Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1.C([O-])([O-])=O.[K+].[K+].[CH:29]([N:32]=[C:33]=[O:34])([CH3:31])[CH3:30]>C1COCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:33]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:34])[CH:16]=1
Reactant: CC(C)N=C=O
Reactant: Nc1c(C(=O)c2cccc(O)c2)cnn1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)NC(=O)Oc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Reaction time: 16 h

Procedure:
5-Amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole, from Example 10, step 2, (0.30 g, 1.01 mmol) was combined with K2CO3 (0.418 g, 3.03 mmol) and THF (6 mL). The mixture was cooled then isopropyl isocyanate (0.12 mL, 1.21 mmol) was warm to room temperature and stirred for 16 hours. The reaction mixture was quenched with water, extracted into ethyl acetate, dried (MgSO4), filtered, and concentrated to dryness. The residue was stirred in methanol and dichloromethane for one hour then filtered to give 0.118 g of 5-amino-1-(4-fluorophenyl)-4-[3-isopropylaminocarbonyloxybenzoyl]pyrazole (mpt. 225.2-230.1° C.).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7](C(OC)=O)[C:8]([O:10][C:11](C)(C)C)=[O:9])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=[N:3]1>C(O)=O>[CH3:1][N:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=[N:3]1
Reactant: COC(=O)C(C(=O)OC(C)(C)C)c1c([N+](=O)[O-])cnn1C
Solvent: O=CO
Product: COC(=O)Cc1c([N+](=O)[O-])cnn1C
Temperature: 50 °C
Yield: 90.2 %

Procedure:
A mixture of 1-tert-butyl 3-methyl 2-(1-methyl-4-nitro-1H-pyrazol-5-yl)malonate (6.92 g, 23.1 mmol) and formic acid (100 mL) was heated at 50° C. for 5 hours before being cooled to room temperature. Formic acid was removed under reduced pressure; the residue was diluted with brine and extracted with DCM 3×. The combined organics were dried (MgSO4) and the solvent removed under reduced pressure. The residue was purified via silica gel chromatography (0-60% EtOAc/heptane) to afford methyl 2-(2-methyl-4-nitro-pyrazol-3-yl)acetate (4.15 g, 90%).
Reaction SMILES: Cl.[OH:2][C:3]([CH3:22])([CH3:21])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:20])[C@@H:12]([NH2:19])[CH2:13][C@@H:14]([O:16][CH2:17][CH3:18])[CH3:15])=[N:6]1.C(N(CC)C(C)C)(C)C.OC(C)(C)CN1C=CC(NC(=O)[C@@H](N2[CH2:51][C:50]([O:52][C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH2:60][CH3:61])[C:54]=3[F:62])=[CH:49][C:48]2=[O:63])CC(C)C)=N1>C(#N)C>[OH:2][C:3]([CH3:22])([CH3:21])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:20])[C@@H:12]([N:19]2[CH2:51][C:50]([O:52][C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH2:60][CH3:61])[C:54]=3[F:62])=[CH:49][C:48]2=[O:63])[CH2:13][C@@H:14]([O:16][CH2:17][CH3:18])[CH3:15])=[N:6]1
Reactant: CCO[C@@H](C)C[C@H](N)C(=O)Nc1ccn(CC(C)(C)O)n1
Reactant: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1F
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cccc(OC2=CC(=O)N([C@@H](C[C@H](C)OCC)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1F
Yield: 50.1 %

