Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1[C:8](=[O:19])[O:9][C:10]2[C:15]([C:16]=1[CH3:17])=[CH:14][CH:13]=[C:12]([OH:18])[CH:11]=2)C.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:33](O)=[O:34]>>[CH:33]([C:11]1[C:12]([OH:18])=[CH:13][CH:14]=[C:15]2[C:10]=1[O:9][C:8](=[O:19])[C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:20])=[C:16]2[CH3:17])=[O:34]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)CCc1c(C)c2ccc(O)cc2oc1=O
Agent: C1N2CN3CN1CN(C2)C3
Product: Cc1c(CCC(=O)O)c(=O)oc2c(C=O)c(O)ccc12
Temperature: 110 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
A mixture of 3-(7-hydroxy-4-methyl-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester (100 mg, 0.36 mmol) and hexamethylenetetramine (203 mg, 1.44 mmol) in trifluoroacetic acid (3.6 mL) was stirred in a closed vial under argon at 110° C. for 2 h. The reaction was poured onto crushed ice (15 mL), warmed to room temperature, and the solid precipitate was filtered off. This mixture of formylated ester and corresponding carboxylic acid was dissolved in dioxane-1N NaOH (1:1) and was stirred at room temperature. After 2 h, 15 mL of dichloromethane was added. The aqueous layer was separated and acidified by portionwise addition of 1N HCl. The precipitate was collected, washed with water, and dried to afford title compound (15 mg, 0.043 mmol, 13%) as a light brown powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][C:47]#[N:48])=[CH:38][CH:37]=2)[CH2:9]1)=O)(C)(C)C.Cl.CO>>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]2[O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][C:47]#[N:48])=[CH:38][CH:37]=2)=[CH:19][CH:18]=1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CC#N)CCC3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCNC[C@@H]2OCc2ccc3c(c2)N(CC#N)CCC3)cc1

Procedure:
In analogy to the procedure described in example 4(b), the (3R,4R)-3-(1-cyanomethyl-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl/methanol to yield the (3R,4R)-[7-(4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-3-yloxymethyl)-3,4-dihydro-2H-quinolin-1-yl]-acetonitrile as a yellow oil; MS: 556 (M+H)+.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][CH:20]1[CH2:22][CH2:21]1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: OCC1CC1
Product: N=C(OCC1CC1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and hydroxymethylcyclopropane, there is obtained cyclopropylmethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 80°-83° C., mass spectrum m/e: M+ 292 (2), 237 (80), 194 (100);
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[F:16][C:17]1[C:22](F)=[C:21]([F:24])[C:20]([F:25])=[C:19]([F:26])[C:18]=1[F:27].O>CN(C)C=O>[F:16][C:17]1[C:18]([F:27])=[C:19]([F:26])[C:20]([F:25])=[C:21]([F:24])[C:22]=1[O:3][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1c(F)c(F)c(OC2(c3ccccc3)CCNCC2)c(F)c1F
Temperature: 50 °C
Yield: 44 %

Procedure:
To a suspension of sodium hydride (60% in oil, 6.4 g) in 50 ml of dry dimethylformamide was added, over a period of ten minutes, a solution of 25 g of 4-hydroxy-4-phenylpiperidine in 100 ml of dry dimethylformamide. After stirring at 50° C., for thirty minutes, the reaction mixture was cooled to ice bath temperature (5° C.). A solution of 18.6 ml of hexafluorobenzene in 100 ml of dry dimethylformamide was then added over a period of thirty minutes, and the resulting mixture stirred at ambient temperature for twenty hours. The mixture was poured into 500 ml water, stirred for five minutes, and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, evaporation of the solvents afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 20% methanol/dichloromethane) to afford 21 g (44%) of 4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:9](/[C:31]([F:34])([F:33])[F:32])=[CH:10]/[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH:19]([NH:23][C:24](=[O:30])[CH2:25][CH:26]([O:28][CH3:29])[CH3:27])[CH2:18][CH2:17]3)=[N:12][OH:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4](/[C:9](/[C:31]([F:34])([F:32])[F:33])=[CH:10]/[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH:19]([NH:23][C:24](=[O:30])[CH2:25][CH:26]([O:28][CH3:29])[CH3:27])[CH2:18][CH2:17]3)=[N:12][O:13][C:42](=[O:44])[CH3:43])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: COC(C)CC(=O)NC1CCc2cc(C(/C=C(/c3cc(Cl)cc(Cl)c3)C(F)(F)F)=NO)ccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(C)CC(=O)NC1CCc2cc(C(/C=C(/c3cc(Cl)cc(Cl)c3)C(F)(F)F)=NOC(C)=O)ccc21
Temperature: 25 °C
Yield: 72.1 %

