Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:6]1[CH2:11][CH2:10][CH:9]([C:12](O)=[O:13])[CH2:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Li].[H-].Cl>O1CCCC1.O>[CH2:1]([C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1=CCC(C(=O)O)CC1
Agent: Cl
Agent: [H-]
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC1=CCC(CO)CC1
Temperature: 25 °C

Procedure:
A solution of 4-pentyl-3-cyclohexen-l-carboxylic acid (3.4 g) in tetrahydrofurn (THF; 55 ml) was added dropwise to a cold (0° C.) solution of lithium aluminim hydride (1.37 g) in tetrahydrofuran (THF, 55 ml), in a flask equipped with a condenser. The reaction mixture was stirred at room temperature for at least three hours, re-cooled to 0° C., and water (8 ml) was then added dropwise. An additional 55 ml of THF was added, and the reaction mixture stirred for three hours. The reaction mixture was then acidified with 2 M HCl (150 ml), and extracted with a 1:1 (v:v) ethyl acetate:hexane mixture. The combined organic layers were extracted with saturated sodium chloride and dried over sodium sulfate. The solvent was removed in vacuo, and the resultant oil was distilled (92°-95° C. at c.a. 1 mm Hg) to produce 4-pentyl-3-cyclohexen-1-methanol.
Reaction SMILES: [Na].[CH3:2]CN(C(C)C)C(C)C.[OH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[O:13].[F:18][C:19]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:20]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[N:33]=[C:32]3[CH2:34][NH:35][CH2:36][CH2:37][C:31]3=[N:30][C:29]=2[NH:38][CH:39]([CH3:41])[CH3:40])[CH2:24][CH2:23]1.C=O>CO>[F:18][C:19]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:20]=1[O:21][CH:22]1[CH2:23][CH2:24][N:25]([C:28]2[N:33]=[C:32]3[CH2:34][N:35]([CH3:2])[CH2:36][CH2:37][C:31]3=[N:30][C:29]=2[NH:38][CH:39]([CH3:41])[CH3:40])[CH2:26][CH2:27]1.[C:12]([OH:13])([C:14]([F:17])([F:16])[F:15])=[O:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Agent: C=O
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(C)CC2
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyhydroborate (12.3 mg, 0.058 mmol) was added to a solution of DIPEA (10 μL, 0.058 mmol), 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (15.0 mg, 0.029 mmol) and formaldehyde (2 μL, 0.029 mmol) in MeOH (290 μL) at rt. After 30 min, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (12.3 mg, 80%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.25 (d, J=6.6 Hz, 6H), 1.90-2.00 (m, 2H), 2.07-2.16 (m, 2H), 2.96-3.05 (m, 3H), 3.08 (br s, 4H), 3.33-3.42 (m, 2H), 3.43-3.85 (m, 2H), 4.14-4.38 (m, 3H), 4.44-4.51 (m, 1H), 6.84-6.91 (m, 1H), 6.95-7.02 (m, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 418.3.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)OCC1.[CH2:13](Br)[CH:14]=[CH2:15]>>[CH2:15]([O:12][CH2:11][CH:8]1[CH2:7][CH2:6][C:5](=[O:1])[CH2:10][CH2:9]1)[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: OCC1CCC2(CC1)OCCO2
Product: C=CCOCC1CCC(=O)CC1

Procedure:
The title compound was prepared as white solid from reaction of (1,4-dioxa-spiro[4.5]dec-8-yl)-methanol and allyl bromide (Aldrich) followed by de-protection using the procedure described in Example 34.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].C(N(CC)CC)C.[NH2:14][CH2:15][CH2:16][CH2:17][Si:18]([O:23][CH3:24])([O:21][CH3:22])[O:19][CH3:20]>O1CCOCC1>[CH3:1][N:2]([CH3:6])[C:3]([NH:14][CH2:15][CH2:16][CH2:17][Si:18]([O:23][CH3:24])([O:19][CH3:20])[O:21][CH3:22])=[O:4]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: CN(C)C(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CO[Si](CCCNC(=O)N(C)C)(OC)OC
Temperature: 50 °C
Yield: 82.5 %

