Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([CH2:11][NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)=[O:14])#[N:10].C(O)CC.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:18]2[CH:19]=[CH:20][C:15]([C:13]([NH:12][CH2:11][C:9]#[N:10])=[O:14])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N#CCNC(=O)c1ccc(B(O)O)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCO
Product: N#CCNC(=O)c1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 90 °C

Procedure:
To a solution of 2,4-dichloropyrimidine (3.2 g, 0.22 mmol) and 4-(cyanomethylcarbamoyl)phenylboronic acid (3.0 g, 15 mmol) in toluene (146 mL) were added n-propanol (44 mL), aqueous sodium bicarbonate (2M, 22 mL) and tetrakis(triphenylphosphine)palladium[0] (850 mg, 0.7 mmol). The reaction was heated at 90° C. for 24 h, then partitioned between ethyl acetate and water. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions washed with brine, dried (Na2SO4) filtered and concentrated. Silica gel chromatography using 30-70% ethyl acetate/petroleum spirit as eluent provided 4-(2-chloropyrimidin-4-yl)-N-(cyanomethyl)benzamide as a pale yellow waxy solid (1.35 g, 33%). 1H NMR (300 MHz, d6-DMSO) δ 9.40 (t, J=5.4 Hz, 1H), 8.88 (d, J=5.2 Hz, 1H), 8.32 (d, J=8.7 Hz, 2H), 8.23 (d, J=5.1 Hz, 1H), 8.05 (d, J=8.7 Hz, 2H), 4.36 (d, J=5.4 Hz, 2H); LC-ESI-MS (method B): rt 5.3 min.; m/z 273.2/275.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:29]=[CH:28][C:11]([CH2:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([N:20]3[C:25](=[O:26])[NH:24][CH2:23][CH:22]=[N:21]3)=[CH:15][C:14]=2[Cl:27])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=[O:31].[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][C:13]2[C:14]([Cl:27])=[CH:15][C:16]([N:20]3[C:25](=[O:26])[NH:24][C:23](=[O:31])[CH:22]=[N:21]3)=[CH:17][C:18]=2[Cl:19])=[CH:28][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCC=NN1c1cc(Cl)c(Cc2ccc(Cc3ccccc3)cc2)c(Cl)c1
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=c1cnn(-c2cc(Cl)c(Cc3ccc(Cc4ccccc4)cc3)c(Cl)c2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.8 %

Procedure:
In 20 ml of dichloromethane was dissolved 438 mg of 2-[4-(4-benzylbenzyl)-3,5-dichlorophenyl]-4,5-dihydro-1,2,4-triazine-3(2H)-one followed by addition of 1.0 g of pyridinium chlorochromate, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was filtered to remove the insoluble substance. The filtrate was concentrated and purified by silica gel chromatography (ethyl acetate/hexane=2/1) to provide 230 mg of the title compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[CH2:7][C:8]32[CH2:12][CH2:11]3)=[CH:4][CH:3]=1.Cl.[NH2:15][OH:16].CC([O-])=O.[Na+]>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[N:15]/[OH:16])/[CH2:7][C:8]32[CH2:12][CH2:11]3)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CC2(CC2)c2cc(Br)ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O/N=C1\CC2(CC2)c2cc(Br)ccc21
Yield: 99.8 %

