Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[NH2:12][NH2:13]>>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH:12][NH2:13])=[O:10]
Reactant: NN
Reactant: COC(=O)c1ccccc1N
Product: NNC(=O)c1ccccc1N

Procedure:
The intermediate o-aminobenzhydrazide is prepared by refluxing 151 g (1.0 mol) methyl anthranilate and 55 g (1.1 mol) 64% aqueous hydrazine in a 250 ml round bottom flask for 2 hours. The product is recrystallized from 1.0 liter ethyl alcohol yielding 75 g of a light yellow solid, melting at 119°-121° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([OH:27])[CH:19]=3)=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([OH:27])[CH:19]=4)=[CH:13][CH:12]=3)=[N:6][CH:7]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1)Nc1ccc(Br)cn1
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1)Nc1ccc(-c2cccc(Cl)c2)cn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
To 120 mg (0.1 mmol) of above resin-bound bound N-(5-bromo-pyridin-2-yl)-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetamide in 2.0 mL of DME were added 48.0 mg (0.3 mmol) of 3-chlorophenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh3)4, and 0.3 mL (0.6 mmol) of 2N Na2CO3 solution. The mixture was heated to 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography (silica gel, DCM) to give 20 mg (40%) of the title compound.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[I:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=1.C(N(C(C)C)C(C)C)C.[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([NH:55][CH:56]2[CH2:58][CH2:57]2)[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43]>CN(C)C=O>[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([N:55]([CH:56]2[CH2:57][CH2:58]2)[C:28](=[O:30])[C:27]2[CH:26]=[CH:25][C:24]([I:23])=[CH:32][CH:31]=2)[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:43])[CH3:44]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2ccc(I)cc2)C2CC2)CC1
Reaction time: 0.17 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (2.67 g) is added to a solution of 4-iodo-benzoic acid (2.06 g) and ethyldiisopropylamine (2.88 mL) in N,N-dimethylformamide (15 mL) at room temperature. The solution is stirred for 10 min prior to the addition of 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester (2.00 g). The resulting mixture stirred at room temperature overnight. The mixture is concentrated in vacuo and the residue is mixed with water and ethyl acetate. The organic phase is separated, washed with water and aqueous NaHCO3 solution, dried, and the solvent is evaporated. The crude product is used for the next reaction step without further purification. LC (method 5): tR=2.32 min; Mass spectrum (ESI+): m/z=471 [M+H]+.
Reaction SMILES: [O:1]([CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][N:24]([CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:23]2)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:32]1([CH2:31][CH2:30][CH2:29][N:24]2[CH2:23][C:22]3[C:26](=[CH:27][CH:28]=[C:20]([CH2:19][OH:1])[CH:21]=3)[CH2:25]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)[Si](OCc1ccc2c(c1)CN(CCCc1ccccc1)C2)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)CN(CCCc1ccccc1)C2
Reaction time: 1 h

Procedure:
To a solution of 3.699 g (7.316 mM) of 5-(tert-butyldiphenylsiloxymethyl)-2-(3-phenylpropan-1-yl)-2,3-dihydro-1H-isoindole in 50 ml of tetrahydrofuran was added 8.78 ml (8.78 mM) of 1.0N-tetrabutylammonium fluoride-tetrahydrofuran at room temperature and the mixture was stirred for 1 hour. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 to ethyl acetate) to provide the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][C:10]2[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:9]=2[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[S:7]1(=[O:25])=[O:24].[CH:26]1([NH2:29])[CH2:28][CH2:27]1.Cl>>[F:16][C:13]1[CH:14]=[CH:15][C:9]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[S:7](=[O:25])(=[O:24])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:29][CH:26]3[CH2:28][CH2:27]3)[CH2:11][C:10]=2[CH:12]=1
Reactant: NC1CC1
Reactant: O=S1(=O)N(CCCCBr)Cc2cc(F)ccc2N1c1ccccc1F
Agent: Cl
Product: O=S1(=O)N(CCCCNC2CC2)Cc2cc(F)ccc2N1c1ccccc1F
Yield: 85 %

