Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][N:6]1[C:19]2C(=[CH:15][CH:16]=[CH:17][CH:18]=2)C(=O)[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2)[CH3:2].[C:23]([Cl:28])(=O)[C:24]([Cl:26])=O>ClCCl>[Cl-:26].[Cl:28][C:23]1[C:24]2[C:19]([N+:6]([CH2:5][CH2:4][N:3]([CH2:21][CH3:22])[CH2:1][CH3:2])=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: CCN(CC)CCn1c2ccccc2c(=O)c2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCN(CC)CC[n+]1c2ccccc2c(Cl)c2ccccc21
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 11.5 g of 10-[2-(diethylamino)ethyl]-9-acridanone in 250 ml of dichloromethane is treated at -5° and within 0.5 hour with 6.7 ml of oxalyl chloride, stirred at room temperature for 1 hour, the yellow crystals (9-chloro-10-[2-(diethylamino)ethyl]acridinium chloride) which have formed are filtered and washed successively with methylene chloride and petroleum ether. The material obtained is taken up in 200 ml of methanol, treated with 3.6 g of thiosemicarbazide and stirred at room temperature for about 18 hours. The precipitated salt is filtered and washed successively with ethanol and ether. There is obtained 10-[2-(diethylamino)ethyl]-9-acridanone thiosemicarbazone dihydrochloride (crystallizing with 1 mol of methanol) of melting point 124° (decomposition). This material is treated with 1N sodium hydroxide solution and extracted with dichloromethane. The solution is washed with water, dried and evaporated, whereupon the product is crystallized from acetonitrile. There is obtained 10-[2-(diethylamino)ethyl]-9-acridanone thiosemicarbazone of melting point 154°-156°.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1([CH2:14][CH2:15][C:16]([OH:18])=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC1(C)[O:24][C@H:23]([CH2:25][O:26][C:27]2[C:36]([CH3:37])=[CH:35][C:30]([C:31](=[NH:34])[NH:32]O)=[CH:29][C:28]=2[CH3:38])[CH2:22][O:21]1.C(N=C=NC(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C(O)(C(F)(F)[F:75])=O>ClCCl>[OH:24][C@@H:23]([CH2:22][OH:21])[CH2:25][O:26][C:27]1[C:36]([CH3:37])=[CH:35][C:30]([C:31]2[N:34]=[C:16]([CH2:15][CH2:14][C:3]3([C:8]4[CH:9]=[CH:10][C:11]([F:75])=[CH:12][CH:13]=4)[CH2:4][CH2:5][CH2:6][CH2:7][C:2]3=[O:1])[O:18][N:32]=2)=[CH:29][C:28]=1[CH3:38]
Reactant: O=C(O)CCC1(c2ccccc2)CCCCC1=O
Reactant: Cc1cc(C(=N)NO)cc(C)c1OC[C@@H]1COC(C)(C)O1
Reactant: O=C(O)C(F)(F)F
Agent: CC(C)N=C=NC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(-c2noc(CCC3(c4ccc(F)cc4)CCCCC3=O)n2)cc(C)c1OC[C@@H](O)CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34 %

