Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:4]([OH:6])=[O:5].ON1C(=O)CC[C:17]1=O.C(N=C=NC(C)C)(C)C.[Cl:32][C:33]1[S:37][C:36]([C:38]([OH:40])=O)=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C.[Si](C=[N+]=[N-])(C)(C)C.Cl>C(Cl)Cl>[CH3:17][O:5][C:4](=[O:6])[C@@H:3]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][NH:1][C:38]([C:36]1[S:37][C:33]([Cl:32])=[CH:34][CH:35]=1)=[O:40]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: O=C1CCC(=O)N1O
Agent: CC(C)N=C=NC(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNC(=O)c1ccc(Cl)s1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
Commercially available (S)-3-amino-2-tert-butoxycarbonylamino-propionic acid (BOC-Dap-OH) (18.09 g, 88.56 mmol) was suspended in 100 ml DCM with N-hydroxy-succinimide (16.99 g, 147.61 mmol) and N,N′-diisopropylcarbodiimide (11.43 ml, 73.8 mmol), then 5-Chloro-thiophene-2-carboxylic acid (12 g, 73.8 mmol) and DIPEA (25.51 ml, 147.61 mmol) in 60 ml DCM were slowly added. The mixture was stirred at RT for 2 h, then cooled to 0° C. and TMS-diazomethane was slowly added. The reaction was stirred for 2 h at RT, HCl solution (0.5 M) was added and the organic layer was separated, washed with H2O, dried with Na2SO4, filtered and evaporated to dryness. The resulting solid was triturated 16 h with diisopropyl ether, filtered and washed with diisopropyl ether and dried under vacuum at 60° C. 24.4 g of crude product were obtained and used without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[O:21]1[C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=[N:22]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:26]([C:25]2[O:21][N:22]=[CH:23][CH:24]=2)=[O:27])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccno1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccno1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and isoxazole-5-carboxylic acid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1[NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30].[CH3:34]I.Cl>CN(C)C=O>[CH3:34][N:27]([C:5]1[CH:6]=[C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=3)([C:15]([F:18])([F:16])[F:17])[O:12][N:11]=2)[CH:8]=[CH:9][C:4]=1[Cl:3])[C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]
Reactant: O=C(Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl)C(F)(F)F
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)C(F)(F)F)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl
Reaction time: 0.33 h
Yield: 100.8 %

Procedure:
Sodium hydride (600 oily) was suspended in N,N-dimethylformamide (15 mL), and thereto was added dropwise a solution of {N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}-2,2,2-trifluoroacetamide (3.6 g) obtained by Reference Production Example 6 in N,N-dimethylformamide (15 mL) at room temperature, and then the mixture was stirred at the same temperature for 20 minutes. To the mixture was added methyl iodide (1.52 g), and the mixture was further stirred for 1 hour. To the reaction mixture was added 2N hydrochloric acid, and the mixture was extracted with tert-butyl methyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain N-methyl-N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}-2,2,2-trifluoroacetamide (3.73 g).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[N:4]=1.[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>N1C=CC=CC=1>[ClH:17].[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:1])[CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[N:4]=1)=[O:21]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: CN1CCC(N(C)c2cccc(N)n2)CC1
Solvent: c1ccncc1
Product: CN1CCC(N(C)c2cccc(NC(=O)c3ccc(F)cc3Cl)n2)CC1
Product: Cl
Yield: 65.8 %

