Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].[C:14]([O:17][CH2:18][CH:19]([O:25][CH2:26]Cl)[CH2:20][O:21][C:22](=[O:24])[CH3:23])(=[O:16])[CH3:15].C(Cl)(Cl)Cl>CN(C)C=O.O.CO>[C:22]([O:21][CH2:20][CH:19]([O:25][CH2:26][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[Cl:11])[CH2:18][O:17][C:14](=[O:16])[CH3:15])(=[O:24])[CH3:23]
Reactant: CC(=O)OCC(COC(C)=O)OCCl
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)OCC(COC(C)=O)OCn1cnc2c(Cl)nc(N)nc21
Yield: 7.2 %

Procedure:
A suspension of 1.44 g (8.53 mmoles) of 2-amino-6-chloropurine in 34 ml of anhydrous dimethylformamide under a nitrogen blanket was treated with 203 mg (8.53 mmoles, 340 mg of 60% dispersion in mineral oil) of sodium hydride. After twenty minutes the reaction mixture became a solution and 1.92 g (8.53 mmoles) of chloromethyl 1,3-diacetoxy-2-propyl ether in about 7 ml of anhydrous dimethylformamide was added. The reaction was monitored by t.1.c. on silica in a 90:10:1 (CHCl3 :CH3OH:H2O) system to observe disappearance of the side chain precursor. After about two hours the reaction mixture was filtered and concentrated to a cloudy oil in vacuo. The oily product had solidified upon standing and was triturated with ether. The product was isolated by filtration, washed with ether then water, again with ether, and finally dried in vacuo over P2O5 yielding 1.4 g of product. An additional 220 mg of product was obtained by filtration after the ether washes were concentrated to a small volume.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]=[C:26]([CH3:37])[C:27]=1[O:28][CH2:29][C@@H:30]1[CH2:34][O:33]C(C)(C)[O:31]1)[C:21]([NH:23]O)=[NH:22]>>[Cl:17][C:18]1[CH:19]=[C:20]([C:21]2[N:23]=[C:9]([C:8]3[CH:12]=[C:13]([O:15][CH3:16])[N:14]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:7]=3)[O:11][N:22]=2)[CH:25]=[C:26]([CH3:37])[C:27]=1[O:28][CH2:29][C@@H:30]([OH:31])[CH2:34][OH:33]
Reactant: Cc1cc(C(=N)NO)cc(Cl)c1OC[C@@H]1COC(C)(C)O1
Reactant: COc1cc(C(=O)O)cc(C2CCCC2)n1
Product: COc1cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CO)c(Cl)c3)no2)cc(C2CCCC2)n1

Procedure:
The title compound is prepared in analogy to Example 1 starting from 2-cyclopentyl-6-methoxy-isonicotinic acid and (R)-3-chloro-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-5-methyl-benzamidine; LC-MS**: tR=0.89 min, [M+H]+=460.18; 1H NMR (CDCl3): δ 1.72-1.80 (m, 2H), 1.84-1.95 (m, 4H), 2.03 (t br, J=5.8 Hz, 1H), 2.07-2.16 (m, 2H), 2.45 (s, 3H), 2.80 (d br, J=5.0 Hz, 1H), 3.20-3.29 (m, 1H), 3.83-3.93 (m, 2H), 4.02 (s, 3H), 4.11-4.14 (m, 2H), 4.15-4.21 (m, 1H), 7.30 (d, J=1.0 Hz, 1H), 7.50 (d, J=0.8 Hz, 1H), 7.95 (d, J=1.8 Hz, 1H), 8.09 (d, J=1.8 Hz, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[NH:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[CH2:6][C:5]=2[C:4](=O)[CH2:3]1.Cl.[NH2:24][NH2:25].C(N(CC)CC)C>C(O)C>[CH3:1][CH:2]1[CH2:11][C:10]2[N:9]=[N:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[CH:6][C:5]=2[C:4](=[N:24][NH2:25])[CH2:3]1
Reactant: CC1CC(=O)C2=C(C1)NN=C(c1cccc(C(F)(F)F)c1)C2
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1CC(=NN)c2cc(-c3cccc(C(F)(F)F)c3)nnc2C1
Temperature: 25 °C
Yield: 12.4 %

