Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:26][O:27][NH2:28])[N:20]([CH2:21][C:22]([CH3:25])([OH:24])[CH3:23])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1.O>CN(C=O)C>[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:26][O:27][NH:28][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[N:20]([CH2:21][C:22]([OH:24])([CH3:25])[CH3:23])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CC(C)(O)Cn1c(CON)nc2c(N)nc3ccccc3c21
Reactant: CC(C)N=C=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NC(=O)NOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Reaction time: 0.08 h
Yield: 35.4 %

Procedure:
Isopropyl isocyanate (0.234 mL, 2.39 mmol) was added to a stirred solution of 1-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (prepared as described in Example 100, 600 mg, 1.99 mmol) in DMF (5 mL). After 5 minutes, a solid formed. The mixture was stirred for 1 hour and 45 minutes, then additional isopropyl isocyanate (0.234 mL) and DMF (2 mL) was added. The mixture was stirred at room temperature for 45 minutes. Water (40 mL) was added and a solid was isolated by filtration. The solid was washed with water and dried under vacuum to provide 272 mg of N-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}-N′-isopropylurea as a white solid. The filtrate was allowed to stand overnight at room temperature and crystals formed. The crystals were isolated by filtration, washed with acetonitrile, and dried in a vacuum oven at 60° C. to afford additional 38 mg of N-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}-N′-isopropylurea, as yellow crystals, mp 231-233° C.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C([S:47][CH2:48][CH:49]([CH2:53][C:54]1[C:62]([Cl:63])=[CH:61][C:57]2[O:58][CH2:59][O:60][C:56]=2[CH:55]=1)[C:50](O)=[O:51])(=O)C>C(Cl)Cl.C(N(CC)CC)C>[Cl:63][C:62]1[C:54]([CH2:53][CH:49]([CH2:48][SH:47])[C:50]([NH:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[O:51])=[CH:55][C:56]2[O:60][CH2:59][O:58][C:57]=2[CH:61]=1
Reactant: CC(=O)SCC(Cc1cc2c(cc1Cl)OCO2)C(=O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(CS)Cc1cc2c(cc1Cl)OCO2
Yield: 63.9 %

Procedure:
The operation is carried out as in Stage 5 of Example 1, starting with 121 mg of L-Tryptophan in the form of the hydrochloride, 2 ml of anhydrous methylene chloride, 0.13 ml of triethylamine, 199 mg of BOP and 143 mg of the product obtained in Stage 5 above, dissolved in 3 ml of anhydrous methylene chloride. Purification is carried out by chromatography on silica with chloroform-ethyl acetate: 90-10 as eluant. In this way 133 mg of expected product (yellow gum) is obtained.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.P(Cl)(Cl)([Cl:19])=O>>[NH2:1][C:2]1[N:3]=[C:4]([Cl:19])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=O
Product: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Temperature: 70 °C
Yield: 43.7 %

Procedure:
Following the method of Hull (J. Chem. Soc. 1957, 4845), a stirred suspension of 25.2 g (119 mmol) 2-amino-6-oxo-4-phenyl-1,6-dihydro-pyrimidine-5-carbonitrile in 27.1 ml (297 mmol) phosphorus oxychloride was heated at reflux for 2 h. The reaction mixture was then cooled to about 70° C. and poured cautiously onto rapidly stirred ice-water such that the temperature remained around 10° C. The resulting crystals were collected by filtration to afford 12.0 g (44%) 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile as a light beige crystalline solid. This material was pure enough to be used in subsequent steps, however analytically pure material was obtained by chromatography (ethyl acetate/hexane 1/1) which afforded 5.9 g (22%) 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile as a light yellow crystalline solid. EI-MS m/e (%): 232 (M{37Cl}+, 26), 230 (M{35Cl}+, 80), 190 ([M—Cl]+, 100), 153 (38).
Reaction SMILES: Cl.[C:2]12([CH2:12][CH2:13][NH2:14])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH:14][CH2:13][CH2:12][C:2]12[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2)=[O:19]
Reactant: NCCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Product: O=C(NCCC12CC3CC(CC(C3)C1)C2)c1ccccc1Cl

