Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:18][C:19](=[O:44])[CH:20]([NH:27][C:28](=[O:43])[CH:29](C(=O)C(C)(C)C)[CH2:30]C1C=CC=CC=1)[CH2:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1)[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:45]([OH:47])[CH3:46]>[Pd]>[CH2:1]([C@H:8]([NH:18][C:19](=[O:44])[C@@H:20]([NH:27][C:28](=[O:43])[C@@H:29]([CH2:46][C:45](=[O:47])[C:11]([CH3:14])([CH3:12])[CH3:10])[CH2:30][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1)[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:15])[CH3:16])[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: C=C[C@@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)C(Cc1c[nH]cn1)NC(=O)C(Cc1ccccc1)C(=O)C(C)(C)C)C(C)C
Agent: [Pd]
Product: CC[C@@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)C(C)(C)C)Cc1ccccc1)C(C)C

Procedure:
120 mg of N-[(1S,2S,4S)-1-benzyl-2-hydroxy-4-isopropyl-5-hexenyl]-α-(α-pivaloylhydrocinnamamido)imidazole-4-propionamide in 10 ml of ethanol were hydrogenated at room temperature for 2 hours in the presence of 20 mg of palladium-on-carbon. Thereafter, the catalyst was filtered off and the solvent was evaporated under reduced pressure, to obtain (S)-N-[(1S,2S,4S)-1-benzyl-2-hydroxy-4-isopropylhexyl]-α-[(R)-α-(3,3-dimethyl- 2-oxobutyl)hydrocinnamamido]imidazole-4-propionamide as a foam. MS: 617 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:43]5[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][OH:37])[CH2:41][CH2:42]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Reactant: OCCN1CCNCC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCN(CCO)CC1
Yield: 13.5 %