Procedure:
To an ethanol solution (3 mL) of 7-methyl-3-(3-trifluoromethylphenyl)-4,6,7,8-terahydro-1H-cinnolin-5-one (230 mg, 0.74 mmol) obtained in Example 65 were added hydrazine hydrochloride (77.3 mg, 0.74 mmol) and triethylamine (0.206 mL, 1.48 mmol) and stirred at room temperature over night. The reaction liquid was concentrated, followed by purification of residue with silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain an objective compound (29.5 mg, 12.5%).
Reaction SMILES: C(N1CCC(C2C=CC=CC=2)CC1)(=O)C.C(Cl)(=O)CC.[Cl-].[Cl-].[Cl-].[Al+3].[C:25]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40](=O)[CH2:41][CH3:42])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][CH3:42])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)(=[O:27])[CH3:26]
Reactant: CCC(=O)c1ccc(C2CCN(C(C)=O)CC2)cc1
Agent: CC(=O)N1CCC(c2ccccc2)CC1
Agent: CCC(=O)Cl
Agent: [Al+3]
Product: CCCc1ccc(C2CCN(C(C)=O)CC2)cc1

Procedure:
The starting material can be produced, for example, by reaction of 18 g of N-acetyl-4-phenyl-piperidine and 11.5 g of propionic acid chloride, in the presence of aluminium trichloride, to N-acetyl-4-(4-propionylphenyl)-piperidine and then catalytic hydrogenation thereof to give N-acetyl-4-(4-n-propylphenyl)-piperidine, b.p.0.03 =160°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: OB(O)c1cccc(F)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: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1cccc(F)c1
Yield: 73.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 3-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.051 g (74%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-2-carboxamide as a white solid.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:32][CH2:33][CH3:34])[C:13]2[C:22]3[CH:21]=[C:20]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:30])[C:14]=2[N:31]=1)[CH3:8]>ClCCl>[NH2:30][C:15]1[C:14]2[N:31]=[C:11]([CH2:10][O:9][CH2:7][CH3:8])[N:12]([CH2:32][CH2:33][CH3:34])[C:13]=2[C:22]2[CH:21]=[C:20]([O:23][CH:24]3[CH2:25][CH2:26][N:27]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:28][CH2:29]3)[CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CC(C)N=C=O
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(OC4CCNCC4)cc3c21
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OC4CCN(C(=O)NC(C)C)CC4)cc3c21
Yield: 83.5 %

Procedure:
Isopropyl isocyanate (0.190 mL, 1.90 mmol) was added dropwise to a solution of 2-(ethoxymethyl)-8-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 411, 0.730 g, 1.90 mmol) in dichloromethane (15 mL) at room temperature. The reaction was diluted with dichloromethane and stirred vigorously. A precipitate formed that was isolated by filtration to afford 0.743 g of 4-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}-N-isopropylpiperidine-1-carboxamide as a white solid, mp 236.5-239° C.
Reaction SMILES: [C:1]([CH2:5][C:6](Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:9]1([C:12]2[N:16]3[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]3=[N:14][C:13]=2[NH2:22])[CH2:11][CH2:10]1.N1C=CC=CC=1>C(#N)C>[CH:9]1([C:12]2[N:16]3[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]3=[N:14][C:13]=2[NH:22][C:6](=[O:7])[CH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10]1
Reactant: Nc1nc2ccc(F)cn2c1C1CC1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)CC(=O)Nc1nc2ccc(F)cn2c1C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl acetyl chloride (0.040 mL, 0.00029 mol) was added to a solution of 3-Cyclopropyl-6-fluoro-imidazo[1,2-a]pyridin-2-ylamine (compound f, 0.054 g, 0.00027 mol) in acetonitrile (5.00 mL) containing pyridine (0.0637 g, 0.00081 mol) and the mixture stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and crude product purified by column chromatography (50% ethyl acetate/hexanes to neat ethyl acetate) to give N-(3-cyclopropyl-6-fluoro-imidazo[1,2-a]pyridin-2-yl)-3,3-dimethyl-butyramide as a yellow solid. Rf 0.41, 5% methanol/dichloromethane; MS m/z 289 (M+H). SH-SY5Y_EC50 (μM): 2.5464.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[CH2:10]([OH:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-].[Na+]>CS(C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N+:3]=1[O-:9]
Reactant: [O-][n+]1c(Cl)cccc1Cl
Reactant: CCCCCCCCO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCCOc1cccc(Cl)[n+]1[O-]