Procedure:
In an analogous manner to Example 11 step 5, 3-(4-bromobutyl)-6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.11 g, 0.25 mmol) was reacted to cyclopropylamine and then treated with HCl to provide N-{4-[6-fluoro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]butyl}cyclopropanamine (0.094 g, 85%) as a white solid:
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[CH:27]1([C:32](O)=O)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:32]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: O=C(O)C1CCCC1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(C3CCCC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and cyclopentanecarboxylic acid, the title compound was obtained in 62% purity by HPLC. MS(ESI+): m/z=431.1.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)=[N:8][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=3)=[CH:10][C:5]=2[NH:4][N:3]=1.[NH2:34][NH2:35]>CN(C)C=O>[NH2:1][C:2]1[C:6]2[C:7]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:23][CH:22]=3)=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:34][NH2:35])=[O:16])=[CH:19][CH:20]=3)=[CH:10][C:5]=2[NH:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2cc3[nH]nc(N)c3c(-c3ccc(Oc4ccccc4)cc3)n2)cc1
Reactant: NN
Solvent: CN(C)C=O
Product: NNC(=O)c1ccc(-c2cc3[nH]nc(N)c3c(-c3ccc(Oc4ccccc4)cc3)n2)cc1

Procedure:
A solution of methyl 4-(3-amino-4-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)benzoate (28 mg, 0.064 mmol, from Example 192) and hydrazine (20 μL 0.637 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at 100° C. for 3 h. LC-MS showed that only small amount of the desired product was formed. A 35% aqueous solution of hydrazine (0.5 mL) was added. After additional 1 h at 100° C., the mixture was cooled to give a suspension. Water was added and the mixture filtered. The solid was washed with water, dried under vacuum to give Example 194 (19 mg, 67% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 8.18 (2H, δ, J=8.53 Hz), 7.91 (2H, δ, J=8.53 Hz), 7.81-7.85 (2H, m), 7.71 (1H, s), 7.42 (2H, t, J=8.03 Hz), 7.16-7.22 (3H, m), 7.13 (2H, dd, J=8.66, 1.13 Hz); MS (ES+) m/z: 437 (M+H); LC retention time: 2.801 min (analytical HPLC Method A).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[N:2]1.[Cl:9][C:10]1[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=1[CH:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15].N1CCCCC1>CCO>[NH2:17][C:16]1[N:2]2[N:1]=[CH:5][CH:4]=[C:3]2[C:6]([C:7]#[N:8])=[C:12]([C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=2[Cl:9])[C:13]=1[C:14]#[N:15]
Reactant: N#CCc1cc[nH]n1
Reactant: N#CC(C#N)=Cc1ccccc1Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1c(-c2ccccc2Cl)c(C#N)c2ccnn2c1N
Yield: 14.5 %

Procedure:
To a stirred solution of (1H-Pyrazol-3-yl)-acetonitrile (1.56 g, 14.5 mM) from Preparative Example 3 Step C in absolute EtOH (73 mL) at 25° C. was added o-chlorobenzylidene malononitrile (2.74 g, 14.5 mM) and piperidine (0.14 mL, 1.45 mM). The mixture then refluxed for 1.75 hr. The solvent evaporated. Chromatography on silica gel (30×5 cm) with CH2Cl2 afforded 7-Amino-5-(2-chloro-phenyl)-pyrazolo[1,5-a]pyridine-4,6-dicarbonitrile (0.62 g, 15%). HRMS: m/z 293.0472 (M+), Calcd. C15H8N5Cl1: m/z 293.0468; δC (CDCl3) CH: 99.3, 127.6, 129.6, 130.8, 131.6, 145.5; C: 75.7, 86.9, 114.8, 115.1, 131.5, 133.8, 138.4, 145.6, 149.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH:20](Br)[C:19](=[O:24])[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[C:26]([O-:29])(=[O:28])[CH3:27].[K+]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH:20]([O:29][C:26](=[O:28])[CH3:27])[C:19](=[O:24])[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: CN(CCc1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC(Br)C2=O
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)OC1CCc2c(S(=O)(=O)N(C)CCc3ccc(F)cc3)csc2C1=O
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
To a solution of 6-bromo-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-sulfonic acid [2-(4-fluorophenyl)ethyl]-methyl-amide (246 mg) in dimethylsulfoxide (2 mL) was added potassium acetate (108 mg). After stirring for 30 minutes, the solution was diluted with, and extracted with ethyl acetate. After drying the organic layer with anhydrous sodium sulfate, the solvent was removed by evaporation to provide the title compound (200 mg) as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:28]4[CH2:29][CH2:30][CH:31]([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCc1c(CC=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCc1c(CCN2CCC(C(=O)O)CC2)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 31.2 %