Procedure:
Prepare according to procedure in Example 66 starting with N-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34) (200 mg, 0.907 mmol) and 2-chloro-4-fluorobenzoyl chloride (263 mg, 1.36 mmol), and using pyridine as the solvent, to yield 185 mg (49%) of the title compound: mass spectrum (ion spray): m/z=377.2 (M+1); Analysis calc'd for C19H23N4OFCl2.0.6H2O: C, 53.80; H, 5.75; N, 13.21. Found: C, 53.55; H, 5.66; N, 13.28. mp 229–31° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[N:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]1[N:50]=[C:49]2[N:51]([CH3:60])[C:52](=[O:59])[N:53]([CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:48]2=[CH:47][CH:46]=1>ClCCl>[CH3:56][C:55]([CH3:58])([CH3:57])[CH2:54][N:53]1[C:48]2[C:49](=[N:50][C:45]([CH2:44][CH2:43][CH2:42][CH2:41][NH:40][C:6]([C:3]3[CH:4]=[CH:5][O:1][N:2]=3)=[O:8])=[CH:46][CH:47]=2)[N:51]([CH3:60])[C:52]1=[O:59]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(CCCCN)nc21
Reactant: O=C(O)c1ccon1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(CCCCNC(=O)c3ccon3)nc21
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-isoxazolecarboxylic acid (0.02 g, 0.18 mmol), and triethylamine (0.1 mL, 0.72 mmol) in dichloromethane (2 mL) was added HATU (0.07 g, 0.18 mmol). The resulting mixture was stirred 20 minutes. To this mixture was added 38-2 (0.04 g, 0.14 mmol) and the resulting mixture was stirred room temperature overnight. The mixture was washed with water and concentrated. Flash column separation using a 10-70% ethyl acetate/hexane gradient gave 38-3. (0.045 g, 85%). HRMS (M+H)+: observed=386.2188, calculated=386.2187
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5](N)=[O:6])[CH2:3][CH2:2]1.[F:10][C:11]1[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH2:17]Br)=[CH:13][CH:12]=1.[C:21]([O-:24])([O-:23])=O.[K+].[K+]>>[C:5]([OH:15])(=[O:6])/[CH:4]=[CH:8]\[C:21]([OH:24])=[O:23].[C:14]([OH:6])(=[O:15])/[CH:19]=[CH:20]\[C:21]([OH:24])=[O:23].[F:10][C:11]1[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH2:17][N:1]2[CH2:9][CH2:8][CH:4]([CH2:5][C:2]3[CH:3]=[CH:4][CH:8]=[CH:9][N:1]=3)[CH2:3][CH2:2]2)=[CH:13][CH:12]=1
Reactant: Fc1ccc(OCCBr)cc1
Reactant: NC(=O)C1CCNCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(OCCN2CCC(Cc3ccccn3)CC2)cc1
Product: O=C(O)/C=C\C(=O)O

Procedure:
The title compound was prepared from isonipecotamide, 2-(4-fluorophenoxy)ethyl bromide, and K2CO3 in four steps as a pale yellow solid, mp 114-115° C.; 1H NMR (CDCl3) 1.56-1.75 (m, 2H), 1.94 (d, J=15 Hz, 2H), 2.08-2.25 (m, 1H), 2.96-3.18 (m, 4H), 3.33-3.56 (m, 2H), 3.62-3.73 (m, 2H), 4.32 (d, J=4.8 Hz, 2H), 6.26 (s, 4H), 6.91-7.12 (m, 4H), 7.84-7.94 (m, 2H), 8.48 (td, J=7.8 and 1.5 Hz, 1H), 8.63 (d, J=6.0 Hz, 1H); Anal. Calcd for C27H31FN2O9 : C, 59.33; H, 5.71; N, 5.12. Found: C, 59.36; H, 5.68; N, 4.94.
Reaction SMILES: C(OC1C=C[N:12]([C:15]2[CH:20]=CC(O)=[CH:17][CH:16]=2)[C:11](=O)C=1)C1C=CC=CC=1.[CH2:23]([OH:25])[CH3:24]>>[OH:25][CH2:23][C:24]1[CH:17]=[CH:16][C:15]([CH3:20])=[N:12][CH:11]=1
Reactant: CCO
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(O)cc1
Product: Cc1ccc(CO)cn1

Procedure:
Step (5) of Example 1 was repeated except that 4-benzyloxy-1-(4-hydroxyphenyl)-1H-pyridin-2-one and 2-dimethylamino)ethanol were replaced with the compound as obtained in above Step (1) and 5-hydroxymethyl-2-methylpyridine, to provide the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6](C1C2C(=CC=CC=2)N(CC)C=1C)=[O:7])(O)=[O:2].C(C1C=CC=CC=1C(C1C2C(=CC=CC=2)N(CC2C=CC=CC=2)C=1C)=O)(O)=O>>[C:1]1([C:4]2[C:5](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:6][O:7]1)=[O:2]
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Agent: Cc1c(C(=O)c2ccccc2C(=O)O)c2ccccc2n1Cc1ccccc1
Product: O=C1OCc2ccccc21