Procedure:
5.0 g (46.5 mmol) N,N-dimethylcarbamoyl chloride (Sigma-Aldrich, Switzerland) and 40 mL dried dioxane (Sigma-Aldrich, Switzerland) were added to a 250-mL round-bottom two-neck flask equipped with a reflux cooler. 4.71 g (46.5 mmol) triethylamine (Sigma-Aldrich, Switzerland) and 8.34 g (46.5 mmol) 3-aminopropyltrimethoxysilane (Silquest A-1110, Momentive Performance Materials Inc., USA) were added dropwise under nitrogen, with stirring. After the exothermic reaction subsided, the resulting whitish suspension was stirred at 90° C. for 3 hours. A gradual color change to orange was observed. After cooling to 50° C., the solid was separated by double filtration, and the solvent was removed at 60° C. for 1 hour on a rotary evaporator. 9.6 g of the desired silane was obtained as a brown liquid. The silane was designated as DMA1100 and used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[CH:21][CH:22]=2)=[C:15]2[C:10]([C:11]([C:25]([F:28])([F:27])[F:26])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.CS(Cl)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].[F:47][C:48]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=1O>ClCCl>[CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:52]3[CH:53]=[C:48]([F:47])[CH:49]=[CH:50][C:51]=3[F:54])[CH:18]=2)=[C:15]2[C:10]([C:11]([C:25]([F:27])([F:28])[F:26])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccccc2)c1
Reactant: Oc1cc(F)ccc1F
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(F)c(OCc2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)c2)c1
Temperature: -30 °C
Reaction time: 1.5 h

Procedure:
Thirty-eight milligrams (38 mg; 0.1 mmol) of [3-(2-benzyl-7-trifluoromethyl-2H-indazol-3-yl)-phenyl]-methanol (see preparation of Example 7) were dissolved in 1 ml of dichloromethane followed by the addition of 28 μl of Et3N (0.2 mmol). The mixture was cooled to −30° C. and 12 μl of MsCl were added. Stirring continued at 0° C. for 1.5 hours. To the resulting solution, 85 mg of Cs2CO3 (0.25 mmol) were added followed by the addition of 65 mg (0.5 mmol) of 2,5-difluorophenol. Then the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 1M aq HCl and product was extracted with dichloromethane. Flash column chromatography (SiO2, dichloromethane/heptane, 1:1, as an eluant) afforded 2-benzyl-3-{3-[(2,5-difluorophenoxy)methyl]phenyl}-7-(trifluoromethyl)-2H-indazole in 41% yleld.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:25]#[N:26].[Na+]>CN(C=O)C>[CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:25]#[N:26])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: Clc1nc(NCc2ccccc2)c2c(-c3ccccc3)ccn2n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1nc(NCc2ccccc2)c2c(-c3ccccc3)ccn2n1
Temperature: 100 °C
Yield: 41.3 %

Procedure:
To a stirred solution of N-benzyl-2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.500 g, 1.49 mmol) dissolved in DMF (5 mL) was added sodium cyanide (0.366 g, 7.47 mmol). The reaction mixture was heated to 100° C. for 24 h and cooled. Reaction was quenched by adding ice cold water (100 mL) and was extracted with EtOAc (50×3 mL). The organic layer was separated and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 24 g, 10% EtOAc/hexanes) to afford 4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazine-2-carbonitrile (0.200 g, 41.2%). LCMS Condition B-45: retention time 2.95 min, [M−1]=324.2. HPLC Condition B-2: retention time 25.49 min, Purity 98.76%. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.68 (s, 2H), 6.92-6.96 (m, 2H), 7.26 (m, 10H), 7.86 (d, J=2.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=O)=[N:21]1>CO.N1CCCCC1>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](/[CH:29]=[C:8]2\[O:9][C:5]3[C:4]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]4)=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:21]1
Reactant: CN1CCN(Cc2cc(Cl)cc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CN1CCN(Cc2cc(Cl)cc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 23.9 %

