Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.O[CH2:28][C@H:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]1>ClCCl>[I:25][CH2:28][C@H:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)C1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](CI)C1
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
Triphenylphosphine (182.2 g, 695 mmol) and imidazole (47.4 g, 696 mmol) were dissolved in dichloromethane (1.6 L), and iodine (70.4 g, 555 mmol) was then added to the above obtained solution under ice-cold condition. The obtained mixture was stirred for 10 minutes. After that, a dichloromethane solution (200 mL) of the (S)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (55.8 g, 278 mmol) synthesized by a method described in the known method (Bioorg. Med. Chem. Lett., 19, 2829-2834 (2009)) was further added to the reaction solution, and the obtained mixture was then stirred at room temperature for 15 hours. Thereafter, the reaction solution was washed with an aqueous solution of sodium sulfite, was then dried over anhydrous sodium sulfate, and was then concentrated in vacuo. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate=2%→25%) to obtain (S)-tert-butyl 3-(iodomethyl)pyrrolidine-1-carboxylate (73.2 g, 85%) in the form of a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22](I)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:22]2[N:21]=[CH:20][N:19]([C:11]3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[N:10]=3)[CH:23]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(I)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)c1

Procedure:
N-tert-Butyl-3-{1-[6-(3,4-dichloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(3,4-dichloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.74) (0.485 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.084 g) which was subsequently deprotected.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:19][CH:20]=[CH2:21])[C@@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH:36]([C:39]1[CH:44]=[CH:43][C:42]([S:45]([NH2:48])(=[O:47])=[O:46])=[CH:41][CH:40]=1)([CH3:38])[CH3:37].[H-].[Na+]>FC(F)(F)C1C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:19][CH:20]=[CH2:21])[C@@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:48][S:45]([C:42]3[CH:43]=[CH:44][C:39]([CH:36]([CH3:38])[CH3:37])=[CH:40][CH:41]=3)(=[O:46])=[O:47])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(S(N)(=O)=O)cc1
Reactant: C=CCN(C(=O)OC(C)(C)C)[C@@H]1CCc2cc(Br)ccc2C1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: FC(F)(F)c1ccccc1
Product: C=CCN(C(=O)OC(C)(C)C)[C@@H]1CCc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)ccc2C1
Reaction time: 0.08 h
Yield: 115.5 %

Procedure:
In an inert atmosphere (argon), allyl-((R)-6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (2.04 g, 5.5 mmol) was dissolved in trifluortoluol (10 ml) at room temperature. Tris(dibenzylideneacetone)dipalladium (230 mg, 0.25 mmol) and tri-tert-butyl-phosphane (152 mg, 0.75 mmol) were added to the reaction mixture. In a separate flask, 4-isopropyl-benzenesulfonamide (996 mg, 5 mmol) was dissolved in trifluortoluol (20 ml) at 65° C. Sodium hydride (50% in oil) (240 mg, 5 mmol) was added, stirred for 5 minutes and added to the reaction mixture. The reaction mixture was dispensed into 5 vials and stirred for 1 hour at 160° C. in the microwave (CEM). The combined reaction mixture was evaporated to dryness. H20 (50 ml) was added and extracted three times with 50 ml diethylether. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness to yield 2.8 g of crude product. The crude product was purified with silica gel chromatography with cyclohexane/ethyl acetate (85:15) as eluent, yielding the purified product (1.13 g, 45
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[CH3:16])(=O)=O.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[C:27]1[N:28]=[C:29]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:30]2[CH2:36][NH:35][CH2:34][CH2:33][C:31]=2[N:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C.O.[Pd+2]>[CH3:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[C:21]=1[C:27]1[N:28]=[C:29]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:30]2[CH2:36][N:35]([C:7]3[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=3[CH3:16])[CH2:34][CH2:33][C:31]=2[N:32]=1
Reactant: Cc1ccc(C(C)C)cc1OS(=O)(=O)C(F)(F)F
Reactant: COCCCOc1nc(-c2c(C)cccc2C)nc2c1CNCC2
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COCCCOc1nc(-c2c(C)cccc2C)nc2c1CN(c1cc(C(C)C)ccc1C)CC2
Temperature: 140 °C