Procedure:
A solution of 3-(1-(4-fluorophenyl)-2-oxocyclohexyl)propanoic acid (30 mg, 0.114 mmol, Preparation 1B) and (R)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-N-hydroxy-3,5-dimethylbenzimidamide (33.4 mg, 0.114 mmol) in dichloromethane (900 μL) was treated with N,N′-diisopropylcarbodiimide (19 μL, 0.125 mmol). The reaction mixture was stirred at room temperature for 1.5 h and concentrated. The residue was dissolved in acetonitrile (900 μL) and treated with a solution of 1N tetra-n-butylammonium fluoride in THF (57 μL, 0.057 mmol). After 2.5 h, additional 1N tetra-n-butylammonium fluoride solution in THF (28 μL, 0.028 mmol) was added and stirring was continued for 16 h. The reaction mixture cooled to 0° C. and treated with TFA (1.5 mL). After 1 min, the ice bath was removed and stirring was continued for additional 55 min. The reaction mixture was concentrated and the residue was purified by reversed-phase autoprep HPLC (Phenomenex S10 30×100 mm, 40 min gradient time, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH—0.1% TFA; Final solvent: 90% aq. MeOH—0.1% TFA) to obtain 2-(2-(3-(4-((S)-2,3-dihydroxypropoxy)-3,5-dimethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)-2-(4-fluorophenyl)cyclohexanone (23.2 mg, 34% yield) as a white solid. LC/MS: m/e 483.16 (M+H)+. 1H NMR (400 MHz, CD3OD): δ ppm 7.59 (s, 2H), 7.20-7.23 (m, 2H), 7.06-7.10 (m, 2H), 3.91-3.99 (m, 1H), 3.82-3.89 (m, 1H), 3.74-3.81 (m, 1H), 3.59-3.72 (m, 2H), 2.75-2.86 (m, 1H), 2.33-2.2 (m, 2H), 2.56-2.74 (m, 2H), 2.30-2.42 (m, 2H), 2.29 (s, 6H), 2.19-2.26 (m, 1H), 2.00-2.12 (m, 1H), 1.90-2.00 (m, 1H), 1.63-1.85 (m, 4H).
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH3:27])[CH2:7][CH2:6]1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1>[CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH3:27])[CH2:7][CH2:6]1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OC(C)C)CC3)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2ccc(CC(=O)O)cc2)ccc1C1(OC(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
Using General Procedure I; a solution of methyl {4-[4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-phenyl }-acetate (Compound 84, 100.0 mg, 0.28 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 60.0 mg (62%) of the title compound as a colorless solid.
Reaction SMILES: C(C(=COCC)C(NC(OCC)=O)=O)#N.ClC1C=C(C=CC=1Cl)N.C(O)C.[C:28]([C:30](=[CH:39][NH:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=1)[C:31]([NH:33][C:34](OCC)=[O:35])=[O:32])#[N:29]>C1C2C(=CC=CC=2)CCC1>[C:28]([C:30]1[C:31](=[O:32])[NH:33][C:34](=[O:35])[N:40]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=2)[CH:39]=1)#[N:29]
Reactant: CCOC(=O)NC(=O)C(C#N)=CNc1ccc(Cl)c(Cl)c1
Agent: CCOC=C(C#N)C(=O)NC(=O)OCC
Agent: Nc1ccc(Cl)c(Cl)c1
Solvent: c1ccc2c(c1)CCCC2
Solvent: CCO
Product: N#Cc1cn(-c2ccc(Cl)c(Cl)c2)c(=O)[nH]c1=O

Procedure:
A mixture of α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide (0.047 mol), 3,4-dichloroaniline (8.15 g) and ethanol (70 ml) is heated to prepare α-cyano-β-(3,4-dichloroanilino)-N-ethoxycarbonylacrylamide, which is cyclized by heating overnight in tetralin to yield 5-cyano-1-(3,4-dichlorophenyl)uracil, m.p. 206.5°-207.5°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.CO.[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([C:5]1[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH3:13]
Reactant: CNC
Reactant: Clc1ccc(Cl)nn1
Solvent: CO
Product: CN(C)c1ccc(Cl)nn1
Yield: 96.3 %

Procedure:
3-(N,N-Dimethylamino)-6-chloropyridazine (108f, 510 mg, 96%) was prepared in the same manner as in Example 29 as a white solid using 3,6-dichloropyridazine (107, 500 mg, 3.36 mmol) and a 2.0 M dimethylamine methanol solution (NHMe2 in MeOH, 5 mL, 10 mmol).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=O)C.O.[OH-].[Na+]>C1COCC1>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:6]=1[CH2:4][OH:3]
Reactant: CCOC(=O)c1c(-c2ccncc2)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2ccncc2)c1CO
Reaction time: 2 h
Yield: 65.3 %

Procedure:
To a solution of 5-methyl-3-pyridin-4-yl-isoxazole-4-carboxylic acid ethyl ester (7.06 g, 17.3 mmol) in THF (350 mL) was added at 5° C. lithiumaluminumhydride (635 mg, 16.7 mmol). After stirring for 2 h at this temperature further lithiumaluminumhydride (318 mg, 8.4 mmol) was added and stirred for 1 h at 5° C. Water (1.9 mL) was added carefully followed by aqueous sodium hydroxide (15%, 1.9 mL) and water (0.540 mL). The resulting suspension was stirred for 15 min at ambient temperature and filtered over Hyflo®. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=50:50 to 0:100) afforded the title compound (2.15 g, 65%) as a light yellow solid. MS: m/e=191.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:25])[C@H:19]([OH:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:26])=[CH:7][CH:8]=2)[N:3]=1.[F:27][C:28]1[CH:29]=[CH:30][C:31]([O:37][CH3:38])=[C:32](B(O)O)[CH:33]=1.C([O-])([O-])=O.[K+].[K+].C(#N)C>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.O>[F:27][C:28]1[CH:33]=[CH:32][C:31]([O:37][CH3:38])=[C:30]([C:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:25])[C@H:19]([OH:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][C:6]([CH3:26])=[CH:7][CH:8]=3)[N:3]=2)[CH:29]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(C)C)CC3)nc(Cl)nc2c1
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: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(F)cc1-c1nc(N2CCN(C(=O)[C@H](O)CC(C)C)CC2)c2ccc(C)cc2n1
Temperature: 160 °C
Yield: 70 %