Procedure:
A suspension of (2S,4S)-2-amino-4-ethoxy-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide hydrochloride salt (prepared as in Example 95, 124.5 mg, 0.335 mmol) in acetonitrile (7 mL) was treated with N,N-diisopropylethylamine (0.25 mL). At this time a solution of (E)-4-bromo-3-(3-ethoxy-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 114, 117 mg, 0.337 mmol) in acetonitrile (2 mL) was added and the resulting solution refluxed for 64 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue dissolved in tetrahydrofuran (2 mL) and transferred to an Emrys Optimizer microwave tube and microwaved at 160° C. for 1.5 h. The mixture was concentrated in vacuo and the residue was purified by ISCO flash chromatography (RediSep silica 12 g, 10% to 70% (10% methanol/dichloromethane)/hexanes,) which afforded (2S,4S)-4-ethoxy-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (87 mg, 50%): HR-ES-MS (m/z) calculated for C26H35FN4O6 [M+H]+ 519.2614, observed 519.2615. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.95-1.19 (m, 12H), 1.36 (t, J=6.0 Hz, 3H), 1.75-2.02 (m, 2H), 3.15-3.30 (m, 1H), 3.33 (br. s., 1H), 3.40-3.55 (m, 1H), 3.89 (br. s., 2H), 4.06-4.21 (m, 2H), 4.29 (d, J=18.4 Hz, 1H), 4.49 (d, J=18.4 Hz, 1H), 4.67 (br. s., 1H), 4.85-4.99 (m, 2H), 6.44 (br. s., 1H), 6.91-7.06 (m, 1H), 7.05-7.29 (m, 2H), 7.53 (br. s., 1H), 10.69 (br. s., 1H).
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[C:3]#[CH:4].[Cl:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11]>>[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([NH:1][CH:2]([CH3:5])[C:3]#[CH:4])=[O:11]
Reactant: C#CC(C)N
Reactant: O=C(Cl)CCCCl
Product: C#CC(C)NC(=O)CCCCl

Procedure:
The compound 3-amino-1-butyne was treated with γ-chlorobutyryl chloride giving 3-(γ-chlorobutyramido)-1-butyne, m.p. 50°-51°C., which was ring-closed to N-(1-methylpropargyl)-pyrrolidin-2-one with the boiling point 71°C. at 0.8 mm Hg. Treatment of this product with formaldehyde and pyrrolidine yielded a reaction product which was isolated and purified as the sesquioxalate. It melted at 117°-119°C. after recrystallization from ethanol-ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:14][OH:15].C(N(CC)CC)C.Cl[CH2:24][CH2:25][C:26]([C:28]1[O:29][CH:30]=[CH:31][CH:32]=1)=[O:27]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:25]([CH3:24])[C:26]([C:28]3[O:29][CH:30]=[CH:31][CH:32]=3)=[O:27])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:14][OH:15]
Reactant: O=C(CCCl)c1ccco1
Reactant: OCc1ccc(N2CCNCC2)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C(=O)c1ccco1)N1CCN(c2ccc(CO)c(Cl)c2)CC1
Reaction time: 1 h

Procedure:
At ~25°, a solution of 2-chloro-4-(1-piperaziny)-benzenemethanol 3.0 g, 13.2 mmole) in 30 ml of tetrahydrofuran and 4 ml of triethylamine was added during five minutes to a solution of 3-chloro-1-(2-furanyl)-1-propanone (2.8 g. 13.3 mmole based on 75% purity). The mixture was stirred at 25° for one hour (a white precipitate formed) and was then heated under reflux for one half hour. The mixture was then filtered and the filtrate was evaporated at reduced pressure (<40°) to give an orange, heavy oil. The oil was triturated at 25° first with petroleum ether (30°-60°; two times, 50 ml) and then with diethyl ether. The orange-brown solid was collected, washed with a little diethyl ether, recrystallized from 25 ml of toluene, and finally triturated with diethyl ether (two times, 20 ml) and dried to give 3.10 g (67%), mp 95°-98° (Table 3).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:16][CH:15]2[CH3:29])[CH:3]=1.[CH:30]1C=CC(CS(Cl)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C:24]3[CH:30]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:21])=[O:22])[CH2:16][CH:15]2[CH3:29])[CH:3]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC1CN(S(=O)(=O)c2ccccc2)CCN1Cc1cc(Cl)ccc1OCC(=O)O
Product: CC1CN(S(=O)(=O)Cc2ccccc2)CCN1Cc1cc(Cl)ccc1OCC(=O)O

Procedure:
Prepared by the method of example 30, using the product of example 53 part (b) and benzenemethanesulfonyl chloride to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][C:12]1[S:13][C:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20](F)[CH:19]=2)=[C:15]([CH3:17])[N:16]=1)=[O:10])[CH3:2].[N:30]1(C2C=C(C3SC(N)=NC=3C)C=CC=2S(C)(=O)=O)[CH:34]=[CH:33][N:32]=[CH:31]1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][C:12]1[S:13][C:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([N:30]3[CH:34]=[CH:33][N:32]=[CH:31]3)[CH:19]=2)=[C:15]([CH3:17])[N:16]=1)=[O:10])[CH3:2]
Reactant: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1
Product: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(-n3ccnc3)c2)s1

