Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:40][CH:39]=2)=[CH:34][C:33]=1[C:49]1[CH:58]=[CH:57][C:56]2[C:55]([CH3:60])([CH3:59])[CH2:54][CH2:53][C:52]([CH3:62])([CH3:61])[C:51]=2[CH:50]=1)(C(C)(C)C)(C)C.O>O1CCCC1>[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:40][CH:39]=2)=[CH:34][C:33]=1[C:49]1[CH:58]=[CH:57][C:56]2[C:55]([CH3:60])([CH3:59])[CH2:54][CH2:53][C:52]([CH3:61])([CH3:62])[C:51]=2[CH:50]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCO[Si](C)(C)C(C)(C)C)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCO)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
6.8 ml (6.8 mmol) of a solution of tetrabutylammonium fluoride (1 M) are added to a solution of 2.8 g (4.5 mmol) of ethyl 4′-[4-(tert-butyldimethylsilanyloxy)butoxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate in 20 ml of tetrahydrofuran. The reaction mixture is stirred for 4 h at ambient temperature. The reaction is stopped by adding 20 ml of water and the mixture is then extracted with ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvents are evaporated off. The crude obtained in the form of an oil is chromatographed on silica gel (heptane/ethyl acetate: 70/30), to give 2.10 g of ethyl 4′-(4-hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate in the form of a colorless oil (yield=93%).
Reaction SMILES: [O:1]1[CH2:23][CH:2]1[CH2:3][N:4]([CH:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[H-].[Na+].[Na].[CH3:27][N:28]([CH3:32])[C:29](Cl)=[O:30]>CN(C)C=O>[O:1]1[CH2:23][CH:2]1[CH2:3][N:4]([CH:15]([CH3:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[S:5]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:29](=[O:30])[N:28]([CH3:32])[CH3:27])=[CH:12][CH:13]=1)(=[O:7])=[O:6]
Reactant: CC(c1ccccc1)N(CC1CO1)S(=O)(=O)c1ccc(O)cc1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(c1ccccc1)N(CC1CO1)S(=O)(=O)c1ccc(OC(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
1 g (3 mmol) of N-(2,3-epoxypropyl)-N-α-methylbenzyl-4-hydroxybenzenesulfonamide and 180 mg (3.75 mmol) of 50% sodium hydride were added to 15 ml of dry N,N-dimethylformamide, followed by agitating at room temperature for 30 minutes. To the resulting sodium salt was added 400 mg (3.83 mmol) of N,N-dimethylcarbamoyl chloride for reaction at 60° C. for 1 hour. After completion of the reaction, the excess of the solvent and N,N-dimethylcarbamoyl chloride were removed by distillation under reduced pressure. The residue was dissolved in chloroform and sufficiently washed with water and the chloroform solution was dehydrated over anhydrous magnesium sulfate, followed by distilling off the solvent to obtain a crude product. The crude product was purified by the silica gel chromatography to obtain 980 mg of N-(2,3-epoxypropyl)-N-α-methylbenzyl-4-(N,N-dimethylcarbamoyloxy)-benzenesulfonamide (Compound No. 57). The nD26.0 value was found to be 1.5320. The results of the elemental analysis are shown below.
Reaction SMILES: [CH2:1]([CH:5]([CH:7]1[CH:12]([CH3:13])[CH2:11][CH:10]([CH3:14])[CH2:9][CH2:8]1)[OH:6])[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.C(O)(C)C>O.C1(C)C=CC=CC=1>[CH2:1]([CH:5]1[CH:7]2[CH2:8][CH2:9][C:10]([CH3:14])([CH2:11][CH:12]2[CH3:13])[O:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(O)C1CCC(C)CC1C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCCCC1OC2(C)CCC1C(C)C2
Yield: 70.9 %

Procedure:
A solution of 500 grams of alpha-n-butyl-4,6-dimethyl-3-cyclohexane methanol, 600 grams of sulfuric acid, 1400 grams of water and 500 grams of isopropyl alcohol is heated at reflux for 14 hours. The reaction mass is cooled, diluted with 1500 ml of H2O and 200 ml of toluene. The aqueous layer is discarded and the organic layer is washed twice with water, neutralizing with aqueous sodium hydroxide on the second wash. Distillation through a 1.5"×12" Goodloe column affords 351 grams of 3-n-butyl-1,5-dimethyl-2-oxabicyclo[2.2.2]octane (b.p. 90° C., 3 mm Hg pressure).
