Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH:19]=[O:20])=[C:17]2[C:12]([C:13](=[O:32])[C:14]([CH3:31])=[C:15]([CH:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:23][CH2:22]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([Mg]Br)[CH2:35][CH2:34]1.Cl.O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:18]([CH:19]([CH:33]2[CH2:35][CH2:34]2)[OH:20])=[C:17]2[C:12]([C:13](=[O:32])[C:14]([CH3:31])=[C:15]([CH:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:23][CH2:22]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)N1CCC(c2oc3c(C=O)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Reactant: Br[Mg]C1CC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)N1CCC(c2oc3c(C(O)C4CC4)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 7-(benzyloxy)-3-methyl-4-oxo-2-(1-propanoylpiperidin-4-yl)-4H-chromene-8-carbaldehyde (200 mg, 0.46 mmol) obtained in Example 34-2 in tetrahydrofuran (6 mL), a 1 N solution of cyclopropyl magnesium bromide in tetrahydrofuran (1.5 mL, 1.50 mmol) was added dropwise at −30° C., and the mixture was gradually heated to 0° C. over 45 minutes and then stirred at 0° C. for 2 hours. A 1 N aqueous hydrochloric acid solution (5 mL) was added dropwise to the reaction solution, and then water was added to the mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=60/40→0/100) to obtain 159 mg of the title compound (yield: 68%) as an oil.
Reaction SMILES: [F:1][B-](F)(F)F.[C:6]([OH:14])(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[C:6]([F:1])(=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: F[B-](F)(F)F
Reactant: O=C(O)c1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C(F)c1ccccc1
Reaction time: 4 h
Yield: 72.5 %

Procedure:
To a suspension of diethylaminosulfinium tetrafluoroborate (344 mg, 1.5 mmol) in dichloromethane (3.0 mL) at room temperature is added benzoic acid (122 mg, 1.0 mmol) and DBU (224 μl, 1.5 mmol). The reaction mixture is stirred for 4 hours, then an 10% aqueous solution of HCl is added and stirring is continued for 15 minutes. The resulting mixture is extracted twice using dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated. The crude material is diluted with pentane and the solution is passed through a pad of silica gel with pentane elution. Solvent are evaporated in vacuum to provide benzoyl fluoride (90 mg, 74%) as a clear liquid. 1H NMR (CDCl3, 300 MHz) δ 7.94 (d, J=7.8, 2H), 7.62 (t, J=7.3 Hz, 1H), 7.43 (t, J=8.2 Hz, 2H); 19F NMR (CDCl3, 282 MHz) δ 17.5 (s, 1F); 13C NMR (CDCl3, 75 MHz) δ 157.3 (d, 1JC-F=344.3 Hz), 135.5, 131.5 (d, 3JC-F=4.0 Hz), 129.2, 125.0 (d, 2JC-F=60.4 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15](C#N)[C:16](=[O:24])[CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12.O.[OH-].[Na+]>Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH2:15][C:16](=[O:24])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12
Reactant: CCOC(=O)CCC(=O)C(C#N)c1ccc2c(c1)Cc1cccnc1O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCC(=O)Cc1ccc2c(c1)Cc1cccnc1O2
Yield: 83.5 %

Procedure:
4.8 g of ethyl 5(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)-5-cyano-4-oxovalerate is dissolved in 10 ml of concentrated hydrochloric acid. 30 ml of water is added at a stretch to the solution with stirring under ice-cooling, and the mixture is stirred under reflux for 5 hours. The reaction mixture is ice-cooled and adjusted to approximately pH 3 by addition of 30% sodium hydroxide. The resulting oil layer is extracted with chloroform, and the extract is dried over anhydrous sodium sulfate and concentrated. The oily residue, on standing, becomes solid. The solid is recrystallized from a mixture of dioxane and water (1:1) to give 3.4 g of 5-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)-4-oxovaleric acid as white needles melting at 146°-147°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([O:14][CH3:15])[CH2:5][NH:6]C(OC(C)(C)C)=O.C(Cl)[Cl:18]>C(O)(C(F)(F)F)=O>[ClH:18].[CH3:1][O:2][C:3](=[O:16])[C@H:4]([O:14][CH3:15])[CH2:5][NH2:6]
Reactant: ClCCl
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)OC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](CN)OC
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-tert-Butoxycarbonylamino-2-methoxypropionic acid methyl ester (500 mg. 2 mmol) was dissolved in 10% TFA in DCM (20 mL), and the reaction mixture was stirred at 30 min at ambient temperature. Solvent was removed and the residue co-evaporated twice for 30 mL of 1 N hydrochloric acid in ether. Yield: 320 mg (88%).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[ClH:15].Cl.[CH2:17]([NH:24][C:25]([NH:27][C:28]([NH2:30])=[NH:29])=[NH:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[ClH:15].[NH2:30][C:28]1[NH:27][C:25]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:26][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[N:29]=1
Reactant: CCCCCCCCCCCCC=O
Reactant: N=C(N)NC(=N)NCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCCC1N=C(N)NC(NCc2ccccc2)=N1