Procedure:
A solution of 5-chloro-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.12 g, 0.43 mmol) in methanol (5.0 mL) was added with 1H-indazole-3-carboxaldehyde (0.063 g, 0.43 mmol). Then, the mixture was added with 7 drops of piperidine, and then the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (eluted with chloroform/methanol (99:1→90:10)) to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-5-chloro-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.042 g, 24%).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:25][O:26][C:27](=[O:30])[CH2:28][NH2:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:25][O:26][C:27](=[O:30])[CH2:28][NH:29][CH2:16][C:13]1[S:12][C:11]([NH:10][C:8]([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:9])=[N:15][CH:14]=1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: COC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: COC(=O)CNCc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Yield: 38.6 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (31 mg. 0.095 mmol), glycine methyl ester hydrochloride (24 mg, 0.20 mmol) and sodium triacetoxyborohydride (61 mg, 0.286 mmol) to afford 15 mg (39%) of the desired product after purification.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][NH:7][C:8](=[S:11])SC)([OH:3])=[O:2].[N-:12]=[N+:13]=[N-:14].[Na+].[OH-].[Na+]>>[C:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:8]([SH:11])=[N:14][N:13]=[N:12]1)([OH:3])=[O:2]
Reactant: CSC(=S)NCCCC(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCn1nnnc1S

Procedure:
Reaction of methyl 3-carboxypropyldithiocarbamate with sodium azide and sodium hydroxide as described in Example 7 gave 1-(3-carboxypropyl)tetrazole-5-thiol, m.p. 99°-101°.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=2)[CH2:4]1>Cl>[ClH:1].[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=2)[CH2:4]1
Reactant: COC(=O)Cc1ccc2c(c1)CC(N)C2
Agent: Cl
Product: NC1Cc2ccc(CC(=O)O)cc2C1

Procedure:
3.6 g of methyl 2-aminoindane-5-acetate-hydrochloride are refluxed for 3 hours in 160 ml of semiconcentrated hydrochloric acid. The hydrochloric acid is distilled off and the remaining product is triturated with a little ethanol, suction filtered and dried in vacuo.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]=[C:9]=[S:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([NH2:18])=[N:16][CH:17]=1.C(OCC)(=O)C>CN(C=O)C>[Br:11][C:12]1[CH:13]=[C:14]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([NH:18][C:9]2[S:10][C:2]3[C:7]([N:8]=2)=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][CH:17]=1
Reactant: S=C=Nc1cccnc1Cl
Reactant: Nc1ncc(Br)cc1Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1cnc(Nc2nc3cccnc3s2)c(Oc2ccccc2)c1
Temperature: 120 °C
Yield: 77.1 %

Procedure:
Heated a mixture of 2-chloro-3-isothiocyanatopyridine (0.257 g, 1.51 mmol) and 5-bromo-3-phenoxypyridin-2-amine (0.400 g, 1.51 mmol) in DMF (4 mL) at 80° C. for 3 hours. Heated at 120° C. overnight. Cooled, partitioned between 2N NaOH and ethyl acetate. Washed the organic layer twice with water, brine, dried, and concentrated. Subjected the residue to Biotage, eluting with 3:1 hexane:ethyl acetate to afford the title compound (0.465 g, 77.2% yield) as a white powder. 1H NMR (d6-DMSO) δ 7.15 (d, 2H), 7.23 (t, 1H), 7.40-7.50 (m, 4H), 7.92 (s, 1H), 8.34 (s, 1H), 8.37 (d, 1H), 11.63 (bs, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[C:8]([CH2:9][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)#[N:7].[NH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CNCCN1
Solvent: C1CCNCC1
Product: N#CCN1CCNCC1

Procedure:
The secondary amine of a functionalized piperazine or piperidine can be alkylated with a haloacetonitrile under basic conditions to yield a cyanomethyl piperazine or piperidine analogue. In a typical procedure N-benzoyl piperazine was added to a solution of chloroacetonitrile and TEA in THF and stirred at r.t. for between 2 and 5 days. A resulting precipitate is removed by filtration, the filtrate is concentrated in vacuo, and the residue purified via chromatography to yield the cyanomethyl intermediate YCH2CN. The alkylation with haloacetonitrile can also be carried out with an alternate base, such as 4-methylmorpholine or diisopropylethyl amine.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][NH:19][C:20]([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:20]([N:19]([CH3:18])[C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CNC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid was reacted with N,2-dimethylpropan-2-amine (CAN 94896-77-2) in the presence of TBTU and DIEA to give the title compound as colorless oil; MS (EI): m/e=303.4 [MH+].
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:23]=4[CH3:29])[CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[O:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42](Cl)=[O:43]>CN(C=O)C>[CH3:29][C:23]1[CH:24]=[C:25]([NH:28][C:42]([C:38]2[O:37][CH:41]=[CH:40][CH:39]=2)=[O:43])[CH:26]=[CH:27][C:22]=1[C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14](=[O:15])[NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][CH:11]=2)[CH:17]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1cc(N)ccc1-c1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2ccco2)ccc1-c1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2)c1
Reaction time: 18 h