Procedure:
The urea intermediate from Example 65A (200 mg, 0.38 mmol) and 1-(2-hydroxyethyl)piperazine (0.139 mL, 1.14 mmol) in the manner described in Example 57B to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea as a colorless solid (32 mg, 14%). 1H NMR (300 MHz, DMSO-d6) δ 9.58 (brs, 1H), 9.00 (brs, 1H), 8.69 (s, 1H), 7.84 (s, 1H), 7.26-7.49 (m, 5H), 6.49 (s, 1H), 4.26-4.37 (m, 3H), 3.99 (s, 3H), 3.40-3.50 (m, 2H), 2.75-2.79 (m, 2H), 2.30-2.50 (m, 9H), 1.27 (s, 9H); LC-MS (ESI) m/z 622 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][C@@H:26]([CH3:30])[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].O>CS(C)=O>[CH3:30][C@@H:26]1[N:27]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:28][CH2:29][N:24]([C:22]([O:21][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:23])[CH2:25]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])nc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
Into a solution of 5-bromo-2-nitropyridine (30 g, 148 mmol) in DMSO (350 mL) were added K2CO3 (14 g, 104 mmol) and (3S)-tert-butyl-3-methylpiperazine-1-carboxylate (10.0 g, 50 mmol). The mixture was stirred at 65° C. overnight and then after cooling to room temperature, poured into water (700 mL). The solid precipitate was collected and dried under vacuum. It was further purified on a flash column eluting with 20:1 petroleum ether/ethyl acetate and then with CH2Cl2 to give 105a as a yellow solid (8.05 g, 50%). LCMS: [M+H]+ 323
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[CH3:24][S:25][CH2:26][CH2:27]O>>[CH3:22][C:7]1([CH3:21])[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=3)[C:16]=2[C:17](=[O:18])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:27][CH2:26][S:25][CH3:24])=[CH:23][C:6]1=2
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CSCCO
Product: CSCCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 2-methylthioethanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][C:12]1[C:13]([F:20])=[CH:14][C:15]([F:19])=[C:16]([OH:18])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:20][C:13]1[CH:14]=[C:15]([F:19])[C:16]([O:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:17][C:12]=1[NH2:11]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Nc1cc(O)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cn2)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 2-chloro-5-nitropyridine (5.55 g, 35 mmol), 5-amino-2,4-difluorophenol (5.08 g, 35 mmol) and potassium carbonate (4.84 g, 35 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized from diethyl ether to give the title compound (9.35 g, quantitatively) as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[C:9](=[O:19])[N:8](C(OC(C)(C)C)=O)[C:5]2=[N:6][CH:7]=1.Br[C:28]1[CH:29]=[C:30]2NC(=O)N(C(OCCCC)=O)[C:31]2=[N:32][CH:33]=1.[C:45]1([C@@H](O)C)[CH:50]=CC=[CH:47][CH:46]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:13]1([C@H:11]([N:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:47]4[CH:46]=[CH:45][CH:50]=[C:31]5[C:30]=4[CH:29]=[CH:28][CH:33]=[N:32]5)[CH:3]=3)[NH:8][C:9]2=[O:19])[CH3:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[C@H](c1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ncc(Br)cc21
Reactant: C[C@H](O)c1ccccc1
Reactant: CCCCOC(=O)n1c(=O)[nH]c2cc(Br)cnc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)n1c(=O)[nH]c2ncc(-c3cccc4ncccc34)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
(R)-tert-Butyl 6-bromo-2-oxo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridine-3(2H)-carboxylate. To a solution of tent-butyl 6-bromo-2-oxo-1H-imidazo[4,5-b]pyridine-3(2H)-carboxylate (1.6 g, 5.09 mmol), (S)-1-phenylethanol (0.75 g, 6.11 mmol) and triphenylphosphine (1.6 g, 6.11 mmol) in tetrahydrofuran (45 mL) was added diisopropyl azodicarboxylate (1.19 mL, 6.11 mmol). After stirring at room temperature for 1 h, the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography to afford the title compound (0.60 g, 28% yield). MS (ESI) m/z 418.2 [M+1]+.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:32]=[CH:31][C:9]3[C:10]4[C:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)=[CH:13][N:12]([C:18]2[N:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.Br[CH2:34][C:35]([NH2:37])=[O:36].CO>C(Cl)Cl>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[N:19]1[C:18]([N:12]2[N:11]=[C:10]3[C:14]([CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([CH:4]5[CH2:3][N:2]([CH2:34][C:35]([NH2:37])=[O:36])[CH2:5]5)[CH:32]=[CH:31][C:9]=43)=[CH:13]2)=[N:22][CH:21]=[N:20]1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Reactant: NC(=O)CBr
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: NC(=O)CN1CC(c2ccc3c(c2)OCCc2cn(-c4ncnn4-c4ccc(F)cc4F)nc2-3)C1

Procedure:
Following the procedure for 143, 8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with bromo acetamide, the crude product was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 172 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 8.42 (s, 1H); 8.28 (s, 1H); 7.81 (td, J=8.75, 5.92 Hz, 1H); 7.63 (ddd, J=10.33, 9.01, 2.79 Hz, 1H); 7.39-7.27 (m, 2H); 7.11 (s, 1H); 7.03 (s, 1H); 6.96-6.89 (m, 2H); 4.23 (t, J=5.01 Hz, 2H); 3.66 (t, J=7.02 Hz, 2H); 3.62-3.52 (m, 1H); 3.16 (t, J=6.65 Hz, 2H); 3.10-2.98 (m, 4H). LCMS: RT=7.00 min, M+H+=478
Reaction SMILES: C1([Li])C=CC=CC=1.[Cl-].[C:9]1([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:13][CH:12]=[CH:11][CH:10]=1.[CH2:34]([N:38]([CH2:47][CH2:48][CH2:49][CH3:50])[C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=1)[CH2:35][CH2:36][CH3:37].II>C1(C)C=CC=CC=1.O.O1CCCC1>[CH2:34]([N:38]([CH2:47][CH2:48][CH2:49][CH3:50])[C:39]1[CH:46]=[CH:45][C:42]([CH:43]=[CH:14][C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:41][CH:40]=1)[CH2:35][CH2:36][CH3:37]
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCN(CCCC)c1ccc(C=O)cc1
Agent: II
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)c1ccc(C=Cc2cccs2)cc1
Reaction time: 1 h
Yield: 94.8 %