Procedure:
A solution of 6′-bromospiro[cyclopropane-1,1′-inden]-3′(2′H)-one (2.1 g, 8.86 mmol), hydroxylamine HCl (1.23 g, 17.7 mmol) and NaOAc (4.32 g, 53.1 mmol) in MeOH (160 mL) was stirred overnight at room temperature. The reaction was concentrated, slurried water (40 mL), then sonicated and filtered. The precipitate was dried under high vacuum to give (E)-6′-bromospiro[cyclopropane-1,1′-inden]-3′(2′H)-one oxime (2.23 g, 100% yield) as a white solid. MS (EI) m/z=253.1[M+1]+.
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.[Cl:11][S:12](O)(=[O:14])=[O:13].S(Cl)(Cl)=O>>[Cl:11][S:12]([C:8]1[S:7][C:6]2[N:1]=[CH:2][NH:3][C:4](=[O:10])[C:5]=2[CH:9]=1)(=[O:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: O=c1[nH]cnc2sccc12
Solvent: O=S(Cl)Cl
Product: O=c1[nH]cnc2sc(S(=O)(=O)Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3,4-Dihydrothieno[ 2,3-d] pyrimidin-4-one (50 g) was added portionwise to chlorosulphonic acid (243 ml), maintaining the temperature below 0° C. Thionyl chloride (121 ml) was added dropwise, and the mixture stirred for a further 30 minutes at room temperature; then two hours at reflux. It was then cooled, and poured carefully on to ice. The precipitate was washed and dried to give 6-chlorosulphonylthieno[ 2,3-d] pyrimidin-4-one (84 g). This compound (30 g) and dimethylamine (450 ml) were mixed at -10°, then allowed to stir at room temperature for two hours. The mixture was poured into water and acidified with hydrochloric acid. The precipitate was washed with water and ethanol, and dried to give the 6-dimethylsulphonamido-4-one (23.8 g). This material was converted into the 4-chloro derivative as described in Example 19 above and thence into the title compounds by treatment with amines basically as described in Example 5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.[CH:10]1[CH:15]=[C:14]([CH:16]([CH:19]=O)[CH:17]=O)[N:13]=[CH:12][CH:11]=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:19]=[C:16]([C:14]3[CH:15]=[CH:10][CH:11]=[CH:12][N:13]=3)[CH:17]=[N:9]2)[N:3]=1
Reactant: O=CC(C=O)c1ccccn1
Reactant: NNc1cccc(Br)n1
Solvent: CCO
Product: Brc1cccc(-n2cc(-c3ccccn3)cn2)n1
Temperature: 70 °C

Procedure:
2-Bromo-6-hydrazinopyridine (500 mg, 2.7 mmol) was dissolved in ethanol (10 mL) and 2-(2-pyridyl)malondialdehyde(403 mg, 2.7 mmol) was added. The reaction was heated at 70° C. for 16 h. The solvents were removed the ethanol in vacuo and the residue was chromatographed on silica gel eluting with hexanes:EtOAc (1:4) to afford 2-bromo-6-(4-pyridin-2-yl-1H-pyrazol-1-yl)pyridine as a light yellow solid. 1H-NMR (CDCl3, 300 MHz) δ 9.0 (s, 1H), 8.62-8.61 (d, J=3 Hz 1H), 8.27 (s, 1H), 7.97-7.94 (d, J=9 Hz, 1H), 7.74-7.57 (m, 3H), 7.39-7.37 (d, J=3 Hz, 1H) 7.19-7.15 (t, 1H). MS (ESI) 301.0 (M++H), 303.0 (M+H+2).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([N+:17]([O-])=O)[CH:10]=1)[CH2:4][CH3:5])[CH3:2]>C(O)C.[Pd]>[CH2:4]([N:3]([CH2:1][CH3:2])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([NH2:17])[CH:10]=1)[CH3:5]
Reactant: CCN(CC)CCOc1ccc(OC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CCN(CC)CCOc1ccc(OC)c(N)c1

Procedure:
N,N-diethyl-2-(4-methoxy-3-nitrophenoxy)ethylamine (0.29 g, 1.1 mmol) was hydrogenated over Pd (5% on C, 50% wet, 0.12 g) in ethanol (5 ml) for 16 hours. The catalyst was filtered off and the solvent removed under reduced pressure to afford the title compound as a red oil. MS (m/z)=239 (M+H+); Calc'd for C13H22N2O2=238.33.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C>ClCCl>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccccn1
Reaction time: 3 h