Procedure:
The title compound is prepared by the same procedure as 4-{3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 148).
Reaction SMILES: [C:1]([OH:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O[CH:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[C:1]([O:18][CH:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC(O)CC(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCC)CC(=O)OC(C)(C)C
Yield: 91 %

Procedure:
Hexadecanoic acid (1.92 g) and tert-butyl 3-hydroxyoctanoate (324 mg) was reacted to afford an oil of tert-butyl 3-hexadecanoyloxyoctanoate (620 mg) in the similar method to that of Preparation 1-(2).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:19]#[C:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26].[H][H]>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31]1)=[O:26]
Reactant: [H][H]
Reactant: O=C(NCCCC#Cc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)C1CCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(NCCCC=Cc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)C1CCCC1

Procedure:
Dissolve 7-chloro-6-[5-(cyclopentanecarbonyl-amino)-pent-1-ynyl]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (726 mg) in EtOAc (20 mL). Add 10% Pd/C (Degussa type, 100 mg) and then stir the mixture under 15 psi of hydrogen for 10 min. As reaction is not completed, add extra catalyst (147 mg) and stir under 15 psi of hydrogen for an extra 15 min. Filter the reaction mixture through a short pad of Celite® and concentrate in vacuo to obtain the desired intermediate that was used in the next step without further purification. MS (ES+) m/z=457.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.Cl.[CH2:16]([O:18][C:19](=[O:22])[CH2:20][NH2:21])[CH3:17].C(N(CC)CC)C>CN(C)C=O>[CH2:16]([O:18][C:19](=[O:22])[CH2:20][NH:21][C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]2[C:8]=1[CH3:14])=[O:13])[CH3:17]
Reactant: CCOC(=O)CN
Reactant: Cc1c(C(=O)O)nc2ccc(Cl)nn12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1nc2ccc(Cl)nn2c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
3.9 g of ethyl 6-chloro-3-methylimidazo[1,2-b]pyridazine-2-carboxylate was suspended in 40 ml of tetrahydrofuran; 30 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 3 hours. The mixture was concentrated under reduced pressure. The residue was adjusted to pH 4 by the addition of 50 ml of water and 1 N hydrochloric acid; the crystal precipitated was collected by filtration and dried to yield 2.55 g of 6-chloro-3-methylimidazo[1,2-b]pyridazine-2-carboxylic acid. 1.27 g of this carboxylic acid was dissolved in 20 ml of N,N-dimethylformamide; 1.07 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 30 minutes. To this mixture, 0.922 g of glycine ethyl ester hydrochloride and 0.915 ml of triethylamine were added, followed by further stirring for 3 hours. 60 ml of ice water was added to the reaction mixture; the crystal precipitated was collected by filtration, washed with water and dried to yield 1.18 g of the title compound.
Reaction SMILES: [C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([CH3:41])[C:20](=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[C:30]([O:32]C(C)(C)C)=[O:31])[CH2:13][CH2:12]1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([CH3:41])[C:20](=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[C:30]([OH:32])=[O:31])[CH2:13][CH2:12]1)=[O:9]
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1cccc(C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The compound (80.0 mg, 0.124 mmol) obtained in Example 43a was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1 mL) was added under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give a crude title compound.
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[NH2:10]O>>[NH2:9][C:1]1[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:4][N:10]=1
Reactant: NO
Reactant: N#Cc1ccccc1N
Product: Nc1n[nH]c2ccccc12

Procedure:
is prepared by reacting anthranilonitrile with hydroxylamine, and the amidoxime thus prepared is then reacted with ester to produce a 3-aminoindazole of the following formula (3):
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].[CH:10]([NH2:13])([CH3:12])[CH3:11]>>[CH:10]([NH:13][CH2:3][CH2:2][C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])([CH3:12])[CH3:11]
Reactant: CC(C)N
Reactant: C=CC(=O)OCCCC
Product: CCCCOC(=O)CCNC(C)C
Yield: 81.2 %