Procedure:
(R)-1-(4-(2-Chloro-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one (50 mg, 0.13 mmol), 5-fluoro-2-methoxyphenylboronic acid (27 mg, 0.16 mmol), Pd(Ph3P)4 (9.2 mg, 0.008 mmol), and K2CO3 (37 mg, 0.27 mmol) were placed into a microwave tube charged with a stir bar. Acetonitrile (2 mL) and H2O (400 μL) were added, and the vessel was capped and heated at 160° C. for 12 minutes in the microwave reactor. The reaction was partitioned between EtOAc and H2O, the layers were separated, and the aqueous layer was extracted once more with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to an orange gel. The reaction was purified by silica gel chromatography using 10%-30% EtOAc in CH2Cl2/hexanes (2:1) to afford (R)-1-(4-(2-(5-fluoro-2-methoxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one as a white foam (70%). LC/MS: m/z 467.30 (M+H)+ at 2.38 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:51])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][C:27]=4[C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)[CH2:21][CH2:20]3)=[CH:15][C:14]=2[O:41][C:42]2[CH:43]=[C:44]3[CH:50]=[CH:49][NH:48][C:45]3=[N:46][CH:47]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:52]([O-:54])=[O:53].[NH2:55][CH:56]1[CH2:61][CH2:60][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:58][CH2:57]1.CCN(C(C)C)C(C)C>O1CCOCC1.C(OCC)(=O)C>[NH:48]1[C:45]2=[N:46][CH:47]=[C:42]([O:41][C:14]3[CH:15]=[C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH2:25][C:26]5[CH2:31][CH2:30][C:29]([CH3:32])([CH3:33])[CH2:28][C:27]=5[C:34]5[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=5)[CH2:23][CH2:24]4)[CH:17]=[CH:18][C:13]=3[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:55][CH:56]4[CH2:57][CH2:58][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:60][CH2:61]4)=[C:3]([N+:52]([O-:54])=[O:53])[CH:4]=3)(=[O:10])=[O:9])=[O:51])[CH:43]=[C:44]2[CH:50]=[CH:49]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(Cl)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCN(C(=O)OC(C)(C)C)CC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 82 (800 mg) and tert-butyl 4-aminopiperidine-1-carboxylate (203 mg) in dioxane (10 mL) was added Hunig's Base (1 mL). The mixture was stirred at 120° C. overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with water, brine and dried over Na2SO4. After filtration and evaporation of solvent, the residue was loaded on a silica gel cartridge and eluted with 3% methanol in dichloromethane to give the title compound.
Reaction SMILES: CB(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:13]N(C)C=O.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([C:29]2[C:34]([Cl:35])=[CH:33][C:32](Br)=[CH:31][N:30]=2)[C:27]=1[CH3:28])=[O:22])[CH3:19]>O>[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([C:29]2[C:34]([Cl:35])=[CH:33][C:32]([CH3:13])=[CH:31][N:30]=2)[C:27]=1[CH3:28])=[O:22])[CH3:19]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cnn(-c2ncc(Br)cc2Cl)c1C
Agent: CB(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cnn(-c2ncc(C)cc2Cl)c1C
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Methylboronic acid (457 mg), tripotassium phosphate (3.40 g) and 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (296 mg) were added to a N,N-dimethylformamide solution (36 ml) of 1-(5-bromo-3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.50 g) described in Reference Example 44(2), and the mixture was stirred at 100° C. for three hours. Methylboronic acid (154 mg) and 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (103 mg) were subsequently added and the mixture was further stirred for three hours. The reaction solution was cooled to room temperature and left stand for 16 hours, and methylboronic acid (153 mg) and 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (114 mg) were further added and the mixture was stirred again at 100° C. for five hours. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with water and extracted with ethyl acetate three times. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-(3-chloro-5-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.03 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[CH3:10][N:11]1[C:15]([CH3:16])=[C:14]([C:17]([OH:19])=O)[C:13](=[O:20])[N:12]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.[CH:38]1[CH:43]=[N:42][C:41]2[N:44](O)N=N[C:40]=2[CH:39]=1>C(Cl)Cl>[NH2:44][C:41]1[CH:40]=[C:39]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:17]([C:14]3[C:13](=[O:20])[N:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:11]([CH3:10])[C:15]=3[CH3:16])=[O:19])=[CH:3][C:4]=2[Cl:9])[CH:38]=[CH:43][N:42]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(Cl)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 20 h
Yield: 277.8 %