Reaction SMILES: NC1C=CC(C)=C(C(C2C=CC(NC3C=CC(C(F)(F)F)=CC=3)=CC=2Cl)=O)C=1.[Cl:29][C:30]1[CH:35]=[C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:45]([C:47]1[CH:52]=[C:51]([N+:53]([O-])=O)[CH:50]=[CH:49][C:48]=1[CH3:56])=[O:46]>>[NH2:53][C:51]1[CH:50]=[CH:49][C:48]([CH3:56])=[C:47]([C:45]([C:31]2[CH:32]=[CH:33][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)=[CH:35][C:30]=2[Cl:29])=[O:46])[CH:52]=1
Reactant: COc1ccc(Nc2ccc(C(=O)c3cc([N+](=O)[O-])ccc3C)c(Cl)c2)cc1
Agent: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Product: COc1ccc(Nc2ccc(C(=O)c3cc(N)ccc3C)c(Cl)c2)cc1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 415, using compound 446 (0.31 mmol). The crude product was used without any further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].O>[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8]
Reactant: Cc1ccccc1Br
Reactant: Cc1cccc(C)c1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: Cc1ccccc1-c1c(C)cccc1C
Yield: 96.8 %

Procedure:
The general procedure described in Example 3 was used with 2-bromotoluene (0.120 mL, 1.00 mmol), 2,6-dimethylphenylboronic acid (225 mg, 1.50 mmol), Pd(OAc)2 (4.5 mg, 0.020 mmol, 2 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (20.0 mg, 0.040 mmol, 4 mol %), K2CO3 (276 mg, 2.00 mmol), water (1.5 mL), 22 h, room temperature. The product was isolated as a colorless oil (190 mg, 97%). 1H NMR (400 MHz, CDCl3) δ: 7.30-7.10 (m, 6H), 7.02-7.00 (m, 1H), 1.99 (s, 3H), 1.96 (s, 6H). 13C NMR (125 MHz, CDCl3) δ: 141.1, 140.7, 136.1, 135.9, 130.0, 129.1, 127.4, 127.1, 127.1, 126.1, 20.7, 19.7.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:4]=1.C[O:19][C:20](=[O:31])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][C:24]=1[CH3:30]>>[CH3:30][C:24]1[CH:25]=[C:26]([S:29][CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:4]=2)[CH:27]=[CH:28][C:23]=1[O:22][CH2:21][C:20]([OH:31])=[O:19]
Reactant: FC(F)(F)c1ccc(-c2cc(CCl)on2)cc1
Reactant: COC(=O)COc1ccc(S)cc1C
Product: Cc1cc(SCc2cc(-c3ccc(C(F)(F)F)cc3)no2)ccc1OCC(=O)O

Procedure:
Preparation of 5-chloromethyl-3-(4-trifluoromethyl-phenyl)-isoxazole (compound 45A) A solution of 4-trifluoromethyl-benzaldehyde oxime (8.9 g, 47.1 mmol) in 100 mL DCM was added to a rapidly stirred solution of propargyl chloride (47.1 mmol), triethyl amine (4.71 mmol) and 91 mL of commercial bleach (6.5% by weight) all in 50 mL DCM at 0° C. After 1 hour the layers were separated and the organic layer dried (Na2SO4), and concentrated in vacuo. Purification by flash column chromatography (gradient elution: 5% EtOAc/hexane to 25% EtOAc/hexane) gave the title compound (2.9 g, 23%) MS m/z 262 (M+1). Step 2. Preparation of {2-Methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-phenoxy}-acetic acid methyl ester (compound 45B) The title compound was prepared in a manner analogous to Example 1F using 45A and 2C. MS m/z 438 (M+1). Step 3. Preparation of {2-Methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-3-phenoxy}-acetic acid (compound 45) The title compound was prepared in a manner analogous to Example 1 using 45B. IR cm−1: 1747; 400 MHz 1H NMR (DMSO-d6) δ 12.97 (br(s), 1H), 7.99 (d, 2H, J=8.0 Hz), 7.81 (d, 2H, J=8.0 Hz), 7.21 (s, 1H), 7.16 (d, 1H, J=8.5 Hz), 6.86 (s, 1H), 6.74 (d, 1H, J=8.5 Hz), 4.63 (s, 2H), 4.30 (s, 2H), 2.09 (s, 3H); MS m/z 424 (M+1).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1[S:14][C:15]2[CH2:21][CH2:20][CH2:19][CH:18]([CH2:22][OH:23])[C:16]=2[N:17]=1>>[CH3:12][C:13]1[S:14][C:15]2[CH2:21][CH2:20][CH2:19][CH:18]([CH2:22][O:23][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[C:16]=2[N:17]=1
Reactant: Cc1nc2c(s1)CCCC2CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2CCCc3sc(C)nc32)cc1
Yield: 89 %

Procedure:
This compound is prepared by action of p-toluenesulfonyl chloride on above alcohol (IV), according to the process of Example 1. M.p.=97°-98° C. Yield: 89%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]Cl)=[N:6][CH:7]=1.[CH3:10][S-:11].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:11][CH3:10])=[N:6][CH:7]=1
Reactant: C[S-]
