Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]2([CH3:19])[CH3:18])[C:3]([OH:5])=O.[CH3:21][O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1.CCN(CC)CC>O=S(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl.[NH4+].[Cl-]>[F:20][C:2]([F:1])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]2([CH3:18])[CH3:19])[C:3]([NH:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([O:22][CH3:21])=[O:31])=[O:5]
Reactant: CC1(C)CCC(C)(C)c2cc(C(F)(F)C(=O)O)ccc21
Reactant: COC(=O)c1cccc(N)c1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)C(F)(F)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
2,2-Difluoro-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)acetic acid 16 (0.53 g, 1.88 mmol) was dissolved in SOCl2 and two drops of DMF were added at 0° C. The mixture was stirred at 0° C. for 0.5 h, evaporated and the crude product was dissolved in CH2Cl2 (5 mL). B) Methyl-3-aminobenzoate (284 mg, 1.88 mmol) and DMAP (23 mg, 0.19 mmol) were dissolved in CH2Cl2 (5 mL) and Et3N (2.6 mL) was added at 0° C. A) was added in B) at 0° C. and this mixture was stirred at 0° C. for 10 min and abandoned at RT for 1 h. The mixture was poured in aqueous NH4Cl 5% (100 mL) and extracted with EtOAc (3×50 mL). The organic layer was washed with NaHCO3 (2×100 mL), brine (2×100 mL), dried with MgSO4, filtered and evaporated. The crude product was purified by column chromatography using as eluent cyclohexane:EtOAc=90:10.Methyl 3-(2,2-difluoro-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)acetamido)benzoate 19 was obtained (0.55 g, 70% yield) as a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][Cl:6].[OH:7][C:8]1[N:13]=[C:12]([OH:14])[C:11]([F:15])=[CH:10][N:9]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O.CN(C)C=O>[Cl:6][CH2:5][CH2:4][CH2:3][CH2:2][N:9]1[CH:10]=[C:11]([F:15])[C:12](=[O:14])[NH:13][C:8]1=[O:7]
Reactant: ClCCCCBr
Reactant: Oc1ncc(F)c(O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: O
Product: O=c1[nH]c(=O)n(CCCCCl)cc1F
Temperature: 20 °C
Reaction time: 1 h

Procedure:
2.6 g (15.0 mmol) of 1-bromo-4-chlorobutane were added dropwise to a solution of 1.95 g (15.0 mmol) of 2,4-dihydroxy-5-fluoropyrimidine in 50 ml of dimethyl sulfoxide and 20.0 ml of N,N-dimethylformamide (DMF) at 0° C. 2.07 g (15.0 mmol) of K2CO3 were added in portions over the course of 1 hour, and the mixture was stirred at 20° C. for 1 hour (dialkylated product is already identifiable). Water was then added to the reaction mixture, and the aqueous mixture was extracted twice with diethyl ether and twice with methylene chloride. The aqueous phase was adjusted to pH 3-4 with hydrochloric acid and then the aqueous phase was extracted with methylene chloride. The organic phase was then dried, the desiccant was removed by filtration, and the solvent was evaporated to dryness in vacuo; yield: 0.6 g. 1-(4-Chlorobutyl)-5-fluoropyrimidine-2,4(1H,3H)-dione was employed without further purification in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([C:32]([O:34][CH2:35][CH3:36])=[CH2:33])[C:28](=[O:37])[N:27]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:43](OCCCC)=[CH2:44].C(N(C(C)C)CC)(C)C>ClCCl.[Pd](Cl)Cl.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([C:32]([O:34][CH2:35][CH2:36][CH2:43][CH3:44])=[CH2:33])[C:28](=[O:37])[N:27]([CH:38]5[CH2:39][CH2:40][CH2:41][CH2:42]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Reactant: C=COCCCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C=C(OCCCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 95 °C
Reaction time: 20 h
Yield: 75.2 %

