Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH2:14][C:15](=[O:20])[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:22]#[CH:23])[OH:21])[CH3:2].CO.Cl>O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:22]#[CH:23])[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=C(CCC(=O)C4)[C@H]3CC[C@@]21CC
Agent: Cl
Solvent: CO
Solvent: O
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC

Procedure:
Stir 13β-ethyl-17α-ethynyl-17β-hydroxy-gon-5(10)-en-3-one (0.1 g.) with a mixture of methanol (36 cc.), water (1.6 cc.) and concentrated hydrochloric acid (2.4 cc.) for 1 hour. Add water and extract the mixture with ether. Wash, dry and evaporate the ethereal solution and recrystallize the residue from ether-hexane to obtain the title compound, m.p. 203°-6° undepressed on admixture with authentic material. Infrared spectrum 3.05, 3.5, 6.05, 9.4 μ.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([NH:8][N:9]=[C:10]([C:15](=[O:19])[CH2:16][O:17][CH3:18])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][CH:7]=1.[CH3:21]OC(OC)N(C)C>>[Br:1][C:2]1[C:3]([F:20])=[C:4]([N:8]2[CH:21]=[C:16]([O:17][CH3:18])[C:15](=[O:19])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)C(=NNc1cccc(Br)c1F)C(=O)OC
Reactant: COC(OC)N(C)C
Product: COC(=O)c1nn(-c2cccc(Br)c2F)cc(OC)c1=O
Temperature: 0 °C
Yield: 75 %

Procedure:
A mixture of methyl 2-[(3-bromo-2-fluorophenyl)hydrazono]-4-methoxy-3-oxobutanoate (5.36 g, 15.4 mmol) in N,N-dimethylformamide dimethyl acetal (54 mL) was heated to reflux for 2 h and cooled to 0° C. The precipitates were collected by filtration, washed with hexane and dried to yield the title compound (4.16 g, 75% yield) as a brown solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.80 (3H, s), 3.83 (3H, s), 7.40 (1H, td, J=8.1, 1.1 Hz), 7.75-7.84 (1H, m), 7.94 (1H, ddd, J=8.1, 6.4, 1.7 Hz), 8.60 (1H, d, J=1.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[C:4]([CH:26]=[CH2:27])[CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:27][CH2:26][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:9])=[O:10])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C=Cc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Reactant: C1CCNC1
Product: O=C(O)c1c(NS(=O)(=O)c2ccc(F)cc2CCN2CCCC2)ccc2c1OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Example 39, starting from (1aRS,7bSR)-5-(4-fluoro-2-vinylbenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (Intermediate 74) and pyrrolidine as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][CH:40]([C:44](O)=[O:45])[C:41](O)=[O:42])([CH3:32])[CH3:31]>C(Cl)Cl>[OH:45][C:44]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[O:10][C:41](=[O:42])[C:40]=1[S:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH:30]([CH3:32])[CH3:31]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc(O)cc2)oc1=O

Procedure:
The title compound was prepared by Method A using 4'-hydroxyacetophenone (0.657 g, 4.83 mmol), trimethylsilyl triflate (2.05 mL, 10.62 mmol), triethylamine (2.69 mL, 19.32 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (1.00 g, 3.22 mmol) m.p. 250° C.; (dec.) ; 1H NMR (400 MHz, DMSO-d6) δ 1.24 (d, 6H), 3.40 (m, 1H), 6.70 (s, 1H), 6.90 (t, 3H), 7.05 (t, 1H), 7.10 (t, 1H), 7.26 (d, 1H), 7.70 (d, 2H).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].I[CH:10]([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH:10]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)([CH3:12])[CH3:11]
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)n1cnc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.2 %

Procedure:
4-nitroimidazole (0.500 g, 4.42 mmol), 2-iodopropane (0.553 ml, 5.53 mmol) and powdered K2CO3 (0.917 g, 6.63 mmol) were combined and stirred in DMF (25 ml) at 50° C. After 5 h, the reaction was cooled to RT. The reaction was diluted with EtOAc and filtered to remove inorganic salts, rinsing forward with EtOAc. The filtrate was evaporated to near dryness. The residue was diluted in EtOAc, washed with H2O (2×) and brine (1×), dried (MgSO4) and evaporated to afford 1-isopropyl-4-nitro-1H-imidazole (0.66 g, 96% yield) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 8.51 (s, 1H) 7.98 (s, 1H), 4.52-4.49 (m, 1H), 1.44 (d, 6H); MS (ESI) m/z: 156.0 (M+H+), 178.0 (M+Na+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[OH:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1cccc(O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1C
Temperature: 110 °C

