dryness, redissolved in MeOH and subjected HPLC purification to give the title compound (10.6 mg, 0.015 mmol). Purity by HPLC >95%. M+H+695.17.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2([C:16]#N)[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][C:5]=1[F:18].[N:20]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=1)=[C:21]=[S:22].C[OH:36].Cl>CN(C=O)C.O>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([N:20]2[C:16](=[O:36])[C:11]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[N:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:2][CH3:1])=[O:19])=[C:5]([F:18])[CH:6]=3)[C:21]2=[S:22])=[CH:24][C:25]=1[C:31]([F:32])([F:34])[F:33])#[N:28].[CH3:1][NH:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11]3([CH2:15][CH2:14][CH2:13]3)[C:16](=[O:36])[N:20]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:32])([F:34])[F:33])[CH:24]=3)[C:21]2=[S:22])=[CH:6][C:5]=1[F:18])=[O:19]
Reactant: CO
Reactant: CNC(=O)c1ccc(NC2(C#N)CCCC2)cc1F
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1F
Product: CNC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCCC3)cc1F
Temperature: 130 °C
Yield: 7 %

Procedure:
A mixture of N-Methyl 2-fluoro-4-(1-cyanocyclopentyl)aminobenzamide (Formula 43) (57 mg, 0.22 mmol) and 4-isothiocyanato-2-trifluoromethyl benzonitrile (0.15 g, 0.65 mmol) in DMF (3 mL) was heated under microwave irradiation (open vessel) at 130° C. for 12 hours. To this mixture was added methanol (20 mL) and aq. 1 N HCl (5 mL). The second mixture was refluxed for 1.5 h. After being cooled to room temperature, the reaction mixture was poured into cold water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over MgSO4, concentrated and the residue was purified with silica gel column chromatography (dichloromethane:acetone, 95:5) to give 4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-4-oxo-2-thioxo-1,3-diazaspiro[4.4]nonan-1-yl)-2-fluoro-N-methylbenzamide, RD162″ (Formula 44) (8 mg, 7%) as a pale yellowish solid. 1H NMR δ 8.28 (dd, 1H, J=8.4, 8.4 Hz), 7.98 (d, 1H, J=8.3 Hz), 7.96 (d, 1H, J=1.8 Hz), 7.84 (dd, 1H, J=8.3, 1.8 Hz), 7.27 (dd, 1H, J=8.4, 1.8 Hz), 7.17 (dd, 1H, J=11.7, 1.8 Hz), 6.67-6.77 (m, 1H), 3.07 (d, 3H, J=4.3 Hz), 2.32-2.41 (m, 2H), 2.13-2.21 (m, 2H), 1.85-1.96 (m, 2H), 1.49-1.59 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:5]2[C:10]([CH3:11])=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>ClCCl.C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:13][CH2:14][N:15]([C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([N:19]([CH3:29])[CH3:18])=[CH:21][CH:22]=3)=[O:28])[CH2:16][CH2:17]2)[C:5]2[C:10]([CH3:11])=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Cc1csc2nc(N)nc(N3CCNCC3)c12
Reactant: CN(C)c1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CC#N
Product: Cc1csc2nc(N)nc(N3CCN(C(=O)Nc4ccc(N(C)C)cc4)CC3)c12
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of Example 22 (70 mg, 0.28 mmol) in dichloromethane (2 mL) and acetonitrile (2 mL) was added 4-(dimethylamino)phenyl isocyanate (48 mg, 0.29 mmol). The reaction mixture was stirred overnight. The solvents were evaporated in vacuo and the crude residue was purified by flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually increasing from 1% to 4% methanol in dichloromethane), yielding the title compound (75 mg) as a white powder. 13C NMR δ (75 MHz, CDCl3) 171.76, 164.09, 158.58, 155.98, 147.34, 129.12, 128.44, 122.79 (2C), 114.11 (2C), 113.95, 113.07, 49.96 (2C), 43.42 (2C), 40.79 (2C), 16.75. MS (m/z) 412 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:14]([S:15][CH3:16])=[N:13][C:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[C:11]2[C:6]=1[C:7]1[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[CH:26][C:8]=1[NH:9][C:10]2=[O:25])#[N:4].I[CH2:44][CH3:45].O>O1CCCC1.CN(C)C=O>[C:3]([C:5]1[C:14]([S:15][CH3:16])=[N:13][C:12]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[C:11]2[C:6]=1[C:7]1[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[CH:26][C:8]=1[N:9]=[C:10]2[O:25][CH2:44][CH3:45])#[N:4].[C:3]([C:5]1[C:14]([S:15][CH3:16])=[N:13][C:12]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[C:11]2[C:6]=1[C:7]1[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[CH:26][C:8]=1[N:9]([CH2:44][CH3:45])[C:10]2=[O:25])#[N:4]
Reactant: COc1ccc(-c2nc(SC)c(C#N)c3c2c(=O)[nH]c2cc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc23)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCOc1nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2c2c(C#N)c(SC)nc(-c3ccc(OC)cc3)c12
Product: CCn1c(=O)c2c(-c3ccc(OC)cc3)nc(SC)c(C#N)c2c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc21
Temperature: 60 °C
Reaction time: 0.42 h
Yield: 24 %
Yield: 56 %