Procedure:
A 5-L, three-necked, round-bottomed flask, equipped with a mechanical stirrer, a thermocouple, and a nitrogen inlet/outlet vented through a silicone oil bubbler was placed under a nitrogen atmosphere and charged with 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (300 g, 0.51 mol, prepared as in Example 2), butyl vinyl ether (154 g, 1.54 mol, ALDRICH), n-butanol (1.5 L, ALDRICH), and diisopropyl ethylamine (107 mL, 0.62 mol, ALDRICH). The slurry was placed under approximately 50 Torr vacuum and then refilled with nitrogen 3 times. To this was added 8.3 g (0.01 mol) bis-(diphenylphosphinoferrocene) palladium dichloride dichloromethane (JOHNSON MATTHEY, Lot 077598001) and the resulting slurry was purged an additional three times as described above. The mixture was then heated to 95° C. and stirred for 20 h. The resulting thin red slurry was diluted with 2 L of heptane and cooled to approximately 5° C. At this temperature, 400 mL saturated aqueous potassium carbonate was added and the mixture was filtered and rinsed with 250 mL of heptane. After drying in an oven for 16 h at 45° C., 231.7 g (75% yield) of the title compound was obtained as a yellow solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:17][CH:16]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14]2)(=O)=O)=CC=1.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[CH2:30]([N:37]1[CH2:12][CH:13]2[O:17][CH:16]([CH2:15][CH2:14]2)[CH2:18]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(COS(=O)(=O)c3ccc(C)cc3)O2)cc1
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(CN2CC3CCC(C2)O3)cc1

Procedure:
112 g (250 mmol) of 2,5-anhydro-3,4-dideoxy-1,6-bis-O-[(4-methylphenyl)sulfonyl]-hexitol from step 1 and 90.7 g (840 mmol) of benzylamine in 500 ml of toluene are heated under reflux for 20 hours. The precipitate is then filtered off with suction and washed with toluene. The combined toluene phases are concentrated in a rotary evaporator and distilled in vacuo. After a benzylamine fore-run, the product is obtained.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([F:14])[CH:8]=1.[C:15](=[O:17])=[O:16].O>CCOCC>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:15]([OH:17])=[O:16])=[CH:8][C:9]=1[F:14]
Reactant: Fc1cc(Br)ccc1Cl
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: O=C(O)c1ccc(Cl)c(F)c1
Temperature: -78 °C

Procedure:
n-Butyl lithium (2.5M in hexanes, 176 ml) was added to a stirred solution of 1-bromo-4-chloro-3-fluorobenzene (83.38 g) in dry ether. Stirring was maintained for a further 2.5 hours at -78° C., and the mixture poured onto excess solid carbon dioxide pellets, allowed to reach room temperature and water added. The mixture was washed with ether, acidified, extracted (ethyl acetate) and dried (magnesium sulphate). After evaporation the residue was triturated with petroleum ether to give 4-chloro-3-fluorobenzoic acid (66.4 g) as a white solid, m.p. 192°-192.5° C.
Reaction SMILES: P([O-])([O-])([O-])=O.[F:6][C:7]([F:17])([F:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].CC(O)C>C(OCC)(=O)C>[F:6][C:7]([F:16])([F:17])[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9]
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: OC(c1ccccc1)C(F)(F)F
Temperature: 30 °C
Reaction time: 18 h

