Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26].CCN(CC)CC>C1COCC1>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25](=[O:26])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1Cl
Reaction time: 6 h
Yield: 92.7 %

Procedure:
To a stirred mixture of tert-butyl 4-amino-3-methylphenylacetate (1.00 g, 4.52 mmol), 2-chlorophenyl isocyanate (0.55 ml, 4.52 mmol) in THF (10 ml) was added Et3N (0.13 ml, 0.90 mmol) at room temperature. After 6 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane, to give tert-butyl 4-[N′-(2-chlorophenyl)ureido]-3-methylphenylacetate (1.57 g, 93%) as a pale yellow powder. mp 104-106° C. (dec.); 1H-NMR (CDCl3) δ1.45 (s, 9H), 2.28 (s, 3H), 3.51 (s, 2H), 6.33 (br, 1H), 6.96 (t, J=7.6 Hz, 1H), 7.08 (br, 1H), 7.16-7.30 (m, 4H), 7.42 (m, 1H), 8.2 (d, J=8.1 Hz, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]2[CH3:34])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH2:24][OH:25])[CH:23]=3)=[N:14][C:12]=2[N:13]=1.[P:35](=O)([OH:38])([OH:37])[OH:36]>C(OCC)(=O)C>[P:35]([O:25][CH2:24][C:22]1[CH:23]=[C:18]([C:15]2[CH:16]=[CH:17][C:11]3[C:10]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]4[CH3:34])=[N:9][C:8]([N:3]4[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]4[CH3:1])=[N:13][C:12]=3[N:14]=2)[CH:19]=[CH:20][C:21]=1[O:26][CH3:27])([OH:38])([OH:37])=[O:36]
Reactant: O=P(O)(O)O
Reactant: COc1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1CO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1COP(=O)(O)O
Temperature: 25 °C

Procedure:
On a 50 mg scale using a 1:1.1 molar ratio of (5-{2,4-Bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol:Phosphoric acid. 50 mg of (5-{2,4-Bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol was dissolved in the minimal amount of Ethyl Acetate, this solution was then added drop-wise to a vial containing the phosphoric acid which caused a yellow solid to immediately precipitate. The experiment was then left to stir over night at room temperature before filtering and isolating the precipitate.
Reaction SMILES: [CH:1]1([S:7]([CH2:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([N:33]=[N+:34]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[CH:1]1([S:7]([C:10]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[N+:33]=[N-:34])(=[O:8])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Oc1ccc(S(=O)(=O)CS(=O)(=O)C2CCCCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)C2CCCCC2)cc1
Reaction time: 0.17 h
Yield: 34 %

Procedure:
The cyclohexylsulfonyl(4-acetyloxyphenylsulfonyl)methane in Synthesis Example 12, 5 g (0.014 mol), was dispersed in 100 g of dichloromethane. To the dispersion was added 2.3 g (0.015 mol) of p-toluenesulfonylazide. With stirring under ice cooling, 2.9 g (0.015 mol) of DBU was added to the dispersion, and after 10 minutes, 55 g of a 0.2N aqueous hydrochloric acid was added to stop reaction. The organic layer was separated and washed with 50 g of water. The organic layer was concentrated and 6 g of the residue was purified by silica gel column chromatography using dichloromethane as an elute. The thus obtained oily product was combined with 20 g of hexane for crystallization, followed by filtration and vacuum drying. There was obtained 2 g (yield 34%) of fine yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH:14]=O)=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([CH2:14][N:30]3[CH2:31][CH2:32][CH:27]([C:23]4[CH:22]=[C:21]([NH:20][C:18](=[O:19])[CH:17]([CH3:16])[CH3:33])[CH:26]=[CH:25][CH:24]=4)[CH2:28][CH2:29]3)=[CH:12][NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: COc1ccc(-c2n[nH]cc2C=O)cc1
Product: COc1ccc(-c2n[nH]cc2CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1

Procedure:
Prepared by Procedure F and Scheme R using 3-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 433.1 (M+H)+.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[Cl:18][CH2:19][CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O>O.ClCCl>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:20][CH2:19][Cl:18])=[CH:13][CH:12]=1
Reactant: Oc1ccc(-c2ccc(F)cc2F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(-c2ccc(OCCCl)cc2)c(F)c1