Procedure:
In a stream of argon, to 70 ml of tetrahydrofuran was added 10.45 g of phenyllithium (19% solution in dibutylether) (23.6 mmol), and 8.09 g (20.5 mmol) of 2-thenyl triphenylphosphonium chloride was added thereto under cooling. To this mixture was added dropwise 4.92 g (21.0 mmol) of 4-(dibutylamino)benzaldehyde. The mixture was stirred at the same temperature for 1 hour. After the reaction mixture was poured into water, extraction with toluene, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give an orange liquid. This liquid was dissolved in 200 ml of toluene and 200 mg of iodine was added thereto. After stirred at room temperature for 15 minutes, the mixture was added to water and the phases were separated. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 6.09 g of an orange oily matter (yield: 94.8%).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[I:6][C:7]1[CH:8]=[C:9]([S:13](Cl)(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:1]([NH:5][S:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([I:6])[CH:8]=1)(=[O:15])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1cccc(I)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NS(=O)(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butylamine (300 mg) was added to a stirred, cooled (ice-bath) solution of 3-iodobenzenesulfonyl chloride (Bromidge et al, J. Med. Chem., 1999, 42(2), 202-205) and triethylamine (420 mg) in dichloromethane (7 ml). The mixture was then stirred for 2 h at room temperature, diluted with dichloromethane (10 ml) and washed with 2M hydrochloric acid (5 ml). The mixture was separated on a hydrophobic frit and the organic phase was evaporated to give the title compound (1.26 g). LCMS ES+ve 340 (MH)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[C@H](O)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][C@H:26]([OH:25])[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: O[C@H]1CCNC1
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-pyrrolidin-3-ol and isolated as colorless gum (12.5 mg, 69%). MS (m/e): 387.3 (MH+).
Reaction SMILES: [OH:1][C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=O)[C@@H:11]1[CH2:10][CH:9]=[C:8]1[C@:3]2([CH3:23])[CH2:4][CH2:5][C:6]([O:21][CH3:22])=[CH:7]1.[N+:24]([CH:26](P(=O)(OCC)OCC)[CH3:27])#[C-:25]>>[N+:24]([C:26](=[C:15]1[C@:16]2([CH3:17])[C@H:12]([C@H:11]3[C@:2]([OH:1])([CH2:19][CH2:18]2)[C@:3]2([CH3:23])[C:8]([CH:7]=[C:6]([O:21][CH3:22])[CH2:5][CH2:4]2)=[CH:9][CH2:10]3)[CH2:13][CH2:14]1)[CH3:27])#[C-:25]
Reactant: COC1=CC2=CC[C@H]3[C@@H]4CCC(=O)[C@@]4(C)CC[C@]3(O)[C@@]2(C)CC1
Reactant: [C-]#[N+]C(C)P(=O)(OCC)OCC
Product: [C-]#[N+]C(C)=C1CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@@]3(O)CC[C@]12C
Yield: 69 %

Procedure:
Using the procedure of Example 27, 3.10 g of 9α-hydroxy-3-methoxyandrosta-3,5-dien-17-one and 8.02 g of diethyl α-isocyanoethylphosphonate were reacted for 5 hours to produce 2.39 g of the title compound as a mixture of 2 diastereomers. Chromatography was performed on silica gel with toluene/acetone 9/1 containing 0,1% triethylamine as eluent.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1)[C:2]#[CH:3].Br[C:17]1[C:18]([NH:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=1.C(N(CC)CC)C>CN(C=O)C.O.[Cu]I.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>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][NH:25][C:18]1[C:17]([C:3]#[C:2][CH2:1][N:4]2[CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[CH2:6][CH2:5]2)=[CH:22][N:21]=[C:20]([C:23]#[N:24])[N:19]=1
Reactant: C#CCN1CCN(c2ccccn2)CC1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CNc1nc(C#N)ncc1C#CCN1CCN(c2ccccn2)CC1
Temperature: 80 °C
Yield: 97 %