Reactant: ClCc1ccc(Br)cn1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To the stirred solution of 5-Bromo-2-chloromethyl-pyridine (3.5 gm, 16.99 mmol) in DMF (25 mL) at 0° C. is added Sodium thiomethoxide (1.31 gm, 18.68 mmol) resulting reaction mixture is stirred at 0° C. for 2 h. After completion quenched with water and extracted with ethyl acetate (3×100 mL). The Combined organic layer is washed with brine and organic layer dried over sodium sulphate, evaporate under reduced pressure. The crude is purified by column chromatography using silica 100-200 mesh using 10% EtOAc: Hexane as eluent to afford title compound (3 g) as brown colored liquid. 1NMR (400 MHz, DMSO) δ: 2.00 (s, 3H), 3.75 (s, 2H), 7.39 (d, J=8.32 Hz, 1H), 7.99-8.02 (dd, J1=2.44 Hz, J2=8.32 Hz, 1H), 8.60 (d, J=2.28 Hz, 1H). LC-MS (m/z): M+H=220.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])[CH2:33][CH2:32]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: Clc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccccc4Cl)CC3)c(OC)nc2c1
Yield: 89 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 89%). 1H NMR (300 MHz, CDCl3): δ 3.13 (s, 4H), 3.78 (s, 4H), 3.90 (s, 3H), 4.12 (s, 3H), 6.98-7.37 (m, 7H), 7.76 (d, J=9.9 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[C:6](I)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].O.C[N:22]([CH:24]=O)C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[C:6]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:24]#[N:22])[CH:5]=2)[CH:5]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(I)cc(CO)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1cc(CO)cc(-c2cccc(C#N)c2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
3.08 g of the 5-hydroxymethyl-3-iodobenzoic acid methyl ester obtained in the production example 2 was dissolved in 50 ml of dry DMF under the flow of nitrogen and then mixed with 2.32 g of the compound in the production example 3, 2.18 g of potassium carbonate and 456 mg of tetrakis(triphenylphosphine) palladium (0). The obtained mixture solution was heated and stirred at 90° C. overnight, mixed with water to stop the reaction, and then extracted with ethyl acetate. The obtained ethyl acetate layer was dried over MgSO4, and the solvent was distilled away. The residue was purified by silica gel column chromatography to obtain 2.05 g (73%) of the title compound. Colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:11]([OH:12])[CH:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH3:21])[N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:22]#[N:23])[CH:8]=2)[O:3]1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[CH3:1][C:2]1([CH3:24])[C:11]([O:12][C:25](=[O:27])[CH3:26])=[C:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH3:21])[N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:22]#[N:23])[CH:8]=2)[O:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1nc(NC2c3cc(C#N)ccc3OC(C)(C)C2O)ccc1=O
Product: CC(=O)OC1=C(Nc2ccc(=O)n(C)n2)c2cc(C#N)ccc2OC1(C)C

Procedure:
2.0 g of 2,2-dimethyl-4-(1-methyl-1,6-dihydro-6-oxo-3-pyridazinyl-amino)-6-cyano-3-chromanol are boiled in 20 ml of acetic anhydride for 2 hours. Customary working-up gives 2,2-dimethyl-3-acetoxy-4-(1-methyl-1,6-dihydro-6-oxo-3-pyridazinyl-amino)-6-cyano-3-chromene, m.p. 110°-112°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.C(OCC)(=O)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>CC(P(C(C)(C)C)C(C)(C)C)(C)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.[Pd].CCOC(C)=O.O>[F:8][C:6]1[CH:7]=[C:2]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:3]=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]=1[F:9]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cc(F)c(F)c(OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
5-bromo-1,2-difluoro-3-[(phenylmethyl)oxy]benzene (10 g, 33.3 mmol), diethyl propanedioate (6.9 g, 43.3 mmol), Cs2CO3 (108 g, 333 mmol), and dioxane (200 mL) were combined in a sealed flask and N2 was bubbled through the solution for 15 minutes. Pd(t-Bu3P)2 (1.7 g, 3.33 mmol) was then added and the flask was sealed. The solution was heated to 80° C. and stirred vigorously. After 8 h, the temperature was increased to 120° C. After 3 days, it was cooled and H2O and EtOAc were added. The aqueous layer washed with EtOAc (3×). The combined organic extracts were concentrated, and purified by Biotage (in two batches) to afford 1.82 g of the title compound (21%).