Procedure:
150 ml of ethanol, 6.5 g (32.8 mmol) of 1-tridecanal and 0.9 ml of concentrated hydrochloric acid were added to 5.0 g (22.0 mmol) of N1-benzyl-biguanide hydrochloride. The mixture was refluxed for 17 hours, and concentrated under reduced pressure to remove the solvent. The residue was dissolved in 100 ml of ethanol, and the solution was added to 50 ml of water and 10 ml of 5N aqueous sodium hydroxide. The mixture was refluxed for 2 hours, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with water. After addition of 5 ml of concentrated hydrochloric acid, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1.5)), and further recrystallized from 80% aqueous ethanol to obtain 1.2 g of colorless crystals having a melting point of 168 to 170° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=[N:51][C:46]2[CH:47]=[CH:48][CH:49]=[N:50][C:45]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC1C=NC=CC=1>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:51][C:46]1[CH:45]=[N:50][CH:49]=[CH:48][CH:47]=1)=[O:9]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(Cl)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(Cl)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Reaction time: 72 h

Procedure:
To a solution of 5-chloro-4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 67; 90 mg, 0.24 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.08 ml, 0.48 mmol), HATU (164 mg, 0.43 mmol) and 3-aminopyridine (27.0 mg, 0.29 mmol). The solution was stirred for 72 hours. The solvent removed in vacuo and purified by MDAP to give the title compound as a white solid. 55 mg.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:12]=[O:13])=[CH:5][N:6]2[CH3:11].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:14]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]([CH:12]=[O:13])=[CH:5][N:6]3[CH3:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cn1cc(C=O)c2c(Br)cccc21
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C=O)c2c(-c3ccccc3)cccc21
Temperature: 100 °C
Reaction time: 18.5 h