Procedure:
1.1 equivalents of pivalic acid chloride dissolved in 100 ml of dichloromethane are added dropwise at 0° C. to a solution containing one equivalent of 2-aminopyridine and 1.25 equivalents of triethylamine in 400 ml of dichloromethane. Once the addition is complete, the reaction mixture is brought to room temperature for three hours, and then the reaction mixture is washed with a saturated NaHCO3 solution. After drying of the organic phase, filtration and concentration under reduced pressure, the resulting residue is crystallised from hexane, enabling the expected product to be isolated by filtration.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Cl.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1>CCO>[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:5]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)=[CH:15][CH:14]=1
Reactant: C1CNCCNC1
Reactant: ClCc1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)Cl
Product: c1cc(CN2CCCNCC2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
A solution of acetyl chloride (6.34 mL, 0.084 mol, 4 equiv) dissolved in anhydrous EtOH (50 mL) was stirred for 0.5 h and added to a solution of homopiperazine (10.4 g, 0.1 mol, 5 equiv) in EtOH (250 mL). The reaction mixture was heated to reflux for 1 h, cooled to 25° C. and a solution of 4-picolyl chloride hydrochloride 93.44 g, 0.021 mol) in EtOH (40 mL) was added. The reaction mixture was heated to reflux for 16 h, cooled to 25° C. and the solvent was removed under vacuum. The residue was diluted with CH2Cl2 (300 mL) and was washed with 2N KOH (1×300 mL). The aqueous layer was extracted with CH2Cl2 (1×300 mL) and the organic phase was washed with 2N KOH (150 mL), dried (MgSO4) and concentrated. Chromatography (SiO2, 5% H2O-5% NH4OH—1PrOH) afforded the desired product (2.88 g, 4.01 g theoretical, 72%) as a yellow oil. TLC Rf 0.45 (5% H2O-5% NH4OH—1PrOH): 1H NMR (CDCl3, 300 MHz) δ 8.77 (d, J=5.9 Hz, 2H), 7.53 (d, J=5.7 Hz, 2H), 3.91 (s, 2H), 3,19 (m, 4H), 2.92 (m, 4H), 2.04 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]([CH2:8][O:9]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:4]1=[O:36])[CH3:2]>C(#N)C.C(O)=O>[CH2:1]([N:3]1[CH:7]([CH2:8][OH:9])[CH2:6][CH:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:4]1=[O:36])[CH3:2]
Reactant: CCN1C(=O)C(Cc2ccccc2)CC1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: O=CO
Product: CCN1C(=O)C(Cc2ccccc2)CC1CO
Reaction time: 3 h
Yield: 66.2 %