Procedure:
27.8 g of n-butyl acrylate are added dropwise to 15.6 g of isopropylamine under ice-cooling and stirring. The mixture is further stirred at room temperature for 5 hours. Then, the reaction mixture is distilled under reduced pressure. 33 g of n-butyl 3-isopropylaminopropionate are thereby obtained as a colorless oil.
Reaction SMILES: C[Si](C)(C)[C:3]([F:6])([F:5])[F:4].[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:11]=1[CH:12]=[O:13].Cl>C(COC)OC.[F-].[Cs+]>[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:11]=1[CH:12]([OH:13])[C:3]([F:6])([F:5])[F:4]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: OC(c1c(Cl)cccc1Cl)C(F)(F)F
Temperature: 15 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
Add 1.75 g of trimethyl(trifluoromethyl)silane to a solution of 2.1 g of 2,6-dichlorobenzaldehyde in 60 cm3 of dimethoxyethane. The reaction mixture becomes clear with a yellow sheen; it is then cooled on a water/ice bath to about 15° C. Add 0.055 g of caesium fluoride in one go. Stir for 4 hours at a temperature close to 20° C. The reaction mixture is then poured into 7.2 cm3 of a 4N aqueous solution of hydrochloric acid. The aqueous phase is decanted then extracted three times with 40 cm3 of diethyl oxide. The organic phases are combined and then dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2 kPa). We obtain 2.9 g of 1-(2,6-dichlorophenyl)-2,2,2-trifluoroethanol in the form of an oil with a yellow sheen, which has the following characteristics:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3].[Cl:8][C:9]1[C:18]2[N:17]([CH3:19])[O:16][C@H:15]3[NH:20][C@H:21]([C:23]([O:25][C@@H:26]4[C@:35]5([OH:36])[C@@H:30]([C@H:31]([CH:38]([CH3:40])[CH3:39])[CH2:32][CH2:33][CH:34]5[CH3:37])[CH:29]=[C:28]([CH3:41])[CH:27]4[OH:42])=[O:24])[CH2:22][C@@:14]3([OH:43])[C:13]=2[CH:12]=[CH:11][CH:10]=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:8][C:9]1[C:18]2[N:17]([CH3:19])[O:16][C@H:15]3[NH:20][C@H:21]([C:23]([O:25][C@@H:26]4[C@:35]5([OH:36])[C@@H:30]([C@H:31]([CH:38]([CH3:39])[CH3:40])[CH2:32][CH2:33][C@H:34]5[CH3:37])[CH:29]=[C:28]([CH3:41])[C@H:27]4[O:42][C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3])=[O:24])[CH2:22][C@@:14]3([OH:43])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CC1=C[C@@H]2[C@H](C(C)C)CCC(C)[C@]2(O)[C@@H](OC(=O)[C@@H]2C[C@@]3(O)c4cccc(Cl)c4N(C)O[C@H]3N2)C1O
Reactant: C=CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)C)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
Allyl chloroformate (17.4 mg) was added to a stirred, cooled (0° C.) solution of (1S,4aS,5S,8aR)-2,8a-dihydroxy-3,8-dimethyl-5-(1-methylethyl)-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 144, 50 mg) and 4-dimethylaminopyridine (35 mg) in dichloromethane (5 ml) under an atmosphere of nitrogen. After 30 minutes, the reaction was allowed to warm to room temperature over 15 hours. The reaction mixture was diluted with dichloromethane (25 ml), washed with aqueous citric acid (10% w/w, 3×15 ml) and dried (MgSO4). After evaporation of solvent in vacuo, the residue was purified by flash column chromatography on silica (5 g) eluting with 1:1 ethyl acetate:hexane to give the product (44 mg, 76%).
Reaction SMILES: C1([C:7]2[C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[C:16](C3C=CC=CC=3)=[CH:15][CH:14]=[N:13]4)[N:10]=[CH:9][CH:8]=2)C=CC=CC=1.BrBr.O.Cl.BrBr>C(O)C>[N:10]1[C:11]2[C:20](=[CH:19][CH:18]=[C:17]3[C:12]=2[N:13]=[CH:14][CH:15]=[CH:16]3)[CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Agent: BrBr
Agent: Cl
Solvent: O
Solvent: CCO
Product: c1cnc2c(c1)ccc1cccnc12