Procedure:
To a cold solution (0° C.) of 4-bromo-indole-3-carboxaldehyde (0.767 g, 3.4 mmol) in dry DMF (2 mL) was added NaH (60% dispersion in mineral oil, 173 mg, 4.37 mmol). The resulting mixture was stirred at 0° C. for 20 min. Iodomethane (0.8 mL, excess) was added to the reaction mixture in a drop wise fashion. The cooling bath was removed and the resulting mixture was stirred at room temperature for 1.5 h. The mixture was quenched with water and was extracted repeatedly from EtOAc. The combined organic extracts were washed with water (twice) and brine. After drying over magnesium sulfate, solvent was removed. The resulting solid was taken in hexane and sonicated for 30 min, filtered to provide the product, 4-bromo-1-methyl-indole-3-carboxaldehyde (0.687 g, 85% yield). A mixture of 4-bromo-1-methyl-indole-3-carboxaldehyde (109 mg, 0.45 mmol), phenyl boronic acid (85 mg, 0.69 mmol) in DMF (4 mL) was degassed (argon). To the mixture was added bis(triphenylphosphine)-palladium II chloride (25 mg, 0.035 mmol) followed by addition of 2M Na2CO3 solution (2 mL, 4 mmol) and the mixture was stirred under argon at 100° C. for 18.5 h and then at reflux for 3 h. The mixture was cooled to room temperature. The reaction mixture was diluted with water and extracted repeatedly with ethyl acetate. The combined extract was washed with water (twice) and brine. After drying over anhydrous magnesium sulfate, solvent was removed in vacuo and the crude product was purified by flash chromatography (hexane:EtOAc 1:1). The desired product was isolated as syrup (79% yield). MS: 236, 238.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.[Cl:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([N:18]=[C:19]=[S:20])=[C:12]([F:21])[CH:11]=1>CCOCC>[Cl:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([NH:18][C:19]([N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]2[CH2:2][OH:1])=[S:20])=[C:12]([F:21])[CH:11]=1
Reactant: OCC1CCCCN1
Reactant: COc1cc(N=C=S)c(F)cc1Cl
Solvent: CCOCC
Product: COc1cc(NC(=S)N2CCCCC2CO)c(F)cc1Cl
Temperature: 30 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
11.5 g (0.10 mol) of 2-hydroxymethylpiperidine are dissolved in 100 ml of ether, and 21.8 g (0.10 mol) of 4-chloro-2-fluoro-5-methoxyphenyl isothiocyanate are added dropwise at RT. The mixture is stirred for 2 hours at 30° C., washed with twice 100 ml of water and dried over sodium sulfate, and the solvent is removed. 32.6 g (98% of theory) of 1-[N-(4-chloro-2-fluoro-5-methoxyphenyl)thiocarbamoyl]-2-hydroxymethylpiperidine are obtained in the form of a pale yellow viscous oil.
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:25]1[CH:29]=[C:28]([C:30]2[C:31]3[CH:38]=[CH:37][N:36](COCC[Si](C)(C)C)[C:32]=3[N:33]=[CH:34][N:35]=2)[CH:27]=[N:26]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])=[O:13])[CH2:8][CH:7]1[CH2:23]O)#[N:2].COCCN(CCOC)S(F)(F)[F:53].C(O)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH2:3][CH:4]([N:25]1[CH:29]=[C:28]([C:30]2[C:31]3[CH:38]=[CH:37][NH:36][C:32]=3[N:33]=[CH:34][N:35]=2)[CH:27]=[N:26]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])=[O:13])[CH2:8][CH:7]1[CH2:23][F:53])#[N:2]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCN(C(=O)c5ccc(C#N)cc5F)CC4CO)c3)ncnc21
Solvent: ClCCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: N#CCC(CN1CCN(C(=O)c2ccc(C#N)cc2F)CC1CF)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 0 °C
Reaction time: 1.17 h

Procedure:
A solution of 4-{[4-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-(hydroxymethyl)piperazin-1-yl]carbonyl}-3-fluorobenzonitrile (13 mg, 0.020 mmol; Peak 1 from Example 156, Step 5) in methylene chloride (0.87 mL, 14 mmol) was cooled to 0° C., then 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ(4)-sulfanyl)ethanamine (11 μL, 0.060 mmol, Aldrich) was added, followed by ethanol (0.24 μL, 0.0040 mmol). The mixture was stirred at 0° C. for 70 min, then at RT for 20 min, and quenched by the addition of 5% sodium bicarbonate. The mixture was then extracted with EtOAc. The extract was washed with water (2×), brine, dried over sodium sulfate, decanted and concentrated. The yellow solid obtained was then dissolved and stirred for 1 h in a 1:1 mixture of TFA:DCM (1.74 mL). Solvent was removed in vacuo and the residue was stirred in a solution of methanol (0.43 mL) containing aqueous ammonium hydroxide (0.13 mL). After reaction was complete as determined by LCMS, solvent was removed in vacuo. Purification via preparative HPLC-MS (C18, eluting with a gradient of H2O/MeCN containing 0.15% NH4OH) afforded two regioisomeric products, the second peak to elute was the desired piperazine product (2 mg, 19%). 1H NMR (500 MHz, CD3OD, rotamers): δ 8.66 (s, 0.45H), 8.65 (s, 0.55H), 8.62 (s, 0.45H), 8.60 (s, 0.55H), 8.37 (s, 0.45H), 8.37 (s, 0.55H), 7.68-7.58 (m, 2H), 7.55-7.48 (m, 2H), 6.94 (d, 0.45H), 6.93 (d, 0.55H), 4.90-4.43 (m, 3H), 3.81-3.60 (m, 2H), 3.33-3.05 (m, 6H), 2.90-2.50 (m, 3H); 19F NMR (400 MHz, CD3OD): −230.21 (t, 1F), −115.45 (br s, 1F); LCMS (M+H)+: 516.3.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH3:20])[CH3:11])[CH3:2].C([Li])CCC.Cl[P:27]([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29]>C(OCC)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]([N:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH3:20])[P:27]([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH3:11])[CH3:2]
Reactant: CC(C)P(Cl)C(C)C
Reactant: CCc1ccccc1N=C(C)Nc1ccccc1CC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCc1ccccc1N=C(C)N(c1ccccc1CC)P(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
N′-(2-ethylphenyl)-N-(2-ethylphenyl)acetamidine (NS Amidine I) (0.798 g, 3.0 mmol) was dissolved in 50 mL of diethylether and cooled to 0° C. Butyllithium (1.50 mL of 2.0 M solution in pentane, 3.0 mmol) was added dropwise, producing a light yellow solution. The solution was warmed to room temperature and stirred for 2 hours. Chlorodiisopropylphosphine (0.48 mL, 3.0 mmol) was added slowly at room temperature. A white suspension formed, which was stirred overnight at room temperature. The slurry was filtered to remove a small amount of white solid, presumably lithium chloride, and the solvent was removed in vacuo to produce 1.14 g (99%) of yellow oil.
Reaction SMILES: [CH:1]12[C:10](=[O:11])O[C:7](=[O:8])[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH3:12]>>[CH:1]12[C:10](=[O:11])[NH:12][C:7](=[O:8])[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2
Reactant: N
Reactant: O=C1OC(=O)C2CCCCC12
Product: O=C1NC(=O)C2CCCCC12
Reaction time: 2 h

