Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:24][CH:20]3[CH2:21][NH:22][CH2:23][CH:19]3[CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[C:10]([CH3:15])=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:25]([CH2:27][C:28](O)=[O:29])#[N:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:24][CH:20]3[CH2:21][N:22]([C:28](=[O:29])[CH2:27][C:25]#[N:26])[CH2:23][CH:19]3[CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[C:10]([CH3:15])=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1nn(C)cc1Nc1ncc(Cl)c(NC2CC3CNCC3C2)n1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn(C)cc1Nc1ncc(Cl)c(NC2CC3CN(C(=O)CC#N)CC3C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To a solution of 5-chloro-N2-(1,3-dimethyl-1H-pyrazol-4-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (186.6 mg, 0.54 mmol) and 2-cyanoacetic acid (64.8 mg, 0.76 mmol) in a mixture of DCM (20 mL) and DMF (5 mL) were added HATU (374.3 mg, 0.98 mmol) and Et3N (151.8 mg, 1.50 mmol). After addition, the reaction mixture was stirred at rt for 1 h, quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/50) to give the title compound as a beige solid (124.5 mg, 55.9%).
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([OH:17])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:37]([NH:44][C:45](=[O:52])[C@H:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[NH2:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:44]([CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:45](=[O:52])[C@H:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[NH2:47])=[O:17])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(C)C[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 67.9 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (108 mg, 0.37 mmol, 1.0 eq), triethylamine (156 uL, 1.11 mmol, 3.0 eq), and THF (1.5 mL), was treated with isobutyl chloroformate (53 uL, 0.41 mL, 1.1 eq), then with L-leucine N-benzylamide (123 mg, 570 umol, 1.5 eq). Workup as before provided 124 mg (68%) of L-leucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].C(O)(=O)[CH:14]([CH2:16][C:17](O)=O)[OH:15].S(=O)(=O)(O)O.CN(C)C1C=C2C(C=CC(=O)O2)=CC=1>>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]2[C:7]([CH:17]=[CH:16][C:14](=[O:15])[O:10]2)=[CH:8][CH:9]=1)[CH3:12]
Reactant: CCN(CC)c1cccc(O)c1
Reactant: O=C(O)CC(O)C(=O)O
Agent: CN(C)c1ccc2ccc(=O)oc2c1
Agent: O=S(=O)(O)O
Product: CCN(CC)c1ccc2ccc(=O)oc2c1

Procedure:
m-Diethylaminophenol 7.4g, malic acid 6.0g and 85% sulfuric acid 12.0ml were treated as for the 7-dimethylamino-coumarin, although the alumina column cut could not be induced to crystallize. It was rechromatographed, eluting first with benzene thoroughly, and then developing with dichloromethane. After two crystallizations from cyclohexane, cream colored crystals 0.5g (5%), m.p. 87.5°-88.0° were obtained, found C 71.94; H 7.09; N 6.35; C13H15NO2 requires C 7.19; H 6.92; N 6.45%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[N:8]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([C:18]([F:28])([F:17])[F:27])=[CH:24][CH:23]=3)[C:9]=2[CH:10]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: CN1CCc2[nH]c3cc(F)cc(F)c3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3c(F)cc(F)cc3n2CCc2ccc(C(F)(F)F)nc2)C1

Procedure:
The title compound is prepared from a mixture of 7,9-difluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17]CC)=O)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCCC(C(Cl)=O)C1)(=O)C1C=CC=CC=1.[CH2:37]([NH2:45])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>>[CH2:37]([NH:45][C:15]([CH:11]1[CH2:12][CH2:13][CH2:14][N:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10]1)=[O:17])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCN
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Agent: O=C(Cl)C1CCCN(C(=O)c2ccccc2)C1
Product: CCCCCCCCNC(=O)C1CCCN(C(=O)c2ccccc2)C1

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with 1-benzoyl-3-piperidinecarbonyl chloride (219.0 mg; 0.87 mmol) and commercially available octylamine (144 μl; 0.87 mmol). The crude product was purified by chromatography on silica, eluting with 100% ethyl acetate, giving N-(n-octyl) 1-benzoyl-3-piperidinecarboxamide (207.5 mg) as a colorless waxy oil. MS m/z (positive ion) 345 (MH+; 100), 216 (30).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[CH2:9]([NH:11][CH2:12][C:13]([CH2:19][NH:20][C:21]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([OH:18])[C:14]([F:17])([F:16])[F:15])[CH3:10]>>[CH2:9]([N:11]([CH2:12][C:13]([OH:18])([CH2:19][NH:20][C:21]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:14]([F:17])([F:16])[F:15])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH3:10]
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: O=C(O)c1cccs1
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1cccs1