Procedure:
To 0.02 g of the aforementioned wet bodies was added 500 μl of 50 mM phosphate buffer (pH 7.0) containing 1% 2,2,2-trifluoroacetophenone and 5% 2-propanol, followed by stirring at 30° C. for 18 hours. Then, after adding 500 μl of ethyl acetate to the reaction mixture, the mixture was subjected to centrifugal separation to obtain the organic phase. The organic phase was subjected to an analysis of the content by way of gas chromatography under the following condition. 2,2,2-Trifluoro-1-phenylethanol was produced at a ratio of 49.4% based on the amount of 2,2,2-trifluoroacetophenone used in the reaction. Furthermore, optical purity of 2,2,2-trifluoro-1-phenylethanol in the organic phase was measured under the following condition. The (S)-form of 99% e.e. was demonstrated.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1>C1COCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:17][CH:16]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a cooled solution (−78° C.) of (trimethylsilyl)acetylene (4.2 mL, 30 mmol) in THF (25 mL) is added dropwise (2.5M) n-butyllithium (11.6 mL, 29 mmol) and stirred for 30 min followed by slow addition of (0.5M) zinc chloride (58 mL, 29 mmol). The resulting solution is allowed to warm to 20° C. followed by addition of 4-iodo-benzoic acid methyl ester (5.24 g, 20 mmol) (reference example 48) and tetrakis(triphenylphosphine)palladium(0) (1.16 g, 1 mmol) in THF (10 mL). The resulting mixture is heated to 55° C. and stirred for 2 hours then cooled to 20° C. The reaction mixture is diluted with ethyl acetate, washed with sat.NH4Cl soln, water and brine, dried over MgSO4 and concentrated to give 4.65 g of title compound. 1H NMR (CDCl3) δ 0.26 (s, 2H), 3.91 (s, 3H), 7.52 (d, J=8 Hz, 2H), 7.97 (d, J=8 Hz, 2H). MS (EI) m/z 232 (M+).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11].[C:13](O)(=O)[CH2:14][CH2:15][C:16]#[CH:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O1CCOCC1>[CH2:16]([C:17]1[O:1][N:2]=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][CH3:11])[N:12]=1)[CH2:15][C:14]#[CH:13]
Reactant: COc1ccccc1C(N)=NO
Reactant: C#CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: C#CCCc1nc(-c2ccccc2OC)no1
Temperature: 80 °C
Reaction time: 3 h
Yield: 36.4 %

Procedure:
In a reactor tube, a mixture of N′-hydroxy-2-methoxybenzamidine (598 mg, 3.6 mmol), 4-pentynoic acid (350 mg, 3.6 mmol), HOBT (0.55 g, 3.6 mmol) and EDCI.HCl (1.03 g, 5.4 mmol) in dioxane (7.4 mL) was stirred at R.T for 3h. After this time the mixture was heated at 80° C. overnight in a reaction block. The mixture was concentrated and the crude product was purified by flash chromatography (Prepacked column 25 g with DCM as eluent) to afford 299 mg of 5-(but-3-ynyl)-3-(2-methoxyphenyl)-1,2,4-oxadiazole (36%) as yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([CH2:26][NH:27][CH2:28][C:29]3[NH:30][CH:31]=[CH:32][N:33]=3)=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42][N:43]1[CH:47]=[CH:46][N:45]=[C:44]1[CH:48]=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(Cl)(Cl)Cl.C(O)(=O)C>[CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH2:28][C:29]3[NH:33][CH:32]=[CH:31][N:30]=3)[CH2:48][C:44]3[N:43]([CH3:42])[CH:47]=[CH:46][N:45]=3)=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ccnc1C=O
Reactant: O=C(Nc1ccc(CN(C(=O)OCc2ccccc2)C2CCCCC2)cc1)c1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: Cn1ccnc1CN(Cc1ccc(CNc2ccc(CN(C(=O)OCc3ccccc3)C3CCCCC3)cc2)cc1)Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
The compound (236 mg) obtained in Example 87-4 and 1-methyl-2-imidazole carboxaldehyde (46.5 mg) were dissolved in anhydrous methanol (7.1 ml). The solution was added with sodium cyanoborohydride (54.0 mg) and then adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 16 hours. After the reaction, the solvent was distilled-off. A 1 mol/l sodium hydroxide aqueous solution was added to the residue, and chloroform extraction was then carried out. The extract was washed with saturated saline solution and then dried with magnesium sulfate, followed by distilling the solvent off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (212 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(S(C)(=O)=O)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 70.4 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(methylsulfonyl)phenylboronic acid (20.8 mg, 0.104 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give 2′-amino-1′-methyl-6-(3-(methylsulfonyl)phenyl)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (16.89 mg, 70%). 1H-NMR (MeOD): 2.01 (m, 1H), 2.31 (m, 1H), 3.14 (m, 3H), 3.21 (m, 3H), 5.22 (m, 0.2H), 5.83 (m, 0.7H), 6.89 (m, 1H), 7.18 (m, 1H), 7.23 (m, 1H), 7.32 (m, 2H), 7.39 (m, 2H), 7.45 (m, 1H), 7.57 (m, 1H), 7.76 (m, 2H), 7.96 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)=[CH:16][CH:15]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH2:35][CH2:36][CH2:37][NH:38]3)=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:42][CH2:43][CH2:44][OH:45]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)=[CH:18][CH:19]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH2:35][CH2:36][CH2:37][N:38]3[CH2:42][CH2:43][CH2:44][OH:45])=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCCBr
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC3CC3)cc2)[C@@H](OCc2ccc3c(c2)NCCC3)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC3CC3)cc2)[C@@H](OCc2ccc3c(c2)N(CCCO)CCC3)C1

