Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.Cl.[CH2:22]([N:24]([CH2:33][CH3:34])[CH2:25][CH2:26][CH2:27][C:28](=O)[C:29]([OH:31])=[O:30])[CH3:23]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:28]([C:29]([OH:31])=[O:30])[CH2:27][CH2:26][CH2:25][N:24]([CH2:33][CH3:34])[CH2:22][CH3:23])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CCN(CC)CCCC(=O)C(=O)O
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Agent: Cl
Solvent: CO
Product: CCN(CC)CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(=O)O
Reaction time: 2 h

Procedure:
To a stirred solution of 2.85 g. (0.01 mole) of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 100 ml. of methanol is added 2.24 g. (0.01 mole) of 5-(diethylamino)-2-oxo-valeric acid, hydrochloride [prepared by the method of Libman and Kutznetsov J. Gen. Chem. (USSR), 33, 1938 (1963)]. The mixture is kept under nitrogen at ambient temperature for 2 hours and then concentrated in vacuo. The residue is mixed with aqueous sodium bicarbonate and extracted with methylene chloride. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue of 7-chloro-2-[[1-carboxy-4-(diethylamino)-butylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine is used without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]([Br:16])=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:44][C@H:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@@H:46]1[OH:51].C(N(CC)CC)C>ClCCl.CN(C=O)C>[NH2:2][C:3]1[C:12]([C:13]([NH:44][C@H:45]2[CH2:50][CH2:49][CH2:48][CH2:47][C@@H:46]2[OH:51])=[O:15])=[CH:11][C:10]([Br:16])=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2
Reactant: Nc1c(C(=O)O)cc(Br)c2cnccc12
Reactant: N[C@H]1CCCC[C@@H]1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1c(C(=O)N[C@H]2CCCC[C@@H]2O)cc(Br)c2cnccc12
Reaction time: 3 h

Procedure:
To a solution of 5-amino-8-bromoisoquinoline-6-carboxylic acid hydrochloride (1.00 g, 3.29 mmol) in 10 mL of dichloromethane and 2 mL of DMF was added (1H-1,2,3-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (1.65 g, 3.74 mmol), (1S,2S)-2-aminocyclohexanol (0.430 g, 3.74 mmol), and triethylamine (1.20 mL, 8.62 mmol). After 3 h, the mixture was diluted with additional dichloromethane, washed with water, saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-3% methanol in dichloromethane, to provide crude 5-amino-8-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]isoquinoline-6-carboxamide.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N-:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1.CCN(CC)CC.N1C=CC=CC=1.Cl.CS(C)=[O:34]>C(Cl)Cl>[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:34])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)=[O:1]
Reactant: OCc1ccccc1[N-]Cc1cccc(O)c1
Reactant: CS(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1ccccc1NC(=O)c1cccc(O)c1

Procedure:
To a solution of N-(2-hydroxymethylphenyl)-3-hydroxybenzyl amide (6.5 g, 26.7 mmol) in CH2Cl2 (120 ml) at 0° C. was added NEt3 (13.0 ml, 93.4 mmol) and pyridine.SO3 complex (12.7 g, 80.1 mmol ) in DMSO, 50 mL) and the solution was stirred 4 h at 25° C. The reaction was poured into ice and 10% HCl, and the layers were partitioned. The aqueous layer was washed 2× with CH2Cl2. All CH2Cl2 layers were combined and washed with H2O, saturated NaHCO3, brine, and dried (MgSO4). The solution was filtered and concentrated in vacuo to obtain the crude product which was purified on SiO2 gel using hexane/EtOAc 7/3 to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:50]=[CH:49][C:37]([C:38]([NH:40][CH:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH3:48])[CH2:43][CH2:42]2)=[O:39])=[CH:36][C:35]=1[O:51][CH3:52]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:50]=[CH:49][C:37]([C:38]([NH:40][CH:41]5[CH2:42][CH2:43][N:44]([CH2:47][CH3:48])[CH2:45][CH2:46]5)=[O:39])=[CH:36][C:35]=4[O:51][CH3:52])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Reactant: CCN1CCC(NC(=O)c2ccc(N)c(OC)c2)CC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCC3)CC(F)(F)C(=O)N4C)c(OC)c2)CC1
Yield: 41.6 %

