Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[C:4]([C:11]#[N:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[C:26]([N:30]=[C:31]=[O:32])([CH3:29])([CH3:28])[CH3:27].O>ClCCl>[C:26]([NH:30][C:31]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([F:1])=[C:3]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:4]([C:11]#[N:12])=[C:5]2[CH2:10]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N=C=O
Reactant: N#Cc1c(-c2ccccc2)c(F)n2c1CNCC2
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CCn2c(F)c(-c3ccccc3)c(C#N)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To a solution cooled to 0° C. of 0.75 g (3.1 mmol) of 6-fluoro-7-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile in 50 ml of dichloromethane are added 1.4 ml (10 mmol) of triethylamine and then 0.37 g (3.7 mmol) of tert-butyl isocyanate (CAS1609-86-5) dropwise. After stirring for 2 hours at room temperature, the medium is poured into water, the organic phase is separated out and dried over sodium sulfate, and the solvent is evaporated off under reduced pressure to give a solid in the form of a green foam, which is purified by chromatography on a column of silica gel, eluting with a mixture of 20 to 50% ethyl acetate in cyclohexane, to give 0.36 g of N-tert-butyl-8-cyano-6-fluoro-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide in the form of an orange-coloured gummy solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:24])[C:8]1[C:13]([C:14]2([Cl:23])[CH2:18][C:17]([F:19])=[C:16]([N:20]=[C:21]=[S:22])[S:15]2)=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:24])[C:8]1[C:13]([C:14]2([Cl:23])[CH2:18][C:17]([F:19])=[C:16]([NH:20][C:21]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]3)=[S:22])[S:15]2)=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: COC(=O)COC(=O)c1ccccc1C1(Cl)CC(F)=C(N=C=S)S1
Reactant: C1CCNNC1
Solvent: Cc1ccccc1
Product: COC(=O)COC(=O)c1ccccc1C1(Cl)CC(F)=C(NC(=S)N2CCCCN2)S1
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of 4.8 g of 2-chloro-4-fluoro-5-isothiocyanato-thiolbenzoic acid (methoxycarbonylmethyl) ester obtained in accordance with Example P3 in 50 ml of toluene is added dropwise, with stirring, at 20°-25° C. to a solution of 1.4 g of hexahydropyridazine in 20 ml of toluene. Stirring is continued for a further 8 hours at room temperature. Concentration by evaporation in vacuo yields 4.4 g of 2-chloro-4-fluoro-5-(1-hexahydropyridazinyl-thiocarbonylamino)-thiolbenzoic acid (methoxycarbonylmethyl) ester in resinous form.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][C:23]2[O:27][N:26]=[C:25]([CH2:28][CH3:29])[N:24]=2)[CH:10]=[CH:11][C:12]=1[O:13][Si](C(C)(C)C)(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:28]([C:25]1[N:24]=[C:23]([CH:22]=[CH:21][C:9]2[CH:8]=[C:7]([OH:6])[C:12]([OH:13])=[CH:11][CH:10]=2)[O:27][N:26]=1)[CH3:29]
Reactant: CCc1noc(C=Cc2ccc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1noc(C=Cc2ccc(O)c(O)c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
{2-[3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-phenyl]-vinyl}-3-ethyl-[1,2,4]oxadiazole (compound of Example 2, Method B, Step 2; 0.35 g, 0.75 mmol) was dissolved in THF (10 mL) followed by addition of 1 M solution of TBAF (tetra butyl ammonium fluoride) in THF (0.77 mL, 2.25 mmol) at room temperature over a period of 5 min. After stirring at room temperature for 3 h, the solvent was evaporated and the reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with water (5 mL) and stirred for 10 min followed by extraction with ethyl acetate (2×10 mL). The combined organic layers were washed with water (2×10 mL) and brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by column chromatography (silica gel, 0.5% methanol in chloroform) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH:13]([Br:17])[C:14](Br)=[O:15].[OH-].[Na+]>O.CC(C)=O>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH:13]([Br:17])[C:14]([NH:3][C:2]([NH2:4])=[NH:1])=[O:15]
Reactant: N=C(N)N
Reactant: O=C(Br)C(Br)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: N=C(N)NC(=O)C(Br)c1c(Cl)cccc1Cl
Reaction time: 1 h