Procedure:
75 mg (1.86 mmol) of sodium hydride 60% dispersion in oil is added to 0.52 g (1.93 mmol) of tert-butyl 4-(1-cyano-4-(4-methoxyphenyl)-2-(methylthio)-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)piperazine-1-carboxylate dissolved in 14 ml of tetrahydrofuran and 17 ml of anhydrous dimethylformamide. The reaction medium is carried at 60° C. for 45 minutes before the addition of 127 μl (1.86 mmol) of hot iodoethane solution. The reaction mixture is stirred at 60° C. for additional 25 minutes. After returning to room temperature, water is added and then the product is extracted several times with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried on magnesium sulfate and concentrated. The residue is purified by silica gel chromatography (eluent: 7:3 cyclohexane/ethyl acetate) to yield 130 mg (24%) of tert-butyl 4-(1-cyano-5-ethoxy-4-(4-methoxyphenyl)-2-(methylthio)benzo[c][2,7]naphthyridin-8-yl)piperazine-1-carboxylate in the form of a yellow solid and 360 mg (56%) of tert-butyl 4-(1-cyano-6-ethyl-4-(4-methoxyphenyl)-2-(methylthio)-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)piperazine-1-carboxylate in the form of a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]([CH2:18][C@@H:19]([OH:29])[C@@H:20]([NH2:28])[CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH3:32][O:33][C:34]1[C:35](=O)[C:36](=[O:40])[C:37]=1[O:38]C.CCN(CC)CC>CCO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:18][C@@H:19]([OH:29])[C@@H:20]([NH:28][C:35]2[C:36](=[O:40])[C:37](=[O:38])[C:34]=2[O:33][CH3:32])[CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])=[CH:30][CH:31]=1)#[N:2]
Reactant: C[Si](C)(C)CCOC(=O)N(Cc1ccc(C#N)cc1)C[C@@H](O)[C@@H](N)CC1CCCCC1
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1c(N[C@@H](CC2CCCCC2)[C@H](O)CN(Cc2ccc(C#N)cc2)C(=O)OCC[Si](C)(C)C)c(=O)c1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of (2R,3S)-1-(N-(4-cyanobenzyl)-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-2-hydroxy-3-amino-4-cyclohexylbutane (764 mg, 1.68 mmol) in EtOH (20 mL) was treated with 3,4-dimethoxycyclobut-3-ene-1,2-dione (300 mg, 2.10 mmol, 1.25 equiv) and Et3N (212 mg, 1.25 equiv). The resulting solution was allowed to stir at rt for 17 h. The excess 3,4-dimethoxycyclobut-3-ene-1,2-dione was removed by flash chromatography on silica gel, eluting with 0-65% EtOAc in hexanes. Analysis of the compound by LC-MS showed that it was of sufficient purity to employ in the subsequent steps.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.[CH3:25][CH:26]([CH3:34])[CH2:27][C:28](=[O:33])[CH2:29][C:30](=O)[CH3:31]>>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:5]2[C:4]3[C:3](=[CH:20][C:19]([O:21][CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=3)[N:2]=[C:30]([CH3:31])[C:29]=2[C:28](=[O:33])[CH2:27][CH:26]([CH3:34])[CH3:25])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: CC(=O)CC(=O)CC(C)C
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: Cl
Product: COc1ccc(-c2c(C(=O)CC(C)C)c(C)nc3cc(OC)c(OC)cc23)cc1OC