Procedure:
A mixture of 0.0605 g (0.20 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0571 g (0.30 mmole) of toluenesulfonic acid monohydrate, 0.0555 g (0.20 mmole) of 4-amino-N-(1-ethyl-piperidin-4-yl)-3-methoxy-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 25 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (90:10:1) and then recrystallization from acetonitrile to give 0.0452 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethyl-piperidin-4-yl)-3-methoxy-benzamide (I-10) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=[CH2:32].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC#N>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:32]=[CH:31][C:30]([O:34][CH3:35])=[O:33])[CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1cccnc1
Temperature: 100 °C
Yield: 97 %

Procedure:
A mixture of 3-bromopyridine (4.82 mL, 0.05 mol), palladium acetate (0.22 g, 0.02 equiv.), tri-(o-tolyl)phosphine (0.61 g, 0.04 equiv.), methyl acrylate (9.01 mL, 2 equiv.), triethylamine (12.5 mL) and CH3CN (25 mL) was sealed in a bomb and heated to 100° C. for 3.5 hours. The mixture was cooled in an ice-bath, the bomb was vented and the reaction mixture was concentrated in vacuo. The residue was extracted with 0.5N HCl/Et2O (3×), the organic layer was backwashed with additional 0.5N HCl and the aqueous layers were combined, basified with saturated NaHCO3 and extracted with ether. The ether layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 7.89 g (97%) of methyl 3-(3-pyridyl)-2-propenoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]([CH2:33][CH3:34])[CH:23]2[CH2:32][CH2:31][C:26]3(OCC[O:27]3)[CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].O.CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:22]([CH2:33][CH3:34])[CH:23]2[CH2:24][CH2:25][C:26](=[O:27])[CH2:31][CH2:32]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8]
Reactant: CCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCC(=O)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a stirred solution of 5-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(1,4-dioxaspiro[4.5]decan-8-yl)amino)-2-methylbenzamide (2.0 g, 4.1 mmol) in acetone: water (14 mL+6 mL) was added PTSA (3.1 g, 16 mmol). The resulting reaction mixture was stirred at 70° C. overnight. On completion, the solvent was removed under reduced pressure and the residue was basified with aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water, dried, concentrated under reduced pressure to give the title compound (1.5 g, 83%) which was used directly in the next step.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6](=O)[C:7](F)(F)F)=O.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22].O1C=CC=C1>C(Cl)Cl>[O:5]1[CH:6]=[CH:7][CH:2]=[C:3]1[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][Br:14])=[O:22]
Reactant: O=C(O)CCCCCCBr
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccoc1
Solvent: ClCCl
Product: O=C(CCCCCCBr)c1ccco1
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
A solution of 135 mmol of trifluoroacetic anhydride in 50 ml of dry methylene chloride was added to a stirred solution of 130 mmol of 7-bromoheptanoic acid in 200 ml of dry methylene chloride. After 15 minutes, a solution of 390 mmol of furan in 25 ml of dry methylene chloride was added in a steady stream to the reaction mixture, and the resultant mixture stirred at 25° C. for 2.0 hrs. The methylene chloride and trifluoroacetic acid were removed by evaporation in vacuo. The residue was dissolved in ether, washed with water and distilled in vacuo to afford the title compound, bp 114° (0.01 mm Hg), 89.7% yield.
Reaction SMILES: Cl.[F:2][C:3]([F:32])([F:31])[C:4]1[CH:5]=[C:6]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:7]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)=[O:8].[N+:33]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Cl)=[CH:38][CH:37]=1)([O-:35])=[O:34].C(N(CC)CC)C>O1CCCC1>[F:30][C:27]([F:29])([F:28])[C:25]1[CH:24]=[C:6]([CH:5]=[C:4]([C:3]([F:2])([F:31])[F:32])[CH:26]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:40][C:39]2[CH:42]=[CH:43][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=2)[CH2:11][C@H:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)=[O:8]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2ccc([N+](=O)[O-])cc2)C[C@H]1Cc1ccc(Cl)c(Cl)c1
Yield: 71.4 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)piperazine hydrochloride (200 mg), 4-nitrobenzyl chloride (158 mg) and triethylamine (268 μl) in tetrahydrofuran (5 ml) was refluxed overnight. After cooling, the precipitates were filtered off and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of toluene and ethyl acetate as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-(4-nitrobenzyl)piperazine (169.8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.O([Si](C)(C)C)[K:21]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:13][NH:14][CH2:15][C:16]([F:17])([F:18])[F:19])[C:9]([O-:11])=[O:10])=[CH:6][CH:7]=1.[K+:21]
Reactant: C[Si](C)(C)O[K]
Reactant: COC(=O)C(CNCC(F)(F)F)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C([O-])C(CNCC(F)(F)F)c1ccc(Cl)cc1
Product: [K+]
Reaction time: 18 h
Yield: 117.6 %