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[OH:9][C@@H:10]([CH2:15][O:16][CH3:17])[C:11]([O:13][CH3:14])=[O:12].N1C=CN=C1>CN(C=O)C>[Si:5]([O:9][C@@H:10]([CH2:15][O:16][CH3:17])[C:11]([O:13][CH3:14])=[O:12])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC[C@H](O)C(=O)OC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-butylchlorodimethylsilane (661 mg, 4.38 mmol) in DMF (2.5 mL) was added dropwise to a stirred solution of (S)-methyl 2-hydroxy-3-methoxypropanoate C4a (490 mg, 3.65 mmol) and 1H-imidazole (497 mg, 7.31 mmol) in DMF (5 mL) at 20° C., over a period of 2 minutes. The resulting solution was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated, diluted with EtOAc (50 mL) and washed sequentially with water (4×15 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. Purification by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane afforded (S)-methyl 2-(tert-butyldimethylsilyloxy)-3-methoxypropanoate (750 mg).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:12](=O)([O-])[O-:13].[K+].[K+]>C(=O)(OCC)OCC>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]2[CH2:3][O:4][C:12](=[O:13])[NH:1]2)=[CH:6][CH:7]=1
Reactant: NC(CO)c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(=O)OCC
Product: O=C1NC(c2ccc(F)cc2)CO1
Temperature: 130 °C
Reaction time: 2.5 h
Yield: 581.7 %

Procedure:
600 mg of 2-amino-2-(4-fluorophenyl)ethan-1-ol and 80 mg of potassium carbonate were suspended in 914 mg of diethyl carbonate, and the mixture was stirred at 130° C. for 2.5 hours, and further stirred at 100° C. for 2.5 hours while removing the ethanol that was generated. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 610 mg of the objective compound as pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[F:20].[CH3:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[Cl-].[NH4+]>C(Cl)(Cl)Cl>[CH3:21][CH:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[N:5]=[C:4]([Cl:11])[C:3]=2[C:12]2[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=2[F:20])[CH2:24][CH2:23]1
Reactant: Fc1cc(F)c(-c2c(Cl)nc3nccn3c2Cl)c(F)c1
Reactant: CC1CCNCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Product: CC1CCN(c2c(-c3c(F)cc(F)cc3F)c(Cl)nc3nccn23)CC1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
Under ice-cooling, 0.64 g of 5,7-dichloro-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidine and 0.79 g of 4-methylpiperidine were mixed. The mixture was allowed to stand at room temperature for one hour, and chloroform and aqueous saturated ammonium chloride solution were added to the reaction mixture. The separated organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was washed with t-butyl methyl ether to give 0.62 g of 5-(4-methylpiperidin-1-yl)-6-(2,4,6-trifluorophenyl)-7-chloroimidazo[1,2-a]pyrimidine
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCCC)[NH:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[C:33]([O:37][C:38](=[O:47])[N:39]([CH2:41][CH:42]([OH:46])[CH2:43][NH:44][CH3:45])[CH3:40])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38](=[O:47])[N:39]([CH2:41][CH:42]([OH:46])[CH2:43][N:44]([C:20]1[S:21][C:17](=[CH:16][C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][C:4]=2[C:29]([F:30])([F:31])[F:32])[N:8]=[CH:9]3)[C:18](=[O:26])[N:19]=1)[CH3:45])[CH3:40])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNCC(O)CN(C)C(=O)OC(C)(C)C
Product: CN(CC(O)CN(C)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)C(=O)OC(C)(C)C

Procedure:
[3-({5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-2-hydroxy-propyl]-methyl-carbamic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazolidin-4-one and (2-Hydroxy-3-methylamino-propyl)-methyl-carbamic acid tert-butyl ester following General Procedure B.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23]([OH:25])=O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[CH:5]([CH2:4][N:3]([CH3:2])[C:23](=[O:25])[CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8]2