Procedure:
0.5 g of N-[5-{(Z)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-hydroxyimino-2-butenyl}-indane-1-yl]-3-methoxybutyric acid amide and 0.22 g of triethylamine were dissolved in 10 ml of tetrahydrofuran, and 0.1 g of acetyl chloride was added to the resulting solution under ice-cold conditions, followed by stirring at room temperature for one night. The reaction solution was poured into ice-water, extracted with ethyl acetate, washed with saturated brine, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=7/3 (volume ratio)) to obtain 0.39 g of the target compound. Yield was 69%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(Cl)Cl>[Pd].CO>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[NH2:8]
Reactant: O=[N+]([O-])c1ccc(N2CCCC2)c(F)c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(N2CCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a solution of 1-(2-fluoro-4-nitrophenyl)pyrrolidine (1.60 g, 7.62 mmol) in mixed solvents of CH2Cl2 (20 mL) and MeOH (20 mL) was added catalyst Pd/C (0.16 g). The reaction was stirred at rt under H2 overnight, and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V) 5:1) to give the title compound as a white solid (1.20 g, 88%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:19]1[N:20]=[CH:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[N:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][N:15]([C:19]4[N:20]=[CH:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[N:23][CH:24]=4)[CH2:14][CH2:13]3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CC(N2CCC(CC3CCNCC3)CC2)C1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cnc(N2CCC(CC3CCN(C4CCC4)CC3)CC2)cn1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
1-Cyclobutyl-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 6) (0.59 g), methyl 5-chloro-2-pyrazinecarboxylate (0.43 g) and potassium carbonate (0.69 g) were dissolved in acetonitrile (5 ml) and heated at 120° C. for 10 min in the microwave reactor, followed by a further 15 min. The crude mixture was passed through an SCX column (10 g, eluting with methanol [80 ml] then 2 N NH3 in methanol [80 ml]). The basic fractions were evaporated to give the title compound (E1) as a yellow solid (0.665 g). MS electrospray (+ion) 373 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([O:11][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=[C:8]([O:10][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCCCc2ccccc2)cc(OCCCc2ccccc2)c1
Yield: 74.2 %

Procedure:
A mixture of 1.68 g (0.01 mol) of 3,5-dihydroxybenzoic acid methyl ester, 3.4 mL (0.022 mol) of 3-bromopropylbenzene and 2.8 g (0.02 mol) of potassium carbonate in 50 mL of anhydrous DMF was stirred and heated at 100° for 18 hours. The solvent was removed at reduced pressure, the residue was acidified and the product was extracted with ethyl acetate. The dried extract was concentrated to dryness and the residue was purified by chromatography on 150 g of silica gel using 10 % ethyl acetate-hexane to give 3.0 g of 3,5-bis(3-phenylpropoxy)benzoic acid methyl ester as an oil. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C@H:11]([CH2:16][OH:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:19](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CN=C1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C@H:11]([CH2:16][O:17][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)C[C@@H](CO)NC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Subsequently, to a solution of [(1S)-1-(hydroxymethyl)-3-methylbutyl]carbamic acid benzyl ester (4.84 g, 19.3 mmol) in dimethylformamide (145 ml) were added t-butyldiphenylsilyl chloride (6.01 ml, 23.1 mmol) and imidazole (1.57 g, 23.1 mmol) in an ice bath, and then the mixture was stirred at room temperature for 8 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (19:1→7:1) as the eluant to afford [(1S)-1-(t-butyldiphenylsilyloxymethyl)-3-methylbutyl]carbamic acid benzyl ester (9.22 g, yield 98%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)=[O:8])=[C:5](OCC2CO2)[CH:4]=1.C(N)(C)(C)C>C(O)C>[NH:14]1[C:15]2[C:11](=[C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: COc1ccc(C(=O)Nc2cccc3[nH]ccc23)c(OCC2CO2)c1
Solvent: CC(C)(C)N
Solvent: CCO
Product: COc1ccc(C(=O)Nc2cccc3[nH]ccc23)cc1