Procedure:
1-(2-Propynyl)-4-(2-pyridinyl)-piperazine (prepared from 1-(2-pyridinyl)-piperazine and propargyl bromide) (1.5 mmol) is dissolved in DMF at room temperature under nitrogen atmosphere. To the solution, 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (1 mmol), triethylamine (3 mmol), copper(I) iodide (0.1 mmol), and dichlorobis(triphenylphosphine)palladium(II) (0.05 mmol) are added successively. The mixture is heated at 80° C. under nitrogen atmosphere for 3 h. After cooling at room temperature, the mixture is diluted with H2O and extracted with AcOEt. The organic layer is dried over magnesium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:5) to give 4-(2,2-dimethyl-propylamino)-5-[3-(4-pyridin-2-yl-piperazin-1-yl)-prop-1-ynyl]-pyrimidine-2-carbonitrile. Yield 97%. Rf=0.30 (n-hexane:AcOEt 1:5). 1H NMR (400 MHz, CDCl3) δ 0.95 (s, 9H), 2.75-2.73 (m, 4H), 3.36 (d, 2H), 3.63-3.60 (m, 4H), 3.69 (s, 2H), 5.78 (brs, 1H), 6.63-6.67 (m, 2H), 7.47-7.52 (m, 1H), 8.19-8.21 (m, 2H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[N:8]1([CH2:14][C:15]2[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C@H:19]3[O:28][C:29]2[CH:41]=[CH:40][C:32]3[C@H:33]([CH2:36][C:37]([OH:39])=[O:38])[CH2:34][O:35][C:31]=3[CH:30]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)C(C)C)(C)C.[OH-].[Na+].Cl>C(#N)C.O>[C:1]([N:11]1[CH2:12][CH2:13][N:8]([CH2:14][C:15]2[C:23]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C@H:19]3[O:28][C:29]2[CH:41]=[CH:40][C:32]3[C@H:33]([CH2:36][C:37]([OH:39])=[O:38])[CH2:34][O:35][C:31]=3[CH:30]=2)[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCNCC3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCN(Cc2c(C(F)(F)F)ccc3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Acetic anhydride (0.03 mL) is added to a solution of {(S)-6-[(R)-4-piperazin-1-ylmethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid (0.22 g) and N,N-diisopropyl-ethylamine (0.11 mL) in acetonitrile (5 mL) at room temperature. The solution is stirred at room temperature for 1.5 h. 4 M aqueous NaOH solution (0.1 mL) is added and the solution is stirred for another 30 min. Water is added and the resulting solution is acidified with 4 M HCl solution (pH ca. 3-4). The resulting mixture is extracted with ethyl acetate, and the combined extracts are washed with brine and dried (Na2SO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate) to give the title compound. LC (method 1): tR=0.95 min; Mass spectrum (ESI+): m/z=519 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].NC(N)=[S:15].[OH-].[K+]>CCO>[SH:15][CH2:2][CH2:3][CH2:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C)(C)CCCBr
Reactant: NC(N)=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)CCCS
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.9 %