Procedure:
The compound 2',4'-difluoro-4(2-chloroethoxy)biphenyl is prepared by a process wherein to a solution of 15 g of sodium hydroxide in 30 ml of water there is added 68.2 g of 4-(2',4'-difluorophenyl)phenol and 106 g of 2-chloroethyl-p-toluene-sulfonate. The mixture is heated to about 95°-100° C. while stirring (at 96°-98° C. an exothermic reaction occurs) and maintained at this temperature for 5 hours. The resulting material is diluted with dichloromethane, washed with water, and evacuated until dry. The crude product is crystallized using isopropyl alcohol to yield 62 g (69% of theory) of the final product. If a further crop (9 g) of pure product can be obtained from the mother liquor, the total yield of the product is 80% of theory.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[IH:19].CS[C:22]1[NH:23][CH2:24][CH2:25][N:26]=1>N1C=CC=CC=1>[IH:19].[NH:26]1[CH2:25][CH2:24][N:23]=[C:22]1[NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CCOC(=O)c1ccc2c(cnn2CCCN)c1
Reactant: CSC1=NCCN1
Agent: I
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc2c(cnn2CCCNC2=NCCN2)c1
Temperature: 80 °C
Yield: 75 %

Procedure:
The crude product of Example 1198 Part A was combined with 2-methylthio-4,5-dihydroimidazole hydriodide (2.71 g, 11.1 mmol) and pyridine (125 mL), and the mixture was heated at 80° C. for 5 h. The mixture was allowed to cool to room temperature and concentrated under vacuum. The residue was purified by flash chromatography (dichloromethane:methanol 80:20) to provide the title product (3.73 g, 75%) as a gum: 1H NMR (DMSO-d6) δ 8.50 (s, 1H), 8.30 (s, 1H), 8.24 (bs, 1H), 7.98 (d, 1H), 7.75 (d, 1H), 4.49 (t, 2H), 4.34 (q, 2H), 3.57 (s, 4H), 3.13 (m, 2H), 2.05 (m, 2H), 1.35 (t, 3H); High resolution mass spectrum (NH3 --CI) calculated (M+H+) 316.1774, found 316.1765.
Reaction SMILES: [CH2:1]=[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[O:3]1.C(N(CC)CC)C.[C-]#N.[K+].[CH3:21][C:22]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C(#N)C>[O:10]=[C:4]1[CH:5]2[CH2:9][CH:8]([CH2:7][CH2:6]2)[C:2]([O:3][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:32])[F:33])=[N:30][C:22]=2[CH3:21])=[CH:1]1
Reactant: C=C1OC(=O)C2CCC1C2
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(C(F)(F)F)ccc1C(=O)OC1=CC(=O)C2CCC1C2
Temperature: 20 °C