Procedure:
To a suspension of 4-amino-2-chlorophenol (4.0 g, 28.00 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (7.4 g, 30.11 mmol) in DCM (70 mL) were added EDCI (6.65 g, 30.11 mmol) and HOAT (0.76 g, 5.68 mmol). The mixture was stirred at 45° C. for 20 hours, then cooled to rt and filtered. The filter cake was washed with DCM (20 mL×3), and dried at 50° C. in a vacuum oven overnight to give the title product as a gray solid (7.1 g, 72.1%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[O:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)([O-:3])=[O:2].Br[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:28][S:25]([C:22]1[CH:23]=[CH:24][C:19]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([O:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:6]=2)=[N:20][CH:21]=1)(=[O:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(O)cc1OC1CCOCC1
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(OC3CCOCC3)c2)nc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
A mixture of 4-nitro-3-(tetrahydro-2H-pyran-4-yloxy)phenol (23.0 g), 2-bromo-5-(methylsulfonyl)pyridine (22.7 g), cesium carbonate (62.6 g), and N,N-dimethylformamide (200 mL) was stirred at 100° C. for 1.5 hr. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained solid was washed with diethyl ether-hexane to give the title compound (30.0 g, yield 81%) as a brown solid.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[C:34]([CH:38]1[CH2:43][CH2:42][CH2:41][CH:40]([CH2:44][CH2:45][CH:46]=O)[CH2:39]1)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([CH:38]1[CH2:43][CH2:42][CH2:41][CH:40]([CH2:44][CH2:45][CH:46]=[CH:2][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:39]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)C1CCCC(CCC=O)C1
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(C)(C)C1CCCC(CCC=CCc2ccccc2)C1
Yield: 61.1 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (2.60 g, 5.81 mmol, 1.0 equiv.), n-BuLi (1.3 M in hexanes, 4.5 mL, 5.81 mmol, 1.0 equiv.) and 3-(3-tert-butylcyclohexyl)propanal (1.45 g, 7.39 mmol, 1.3 equiv.), 1.01 g (61%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane).
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:11][I:12]>CO>[I-:12].[CH3:10][O:9][C:1]([C:2]1[CH:7]=[CH:6][N+:5]([CH3:11])=[CH:4][CH:3]=1)=[O:8]
Reactant: CI
Reactant: COC(=O)c1ccncc1
Solvent: CO
Product: COC(=O)c1cc[n+](C)cc1
Product: [I-]
Yield: 97.2 %

Procedure:
700 g of methyl isonicotinate and 1.4 kg of methyl iodide were admixed in 2.0 liters of methanol and the resultant solution was stirred and refluxed for 5 hours. After cooling, the mixture was filtered off and the product was washed with ether and dried to obtain 1.385 kg of 4-methoxycarbonyl-1-methylpyridinium iodide (97.2% yield).
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:5].CC([O-:26])(C)C.[K+]>CCOCC>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[CH:11][CH:10]=[C:9]2[C@@H:7]2[CH2:8][C@H:6]2[C:4]([OH:5])=[O:26])=[CH:14][CH:15]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2cccc([C@@H]3C[C@H]3C(=O)N(C)OC)c2c1
Agent: [K+]
Solvent: CCOCC
Product: COc1ccc2cccc([C@@H]3C[C@H]3C(=O)O)c2c1

Procedure:
6 g (21 mmol) of the compound obtained in Step G in 50 ml of anhydrous ether and 15.4 g of potassium tert-butylate are stirred for 2 days at room temperature. 3.2 g of a light brown solid are collected and reacted without purification.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:15])[CH2:11]C(C)=O)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:16]([OH:19])[CH2:17][OH:18].O.[C:21]1(C)C=CC(S(O)(=O)=O)=C[CH:22]=1.C(C1C=C(C(C)(C)C)C=C(C(C)(C)C)C=1O)C1C=C(C(C)(C)C)C=C(C(C)(C)C)C=1O>C1C=CC=CC=1>[C:1]([O:6][CH:7]([C:21]1([CH3:22])[O:19][CH2:16][CH2:17][O:18]1)[CH2:8][O:9][C:10](=[O:15])[CH3:11])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCO
Reactant: C=C(C)C(=O)OCCOC(=O)CC(C)=O
Agent: CC(C)(C)c1cc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Solvent: c1ccccc1
Solvent: O
Product: C=C(C)C(=O)OC(COC(C)=O)C1(C)OCCO1