Procedure:
To a solution of 0.072 mols guanidine (from 6.9 g guanidine hydrochloride and 3 g NaOH) in 100 ml water, 20 g (0.06 mols) 2-(2,6-dichlorophenyl)-2-bromo-acetyl-bromide in 50 ml acetone and 2.4 g (0.06 mols) NaOH in 50 ml water at 10 degrees C. are simultaneously added dropwise. After one hour, the organic phase is extracted with methylene chloride, filtered, and further extracted in a counter-current manner with 1 N hydrochloric acid. The acid phase is then adjusted to an alkaline pH and extracted with CH2Cl2. Subsequent to the evaporation of the methylene chloride, the guanidine base is obtained. It has decomposition point of 155 degrees C. The hydrochloride is prepared in the usual way using ethanolic hydrochloric acid, and is recrystalized from a mixture of acetic acid and ethanol. The decomposition point is 228-229 degrees C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:28]3[CH2:32][CH2:31][CH2:30][C:29]3=[O:33])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3S(C)(=O)=O)CC2)c(C)c1

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (451 mg) described in Preparation Example 110 and pyrrolidin-2-one (80 μL) and by the reaction and treatment in the same manner as in Example 1, the title compound (244 mg) was obtained.
Reaction SMILES: O.Cl.Cl[CH2:4][CH2:5][N:6]([CH3:8])[CH3:7].[Cl:9][C:10]1[CH:18]=[CH:17][C:16]2[N:15]3[CH:19]=[CH:20][CH:21]=[C:14]3[C:13](=[N:22][OH:23])[C:12]=2[CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:9][C:10]1[CH:18]=[CH:17][C:16]2[N:15]3[CH:19]=[CH:20][CH:21]=[C:14]3[C:13](=[N:22][O:23][CH2:4][CH2:5][N:6]([CH3:8])[CH3:7])[C:12]=2[CH:11]=1
Reactant: CN(C)CCCl
Reactant: ON=C1c2cc(Cl)ccc2-n2cccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)CCON=C1c2cc(Cl)ccc2-n2cccc21

Procedure:
Add 5 ml of water, 0.94 g (6.5 mmol) of 1-chloro-2-(N,N-dimethylamino)ethane hydrochloride and 1.19 g (5.44 mmol) of 7-chloro-9-hydroxyiminopyrrolo[1,2-a]indole (Preparation 46) in succession to a solution of 1.56 g (14.7 mmol) of sodium carbonate in 100 ml of acetone, then heat the reaction mixture at reflux for 36 hours. The acetone is removed under reduced pressure and the residue is taken up in 50 ml of water and extracted with diethyl ether. The ethereal phase is washed with water, dried over magnesium sulfate, rendered colourless with animal charcoal, and then concentrated to dryness to yield the title product in the form of an oil (base).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23]([C:25]3[S:29][C:28]([O:30]C)=[N:27][CH:26]=3)=[O:24])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C@@H:15]([NH:22][C:23]([C:25]3[S:29][C:28](=[O:30])[NH:27][CH:26]=3)=[O:24])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cnc(OC)s1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1c[nH]c(=O)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-methoxythiazole-5-carboxamido)butanoate, intermediate 13, (170 mg, 0.37 mmol) in dioxane (5 mL) is added a solution of 4 M HCl in dioxane (0.5 mL, 2.00 mmol). The crude is stirred at room temperature for 3 hrs. The crude is concentrated. Part of the crude is purified via RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN) to give (95 mg) of (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-oxo-2,3-dihydrothiazole-5-carboxamido)butanoate as a white solid. HPLC retention time=1.82 minutes (condition D); MS (m+1)=445.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J=7.1 Hz, 3 H) 2.46-2.70 (m, 2 H) 2.78-2.97 (m, 1 H) 3.07 (dd, J=13.0, 6.2 Hz, 1 H) 4.11-4.28 (m, 2 H) 4.51-4.69 (m, 1 H) 6.64 (d, J=8.1 Hz, 1 H), 7.19-7.42 (m, 5 H) 7.44 (d, J=6.1 Hz, 1 H) 7.48-7.62 (m, 3 H), 9.54 (br. s., 1 H).
Reaction SMILES: [S:1]=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:6]2[S:5][C:4](=[O:7])[NH:3][C:2]2=[S:1])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]
Reactant: O=C1NC(=S)CS1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: C1CCNCC1
Product: O=C1NC(=S)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)S1
Temperature: 100 °C