Procedure:
2.07 g (0.015 mol) of distilled 4-methylene-3-oxabicyclo[3.2.1]octan-2-one and 3.34 g (0.033 mol) of triethylamine are stirred for 2.5 hours at a temperature of 60° C. in 50 ml of acetonitrile in the presence of 98 mg (1.5 mmol) of potassium cyanide. Cooling to a temperature of 20° C. is then carried out and 2.35 g (0.11 mol) of 2-methyl-6-trifluoromethyl-nicotinoyl chloride, freshly prepared according to WO 00/15615, dissolved in a small amount of acetonitrile are added. The 2-methyl-6-trifluoromethylnicotinic acid 4-oxobicyclo[3.2.1]oct-2-en-2-yl ester (known from WO 00/15615) obtained in situ as intermediate is fully converted within a period of 3.5 hours (monitoring by thin-layer chromatography). The reaction mixture is then acidified with dilute hydrochloric acid and extracted with ethyl acetate against water at a pH value of 2, dried over Na2SO4 and concentrated by evaporation. The product is purified by means of column chromatography (eluant: ethyl acetate/hexane 4:1) to yield 3.16 g of 90% 4-hydroxy-3-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)-bicyclo[3.2.1]oct-3-en-2-one (58.3% based on the 4-methylene-3-oxabicyclo[3.2.1]octan-2-one used or 83.3% based on the 2-methyl-6-trifluoromethylnicotinoyl chloride used).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.[C:8]1([S:14]([N:17]2[C:21]3=[N:22][CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25](Cl)=[C:20]3[CH:19]=[CH:18]2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C>C(O)C>[C:8]1([S:14]([N:17]2[C:21]3=[N:22][CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]([NH:1][CH:2]4[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]4)=[C:20]3[CH:19]=[CH:18]2)(=[O:15])=[O:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: NC1CCC(O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCC(O)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To a solution of 3-Amino-cyclopentanol (about 2.5 g) in ethanol (50 mL) were added 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (7 g, 20.4 mmol) and diisopropylethylamine (DIPEA) (7.2 g, 60 mmol), then the reaction mixture was stirred at 80° C. for 3 hours. The reaction mixture was purified by column chromatography (Hexanes/ethyl acetate=3:1) to give 7.4 g (76%) of 3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclopentanol. 1H NMR (400 MHz, CDCl3) δ: 9.56 (s, 1H), 9.54 (s, 1H), 8.19-8.16 (m, 2H), 7.62-7.56 (m, 4H), 6.82-6.81 (m, 1H), 4.56-4.50 (m, 2H), 2.25-1.96 (m, 6H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[Si:22]([O:29][C@@H:30]([CH3:58])[C@@H:31]([NH:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]#[N:56])=[C:51]([Cl:57])[CH:50]=1)[C:32]([NH:34][NH:35][C:36](=[O:47])[C:37]1[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1)=O)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl>[Si:22]([O:29][C@@H:30]([CH3:58])[C@@H:31]([NH:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]#[N:56])=[C:51]([Cl:57])[CH:50]=1)[C:32]1[O:47][C:36]([C:37]2[CH:38]=[CH:39][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:41][CH:42]=2)=[N:35][N:34]=1)([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:24])[CH3:23]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(Cl)c1)c1nnc(-c2ccc(S(C)(=O)=O)cc2)o1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
Polymer supported triphenylphosphine (2.08 g, 6.24 mmol) was diluted in 200 ml of DCM followed by addition of I2 (1.58 g, 6.24 mmol) and TEA (2.31 mL, 16.64 mmol) at 0° C. N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyanophenylamino)butanoyl)-4-(methylsulfonyl)benzohydrazide (2.35 g, 4.16 mmol) 200 mL DCM was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stirred. The temperature was allowed to warm to room temperature and stirred for an additional 10 min. The reaction was quenched with 55 mL saturated sodium thiosulfate and the biphasic mixture was separated. The aqueous layer was extracted with EtOAc (3×70 mL) and the combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting crude oil was purified by flash chromatography (SiO2) [EtOAc-hexanes (1:2), then (1:1) as eluent] to provide the title compound (2.16 g, 95%). The crude material was used directly in the next step.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:21]([O:28][C@@H:29]([CH2:36][CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[C@H:30]([CH3:35])/[CH:31]=[CH:32]/[CH2:33][OH:34])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.[O-]S([O-])(=O)=O.[Cu+2]>[Si:21]([O:28][C@@H:29]([CH2:36][CH2:37][O:38][Si:39]([C:42]([CH3:43])([CH3:45])[CH3:44])([CH3:40])[CH3:41])[C@H:30]([CH3:35])/[CH:31]=[CH:32]/[CH2:33][O:34][C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:23])[CH3:22]
Reactant: C[C@H](/C=C/CO)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu+2]
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Product: C[C@H](/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 99.5 %