Procedure:
21.4 g (0.1 mol) of 2-acetoacetoxyethyl methacrylate, 18.62 g (0.3 mol) of ethylene glycol and 0.19 g (1 mmol) of p-toluenesulfonic acid monohydrate (1 mol % of p-TsOH) are dissolved in 200 ml of benzene and boiled under reflux under a water separator. 1.7 g (5 mol %) of 2,2,4,6-Ralox® [2.2'-methylene-bis-(4,6-di-tert-butylphenol), a commercial product from Raschig GmbH, Germany] are added as a polymerization inhibitor.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]([NH:19][C:20]([C:22]3[NH:26][N:25]=[C:24]([C:27]4[N:28]=[CH:29][N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:31]=4)[CH:23]=3)=[O:21])[CH3:18])[N:12]=2)[CH:5]=[C:6]([F:10])[C:7]=1[C:8]#[N:9].C(O)=O.C1COCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]([NH:19][C:20]([C:22]3[NH:26][N:25]=[C:24]([C:27]4[N:28]=[CH:29][NH:30][CH:31]=4)[CH:23]=3)=[O:21])[CH3:18])[N:12]=2)[CH:5]=[C:6]([F:10])[C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n[nH]1
Solvent: O
Solvent: C1CCOC1
Solvent: O=CO
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2c[nH]cn2)n[nH]1
Temperature: 25 °C
Yield: 27.7 %

Procedure:
Into (S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxamide (0.139 mmol, 0.095 g) was added 4 ml of a solution containing formic acid (41.8 mmol, 1.926 g), THF (20 ml) and water (1 ml). The resulting mixture was stirred first at RT after which the temperature was raised to 50° C. for 2 h. The solvent was evaporated, ACN was added and evaporated again. This was repeated once more. The crude product was purified by preparative HPLC. 0.0169 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.27 (d, 3H), 4.14 (dd, 1H), 4.45 (dd, 1H), 4-57-4.64 (m, 1H), 6.29 (bs), 6.63 (d, 1H), 6.90 (s, 1H), 7.32 (d, 1H), 7.51 (d, 1H), 7.52 (s, 1H), 7.63 (dd, 1H), 7.73 (d, 1H), 7.84-7.86 (m, 1H) LC-MS: [M+1]=439.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)([C:14]#[N:15])[CH3:13])[CH:6]=2.[Cl:30]N1C(=O)CCC1=O>C(#N)C.O>[C:14]([C:12]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=1)([CH3:13])[CH2:11][N:7]1[C:6]([Cl:30])=[C:5]2[C:9]([CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4]2)=[N:8]1)#[N:15]
Reactant: CC(C#N)(Cn1cc2ccc(Cl)cc2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: O
Product: CC(C#N)(Cn1nc2cc(Cl)ccc2c1Cl)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Yield: 85.1 %

Procedure:
A mixture of N-[2-(6-chloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (50 mg, described in Example 132), and N-chlorosuccinimide (16 mg) in acetonitrile (1 mL) was heated to 60° C. for 3.5 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound (46 mg, 85%). MS (ES): M/Z [M+H]=457. 1H NMR: (400 MHz, CHLOROFORM-d): 1.92 (s, 3H), 4.80 (d, J=14.3 Hz, 1H), 5.03 (d, J=14.3 Hz, 1H), 7.15 (dd, J=9.0, 1.4 Hz, 1H), 7.35 (d, J=8.5 Hz, 2H), 7.57 (d, J=9.0 Hz, 1H), 7.63 (s, 1H), 7.93 (d, J=8.7 Hz, 2H) and 8.65 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]([C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[H][H]>[Pd].C1COCC1.C(OCC)(=O)C>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][N:6]([C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:24])[CH3:12]
Reactant: [H][H]
Reactant: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cccc(N)c1

Procedure:
A mixture of 3.3 g of N-(3-nitrobenzoyl)-N-(2-ethoxy-2-oxoethyl) glycine ethyl ester and 0.5 g of 10% palladium on carbon in 40 ml THF and 40 ml ethyl acetate was stirred in a hydrogen atmosphere for 16 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to an oil which was purified by HPLC using 50% ethyl acetate-hexane to remove an impurity and ethyl acetate to elute 3.1 g of N-(3-aminobenzoyl)-N-(2-ethoxy-2-oxoethyl)glycine ethyl ester as an oil. The nmr and mass spectra were consistent with the structure.