Procedure:
A solution of 4′-amino-2′-methyl-biphenyl-3-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (40 mg) and triethylamine (0.4 ml) in dry DMF (3 ml) was treated with furan-2-carbonyl chloride (0.015 ml) and the mixture stirred at 20 C for 18 h. The mixture was then partitioned between water and dichloromethane. The dried extract was then evaporated and the residue purified on silica gel. Elution with dichloromethane:ethanol:0.880 ammonia; 400:8:1 gave a colourless foam (46 mg).
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.[C:31](OC(=O)C)(=[O:33])[CH3:32].N1C=CC=CC=1>O>[C:31]([O:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1)(=[O:33])[CH3:32]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3ccccc32)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-hydroxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.58 g) are added acetic anhydride (8.0 ml) and pyridine (2.0 ml). The mixture is stirred at room temperature for 1 hour. Water is added to the reaction mixture and the precipitated crystal is collected by filtration, and recrystallized from ethyl acetate/n-hexane to give 5-acetyloxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.56 g) as white powder, m.p. 193°-194° C.
Reaction SMILES: C(O)=O.[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH2:17][CH3:18].Br[CH2:20][C:21](=[O:37])[CH2:22][C@H:23]1[C@H:28]([O:29][CH3:30])[CH2:27][CH2:26][CH2:25][N:24]1[C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32]>>[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[N:10]([CH2:20][C:21](=[O:37])[CH2:22][C@H:23]3[C@H:28]([O:29][CH3:30])[CH2:27][CH2:26][CH2:25][N:24]3[C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH2:17][CH3:18]
Reactant: CCSc1cc2c(=O)[nH]cnc2cc1Br
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Solvent: O=CO
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(Br)c(SCC)cc2c1=O

Procedure:
In the manner of Example 4, 0.743 g (0.00224 mol) of 7-bromo-6-ethylthioquinazolin-4(3H)-one formic acid salt and 0.750 g (0.00224 mol) of allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxy-1-piperidinecarboxylate were converted into the title compound. After flash chromatography on silica gel (eluant 3% methanol in chloroform) there was obtained the pure product: yield 0.61 g (51%) mass spectrum m/e 537 (molecular ion with expected isotope pattern), 41 (parent peak, CH2 =CH--CH2 +) among others. 1H--NMR(CDCl3) 1.4 ppm (triplet, 3H, SCH2CH3), 1.4-2.1 (multiplet, 4H, OCHCH2CH2CH2N), 2.8-3.4 (multiplet, 6H, NCH2, SCH2CH3, COCH2CH), 3.4 (singlet, 3H, OCH3), 4.0 (broad singlet, 1H, CHNCO), 4.6 (doublet, 2H, CH2CH=CH2), 5.0 (singlet, 2H, NCH2CO), 5.0-5.5 (multiplet, 2H, CH=CH2), 5.6-6.1 (octet, 1H, CH2 =CH), 7.3 (singlet, 1H, aromatic H), 7.9 (singlet, 2H, aromatic H, N=CH--N).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15](=[O:17])[CH3:16])[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.[OH-].[K+].C([O:24][C:25](=[O:36])/[CH:26]=[CH:27]/[C:28]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1)(C)(C)C>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:15](=[O:17])/[CH:16]=[CH:34]/[C:31]2[CH:30]=[CH:29][C:28](/[CH:27]=[CH:26]/[C:25]([OH:36])=[O:24])=[CH:33][CH:32]=2)[CH:5]=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: CC(=O)c1cc(Cl)cc(N2CCN(C)CC2)c1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCN(c2cc(Cl)cc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)c2)CC1
Temperature: -20 °C
Reaction time: 1 h
Yield: 8.2 %

