Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([SH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18].C(OCC)C>CS(C)=O>[C:1]12([S:11][C:19]3[CH:20]=[CH:21][CH:22]=[C:15]([Br:14])[C:16]=3[C:17]#[N:18])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: SC12CC3CC(CC(C3)C1)C2
Reactant: N#Cc1c(F)cccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#Cc1c(Br)cccc1SC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1-Adamantanethiol (278 mg) was dissolved in dimethyl sulfoxide (10 mL). Sodium hydride (60% in mineral oil, 42 mg) was added, and the solution was stirred at room temperature for 20 minutes. 2-Bromo-6-fluorobenzonitrile (300 mg) was added and the solution was heated to 130° C. for 1 hour. The solution was cooled, added to diethyl ether, washed with 1 M aqueous HCl three times, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under vacuum to yield the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1>C(#N)C>[S:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:11][CH2:12]1
Reactant: C1CSCCN1
Reactant: N#Cc1ccc(F)cc1
Solvent: CC#N
Product: N#Cc1ccc(N2CCSCC2)cc1
Temperature: 100 °C
Reaction time: 40 h
Yield: 53.3 %

Procedure:
4-fluorobenzonitrile (500 mg, 4.13 mmol) and thiomorpholine (1.18 ml, 12.4 mmol) was dissolved in acetonitrile (2 ml) and stirred at 100° C. for 40 hours. The reaction was cooled, evaporated and purified by flash chromatography using pet.ether/EtOAc (4:1) as eluent to give 450 mg (53%) of the title compound as pale solids.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:17]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:26])C=1.[OH-].[Ca+2].[OH-]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:26])[C:7]=2[CH:17]=1)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1C=C2
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)S(=O)c1ccccc1C=C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 G. 3-cyanodibenzo[b,f]thiepin (0.021 mole) are dissolved in 300 cc. methylene chloride and 3.45 g. m-chloroperbenzoic acid (0.020 mole) are added in portions. The solution is stirred for two hours at room temperature, then excess calcium hydroxide is added. The mixture is stirred for a few minutes and filtered through celite, the filtrate is evaporated down and the residue chromatographed on silica gel, eluting with a 50:50 mixture of chloroform and benzene. A small amount of starting material is recovered, and the yield of sulfoxide is 4.92 g. (92%), light yellow solid, m.p. 220° C.-222° C.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[C:19]([NH:37][NH2:38])=[N:20][C:21]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[C:22]([Cl:30])[C:23]=1[O:24][CH2:25][C:26]([F:29])([F:28])[F:27]>C(O)(=O)C>[Cl:17][C:18]1[C:19]([N:37]=[N:38][C:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[OH:16])=[N:20][C:21]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[C:22]([Cl:30])[C:23]=1[O:24][CH2:25][C:26]([F:27])([F:28])[F:29]
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Reactant: NNc1nc(OCC(F)(F)F)c(Cl)c(OCC(F)(F)F)c1Cl
Solvent: CC(=O)O
Product: Oc1c(N=Nc2nc(OCC(F)(F)F)c(Cl)c(OCC(F)(F)F)c2Cl)c2ccccc2c2ccccc12
Temperature: 105 °C

Procedure:
Next, a reaction flask was loaded with acetic acid (30 ml) and 9,10-phenanthrenequinone (1.25 g), and the temperature was raised to 105° C. with stirring to dissolve 9,10-phenanthrenequinone. To this mixture, 3,5-dichloro-2-hydrazino-4,6-bis(2,2,2-trifluoroethoxy)pyridine (2.5 g) was added in 15 minutes. After stirring at 100 to 105° C. for two hours, the heating was stopped and the reaction mixture was left to cool and filtrated. The filtrated crystals were stirred for 30 minutes in methanol (100 ml), and then filtrated and dried to give intended crystals (2.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:16]([O-])=O)=[CH:4][C:5]([Cl:15])=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[CH2:13][OH:14])[CH:7]=1>CO.C1COCC1.[Pt]>[NH2:16][C:3]1[C:2]([NH2:1])=[CH:7][C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[CH2:13][OH:14])=[C:5]([Cl:15])[CH:4]=1
Reactant: Nc1cc(N2CCC[C@@H]2CO)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(Cl)c(N2CCC[C@@H]2CO)cc1N