Procedure:
A solution of methyl 2-(4-chlorophenyl)-3-(2,2,2-trifluoroethylamino)propanoate (235 mg, 0.795 mmol) in THF (3.0 mL) was treated with KOTMS (153 mg, 1.19 mmol) at room temperature. The reaction was allowed to stir 18 hours to completion, and the mixture was diluted with ether. The resulting precipitate was isolated by filtration and placed under high vacuum for two hours to afford the potassium 2-(4-chlorophenyl)-3-(2,2,2-trifluoroethylamino)propanoate (299 mg, 118%, excess salts) as a white solid. LCMS (APCI+) m/z 282.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:13]=[C:12]3[N:14]([CH3:26])[C:15](=[O:25])[N:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])[CH2:17][C:11]3=[CH:10][N:9]=2)[CH2:3][CH2:2]1.Br[CH2:28][CH2:29][OH:30].C(N(CC)CC)C>C1(C)C=CC=CC=1.CN1C(=O)N(C)CCC1>[OH:30][CH2:29][CH2:28][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:13]=[C:12]3[N:14]([CH3:26])[C:15](=[O:25])[N:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])[CH2:17][C:11]3=[CH:10][N:9]=2)[CH2:3][CH2:2]1
Reactant: OCCBr
Reactant: Cc1ccccc1N1Cc2cnc(NC3CCNCC3)nc2N(C)C1=O
Solvent: CCN(CC)CC
Solvent: CN1CCCN(C)C1=O
Solvent: Cc1ccccc1
Product: Cc1ccccc1N1Cc2cnc(NC3CCN(CCO)CC3)nc2N(C)C1=O
Temperature: 100 °C
Yield: 62.2 %

Procedure:
A mixture of 7-(piperidin-4-ylamino)-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.1 g, 0.284 mmol) (prepared as described in Example 25), 2-bromoethanol (0.024 mL, 0.34 mmol), and triethylamine (0.047 mL, 0.34 mmol) in 10 mL of toluene and 1.5 mL of DMPU was heated at 100° C. for 17 hours. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 40:10:2 ethyl acetate/methanol/isopropylamine as eluant to give 70 mg (52%) of 7-[1-(2-hydroxyethyl)piperidin-4-ylamino]-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][Si](C(C)(C)C)(C)C)=[C:6](Br)[C:5]([CH3:17])=[CH:4][C:3]=1O.[CH:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][O:32][CH3:33])[CH:25]=O)([CH3:21])[CH3:20].C(O)(C(F)(F)F)=O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:25][C:24]2[CH:27]=[CH:28][C:29]([O:30][CH2:31][O:32][CH3:33])=[C:22]([CH:19]([CH3:21])[CH3:20])[CH:23]=2)[C:5]([CH3:17])=[CH:6][C:7]=1[OH:8]
Reactant: Cc1cc(O)c(C)c(O[Si](C)(C)C(C)(C)C)c1Br
Reactant: COCOc1ccc(C=O)cc1C(C)C
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COCOc1ccc(Cc2cc(C)c(O)cc2C)cc1C(C)C

Procedure:
Intermediate 2,5-dimethyl-4-(3′-iso-propyl-4′-methoxymethoxybenzyl)phenol was prepared from 2,5-dimethyl-4-bromo-t-butyldimethylsilyloxyphenol, and 3-iso-propyl-4-methoxymethoxybenzaldehyde according to the procedure described in (G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607) and transformed into the title compound by the procedure used for the synthesis of compound 7-13, step b followed by example 7, step b, (0.14 g, 90%); 1H NMR (300 MHz, CD3OD): δ 6.88 (d, J=8.7 Hz, 2H), 6.79 (s, 1 H), 6.64-6.72 (m, 2 H), 4.20 (d, J=10.2 Hz, 2 H), 3.80 (s, 2 H), 3.10-3.15 (m, 1 H), 2.22 (s, 3 H), 2.20 (s, 3 H), 1.17 (d, J=6.9 Hz, 6 H); LC-MS m/z 365 [C20H25O6P+H]+; HPLC conditions: ODSAQ AQ-303-5 column; mobile phase=CH3OH: 0.05% TFA (7:3) flow rate=1.0 mL/min; detection=UV@254 nm retention time in min: 10.96; Anal Calcd for (C20H25O6P+0.3H2O): C, 61.84; H, 6.92. Found: C, 61.60; H, 6.72.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=1.[F:13][C:14]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[C:16]([F:26])[C:15]=1B(O)O>>[F:26][C:16]1[CH:17]=[C:18]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[CH:19]=[C:14]([F:13])[C:15]=1[C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=1
Reactant: OB(O)c1c(F)cc(N2CCOCC2)cc1F
Reactant: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Product: NC(=O)c1cc(-c2c(F)cc(N3CCOCC3)cc2F)sc1[N+](=O)[O-]