Procedure:
Trityl chloride (4.1 g, 14.7 mmol) and DMAP (1.8 g, 14.7 mmol) were added to a solution of alcohol 11 (2.75 g, 7.1 mmol) in pyridine (71 mL). The mixture was heated to reflux for 18 h, cooled to ambient temperature and added to a solution of sat'd CuSO4 (200 mL). The mixture was extracted with Et2O (2×20 mL) and the combined organic extracts were washed sat'd CuSO4 (2×20 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (EtOAc/hexane 1:19) provided 12 (4.46 g, quantitative) as a pale yellow oil: IR (CHCl3) 2954, 2856, 1471, 1448, 1254, 1095, 835, 773, 705 cm−1; 1H NMR (300 MHz, CDCl3) ε7.56 (m, 6H), 7.32 (m, 9H), 5.79 (dd, J=15.6, 6.7 Hz, 1H), 5.65 (dd, J=15.7, 5.0 Hz, 1H), 3.85 (m, 1H), 3.74 (m, 1H), 3.66 (d, J=4.9 Hz, 1H), 2.43 (m, 1H), 1.70 (q, J=6.5 Hz, 2H), 1.21 (d, J=6.9 Hz, 3H), 0.99 (s, 9H), 0.97 (s, 9H), 0.154 (s, 3H), 0.150 (s, 3H), 0.13 (s, 3H), 0.12 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 144.4, 134.2, 128.7, 127.7, 126.9, 126.8, 86.8, 72.6, 65.1, 60.2, 42.1, 36.6, 26.0, 18.3, 18.1, 15.3, −4.4, −5.3; LRMS (EST) 653.3 [M+Na]+, 422.4, 243.2; HRMS (ESI) calcd for C39H58O3Si2Na 653.3822 [M+Na]+, found 653.3851; [α]20D−1.9 (c 0.42, CHCl3).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:23])[N:9]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:10]=[C:4]2[C:3]=1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:22][C:13]1[C:12]([CH2:11][N:9]2[C:8](=[O:23])[N:5]3[CH:6]=[CH:7][C:2]([C:35]4[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=4)=[C:3]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:4]3=[N:10]2)=[CH:17][CH:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[N:14]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(Cl)ccn2c1=O
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: [Na+]
Solvent: Cc1ccccc1
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(C(F)(F)F)cc3)ccn2c1=O
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 7-chloro-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (72 mg, 0.17 mmol), 4-trifluoromethylphenylboronic acid (65 mg, 0.34 mmol), and 2.0 M aqueous sodium carbonate (0.37 mL) in toluene (1.5 mL) was added (Ph3P)4Pd (30 mg, 0.025 mmol) in one portion, and the resulting yellow mixture was vigorously stirred under argon at 100° C. for 1.5 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The EtOAc layer was washed with water, then saturated aqueous NaCl twice, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of EtOAc (0-80%) in hexanes to afford the desired product, which was contaminated with triphenylphosphine oxide. The product was further purified by preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 90% B over 12 min (A=90% water, 10% methanol and B=90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The yellow residue was dissolved in acetonitrile, frozen and lyophilized to afford 40 mg of the title compound as a light yellow powder. HPLC/MS: retention time=2.92 min, [M+H]+=530.4.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[NH2:18].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[NH:18][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Clc1nc(Cl)nc(Nc2c(Cl)cccc2Cl)n1
Yield: 91.2 %