Procedure:
The sub-title compound was prepared from (R)-1-(5-amino-2-chloro-4-nitro-phenyl)-2-hydroxymethyl-pyrrolidine (220 mg, 0.8 mmol) and Pt/C (50 mg) in MeOH (6 mL) and THF (6 mL) in analogy to example 1 step (f).
Reaction SMILES: Br[C:2]1[C:3](C2C=CC=CC=2)=[N:4][NH:5][CH:6]=1.C1C=C[C:16](/[CH:19]=[CH:20]/[C:21](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:17][CH:18]=1.C1C=C[C:34](/[CH:37]=[CH:38]/[C:39](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd:67].[Pd].Cl.C1COCC1>O>[CH2:2]([C:3]1[N:4]([C:48]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:42]2[CH:34]=[CH:37][CH:38]=[C:39]([OH:40])[CH:41]=2)[N:5]=[C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:23]=1[C:21]1[CH:18]=[CH:17][CH:16]=[CH:19][CH:20]=1)[CH3:6].[Pd:67]
Reactant: Brc1c[nH]nc1-c1ccccc1
Reactant: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(-c2ccccc2)c(-c2ccccc2)nn1-c1ccccc1-c1cccc(O)c1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
The reaction of Example 1 (reaction scale: 10 mmol of bromophenyl pyrazole) was conducted with 0.5 mole % of Pd2(dba)3. After the reaction was judged to be essentially complete, 5N aqueous HCl (1.25 mL/g of bromophenyl pyrazole starting material) was added followed by THF (12.5 mL/g) and water (2.5 mL/g). The mixture was heated to 50° C. to dissolve the precipitates, then cooled to 25° C. and filtered twice through a Darco zeta pad. To the filtrate was added TMT (5 mol %). The mixture was stirred at ambient temperature for 14 h and filtered again four times through the same Darco zeta pad employed in the previous filtration. The THF was removed by evaporation, and water (2.5 mL/g) and ethanol (2.5 mL/g) were added to precipitate the product, affording 2′-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)-[1,1′]-biphenyl-3-ol containing 146 ppm of palladium.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[C:42]3[C:38]([CH2:39][C:40](=[O:44])[NH:41]3)=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.CS(C)=O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:35]2[CH:43]=[C:42]3[C:38]([CH2:39][C:40](=[O:44])[NH:41]3)=[CH:37][CH:36]=2)[CH:3]=1)=[O:15]
Reactant: CC1(C)OB(c2ccc3c(c2)NC(=O)C3)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4c(c3)NC(=O)C4)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-indol-2-one (63.1 mg, 0.243 mmol), DMSO (1.5 mL), sodium carbonate (0.281 mL, 0.562 mmol), and bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol). The final product was collected as 10 mg (11%). LCMS E-S (M+H)=471.1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (d, J=6.8 Hz, 6H), 2.13 (s, 3H), 2.22 (s, 3H), 3.58 (s, 2H), 4.41 (d, J=4.8 Hz, 2H), 5.31 (quin, J=6.6 Hz, 1H), 5.91 (s, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.73 (d, J=1.0 Hz, 1H), 7.87 (dd, J=7.8, 1.5 Hz, 1H), 8.12 (s, 1H), 8.37 (s, 1H), 9.00 (t, J=4.8 Hz, 1H), 10.55 (s, 1H), 11.58 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6]([O:8]C)=O.[S:19]1[C:23]([C:24]2[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:26][CH:25]=2)=[CH:22][C:21]2[CH:38]=[CH:39][CH:40]=[CH:41][C:20]1=2>>[N:31]1([CH2:30][CH2:29][O:28][C:27]2[CH:36]=[CH:37][C:24]([C:23]3[S:19][C:20]4[CH:41]=[CH:40][CH:39]=[CH:38][C:21]=4[C:22]=3[C:6]([C:5]3[CH:10]=[CH:11][C:12]([CH2:13][N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:8])=[CH:25][CH:26]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: c1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1
Reactant: COC(=O)c1ccc(CN2CCCC2)c(OC)c1
Product: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)ccc1CN1CCCC1
Yield: 51 %

