Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][OH:28])=[CH:21][CH:20]=1.[OH-].[Li+]>C(O)(=O)C.C(=O)(O)[O-].[Na+].O>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][OH:28])=[CH:23][CH:24]=3)[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Reactant: Nc1ccc(CCCO)cc1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: OCCCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
4-Chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.090 g, 0.40 mmol) and 3-(4-aminophenyl)propan-1-ol (0.060 g, 0.40 mmol) were suspended in acetic acid (2 mL). The mixture was heated to 120° C. for 1 h. After this time, the reaction was cooled, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The mixture was concentrated, redissolved in methanol (5 mL), and lithium hydroxide (4 equiv) was added. The mixture stirred for 1 h, diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/ethyl acetate) to afford the title compound (0.061 g, 40%) as a white solid. MW=379.88. 1H NMR (DMSO-d6, 500 MHz) δ 8.83 (s, 1H), 8.28-8.21 (m, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.54-7.49 (m, 2H), 7.20 (d, J=8.5 Hz, 2H), 3.44 (t, J=6.5 Hz, 1H), 2.92-2.85 (m, 4H), 2.61 (t, J=7.5 Hz, 2H), 2.10 (quin, J=7.5 Hz, 2H), 1.76-1.74 (m, 2H); APCI MS m/z 380 [M+H]+.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].I[C:14]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[C:16]([CH3:35])[N:15]=1.[O:36]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:20][C:19]1[C:14]([C:46]2[CH:47]=[CH:48][C:43]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:44][CH:45]=2)=[N:15][C:16]([CH3:35])=[CH:17][CH:18]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccc(Oc4ccccc4)cc3)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 4-phenoxyphenylboronic acid (81 mg) under an argon atmosphere, and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (53 mg, yield 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH:22]1([CH2:27][C:28](O)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)C.CCCCCC.C(OCC)(=O)C>[CH:22]1([CH2:27][C:28]([NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C(O)CC1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CC1CCCC1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 14.8 %

Procedure:
Preparation of example 13 from the title compound of Example 7 (15 mg, 0.054 mmol), cyclopentyl-acetic acid (8 mg, 0.062 mmol), triethylamine (0.030 mL, 0.22 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) in dimethylformamide (1.0 mL) was carried out analogously to Example 11. Silica gel chromatography (1:1 ethyl acetate:hexane), also in an analogous manner, followed by diethyl ether trituration afforded the title compound (3 mg, 0.008 mmol) as a yellow powder in 14% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]2[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6]2)[CH2:4][CH:3]=1.CC1C=CC(C(C)=C)CC1>>[C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC1=CCC2CC1C2(C)C
Agent: C=C(C)C1C=CC(C)CC1
Product: CC1=CC=C(C(C)C)CC1
Yield: 82 %

Procedure:
The procedure of Example 1 is repeated, except that the α-pinene is substituted, on a weight-for-weight basis, with isolimonene or 2,8-p.menthadiene, to give, in a yield of 82%, a 2A grade resin having a Ring and Ball value of 95° C.
Reaction SMILES: [S:1]([Cl:4])(Cl)=[O:2].[Na+].[F:6][C:7]([F:14])=[CH:8][CH2:9][CH2:10]S([O-])=O>CCCCCC>[F:6][C:7]([F:14])=[CH:8][CH2:9][CH2:10][S:1]([Cl:4])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=S([O-])CCC=C(F)F
Agent: [Na+]
Solvent: CCCCCC
Product: O=S(Cl)CCC=C(F)F
Temperature: 25 °C