Procedure:
To 5-isopropyl-2-methylphenyl trifluoromethanesulfonate, prepared as described in Example 15 (153 mg, 0.541 mmol) in a microwave vial was added a solution of 2-(2,6-dimethylphenyl)-4-(3-methoxypropoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine in THF (4 mL). Next, Cs2CO3 (235 mg, 0.721 mmol) was added and the reaction mixture was degassed via a series of argon/vacuum cycles. The reaction mixture was then charged with chloro(2-dicyclohxylphosphino-2′,4′,6%-triisopropyl-1,1′-biphenyl)-[2-(2-aminoethyl)phenyl)]-palladium(II) (CAS#1028206-56-5, 26.6 mg, 0.036 mmol). The vessel was then sealed and heated via microwave irradiation at 140° C. for 90 minutes. The reaction was then cooled to room temperature and diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted once with ethyl acetate. The organic layers were combined, dried over Na2SO4 filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (5-50% ethyl acetate/heptanes) to provide 2-(2,6-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-4-(3-methoxypropoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, CD2Cl2) δ ppm 1.25 (d, J=7.1 Hz, 6 H) 2.08 (quin, J=6.3 Hz, 2 H) 2.28 (s, 6 H) 2.49 (s, 3 H) 2.92 (dt, J=13.8, 6.9 Hz, 1 H) 3.28 (s, 3 H) 3.49 (t, J=5.9 Hz, 2 H) 3.58 (t, J=5.7 Hz, 2 H) 3.81 (t, J=5.6 Hz, 2 H) 4.37 (s, 2 H) 4.71 (t, J=6.4 Hz, 2 H) 7.12 (dd, J=7.7, 1.4 Hz, 1 H) 7.17 (s, 1 H) 7.20-7.27 (m, 3 H) 7.36-7.41 (m, 1 H); MS (ESI+) m/z 460.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:21][CH:20]([CH3:22])S[CH:18]([CH3:23])[CH2:17]1.O[O:25][S:26]([O-:28])=O.[K+].C(=O)(O)[O-].[Na+].OOS([O-])=O.[K+].C(=O)(O)[O-].[Na+]>COCCOC.O.ClCCl.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:17][CH:18]([CH3:23])[S:26](=[O:28])(=[O:25])[CH:20]([CH3:22])[CH2:21]1
Reactant: CCOC(=O)c1cc(Br)cc2c(C3CC(C)SC(C)C3)c[nH]c12
Reactant: O=S([O-])OO
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cc(Br)cc2c(C3CC(C)S(=O)(=O)C(C)C3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
Ethyl 5-bromo-3-(2,6-dimethyltetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxylate (0.212 g, 0.535 mmol) was dissolved in 1,2-Dimethoxyethane (DME) (13 mL). A solution of 0.0004M EDTA (3.61 mL, 0.0014 mmol) was added followed by the portion-wise addition of a suspension of Oxone (0.986 g, 1.60 mmol) and Sodium bicarbonate (0.449 g, 5.35 mmol), in 3 mL water. The reaction was stirred overnight at room temperature. An Oxone/sodium bicarbonate solution in the same amounts as above was added to the reaction and stirred for 3 hours. The reaction was diluted with water and dichloromethane. The organic layer was washed 2× water. The combined aqueous layers were backextracted with dichloromethane. The combined organics were washed with water, brine, dried with MgSO4, concentrated. The crude compound was purified by Combiflash silica column chromatography using 0-5% Ethylacetate/dichloromethane on silica to give 0.189 g (82%) of the title compound.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([O:9][C:10](=[O:31])[NH:11][CH2:12][C@H:13]([OH:30])[CH2:14][NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([F:25])[CH:24]=1)[N:21]([CH2:26][CH2:27][F:28])[C:20](=[O:29])[CH2:19]2)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([O:9][C:10](=[O:31])[NH:11][CH2:12][C@@H:13]1[O:30][C:1](=[O:2])[N:15]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([F:25])[CH:24]=2)[N:21]([CH2:26][CH2:27][F:28])[C:20](=[O:29])[CH2:19]3)[CH2:14]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NC[C@H](O)CNc1cc(F)c2c(c1)CC(=O)N2CCF
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2cc(F)c3c(c2)CC(=O)N3CCF)C(=O)O1
Reaction time: 0.5 h