Procedure:
Using the procedure of Step E of Example 52, 6 g of the product of Step B, 100 ml of ethanol, 9.2 ml of tert.-butylamine were refluxed for 3 hours to obtain 6.1 g of 2-[3-(1,1-dimethylethyl)-amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-4-methoxy-benzamide. The product was dissolved in 300 ml of refluxing isopropanol and 1.8 g of benzoic acid were added thereto. The mixture was partially concentrated, iced and filtered and the product was dried under reduced pressure to obtain 5.1 g of the benzoate salt melting at 195° C. after crystallization from ethanol.
Reaction SMILES: [CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]([CH:13]([NH:16][C:17]([CH:19]3[CH2:24][CH:23]4[CH2:25][CH:20]3[CH:21]=[CH:22]4)=O)[CH2:14][CH3:15])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[CH:20]12[CH2:25][CH:23]([CH:22]=[CH:21]1)[CH2:24][CH:19]2[C:17]1[N:8]2[C:9]([C:10](=[O:12])[NH:11][C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:7]2)=[C:13]([CH2:14][CH3:15])[N:16]=1
Reactant: CCC(NC(=O)C1CC2C=CC1C2)c1nnc(C2CCCC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2CC3C=CC2C3)n2nc(C3CCCC3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 200 mg (0.58 mmol) crude N-[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]bicyclo[2.2.1]hept-5-ene-2-carboxamide, 165 mg (1.1 mmol) phosphoric trichloride are stirred at reflux for 4 hours, proportionate amounts of the solvents are used. The isomers are purified by chromatography (preparative HPLC).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C@H:27]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28]1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:32][C@H:29]2[CH2:30][CH2:31][C@H:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH2:28]2)[C:3]=1[F:20]
Reactant: N[C@H]1CC[C@H](c2ccccn2)C1
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@H]1COc2c(N[C@H]3CC[C@H](c4ccccn4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 100 °C
Reaction time: 7 h
Yield: 18.5 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (1.30 g, 4.69 mmol), (1S,3S)-3-(2-pyridyl)cyclopentylamine (913 mg, 5.63 mmol) and triethylamine (1.30 mL, 9.33 mmol) in anhydrous DMSO (8 mL) was stirred at 100° C. for 7 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (EtOAc) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[(1S,3S)-3-(2-pyridyl)cyclopentylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (364 mg, 19%) as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:24]=4[O:23][CH3:22])[CH2:29]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc2c(c(OC)c1)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Agent: Cl
Product: COc1cc2c(c(OC)c1)CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3ccccc13)C2
Yield: 23.5 %