Procedure:
Prepared according to the method of Example 1 from 1-adamantaneethylamine hydrochloride (0.055 g) and 2-chlorobenzoyl chloride (0.033 ml) to give the title compound as a white solid (0.074 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10](OC)OC)=[C:4]([CH3:15])[CH:3]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:15])[C:5]2[O:8][CH:9]=[CH:10][C:6]=2[CH:7]=1
Reactant: COC(COc1ccc(Br)cc1C)OC
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cc2ccoc12
Temperature: 25 °C

Procedure:
Polyphosphoric acid (2.0 g) was added to a solution of 4-bromo-1-[(2,2-dimethyloxyethyl)oxy]-2-methylbenzene (6.24 g) in toluene (100 ml) and the resulting mixture was warmed to reflux for 4 hours. The reaction mixture was cooled to room temperature and the supernatant organic layer decanted off. The black residue was basified with 2N aqueous Na2CO3 and extracted with ethyl acetate (100 ml). The organic layers were combined, washed with brine (2×100 ml), dried over MgSO4, ifitered, and the solvent removed under reduced pressure. Purification by MPLC (2% ethyl acetatein-hexane) gave 5-bromo-7-methyl-benzofaran as a colourless oil (2.77 g). 1H NMR (360 MHz,CDCl3)δ2.48 (3H, s), 6.68 (1H, d, J=3.6 Hz), 7.13 (1H, s), 7.53 (1H, s), 7.60 (1H, d, J=3.6 Hz).
Reaction SMILES: C(O[CH:5]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=2[NH:7][C:6]1=[O:22])(=O)C.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.[K].[I-].[Na+]>CN(C)C=O>[CH:9]1([C:10]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:7][C:6](=[O:22])[CH:5]([N:27]3[C:26](=[O:28])[C:25]4=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]4[C:23]3=[O:33])[N:11]=2)[CH2:8][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(=O)OC1N=C(C2CCCCC2)c2ccccc2NC1=O
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C(C2CCCCC2)=NC1N1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Yield: 69.8 %

Procedure:
To a solution of (3RS)-3-acetoxy-5-cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (2.00 g) in N,N-dimethylformamide (15 ml) was added potassium phthalimide (1.85 g) under stirring and heated at 60° C. To the mixture was added sodium iodide (12.64 g) and stirred for 3 hours at 100° C. The hot resultant mixture was poured into ice-water to give a crude product. The precipitated crude product was collected by filtration. Dryness under the reduced pressure at 40° C. gave (3RS)-5-cyclohexyl-2,3-dihydro-3-phthalimido-1H-1,4-benzodiazepin-2-one (1.80 g) as an yellow powder, which was used in a following reaction step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:3][CH2:2]1.[CH3:21][C:22]([CH3:30])([C:24]1[N:28]=[C:27]([CH3:29])[O:26][N:25]=1)[NH2:23]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:23][C:22]([C:24]3[N:28]=[C:27]([CH3:29])[O:26][N:25]=3)([CH3:30])[CH3:21])=[O:20])=[N:8][C:9]=2[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCc2ccccn2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CC3)c(OCc3ccccn3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(pyridin-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 189 b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=394.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[O:14])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[ClH:15].Cl.[Cl:17][C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][SH:32])[CH2:25][CH2:24]2)=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:17].[ClH:15].[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[SH:32][CH2:31][CH2:30][CH2:29][N:26]2[CH2:27][CH2:28][N:23]([CH2:22][C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:34][CH:33]=3)[CH2:24][CH2:25]2)[OH:14])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(O)=[SH]CCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Yield: 55.2 %

Procedure:
The procedure described in Example 2 was followed, using 1.1 g of 4-ethoxycarbonylphenyl isocyanate, 2.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.85 g (28% of theory) of N-(4-ethoxycarbonylphenyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 231°-233° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]3[C:12](=[CH:13][C:2]1=2)[CH2:11][CH2:10][CH2:9][CH2:8]3.C(O)(=[O:16])C>C(O)(=O)CC>[O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]3[C:12](=[CH:13][C:2]1=2)[CH2:11][CH2:10][CH2:9][C:8]3=[O:16]
Reactant: CC(=O)O
Reactant: c1c2c(cc3c1CCO3)CCCC2
Solvent: CCC(=O)O
Product: O=C1CCCc2cc3c(cc21)CCO3
Temperature: 5 °C