Procedure:
If the 3-(2'-carboxybenzoyl)-1-ethyl-2-methyl-indole in Example 1 is replaced by an equimolar amount of 3-(2'-carboxybenzoyl)-1-benzyl-2-methyl-indole, with the procedure otherwise being as described in Example 1, there is obtained 4.5 g of a phthalide compound of the formula ##STR12## which melts at 138°-142° C. This colour former develops on silton clay a blue colour of λ max. 600 nm.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH2:11][NH2:12])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[Cl:26][C:27]1[S:31][C:30]([S:32](Cl)(=[O:34])=[O:33])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH2:11][NH:12][S:32]([C:30]2[S:31][C:27]([Cl:26])=[CH:28][CH:29]=2)(=[O:34])=[O:33])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cc(CN)nc(-c2ccccn2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(CNS(=O)(=O)c2ccc(Cl)s2)nc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A mixture of C-(4-Methanesulfonyl-[2,2′]bipyridinyl-6-yl)-methylamine (40.0 mg, 0.153 mmol), triethylamine (58.0 μL, 0.459 mmol), 5-chlorothiophene-2-sulfonyl chloride (42.0 mg, 0.184 mmol) and DCM (2 mL) was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to afford 5-chloro-thiophene-2-sulfonic acid (4-methanesulfonyl-[2,2′]bipyridinyl-6-ylmethyl)-amide as a white solid (20.0 mg, 30%).
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.[C:39](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[OH:1][CH:2]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(O)c1)c1cccc2c1C=CCCC2
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)NC(=O)c2cccc3c2C=CCCC3)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(3-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (313 mg, 2.27 mmol) and methyl iodide (2 ml), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was is washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (115 mg, 28%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>ClCCl.N1C=CC=CC=1>[Br:8][C:3]1[C:2]([NH:1][S:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)(=[O:18])=[O:17])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1cccnc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccnc1Br)c1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of 3-amino-2-bromo-pyridine (0.4 g, 2.3 mmol) in dichloromethane (4 ml) and pyridine (4 ml) was added 4-fluoro-benzenesulfonylchloride (0.45 g, 2.3 mmol) in one portion. The mixture was stirred overnight. The mixture was diluted with dichloromethane and washed with saturated NaCl solution. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified through chromatography (2-5% EtOAc in dichloromethane). MS 331.8 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]([CH3:11])[CH3:10])[CH:5]=[C:4]([CH3:12])[C:3]=1[OH:13].[H-].[Na+].[H][H].CS(O[CH2:23][CH:24]1[CH2:28][O:27][C:26]([CH2:36][Br:37])([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[O:25]1)(=O)=O>CN(C)C=O>[Br:37][CH2:36][C:26]1([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[O:25][CH:24]([CH2:23][O:13][C:3]2[C:4]([CH3:12])=[CH:5][C:6]([CH2:8][N:9]([CH3:10])[CH3:11])=[CH:7][C:2]=2[Cl:1])[CH2:28][O:27]1
Reactant: Cc1cc(CN(C)C)cc(Cl)c1O
Reactant: CS(=O)(=O)OCC1COC(CBr)(c2ccc(Cl)cc2)O1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(CN(C)C)cc(Cl)c1OCC1COC(CBr)(c2ccc(Cl)cc2)O1
Reaction time: 7 h

Procedure:
4 g=20 mmoles of 2-chloro-4-(N,N-dimethylaminomethyl)-6-methylphenol are added in portions, while cooling with an ice bath and stirring, to a suspension of 0.6 g=20 mmoles of sodium hydride (an 80% strength dispersion in oil) in 30 ml of absolute dimethylformamide at such a rate that the temperature does not exceed 20° C. Stirring is continued at 20° C. until the evolution of hydrogen is complete, 8.26 g=20 mmoles of 2-bromomethyl-2-(4-chlorophenyl)-1,3-dioxolan-4-ylmethyl methanesulfonate (compound of the formula (IV)) are then introduced in portions, stirring is continued for 7 hours at 60° C. and the mixture is worked up as described in Example 1a. This gives 7 g (71% of theory) of a highly viscous, noncrystalline oil.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH:7]1([OH:14])[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1>C1(C)C=CC=CC=1>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:13][CH:10]1[CH2:11][CH2:12][CH:7]([OH:14])[CH2:8][CH2:9]1
Reactant: C1=COCCC1
Reactant: OC1CCC(O)CC1
Solvent: Cc1ccccc1
Product: OC1CCC(OC2CCCCO2)CC1
Reaction time: 17 h
Yield: 0.1 %