Procedure:
Thionyl chloride (200 ml) in dry n-hexane (400 ml) was stirred at ambient temperature and 4,4-difluorobut-3-enyl-sulfinic acid sodium salt ( 44 g) was added in portions. On complete addition the mixture was heated to reflux under nitrogen for 4.5 hours, cooled to ambient temperature then filtered. The filtrate was evaporated under reduced pressure to give a liquid which was distilled and the fraction collected at bp 50-60° C. at 0.1 mm Hg to yield
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8][CH:7]=1.N1CCCCC1.[I-:22].[CH3:23][N+:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]>CO>[I-:22].[CH3:23][N+:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]=[CH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([O:14][CH3:15])[O:2][CH3:1])=[CH:7][CH:8]=1
Reactant: COC(COc1ccc(C=O)cc1)OC
Reactant: Cc1cccc[n+]1C
Agent: [I-]
Solvent: C1CCNCC1
Solvent: CO
Product: COC(COc1ccc(C=Cc2cccc[n+]2C)cc1)OC

Procedure:
In 7 ml of methanol were dissolved 1.61 of N-methyl-α-picolinium iodide and 1.70 g of p-formylphenoxyacetaldehyde dimethyl acetal. The resultant mixture, after addition thereto of 0.3 ml of piperidine, was refluxed for four hours. When the reaction solution was cooled, there ensued precipitation of crystals. The crystals were recovered, washed with a small amount of cooled methanol and washed thoroughly with acetone. Thus, there was obtained 2.11 g of 1-methyl-2-{p-(2,2-dimethoxyethoxy)-styryl}-pyridinium iodide having a melting point of 192° to 197° C. By following the same procedure, but using the n-methyl-α-picolinium iodide in combination with m-formylphenoxyacetaldehyde dimethylacetal and n-methyl-γ-picolinium p-tolunesulfonate in combination with p-formylphenoxyacetaldehyde dimethylacetal, as the raw materials, there were respectively obtained 1-methyl-2-{m-(2,2-dimethoxyethoxyl)-styryl}-pyridinium iodide having a melting point of 181° to 186° C., 1-methyl-2-{o-(2,2-dimethoxyethoxy)-styryl}-pyridinium iodide having a melting point of 169° to 173° C., and 1-methyl-4-{p-(2,2-dimethoxyethoxy)-styryl}-pyridinium p-toluenesulfonate having a melting point of 219° to 226° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([SH:18])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([O:21][C:22](=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br)[CH3:20].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:19]([O:21][C:22](=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:18][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[CH3:20]
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCOC(=O)CCCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 73.3 %

Procedure:
To a solution of 7.57 g (0.03 mole) 4,5-diphenyl-2-imidazolethiol in 75 ml dimethylformamide was added, dropwise, 7.23 g (0.03 mole) ethyl-8-bromooctanoate in 25 ml dimethylformamide. The reaction mixture was stirred at reflux under nitrogen overnight. The cooled solution was poured into 5% sodium bicarbonate and ice and then extracted with ethyl acetate. The organic layer was backwashed with 5% sodium bicarbonate, water, and saturated sodium chloride solution, then dried over magnesium sulfate and the solvent was removed under vacuum. The residue was chromatographed using hexane:ethyl acetate (7:3). The resulting solid was recrystallized from ethanol and triturated with hexane to give 9.12 g (0.022 mole) of the title compound as a white solid, mp=77°-79° C. H1NMR(DMSO-d6): δ12.6(s,1H), 7.7-7.1(m,10H), 4.0(q,2H,J=8Hz), 3.1(t,2H,J=7Hz), 2.3(t,2H,J=17Hz), 1.8-1.1(m,13H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)=[C:2]=[O:3].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH:30][C@@H:31]3[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]3[NH2:37])[CH2:25]2)=[CH:20][CH:19]=1)([O-:17])=[O:16]>>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C@@H:31]3[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]3[NH:37][C:2]([NH:1][C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:6][CH:5]=3)=[O:3])[CH2:25]2)=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc([N+](=O)[O-])cc2)C1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ccc([N+](=O)[O-])cc2)C1
Yield: 38.3 %