Procedure:
To a solution of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]acetaldehyde (D52) (100 mg), ethyl 4-piperidinecarboxylate (78 mg) and acetic acid (1.428 μL) in dichloromethane (DCM) (8 mL) and N,N-dimethylformamide (DMF) (0.400 mL) stirred under nitrogen at room temperature for 20 min was added sodium triacetoxyborohydride (106 mg). The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated, separated between water and EA, the water phase was extracted by EA. The organic phases were concentrated in vacuo. The residue was dissolved in Isopropanol (8.00 mL) and water (0.800 mL), 20% sodium hydroxide (0.5 mL) was added, then the reaction mixture stirred at room temperature for overnight. The mixture was neutralized with acetic acid, the resulting solution was concentrated and the residue was purified by Mass Directed AutoPrep to afford 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]ethyl}-4-piperidinecarboxylic acid (E24) (40 mg) as a TFA salt (white solid). δH (DMSO-d6, 400 MHz): 1.14 (3H, t), 1.35 (6H, d), 1.85 (2H, m), 2.14 (2H, m), 3.01 (6H, m), 3.27 (3H, m), 3.68 (2H, m), 4.86 (1H, m), 7.36 (3H, m), 7.73 (1H, d), 8.02 (1H, dd), 8.14 (1H, d), 9.56 (1H, br s), 12.66 (1H, br s). δF (DMSO-d6, 376 MHz): −73.8. MS (ES): C27H32ClN3O3S requires 513. found 514.2 (M+H+).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]4[N:23]([C:35]5[CH:36]=[C:37]([N:41]6[S:45](=[O:47])(=[O:46])[NH:44][C:43](=[O:48])[CH2:42]6)[CH:38]=[CH:39][CH:40]=5)[CH:24]=[C:25]([C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=5[Cl:34])[N:26]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:49](=O)[CH3:50]>>[CH:1]1([CH2:7][N:8]([CH2:49][CH3:50])[C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][C:22]4[N:23]([C:35]5[CH:36]=[C:37]([N:41]6[S:45](=[O:47])(=[O:46])[NH:44][C:43](=[O:48])[CH2:42]6)[CH:38]=[CH:39][CH:40]=5)[CH:24]=[C:25]([C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=5[Cl:34])[N:26]=4)=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC=O
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(NCC5CCCCC5)cc4)cc3)c2)S(=O)(=O)N1
Product: CCN(CC1CCCCC1)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3cccc(N4CC(=O)NS4(=O)=O)c3)cc2)cc1

Procedure:
5-{3-[2-[4′-(Cyclohexylmethyl-amino)-biphenyl-4-ylmethyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-[1,2,5]thiadiazolidin-3-one-1,1-dioxide (7 mg, 0.01 mmol) was reacted with acetaldehyde (2 mg, 0.04 mmol) following general procedure X to give 5-{3-[2-[4′-(cyclohexylmethyl-ethyl-amino)-biphenyl-4-ylmethyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7].[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@:24]2([CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=3)[CH2:27]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@:24]2([CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:2][CH2:3][C:4]5[C:5](=[CH:9][CH:10]=[C:11]([O:13][CH3:14])[CH:12]=5)[C:6]4=[O:7])=[CH:33][CH:32]=3)[CH2:27]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@]2(CCN(c3ccc(N)cc3)C2)C1
Reactant: COc1ccc(C(=O)Cl)c(CCCl)c1
Product: COc1ccc2c(c1)CCN(c1ccc(N3CC[C@]4(CCN(C(=O)OC(C)(C)C)C4)C3)cc1)C2=O