Procedure:
In a 20 mL microwave vial 2-chloro-5-nitropyridine (500 mg, 3.15 mmol), 2,3-dimethylphenol (385 mg, 3.15 mmol) and potassium carbonate (1308 mg, 9.46 mmol) were dissolved in N,N-Dimethylformamide (10 mL) to give a dark brown suspension. The reaction vessel was sealed and heated in Biotage Initiator at 110° C. for 1 h. After cooling the reaction was diluted with 25 mL of Et2O. The organic phase was washed with 3×25 mL of water, 10 mL of brine, dried over sodium sulphate, filtered and evaporated under vacuum to afford the title compound as a pale orange oil. (640 mg). 1H NMR (400 MHz, CDCl3): δ ppm 9.07 (1H, d), 8.50 (1H, dd), 7.24-7.19 (1H, m), 7.18-7.14 (1H, m), 7.04 (1H, d), 6.95 (1H, d), 2.38 (3H, s), 2.09 (3H, s); UPLC: 0.81 min, 245 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH2:29][CH3:30])[N:3]=1.[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([C@H:43]2[CH2:48][CH2:47][C@H:46]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:45][CH2:44]2)=[C:36]2[C:40]=1[C:39](=[O:41])[N:38]([CH3:42])[CH2:37]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C@H:43]4[CH2:44][CH2:45][C@H:46]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:47][CH2:48]4)=[C:36]4[C:40]=3[C:39](=[O:41])[N:38]([CH3:42])[CH2:37]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH2:29][CH3:30])[CH:15]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21]
Reactant: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Reactant: CCOC(=O)[C@H]1CC[C@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Product: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Nc2ccc([C@H]3CC[C@H](C(=O)OCC)CC3)c3c2C(=O)N(C)C3)n1

Procedure:
The title compound was prepared according to the procedure for Example 102 using of diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-ethoxybenzyl)phosphonate (Compound 244A, 29.84 mg, 0.064 mmol) and ethyl trans-4-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylate (22.2 mg, 0.070 mmol). 31.2 mg (65%) of the desired product was isolated after work-up/chromatography. 1H NMR (400 MHz, MeOD) δ ppm 8.48 (d, J=7.83 Hz, 1 H), 8.35 (s, 1 H), 7.87 (d, J=8.08 Hz, 1 H), 7.38 (d, J=8.84 Hz, 1 H), 7.05 (s, 1 H), 6.94 (dt, J=8.08, 2.27 Hz, 1 H), 4.52 (s, 2 H), 4.04-4.22 (m, 8 H), 3.28 (s, 2 H), 3.19 (s, 3 H), 2.63 (t, J=11.62 Hz, 1 H), 2.42-2.54 (m, 1 H), 2.13 (d, J=14.15 Hz, 2 H), 1.90-1.99 (m, 2 H), 1.54-1.77 (m, 4 H), 1.41 (t, J=6.95 Hz, 3 H), 1.24-1.33 (m, 9 H). MS (ES+): m/z 748.26/749.29 (100/98) [MH+]. HPLC: tR=1.80 min (Micromass TOF: polar—3 min).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[C:7]([CH2:16][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)=[O:5].[C:36](=O)([O-])[O-].[Na+].[Na+].C=O>C(Cl)(Cl)Cl.O>[CH:16]([C:7]1[N:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:6]=1[C:4]([O:3][CH3:2])=[O:5])=[CH2:36]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=O
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=Cc1nc(C(F)(F)F)ccc1C(=O)OC
Reaction time: 1.5 h

Procedure:
5.7 g (10 mmol) of (3-methoxycarbonyl-6-trifluoromethylpyridine-2-ylmethyl)triphenyl-phosphonium bromide are dissolved at room temperature in a 2-phase system of 25 ml of chloroform and 2.1 g (20 mmol) of sodium carbonate and reacted, in 10 ml of water, with a 35% aqueous solution of 1.7 g (20 mmol) of formaldehyde. After 1.5 hours, the organic phase is separated off and filtered through silica gel. Methyl 2-vinyl-6-trifluoromethylnicotinate is obtained as an oil, 1H-NMR (CDCl3): 8.31, d, CH, 7.10, dd, CH, 7.09, d, CH, 6.68, dd, CH, 5.68, dd, CH, 3.97 ppm, s, OCH3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH:17](OC)OC)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].[CH3:27][CH:28]1[O:33][CH:32]([CH3:34])[CH2:31][NH:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:30]2[CH2:29][CH:28]([CH3:27])[O:33][CH:32]([CH3:34])[CH2:31]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: CC1CNCC(C)O1
Reactant: COC(CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O)OC
Product: CC1CN(CCN2CC(C(=O)N(C)Cc3ccc(Cl)c(Cl)c3)=C(O)C2=O)CC(C)O1

