Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:11]([O:13]CC(C1C=CC=CC=1)=O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl>O1CCCC1.CO.[OH-].[Na+]>[CH2:1]([O:8][CH:9]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:1][CH2:2][CH2:3][CH3:4])[CH:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCCCCC(OCc1ccccc1)C(CCCCCCCCCCCCCC)C(=O)OCC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCC(OCc1ccccc1)C(CCCCCCCCCCCCCC)C(=O)O
Temperature: 70 °C
Yield: 120.3 %

Procedure:
Phenacyl 3t-(t-butyldimethyl siloxy)-2-n-tetradecyl-11icosenoate (V)(798 mg, 1.06 millimole) was dissolved in a mixed solvent of tetrahydrofuran (15.8 ml) and methanol (15.8 ml), and 1N sodium hydroxide solution (3.2 ml) was added. The reaction mixture was heated for 1.5 hours at 70° C., and water (150 ml) was added thereto. The reaction mixture was acidified with 2N hydrochloric acid (pH:about 2) and was extracted twice with ethyl acetate. The organic phase was washed with water and dried over anhydrous sodium sulfate, and the inorganic salt was filtered off, and the solvent was distilled off from the filtrate. The obtained residue was purified over a silicagel column (n-hexane:ethyl acetate=93:7) to give 3-(t-butyldimethylsilyloxy)-2- n-tetradecyl-11-icosenoic acid (VI)(410 mg, yield 60.9%) in the form of pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(N)(=[S:11])C>Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[N:8][C:3]=1[C:1](=[S:11])[NH2:2]
Reactant: N#Cc1ncccn1
Reactant: CC(N)=S
Agent: Cl
Product: NC(=S)c1ncccn1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 2-cyanopyrimidine (15 g) and thioacetamide (20 g) in 100 mL of 10% concentrated HCl in Miff is heated with stirring at 90° C. for three hours and cooled. The solid is collected by filtration, washed with water and dried to afford the title compound.
Reaction SMILES: CC(C1C=CC(OC)=C(OC)C=1)=O.COC1C=CC(NC2N=CC=CC=2C=O)=CC=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]2[C:45]([CH:46]=[CH:47][C:48]([C:50]3[CH:55]=[C:54](OC)[C:53]([O:58][CH3:59])=[C:52]([O:60][CH3:61])[CH:51]=3)=[O:49])=[CH:44][CH:43]=[CH:42][N:41]=2)=[CH:35][CH:34]=1.Cl>CO>[CH3:61][O:60][C:52]1[CH:51]=[C:50]([C:48](=[O:49])[CH:47]=[CH:46][C:45]2[C:40]([NH:39][C:36]3[CH:35]=[CH:34][C:33]([O:32][CH3:31])=[CH:38][CH:37]=3)=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:55]=[CH:54][C:53]=1[O:58][CH3:59]
Reactant: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: COc1ccc(C(C)=O)cc1OC
Agent: COc1ccc(Nc2ncccc2C=O)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(Nc2ncccc2C=CC(=O)c2ccc(OC)c(OC)c2)cc1
Reaction time: 0.08 h
Yield: 88 %

Procedure:
To a solution of 3,4-dimethoxyacetophenone (78.90 mg, 0.438 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 mL) and stirred for 5 minutes. Then added 2-(4-methoxyphenylamino) nicotinaldehyde (100 mg, 0.438 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h the reaction mixture was acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (6i) (150.8 mg, 88% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.[O:17]=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1>C(Cl)Cl>[OH:17][C:18]1([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: FC(F)(F)c1ccnc(Br)c1
Agent: [Li]CCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(C(F)(F)F)ccn2)CC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 58.9 %