Procedure:
A mixture of 1-[3-chloro-5-(4-methyl-piperazin-1-yl)-phenyl]-ethanone (prepared as described in Preparation 4, 300 mg, 1.19 mmol), KOH (133 mg, 2.38 mmol) and (E)-3-(4-formyl-phenyl)-acrylic acid tert-butyl ester (276 mg, 1.19 mmol) in EtOH (10 ml) and H2O (2 ml) was stirred at −20° C. for 1 h and then at room temperature for 12 h. The resulting mixture was partitioned between water and AcOEt and the organic phase was dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (eluent: AcOEt/MeOH 9:1). The collected fractions were evaporated in vacuo and the resulting powder was dissolved in DCM (5 ml) and TFA (1 ml). The solution was stirred at room temperature for 12 h and then the solvent was removed to give 40 mg (E)-3-(4-{(E)-3-[3-chloro-5-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid as its trifluoroacetate salt.
Reaction SMILES: [CH:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]3[CH2:16][CH:15]3[C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH:23]=[C:22]([C:27]#[N:28])[CH:21]=[CH:20]4)[CH:12]=2)[CH2:7][CH2:6][NH:5]1)([CH3:3])[CH3:2].[CH2:29](I)[CH3:30].C(N(CC)CC)C>C1COCC1>[CH2:29]([N:5]1[CH2:6][CH2:7][C:8]2[C:13](=[CH:12][C:11]([CH:14]3[CH2:16][CH:15]3[C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH:23]=[C:22]([C:27]#[N:28])[CH:21]=[CH:20]4)=[CH:10][CH:9]=2)[CH:4]1[CH:1]([CH3:3])[CH3:2])[CH3:30]
Reactant: CCI
Reactant: CC(C)C1NCCc2ccc(C3CC3c3ccc4cc(C#N)ccc4c3)cc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1CCc2ccc(C3CC3c3ccc4cc(C#N)ccc4c3)cc2C1C(C)C

Procedure:
A solution of Example 20A (240 mg, 0.66 mmol), ethyl iodide (0.11 mL, 1.32 mmol), and triethylamine (0.18 mL, 1.32 mmol) in THF at 45° C. was stirred for 4 hours and concentrated. The concentrate was purified by flash column chromatography with 30% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+]([O-])=O)[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].[O:17]([CH3:19])[Li].Cl>CO>[CH3:19][O:17][C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: [Li]OC
Reactant: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(OC)cc([N+](=O)[O-])c1
Temperature: 85 °C
Yield: 55.8 %

Procedure:
methyl 3,5-dinitrobenzoate (1.5 g, 6.63 mmol, 1 eq) in 10 ml anhydrous MeOH under Ar was heated to reflux at 85° C. LiOMe (1.0 M in MeOH, 13.3 ml, 13.3 mmol, 2 eq) was added to the refluxing solution. After 4 h the reaction was cooled to room temperature, and the mixture was adjusted to pH {tilde over ( )} 3 with concentrated HCl. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic layer was washed with saturated aqueous NaHCO3 (×2), water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.7705 g (3.70 mmol, 56% yield) of methyl 3-methoxy-5-nitrobenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10]CC=C)[CH:5]=[O:6].[OH-].[Na+].[C:16]1(C)[CH:21]=C(C)C=C(C)[CH:17]=1>>[CH2:21]([C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([Br:1])[C:9]=1[OH:10])[CH:5]=[O:6])[CH:16]=[CH2:17]
Reactant: C=CCOc1ccc(C=O)cc1Br
Reactant: Cc1cc(C)cc(C)c1
Agent: [Na+]
Agent: [OH-]
Product: C=CCc1cc(C=O)cc(Br)c1O

Procedure:
3-Bromo-4-(2-propenyloxy)benzaldehyde (20.0 g, 0.083 mol) was heated under reflux in 75 ml mesitylene (1,3,5-trimethylbenzene) for 20 hours. After cooling, 250 ml 2N sodium hydroxide were added to the reaction mixture. The aqueous phase was washed two times with diethyl ether. The aqueous phase was subsequently acidified with concentrated hydrochloric acid under ice cooling and then extracted with ethyl acetate. After drying and concentrating the organic phase, there remained an oil that crystallized on cooling.