Procedure:
Compound 750 was prepared from 1-(2,2-dimethoxy-ethyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and 2,6-dimethyl-morpholine using the method described for compound 747. The title compound was isolated as a pale yellow powder (0.014 g, 14% yield). HRMS (M+H) calcd for C21H28N3Cl2O4: 456.14570. found: 456.1472.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:13](=[O:14])/[C:12](=[CH:15]/[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)/[C:11](=[CH:28]\[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)/[C:10]1=[O:35])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([CH2:8][N:9]1[C:13](=[O:14])/[C:12](=[CH:15]/[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)/[C:11](=[CH:28]\[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)/[C:10]1=[O:35])([OH:7])=[O:5]
Reactant: COc1cc(/C=C2/C(=O)N(CC(=O)OC(C)(C)C)C(=O)/C2=C/c2ccccc2)cc(OC)c1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(/C=C2/C(=O)N(CC(=O)O)C(=O)/C2=C/c2ccccc2)cc(OC)c1OC
Reaction time: 4 h
Yield: 80.9 %

Procedure:
To a solution of (3E,4E)-1-t-butoxycarbonylmethyl -3-benzylidene-4-(3,4,5-trimethoxybenzylidene)-2,5-pyrrolidinedione (3.5 g) obtained in Example 42 in dichloromethane (40 ml) is added trifluoroacetic acid (10 ml) at room temperature, and the mixture is allowed to stand for 4 hours. The mixture is evaporated under reduced pressure to remove the solvent, and to the residue is added trichloromethane. The mixture is washed, dried, and evaporated to remove the solvent. The resulting residue is crystallized from diethyl ether to give (3 E,4E)- 1 -carboxymethyl-3-benzylidene-4-(3,4,5-trimethoxybenzylidene) -2,5-pyrrolidinedione (2.5 g) as yellow prisms.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[H-].[Na+].[C:11]([O:15][C:16](=[O:19])[CH2:17]Br)([CH3:14])([CH3:13])[CH3:12].O>C1COCC1>[C:11]([O:15][C:16](=[O:19])[CH2:17][O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COCc1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.5 mL (5.18 mmol) 2-pyridylmethanol in 20 mL THF at 0° C. was added 270 mg (6.75 mmol) NaH and the reaction stirred for 0.25 h. Then 0.82 mL t-butylbromoacetate was added and the reaction warmed to rt and stirred for 12 days. The reaction was poured into 100 mL H2O, extracted with CH2Cl2 (2×100 mL), the combined organic layers washed with brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give 1.16 g (61%) as a brown oil.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH3:21][O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][NH2:27].CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:16]([O:15][C:13]([NH:1][C@H:2]([C:10]([CH2:21][O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][NH2:27])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)CCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)COC(=O)CCCN

Procedure:
The title compound was prepared in the idential manner as in Example 1 from 2.65 of Boc-Phe, 1.69 g (11.0 mmole) of methyl-γ-aminobutyrate hydrochloride salt, 1.25 ml of N-methylmorpholine and 2.27 g (11.0 mmole) of dicyclohexylcarbodiimide in 25 ml of methylene chloride, reacted for 24 hours, to provide a quantitative yield of product (TLC in the above solvent system, Rf 0.84).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([N:9]2[CH2:11][CH:10]2[C:12]([O:14][CH3:15])=[O:13])=[O:8])=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][CH2:19][OH:20].B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([CH2:11][O:20][CH2:19][CH2:18][O:17][CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[O:8])=[CH:4][CH:3]=1
Reactant: COCCO
Reactant: COC(=O)C1CN1C(=O)c1ccc(Cl)s1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COCCOCC(NC(=O)c1ccc(Cl)s1)C(=O)OC
Reaction time: 3 h

Procedure:
A mixture of 0.30 g (about 1 mmol) methyl N-(5-chlorothiophen-2yl)carbonyl-aziridine-2-carboxylate and 0.29 ml (3.7 mmol) 2-methoxyethanol in 4 ml methylene chloride is slowly combined with 0.16 ml boron trifluoride etherate and stirred for 3 h. The reaction mixture is concentrated and purified by chromatography (silica gel, petroleum ether/ethyl acetate 80/20->40/60). Rf value: 0.05 (silica gel; methylene chloride/methanol 80/20)
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH3:24]>CO>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][CH:4]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([NH2:24])=[O:2])(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)C(Cc1ccccc1)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: N
Solvent: CO
Product: NC(=O)C(Cc1ccccc1)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 65 °C