Procedure:
A mixture of cyclohexane-1,2-dicarboxylic anhydride (3 g; 19.5 mmol) and 29% aqueous ammonia (3.4 g) was heated to and kept at an inner temperature of 180 to 190° C. for 2 hours to give the objective compound quantitatively. M.P., 132°-136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:9][CH2:10][N:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:4][CH:3]=1.[C:24]([NH:26][C:27](=[N:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH:41]=1)OC1C=CC=CC=1)#[N:25]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:27]([NH:26][C:24]#[N:25])=[N:35][CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)[CH:41]=2)[CH3:17])=[CH:6][CH:7]=1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Reactant: CN(CCCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Solvent: ClCCl
Solvent: CO
Product: CN(CCCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.99 g (3 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,4-butanediamine and 1.17 g (3 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography (eluant: methylene chloride/methanol 98+2) analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%])=630 ([M+H]+, 7), 230 (100); IR (KBr): 2164 cm-1 (C≡N).
Reaction SMILES: [OH:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[I:26]N1C(=O)CCC1=O>C(Cl)Cl>[OH:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[I:26]
Reactant: O=C(N1CCc2cccc(O)c2CC1)C(F)(F)F
Reactant: O=C1CCC(=O)N1I
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: O=C(N1CCc2ccc(I)c(O)c2CC1)C(F)(F)F
Temperature: 15 °C
Yield: 64.9 %