Procedure:
According to the same manner as that described in Reference Example 6, 2-amino-3',4',4,5-tetramethoxybenzophenone hydrochloride was reacted with 6-methyl-2,4-heptanedione to give 4-(3,4-dimethoxyphenyl)-3-isovaleryl-6,7-dimethoxy-2-methylquinoline. This compound was recrystallized from ethyl acetate-hexane to give colorless prisms. mp. 135°-137° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(OCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(CNS(C)(=O)=O)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 100 °C
Yield: 12.8 %

Procedure:
To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1, 1.1 g (7.7 mmol) of potassium carbonate and 1.1 g (7.7 mmol) of 4-fluorobenzeneboronic acid in 30 mL of toluene was added 0.2 g (0.3 mmol) of dichlorobis(triphenylphoshine)palladium (II). The mixture was heated to 100° C. for 16 hours and cooled to ambient temperature. The mixture was diluted with 20 mL of ethyl acetate, filtered through diatomaceous earth and concentrated in vacuo. Chromatography (50 g of silica gel, 30% ethyl acetate/hexane) of the residue afforded a white solid which was suspended in ethyl ether, filtered and recrystallized from chlorobutane to afford 0.2 g (12%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].C1C=CC2N(O)N=NC=2C=1.[CH2:24]([O:42][CH:43]1[CH:48]([O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH:47]([O:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])[CH2:46][CH:45]([C:87](O)=[O:88])[CH2:44]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][C:87]([CH:45]1[CH2:46][CH:47]([O:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])[CH:48]([O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH:43]([O:42][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][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:44]1)=[O:88]
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)O)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reactant: COC(=O)c1ccc(OC)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)Nc2cc(C(=O)OC)ccc2OC)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
Methyl 3-amino-4-methoxybenzoate (81 mg, 0.44 mmol) was dissolved in chloroform (1 ml), HOBt (7 mg, 0.05 mmol) and 3,4,5-tris(octadecyloxy)cyclohexylcarboxylic acid (199 mg, 0.22 mmol) were added. EDC.HCl (45 mg, 0.23 mmol) was added under ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated, and the residue was precipitated with acetonitrile (10 ml) to give N-(2-methoxy-5-methoxycarbonylphenyl) 3,4,5-tris(octadecyloxy)cyclohexylcarboxamide (225 mg, 0.21 mmol, yield 95%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(CC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f50) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: O=S(Cl)Cl.[NH2:5][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1)=[O:10].[OH:31][C:32]1[CH:39]=[CH:38][C:37]([C:40]2[C:41]([O:46][CH3:47])=[N:42][CH:43]=[CH:44][CH:45]=2)=[CH:36][C:33]=1[CH:34]=O.CO>ClCCl>[CH3:26][N:23]1[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:9]([C:8]3[CH:27]=[CH:28][C:29]4[N:30]=[C:34]([C:33]5[CH:36]=[C:37]([C:40]6[C:41]([O:46][CH3:47])=[N:42][CH:43]=[CH:44][CH:45]=6)[CH:38]=[CH:39][C:32]=5[OH:31])[NH:5][C:6]=4[CH:7]=3)=[O:10])=[CH:17][CH:16]=2)[CH2:21][CH2:22]1
Reactant: COc1ncccc1-c1ccc(O)c(C=O)c1
Reactant: CN1CCN(CCc2ccc(NC(=O)c3ccc(N)c(N)c3)cc2)CC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)Nc4ccc(CCN5CCN(C)CC5)cc4)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
To a suspension of silica gel (6.0 g) in dichloromethane (20 mL) was added SOCl2 (1.5 mL) and the mixture was stirred at the room temperature for 1 h (gas was released from the reaction mixture). 3,4-Diamino-N-{4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenyl}-benzamide (707.0 mg, 2.0 mmol) and 2-hydroxy-5-(2-methoxy-pyridin-3-yl)-benzaldehyde (458.5 mg, 2.0 mmol) were added, and the resulting mixture was stirred at the room temperature for 4 h. After methanol (10 mL) was added, the reaction mixture was stirred at room temperature for another 1 h and was evaporated under reduced pressure. The residue on silica gel was purified by chromatography (250:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (528 mg, 47%). 1H NMR (MeOH-d4) δ 2.25 (s, 3H), 2.35-2.71 (12H), 3.94 (s, 3H), 6.96 (m, 1H), 7.00 (d, J=9 Hz, 1H), 7.11 (d, J=9 Hz, 2H), 7.50-7.60 (4H), 7.66 (d, J=9 Hz, 1H), 7.79 (d, J=9 Hz, 1H), 8.06 (d, J=7 Hz, 1H), 8.10 (s, 1H), 8.14 (s, 1H). ESI-MS m/z 563 (MH+).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([S:8]([OH:11])(=[O:10])=O)=[C:5]([CH3:7])[N:6]=1.[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N-:22][CH:23](C)C)=[CH:18][C:17]=1[CH2:26][NH:27][C@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][C@H:29]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:14])[CH3:13]>>[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:23])[S:8]([C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])(=[O:10])=[O:11])=[CH:18][C:17]=1[CH2:26][NH:27][C@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][C@H:29]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:14])[CH3:13]
Reactant: Cc1nc(C)c(S(=O)(=O)O)s1
Reactant: CC(C)[N-]c1ccc(OC(C)C)c(CN[C@H]2CCCN[C@H]2c2ccccc2)c1
Product: Cc1nc(C)c(S(=O)(=O)N(C)c2ccc(OC(C)C)c(CN[C@H]3CCCN[C@H]3c3ccccc3)c2)s1