Procedure:
To 2-(4-Chloro-benzenesulfonylamino)-3-phenyl-propionic acid methyl ester (750 mg) is added 10 mL of a 1.0 M solution of ammonia in methanol. The reaction is heated for 48 h at 65° C., cooled to room temperature, and the solvent removed. The resultant solid is first triturated with ethyl acetate, filtered, and then triturated with methylene chloride to provide the title compound. 1HNMR (400 MHz, CD3OD) 2.70 (dd, 1H, J=14.0 Hz and 9.6 Hz), 3.01 (dd, 1H, J=14.0 Hz and 5.4 Hz), 3.95 (dd, 1H, J=9.0 Hz and 5.0 Hz), 7.05–7.15 (m, 5H), 7.32–7.36 (m, 2H), and 7.53–7.56 (m, 2H). MS 339.1 m/z (M+1).
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=3[F:21])[NH:6][CH:5]=2)[CH2:3][CH2:2]1.Cl[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:26]=[C:25]([NH2:33])[N:24]=1.Cl.[OH-].[Na+]>O>[CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[CH:20]=[CH:19][C:17]([NH:18][C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[N:26]=[C:25]([NH2:33])[N:24]=4)=[CH:16][C:15]=3[F:21])[NH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]cc(C4CC4)c23)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]cc(C5CC5)c34)c(F)c2)cc(C(F)(F)F)n1

Procedure:
114 mg (0.40 mmol) of 4-[(3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3-fluoroaniline and 95 mg (0.48 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 3.5 ml of water. 0.52 ml (0.52 mmol) of 1N hydrochloric acid are added, and the mixture is heated at reflux overnight. Another 30 mg (0.15 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are then added, and the mixture is heated for another 6 hours. By addition of 1N aqueous sodium hydroxide solution, the pH is adjusted to 10, resulting in the precipitation of crystals. The crystals are filtered off with suction and purified by chromatography on silica gel (mobile phase: dichloromethane/methanol (7N ammonia) 100:1 to 100:3).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[C:9]([OH:18])=[C:10]([C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][C:13]=1[OH:14].[Br:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][CH:22]=1.Cl>CC(C)=O.CCOC(C)=O>[Br:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:14][C:13]2[CH:12]=[CH:11][C:10]([C:15](=[O:17])[CH3:16])=[C:9]([OH:18])[C:8]=2[Cl:7])=[CH:23][CH:22]=1
Reactant: BrCc1ccc(CBr)cc1
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccc(CBr)cc2)c(Cl)c1O

Procedure:
Add K2CO3 (1.48 g, 10.7 mmol) to a solution of 1-(3-chloro-2,4-dihydroxy-phenyl)ethanone (2.00 g, 10.7 mmol) and 1,4-bis(bromomethyl)benzene (2.83 g, 10.7 mmol) in acetone (100 mL). Cool and work up with a 10% HCl solution and EtOAc. Triturate in acetone to remove insoluable material. Dry, filter, and concentrate. Purify the residue by flash chromatography on silica gel (731 mg, 18%): MS (esi negative) m/z 368.9 (rel intensity) (M−H, 55%), 367.0 (45%).
Reaction SMILES: [C:1]([C:3]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:4]=1)#[CH:2].Br[C:23]1[N:32]=[C:26]2[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][N:25]2[N:24]=1.C(N(CC)CC)C>O1CCCC1.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:31][C:28]1[CH:29]=[CH:30][N:25]2[N:24]=[C:23]([C:2]#[C:1][C:3]3[N:7]=[C:6]([N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)[N:5]([CH2:13][C:14]4[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=4)[N:4]=3)[N:32]=[C:26]2[CH:27]=1
Reactant: Clc1ccn2nc(Br)nc2c1
Reactant: C#Cc1nc(N2CCCC2)n(Cc2ccc(OC)cc2)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nc(C#Cc3nc4cc(Cl)ccn4n3)nc2N2CCCC2)cc1
Temperature: 75 °C
Yield: 28.6 %