Procedure:
1-((1R,2R)-2-((S)-1-(4-Nitrophenyl)piperidin-3-ylamino)cyclohexyl)-3-(4-(trifluoromethoxy)phenyl)urea was synthesized as described in General Procedure G, using 1-isocyanato-4-(trifluoromethoxy)benzene (15.31 mg, 0.075 mmol) and (1R,2R)—N1-(1-(4-nitrophenyl)piperidin-3-yl)cyclohexane-1,2-diamine (24 mg, 0.075 mmol) to give 15 mg (30% yield) of the title compound as a yellow solid. Anal. Calcd. for C25H30F3N5O4 m/z 521.5, found: 522.3 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.77 (d, J=8.80 Hz, 2H), 7.22 (d, J=8.80 Hz, 2H), 6.99 (d, J=8.25 Hz, 2H), 6.67 (d, J=8.80 Hz, 2H), 3.67 (br. s., 1H), 3.63-3.56 (m, 1H), 3.56-3.49 (m, 1H), 3.29 (br. s., 3H), 3.07-2.96 (m, 1H), 2.11-2.20 (m, 2H), 1.99-1.58 (m, 7H), 1.43 (d, J=12.65 Hz, 1H), 1.30-1.12 (m, 2H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][CH3:16])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1.[OH-].[Na+].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>CC(C)=O>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25]([NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][CH3:16])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)=[O:26]
Reactant: CCC(C(=O)O)c1ccc(CCN)cc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCC(C(=O)O)c1ccc(CCNC(=O)c2cc(Cl)ccc2OC)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
6.2 g 2-[4-(2-Aminoethyl)-phenyl]-butyric acid hydrochloride are suspended in 100 ml acetone. After the addition of 50 ml 2 N aqueous sodium hydroxide solution, a solution of 4.8 g 5-chloro-2-methoxybenzoyl chloride in 50 ml acetone is added dropwise thereto at ambient temperature and the reaction mixture then stirred for 2 hours at 50° C. After cooling, the reaction mixture is evaporated in a vacuum and the aqueous solution acidified with dilute hydrochloric acid. The 2-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-butyric acid obtained solidifies upon triturating with diisopropyl ether and is recrystallized from diisopropyl ether. The yield is 3.2 g (42.5% of theory); m.p. 120°-122° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:11][C:12]1[N:13]=[C:14]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:15]([C:22]2[CH:23]=[CH:24][C:25](=[O:31])[N:26]([CH:28]([CH3:30])[CH3:29])[N:27]=2)=[N:16][C:17]=1S(C)(=O)=O.Cl>CC(N(C)C)=O>[NH2:11][C:12]1[N:13]=[C:14]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:15]([C:22]2[CH:23]=[CH:24][C:25](=[O:31])[N:26]([CH:28]([CH3:30])[CH3:29])[N:27]=2)=[N:16][C:17]=1[O:10][C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1
Reactant: CC(C)n1nc(-c2nc(S(C)(=O)=O)c(N)nc2-c2ccccc2)ccc1=O
Reactant: Oc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)n1nc(-c2nc(Oc3ccc(F)cc3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 27.5 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a suspension of NaH (60% in oil suspension) (31.1 mg) in DMA (0.6 ml) was added 4-fluorophenol (87.3 mg) and the mixture was stirred at 25-30° C. for 30 minutes. 6-[5-Amino-6-(methylsulfonyl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (150 mg) was added and the mixture was heated at 100-105° C. for 15 hours. After addition of 0.1N HCl (3 ml), an aqueous layer was removed by decantation to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give a solid. The solid was crystallized from a mixture of acetone and n-hexane to give 6-[5-amino-6-(4-fluorophenoxy)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (70 mg)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=2[CH2:22][N:23]([C:33]([O:35][CH3:36])=[O:34])[C@@H:24]([CH3:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=1)[CH3:2]>[Pd].CCO>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[CH2:22][N:23]([C:33]([O:35][CH3:36])=[O:34])[C@@H:24]([CH3:32])[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc([N+](=O)[O-])cc2CN(C(=O)OC)[C@@H](C)Cc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1cccc(Oc2ccc(N)cc2CN(C(=O)OC)[C@@H](C)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[3-(2-{[Methoxycarbonyl-((S)-1-methyl-2-phenyl-ethyl)-amino]-methyl}-4-nitro-phenoxy)-phenyl]-acetic acid ethyl ester (0.174 g, 0.34 mmol) and palladium on carbon (10%; 0.060 g) were combined in EtOH (20 mL) and stirred under H2 in a Parr apparatus overnight at room temperature. Once no starting material was seen by analytical LCMS, the mixture was filtered through Celite, and the filter cake was washed with EtOH. The filtrate was concentrated to give the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH:13]=[CH:14][C:15]=1[F:16])#[N:9].O.N>>[F:16][C:15]1[CH:14]=[CH:13][C:12]([N:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[CH:11][C:10]=1[C:8]#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(F)c(C#N)c2)CC1
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(N2CCNCC2)ccc1F
Temperature: 25 °C
Yield: 101.2 %