Procedure:
Phosgene (20% solution in toluene, 0.414 ml, 4.24 mmol) is added to (R)-{3-[7-fluoro-1-(2-fluoro-ethyl)-2-oxo-2,3-dihydro-1H-indol-5-ylamino]-2-hydroxy-propyl}-carbamic acid tert-butyl ester (0.150 g, 0.424 mmol) and triethylamine (0.295 ml, 2.12 mmol) in dichloromethane (3 ml) at 0° C. and stirred for 30 minutes. The mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated to give the title compound as a light brown solid. HPLC r.t. 4.70 min; MS for C19H23F2N3O5 m/z 380.3 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][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.P(=O)(O)(O)O.[CH3:19]O>>[CH3:19][N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: CO
Agent: O=P(O)(O)O
Product: CN(c1ccccc1)c1ccccc1
Temperature: 140 °C
Yield: 99.2 %

Procedure:
The reaction apparatus was filled with 2 kg (11.8 mol) of diphenylamine and 200 g (1.74 mol) of phosphoric acid. Methanol was introduced at a rate of 50 ml/h for 40 hours at a reaction temperature of 200°C. The reaction mixture was then cooled to 140°C and the upper phase run-off. 1.822 kg of N-methyldiphenylamine (99.2 %) were obtained.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1[CH:25]=[C:26]([CH:48]([OH:51])[CH2:49][CH3:50])[CH:27]=[CH:28][C:29]=1[C:30]1[S:31][C:32]2[C:37]([N:38]=1)=[CH:36][CH:35]=[C:34]([C:39]1([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40]1)[N:33]=2.ClCCl.C([O-])(O)=O.[Na+]>>[F:23][C:24]1[CH:25]=[C:26]([C:48](=[O:51])[CH2:49][CH3:50])[CH:27]=[CH:28][C:29]=1[C:30]1[S:31][C:32]2[C:37]([N:38]=1)=[CH:36][CH:35]=[C:34]([C:39]1([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:40][CH2:41]1)[N:33]=2
Reactant: CCC(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dess-Martin periodinane (0.524 g, 1.24 mmol) was added to a solution of 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)propan-1-ol (0.500 g, 1.24 mmol) in dichloromethane (25.00 ml, 1.24 mmol), and the reaction was stirred at ambient temperature for 60 min. Saturated aq. NaHCO3 was added and the reaction stirred for 5 min. The organic layer was dried, filtered, and concentrated in vacuo and the residue purified by silica gel chromatography: ISCO 120 g column, 20-30% (3% Et3N in EtOAc)/Hex to give 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)propan-1-one. MS (ESI) m/z: Calculated: 402.1; Observed: 403.0 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1CCCCC1.Cl>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[CH:16][C:17]([OH:19])=[O:18]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COc1cc(C=CC(=O)O)cc(OC)c1OC
Yield: 88 %