Procedure:
30 g of the compound of Example 16 are dissolved in 130 ml of acetic acid and 32 ml of propionic acid, and then cooled to between 0° and 5° C. A solution of Jones's reagent is added, the temperature being maintained at approximately 5° C. The mixture, maintained for one hour at this temperature, is concentrated under vacuum and then taken up with sodium bicarbonate solution in the presence of ether. After filtration, the ether phase is decanted and washed with saturated sodium chloride solution to obtain, after evaporation and drying, an oil which crystallizes.
Reaction SMILES: [C:1]12([CH:11]=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:13]([O:17][C:18](=[O:35])[CH:19]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:28]=1[NH2:34])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:16])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[C:13]([O:17][C:18](=[O:35])[CH:19]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:28]=1[NH:34][CH2:11][C:1]12[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:14])([CH3:15])[CH3:16]
Reactant: O=CC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(Br)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(Br)cc1NCC12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h

Procedure:
To a solution of adamantane-1-carbaldehyde (3.77 g, 23 mmol) in acetic acid (45 ml) was added 2-(2-amino-4-bromo-phenyl)-malonic acid di-tert-butyl ester (4.44 g, 11.5 mmol) followed by addition of sodium triacetoxyborohydride (3.41 g, 16 mmol). The reaction mixture stirred for 30 minutes. After removal of the acetic acid, the reaction mixture was then partitioned between water and chloroform. Powdered K2CO3 was added and the pH of the aqueous layer was adjusted to 8. After separation, the organic layer was then washed with brine, dried over MgSO4, filtered and concentrated under vacuum to give the crude title compound of 9A as a brown oil (7.81 9), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>ClCCl.O.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:10][CH2:9][C:3]1[CH:4]=[C:5]([I:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1cc(I)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(I)cc1CBr
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a mixture of 2-chloro-5-iodotoluene (4.07 g, 16.12 mmol), N-bromosuccinimide (3.16 g, 17.73 mmol) in dichloromethane (258 mL) and water (258 mL) was added 2,2′-azodiisobutyronitrile (0.132 g, 0.81 mmol). The reaction mixture was irradiated with a halogen sun lamp (150 watt) for 2 h and then cooled to room temperature. The two-phase reaction mixture was separated, and the aqueous layer was extracted with dichloromethane (50 mL). The combined organic layers were washed with water (2×150 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound as an orange oil (5.20 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][C:13](=[N:17]O)[C:14]=2[C:15]=1[OH:16])=[O:5])[CH3:2]>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH:13]([NH2:17])[C:14]=2[C:15]=1[OH:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(c1O)C(=NO)CCC2
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2c(c1O)C(N)CCC2
Reaction time: 5 h

Procedure:
4-Hydroxy-5,6,7,8-tetrahydro-5-hydroxyimino-3-quinolinecarboxylic acid ethyl ester (2.5 g) was suspended in 90 ml of acetic acid, and 2.6 g of zinc dust was added to the suspension with its internal temperature kept at 60° C. The resulting reaction mixture was stirred for 5 hours. After the reaction mixture was filtered to remove the insoluble matter, the filtrate was concentrated to obtain the desired compound as a crude product. This crude product was used in the succeeding Example 10 without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][NH2:14])[C:6](=O)[C:5]12[O:20][CH2:19][CH2:18][CH2:17][O:16]1.N.C1COCC1>CCOC(C)=O>[N:14]1[CH2:13][CH2:12][CH2:11][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([NH2:1])=[CH:3][C:4]=3[C:5]3([O:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:6]=12
Reactant: NCCCN1C(=O)C2(OCCCO2)c2cc(N)ccc21
Agent: N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)C1(OCCCO1)C1=NCCCN12
Temperature: 25 °C
Yield: 76 %

Procedure:
5′-Amino-1′-(3-aminopropyl)spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (1.56 g, 5.63 mmol) was dissolved in 2M EtOAc.NH3 (1.90 mL) and THF (10 mL) and heated in a steel pressure vessel at 135° C. for 16 hr. The reaction mixture was cooled to room temperature and combined with silica gel and concentrated. The adsorbate was purified on Biotage KP silica gel eluting with a step gradient of CH2Cl2/CH3OH/NH4OH (95/3/2) to (85/10/5) to give the title compound as a bright yellow-orange solid (1.11 g, 76% yield). NMR (300 Mz, DMSO-d6): consistent.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH:8]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1.F[B-](F)(F)F.[CH3:21][O+](C)C>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:21])=[N:14]1
Reactant: C[O+](C)C
Reactant: O=C1CCCCC(CCC2OCCO2)N1
Agent: F[B-](F)(F)F
Product: COC1=NC(CCC2OCCO2)CCCC1