Procedure:
Trifluoroacetic acid was added to 500 mg of t-butyl 4-(3-cyano-4-fluorophenyl)-1-piperazinecarboxylate (compound in Production Example 354) and stirred at room temperature for several hours. After the reaction solution was cooled on ice, ammonia water was added thereto and stirred, the aqueous layer was extracted with dichloromethane, and all the organic layer was combined, dried and concentrated to give 340 mg of the title compound.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)=[N:10][C:5]2=[N:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:31]([Sn](CCCC)(CCCC)C=C)[CH2:32]CC>[N+](CC)(CC)(CC)CC.[Cl-].C1COCC1.O.ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:19]1([C:8]2[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)=[N:10][C:5]3[N:6]([C:2]([CH:31]=[CH2:32])=[CH:3][N:4]=3)[CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=Cc1ccc(-c2nc3ncc(Br)n3cc2-c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cnc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn12
Temperature: 110 °C

Procedure:
500 mg 4-(3-bromo-6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde, 180 mg K2CO3, 215 mg Et4NCl, 25 mg PdCl2(PPh3)2 and 620 mg tributyl(vinyl)stannane were suspended in 10 mL THF. The mixture was heated to 110° C. for 45 min. This mixture was worked up by diluting with water and extraction with dichloromethane. The organic layers were dried over Na2SO4 and concentrated to yield the crude product, which was purified by chromatography on silica gel (ethyl acetate/dichloromethane).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH:15]=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:21]3[CH:20]=[N:19][C:18]([CH3:17])=[CH:23][CH:22]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH:15]=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C=O)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(C=O)C1

Procedure:
The title compound is prepared from a mixture of 3,4-dihydro-8-methyl-1H-pyrido[4,3-b]indole-2(5H)-carbaldehyde, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11](O)=[C:10]([N+:15]([O-:17])=[O:16])[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([Cl:21])=[C:10]([N+:15]([O-:17])=[O:16])[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c([N+](=O)[O-])c(O)ccn1Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=c1c([N+](=O)[O-])c(Cl)ccn1Cc1ccccc1
Temperature: 25 °C
Yield: 36.9 %

Procedure:
A suspension of 1-benzyl-4-hydroxy-3-nitro-1H-pyridine-2-one (3.30 g, 13.4 mmol) in POCl3 (30.8 g, 201 mmol) was heated at for 1 h. After cooling to room temperature, the solvent was evaporated under reduced pressure, and water was carefully added to the chilled residue. The mixture was neutralized with 2 N NaOH, extracted with CHCl3, washed with brine, dried with MgSO4, and concentrated under reduced pressure. The resulting solid was rinsed with Et2O to give 1-benzyl-4-chloro-3-nitro-1H-pyridin-2-one (1.31 g, 37% yield). 1H-NMR (CDCl3): δ 7.36 (m, 6H), 6.29 (d, 1H, J=7.6 Hz), 5.16 (s, 2H). MS: calculated for C12H9ClN2O3+H 265.0; found: 265.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.ClS([N:15]=[C:16]=O)(=O)=O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]#[N:15])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: N#Cc1c[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To 6-bromo-1H-indole (41.36 g, 211.0 mmol) in DMF (150 mL) at −78° C. was added chlorosulfonyl isocyanate (20 mL, 225 mmol). After complete addition, the mixture was allowed to warm to room temperature and stirred for 2 hrs. The reaction mixture was poured into ice (500 mL) and stirred for 30 minutes. The precipitate was collected on a filter and dried in a vacuum oven to give 6-bromo-1H-indole-3-carbonitrile as a light-beige solid (46.73 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]Br)[CH:10]=2)[NH:5][C:4](=[O:18])[CH:3]=1.[SH:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH:10]=2)[NH:5][C:4](=[O:18])[CH:3]=1
Reactant: Cc1cc(=O)[nH]c2ccc(OCCCCBr)cc12
Reactant: Sc1ccc2ccccc2n1
Product: Cc1cc(=O)[nH]c2ccc(OCCCCSc3ccc4ccccc4n3)cc12