Procedure:
A mixture of 3,4,5-trimethoxybenzaldehyde (5.0 g, 0.025 mol), malonic acid (5.30 g, 0.050 mol), piperidine (4–8 mL) and acetic acid (25–35 mL) were taken in a 100 ml Erlenmeyer flask fitted with a loose funnel at the top. The flask was shaken well and placed inside a microwave oven and irradiated for 4–8 minutes in parts. The cooled mixture was poured into ice cold water and then acidified with 5% HCl. The precipitated yellow solid was filtered and recrystallized with aq. ethanol to afford 3,4,5-trimethoxycinnamic acid in 88% yield; mp 127° C. (lit mp 126–128° C.) whose spectral data was found similar to the reported values 1H NMR (CDCl3) δ 7.73 (1H, d, J=16.0 Hz, —CH═CH—COOH), 6.78 (2H, s, H-2 & H-6), 6.38 (1H, d, J=16.0 Hz, CH═CH—COOH), 3.91 (9H, s, 3-OCH3, 4-OCH3 & 5-OCH3); 13C NMR: δ 172.6 (COOH), 153.8 (C-3 and C-5), 147.4 (C-4), 140.8 (CH═CH—COOH), 129.8 (C-1), 116.8 (CH═CH—COOH), 105.8 (C-2 and C-6), 61.4 (4-OCH3), 56.5 (3-OCH3 and 5-OCH3).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:28])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23](I)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:82][C:83]1[CH:89]=[CH:88][CH:87]=[CH:86][C:84]=1[NH2:85]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:29])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:28])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([NH:85][C:84]4[CH:86]=[CH:87][CH:88]=[CH:89][C:83]=4[Cl:82])[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1
Reactant: Nc1ccccc1Cl
Reactant: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(I)cc1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(Nc2ccccc2Cl)cc1=O
Temperature: 120 °C
Reaction time: 3.5 h
Yield: 80 %

Procedure:
A vial containing 2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (Intermediate 94, 51.5 mg, 0.10 mmol), potassium carbonate (23.5 mg, 0.170 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (6.9 mg, 0.01 mmol), and palladium (II) acetate (2.7 mg, 0.0120 mmol) was evacuated, charged with a nitrogen atmosphere, and treated with toluene (1 mL) and 2-chloroaniline (12.6 μL, 0.12 mmol). The vial was sealed, and the reaction was warmed to 120° C., where it stirred for 3.5 h, followed by stirring at 25° C. overnight. At this point, the reaction was partitioned between ethyl acetate (5 mL) and water (5 mL). The organic layer was washed with a 10% aqueous ammonium chloride solution (5 mL) and a saturated aqueous sodium chloride solution (5 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo onto silica gel. Chromatography (20-90% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenylamino)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as a white/yellow solid (41.2 mg, 80%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[N:31][CH:32]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:27]3[CH:32]=[N:31][CH:30]=[C:29]([CH3:33])[CH:28]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2nc(C)cs2)n1
Reactant: Cc1cncc(Br)c1
Product: Cc1cncc(-c2cc(C)nc(C(=O)Nc3nc(C)cs3)c2)c1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide in accordance with the general method of example 131, step 2 using 5-Bromo-3-picolin instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=325.3 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([NH:9][S:10]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)(=[O:12])=[O:11])[CH3:8].[C:24](OCC)(=[O:30])[C:25](OCC)=[O:26].Cl>C1COCC1>[CH2:7]([N:9]1[C:25](=[O:26])[C:24]([OH:30])=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=2)[S:10]1(=[O:11])=[O:12])[CH3:8]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCNS(=O)(=O)Cc1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCN1C(=O)C(O)=C(c2ccc(C(F)(F)F)cc2)S1(=O)=O
Temperature: 150 °C
Yield: 81.6 %

Procedure:
Potassium tert-butoxide (0.309 g, 1.83 mmol) was added to a solution of N-ethyl-1-[4-(trifluoromethyl)phenyl]methanesulfonamide (0.49 g, 1.83 mmol) and diethyl oxalate (0.322 g, 2.20 mmol) in THF (4 mL) at 0° C. The mixture was heated in a microwave reactor at 150° C. for 10 mins. HCl (1M, 2 mL) was added dropwise to the mixture at 0° C. It was evaporated and the residue was extracted with DCM. The organic layer was dried and evaporated to give the title compound (0.480 g, 81%) as a solid; 1H NMR (500 MHz, CDCl3): δ 8.05 (d, 2H), 7.77 (d, 2H), 3.87 (q, 2H), 1.49 (t, 3H); Mass Spectrum: M−H+ 320.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:24])=[C:14]([C:19]([O:21]CC)=O)[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[CH2:1]([S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:24])=[C:14]([C:19]([NH:31][CH2:30][C:29]3[CH:32]=[CH:33][C:26]([Cl:25])=[CH:27][CH:28]=3)=[O:21])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(SCc3ccccc3)ccc2c1O
Reactant: NCc1ccc(Cl)cc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(SCc3ccccc3)ccc2c1O
Yield: 92.4 %