Procedure:
2,4,6-trichloro-1,3,5-triazine (0.0266 mol) was added to 1,4-dioxane (50 ml) under Ar atmosphere. The solution was stirred until it became homogeneous, then 2,6-dichlorobenzenamine (0.0266 mol) and K2CO3 (0.0362 mol) were added. The reaction mixture was stirred at room temperature for 3 days. The solvent was evaporated. Water was added to the residue and the aqueous phase was extracted with CH2Cl2. The separated organic layer was washed with brine, dried with potassium carbonate, filtered and the filtrate was evaporated, yielding 7.52 g (91.2%) of N-(2,6-dichlorophenyl)-4,6-dichloro-1,3,5-triazin-2-amine (interm. 4).
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([CH2:8][CH2:9][CH3:10])=[CH:6][CH:7]=1.[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH2:14]1)#[CH:12]>C(N(CC)CC)C.COC(C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:19]([C@H:16]1[CH2:15][CH2:14][C@H:13]([C:11]#[C:12][C:2]2[N:3]=[N:4][C:5]([CH2:8][CH2:9][CH3:10])=[CH:6][CH:7]=2)[CH2:18][CH2:17]1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: C#C[C@H]1CC[C@H](CCCCC)CC1
Reactant: CCCc1ccc(Br)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CCCCC[C@H]1CC[C@H](C#Cc2ccc(CCC)nn2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
8.0 g of 3-bromo-6-propylpyridazine (prepared according to Example 3) were dissolved in 50 ml of triethylamine in a sulphonation flask under nitrogen. The solution was cooled to 0° C., treated with 562 mg of bis-(triphenylphosphine)-palladium (II) dichloride and 76 mg of copper (I) iodide and then treated dropwise within 20 minutes with 7.5 g of trans-1-ethynyl-4-pentylcyclohexane. The mixture was subsequently stirred at 0° C. for several hours, then at room temperature overnight and finally at 50° C. for a further 3 hours. For the working-up, the dark coloured mixture was diluted with 100 ml of tert.butyl methyl ether and suction filtered through a paper filter (rinsing with tert.butyl methyl ether). The filtrate was concentrated on a rotary evaporator. The dark coloured crystalline residue was taken up in 150 ml of tert.butyl methyl ether and washed successively with 100 ml of 2% (wt./vol.) ammonium chloride solution and with 100 ml of water. Each of the aqueous phases were back-extracted with a small amount of tert.butyl methyl ether. The combined organic phases were dried over sodium sulphate and concentrated on a rotary evaporator. For the purification, the brown coloured crystals obtained were chromatographed on silica gel with hexane/ethyl acetate (vol. 2:1), there being obtained a fraction of the desired product 3-[2-(trans-4-pentylcyclohexyl)ethynyl]-6-propylpyridazine (5.2 g) and a mixed fraction consisting of 3-bromo-6-propylpyridazine and product (4.8 g). The pure fraction was recrystallized once from ethanol at -20° C. and once from hexane at -20° C. and finally dried well in a vacuum drying oven at 40° C. There were thus obtained 3.4 g (28.5%) of 3-[2-(trans-4-pentylcyclohexyl)ethynyl]-6-propylpyridazine in the form of white crystals of melting point (C-I) 118.5° C., boiling point 210°-220° C./0.08 Torr.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)=[O:8].[N:17]1([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([N:20]2[CH2:21][CH2:22][N:17]([C:23](=[O:24])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:32])[F:33])[CH2:18][CH2:19]2)=[CH:13][CH:14]=1)=[O:8]
Reactant: CC(C)CCCNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: CC(C)CCCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (4-methylpentyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (36% yield). m.p. 43-45° C. 1H NMR (300 MHz, CDCl3) δ 7.71, 7.66-7.52, 7.34, 6.96, 4.06-3.98, 3.87-3.68, 3.63, 3.53, 3.19, 3.25, 3.09, 1.65-1.58, 1.36-1.33, 1.26-1.12, 0.85. 13C NMR (75 MHz, CDCl3) δ 167.6, 166.9, 166.2, 159.0, 158.9, 149.5, 149.4, 134.4, 132.4, 129.5, 129.2, 127.2, 126.9, 126.8, 112.6, 112.5, 51.4, 48.8, 46.4, 44.7, 44.4, 41.3, 37.8, 34.8, 34.0, 29.7, 29.0, 28.7, 27.1, 26.7, 22.5, 22.3, 14.0, 13.9. MS (ES+) m/z 464.2 (M+1), 486.2 (M+Na).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[S:10][C:9]([OH:11])=[N:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:5])[CH3:4]>C(Cl)Cl.C(O)(=O)C>[Br:1][CH2:4][C:3]([C:6]1[S:10][C:9]([OH:11])=[N:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5]
Reactant: CCOC(=O)c1nc(O)sc1C(C)=O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1nc(O)sc1C(=O)CBr
Yield: 94.7 %

Procedure:
A solution of bromine (10.8 g) in methylene chloride (5 ml) was dropwise added to a solution of ethyl 5-acetyl-2-hydroxy-4-thiazolecarboxylate (12.9 g) in a mixture of methylene chloride (150 ml) and acetic acid (10 ml) at 30° C. to 35° C. with stirring and the mixture was stirred at the same temperature for 30 minutes. An insoluble material was filtered off. The filtrate was washed brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether to give ethyl 5-(2-bromoacetyl)-2-hydroxy-4-thiazolecarboxylate (16.7 g). mp 105°-108° C.