Procedure:
According to Method A, 2-(2-chloroethyl)-4-methoxy-benzoyl chloride was reacted with (S)-7-(4-amino-phenyl)-2,7-diaza-spiro[4.4]nonane-2-carboxylic acid tert-butyl ester. In this way the product was obtained with molecular weight 477.61 (C28H35N3O4); MS (ESI): 478 (M+H+).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1.[C:37](Cl)(=[O:39])[CH3:38]>>[C:37]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:34][CH2:35]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1)(=[O:39])[CH3:38]
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f32) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[S:36])[NH:15][NH:16][C:17](=O)[C:18]3[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21]([O:27][CH2:28][O:29][CH3:30])=[CH:20][C:19]=3[O:31][CH2:32][O:33][CH3:34])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+]>>[CH:24]([C:22]1[C:21]([O:27][CH2:28][O:29][CH3:30])=[CH:20][C:19]([O:31][CH2:32][O:33][CH3:34])=[C:18]([C:17]2[N:13]([C:10]3[CH:11]=[CH:12][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:8][CH:9]=3)[C:14](=[S:36])[NH:15][N:16]=2)[CH:23]=1)([CH3:26])[CH3:25]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)NNC(=S)Nc1ccc(N2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=S)n1-c1ccc(N2CCOCC2)cc1

Procedure:
Crude crystals of 4-[4-(morpholin-4-yl)-phenyl]-1-(5-isopropyl-2,4-bis-methoxymethoxy-benzoyl)thiosemicarbazide (IM5-S-a01) and 5% aqueous sodium hydroxide (1 mL) were placed in a test tube and refluxed for 2 hours. After completing the reaction, the reaction mixture was extracted with methylene chloride, and the organic layer was combined drying over anhydrous sodium sulfate. Filtration and evaporation gave crude crystals of 5-(5-isopropyl-2,4-bis-methoxymethoxy-phenyl)-4-(4-morpholin-4-yl-phenyl)-2,4-dihydro-[1,2,4]triazol-3-thione (IM6-S-a01). These crude crystals were subjected to the next reaction without purification in particular.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[C:11]([O:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@@H:16]1Br)(=[O:13])[CH3:12]>C(Cl)Cl.[N-]1C=CN=C1.[Ag+].[Cl-].[Zn+2].[Cl-]>[C:11]([O:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:16]1[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: [Ag+]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccccc1[N+](=O)[O-]
Yield: 15.3 %

Procedure:
If the procedure described in Preparation LXXXIII is followed starting from 2 g (14.4.10-3 mol) of 2-nitrophenol, 2.5 g (14.2.10-3 mol) of silver imidazolate, 6 g (15.7.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 4 g (29.3.10-3 mol) of zinc chloride in 80 ml of methylene chloride, 0.91 g (yield: 15%) of the expected product is obtained after purification by chromatography on silica gel using a hexane/ethyl acetate mixture (2/1 v/v) as the eluent, and precipitation in ether.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[C:9]([Cl:15])=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)=[O:7].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[C:9]([Cl:15])=[C:10]([CH2:14][Br:16])[CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C(=O)c2cccs2)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1cccs1)c1cccc(CBr)c1Cl

Procedure:
A mixture of 11.8 parts of 2-chloro-m-tolyl 2-thienyl ketone, 8.9 parts of N-bromosuccinimide, 100 parts of carbon tetrachloride and 0.25 parts of benzoyl peroxide is stirred and refluxed for 2 hours. The precipitated succinimide is filtered off and washed on the filter with carbon tetrachloride. The filtrate is dried and evaporated, yielding α-bromo-2-chloro-m-tolyl 2-thienyl ketone as a residue.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[F:22][C:23]([F:37])([C:33]([F:36])([F:35])[F:34])[CH2:24][CH2:25][NH:26][C:27](=[O:32])[CH2:28][C:29](O)=[O:30]>>[CH:11]1([CH2:10][N:7]2[C:8](=[O:9])[C@@H:2]([NH:1][C:29](=[O:30])[CH2:28][C:27]([NH:26][CH2:25][CH2:24][C:23]([F:22])([F:37])[C:33]([F:36])([F:34])[F:35])=[O:32])[C:3]3[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=3[C:5]3[CH:17]=[CH:16][CH:15]=[CH:14][C:6]2=3)[CH2:13][CH2:12]1
Reactant: O=C(O)CC(=O)NCCC(F)(F)C(F)(F)F
Reactant: N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Product: O=C(CC(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21)NCCC(F)(F)C(F)(F)F