Procedure:
The title compound was prepared as described in Intermediate 10 Step 5 using 5-bromo-2-nitrothiophene-3-carboxamide (Intermediate 10 Step 4) (582 mg, 2.32 mmol) and (2,6-difluoro-4-morpholin-4-ylphenyl)boronic acid (TFA salt) (830 mg, 2.33 mmol) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:16]1N=NC(N)=[C:18](C2C=CC=CC=2)[CH:17]=1.ClCC(=O)C>O1CCCC1.O>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:5]2[N:6]([CH:16]=[C:17]([CH3:18])[N:8]=2)[N:7]=1
Reactant: Nc1nnc(Cl)cc1-c1ccccc1
Reactant: Nc1cc(-c2ccccc2)c(Cl)nn1
Agent: CC(=O)CCl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cn2nc(Cl)c(-c3ccccc3)cc2n1

Procedure:
The mixture of 6-chloro-5-phenyl-pyridazin-3-yl-amine and 6-Chloro-4-phenyl-pyridazin-3-yl-amine (intermediate example Int-1-0, step 3, 65 g=316 mmol) in 65 mL tetrahydrofurane and 650 mL water was heated with 74.5 g (800 mmol) chloroacetone in analogy to the synthesis of the intermediate example Int-1-0, step 4, for 18 hours at reflux. After the usual work up and purification of the residue by chromatography (Biotage Isolera, Kronlab 8 cm, eluents: dichloromethane/methanol) and subsequent crystallization (methyl-tert.butylether/hexane) 11.69 g (30.4%) of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[F:20])[CH:11]2[CH3:21])=[N:4][C:5]([Cl:9])=[N:6][C:7]=1[CH3:8].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[ClH:9].[CH3:1][C:2]1[C:3]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[F:20])[CH:11]2[CH3:21])=[N:4][C:5]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(Cl)nc(N2CCc3c(F)cccc3C2C)c1C
Reactant: Nc1ccccc1
Product: Cc1nc(Nc2ccccc2)nc(N2CCc3c(F)cccc3C2C)c1C
Product: Cl
Yield: 62.3 %