Procedure:
By essentially following the procedure used to prepare Example 137, Part C, the title compound was prepared from methyl 3-methoxy-4-[(1-pyrrolidinyl)methyl]benzoate (Part B) and 1-[2-[4-(benzo[b]thiophen-2-yl)phenoxy]ethyl]pyrrolidine (Example 4, Part A) in 51% yield as a yellow foam. The flash chromatography was carried out by eluting with a gradient of EtOAc(100-90%)/Et3N(0-5%)/MeOH(0-5%).
Reaction SMILES: [C-:1]#[N:2].[Na+].[F:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[CH:7](Cl)[CH3:8]>CS(C)=O>[F:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[CH:7]([C:1]#[N:2])[CH3:8]
Reactant: CC(Cl)c1ccccc1F
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C#N)c1ccccc1F
Temperature: 90 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
In 300 ml of dimethyl sulfoxide was dissolved 35 g of sodium cyanide by heating at 90° C., and 45 g of 2-fluoro-α-methylbenzyl chloride was added. The mixture was stirred at 90° C. for 4 hours, and then cooled. Ice-water was added and the mixture was extracted with n-hexane. The n-hexane layer was washed with water and dried over anhydrous magnesium sulfate and the solvent was evaporated off. The residue obtained was purified by distillation under reduced pressure to afford 36 g of 2-fluoro-α-methylbenzyl cyanide, b.p.0.5 55° C.
Reaction SMILES: [C:1]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16][O:17]S(C)(=O)=O)=[CH:9][CH:8]=1)([O:3][CH2:4][CH3:5])=[O:2].[C:34]1(O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:4]([O:3][C:1]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH2:16][O:17][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:11][CH:12]=1)=[O:2])[CH3:5]
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(I)cc2)cc1
Reactant: Oc1ccccc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2ccccc2)NS(=O)(=O)c2ccc(I)cc2)cc1
Yield: 63.4 %