Procedure:
The 0.82 g (0.0050 moles) of 2,6-dichloropyridine N-oxide and 0.658 g (99%) (0.0050 moles) of 1-octanol was reacted with 0.200 g (0.0050 moles) of ground sodium hydroxide in 8.2 ml of DMSO at 80° C. for 4.5 hours to give 2-chloro-6-octyloxypyridine N-oxide. It was reacted with 0.600 g (0.015 moles) of ground sodium hydroxide at 80° C. for 2.5 hours to give 1-hydroxy-6-octyoxypyridine-2(1H)-one. After cooling, it was added 74 ml of water and was adjusted with 6N HCL to pH 3. The precipitate was filtered and washed with water to give 0.577 g (48%). It was recrystallized from ethanol and hexanes: mp 119°-120° C.
Reaction SMILES: C[O:2][C:3](=[O:40])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:39])[NH:27][CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH2:31][C:32](=[O:38])[NH:33]3)=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[O:38]=[C:32]1[CH2:31][C:30]2[C:34](=[CH:35][CH:36]=[CH:37][C:29]=2[CH2:28][NH:27][C:26]([C:19]2[S:18][C:17]([C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[O:8])[C:3]([OH:40])=[O:2])=[O:16])=[C:21]([C:22]([F:25])([F:24])[F:23])[CH:20]=2)=[O:39])[NH:33]1
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc3c2CC(=O)N3)cc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1Cc2c(CNC(=O)c3cc(C(F)(F)F)c(C(=O)N[C@@H](CNC(=O)c4cccs4)C(=O)O)s3)cccc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (S)-2-({5-[(2-oxo-2,3-dihydro-1H-indol-4-ylmethyl)-carbamoyl]-3-trifluoromethyl-thiophene-2-carbonyl}-amino)-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (53 mg, 0.089 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (37 mg, 0.89 mmol) in water (6 mL). The mixture was then stirred at room temperature 5 h. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 0.0466 g (90%). MS m/e 581.0 (M+H+).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]2[N:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:3][CH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:16][CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-c2ccccc2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: ClCc1ccc(-c2ccccc2)nc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Thionyl chloride (10 ml) was slowly added to a solution of 6-phenyl-3-pyridylmethanol (11.60 g) in toluene (100 ml) at room temperature, which was stirred at 100° C. for 1 hour. After cooling, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated to obtain 5-chloromethyl-2-phenylpyridine (11.49 g, yield 89%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 95–96° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:42]3[CH2:43][CH2:44][CH:39]([CH3:38])[CH2:40][CH2:41]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CC1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CC1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 4-methylpiperidine according to conditions described in general procedure C. Mp: 117-118° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.84-0.94 (m, 5 H), 1.49-1.52 (m, 3 H), 2.67 (t, J=12.0 Hz, 2 H), 3.25 (m, 4 H), 3.73 (m, 4 H), 4.30 (s, 2 H), 6.19-6.20 (m, 1 H), 7.03-7.06 (m, 1 H), 7.27 (d, J=8.4 Hz, 1 H), 7.41-7.63 (m, 5 H), 7.83-7.85 (m, 1 H), 7.98-8.01 (m, 1 H), 8.25-8.27 (m, 1 H), 10.47 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.N1C=CC=CC=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(O)(=O)C>O1CCCC1>[NH2:1][C:2]1[C:7]([NH:8][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Nc1ccc(Cl)nc1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1nc(Cl)ccc1NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
1.2 g (8.8 mmol) of 2,3-diamino-6-chloro-pyridine are dissolved in 20 ml tetrahydrofuran and, after the addition of 2 ml pyridine at 0° C., mixed with 2 ml of benzyl chloroformate. After heating to ambient temperature the mixture is combined with ice water, adjusted to pH 4 with glacial acetic acid and extracted with ethyl acetate. The combined organic extracts are dried and evaporated down. The residue is chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (9:1 and 1:1).
Reaction SMILES: [N:1]1([C:6]2[CH:23]=[CH:22][C:9]([C:10]([C:12]3[C:13]([C:18](OC)=[O:19])=[N:14][CH:15]=[CH:16][CH:17]=3)=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:25][NH2:26]>CCO>[N:1]1([C:6]2[CH:23]=[CH:22][C:9]([C:10]3[C:12]4[CH:17]=[CH:16][CH:15]=[N:14][C:13]=4[C:18](=[O:19])[NH:25][N:26]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ncccc1C(=O)c1ccc(-n2ccnc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2ccc(-n3ccnc3)cc2)c2cccnc12