Procedure:
Add 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.037 g, 4.0 mmol) and diisopropylamine (60.7 mg, 0.6 mmol) to anhydrous DCM (350 mL) and stir at 10-20° C. Add slowly a solution of N-iodosuccinimide (1.035 g, 4.6 mmol) in DCM (100 mL) over a period of 3 h. Stir the reaction mixture overnight and gradually warm to ambient temperature. Quench the reaction with saturated aqueous NaHCO3, separate the organic layer, wash the organic layer with 0.1N aqueous HCl, brine, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with EtOAc/hexane (1:20 to 1:10) to give the desired intermediate as a white solid (1.0 g, 65%). MS (ES+) m/z: 386 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][S:9]/[C:8]/2=[N:13]\[CH:14]([CH3:16])[CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([O-:20])(=[O:19])C.[Na+].[C:22](O)(=O)[CH3:23]>CC(=O)OCC>[O:19]1[C:1]2[CH:6]=[CH:5][C:22](/[CH:23]=[C:10]3/[C:11](=[O:12])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)/[C:8](=[N:13]/[CH:14]([CH3:16])[CH3:15])/[S:9]/3)=[CH:3][C:2]=2[O:20][CH2:17]1
Reactant: CC(=O)O
Reactant: CC(=O)[O-]
Reactant: CC(C)/N=C1\SCC(=O)N1c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)/N=C1\S/C(=C\c2ccc3c(c2)OCO3)C(=O)N1c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3-phenyl-2-[(Z)-isopropylimino]-thiazolidin-4-one (150 mg, 0.64 mmol), piperonat (192 mg, 1.28 mmol) and sodium acetate (105 mg, 1.28 mmol) in acetic acid (3 mL) is stirred at 110° C. for 4 h. The dark yellow to brown solution is cooled to rt, diluted with EA (75 mL), washed with sat. aq. NaHCO3, followed by water, and evaporated. The crude product is purified by crystallisation from a small amount of methanol (approx. 5 mL) to give 5-benzo[1,3]dioxol-5-ylmeth-(Z)-ylidene-2-[(Z)-isopropylimino]-3-phenyl-thiazolidin-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[N:10][C:9]2[C:8](=O)[N:7]=[CH:6][NH:5][C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.P(Cl)(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:24][C:8]1[C:9]2[N:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc[nH]c2cc(Cl)cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1cnc2c(Cl)ncnc2c1
Temperature: 25 °C

Procedure:
To a mixture of 7-chloropyrido[3,2-d]pyrimidin-4(1H)-one (250 mg, 1.377 mmol) in toluene (12 mL) were added DIPEA (0.73 mL, 4.20 mmol) and phosphorus oxychloride (0.391 mL, 4.27 mmol), and the reaction was stirred at reflux for 1 hour. After cooling to RT, the reaction mixture was concentrated to provide the title compound. LC/MS (ESI+) m/z=200 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][CH3:14])[C:5]=1[C:6]([NH2:8])=[NH:7].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1>>[ClH:1].[NH2:8][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[F:3])[N:13]([CH3:14])[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:7]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: CNc1cccc(F)c1C(=N)N
Agent: Cl
Product: CCOC(=O)N1CCC2(CC1)N=C(N)c1c(F)cccc1N2C

Procedure:
This was prepared by the method of Example 173 using 2-fluoro-6-(methylamino)benzamidine dihydrochloride (Example K) and ethyl 4-oxopiperidine-1-carboxylate to give the title compound, m.p. 234°-235° C.
Reaction SMILES: Cl.[CH3:2][C:3]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]2[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:7])[C:4]([OH:6])=O.[CH3:28][NH2:29]>O1CCOCC1>[CH3:28][NH:29][C:4](=[O:6])[C:3]([CH3:7])([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]2[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH3:2]
Reactant: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)O)ccc21
Reactant: CN
Agent: Cl
Solvent: C1COCCO1
Product: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)NC)ccc21

Procedure:
The above compound was prepared from 2-methyl-2-[2-methyl-1-propyl-3-(4-pyridyl)-1H-indole-5-yloxy]propanoic acid hydrochloride and methylamine in dioxane using a procedure analogous to that of Example 128.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)=[CH:5][NH:4][N:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[CH:22]([N:25](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CN>CN(C=O)C.C1COCC1>[CH3:22][NH:25][C:12](=[O:14])[C:11]1[CH:15]=[C:7]([C:6]2[C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:4][CH:5]=2)[CH:8]=[N:9][CH:10]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cncc(-c2c[nH]n(-c3ccccn3)c2=O)c1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cncc(-c2c[nH]n(-c3ccccn3)c2=O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
45.0 mg (159 μmol) of the compound from Example 44 are dissolved in 1 ml DMF, 1.9 mg (16 μmol) 4-N,N-dimethylaminopyridine, 24.7 mg (191 μmol) N,N-diisopropylethylamine and 100 mg (191 μmol) (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate are added and the mixture is stirred at RT for 15 min. 120 μl (239 μmol) of a 2 M solution of methylamine in THF are added and the mixture is stirred overnight at RT. To bring the conversion to completion, a further 120 μl (239 μmol) of the 2 M solution of methylamine in THF are added and the mixture is stirred again overnight at RT. The reaction mixture is purified directly by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient).