Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].CN(C)C=O.[CH3:12][C:13]1[N:17]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:29]=[C:30]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:31]=[C:32]([C:33]#[N:34])[C:15]=2[N:14]=1>O>[CH3:12][C:13]1[N:17]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:29]=[C:30]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:31]=[C:32]([C:33]3[NH:34][N:3]=[N:2][N:1]=3)[C:15]=2[N:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc2c(C#N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(-c3nnn[nH]3)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Yield: 13 %

Procedure:
In a two 5 mL MW vial was added in 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carbonitrile, prepared as described in Example 24 (80 mg, 0.209 mmol), sodium azide (109 mg, 1.673 mmol) and ammonium chloride (90 mg, 1.673 mmol) and N,N-Dimethylformamide (DMF) (2 mL). The reaction mixture was subjected to MW irradiation for 15 min at 180° C., then 80 min at 185° C. LC-MS analysis only showed 30% conversion; however, heating for longer time caused the decomposition of the product. The two reaction mixtures were combined. The combined mixture was added in water (10 mL) and extracted with DCM (30 mL×4). The combined organic phases were washed with saturated NH4Cl solution, dried, and concentrated. The reaction was subjected to purification on a silica column (20˜60% EtOAc/Hexane) and then (1˜5% MeOH/DCM) to give the product (24 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.53 (s, 3H) 3.08-3.15 (m, 4H) 3.68-3.75 (m, 4H) 6.10 (s, 2H) 6.40 (d, J=7.33 Hz, 1H) 7.26-7.39 (m, 2H) 7.56-7.74 (m, 3H) 7.88 (d, J=8.34 Hz, 1H) 8.03 (d, J=8.08 Hz, 1H) 8.26 (d, 1H). MS(ES+) m/e 426.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][O:8][CH2:9][CH2:10][C:11]([CH2:13][OH:14])=[CH2:12])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][CH2:9][CH2:10][C:11]([CH2:13][O:14][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH2:12])=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=C(CO)CCOCc1ccc(OC)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=C(CCOCc1ccc(OC)cc1)COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Combine 4-(p-methoxybenzyloxy)-2-hydroxymethylbut-1-ene (0.77 g, 3.46 mmol) with pyridine (3 mL) and add dropwise benzoyl chloride (603 μL, 5.2 mmol). Stir the mixture at room temperature for 20 hours. Dilute the reaction mixture with diethyl ether (100 mL) and washed 3X with saturated sodium bicarbonate solution, dry over MgSO4 and concentrate in vacuo. Chromatograph on silica gel eluting with 1/9 ethyl acetate/hexane to give the title compound as an oil. Rf =0.28, silica gel, 1/9 ethyl acetate/hexane.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9]O[C:11]=2[CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)/[CH:17]=[CH:18]\[C:19]([OH:21])=[O:20]>>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH3:15])=[C:18]([CH:17]=[CH:9][N:8]=2)[C:19]([OH:21])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)/C=C\C(=O)O
Reactant: CCCCc1ocnc1-c1ccccc1
Product: CCCCc1c(C(=O)O)ccnc1-c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 4-phenyl-5-butyloxazole (12,5 g, 25 mmol) and maleic acid (3.5 g, 30 mmol) is heated at 100° C. for 30 min. After cooling, the semisolid mass is triturated with ether and the solid collected by filtration. 1H NMR (δ, CDCl3, 400 MHz) 11.68 (brs, 1H), 8.72 (d, J=6.0 Hz, 1H), 7.73 (d, J=5.6 Hz, 1H), 7.48-7.51 (m, 2H), 7.42-7.44 (m, 2H), 6.25 (s, 1H), 2.86 (d, J=7.6 Hz, 2H), 1.36 (m, 2H), 1.11 (dt, J=7.6, 7.2 Hz, 2H), 0.68 (t, J=7.6 Hz, 3H). MS (M+1): 256, (M−1) 254.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[N:7]2.[CH:22]([Sn](CCCC)(CCCC)CCCC)=[CH2:23]>C1(C)C=CC=CC=1.C(#N)C>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH:22]=[CH2:23])[N:7]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccccc1CNc1ccc2c(Br)cccc2n1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: C=Cc1cccc2nc(NCc3ccccc3OC)ccc12

Procedure:
(5-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (prepared from 5-bromo-2-chloroquinoline and 2-methoxy-benzylamine as described in example 3, step A, 1 g, 2.9 mmol) was dissolved in 30 mL toluene. Vinyltributyltin (952 mg, 3.0 mmol) and tetrakis(triphenylphosphin)palladium (67 mg, 0.058 mmol) was added. The reaction mixture was refluxed overnight. The mixture was diluted with 100 mL acetonitrile and extracted three times with heptane (100 mL each). The acetonitrile phase was dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->80:20 gradient). The title compound was obtained as a yellow oil (544 mg, 64%), MS: m/e=291.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](Cl)=[N:10][OH:11].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[C:21][C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:23].C(=O)(O)[O-].[Na+].[Cl-]>C(O)(C)C.CCOCC>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:11][N:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:21]=1[C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:23]
Reactant: ON=C(Cl)c1ccc(Cl)cc1Cl
Reactant: O=C(C#Cc1ccccc1Cl)c1cccnc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOCC
Product: O=C(c1cccnc1)c1c(-c2ccc(Cl)cc2Cl)noc1-c1ccccc1Cl
Temperature: 55 °C
Yield: 84 %

Procedure:
A mixture of 56 mg (0.25 mmol) of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride, 60 mg (0.25 mmol) of 3-(2-chlorophenyl)-1-(3-pyridyl)-2-propyn-1-one, and 30 mg (0.36 mmol) of sodium bicarbonate in 2.5 mL of isopropyl alcohol was heated at 55° C. overnight with shaking. An additional 30 mg of carboximidoyl chloride and 15 mg of sodium bicarbonate was then added, and the mixture was heated for another 20 hrs. The reaction mixture was cooled, diluted with ether, and then washed with saturated sodium bicarbonate. The ether fraction was dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation. The crude product was purified by prep TLC to give 90 mg (0.21 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)carbonyl]isoxazole. 1H NMR (CDCl3): δ 7.16 (m, 1), 7.60 (m, 2), 7.92 (m, 1), 8.53 (br d, 1), and 8.74 ppm (br s, 1). MS m/z: 428.9 (M+H).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8][C:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)O[C:29](=[O:30])C=2C=1.C=O.[OH-].[Na+]>CC(C)=O.O>[OH:1][C@H:2]1[C@H:7]([NH:8][C:9]2[CH2:13][CH2:12][C:11](=[O:14])[C:10]=2[CH2:29][OH:30])[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:22])[CH3:21]
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC2=CC(=O)CC2)[C@@H]1O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC2=C(CO)C(=O)CC2)[C@@H]1O
Reaction time: 5 h

Procedure:
2,98 of the title compound of example 5 are dissolved in 150 ml of acetone and a drop of a phenolphtalein-solution and the solution is mixed with 2,5 ml of a 37% formaldehyde solution three times every hour. The pH-value of the solution is kept between 8 and 9 by controlled addition of 0,1 aq. sodium hydroxide-solution. After stirring during 5 hours the reaction solution is diluted with water and the organic components are extracted with dichloromethane. Usual work up yields white crystalls of the title compound having a m.p. of 218°-220° C. (from dichloromethane/ethanol).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([CH3:12])[CH:4]=1)#[N:2].S(Cl)([Cl:15])=O.CN(C)C=O>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:15])=[O:8])=[C:5]([CH3:12])[CH:4]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C#N)ccc1C(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)ccc1C(=O)Cl
Yield: 100 %

Procedure:
To a solution of A-4 (4-cyano-2-methylbenzoic acid) (20 g, 0.124 mol) in toluene (200 mL) was added thionyl chloride (18 mL, 0.248 mol), and catalytic amount of dimethylformamide (0.5 mL). The resultant mixture was stirred at 70° C. for 14 h, and concentrated under reduced pressure to give A-5 (4-cyano-2-methylbenzoyl chloride) (24 g, yield 100%), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[C:30](=[O:31])[CH2:29][NH:28][C:27]4=[O:32])=[CH:22][C:21]=3[F:33])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:34][CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1.CN(C=O)C>[CH2:36]([N:28]1[CH2:29][C:30](=[O:31])[N:26]([C:23]2[CH:24]=[CH:25][C:20]([O:19][C:13]3[C:12]4[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[C:10]([O:34][CH3:35])[CH:11]=4)[N:16]=[CH:15][CH:14]=3)=[C:21]([F:33])[CH:22]=2)[C:27]1=[O:32])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COc1cc2c(Oc3ccc(N4C(=O)CNC4=O)cc3F)ccnc2cc1OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(N4C(=O)CN(Cc5ccccc5)C4=O)cc3F)ccnc2cc1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a stirring suspension of 3-(4-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)imidazolidine-2,4-dione (Example 50, 200 mg, 0.42 mmol) and benzyl bromide (0.06 mL, 0.51 mmol) in THF (2 mL) and DMF (1 mL) was added 1 M LiHMDS in THF (0.51 mL). After 3 h at RT, the solvents were removed under reduced pressure and the residue was purified on a silica gel to afford the title compound. Calc'd Mass for C33H26FN3O5, 563, MS (M+1) 564.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[C:11]([C:13]([C:19]#[N:20])=[C:14](SC)[NH:15][CH3:16])#[N:12]>>[C:11]([C:13]([C:19]#[N:20])=[C:14]([NH:15][CH3:16])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)#[N:12]
Reactant: NCCSCc1nccs1
Reactant: CNC(SC)=C(C#N)C#N
Product: CNC(NCCSCc1nccs1)=C(C#N)C#N

Procedure:
By the procedure of Example 1(ii), reacting 2-[(2-aminoethyl)-thiomethyl]thiazole with 1,1-dicyano-2-methylthio-2-methylaminoethylene gives the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.Br[CH:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]1=[O:37]>C(#N)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH:26]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]3=[O:37])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:9]=1
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Reactant: CCOC(=O)CN1CCC(Br)C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CN1CCC(N2CCC(C(=O)c3ccc(OC)cc3)CC2)C1=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
(4-Methoxyphenyl)(piperidin-4-yl)methanone hydrochloride (524 mg, 2.05 mmol) was stirred at room temperature with triethylamine (0.657 mL, 477 mg, 4.71 mmol) in acetonitrile (80 mL). A solution of ethyl 2-(3-bromo-2-oxopyrrolidin-1-yl)acetate (513 mg, 2.05 mmol) in acetonitrile (20 mL) was added to the mix. The reaction was stirred 3 hours at 40° C. and then overnight at 50° C. After 24 hours the reaction was not complete and the reaction was stirred an additional 48 hours at 70° C. then allowed to cool to room temperature. The solvents were removed in vacuo. The crude orange solid was eluted through a silica gel column with a 0 to 10% methanol/dichloromethane gradient to afford the title racemic compound (730 mg, 87% yield, 95% purity) as a thick amber oil. MS (ESI) [m/e, (M+H)+]=389.5. 1H NMR (400 MHz, chloroform-d) δ ppm 7.90-7.95 (m, 2H), 6.91-6.96 (m, 2H), 4.17-4.24 (m, 2H), 3.95-4.17 (m, 2H), 3.88 (s, 3H), 3.56-3.64 (m, 1H), 3.36-3.50 (m, 2H), 3.18-3.29 (m, 1H), 3.04-3.13 (m, 1H), 2.93-3.04 (m, 2H), 2.41-2.56 (m, 1H), 2.20-2.35 (m, 1H), 2.04-2.19 (m, 1H), 1.80-1.95 (m, 4H), 1.26-1.32 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8](Br)[C:7]1=[O:13])[CH3:2].Cl.[N:16]([CH2:19][C@@H:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N+:17]=[N-:18].C(OC(N[C@@H](CC1C=CC=CC=1)CO)=O)(C)(C)C.C(N(CC)CC)C>CCO>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:28][C@H:20]([CH2:19][N:16]=[N+:17]=[N-:18])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]1=[O:13])[CH3:2]
Reactant: CCOC(=O)Cn1ccnc(Br)c1=O
Reactant: [N-]=[N+]=NC[C@@H](N)Cc1ccccc1
Agent: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)Cn1ccnc(N[C@H](CN=[N+]=[N-])Cc2ccccc2)c1=O
Temperature: 110 °C
Reaction time: 72 h

Procedure:
To a solution of (3-bromo-2-oxo-2H-pyrazin-1-yl)-acetic acid ethyl ester (8.75 g, 33.5 mmol, preparation described in example 17, step J) in EtOH (60 ml) was added (S)-1-azidomethyl-2-phenyl-ethylamine hydrochloride (7.5 g, 35.3 mmol, prepared from (S)-(−)-2-(tertbutoxycarbonylamino)-3-phenyl-1-propanol following the procedure of Horwell et al (J. Med. Chem. 1991, 34, 404–414) and Boc removal under standard HCl(g) conditions) and triethylamine (10.8 ml, 77.6 mmol). The pressure flask was flushed with argon, sealed and the reaction mixture was stirred at 110° C. for 3 days. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 20% EtOAc in hexane to 40%) to give (S)-[3-(1-azidomethyl-2-phenylethylamino)-2-oxo-2H-pyrazin-1-yl]-acetic acid ethyl ester as a brown syrup. 1H NMR (CDCl3, 400 MHz): δ 7.36–7.20 (m, 5H); 6.85 (d, J=4.4 Hz, 1H); 6.41 (d, J=4.4 Hz, 1H); 6.20 (bd, J=8 Hz, 1H); 4.58 (A of AB, d, J=17.5 Hz, 1H));); 4.52 (B of AB, d, J=17.5 Hz, 1H)); 4.43–4.33 (m, 1H); 4.25 (q, J=7.3 Hz, 2H); 3.52 (A of ABX, dd, J=12.5, 5 Hz, 1H); 3.40 (B of ABX, dd, J=12.5, 5 Hz, 1H); 3.00 (A of ABX, dd, J=14, 6.7 Hz, 1H); 2.92 (B of ABX, dd, J=14, 7.9 Hz, 1H); 1.29 (t, J=7.3 Hz, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C(Cl)(Cl)Cl.Cl.Cl.[NH2:13][C:14]1[CH:25]=[CH:24][C:17]([CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[CH2:20]([N:19]([CH2:18][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[CH:25][CH:24]=1)[CH2:22][CH3:23])[CH3:21]
Reactant: CCN(CC)Cc1ccc(N)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccc(CN(CC)CC)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
At 0° C., ethyl chloroformate (455 μL) was added to a chloroform solution (13 mL) of N-(4-aminobenzyl)-N,N-diethylamine dihydrochloride (1.0 g) obtained in Reference Example 2-1-(2) and triethylamine (2.2 mL), and stirred at 0° C. for 1.5 hours and then at room temperature for 2 hours. Aqueous sodium hydrogencarbonate solution was added to the reaction liquid to stop the reaction, and this was extracted with chloroform. The organic layer was washed with water and saturated saline water, and then dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform/methanol=9/1) to obtain ethyl N-{4-[(diethylamino)methyl]phenyl}carbamate (530 mg) as an orange oily substance.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=1>CN(C)C=O>[OH:15][C:10]1[CH:11]=[CH:12][C:13]([NH:14][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])=[CH:8][CH:9]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: CN(C)C=O
Product: O=C(O)/C=C\C(=O)Nc1ccc(O)cc1
Reaction time: 2 h

Procedure:
In a reactor, 50 ml of dimethylformamide and 21.6 g (0.22 moles) of maleic anhydride were placed, to which were gradually added 21.8 g (0.20 moles) of p-aminophenol at 20° C. with thorough stirring. After completion of the addition, the reaction was allowed to proceed at 20° C. for 2 hours to yield N-(p-hydroxyphenyl) maleamic acid. To the reaction mixture, a previously formed solution containing 70 ml of dimethylformamide, 11.4 g (0.0803 moles) of phosphorus pentoxide and 5 g (0.049 moles) of sulfuric acid, was added dropwise with the use of a dropping funnel. Thereafter, the reaction was continued at 70° C. for 2 hours. After cooling to room temperature, the resulting reaction mixture was poured into 400 ml of ice water to precipitate N-(p-hydroxyphenyl) maleimide in the form of crystals. The crystals were separated by filtration, washed with water and then dried to obtain 31.3 g (0.165 moles) of N-(p-hydroxyphenyl) maleimide (yield 82.5%).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[CH2:10][C:11]([O-:13])=[O:12].[Na+].Cl>O1CCCC1.O>[CH2:2]([CH:3]([O:6][CH2:10][C:11]([OH:13])=[O:12])[CH2:4][CH3:5])[CH3:1]
Reactant: CCC(O)CC
Reactant: O=C([O-])CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
To a solution of 198 mg of 3-pentanol in tetrahydrofuran (4 ml), 180 mg of sodium hydride was added in nitrogen atmosphere at 0° C., and stirred for an hour at room temperature. To the solution 261 mg of sodium chloroacetate was added, followed by 2 hours' stirring at 100° C. The reaction solution was cooled to room temperature, diluted with water, acidified with 1N hydrochloric acid and extracted with chloroform. The chloroform layer was dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to provide 103 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23]>C(N(CC)CC)C>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:7]1[C:6]2[CH:21]=[C:2]([NH:1][C:26]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:27])[CH:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=1
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(N)ccc21
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)Nc1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2C
Reaction time: 60 h