Procedure:
An acidic resin (Dowex 50W×8, trade name, Dow Chemical Company, 800 mg) and dihydropyran (1.89 ml, 20.7 mol) were added dropwise to a solution of 1,4-cyclohexanediol (4.0 g, 34.4 mol) in toluene (80 ml) at room temperature and vigorously stirred. After 17 hours, the reaction mixture was filtered by the use of Celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 4-(tetrahydro-2H-pyran-2-yloxy)cyclo-hexanol (2.69 g, 65%).
Reaction SMILES: [C:1]1([C:7]2O[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][C:11](=[O:18])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C(O)(=O)C.[CH2:31]([NH2:33])[CH3:32]>O>[CH2:31]([N:33]1[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:11](=[O:18])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:32]
Reactant: CCN
Reactant: CCOC(=O)c1c(-c2ccccc2)oc(-c2ccccc2)cc1=O
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccccc2)n(CC)c(-c2ccccc2)cc1=O
Reaction time: 24 h

Procedure:
3.5 gms of 2,6-diphenyl-3-ethoxycarbonyl-pyr-4-one, 33 mls of methanol, 5 mls of water and 2 mls of glacial acetic acid were mixed. 7.6 mls of 70% aqueous ethylamine was then added slowly and the resulting mixture was allowed to stand at room temperature for 24 hours. The mixture was then diluted with 100 mls of water. The pH was adjusted to 2. Extraction with methylene chloride and evaporation of the solvent provided 3.0 gms of crude ethyl 1-ethyl-2,6-diphenyl-4-oxonicotinate as a brown oil. This material was dissolved in 20 mls of methanol. This solution was then added to 40 mls of 5% aqueous NaOH and heated on a steambath for 5 hours. The reaction mixture was cooled and acidified. Extraction with methylene chloride (3×50 mls) yielded an oily solid after evaporation. Crystallization from methylene chloride/ether yielded 1.6 gms of 1-ethyl-2,6-diphenyl-4-oxonicotinic acid. mp=210°-3° (dec).
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([OH:11])=[O:10].P(Br)(Br)Br>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:7])([CH3:8])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=C[C@@H]1[C@H](C(=O)O)C1(C)C
Agent: BrP(Br)Br
Solvent: Cc1ccccc1
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of cis chrysanthemic acid (1.0 g) in toluene (9 g) was added phosphorus tribromide (0.11 g) at room temperature under a nitrogen atmosphere. Irradiation with a xenon lamp (500 W, Pyrex glass filter) was made for 30 minutes under stirring. After the irradiation was over, similar after-treatment as in Example 1 was applied to obtain chrysanthemic acid (0.90 g). The isomer ratio of the product was: cis, 10.0%; and trans, 90.0%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:44][C:45]1[C:46](=[O:60])[N:47]([CH2:53][C:54]2[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=2)[C:48]([CH3:52])=[CH:49][C:50]=1O>C1COCC1.CN(C=O)C>[Br:44][C:45]1[C:46](=[O:60])[N:47]([CH2:53][C:54]2[CH:55]=[CH:56][N:57]=[CH:58][CH:59]=2)[C:48]([CH3:52])=[CH:49][C:50]=1[O:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1]
Reactant: OCc1ccc(F)cc1F
Reactant: Cc1cc(O)c(Br)c(=O)n1Cc1ccncc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccncc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a cold solution of 2,4-difluorobenzylalcohol (0.569 mL, 5.1 mmol) in THF (5 mL) was added PPh3 (resin, 2.55 g, 7.65 mmol) followed by the addition of DIAD (1.48 mL, 7.65 mmol). The reaction mixture stirred at −10° C. for 15 minutes under nitrogen. A solution of 3-bromo-4-hydroxy-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one (1.0 g, 3.4 mmol), in DMF (10 mL) was added to the resin suspension. The reaction mixture stirred at 0° C. for 1.5 hours and then allowed to stir at room temperature overnight. The resin was filtered and rinsed with fresh MeOH and the filtrate was concentrated. The residue was dissolved in ethyl acetate and purified by flash column chromatography (ethyl acetate). The appropriate fractions were concentrated. 1H-NMR (CD3OD, 400 MHz) δ 8.47 (d, 2H, J=5.6 Hz), 7.63 (q, 1H), 7.15 (d, 1H, J=5.6 Hz), 7.05 (m, 2H), 6.55 (s, 1H), 5.45 (s, 2H), 5.31 (s, 2H), 2.35 (s, 3H); ES-HRMS m/z 421.0366/423.0355 (M+H calculated for C19H16N2O2F2Br requires 421.0358/423.0339).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Sn](CCCC)(CCCC)[C:12]1[S:13][CH:14]=[CH:15][N:16]=1)CCC>C1(C)C=CC=CC=1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:12]1[S:13][CH:14]=[CH:15][N:16]=1
Reactant: Brc1nccs1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Solvent: Cc1ccccc1
Product: c1csc(-c2nccs2)n1
Temperature: 125 °C
Yield: 93.3 %