Procedure:
A mixture of 3-ethynyl-1-(4-methoxybenzyl)-5-(pyrrolidin-1-yl)-1H-1,2,4-triazole (75 mg, 266 μmol, Eq: 1.00), 2-bromo-7-chloro-[1,2,4]triazolo[1,5-a]pyridine (67.9 mg, 292 μmol, Eq: 1.1) and triethylamine (40.3 mg, 55.5 μl, 398 μmol, Eq: 1.5) in tetrahydrofuran (2 ml) was purged with argon, then copper (I) iodide (1.01 mg, 5.31 μmol, Eq: 0.02), bis(triphenylphosphine) palladium(II) chloride (3.73 mg, 5.31 μmol, Eq: 0.02) and triphenylphosphine (1.39 mg, 5.31 μmol, Eq: 0.02) were added, the vessel was capped and heated for 18 hours to 75° C. Still starting material. The mixture was cooled, purged with argon and another portion of copper (I) iodide (1.01 mg, 5.31 μmol, Eq: 0.02), bis(triphenylphosphine) palladium(II) chloride (3.73 mg, 5.31 μmol, Eq: 0.02) and triphenylphosphine (1.39 mg, 5.31 μmol, Eq: 0.02) was added and the mixture was stirred again over night at 75° C. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using ethyl acetate/methanol 0-10% as eluent affording 7-chloro-2-[1-(4-methoxy-benzyl)-5-pyrrolidin-1-yl-1H-[1,2,4]triazol-3-ylethynyl]-[1,2,4]triazolo[1,5-a]pyridine (33 mg 26.8%) as an orange oil. MS: m/e=434.4 (M+H+)
Reaction SMILES: [F:1][C:2]([F:17])([C:6]1([OH:16])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[C:3]([OH:5])=O.CCN(CC)CC.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]2[O:37][N:36]=[C:35]([C@@H:38]3[CH2:42][CH2:41][CH2:40][NH:39]3)[CH:34]=2)[CH:26]=1.C(=O)(O)[O-].[Na+]>C1COCC1.ClC(OCC)=O>[F:17][C:2]([F:1])([C:6]1([OH:16])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[C:3]([N:39]1[CH2:40][CH2:41][CH2:42][C@H:38]1[C:35]1[CH:34]=[C:33]([CH2:32][O:31][C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[O:37][N:36]=1)=[O:5]
Reactant: c1cncc(OCc2cc([C@@H]3CCCN3)no2)c1
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)O)C1
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(COc3cccnc3)on2)C1
Yield: 58.5 %

Procedure:
To a solution of 2,2-difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)acetic acid (3.192 g) and Et3N (4.44 mL) in THF (100 mL), ethyl chloroformate (1.12 mL) was added at room temperature and the mixture was stirred for an hour. To the reaction mixture, a THF (50 mL) solution of the compound (2.607 g) obtained in Example 2-(3) was added dropwise at room temperature and the mixture was stirred at room temperature for 64 hours. To the reaction mixture, saturated aqueous sodium bicarbonate (200 mL) was added and the organic layer extracted with AcOEt (200 mL) was washed with brine (200 mL), dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by NH-form silica gel chromatography (AcOEt/hexane); the resulting compound was recrystallized (Et2O/pentane) to give the titled compound (2.969 g, colorless powder.)
Reaction SMILES: [CH2:1]([CH:4]([CH2:12][CH2:13][CH2:14]C)[CH:5]([OH:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8])C=C.[CH3:16]C(CC=C)C(=O)C>>[OH:11][C:5]([CH3:16])([CH:4]([CH3:1])[CH2:12][CH:13]=[CH2:14])[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: C=CCC(C)C(C)=O
Reactant: C=CCC(CCCC)C(O)CC(=O)OC
Product: C=CCC(C)C(C)(O)CC(=O)OC

Procedure:
The compound of interest (11.7 g, 60%) was obtained as an oil substance (diastereomeric mixture) in the same way as in paragraph (10-a) using 3-methyl-5-hexen-2-one (17 g, 106 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:13](=O)[CH2:14]Br>>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:13]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[CH:14]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C(=O)CBr)cc1OC
Reactant: Nc1ccccn1
Product: COc1ccc(-c2cn3ccccc3n2)cc1OC

Procedure:
The title compound, pale yellow solid, m.p. 96° C. and MS: m/e=254.1 (M+), was prepared in accordance with the general method of example 1 from 2-amino-pyridine and 3,4-dimethoxy-phenacylbromide.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: BrCCc1ccccc1
Product: CCOC(CNCCc1ccccc1)OCC
Yield: 93.7 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-1, 2,2-diethoxyethanamine (5.82 ml, 40 mmol) was reacted with (2-bromoethyl)benzene (2.70 ml, 20 mmol) and the obtained residue was purified by Büch silica gel column chromatography (chloroform only) to obtain the title compound (4.45 g, 94%).