Procedure:
5 g (0.018 M) of 7-amino-1,3-dihydro-1-methyl-5-(o-fluorophenyl)-2H-1,4-benzodiazepin-2-one are heated at reflux for 5 hours with 15 ml of isopropylisocyanate and a catalytic amount of triethylamine. The mixture is left to stand at room temperature for 2.5 days, the product crystallising out partially. The solvent is concentrated partially, cooled with ice and the crystallised product is filtered off. After recrystallisation from methylene chloride/ethyl acetate, there is obtained 1-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-isopropylurea which melts at 185°-188° C. with decomposition.
Reaction SMILES: [CH2:1]([S:13]([C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24])(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]CC.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[CH2:1]([S:13]([C:16]1[CH:21]=[C:20]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24])(=[O:14])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C1CCNC1
Reactant: CCCCCCCCCCCCS(=O)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCCCCCCCS(=O)(=O)c1cc(N2CCCC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
A mixture of 27.5 g of 2-dodecylsulfonyl-4-chloronitrobenzene, 5.5 g of pyrrolidine, 138 g of potassium carbonate and 70 ml of dimethylacetamide was stirred for 3 hours at 90° C. To this reaction mixture was added 210 ml of water, and the precipitated crystal was collected by filtration and recrystallized with acetonitrile to obtain 12.7 g of 2-decylsulfonyl-4-pyrrolidinonitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([CH2:47][CH2:48][NH2:49])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([CH2:47][CH2:48][NH:49][C:31](=[O:32])[CH2:30][NH:29][C:27](=[O:28])[CH2:26][CH:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]2[S:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)(=[O:10])=[O:11])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: O=C(O)CNC(=O)CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)N1CCC(CCNC(=O)CNC(=O)CC2c3ccccc3-c3ccccc3N2S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
The title compound was prepared from {2-[5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetylamino}-acetic acid (Example 12b) and 4-(2-amino-ethyl)-piperidine-1-carboxylic acid tert-butyl ester according to the method described in Example 1e.
Reaction SMILES: [CH3:1][C:2]1([CH:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH3:21][NH:22][CH3:23].[Cl-].[Na+]>O1CCCC1>[OH:17][CH2:18][CH2:19][CH:15]([C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:16]([N:22]([CH3:23])[CH3:21])=[O:20]
Reactant: CNC
Reactant: CC1(C2CCOC2=O)OCCc2c1[nH]c1ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)C(CCO)C1(C)OCCc2c1[nH]c1ccccc21

Procedure:
A solution of the oil containing the two diasteriomers of dihydro-3-(1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)-2(3H)-furanone (described in Example 1, 15 g, 0.055 mole) in tetrahydrofuran (200 ml) and an aqueous solution of dimethylamine (40%, 200 ml) is refluxed for 24 hr. Aqueous sodium chloride solution is added and the solution is extracted with diethyl ether. The organic extract is dried and evaporated to afford an oil consisting of two diastereoisomeric amides of the title compound. The oil is subjected to chromatography on silica gel using acetone-benzene (1:3). The eluates are evaporated and crystallized from benzene-hexane to obtain isomer A of the title compound as crystals (4.5 g), mp 158°-160° C. Further elution of the column with acetone-benzene (1:1), evaporation of the eluates and crystallization of the residue from benzene-hexane gives isomer B of the title compound as crystals (1.5 g), mp 159°-162° C.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:9](I)=[CH:10][N:11]=2)[N:5]=[C:6](Cl)[CH:7]=1.[BrH:13].O>C(O)(=O)C>[Br:13][C:6]1[CH:7]=[C:2]([Br:1])[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: Br
Reactant: Clc1cc(Br)c2ncc(I)n2n1
Solvent: O
Solvent: CC(=O)O
Product: Brc1cc(Br)c2nccn2n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of 5.0 (14.0 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c, 30 mL of hydrogen bromide solution in acetic acid (33%) was stirred at 120° C. for 1 hour under microwave irradiation. The mixture was poured into water and extracted with dichloromethane. The organic phase was washed with sodium thiosulfate and sodium hydrogencarbonate solution and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 3.0 g (78%) of the title compound.