Procedure:
A solution of 2-bromothiazole (2.85 g, 17.4 mmol), 2-(tributylstannyl)thiazole (5.00 g, 13.4 mmol) and tetrakistriphenylphosphine palladium (0.77 g, 0.67 mmol) in toluene (120 mL) was degassed under vacuum for several minutes, backfilled with nitrogen and heated in a sealed pressure vessel at 125° C. for 48 h. The crude reaction mixture was concentrated and the residue was purified by column chromatography (0 to 30% ethyl acetate/hexanes) to yield 2,2′-bithiazole (2.21 g, 12.5 mmol, 93% yield) as a white solid.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:18][CH:19]([F:21])[F:20])[C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([Li])CCC.IC>C1COCC1>[C:1]1([C:7](=[N:14][C:15]([CH3:22])([CH2:18][CH:19]([F:20])[F:21])[C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(CC(F)F)N=C(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C#N)(CC(F)F)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
13.07 g (38.62 mmol) of rac-2-[(diphenylmethylene)amino]-4,4-difluorobutanonitrile from Example 67A were initially charged in 255 ml of abs. THF, and 15.6 ml (39.0 mmol) of n-butyllithium (2.5 N in hexane) were added at −78° C. under argon, and the mixture was stirred at −78° C. for a further 10 min. Subsequently, 22.6 g (154.46 mmol) of iodomethane were added to the reaction solution at −78° C. The reaction mixture was gradually brought to 0° C. over 3.5 h. After complete depletion of the starting material, the reaction solution was quenched with water at 0° C., ethyl acetate was added and the mixture was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate=15/1). 11.4 g of the target compound were obtained (91% of theory, 92% purity).
Reaction SMILES: [NH2:1][N:2]1[C:6]2[N:7]=[C:8]([CH:14]3[CH2:16][CH2:15]3)[CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]=2[CH:4]=[N:3]1.[NH2:17][CH2:18][C:19]1[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=1[CH3:25].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[NH2:1][N:2]1[C:6]2[N:7]=[C:8]([CH:14]3[CH2:16][CH2:15]3)[CH:9]=[C:10]([C:11]([NH:17][CH2:18][C:19]3[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[O:13])[C:5]=2[CH:4]=[N:3]1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Nn1ncc2c(C(=O)O)cc(C3CC3)nc21
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Solvent: ClCCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2cnn3N)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for intermediate 56 using 1-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (73 mg, 0.335 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (76 mg, 0.502 mmol), 1-hydroxy-7-azabenzotriazole (91 mg, 0.669 mmol), DMSO(10 mL), EDC (128 mg, 0.669 mmol), and N-methylmorpholine (0.147 mL, 1.338 mmol). The aq. phase was extracted with EtOAc (5×30 mL). The combined EtOAc extracts were dried over MgSO4, filtered, and concentrated in vacuo. The final product was collected as 0.068 g (58%). LCMS E-S (M+H)=353.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.14 (m, 4 H), 2.13 (s, 3 H), 2.22 (s, 4 H), 4.35 (d, J=4.80 Hz, 2 H), 5.90 (s, 1 H), 6.31 (s, 2 H), 7.41 (s, 1 H), 8.04 (s, 1 H), 8.74 (s, 1 H), 11.58 (br. s., 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[C:3]=1[N+:10]([O-:12])=[O:11].CCN(CC)CC.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=CC=1>CCO>[OH:9][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([C:23]2[S:26][CH:20]=[CH:25][CH:24]=2)[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(O)n1
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(-c2cccs2)c([N+](=O)[O-])c(O)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-chloro-2-hydroxy-6-methyl-3-nitropyridine (188 mg, 1.0 mmol) in 2 mL of EtOH and 0.2 mL (1.4 mmol) of Et3N was added 0.11 mL (1.0 mmol) of PhSH. Precipitation occurred immediately and the solution was allowed to stir at room temperature for 16 h. The solid was filtered and washed with EtOH to afford II-2.