Procedure:
1-Ethyl-3-(phenylmethyl)-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (0.561 g, 1.1 mmol) was stirred for 24 hrs at room temperature in a mixture of acetonitrile (21 ml) and formic acid (3 ml). The reaction was not complete at this stage so the solvent was evaporated and replaced with formic acid (10 ml) and stirring was continued for 3 hrs. Reaction was still not complete so the mixture was concentrated in vacuo (azeotroping with methanol to remove all of the formic acid) and then dissolved in methanol (20 ml). Amberlyst 15® was then added to the mixture and stirring was continued at room temperature overnight. The resin was filtered off, washing with more methanol, and the filtrate was concentrated to a gum (0.625 g). The gum was purified by automated flash silica-gel column chromatography (Biotage SP4), eluting with a 0-100% gradient of ethyl acetate in hexane, to give 1-ethyl-5-(hydroxymethyl)-3-(phenylmethyl)-2-pyrrolidinone (0.170 g) which was used in the next step.
Reaction SMILES: Br.Br.[NH:3]1[CH2:6][CH:5]([NH:7][C:8]2[C:13](=[O:14])[NH:12][CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[CH:16]=3)[CH:9]=2)[CH2:4]1.[C:23](O)(=[O:28])/[CH:24]=[CH:25]/[CH2:26][CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][NH:21][C:17]1[CH:16]=[C:15]([C:10]2[CH:9]=[C:8]([NH:7][CH:5]3[CH2:6][N:3]([C:23](=[O:28])/[CH:24]=[CH:25]/[CH2:26][CH3:27])[CH2:4]3)[C:13](=[O:14])[NH:12][CH:11]=2)[CH:20]=[CH:19][N:18]=1
Reactant: CNc1cc(-c2c[nH]c(=O)c(NC3CNC3)c2)ccn1
Reactant: CC/C=C/C(=O)O
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC/C=C/C(=O)N1CC(Nc2cc(-c3ccnc(NC)c3)c[nH]c2=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
To a solution of 5-(azetidin-3-ylamino)-2′-(methylamino)-[3,4′-bipyridin]-6(1H)-one di-hydrobromide (Example 14, Step 4, 80 mg, 0.19 mmol), in DMF (1 mL) was added (E)-pent-2-enoic acid (28 mg 0.28 mmol), HATU (105 mg, 0.277 mmol), and DIPEA (120 mg, 0.923 mmol). The reaction mixture was stirred at RT under nitrogen for 16 h. The residue was purified by Prep. HPLC to afford (E)-2′-(methylamino)-5-((1-(pent-2-enoyl)azetidin-3-yl)amino)-[3,4′-bipyridin]-6(1H)-one (34 mg, 42%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 12.02 (s, 1H), 8.10 (d, J=5.3 Hz, 1H), 7.11 (d, J=2.1 Hz, 1H), 6.97 (dt, J=15.3, 6.4 Hz, 1H), 6.62 (dd, J=5.3, 1.6 Hz, 1H), 6.38 (d, J=1.8 Hz, 2H), 5.85 (dt, J=15.3, 1.7 Hz, 1H), 5.48 (d, J=6.6 Hz, 1H), 4.80 (d, J=5.5 Hz, 1H), 4.60 (t, J=7.9 Hz, 1H), 4.55-4.46 (m, 1H), 4.33 (dt, J=12.5, 6.3 Hz, 1H), 4.07 (m, 2H), 2.97 (d, J=4.9 Hz, 3H), 2.22 (m, 2H), 1.06 (t, J=7.4 Hz, 3H); MS (ES) m/z 354 (M+H).
Reaction SMILES: CC([N:5]([C:9]([CH3:32])([CH3:31])[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[C:25]3[C:26]([CH3:30])([CH3:29])[CH2:27][O:28][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[N:17][CH:18]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:29][C:26]1([CH3:30])[C:25]2[C:20]([O:19][C:16]3[N:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[C:9]([CH3:32])([CH3:31])[NH2:5])=[CH:14][N:15]=3)=[CH:21][CH:22]=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CC1(C)COc2cccc(Oc3ncc(NC(=O)C(C)(C)N(C(=O)[O-])C(C)(C)C)cn3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(N)C(=O)Nc1cnc(Oc2cccc3c2C(C)(C)CO3)nc1
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of 1,1-dimethylethyl[2-({2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}amino)-1,1-dimethyl-2-oxoethyl]carbamate (Intermediate 142, 30 mg, 0.068 mmol) in dry Dichloromethane (DCM) (1.6 mL) at 0° C. TFA (0.4 ml, 5.19 mmol) was slowly added and the reaction mixture was stirred for 1 h at the same temperature. The solvent and the excess of TFA were evaporated end the residue was dissolved in DCM (5 ml) and an aqueous saturated solution of NaHCO3 was added while the pH was allowed to reach ˜8-9. Two phases were separated and the organic layer was dried (Na2SO4), filtered and evaporated affording the title compound (20 mg) as a white solid.
Reaction SMILES: [CH3:1]CN(C(C)C)C(C)C.[CH3:10][CH2:11][C@H:12]([C@H:14]([NH:59][C:60]([C@@H:62]1[N:67]([CH3:68])[CH2:66][CH2:65][CH2:64][CH2:63]1)=[O:61])[C:15]([N:17]([C@@H:26]([CH:56]([CH3:58])[CH3:57])[CH2:27][C@@H:28]([O:52][C:53]([CH3:55])=[O:54])[C:29]1[S:33][CH:32]=[C:31]([C:34]([NH:36][C@H:37]([CH2:46][C@@H:47]([C:49]([OH:51])=[O:50])[CH3:48])[CH2:38][C:39]2[CH:40]=[CH:41][C:42](O)=[CH:43][CH:44]=2)=[O:35])[N:30]=1)[CH2:18][O:19][C:20]([CH2:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[O:16])[CH3:13]>CN(C=O)C>[CH3:10][CH2:11][C@@H:12]([C@H:14]([NH:59][C:60]([C@@H:62]1[N:67]([CH3:68])[CH2:66][CH2:65][CH2:64][CH2:63]1)=[O:61])[C:15]([N:17]([C@@H:26]([CH:56]([CH3:58])[CH3:57])[CH2:27][C@@H:28]([O:52][C:53]([CH3:55])=[O:54])[C:29]1[S:33][CH:32]=[C:31]([C:34]([NH:36][C@H:37]([CH2:46][C@@H:47]([C:49]([OH:51])=[O:50])[CH3:48])[CH2:38][C:39]2[CH:44]=[CH:43][C:42]([CH3:1])=[CH:41][CH:40]=2)=[O:35])[N:30]=1)[CH2:18][O:19][C:20]([CH2:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[O:16])[CH3:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC[C@@H](C)[C@H](NC(=O)[C@H]1CCCCN1C)C(=O)N(COC(=O)CC(C)C)[C@H](C[C@@H](OC(C)=O)c1nc(C(=O)N[C@@H](Cc2ccc(O)cc2)C[C@H](C)C(=O)O)cs1)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H]1CCCCN1C)C(=O)N(COC(=O)CC(C)C)[C@H](C[C@@H](OC(C)=O)c1nc(C(=O)N[C@@H](Cc2ccc(C)cc2)C[C@H](C)C(=O)O)cs1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 136.4 %