Procedure:
A mixture of 3-[4-(1H-imidazol-1-yl)benzoyl]-2-carbomethoxypyridine (1.21 g, 3.94 mmol) in 50 mL of EtOH is treated with 0.22 g (4.33 mmol) of hydrazine monohydrate and heated to reflux for 1 day. The white solid which precipitates from the reaction mixture is filtered and recrystallized from DMF-H2O to give 5-[4-(1H-imidazol-1-yl)phenyl]-8-oxo-7,8-dihydropyrido[2,3-d]pyridazine. M.P. 359°-361° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][S:9]([CH3:11])=[O:10])[CH:7]=1.[N-:12]=[N+]=[N-].[Na+].OS(O)(=O)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][S:9](=[NH:12])([CH3:11])=[O:10])[CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)Cc1cncc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=N)(=O)Cc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49.4 %

Procedure:
3-Bromo-5-methanesulfinylmethyl-pyridine (3.0 g, 13 mmol) is dissolved in chloroform (100 mL) and the solution is cooled to 0° C. Sodium azide (1.3 g, 21 mmol) is added and the reaction mixture is stirred for 5 minutes. Then concentrated H2SO4 (10 mL) is slowly added at 0° C. and then the mixture is heated up to 50° C. for 16 hrs. After cooling down to room temperature, ice cold water is added and the mixture is extracted with CH2Cl2. The aqueous layer is separated, basified with saturated Na2CO3 solution and extracted with more CH2Cl2. Organic layers are combined, dried over anhydrous Na2SO4 and concentrated to give the crude product. Purification by flash column chromatography affords 1.6 g of 3-bromo-5-[imino(methyl)oxo-λ6-sulfanyl]methyl-pyridine.
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:13][O-].[Na+]>CO>[CH3:13][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:1][OH:12]
Reactant: C[O-]
Reactant: CCCCCCCCCCCO
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCC(C)CO