Procedure:
Prepared similarly to Example 11 from 2-thiophenecarboxylic acid and 3-(ethylamino)-1,1,1-trifluoro-2-{[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li][CH2:25][CH2:26][CH2:27][CH3:28].[C:29]1([C:35]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[O:36][CH2:37][C:38]2[N:43]=C(C=O)C=[CH:40][CH:39]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[NH4+].[Cl-]>C1COCC1.O>[CH3:2][O:3][CH:25]=[CH:26][C:27]1[CH:28]=[CH:40][CH:39]=[C:38]([CH2:37][O:36][C:35]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[N:43]=1
Reactant: [Li]CCCC
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COC=Cc1cccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A stirred solution of (methoxymethyl)triphenylphosphonium chloride (2.79 g, 8.13 mmol) in THF (50 mL) at 0° C. was treated dropwise with n-BuLi (1.6-M in hexanes, 5.08 mL, 8.13 mmol), stirred for 1 h, treated with a solution of 6-(triphenylmethoxy)methylpyridine-2-carboxaldehyde (1.54 g, 4.06 mmol) in THF (15 mL) and allowed to warm to room temperature overnight. The reaction was treated with saturated NH4Cl solution (5 mL), diluted with water (50 mL), extracted with EtOAc (2×50 mL) and the combined organic phase diluted with iso-hexane (50 mL), dried (MgSO4), filtered through silica and concentrated in vacuo to give 2-(2-methoxyethenyl)-6-(triphenylmethoxy)methylpyridine (1.58 g) as a yellow oil. A solution of this crude alkene and 10% Pd/C (216 mg, 0.203 mmol) in EtOAc (50 mL) was stirred under a hydrogen atmosphere for 16 h, filtered through Celite and concentrated in vacuo to give the title compound (1.08 g, 65%) as a yellow oil; NMR δH (400 MHz, CDCl3) 7.67-7.64 (1H, m), 7.52-7.49 (6H, m), 7.32-7.21 (10H, m), 7.09-7.07 (1H, m), 4.34 (2H, s), 3.69 (2H, t, J 6.5 Hz), 3.32 (3H, s) and 2.98 (2H, t, J 6.5 Hz); M/Z 410 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>ClCCl>[CH3:26][S:23]([O:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCO[C@H](COS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a solution of (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (3.0 g, 13.8 mmol) and triethylamine (4.2 g, 41.4 mmol) in dichloromethane (80 mL) at 0° C. was dropwise added mesyl chloride (1.9 g, 16.5 mmol). The reaction mixture was stirred at 0° C. for 2 hour, and then diluted with dichloromethane (100 mL). The organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated to afford (S)-tert-butyl 2-((methylsulfonyloxy)methyl)morpholine-4-carboxylate as a purple oil (4.0 g, 98%), which was directly used in the next step without further purification. MS (ES+) C11H21NO6S requires: 295, found: 240 [M+H-56]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]2[C:12]([C:13](=[O:19])[C:14]=1[CH2:15][N:16]=[N+]=[N-])=[CH:11][CH:10]=[C:9]([C:20]([F:23])([F:22])[F:21])[N:8]=2)=[O:4].[ClH:30].C(OCC)(=O)C>O1CCOCC1.CO.[Pt](=O)=O>[ClH:30].[CH3:1][O:2][C:3]([C:5]1[N:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]2[C:12]([C:13](=[O:19])[C:14]=1[CH2:15][NH2:16])=[CH:11][CH:10]=[C:9]([C:20]([F:21])([F:23])[F:22])[N:8]=2)=[O:4]
Reactant: COC(=O)c1c(CN=[N+]=[N-])c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1c(CN)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
In a 100 mL pear-shaped flask, 3-azidomethyl-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (490 mg, 1.21 mmol), platinum (IV) oxide (100 mg, 0.440 mmol) and a 4N HCl in 1,4-dioxane (2.4 g, 2 mL) were combined with ethyl acetate (12 mL) to give a brown suspension which was hydrogenated at atmospheric pressure at 25° C. for 11 hr. The reaction mixture was diluted with methanol (200 mL), stirred for 1 hr at room temperature, filtered through a small celite pad, and concentrated under vacuum to give 3-aminomethyl-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester hydrochloride (0.54 g, 107% crude yield) as a light brown solid. Material was used without any further purification. 1H NMR (DMSO-d6) δ ppm 8.93 (d, J=8.2 Hz, 1H) 8.21 (br. s., 2H) 8.04 (d, J=8.2 Hz, 1H) 6.80-7.72 (m, 4H) 3.88 (br. s., 2H) 3.54 (s, 3H). MS calcd. for C18H14F3N3O3 [(M+H)+] 378.0, obsd. 378.0, [(M+H-NH3)+] 361.0, obsd. 361.0, [(M+H-NH3+CH3CN)+] 402.0, obsd. 402.0.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Cl[C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:39])[CH:33]([OH:38])[CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>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.CC#N.CC#N.O>[F:18][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[CH2:27][CH2:28][N:29]([C:32](=[O:39])[C@H:33]([OH:38])[CH2:34][CH:35]([CH3:36])[CH3:37])[CH2:30][CH2:31]2)[CH:21]=1
Reactant: CC1(C)OB(c2ccccc2C(F)F)OC1(C)C
Reactant: CC(C)CC(O)C(=O)N1CCN(c2cccc(Cl)c2)CC1
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: CC(C)C[C@@H](O)C(=O)N1CCN(c2cccc(-c3ccccc3C(F)F)c2)CC1
Temperature: 150 °C