Procedure:
The product of Example 105 is reacted with trimethyloxonium tetrafluoroborate by the method of Example 3 to generate the title compound.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([CH2:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].NC1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][CH2:30][C@@H:29]([N:32]([CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH3:33])[CH2:28]2)=[CH:23][CH:22]=1>>[CH:17]1([CH2:16][CH2:15][C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([C:14]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:31][CH2:30][C@@H:29]([N:32]([CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH3:33])[CH2:28]5)=[CH:23][CH:22]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)[CH2:18][CH2:19]1
Reactant: COC(=O)c1sc(CCC2CC2)cc1N=CN(C)C
Reactant: CN(CCS(C)(=O)=O)[C@@H]1CCN(c2ccc(N)cc2)C1
Product: CN(CCS(C)(=O)=O)[C@@H]1CCN(c2ccc(-n3cnc4cc(CCC5CC5)sc4c3=O)cc2)C1

Procedure:
5-(2-Cyclopropylethyl)-3-(dimethylaminomethyleneamino)thiophene-2-carboxylic acid methyl ester was reacted with [(R)-1-(4-aminophenyl)pyrrolidin-3-yl]-(2-methanesulfonylethyl)methylamine by method A1. The product with the molecular weight of 500.57 (C25H32N4O3S2) was obtained in this way; MS (ESI): 501 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[NH2:14][C:15]1[CH:16]=[C:17]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]2([C:34]([C:36]2([CH2:51][C:52]([O:54][CH3:55])=[O:53])[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]2[C:42]2[CH:47]=[CH:46][C:45]([NH:48][CH3:49])=[C:44]([NH2:50])[CH:43]=2)=[O:35])[CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:18]=[CH:19][C:20]=1[NH:21][CH3:22]>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][C:11]([NH:50][C:44]2[CH:43]=[C:42]([CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][C:36]3([C:34]([C:24]3([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]3[C:17]3[CH:18]=[CH:19][C:20]([NH:21][CH3:22])=[C:15]([NH:14][C:11](=[O:13])[CH2:10][O:9][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)[CH:16]=3)=[O:35])[CH2:51][C:52]([O:54][CH3:55])=[O:53])[CH:47]=[CH:46][C:45]=2[NH:48][CH3:49])=[O:13])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(OCC(=O)O)cc1
Reactant: CNc1ccc(C2CCCCC2(CC(=O)OC)C(=O)C2(CC(=O)OC)CCCCC2c2ccc(NC)c(N)c2)cc1N
Solvent: C1CCOC1
Product: CNc1ccc(C2CCCCC2(CC(=O)OC)C(=O)C2(CC(=O)OC)CCCCC2c2ccc(NC)c(NC(=O)COc3ccc(C#N)cc3)c2)cc1NC(=O)COc1ccc(C#N)cc1
Reaction time: 4 h

Procedure:
620 mg (3.5 mmol) of 4-cyanophenyloxyacetic acid and 570 mg (3.5 mmol) of 1,1′-carbonylduimidazole were refluxed in 50 mL of tetrahydrofuran for 15 minutes. Then 1.0 g (3.28 mmol) of 3-amino-4-methylaminophenyl-(1-methoxycarbonylmethylcyclohex-1-yl) ketone were added and the mixture was boiled for a further 4 hours. Then the solvent was evaporated off and the crude product thus obtained was purified by column chromatography (150 g silica gel; eluant: dichloromethane with 0 to 2% ethanol). Yield: 1.4 g (93% of theory), C26H29N3O5 (463.5); Rf value: 0.44 (silica gel; dichloromethane/ethanol=19:1).
Reaction SMILES: [CH3:1][CH:2]1[C:14](=[O:15])[C:6]2[S:7][CH:8]=[C:9]([S:10](Cl)(=[O:12])=[O:11])[C:5]=2[CH2:4][CH2:3]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH:25][CH3:26])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][N:25]([CH3:26])[S:10]([C:9]2[C:5]3[CH2:4][CH2:3][CH:2]([CH3:1])[C:14](=[O:15])[C:6]=3[S:7][CH:8]=2)(=[O:12])=[O:11])=[CH:21][CH:22]=1
Reactant: CNCCc1ccc(F)cc1
Reactant: CC1CCc2c(S(=O)(=O)Cl)csc2C1=O
Product: CC1CCc2c(S(=O)(=O)N(C)CCc3ccc(F)cc3)csc2C1=O