Procedure:
Prepared analogous to Example 122 from 4-methyl-6-(4-bromo-butoxy)-carbostyril and 2-mercapto-quinoline.
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:16]([Si:18]([CH3:21])([CH3:20])[CH3:19])#[CH:17].N1CCCCC1>[Cu]I>[CH3:19][Si:18]([C:16]#[C:17][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1)([CH3:21])[CH3:20]
Reactant: Ic1ccc(OCCN2CCCC2)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: C1CCNCC1
Product: C[Si](C)(C)C#Cc1ccc(OCCN2CCCC2)cc1
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere and while cooling with ice a reaction mixture of 1.5 g (4.72 mmol) 1-[2-(4-iodo-phenoxy)-ethyl]-pyrrolidine, 0.735 ml (5.2 mmol) ethynyl-trimethyl-silane, 15 mL piperidine, 115.5 mg (0.1 mmol) tetrakis-triphenylphosphane-palladium and 19 mg (0.1 mmol) CuI is stirred for 1 h. Then the reaction mixture is evaporated down, the residue is taken up in 20 mL water and extracted with EtOAc. The organic phase is dried over Na2SO4. The purification is carried out by column chromatography on silica gel (EtOAc/MeOH/NH3 95:5:0.5).
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([O:8][CH2:9][C:10]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:12]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[N:11]=1)([CH3:7])[CH3:6])C.[Li+].[OH-].Cl>C1COCC1.O>[Cl:33][C:27]1[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:26]=1[N:12]1[C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=2)=[C:14]([CH3:15])[C:10]([CH2:9][O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:34])=[O:3])=[N:11]1
Reactant: CCOC(=O)C(C)(C)OCc1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(C(F)(F)F)cc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(COC(C)(C)C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 735 mg of 2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionic acid ethyl ester in 5 ml THF was added a solution of 51 mg of LiOH in 1 ml water at room temperature. After 5 h the mixture was brought to pH 2 by addition of 1 M hydrochloric acid. The reaction mixture was concentrated under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was used in the next reaction step. Yield: 677 mg.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[C:4]=1[NH:5][CH2:6][C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[CH3:2].[Cl:19][CH2:20][C:21](Cl)=[O:22].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:19][CH2:20][C:21]([N:5]([CH2:6][C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[C:4]1[C:13]([CH2:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:3]=1[CH2:1][CH3:2])=[O:22]
Reactant: C=CCOC(=O)CNc1c(CC)cccc1CC
Reactant: O=C(Cl)CCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCOC(=O)CN(C(=O)CCl)c1c(CC)cccc1CC
Reaction time: 2 h

Procedure:
24.7 Grams of allyl 2,6-diethylanilinoacetate and 11.3 g of monochloroacetic acid chloride were dissolved in 100 ml of benzene, 11.0 g of triethylamine was then added dropwise thereto with stirring maintaining the reaction temperature at 10°-20° C., and, thereafter, stirring was continued for further 2 hours at a room temperature. The reaction solution was washed with successive, 5% sodium hydroxide aqueous solution, 5% hydrochloric acid aqueous solution, and water. Then, the benzene layer was dried over anhydrous sodium sulfate. Thereafter, benzene was removed under reduced pressure to obtain the end product, allyl N-chloroacetyl-2,6-diethylanilinoacetate. nD21.5 : 1.5288.