Procedure:
A solution containing 0.67 g (0.005 mol) of 4-thioxothiazolidin-2-one, 0.92 g (0.005 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.05 ml of piperidine in 10 ml of acetic was heated for 8 h at 100° C. The product was filtered and washed with 2-propanol. Yield 1.14 g (76.5%), mp >350° C. (decomp.).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[C:21]([N:22]3[CH2:27][CH2:26][CH:25]([CH2:28][OH:29])[CH2:24][CH2:23]3)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:9]1)=O)(C)(C)C.[ClH:30].CO>>[ClH:30].[NH:8]1[CH2:9][CH:10]([C:12]2[C:21]([N:22]3[CH2:23][CH2:24][CH:25]([CH2:28][OH:29])[CH2:26][CH2:27]3)=[N:20][C:19]3[C:14]([N:13]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nc3ccccc3nc2N2CCC(CO)CC2)C1
Agent: Cl
Solvent: CO
Product: OCC1CCN(c2nc3ccccc3nc2C2CNC2)CC1
Yield: 99 %

Procedure:
A solution of (47) (670 mg, 1.68 mmol) in 4N HCl/MeOH (25 mL) was stirred at RT for 30 min. The reaction mixture was concentrated to give [1-(3-azetidin-3-yl-quinoxalin-2-yl)-piperidin-4-yl]-methanol hydrochloride (48) (560 mg, 1.67 mmol, yield 99%).
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:16][CH3:17])=[N:14][CH:15]=3)[O:9][C:5]=2[CH:4]=1.Cl>C(Cl)Cl.C(OCC)C>[CH3:17][NH:16][C:13]1[N:14]=[CH:15][C:10]([C:8]2[O:9][C:5]3[CH:4]=[C:3]([OH:2])[CH:19]=[CH:18][C:6]=3[N:7]=2)=[CH:11][CH:12]=1
Reactant: CNc1ccc(-c2nc3ccc(OC)cc3o2)cn1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CNc1ccc(-c2nc3ccc(O)cc3o2)cn1
Reaction time: 0.25 h
Yield: 22.8 %

Procedure:
5-(6-Methoxy-1,3-benzoxazol-2-yl)-N-methylpyridin-2-amine (50 mg, 0.20 mmol) was dissolved in CH2Cl2 (10 mL) and made acidic with 2M HCl in diethylether. The solvent was removed in vacuo and hydrogen bromide (48% aq., 2 mL) was added. The reaction was run in a microwave reactor at 120° C. for 15 minutes. The mixture was then made basic with sodium bicarbonate and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by preparative HPLC, to give the title compound (11 mg) as a white solid. 1H NMR δ ppm 9.95 (br. s, 1H) 8.72 (d, 1H) 7.99 (dd, 1H) 7.46 (d, 1 H) 7.28 (d, 1 H) 7.03 (d, 1H) 6.79 (dd, 1H) 6.58 (d, 1H) 2.85 (d, 3H); MS m/z (M+H) 242, (M−H) 240.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:25]O)[CH:19]=[CH:20][C:21]=1[CH:22]1[CH2:24][CH2:23]1>>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:25][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH:19]=[CH:20][C:21]=1[CH:22]1[CH2:24][CH2:23]1
Reactant: OCc1ccc(C2CC2)c(Cl)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(C3CC3)c(Cl)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-chloro-4-cyclopropylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 0.68-0.71 (2H, m), 1.01-1.06 (2H, m), 2.16-2.23 (1H, m), 5.17 (2H, s), 5.73 (1H, d, J=2.0 Hz), 6.94 (1H, d, J=8.0 Hz), 7.20 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.40 (1H, dd, J=1.2 Hz, 5.2 Hz), 7.45 (1H, d, J=1.6 Hz), 7.56 (1H, d, J=1.6 Hz), 8.03 (1H, s), 8.71 (1H, d, J=4.8 Hz). [M+H] Calc'd for C19H15ClN4O, 351. Found, 351.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[CH3:2].Cl.[NH2:6][CH2:7][C:8]([CH3:14])([CH3:13])[CH2:9][C:10](O)=[O:11]>C(O)C>[ClH:4].[CH2:1]([O:3][C:10](=[O:11])[CH2:9][C:8]([CH3:14])([CH3:13])[CH2:7][NH2:6])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(CN)CC(=O)O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(C)(C)CN
Temperature: 85 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
Acetyl chloride (31 ml) was added dropwise over a time period of 5 minutes to ethanol (180 ml) while stirring and cooling in ice water bath. After additional 5 minutes, the obtained solution was added to a solution of 4-amino-3,3-dimethyl-butyric acid hydrochloride (30.07 grams, 180 mmol) in ethanol (20 ml). The mixture was refluxed at 85° C. for 16 hours, and the solvent was removed under reduced pressure to give to 4-amino-3,3-dimethyl-butyric acid ethyl ester hydrochloride (33.11 grams, 94% yield) as oil.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][CH2:10][C@@H:11]([OH:15])[C:12]([OH:14])=[O:13])=[O:8])=[CH:5][CH:4]=1)=O.[C:18]([CH:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)([CH3:21])([CH3:20])[CH3:19].C(O)(=O)C.C([BH3-])#N.[Na+]>CN1CCCC1=O.COC(OC)OC.CO>[C:18]([CH:22]1[CH2:23][CH2:24][CH:25]([NH:28][CH2:1][C:3]2[CH:17]=[CH:16][C:6]([C:7]([NH:9][CH2:10][C@@H:11]([OH:15])[C:12]([OH:14])=[O:13])=[O:8])=[CH:5][CH:4]=2)[CH2:26][CH2:27]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: O=Cc1ccc(C(=O)NC[C@@H](O)C(=O)O)cc1
Reactant: CC(C)(C)C1CCC(N)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: CC(C)(C)C1CCC(NCc2ccc(C(=O)NC[C@@H](O)C(=O)O)cc2)CC1
Reaction time: 4 h