Procedure:
Bis (4,7-diphenyl-1,10-phenanthroline)cobalt(III) chloride, (DIP)2Co(III)Cl2, was prepared as follows: 4,7-diphenyl-1,10-phenanthroline (Aldrich) was dissolved in a minimum volume of ethanol to which one half stoichiometric CoCl2.6H2O was added. The green-brown solution was oxidized by using Br2 /H2O, and a heavy orange precipitate formed immediately. The solution was refluxed for 1 h, and concentrated hydrochloride was added. The bromine oxidation was then repeated. The crude complex was recrystallized in aqueous ethanol. Other cobalt(III) complexes of this invention may be prepared by this method by substituting the appropriate ligand for 4,7-diphenyl-1,10-phenanthroline.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:5]=2[CH:4]=[N:3]1.[CH:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH:32]([CH3:34])[CH3:33])[C:25](O)=[O:26])=[O:21].CCN=C=NCCCN(C)C.CCN(CC)CC>ClCCl>[CH:32]([O:31][C:30]1[CH:29]=[CH:28][C:24]([C:25]([N:17]2[CH2:18][CH2:19][C:14]3([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:6]=4[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[O:13]3)[CH2:15][CH2:16]2)=[O:26])=[CH:23][C:22]=1[CH:20]=[O:21])([CH3:34])[CH3:33]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C=O
Reactant: Cn1ncc2c1-c1ccccc1OC21CCNCC1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)cc1C=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.6 %

Procedure:
1-Methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (250 mg, 0.76 mmol), 3-formyl-4-isopropoxy-benzoic acid (160 mg, 0.76 mmol), EDCI (160 mg, 0.84 mmol), and Et3N (430 μL, 3.1 mmol) were combined in dichloromethane (7.1 mL) and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was washed with a 1 M HCl (×2), a saturated aqueous solution of NaHCO3 (×2) and a saturated aqueous solution of NaCl. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in dichloromethane) to yield 2-isopropoxy-5-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzaldehyde (117 mg, 34%) as a light yellow solid. ESI-MS m/z calc. 445.2, found 446.3 (M+1)+; Retention time: 1.74 minutes (3 min run).
Reaction SMILES: Cl[C:2]([C:4]1[C:5]([CH:21]2[CH2:24][CH2:23][CH2:22]2)=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]([CH:14]([F:16])[F:15])=[N:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:3].[CH3:25][CH:26]([SH:28])[CH3:27]>>[F:16][CH:14]([F:15])[C:7]1[C:6]([C:17]([O:19][CH3:20])=[O:18])=[C:5]([CH:21]2[CH2:22][CH2:23][CH2:24]2)[C:4]([C:2]([S:28][CH:26]([CH3:27])[CH3:25])=[O:3])=[C:9]([C:10]([F:12])([F:11])[F:13])[N:8]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)Cl)c1C1CCC1
Reactant: CC(C)S
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)SC(C)C)c1C1CCC1

Procedure:
Methyl 5-chlorocarbonyl-4-cyclobutyl-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate prepared similarly to the procedure in step 7 of U.S. Pat. No. 4,988,384 was reacted with 2-propanthiol according to the procedure in example 141 of U.S. Pat. No. 4,692,184 to give the product as an oil, nD25 1.4946.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12](=[O:22])[CH:13](Br)[C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[NH2:8][C:7]1[C:2]2[N:3]([C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([C:12]([O:11][CH2:9][CH3:10])=[O:22])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cccnc1N
Reactant: CCOC(=O)C(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1nc2c(N)cccn2c1C(=O)OCC
Yield: 32.8 %

Procedure:
A solution of 2,3-diaminopyridine (13.1 g, 0.12 mol) , 2-bromo-3-oxo-succinic acid diethyl ester (31 g, 0.12 mol) and sodium carbonate (13.2 g, 0.12 mol) in 1,2-dimethoxyethane (200 ml) was refluxed for 20 h. The solvent was evaporated under reduced pressure and the residue was suspended in methylene chloride and filtrated through silica gel. The filtrate was evaporated under reduced pressure to give 10.9 g (33%) of the title compound as an oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3cccnc3)c2)OC1(C)C
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 3-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pyridine as described in Example 1 to give 2-[3-(4-fluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as a white solid. Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (400 MHz, DMSO) 1.56 (6H, s), 7.73 (1H, dd, J 11 and 9), 7.81-7.90 (3H, m), 8.09 (1H, dd, J 7 and 2), 8.42 (1H, dd, J 7 and 1), 8.55 (1H, s), 8.81 (1H, dd, J 5 and 1), 9.06 (1H, s), 9.39 (1H, d, J 7).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[NH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCBr
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCCN1CCCC1
Temperature: 120 °C

Procedure:
4-Bromo-but-1-ene (81 mg, 0.6 mmol) was added dropwise to a stirred suspension of pyrrolidine (50 μL, 0.6 mmol) and Cs2CO3 (196 mg, 0.6 mmol) in 1 mL DMF. The mixture was heated to 120° C. using microwave for 20 min, then filtered and used for the next step directly without purification.