Reactant: CNCC1CCCc2cc(OC)ccc21
Reactant: O=C(O)Cc1cccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCCC2CN(C)C(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
The product from Example 3 was converted to the free base (6 g) and dissolved in dry tetrahydrofuran (THF) (125 ml). Then 2-thiopheneacetic acid (3.62 g) and 1-hydroxybenzotriazole (5.1 g) was added followed by the dropwise addition of N,N'-dicyclohexylcarbodiimide (DCC) 6.7 g in dry THF (50 ml). The reaction was stirred at room temperature overnight, then filtered and evaporated to dryness. The oil was dissolved in EtOAc and upon standing precipitation occurred. This was filtered, and the filtrate washed with 1 N NaOH, then 1 N HCl and brine. The organic phase was dried (MgSO4), filtered and concentrated to afford the product, 7.4 g, 91% yield.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([N:20]2C=CN=C2)=[O:19])[C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=1.N.O>CN(C)C=O>[C:18]([C:4]1[C:3]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=2)=[C:2]([Cl:1])[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]=12)(=[O:19])[NH2:20]
Reactant: CC(C)(C)OC(=O)N1CCn2c(Cl)c(-c3cccc(C#N)c3)c(C(=O)n3ccnc3)c2C1
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2c(Cl)c(-c3cccc(C#N)c3)c(C(N)=O)c2C1
Temperature: 110 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To a solution of 3.28 g (7.26 mmol) of tert-butyl 6-chloro-7-(3-cyanophenyl)-8-(1H-imidazol-1-ylcarbonyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in 4 ml of dimethylformamide in an autoclave are added 6 ml of 33% aqueous ammonia. The mixture is stirred for 3 hours at 110° C. and, after cooling, is then poured into 80 ml of water and the solid is separated out by filtration. The solid is taken up in dichloromethane, the solution is then dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 2.9 g of tert-butyl 8-carbamoyl-6-chloro-7-(3-cyanophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate after drying.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[CH:8][N:9]=[C:10]([OH:13])[CH:11]=2)[S:6][CH:5]=1.S(OC)(O[CH3:18])(=O)=O>CN(C=O)C>[Br:3][C:4]1[C:12]2[C:7](=[CH:8][N:9]=[C:10]([O:13][CH3:18])[CH:11]=2)[S:6][CH:5]=1
Reactant: Oc1cc2c(Br)csc2cn1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Br)csc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
Into a suspension of 60% sodium hydride (18.6 mg, 0.465 mmol) in DMF (1.0 mL) was added a solution of 3-bromothieno[2,3-c]pyridin-5-ol (54.0 mg, 0.232 mmol) in DMF (3 mL) at RT in 5 min under an atmosphere of nitrogen. After 30 min stirring at RT, dimethyl sulfate (26.9 μL, 0.279 mmol) was added. The combined mixture was stirred at RT for 16 h. After that time, the solvent was removed in vacuo. The residue was then purified by ISCO chromatography (0 to 5% MeOH:DCM) to afford 11.2 mg (20%) of the title compound as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 8.95 (d, J=0.8 Hz, 1H), 8.31 (s, 1 H), 7.01 (d, J=0.8 Hz, 1 H), 3.94 (s, 3 H); MS (ESI): 243.94, 245.90 [M+H]+; HPLC tR=4.15 min (ZQ3: polar—5 min).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[C:22]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:35]2[CH2:34][CH2:33][N:32]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[CH2:37][CH2:36]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Product: CCc1cc(NC(=O)N2CCN(c3cccc4ccccc34)CC2)c(OC)nc1C
Yield: 63 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(1-naphthyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.