Procedure:
The above resin bound (R)-3-(4-formylbenzoylamino)-2-hydroxypropionic acid was treated with a 0.5 M solution of 4-tert-butylcyclohexylamine (0.25 mmol) in a mixture of N-methyl-2-pyrrolidinone and trimethylorthoformate (1:1, 0.5 mL) and glacial acetic acid (50 μL) for 1 hour at 25° C. Sodium cyanoborohydride (250 μmol, 16 mg) dissolved in a mixture of N-methyl-2-pyrrolidinone and methanol (1:1, 0.25 mL) was added and the mixture was vortexed at 25° C. for 4 hours followed by filtration and washing with a mixture of N-methyl-2-pyrrolidinone and methanol (1:1, 2×1 mL) 3×1 mL N-methyl-2-pyrrolidinone (3×1 mL) and a mixture of 1,2-dichloropropane and diisopropylethylamine (7:1, 2×0.75 mL).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B1OC(C)(C)C(C)(C)O1)[CH3:2].Br[C:20]1[CH:25]=[CH:24][N:23]2[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=[C:22]2[CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>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].O.C(OCC)(=O)C>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][N:23]2[CH:26]=[C:27]([C:29]([F:31])([F:32])[F:30])[N:28]=[C:22]2[CH:21]=1)[CH3:2]
Reactant: CCSc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: FC(F)(F)c1cn2ccc(Br)cc2n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCSc1ccccc1-c1ccn2cc(C(F)(F)F)nc2c1
Yield: 63.2 %

Procedure:
A mixture of 0.53 g of 2-ethylsulfanylphenylboronic acid pinacol ester, 0.52 g of 7-bromo-2-trifluoromethylimidazo[1,2-a]pyridine, 0.02 g of tris(dibenzylideneacetone)dipalladium(0), 0.05 g of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylphenyl, 1.0 g of tripotassium phosphate and 6 ml of 1,4-dioxane was stirred under heat-reflux for 6 hours. Ethyl acetate and water were added to the cooled reaction mixture, and the mixture was filtered. The filtrate was extracted with ethyl acetate and then dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.40 g of 7-(2-ethylsulfanylphenyl)-2-trifluoromethylimidazo[1,2-a]pyridine (Compound of Present Invention 37).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8](\[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].[Na+].O>O1CCCC1.CN(C)C=O>[O:27]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8](\[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ICCCCC/C=C(\c1ccccc1)c1cccnc1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: C(\CCCCCOc1ccccc1)=C(\c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
(E)-1-Iodo-7-phenyl-7-(3-pyridyl)-6-heptene (0.6 g, 1.6 mmoles) and phenol (0.2 g, 2.1 mmoles) were dissolved in a mixture of tetrahydrofuran (10 ml) and dimethylformamide (2 ml), and sodium hydride (60% dispersion in oil, 0.1 g, 2.5 mmoles) was added to the solution. The mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added water (20 ml), followed by extraction of the product with ether. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography using isopropyl ether-ethyl acetate (2.1) as the developing solvent to give (E)-1-phenoxy-7-phenyl-7-(3-pyridyl)-6-heptene (0.5 g, 73%) (Compound Id-38) as an oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([C:16]1[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:18][O:19][C:20]=1[CH3:21])=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:32]>C(O)(=O)C>[CH2:1]([O:8][CH2:9][C:10]1[NH:12][CH:13]=[C:14]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][O:19][C:20]=2[CH3:21])[N:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CNC(=O)COCc1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1onc(-c2ccccc2)c1-c1c[nH]c(COCc2ccccc2)n1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
To a refluxing solution of 2-benzyloxy-N-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-2-oxo-ethyl]-acetamide (3.35 g, 9 mmol) in acetic acid (10 mL) was added ammonium acetate (14.2 g, 184 mmol) portionwise over 1.5 h. Then the mixture was heated for a subsequent 2 h under reflux and then allowed to cool down to room temperature overnight. The mixture was then poured onto water and extracted with ethyl acetate. The organic layer was then washed with water and brine, dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound (2.36 g, 74%) which was obtained as a light yellow solid. MS: m/e=346.1 [M+H]+.
Reaction SMILES: [OH-].[Na+].CCO.[Cl:6][C:7]1[C:8]([N:34]2[CH2:39][CH2:38][CH:37]([C:40]([O:42]CC)=[O:41])[CH2:36][CH2:35]2)=[N:9][CH:10]=[C:11]([C:13](=[O:33])[NH:14][C:15]2[S:16][C:17]([CH2:26][N:27]([CH2:29][CH2:30][O:31][CH3:32])[CH3:28])=[C:18]([C:20]3[S:21][CH:22]=[C:23]([Cl:25])[CH:24]=3)[N:19]=2)[CH:12]=1.Cl>O>[ClH:6].[Cl:6][C:7]1[C:8]([N:34]2[CH2:39][CH2:38][CH:37]([C:40]([OH:42])=[O:41])[CH2:36][CH2:35]2)=[N:9][CH:10]=[C:11]([C:13](=[O:33])[NH:14][C:15]2[S:16][C:17]([CH2:26][N:27]([CH2:29][CH2:30][O:31][CH3:32])[CH3:28])=[C:18]([C:20]3[S:21][CH:22]=[C:23]([Cl:25])[CH:24]=3)[N:19]=2)[CH:12]=1
Reactant: CCOC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)c(CN(C)CCOC)s3)cc2Cl)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCCN(C)Cc1sc(NC(=O)c2cnc(N3CCC(C(=O)O)CC3)c(Cl)c2)nc1-c1cc(Cl)cs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 189.5 %