Procedure:
Reaction of 2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 8 (23.5% yield): 1H NMR (300 MHz, DMSO-d6) δ 2.70 and 3.00 (2m, 2H), 3.48 and 4.03 (2m, 2H), 3.74 and 3.75 (m, 3H), 3.46 and 3.87 (s, 3H), 4.24 and 4.78 (2s, 2H), 6.33-6.51 (m, 2H), 7.38-7.44 (m, 2H), 7.72-7.78 (m, 1H), 7.91-7.99 (m, 1H), 8.07-8.17 (m, 2H), 8.52-8.62 (m, 2H); MS (ESI) m/z 444 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[C:6]=2[CH:22]=1.[C:23]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[C:24]([CH3:26])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:24]([C:23]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:26])[CH2:9][N:8]=[C:7]([C:14]3[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=3[F:20])[C:6]=2[CH:22]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2c(F)cccc2F)=NC1
Reactant: CC(=O)C(=O)OC(C)(C)C
Product: CC(=NNC1=Nc2ccc(Cl)cc2C(c2c(F)cccc2F)=NC1)C(=O)OC(C)(C)C

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine can be stirred with tert.-butyl pyruvate to give 7-chloro-2-[[1-(t-butyoxycarbonyl)ethylidene]hydrazino]-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: OC(C1CCN(CC2C=CC([N+]([O-])=O)=C(N[C@H]3CC[C@H](C(N)=O)CC3)C=2)CC1)(C)C.[C:31]([C@@H:34]1[CH2:39][CH2:38][C@H:37]([N:40]2[C:44]3[CH:45]=[C:46]([CH2:49][N:50]4[CH2:55][CH2:54][CH:53]([C:56]([OH:59])([CH3:58])[CH3:57])[CH2:52][CH2:51]4)[CH:47]=[CH:48][C:43]=3[NH:42]/[C:41]/2=[N:60]\[C:61](=[O:69])[C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([F:68])[CH:63]=2)[CH2:36][CH2:35]1)(=[O:33])[NH2:32]>>[C:31]([C@H:34]1[CH2:39][CH2:38][C@H:37]([N:40]2[C:44]3[CH:45]=[C:46]([CH2:49][N:50]4[CH2:51][CH2:52][CH:53]([C:56]([OH:59])([CH3:58])[CH3:57])[CH2:54][CH2:55]4)[CH:47]=[CH:48][C:43]=3[NH:42]/[C:41]/2=[N:60]\[C:61](=[O:69])[C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([F:68])[CH:63]=2)[CH2:36][CH2:35]1)(=[O:33])[NH2:32]
Reactant: CC(C)(O)C1CCN(Cc2ccc3[nH]/c(=N\C(=O)c4cccc(F)c4)n([C@H]4CC[C@@H](C(N)=O)CC4)c3c2)CC1
Agent: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(N[C@H]3CC[C@H](C(N)=O)CC3)c2)CC1
Product: CC(C)(O)C1CCN(Cc2ccc3[nH]/c(=N\C(=O)c4cccc(F)c4)n([C@H]4CC[C@H](C(N)=O)CC4)c3c2)CC1

Procedure:
The title compound was prepared in 2 steps from trans-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexane-carboxamide using a method analogous to the preparation of (E)-N-(1-(cis-4-carbamoylcyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-fluorobenzamide (75 mg, 45%). MS, m/z (C30H38FN5O3): calcd, 535.3. found, 536.1 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([CH2:18][OH:19])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([CH2:18][OH:19])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)cc2)nc1CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cn(-c2ccc(Cl)cc2)nc1CO
Temperature: 25 °C
Yield: 90.4 %

Procedure:
A mixture of ethyl 1-(4-chlorophenyl)-3-(hydroxymethyl)-1H-pyrazole-4-carboxylate (Example 1D, 1.5 g, 5.34 mmol), sodium hydroxide (0.388 g, 9.70 mmol) and H2O (50 mL) was heated at reflux for 2 h. After cooled down to room temperature, the reaction mixture was acidified with conc. HCl to pH about 5. The solid was collected via filtration, dried under vacuum to give the desired product as white solid (1.22 g, 90% yield). 1H NMR (DMSO-d6) δ 4.68 (s, 2H), 7.54-7.59 (m, 2H), 7.92-7.94 (m, 2H), 8.95 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[N:21][CH:20]=1.O.[OH-].[Na+]>C(OC(=O)C)(=O)C.CC(O)=O>[CH3:16][O:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:14]/[C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:21][CH:20]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1C=O
Reactant: COC(=O)c1ccc(C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(/C=C/c2c(-c3ccc(F)cc3)nnn2C)nc1
Temperature: 120 °C
Yield: 30.3 %