Procedure:
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3-((2S, 3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl-isopropylamide;
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:29][CH:30]=[C:31]([C:13]2[CH:12]=[N:11][C:7]3[NH:8][CH2:9][CH2:10][N:5]([CH2:4][C:3]4[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:2]=4[Cl:1])[C:6]=3[CH:14]=2)[CH2:32][CH2:33]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc3c(c2)N(Cc2cc(Cl)ccc2Cl)CCN3)CC1
Yield: 35 %

Procedure:
1-(2,5-dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as in General Procedure 4A to give the title compound as a beige solid (35% yield). M.p. 92-95° C., LCMS: m/z=477.28 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.47 (s, 9H), 2.32-2.38 (m, 2H), 3.39-3.46 (m, 2H), 3.52-3.59 (m, 2H), 3.60-3.65 (m, 2H), 3.95-3.99 (m, 2H), 4.43 (s, 2H), 5.18 (s, 1H), 5.69-5.72 (m, 1H), 6.43 (s, 1H), 7.17-7.20 (m, 1H), 7.23 (s, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.50 (s, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:20]=[C:19]2[C:10]([CH:11]=[C:12]3[C:17](=[CH:18]2)[CH:16]=[CH:15][CH:14]=[CH:13]3)=[C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=12.[B:25](OC)([O:28]C)[O:26]C.O>C1COCC1>[CH:14]1[C:15]2[C:20]3[C:19]([CH:18]=[C:17]([B:25]([OH:28])[OH:26])[C:16]=2[CH:11]=[CH:12][CH:13]=1)=[CH:10][C:9]1[C:8](=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:7]=3
Reactant: COB(OC)OC
Reactant: Brc1cc2cc3ccccc3cc2c2ccccc12
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OB(O)c1cc2cc3ccccc3cc2c2ccccc12
Reaction time: 2 h

Procedure:
52 ml (130 mmol) of n-butyllithium (2.5 M in n-hexane) are added dropwise with vigorous stirring at −78° C. to a suspension of 30.7 g (100 mmol) of 5-bromobenz[a]anthracene in 1000 ml of THF, and the mixture is stirred for a further 2 h. 16.7 ml (150 mmol) of trimethyl borate are added to the red solution in one portion with vigorous stirring, the mixture is stirred at −78° C. for a further 30 min., then warmed to room temperature over the course of 3 h, 300 ml of water are added, and the mixture is stirred for 30 min. The organic phase is separated off and evaporated to dryness in vacuo. The solid is taken up in 100 ml of n-hexane, filtered off with suction, washed once with 100 ml of hexane and dried in vacuo. Yield: 24.8 g (91 mmol), 91%, purity about 90% (NMR) of boronic acid, with varying amounts of boronic anhydride and borinic acid. The boronic acid can be used in this form without further purification.