Procedure:
In analogy to the procedure described in example 4(a), the (3R,4R)-4-[4-(3-cyclopropylmethoxy-propoxy)-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was reacted with 1-bromo-3-hydroxy-propane to yield the (3R,4R)-4-[4-(3-cyclopropylmethoxy-propoxy)-phenyl]-3-[1-(3-hydroxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 609 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:10])[CH3:9]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Cc1ccccc1
Product: CC(=O)C(=CN(C)C)c1ccccc1

Procedure:
A mixture of phenylacetone (13.4 grams) and dimethylformamide dimethylacetal (13.0 grams) was heated at 90°-95° C. on a steam bath for about 21/2 hours. A crude oil was produced which was then chromatographed on 600 ml of silica gel using ethyl acetate as an eluent. The final product, whose structure was confirmed by NMR, was a yellow oil which crystallized upon standing, yield 15.5 grams.
Reaction SMILES: [NH2:1][NH2:2].[C:3]([CH2:11][C:12]#[N:13])(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl>[C:4]1([N:1]2[C:12]([NH2:13])=[CH:11][C:3]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[N:2]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1cc(-c2ccccc2)nn1-c1ccccc1
Yield: 178.7 %

Procedure:
To a solution of 1.08 g hydrazine in 10 ml 5N hydrochloric acid was added 1.45 g benzoylacetonitrile (prepared according to the procedure of Example 2), under stirring. The mixture was refluxed for 3 hrs. After cooling, the solution was neutralized with Na2CO3. The yellow precipitate was filtrated, washed with H2O, and dried to get 2.1 g 1,3-diphenyl-5-aminopyrazole.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.FC(F)(F)C(O)=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH:38]2[CH2:42][CH2:41][O:40][C:39]2=[O:43])(O)[C:29]2[CH:34]=[CH:33][C:32]([S:35][CH3:36])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1>ClCCl.O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[C:38]2[CH2:42][CH2:41][O:40][C:39]2=[O:43])[C:29]2[CH:34]=[CH:33][C:32]([S:35][CH3:36])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1
Reactant: CSc1ccc(C(O)(c2ccc(Cl)cc2)C2CCOC2=O)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccc(C(=C2CCOC2=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
5.2 g of trifluoroacetic anhydride and 3.8 ml of trifluoroacetic acid are added to a solution of 8.6 g of 3-[1-(4-chlorophenyl)-1-hydroxy-1-(4-methylthiophenyl)methyl]dihydrofuran-2-one, prepared in Example 6, in 100 ml of dichloromethane. The mixture is stirred at room temperature for 4 hours and then diluted with water and decanted. The organic phase is dried over magnesium sulphate and evaporated under vacuum to give 7.5 g of 3-[1-(4-chlorophenyl)-1-(4-methylthiophenyl)methylidene]dihydrofuran-2-one in the form of an oil, which is used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[I:10]Cl>C(O)(=O)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: ClI
Reactant: N#Cc1ccccc1N
Solvent: CC(=O)O
Product: N#Cc1cc(I)ccc1N
Yield: 65 %