Procedure:
To a solution of pyridine dithioethylamine hydrochloric salt (15.8 mg, 0.071 mmole) in anhydrous DMF (1.5 mL) was added DIEA (25 μL, 0.142 mmole) followed by a solution of tubulysin A (40 mg, 0.047 mmole) in anhydrous DMF (0.5 mL). The reaction mixture was stirred under argon at room temperature for 2 h. The mixture was then evaporated under vacuum. The crude product was purified by silica gel column chromatography (CH2Cl2/MeOH, 15/1) to afford white solid (54 mg) in quantitative yield.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:29][C:30](=O)[CH2:31][C:32]1[NH:33][N:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=1)C>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:30](=[O:29])[CH2:31][C:32]1[NH:33][N:34]=[C:35]([CH:37]([CH3:38])[CH3:39])[N:36]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1nc(C(C)C)n[nH]1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3nc(C(C)C)n[nH]3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Yield: 25 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclobutyloxy-4-methoxy-phenyl)-piperazine and (5-isopropyl-2H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester with heating for 10 h to afford the title compound as tan solid (96 mg, 25%). LC/MS (Method B) 3.39 min, [M+1]+ 504.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:26])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[N+:23]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>O.C(O)C.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:26])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[NH2:23])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(N(C)c2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(N(C)c2ccc(OCc3ccccc3)cc2)c(N)c1
Temperature: 25 °C

Procedure:
A mixture of the product from Example 133B (129.4 mg, 0.3714 mmol), iron powder (128 mg, 2.284 mmol), ammonium chloride (130 mg, 2.433 mmol) in water (1 mL) and ethanol (2 mL) was heated at 70° under a nitrogen atmosphere for 1 hour. The reaction was cooled to room temperature and vacuum filtered, washing the residue with methanol. The filtrate was concentrated under vacuum and azeotroped with toluene (50 mL). The residue was purified by silica gel flash chromatography using methylene chloride as eluent to provide the title compound as a waxy solid (85 mg, 72%).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]#[C:14][CH:15]([OH:18])[CH2:16][CH3:17])[O:4]1>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]#[C:14][C:15](=[O:18])[CH2:16][CH3:17])[O:4]1
Reactant: CCC(O)C#C[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@@H]21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCC(=O)C#C[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 0 °C
Reaction time: 3 h
Yield: 42.6 %

Procedure:
A solution of 1-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pent-1-yn-3-ol (1.3 g) in dichloromethane (100 ml) was added to a stirred suspension of manganese dioxide (60 g) in dichloromethane at 0° C. The mixture was stirred at 0° C. for 3 h, filtered through magnesium sulphate (50 g) and the solvent removed in vacuo to give the title compound as a colourless oil (550 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]>Cl>[F:13][C:12]([F:15])([F:14])[C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:16][C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19]([OH:21])=[O:20])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccccc1C(=O)O
Agent: Cl
Product: O=C(O)c1ccccc1Nc1ccnc2cc(C(F)(F)F)ccc12