Procedure:
To a solution of 5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazole-4-carbaldehyde (308 mg, 1.5 mmol) in acetic anhydride (0.8 mL) and AcOH (141 μL) was added methyl-6-methylnicotinate (227 mg, 1.5 mmol) and the reaction mixture was heated at 120° C. for 144 h. The mixture was then poured into water, sodium hydroxide (2 N) added and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) afforded the title compound (154 mg, 30%) as a light brown solid. MS: m/e=339.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][N:13]([C:28](OC3C=CC([N+]([O-])=O)=CC=3)=[O:29])[CH2:12]2)[O:8][N:7]=1.Cl.[OH:41][CH:42]1[CH2:45][NH:44][CH2:43]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:41][CH:42]1[CH2:45][N:44]([C:28]([N:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([F:26])([F:25])[F:27])=[CH:21][CH:22]=3)[CH2:16][CH:11]([C:9]3[O:8][N:7]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[N:10]=3)[CH2:12]2)=[O:29])[CH2:43]1
Reactant: COCCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CC(O)C3)C2)n1
Temperature: 150 °C

Procedure:
50.5 mg (0.064 mmol, purity 70%) of the compound from Example 67A, 30.2 mg (0.275 mmol) of 3-hydroxyazetidine hydrochloride and 31.7 mg (0.229 mmol) of potassium carbonate were added to 2.1 ml of DMF and heated in a single-mode microwave (Emrys Optimizer) at 150° C. for 20 min. For workup, the reaction solution was combined and filtered, and the residue was purified by means of preparative HPLC. Enantiomer separation of 100 mg of the racemic crude product according to Method 8D gave 7.8 mg of the title compound from Example 98 (enantiomer 1) and 8.0 mg of the title compound from Example 99 (enantiomer 2).
Reaction SMILES: [CH2:1]([N:8]1[C:16]([OH:17])=[N:15][C:14]2[C:9]1=[N:10][C:11]([CH2:19][CH:20](C(OC)=O)[C:21]([O:23]C)=[O:22])=[N:12][C:13]=2[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH2:1]([N:8]1[C:16]([OH:17])=[N:15][C:14]2[C:9]1=[N:10][C:11]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[N:12][C:13]=2[NH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1)C(=O)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1nc(CCC(=O)O)nc2c1nc(O)n2Cc1ccccc1
Yield: 90 %

Procedure:
To dimethyl malonate (493 mg, 3.73 mmol) in DMF (8 ml) was added in an ice bath sodium hydride (75 mg, 3.13 mmol). Then the mixture was stirred at room temperature for 30 minutes. Thereto was added 9-benzyl-2-chloromethyl-8-hydroxyadenine (0.10 g, 0.37 mmol), and the mixture was stirred at room temperature for 21 hours. After removing the solvent, the residue was poured into water, concentrated, and neutralized with hydrochloric acid. The resulting solid was filtered, washed with water and dried in vacuo under heating to give 9-benzyl-2-(2,2-dimethoxycarbonylethyl)-8-hydroxyadenine (92 mg, 0.24 mmol) as a white solid. Thus obtained 9-benzyl-2-(2,2-dimethoxycarbonylethyl)-8-hydroxyadenine (79 mg, 0.20 mmol) was added to a mixed solvent of concentrated hydrochloric acid (2 ml) and 1,4-dioxane (6 ml), and the mixture was refluxed for 6 hours. After the reaction mixture was neutralized in an ice bath with saturated sodium hydrogencarbonate solution, the resulting solid was filtered, washed with water and dried in vacuo under heating to give the captioned compound (55 mg, 0.18 mmol) as a white solid.