Procedure:
From 6-methyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 13) (140 mg) and [2-(4-fluorophenyl)ethyl]methylamine (the compound of Preparation Example 14) (98 mg), the title compound (152 mg) was obtained as an orange oily substance, in the same way as Preparation Example 41.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(F)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 4-fluorobenzene boronic acid according to the general procedure B. Obtained as a yellow solid (1.08 g).
Reaction SMILES: [N:1]1[C:2]([CH2:10][OH:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:12]([Si:15](Cl)([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13].O>ClCCl>[CH:12]([Si:15]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:11][CH2:10][C:2]1[N:1]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[CH:3]=1)([CH3:14])[CH3:13]
Reactant: OCc1cn2ccccc2n1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)[Si](OCc1cn2ccccc2n1)(C(C)C)C(C)C
Yield: 92.8 %

Procedure:
1 g (6.55 mmol) of imidazo[1,2-a]pyridin-2-ylmethanol were solubilised in 25 ml of dichloromethane with magnetic stirring and then 2.145 ml (9.82 mmol) of triisopropylsilyl chloride were slowly added. The mixture was stirred at r.t. for 1 h before being treated with 100 ml of water. The aqueous phase was extracted with 3×50 ml of dichloromethane. The combined organic phases were washed with 100 ml of a saturated NaCl aqueous solution, dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: dichloromethane 100% and then ethyl acetate 100%). 1.85 g (yield=92%) of 2-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine were obtained as a colourless oil. LC-MS: m/z=305 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.57-8.50 (m, 1H), 7.81 (s, 1H), 7.46 (dd, J=9.1, 0.6 Hz, 1H), 7.19 (ddd, J=9.1, 6.7, 1.3 Hz, 1H), 6.84 (td, J=6.8, 1.1 Hz, 1H), 4.88 (d, J=0.6 Hz, 2H), 1.23-1.11 (m, 3H), 1.11-1.02 (m, 18H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=[O:7].[CH2:10]([N:17]=[C:18]=[S:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[CH2:10]([NH:17][C:18]([NH:9][NH:8][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:7])=[S:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: S=C=NCc1ccccc1
Reactant: NNC(=O)c1cccs1
Solvent: CC#N
Product: O=C(NNC(=S)NCc1ccccc1)c1cccs1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a hot solution of 2-thiophencarboxylic acid hydrazide (5.0 g, 35 mmol) in acetonitrile (80 mL) was added neat benzyl isothiocyanate (4.7 mL, 35 mmol) via syringe. When the solvent started to boil, the reaction vessel was removed from the heat source and allowed to cool to room temperature. The resulting crystals were collected by vacuum filtration, washed with diethyl ether and air-dried to yield N-benzyl-2-(thien-2-ylcarbonyl)hydrazinecarbothioamide (9.11 g; 89%; (M+H)+−292.2).
Reaction SMILES: N[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:3]=1.C(O)(=O)C.[BrH:27].N([O-])=O.[Na+]>O>[Br:27][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:3]=1
Reactant: CCOC(=O)c1ccc(N)cc1-c1ccc(OC)c(OC)c1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(Br)cc1-c1ccc(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
Ethyl 4-amino-2-(3,4-dimethoxyphenyl)benzoate (20.0 g; 0.066 mole; compound 252) and acetic acid (200 ml) are introduced into a 1000 ml three-necked flask. After dissolution, 47% strength hydrobromic acid (60 ml) is added, the mixture is cooled to 0° C. and then distilled water (150 ml) is added. Sodium nitrite (4.6 g; 0.066 mole) dissolved in water (30 ml) is poured in. Stirring is continued at between 0° and 5° C. for one hour, then the mixture is poured onto a solution of cuprous bromide (9.5 g; 0.066 mole) in 47% strength hydrobromic acid (100 ml). The reaction mixture is heated to 65% for one hour, the poured into water. The precipitate formed is filtered, rinsed with water and then dried in the air. Ethyl 4-bromo-2-(3,4-dimethoxyphenyl)benzoate (18.4 g; yield: 76.3%) is thus obtained, m.p. 53° C. (compound 250).