Procedure:
(S)-7-amino-5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one was coupled with N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acid in analogy to the description in example 73 to yield N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(3,3,4,4,4-pentafluoro-butyl)-malonamide as white solid.
Reaction SMILES: C(N1C(=O)C=CC(C2N=C(C(O)=O)C(NCC3C=CC(OC)=CC=3)=NC=2C2C=CC=CC=2)=N1)(C)C.[CH:36]([N:39]1[C:44](=[O:45])[CH:43]=[CH:42][C:41]([C:46]2[N:47]=[C:48]([NH:61][CH2:62][C:63]3[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=3)[C:49](C(O)=O)=[N:50][C:51]=2[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[N:40]1)([CH3:38])[CH3:37]>ClC1C=CC=CC=1Cl>[CH:36]([N:39]1[C:44](=[O:45])[CH:43]=[CH:42][C:41]([C:46]2[C:51]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[N:50][CH:49]=[C:48]([NH:61][CH2:62][C:63]3[CH:64]=[CH:65][C:66]([O:69][CH3:70])=[CH:67][CH:68]=3)[N:47]=2)=[N:40]1)([CH3:38])[CH3:37]
Reactant: COc1ccc(CNc2nc(-c3ccc(=O)n(C(C)C)n3)c(-c3ccccc3)nc2C(=O)O)cc1
Agent: COc1ccc(CNc2nc(-c3ccccc3)c(-c3ccc(=O)n(C(C)C)n3)nc2C(=O)O)cc1
Solvent: Clc1ccccc1Cl
Product: COc1ccc(CNc2cnc(-c3ccccc3)c(-c3ccc(=O)n(C(C)C)n3)n2)cc1
Temperature: 177.5 °C
Yield: 52.1 %

Procedure:
A suspension of a mixture of 6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-3-[(4-methoxybenzyl)amino]-5-phenyl-2-pyrazinecarboxylic acid and 5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-3-[(4-methoxybenzyl)amino]-6-phenyl-2-pyrazinecarboxylic acid (9.34 g) in o-dichlorobenzene (37 ml) was heated at 175-180° C. for 5 hours. After cooling, the reaction mixture was purified by column chromatography on silica gel. By eluting with a mixture of n-hexane and EtOAc (50:50 v/v) was obtained 2-isopropyl-6-{6-[(4-methoxybenzyl)amino]-3-phenyl-2-pyrazinyl}-3(2H)-pyridazinone as a solid (4.41 g) and by eluting with a mixture of n-hexane and EtOAc (40:60 v/v) was obtained 2-isopropyl-6-{5-[(4-methoxybenzyl)amino]-3-phenyl-2-pyrazinyl}-3(2H)-pyridazinone as a solid (2.38 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[N:16][N:15]=1.O>CCCCCC.O1CCCC1>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=[N:15][NH:16]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(Br)cc1
Reactant: c1ccc2cnncc2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(C2NN=Cc3ccccc32)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
5.53 ml of a 1.6 M solution of butyllithium in hexane are added dropwise at -78° C. within 20 min. to a solution of 1.48 g of 1-bromo-4-fluoro-benzene in 5 ml of tetrahydrofuran. The resulting white suspension is stirred for a further hour. A solution of 1 g of phthalazine in 5 ml of tetrahydrofuran is added dropwise at -78° C. within 10 min. The reaction mixture is left to warm to room temperature, treated with 50 ml of water and extracted 3 times with 50 ml of dichloromethane each time. The organic phases are combined washed with 50 ml of water and 50 ml of a saturated sodium chloride solution, dried over magnesium sulphate, filtered, the filtrate is concentrated and the residue is chromatographed on 100 g of silica gel with the eluent hexane/ethyl acetate 1:1. 1.49 g (86%) of (RS)-1-(4-fluoro-phenyl)-1,2-dihydro-phthalazine are obtained as a yellow oil. MS: 227 (M+H)+.