Procedure:
2-(2-Difluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (34 mg, 0.11 mmol), 1-[4-(3-Chloro-phenyl)-piperazin-1-yl]-2-hydroxy -4-methyl-pentan-1-one (34 mg, 0.13 mmol), Pd(Ph3P)4 (1.3 mg, 10 μmol), K2CO3 (30.4 mg, 0.22 mmol), CH3CN (900 μL), and H2O (100 μL) were sealed in a microwave vessel and heated by microwave irradiation at 150° C. for 10 minutes. The reaction was filtered and purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to give 2. LCMS: m/z 403.7 (M+H)+ at 3.72 minutes (10% -99% CH3CN/H2O), (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][Cl:26])[C@H:20]([NH:27][C:28](=[S:38])[CH2:29][C:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=2[Cl:37])[C:19]3=[O:39])=[O:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:26][CH2:25][C:24]1[CH2:23][S:22][C@H:21]2[N:18]([C:19](=[O:39])[C@H:20]2[NH:27][C:28](=[S:38])[CH2:29][C:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=2[Cl:37])[C:17]=1[C:15]([OH:16])=[O:14]
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS[C@@H]2[C@H](NC(=S)Cc3cc(Cl)ccc3Cl)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: O=C(O)C1=C(CCl)CS[C@@H]2[C@H](NC(=S)Cc3cc(Cl)ccc3Cl)C(=O)N12
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
A slurry of (6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate diphenylmethyl ester (10.0 g, 15.8 mmol) in CH2Cl2 (200 mL) at 0° C. was treated with anisole (24 mL) and then trifluoroacetic acid (80 mL). The resulting solution was stirred for 1 h at 0° C. and then concentrated under reduced pressure. The residue was stirred with Et2O, and the resulting solid was collected by filtration to give 5.20 g of (6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)-thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a white solid (70% yield), m.p. 125° C. 1H NMR (300 MHz, DMSO-d6) δ3.51 (d, J=18 Hz, 1H), 3.70 (d, J=18 Hz, 1H), 3.91 (s, 2H), 4.52 (d, J=11 Hz, 1H), 4.58 (d, J=11 Hz, 1H), 5.13 (d, J=5 Hz, 1H), 5.70 (dd, J=5, 8 Hz, 1H), 7.24 (dd, J=2, 8 Hz, 1H), 7.47 (dd, J=2, 8 Hz, 2H), 9.28 (d, J=8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH2:20][C:21]#[CH:22])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.ClC1C(C2C=C(O)C(Cl)=CC=2F)=NC=C(C(F)(F)[F:31])C=1.C(Br)C#C>>[Cl:1][C:2]1[C:3]([C:12]2[CH:13]=[C:14]([O:19][CH2:20][C:21]#[CH:22])[C:15]([Cl:18])=[CH:16][C:17]=2[F:31])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: Oc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Reactant: C#CCOc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Agent: C#CCBr
Product: C#CCOc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Yield: 67 %