Procedure:
The same procedures as in Step 2 of Example 3 above were repeated using 5,6-dimethyl-2-chloro-4-(1-methyl-5-fluoro-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (0.1 g, 0.33 mmol) prepared in Step 1 of Example 27 and aniline (0.84 mmol) to afford 82 mg (59.6%) of the titled compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].CN(C)C=O.[CH2:25](I)[CH2:26][CH3:27]>O1CCCC1>[CH2:25]([N:8]1[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9]1)[CH2:26][CH3:27]
Reactant: CCCI
Reactant: c1cc(-c2n[nH]c(-c3ccncc3)n2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCn1nc(-c2ccncc2)nc1-c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3,5-bis(4-pyridyl)-1,2,4-triazole (4.4 g., 0.02 mole) in dry tetrahydrofuran (200 ml.) is added 57% sodium hydride in mineral oil (1 g. 0.024 mole) and the mixture is heated 45 minutes at reflux. The suspension is concentrated to a solid, N,N-dimethylformamide (70 ml.) and n-propyl iodide (0.022 mole) are added. The mixture is stirred 0.5 hour at ambient temperature followed by heating on the steam bath for 4 hours. The solution is concentrated to a gum, water is added and the material solidifies. Following recrystallization from methylcyclohexane there is obtained 1-n-propyl-3,5-bis(4-pyridyl)-1,2,4-triazole, m.p. 88°-89° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([O:13][CH3:14])=[CH:6][C:5]=1[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1>C1COCC1.CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:3][C:4]1[C:5]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:22][CH2:23][N:24]([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:25][CH2:26]3)[CH2:17][CH2:16]2)=[CH:6][C:7]([O:13][CH3:14])=[C:8]([CH:9]=1)[NH2:10]
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(C)cc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(C)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
Sodium borohydride (0.30 g, 7.93 mmol) was added in portions to a stirring suspension of 1-{1-[2-methyl-5-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine (1.09 g, 2.64 mmol) and Nickel(II)chloride hexahydrate (0.19 g, 0.8 mmol) in THF (10 mL) and MeOH (20 mL) at rt. The reaction mixture was allowed to stir at rt for 2 h and then it was concentrated in vacuo. The residue was taken up in DCM and passed through a bed of celite. The resultant filtrate was then concentrated onto silica gel and purified by flash chromatography to afford 5-methyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (0.58 g, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.55 (s, 1H), 6.43 (s, 1H), 4.30 (s, 2H), 3.70 (s, 3H), 3.05-3.15 (m, 4H), 2.89-2.96 (m, 2H), 2.86 (s, 3H), 2.52-2.65 (m, 6H), 2.26-2.41 (m, 1H), 2.06 (s, 3H), 1.74-1.85 (m, 2H), 1.43-1.63 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:16]1N=NC(N)=C(C2C=CC=CC=2)[CH:17]=1.C(OC(OCC)CCl)C>O.C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:5]2[N:6]([CH:16]=[CH:17][N:8]=2)[N:7]=1
Reactant: Nc1cc(-c2ccccc2)c(Cl)nn1
Reactant: Nc1nnc(Cl)cc1-c1ccccc1
Agent: CCOC(CCl)OCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1nn2ccnc2cc1-c1ccccc1
Reaction time: 6 h
Yield: 30.1 %

Procedure:
The mixture of 6-chloro-5-phenyl-pyridazin-3-yl-amine and 6-chloro-4-phenyl-pyridazin-3-yl-amine (20.2 g=0.1 mol) was suspended in 300 mL water and 30 mL THF. After addition of 32 mL (0.51 mol) chloracetaldehyde diethylacetal the reaction mixture was heated for five hours at reflux. Additional 32 mL (0.51 mol) chloracetaldehyde diethylacetal were added and heating was continued for another six hours. The reaction mixture was diluted with ethyl acetate and extracted three times. The organic phase was dried (sodium sulfate), filtrated and the solvent was removed. The residue was purified by chromatography (Biotage, eluents: ethyl acetate/hexane). 6.8 g (30.1%) of the title compound, 6-chloro-7-phenyl-imidazo[1,2-b]pyridazine, and 6.4 g (28.4%) of the regioisomer, 6-chloro-8-phenyl-imidazo[1,2-b]pyridazine, were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[O:5][C:6]1[C:7]2[S:28][CH:27]=[CH:26][C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:11]=1.[Cl:32]/[CH:33]=[CH:34]\[C:35](O)=[O:36].Cl.CN(C)CCCN=C=NCC.C(Cl)(Cl)Cl>N1C=CC=CC=1.CC(O)C>[Cl:32]/[CH:33]=[CH:34]\[C:35]([NH:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:4]([O:5][C:6]2[C:7]3[S:28][CH:27]=[CH:26][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)=[CH:17][CH:18]=3)[N:11]=2)[CH:3]=1)=[O:36]
Reactant: O=C(O)/C=C\Cl
Reactant: CN1CCN(c2ccc(Nc3nc(Oc4cccc(N)c4)c4sccc4n3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2ccc(Nc3nc(Oc4cccc(NC(=O)/C=C\Cl)c4)c4sccc4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
The compound (50 mg, 0.12 mmol) obtained in Step 5 of Example 1 was dissolved in pyridine (1.5 mL), and cis-3-chloroacrylic acid (18 mg, 0.17 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloric acid salt (44 mg, 0.23 mmol) were added thereto, followed by stirring at room temperature for 1 hour. After the reaction was complete, the reaction mixture was dilluted with a mixed solvent (chloroform:2-propanol=3:1 (volume ratio)) and washed with sat. brine. The organic layer was dried with anhydrous sodium sulfate and then filtered and distilled under a reduced pressure. The residue was separated by column chromatography (dichloromethane: methanol=6:1 (volume ratio)) to obtain the title compound (yield: 15 mg, 24%).