Procedure:
A mixture of 4.07 g of ethyl 7-(benzylsulfanyl)-4-hydroxy-3-quinolinecarboxylate from Preparation No. 29 and 8.5 g of 4-chlorobenzylamine is heated at 165° C. for 18 h, then cooled and partitioned between 1 N HCl and chloroform-methanol. The organic phase is dried (MgSO4) and concentrated under reduced pressure, and the residue flash chromatographed on silica using 2-5% methanol in dichloromethane to provide 4.82 g of the title compound.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH3:32][C:33]1[CH:38]=[C:37]([CH:39]=[O:40])[CH:36]=[CH:35][N:34]=1>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([CH:39]([OH:40])[C:37]3[CH:36]=[CH:35][N:34]=[C:33]([CH3:32])[CH:38]=3)=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1cc(C=O)ccn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(O)c1ccnc(C)c1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (494 mg, 1.0 mmol) in anhydrous THF (10 mL) was added 2 M isopropylmagnesiumchloride in THF (1.20 mL, 2.4 mmol) at −40° C. After 5 minutes dry ice-acetone bath was replaced with a ice water bath and stirred at 0° C. for 1 h. Solid 2-methyl-pyridine-4-carbaldehyde (327 mg, 2.7 mmol) was added in one portion and the progress of the reaction was followed by LCMS. The reaction mixture was warmed to room temperature and stirred overnight. It was then quenched with saturated aqueous NH4Cl (2 mL), and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide the desired product which was utilized in the following step without further purification. MS m/z: 536.0 (M+H).
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([N:7]([C:14]([C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[NH2:22])=[O:15])[C:8]2C=CC=CC=2)=[CH:3][CH:2]=1>ClC1C=CC=CC=1>[C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([N:7]2[C:14](=[O:15])[CH:16]3[CH:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)[N:22]=[CH:8]2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(N(C(=O)[C@@H]2CCCC[C@@H]2N)c2ccccc2)cc1
Solvent: Clc1ccccc1
Product: Cc1ccc(N2C=NC3CCCCC3C2=O)cc1

Procedure:
N-p-tolyl-cis-2-amino-1-cyclohexane-carboxanilide (0.01 mole, 2.32 g.) is dissolved in chlorobenzene (40 ml.) and the solution, after the addition of ethyl-o-formiate (1.63 g.) is refluxed for 6 hours. The solvent is distilled off under reduced pressure. The residue is crystallized from petroleum ether. Thus a white, crystalline product, melting at 79° C. to 82° C. is obtained.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=O.[OH:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[CH2:19][NH2:20].O>C1C=CC=CC=1>[OH:3][CH2:1][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:20][CH2:19][CH:18]([OH:17])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH3:15])=[CH:9][CH:8]=1
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1ccccc1F
Solvent: O
Solvent: c1ccccc1
Product: CC(Cc1ccc(OCCO)cc1)NCC(O)c1ccccc1F
Reaction time: 2 h

Procedure:
A mixture of 1-(4-carbomethoxymethoxyphenyl)propan-2-one (2.22 g) and 2-hydroxy-2-(2-fluorophenyl)ethanamine (1.55 g) in benzene (100 ml) was boiled under reflux with azeotropic removal of water using a Dean and Stark trap, for 2 hours. The solution was cooled, evaporated to dryness, the residue dissolved in methanol and sodium borohydride (500 mg) added. After 30 minutes, the methanol was evaporated and the residue partitioned between ethyl acetate and water. The organic layer was dried (magnesium sulphate) and evaporated to leave an oil which was chromatographed on silica gel 60 eluting with 2% methanol/chloroform. N-[2-(4-(2-hydroxyethoxy)phenyl-1-methylethyl]-2-hydroxy-2-(2-fluorophenyl)ethanamine (300 mg) crystallised from hexane, m.p. 80°-95°, as a 55:45 mixture of diastereoisomers.