Procedure:
Ethyl 5-bromo-2,2-dimethylpentanoate (9.1 g, 38.4 mmol) in 100 mL EtOH, was treated with thiourea (3.65 g, 48.0 mmol) and KOH (2.69 g, 48.0 mmol) and stirred at rt for 10 minutes. After gentle heating (40-45 C.) for one hour, the solution was cooled and quenched by adding it to a stirred solution of 100 g ice, 100 mL conc. HCl, and 100 mL water. This aqueous layer was then extracted with 3×200 mL methylene chloride. The combined organics were washed with 5% NaHCO3 (2×200 mL), then sat. NH4Cl (300 mL), and dried over Na2SO4 overnight. The organics were evaporated to yield the product as a clear, pale yellow oil (6.57 g, yield 90%). 1H NMR (300 MHz, CDCl3), d (ppm): 4.11 (q, 2H, J 7.1); 2.47 (t, 2H, J 6.9); 1.70-1.46 (m, 4H); 1.25 (t, 3H, J 7.1); 1.17 (s, 6H). 13C NMR (75 MHz, CDCl3), d (ppm): 177.5, 60.1, 41.9, 39.7, 32.3, 25.00, 24.95, 14.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[C:7]=1[CH:8]=[CH:9][C:10](Cl)=[O:11])#[N:2].[CH2:24]([N:26](CC)[CH2:27]C)C.Cl.CNC>O1CCCC1>[CH3:24][N:26]([CH3:27])[C:10](=[O:11])[CH:9]=[CH:8][C:7]1[N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[N:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(=O)Cl
Reactant: CCN(CC)CC
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)C(=O)C=Cc1c(C#N)cnn1-c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.1 %

Procedure:
To a stirred solution of 0.5 gram (0.001 mole) of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylic acid chloride and 1.3 grams (0.012 mole) of triethylamine in 100 mL of tetrahydrofuran was added 1.0 gram (0.012 mole) of dimethylamine hydrochloride. Upon completion of the addition, the reaction was stirred at ambient temperature for about 18 hours. The reaction mixture was then warmed to 65° C. Where it was stirred for 15 minutes. The reaction mixture was cooled and concentrated under reduced pressure to a residue. The residue was dissolved in ethyl acetate, and the solution was washed with water. The organic layer was treated with decolorizing carbon and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was triturated with petroleum ether, and a solid was collected by filtration, yielding 0.2 gram of N,N-dimethyl-3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylamide; m.p. 116°-120° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[C:17]1([C:23]2([C:26](O)=[O:27])[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:26]([C:23]3([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:25][CH2:24]3)=[O:27])=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=C(O)C1(c2ccccc2)CC1
Product: CC1(C)OB(c2ccc(NC(=O)C3(c4ccccc4)CC3)cc2)OC1(C)C

Procedure:
Intermediate 26 was prepared in analogy to GP 5 by reaction of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine with 1-phenyl-cyclopropanecarboxylic acid.
Reaction SMILES: [F-:1].C([N+]([CH2:15][CH2:16][CH2:17][CH3:18])(CCCC)CCCC)CCC.[OH2:19]>O1CCCC1>[F:1][C:15]([F:1])([F:1])[C@H:16]1[O:19][C@@H:16]([O:19][CH2:17][CH2:18][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:15][CH2:18][C@@H:17]1[OH:19]
Reactant: O
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: [F-]
Solvent: C1CCOC1
Product: CCCCCCO[C@H]1CC[C@H](O)[C@@H](C(F)(F)F)O1

Procedure:
In 20 ml of tetrahydrofuran was dissolved 8.0 g (21 mmol) of the acetal compound as obtained by the aforementioned reaction. To the resultant solution was added 10 ml of a solution of tetra-n-butylammonium fluoride in tetrahydrofuran in 1.0 mol/liter concentration to proceed with reaction at 0° C. for one hour and at room temperature for further 40 hours. The reaction was stopped by the addition of distilled water, and the reaction product was extracted with diethyl ether. Then the extract was washed with brine and dried with magnesium sulfate anhydride. After the diethyl ether was vacuum distilled away, the resultant reaction product was purified by separation by means of silica-gel column chromatography to give the objective compounds comprising 3.0 g (11 mmol) of (2R, 5S, 6S)-tetrahydro-6-trifluoromethyl-2-hexyloxy-5-hydroxypyran and 2.3 g (8 mmol) of (2S, 5S, 6S)-tetrahydro-6-trifulromethyl-2-hexyloxy-5-hydroxypyran.