Procedure:
In a preparation similar to that described above for 3-chloro-2-(4-chloro-3-propargyloxyphenyl)-5-trifluoromethylpyridine, reaction of 1.4 g (4.5 mmol) of 3-chloro-2-(4-chloro-2-fluoro-5-hydroxyphenyl)-5-trifluoromethylpyridine and 0.6 g (5 mmol) of propargyl bromide resulted in 1.1 g of colorless crystals. Yield: 67%; melting point: 97°-98° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:11])[CH2:6][NH:7]CC#C)[CH3:3].C(N([CH:18]([CH3:20])[CH3:19])CC)(C)C.[CH2:21]([S:25](Cl)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOCC>[CH2:21]([S:25]([NH:7][CH:6]([CH2:20][C:18]#[CH:19])[C:5]([O:4][CH2:2][CH3:3])=[O:11])(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCCS(=O)(=O)Cl
Reactant: C#CCNCC(=O)OCC
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOCC
Product: C#CCC(NS(=O)(=O)CCCC)C(=O)OCC
Reaction time: 0.5 h

Procedure:
A solution of propargyl glycine ethyl ester hydrochloride (from treatment of 2.0 g (17.7 mmol) with EtOH/HCl at reflux) in CH2Cl12 (30 μl) and 10 ml (57 mmol) diisopropylethylamine was cooled to 0° C. and 35 ml of butanesulfonyl chloride added dropwise. After 30 minutes, reaction mixture was poured into the cold 10% citric acid solution and saturated with ether. The organic phase was washed with NaHCO3 solution, brine and dried (MgSO4). The crude product was purified by flash column chromatography to afford 2.6 g of 18-1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.[I:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>>[I:19][C:20]1[N:21]=[CH:22][N:23]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:5]=[C:4]([CH3:18])[N:3]=2)[CH:24]=1
Reactant: Ic1c[nH]cn1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(Cl)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared 2-chloro-6-methyl-4-(4-trifluoromethyl-phenyl)pyridine (example A.30) (1.0 g, 3.7 mmol) and commercially available 4-iodo-imidazole (0.857 g, 4.4 mmol) according to the general procedure IVa. Obtained as a yellow solid (0.98 g, 62%). MS (ISP) 430.2 [(M+H)+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[S:18][CH:19]=[CH:20][N:21]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1nccs1
Reactant: Oc1ccccc1OCc1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(COc2ccccc2-c2nccs2)cc1
Temperature: 100 °C
Yield: 48.9 %

Procedure:
o-Benzyloxyphenol (7.5 g, 37.5 mmol) in dry DMF (60 mL) was treated with Me4N+OH-.5H2O (37.5 mmol, 6.8 g) followed by 2-bromothiazole (6.15 g, 37.5 mmol). The stirred solution was heated to about 100° C. under N2 (g) for 16 hours. The mixture was cooled in ice and crystalline, H2O-soluble Me4N+Br- was removed by filtration. The filtrate was concentrated in vacuo and partitioned between Et2O (100 mL) and H2O (60 mL). The organic phase was washed with 1N NaOH (3×) and brine, dried over Na2SO4 and concentrated in vacuo to afford 4.9 g of crude 2-(2-benzyloxyphenyl)thiazole (GCMS m/z 283 (M+)). This material was directly deprotected by treatment with 33% HBr in HOAc (35 mL) for 2 hours at about 20° C.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[C:7]1([S:13]([C:16]2[C:17]([S:27][CH3:28])=[N:18][N:19]3[C:24]([NH2:25])=[CH:23][C:22](Cl)=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[C:7]1([S:13]([C:16]2[C:17]([S:27][CH3:28])=[N:18][N:19]3[C:24]([NH2:25])=[CH:4][C:3]([N:2]([CH3:1])[CH3:6])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[C:7]1([S:13]([C:16]2[C:17]([S:27][CH3:28])=[N:18][N:19]3[C:24]([NH2:25])=[CH:23][C:22]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[N:21][C:20]=23)(=[O:14])=[O:15])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)CCN
Reactant: CSc1nn2c(N)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CSc1nn2c(N)cc(N(C)C)nc2c1S(=O)(=O)c1ccccc1
Product: CSc1nn2c(N)cc(NCCN(C)C)nc2c1S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 17 %
Yield: 48 %