Procedure:
0.4 ml of a 1M sodium hydroxide aqueous solution was added to a 1.5 ml EtOH suspension of 76 mg of ethyl 1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(2-methoxyethyl)(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylate, and the mixture was stirred at 60° C. for 2 hours. 0.6 ml of 1M hydrochloric acid and 0.5 ml of water were added at room temperature, and the resulting precipitate was collected by filtration, washed with 50% ethanol water, and dried under reduced pressure to obtain 73 mg of 1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(2-methoxyethyl)(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.[C:17]([NH2:21])(=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C>COCCOC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH2:19][CH2:18][C:17](=[O:20])[NH2:21]
Reactant: C=CC(N)=O
Reactant: Brc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: NC(=O)CCN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12

Procedure:
A stirred mixture of 5-bromo-3-(2(R)-pyrrolidinylmethyl)-1H-indole (Preparation 2; 600 mg, 2.1 mmol), acrylamide (168 mg, 2.4 mmol), triethylamine (0.60 ml) and 1,2-dimethoxyethane (11.9 ml), under nitrogen, was heated under reflux for 8 hours, allowed to cool, then partitioned between ethyl acetate (400 ml) and water (400 ml). The organic phase was separated, washed with water (400 ml), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a solvent gradient of 0.880 aqueous ammonia:methanol: dichloromethane (0.1:10:90 to 0.4:10:90), to afford the required product as a foam. Rf 0.26 (SS 7). [α]D25 +59° (c=0.1, CH3OH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)=[C:4]([F:28])[CH:3]=1.[CH3:29][O:30][C:31](=[O:41])[C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C(Cl)Cl>[CH3:29][O:30][C:31](=[O:41])[C:32]1[CH:33]=[CH:34][C:35]([NH:38][C:39]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:28])=[O:40])=[CH:36][CH:37]=1
Reactant: COC(=O)c1ccc(N=C=O)cc1
Reactant: CC(C)(C)CC1CNC(c2ccc(Cl)cc2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2ccc(Cl)cc2F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
A mixture of rac-(2S,3S,4S)-2,3-bis(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (150.0 mg, 0.35 mmol) and 4-isocyanato-benzoic acid methyl ester (Aldrich, 86.0 mg, 0.53 mmol) in CH2Cl2 (5 mL) was stirred at rt for 3 h. The reaction mixture was then concentrated and purified by flash column to give rac-4-{[(2S,3S,4S)-2,3-bis-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]amino}-benzoic acid methyl ester (141.6 mg, 66.6%) which was used in the next step without further purification.