Procedure:
The procedure described in Example 125 was repeated, except that (RS)-N-(4-(carbethoxymethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (400 mg) was reacted with phenol (123 mg) to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-phenoxypropanamide (252.62 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19](O)=[O:20])[CH2:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([N:24]1[CH:28]=[C:27]([CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)[CH:26]=[N:25]1)[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]([N:30]([CH2:29][C:27]1[CH:26]=[N:25][N:24]([CH2:22][CH3:23])[CH:28]=1)[C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:38])[CH3:39])=[CH:33][CH:32]=1)=[O:20])[CH2:14][CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2cc(OCc3ccccc3)ccc21
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCn1cc(CN(C(=O)C2CCCc3cc(OCc4ccccc4)ccc32)c2ccc(C(C)C)cc2)cn1
Yield: 64.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 4 using 6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.49 g) as starting materials, 6-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.65 g) was obtained. melting point: 122-124° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[I:12]N1C(=O)CCC1=O>C1COCC1.[Cl-].[Na+].O>[NH2:1][C:2]1[S:3][C:4]([I:12])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1csc(N)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1nc(N)sc1I
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A solution of 14.53 g of 2-amino-4-ethoxycarbonylthiazole in 200 ml of THF was cooled in ice under an argon atmosphere, 20.0 g of N-iodosuccinimide was added to the cooled solution, and the mixture was stirred at the same temperature for 1.5 hr. Brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1 to 1:2) to give 21.12 g of 2-amino-4-ethoxycarbonyl-5-iodothiazole.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:27]([CH3:30])([CH3:29])[CH3:28])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:26])[C:12]1[CH:17]=[C:16]([C:18]#[C:19][Si](C)(C)C)[CH:15]=[CH:14][C:13]=1[O:24][CH3:25])[CH2:2][CH2:3][CH3:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[CH2:1]([C:5]1=[CH:6][N:7]([C:27]([CH3:28])([CH3:30])[CH3:29])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:26])[C:12]1[CH:17]=[C:16]([C:18]#[CH:19])[CH:15]=[CH:14][C:13]=1[O:24][CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(C#C[Si](C)(C)C)ccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(OC)c(C(=O)/N=c2\sn(C(C)(C)C)cc2CCCC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
The product from Example 62A (300 mg, 0.68 mmol) in THF (10 mL) was treated with TBAF (1M) (1.7 mL, 1.7 mmol), stirred at rt for 1 hr, diluted with H2O and extracted with EtOAc (2×). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 183 mg (73%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 0.98 (t, J=7.36 Hz, 3H) 1.36-1.50 (m, 2H) 1.65 (s, 9H) 1.67-1.77 (m, 2H) 2.83 (dd, J=7.98 Hz, 2H) 2.99 (s, 1H) 3.94 (s, 3H) 6.93 (d, J=8.59 Hz, 1H) 7.52 (dd, J=8.59, 2.15 Hz, 1H) 7.93 (s, 1H) 8.28 (d, J=2.15 Hz, 1H); MS (DCI/NH4+) m/z 371 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Cc1cc(Cl)nc(N2CCCCC2)n1
Product: COc1cc(Nc2cc(C)nc(N3CCCCC3)n2)ccc1-n1cnc(C)c1
Yield: 79 %

Procedure:
The title compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.30 mmol) and 4-chloro-6-methyl-2-piperidin-1-yl-pyrimidine (70 mg, 0.33 mmol, example 97a) in analogous manner as described in example 90. The crude product was purified by stirring with diethyl ether. It was obtained in 79% yield as a grey solid. MS ISP (m/e): 379.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.29 (s, 1H), 7.88 (s, 1H), 7.65 (s, 1H), 7.22 (d, 1H), 7.04 (d, 1H), 7.03 (s, 1H), 5.89 (s, 1H), 3.80 (s, 3H), 3.74 (m, 4H), 2.15 (s, 3H), 2.14 (s, 3H), 1.60 (m, 2H), 1.50 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14]CC)=[O:13])=[CH:8][NH:9]2)=[CH:4][C:3]=1[O:18][CH3:19].[OH-].[Na+].Cl>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([OH:14])=[O:13])=[CH:8][NH:9]2)=[CH:4][C:3]=1[O:18][CH3:19]
Reactant: CCOC(=O)c1c[nH]c2cc(F)c(OC)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(=O)c(C(=O)O)c[nH]c2cc1F
Yield: 13.7 %

Procedure:
Ethyl 7-fluoro-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (409 mg, 1.54 mmol) was suspended in a solution of NaOH (3.55 mL of 4% w/v, 3.55 mmol) and the reaction was stirred under reflux for 2 h. After cooling, the reaction mixture was acidified with conc. HCl. The resulting precipitated was collected via filtration, washed with water and dried to yield 7-fluoro-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (50 mg, 14%). LC/MS: m/z 238.3 (M+H)+ at 0.95 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: O=[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[NH:3]1.P(Cl)(Cl)([Cl:14])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:14][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1[nH]c(=O)ccc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 1 h
Yield: 182.2 %