Procedure:
One general synthetic procedure for the methods of the present invention is depicted in Scheme 2 below. lodination of 2-aminobenzonitrile with iodine monochloride in glacial acetic acid (AcOH) at room temperature occurred regioselectively at the position para to the amino group to give 2-amino-5-iodobenzonitrile (9) in 65% yield as reported by others (Harris, N. V.; Smith, C.; Bowden, K. Eur. J. Med Chem. 1992; 27, 7-18). A catalytic amount (0.1 mmol) of commercially available [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)′CH2Cl2 [(dppf)PdCl2—CH2Cl2] (Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.; Hirotsu, K. J. Am Chem. Soc. 1984, 106, 158-163) was added to a THF solution of the organozinc halide (5 mmol) resulting in the formation of a solution having a deep yellow color after a few minutes. After complete addition of (dppf)PdCl2 to the reaction mixture, a solution of aryl halide 9 (2 mmol) in THF was added to the reaction mixture and the mixture was then heated at reflux for 30 min. The cross-coupling reaction was complete by thin layer chromatography (TLC). The intermediate amino nitrile 10 formed by the cross-coupling reaction were purified by column chromatography on silica gel, and their identity and purity were established from their 1H NMR spectra, which contained the expected singlet at approximately δ 3.8, along with OMe, NH2, and aromatic proton peaks consistent with assigned structures (data provided below).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.N1C=CC([NH:14][C:15](N)=[S:16])=N1>>[CH3:1][N:2]1[C:6]([NH:7][C:15]([NH2:14])=[S:16])=[CH:5][C:4]([CH3:8])=[N:3]1
Reactant: NC(=S)Nc1cc[nH]n1
Reactant: Cc1cc(N)n(C)n1
Product: Cc1cc(NC(N)=S)n(C)n1

Procedure:
This material is prepared from 2,5-dimethyl-2H-pyrazol-3-ylamine following the procedure described for (1H-pyrazol-3-yl)-thiourea (35a)
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1.[F:21][C:22]1[C:27](I)=[N:26][CH:25]=[CH:24][N:23]=1>CC(N(C)C)=O.[Zn].[Cu]I>[F:21][C:22]1[C:27]([CH:11]2[CH2:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH2:12]2)=[N:26][CH:25]=[CH:24][N:23]=1
Reactant: IC1CCC2(CC1)OCCO2
Reactant: Fc1nccnc1I
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: CC(=O)N(C)C
Product: Fc1nccnc1C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of activated zinc dust (51 g, 0.78 mol, 1.94 eq.) in anhydrous DMA (100 mL) was added 1,2-dibromoethane (5.5 mL, 0.064 mol, 0.16 eq.), followed by the slow addition of chlorotrimethylsilane (8.1 mL, 0.064 mol, 0.16 eq.) over 5 min. The resulting mixture was stirred for 15 min under nitrogen. Then a solution of 8-iodo-1,4-dioxaspiro[4.5]decane (172 g, 0.639 mol, 1.59 eq.) in anhydrous DMA (300 mL) was added to the above suspension over 30 min keeping the internal temperature below 65° C. The resulting mixture was stirred for 1 hour and cooled to room temperature. The prepared zinc reagent was allowed to stand and the upper clear solution was transferred to a degassed and well stirred solution of 2-fluoro-3-iodopyrazine (see PREPARATION P6.2; 90 g, 0.402 mol, 1.0 eq.), PdCl2(dppf)CH2Cl2 (9.8 g, 0.012 mol, 0.03 eq.), and CuI (4.75 g, 0.025 mol, 0.062 eq.) in anhydrous DMA (300 mL) using a cannula. DMA (100 mL) was used to rinse the remaining zinc dust and the solution was added to the above mixture. The resulting mixture was heated to 80° C. under nitrogen and stirred overnight.