Procedure:
Another synthesis starts from n-undecanol, which is reacted with methanol in the presence of sodium methylate. 2-methyl-undecanol is formed, which is then dehydrogenated to form the aldehyde. (Chemical Abstracts Vol. 74 [1971], 12552 X.)
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])[NH:6][C:7]=1[CH3:8].Br[C:19]1[S:20][C:21]([C:24]([NH2:26])=[O:25])=[CH:22][N:23]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:19]3[S:20][C:21]([C:24]([NH2:26])=[O:25])=[CH:22][N:23]=3)[CH2:16][CH2:17]2)=[O:10])[NH:6][C:7]=1[CH3:8]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br
Reactant: NC(=O)c1cnc(Br)s1
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncc(C(N)=O)s3)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Example 123 by coupling 4-bromo-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 57) with 2-bromo-1,3-thiazole-5-carboxamide (J. Am. Chem. Soc. 1952, 74, 5799).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[O:16][C:15](=O)[CH:14]=1>ClC1C=CC=CC=1Cl>[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:1]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[C:15](=[O:16])[CH:14]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: COC(=O)c1cccc(N)c1
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1cccc(-n2c(C)cc(O)cc2=O)c1
Temperature: 165 °C
Yield: 15.7 %

Procedure:
Methyl 3-aminobenzoate (75.00 g, 496.13 mmol) and 4-hydroxy-6-methyl-2-pyrone (62.57 g, 496.13 mmol) were suspended in 1,2-dichlorobenzene (150 mL) and heated to 165° C. for 15 minutes. The reaction was cooled to room temperature and extracted with 0.54M K2CO3 (4×250 mL). The aqueous layers were acidified (pH 2) with 4N HCl. The precipitate was collected by filtration to afford a yellow-orange solid (20.24 g, 16%). The resulting filtrate was extracted with ethyl acetate (3×1 L). The organic layers were washed with brine (500 mL), dried over MgSO4 and evaporated. The resulting solid was washed with hot H2O to afford a yellow-orange solid (3.84 g, 3%). The two solids were then combined. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (dt, J=1.31, 7.79 Hz, 1H), 7.69 (app t, J=1.78 Hz, 1H), 7.62 (t, J=7.78 Hz, 1H) 7.49 (ddd, J=1.07, 1.07, 7.85 Hz, 1H), 5.89 (dd, J=087, 2.48 Hz, 1H), 5.55 (app d, J=0.94 Hz, 1H), 3.83 (s, 3H), 1.80 (s, 3H). ES-HRMS m/z 260.0895 (M+H C14H13NO4 requires 260.0917).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16](=[O:32])[C:17](=[O:31])[N:18]3[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][Li]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([OH:32])([CH3:33])[C:17](=[O:31])[N:18]3[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [Li]C
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2C(=O)C(=O)N3Cc2cccc(F)c2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2C(C)(O)C(=O)N3Cc2cccc(F)c2)CC1
Temperature: -78 °C

Procedure:
4-[1-(3-Fluoro-benzyl)-2,3-dioxo-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (330 mg) was dissolved in 4 mL of THF and cooled to −78° C. before adding 1.6 M methyl lithium in hexaness (800 uL). The solution was stirred and warmed to room temperature, then stirred for an hour at room temperature. The reaction was quenched by addition of water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography afforded 315 mg of 4-[1-(3-fluoro-benzyl)-3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester. MS: 356 (M−Boc+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([F:21])([F:20])[F:9])[N:7]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccnc(-c2ccccc2C(F)(F)F)n1
Temperature: 110 °C

Procedure:
Under an atmosphere of argon, 250 mg (1.95 mmol) of 2-chloro-4-methylpyrimidine and 583 mg (2.92 mmol) of 2-(trifluoromethyl)phenylboronic acid were dissolved in 8 ml of toluene. 89 mg (0.10 mmol) of tris(dibenzylideneacetone)dipalladium, 77 mg (0.19 mmol) of 2-dicyclohexyl-phosphino-2′-(N,N-dimethylamino)biphenyl and 826 mg (3.89 mmol) of potassium phosphate were then added, and under argon the mixture was heated at 110° C. for 20 h. For work-up, the mixture was diluted at RT with 15 ml of ethyl acetate and 15 ml of water, the organic phase was separated off and the aqueous phase extracted two more times with in each case 15 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1, then 4:1). This gave 249 mg (54% of theory) of the target compound in a purity of 87%.