Procedure:
A mixture of 2-oxo-5-nitro-6-methyl-1,2-dihydropyridine (38.95 g, 253 mmol), phosphorous oxychloride (12.3 mL, 130 mmol), and phosphorous pentachloride (27.9 g, 134 mmol) was heated at 110° C. for 2 hours, whereupon the reaction mixture was charged with an additional portion of phosphorous pentachloride and phosphorous oxychloride (9.9 g and 4.8 mL, respectively). The reaction was stirred 1 hour, then poured into ice-water (600 mL). The brown solid was filtered and washed with cold water, to give 40.88 g of the title compound (94%). MS(m/e): 173 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:27]2[CH2:28][CH2:29][CH:24]([C:22](=[O:23])[C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=3)[CH2:25][CH2:26]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Product: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Yield: 98.7 %

Procedure:
Using 4-bromo-2-methylsulfonylbenzoic acid (2.8 g) and (4-chlorophenyl)piperidin-4-ylmethanone (2.6 g) and by the reaction and treatment in the same manner as in Preparation Example 109, the title compound (4.8 g) was obtained.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([NH:42][CH:43]([CH3:45])[CH3:44])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][NH:42][CH:43]([CH3:45])[CH3:44])=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:13][CH2:14][C:15]2[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=2[CH2:21]1)[CH3:2]
Reactant: CC(C)NC(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCNC(C)C)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 11.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-isopropylacetamide (13 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (2.7 mg) was obtained.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]P(=O)(OC)OC.[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][C:23]#[C:24][CH2:25][N:26]1[C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C@@H:27]1[CH:33]=O>C1COCC1>[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][C:23]#[C:24][CH2:25][N:26]1[C@@H:27](/[CH:33]=[CH:5]/[C:4](=[O:3])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:28][CH2:29][CH2:30][C:31]1=[O:32]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCC#CCN1C(=O)CCC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(=O)/C=C/[C@H]1CCCC(=O)N1CC#CCCCC(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
Sodium hydride (60% dispersion in oil, 8.8 mg, 0.22 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (52 mg, 0.23 mmol) in THF (1 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 1 h at rt, the solution was recooled to 0° C. and 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (crude from previous reaction, ˜0.22 mmol) in THF (1 mL) was added via cannula. The reaction was allowed to warm to rt. After 18.5 h at rt, the reaction was quenched with aqueous acetic acid (50%, 5 mL) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 68 mg (85%) of 7-[(R)-2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[C:9]([C:11]([OH:18])([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])#[CH:10]>>[Br:8][C:4]1[CH:3]=[C:2]([C:10]#[C:9][C:11]([OH:18])([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: C#CC(O)(CCC)CCC
Product: CCCC(O)(C#Cc1cccc(Br)c1)CCC

Procedure:
1,3-Dibromobenzene was coupled with alkynol 20 following the procedure described in Example 10 to give 4-((3-bromophenyl)ethynyl)heptan-4-ol as a yellow liquid. Yield (4.2 g, 65%): 1H NMR (400 MHz, DMSO-d6) δ 7.56-7.52 (m, 2H), 7.36 (dt, J=8.0, 1.2 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 5.18 (s, 1H), 1.60-1.40 (m, 8H), 0.89 (t, J=7.2 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C:6]1OC(=O)[S:8][N:7]=1.[S:15]([C:25]#[N:26])([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C:6]1[N:26]=[C:25]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[S:8][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: O=c1oc(Cc2cccc(Cl)c2)ns1
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(S(=O)(=O)c2nc(Cc3cccc(Cl)c3)ns2)cc1
Yield: 58.4 %

Procedure:
13.00 g (52.6 mmol) of 5-(3-chlorobenzyl)-1,3,4-oxathiazol-2-one and 10.50 g (55.2 mmol) of tosyl cyanide are stirred in 15 ml of 1,2-dichlorobenzene at 160° C. for 1 h. Subsequently, the reaction mixture is cooled and purified by column chromatography. 11.2 g of product are obtained (93.3% purity, 54.5% yield).