Procedure:
0.26 g (3 mmol) of 2-dimethylaminoethylamine in 5 ml of DMF was added to a solution of 0.4 g (1 mmol) of 3-benzenesulphonyl-5-chloro-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine in 10 ml of DMF and stirred at 90° for 1 hr. The reaction solution was evaporated and the residue was partitioned between H2O and CH2Cl2. The aqueous phase was extracted three times with 50 ml of CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (silica gel, CH2Cl2/MeOH 8:1) yielded 0.20 g (48%) of 3-benzenesulphonyl-N5,N5-dimethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine-5,7-diamine as colorless crystals, m.p.>230°, and 0.08 g (17%) of 3-benzenesulphonyl-N5-(2-dimethylamino-ethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine-5,7-diamine as colorless crystals, m.p. 210-212°.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.CO[CH:23]1[CH2:27][CH2:26][CH:25](OC)O1.C(O)(=O)C>O>[N:18]1([C:17]2[CH:19]=[CH:20][C:14]([S:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)(=[O:13])=[O:12])=[CH:15][CH:16]=2)[CH:23]=[CH:27][CH:26]=[CH:25]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc(S(=O)(=O)c2cccc3cnccc23)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(-n2cccc2)cc1)c1cccc2cnccc12
Yield: 76.1 %

Procedure:
A mixture solution of 4-(5-isoquinolylsulfonyl)aniline 300 mg (1.1 mmol), 2,5-dimethoxytetrahydrofuran 160 mg (1.2 mmol) and acetic acid 2 ml was heated and refluxed for 1 hour. Water was added to the reaction solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogencarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was recrystalized from ethyl acetate-hexane to give 5-[4-(pyrrole-1-yl)phenylsulfonyl]isoquinoline 280 mg (83.0%).
Reaction SMILES: BrCC1C=C[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:25]([CH2:28][NH2:29])[CH:26]=[CH2:27].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:23].[Cl:24][C:19]1[CH:18]=[C:17]([C:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:25]([CH2:28][NH:29][CH2:9][CH2:6][CH:5]=[CH2:4])=[CH:26][CH:27]=3)=[CH:14][CH:13]=2)=[O:16])[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: C=CCCN
Reactant: O=C(c1ccc(-c2ccc(CBr)cc2)cc1)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=CCCNCc1ccc(-c2ccc(C(=O)c3ccc(Cl)c(Cl)c3)cc2)cc1
Product: Cl

Procedure:
1.0 g of 3,4-dichlorophenyl 4'-bromomethyl-4-biphenylyl ketone, 1.5 ml of N-allylmethylamine and 0.84 g of potassium carbonate in 25 ml of ethanol are heated to boiling under reflux for 4 hours. The mixture is evaporated and the residue is extracted with ether. The extracts are dried over magnesium sulfate and treated with an ethereal hydrogen chloride solution. The precipitated hydrochloride is filtered and dried. 4'[(Allylmethylamino)methyl]-4-biphenylyl 3,4-dichlorphenyl ketone hydrochloride, m.p. 160° C., is obtained.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]([OH:12])([C:10]#[CH:11])[CH3:9].[CH3:13][C:14]([C:16](Cl)=[O:17])=[CH2:15]>N1C=CC=CC=1>[C:16]([O:12][C:8]([CH3:9])([C:10]#[CH:11])[CH3:7])(=[O:17])[C:14]([CH3:15])=[CH2:13]
Reactant: C#CC(C)(C)O
Reactant: C=C(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C#CC(C)(C)OC(=O)C(=C)C
Reaction time: 6 h
Yield: 62 %

Procedure:
A reactor was charged with 550 parts of benzene, 74 parts of pyridine and 65.5 parts of 2-methyl-3-butyn-2-ol. To this were added 90 parts of methacryl chloride dropwise over one hour while keeping the inner temperature at 20° C. Then the reaction mixture was kept at 50° C. for 6 hours, suction filtered, evaporated and distilled in vacuo. 2-Methyl-3-butyn-2-yl methacrylate boiling at 56°-58° C./12 mmHg was obtained in a yield of 62% of theory. The product was identified by the IR spectrum thereof.