Procedure:
4-Chloro-7-trifluoromethylquinoline and 2-amino benzoic acid are refluxed in dilute hydrochloric acid for 1 hour to give 2-(7-trifluoromethyl-4-quinolylamino)benzoic acid.
Reaction SMILES: N12CCN(CC1)CC2.Cl[C:10]1[C:11]2[S:21][CH:20]=[CH:19][C:12]=2[NH:13][C:14](=[O:18])[C:15]=1[C:16]#[N:17].[N:22]1([C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC(N(C)C)=O>[O:18]=[C:14]1[NH:13][C:12]2[CH:19]=[CH:20][S:21][C:11]=2[C:10]([N:25]2[CH2:26][CH2:27][N:22]([C:28]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)=[O:29])[CH2:23][CH2:24]2)=[C:15]1[C:16]#[N:17]
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: N#Cc1c(Cl)c2sccc2[nH]c1=O
Agent: C1CN2CCN1CC2
Solvent: CC(=O)N(C)C
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2sccc2[nH]c1=O
Temperature: 110 °C
Yield: 89.5 %

Procedure:
1,4-Diazabicyclo[2.2.2]octane (3.19 g, 28.48 mmol) was added to a solution of 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carbonitrile (26) (3.0 g, 14.24 mmol) and piperazin-1-yl-thiophene-2-yl-methanone (3.07 g, 15.60 mmol) in dry DMA. The solution was heated at 110° C. for 1 h. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried to yield 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-thieno[3,2-b]pyridine-6-carbonitrile (4.72 g, 89%) as white solids. MP 293° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.89 (m, 8H), 7.02 (d, J=5.6 Hz, 1H), 7.20 (dd, J=3.6, 5.2 Hz, 1H), 7.54 (dd, J=1.2, 3.6 Hz, 1H), 7.84 (dd, J=1.2, 5.2 Hz, 1H), 8.16 (d, J=5.2 Hz, 1H) ppm; MS m/z=371 amu (M++1).
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11](O)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:11]([O:18][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)COCc1ccccc1

Procedure:
71 ml of ethyl 4-chloro-3-oxobutyrate are reacted with 121.4 g of benzoic acid and 132 ml of triethylamine in 1 l of toluene by the procedure described in Example 4. After removal of the solvent by distillation, the residue is a virtually pure product.
Reaction SMILES: [NH2:1][NH2:2].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=3[CH:19]=2)=O)=[CH:9][CH:8]=1)([O:5][CH3:6])=[O:4].[OH-].[Na+]>C(O)C.O>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:1]=[N:2][C:16]([C:18]3[CH:27]=[CH:26][C:25]4[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=4[CH:19]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([O:5][CH3:6])=[O:4]
Reactant: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)nn2)cc1

Procedure:
0.3 g (10 millimoles) of 100% pure hydrazine were added dropwise at room temperature to a solution of 4.0 g (10 millimoles) of 1-(4-carbomethoxyphenyl)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-butane-1,4-dione (for preparation see Example 9) in 50 ml of ethanol. The reaction mixture was then refluxed for 20 minutes, cooled and then stirred into water, and the yellow crystals were filtered off under suction and dried in a stream of nitrogen. For aromatization of unoxidized dihydropyridazine, the crude product was stirred with periodic acid in ethanol until checking by thin layer chromatography showed that mainly a pure product was obtained. The product was then diluted with water, rendered basic with 2N sodium hydroxide solution and extracted with methylene chloride. The organic phase was washed with water, dried over magnesium sulfate and evaporated down. 3.1 g of the title compound remained as an oil; H-NMR (CF3COOH) : =8.82 and 8.88 ppm (in each case d, 2H, pyridazine-H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:9][C:8]=1[CH3:13]
Reactant: Cc1ccccc1Cl
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(=O)c1ccc(Cl)c(C)c1
Temperature: 130 °C

Procedure:
16 g of propionyl chloride are added dropwise to a mixture of 18 ml of o-chlorotoluene and 22.7 g of aluminum chloride and the reaction mixture is then heated at 130° C. for 3 hours. After cooling to RT, it is poured into a mixture of 100 ml of concentrated HCl and ice, extracted with ether, the organic phase is washed with saturated NaHCO3 solution and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is distilled off under reduced pressure to give 20.7 g of the expected product which crystallizes. B.p.=95° C. under 5 Pa.