Procedure:
To a slightly cloudy solution of 2-bromo-4-(trifluoromethyl)pyridine (4.0 g, 14.2 mmol) in dry methylene chloride (52.7 mL) cooled at −78° C. was added a 1.6 M solution of n-butyllithium in hexanes (9.65 mL). After being stirred for 40 min at −78° C., a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (2.59 g, 12.9 mmol) in dry methylene chloride (10.0 mL) was added dropwise. The reaction was stirred at −78° C. for 1 h and quenched with aqueous NH4Cl. THF was removed by rotary evaporation. The aqueous layer was extracted with methylene chloride three times. The combined organic layers were dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (30:70 EtOAc/hexanes) to give 2.63 g (59%) of desired product as a brown oil. LC-MS calculated for C16H21F3N2O3:(M+H) 347; found 247.0 (M-Boc+1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].Cl.N[C:13]([O:20]CC)=[CH:14][C:15]([O:17][CH2:18][CH3:19])=O.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:18]([O:17][C:15]1[CH2:14][C:13](=[O:20])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[N:10]=1)[CH3:19]
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNc1ccccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC1=NN(c2ccccc2F)C(=O)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(2-Fluorophenyl)hydrazine hydrochloride (1.00 g, 6.15 mmol) was suspended in ethanol (10 mL), treated with ethyl 3-amino-3-ethoxyacrylate hydrochloride (1.20 g, 6.15 mmol, 1.00 equiv), and placed into a preheated oil bath at 70° C. for 5 hours. The mixture was cooled to ambient temperature, poured into saturated aqueous sodium bicarbonate (100 mL), and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (100:0 to 0:100 hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][N:13]([CH:16]2[O:20][CH:19]([CH:21]=[CH:22][P:23]([O:29]C(C)C)([O:25]C(C)C)=[O:24])[CH:18]([O:33][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:17]2[O:42][CH3:43])[C:12](=[O:44])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC1NC(=O)C2N=CN(C3OC(C=CP(O)(O)=O)C(OC(=O)C4C=CC=CC=4)C3OC)C=2N=1)(=O)C(C)C>>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][N:13]([CH:16]2[O:20][CH:19]([CH:21]=[CH:22][P:23]([OH:29])([OH:25])=[O:24])[CH:18]([O:33][C:34](=[O:41])[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:17]2[O:42][CH3:43])[C:12](=[O:44])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1C(OC(=O)c2ccccc2)C(C=CP(=O)(OC(C)C)OC(C)C)OC1n1ccc(NC(=O)c2ccccc2)nc1=O
Agent: COC1C(OC(=O)c2ccccc2)C(C=CP(=O)(O)O)OC1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Product: COC1C(OC(=O)c2ccccc2)C(C=CP(=O)(O)O)OC1n1ccc(NC(=O)c2ccccc2)nc1=O
Yield: 49.6 %

Procedure:
Compound 17.4 (124 mg, 47.5% yield) was synthesized from compound 17.3 (300 mg, 0.462 mmol) using the procedure described for the preparation of compound 16.8.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].Br[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[N+:2]([C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: CCOC(=O)CCBr
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)CCN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
A mixture of 1-(3-nitrophenyl)piperazine hydrochloride (2.6 g, 10.66 mmol), ethyl 3-bromopropionate (2.41 g, 1.7 mL, 13.32 mmol), potassium carbonate (6.1 g, 44.13 mmol) and a catalytic amount of potassium iodide in acetonitrile (30 mL) was heated at reflux for 18 hrs. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was taken up in dichloromethane. The organic phase was washed with water, dried over MgSO4 and evaporated to dryness to afford 3.00 g (91.5%) ethyl 3-[4-(3-nitrophenyl)piperazino]propanoate D6 as an orange oil which crystallised on standing.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[F:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[NH:41][C:42]1[O:43][C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][C:27]([NH:41][C:42]4[O:43][C:44]5[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=5[N:46]=4)=[C:26]([F:25])[CH:31]=3)[C:10]=12
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 83 °C
Reaction time: 19 h
Yield: 25 %

Procedure:
To a solution of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.150 g, 0.340 mmol) in ethylene glycol dimethyl ether (3 mL) and water (1.5 mL) under nitrogen was added N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine (0.151 g, 0.425 mmol), tetrakis(triphenylphosphine)palladium (0) (0.020 mg, 0.017 mmol), and sodium carbonate monohydrate (0.105 mg, 0.850 mmol). The solution was stirred at 83° C. for 19 h. The resulting yellow mixture was concentrated in vacuo to give a yellow oil. Purification by preparative RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 20 min at 21 mL/min using a 8 m Hypersil HS C18, 250×21 mm column, tr=5.7-8.1 min.) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine as an off-white solid (0.046 g, 25%): 1H NMR (DMSO-d6, 400 MHz) δ 10.65 (s, 1H), 8.49 (m, 1H), 8.25 (s, 1H), 7.53 (d, 2H), 7.48 (d, 2H), 7.26 (t, 1H), 7.20 (t, 1H), 4.80 (m, 1H), 3.51-2.50 (m, 11H), 2.33-2.32 (m, 4H), 2.09-2.06 (m, 2H), 1.80-1.40 (m, 3H); RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=6.95 min., 99%; m/z 542 (MH+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]#[C:13][Si](C)(C)C)[CH:9]=[CH:8][C:7]=1[CH3:18])=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH3:18])=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:19])([F:1])[F:20])[CH:11]=1)#[CH:13]
Reactant: Cc1ccc(C#C[Si](C)(C)C)cc1NC(=O)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(C)c(NC(=O)C(F)(F)F)c1
Yield: 78.3 %

Procedure:
To a solution of 2,2,2-trifluoro-N-{2-methyl-5-[(trimethylsilyl)ethynyl]phenyl}-acetamide (10.9 g, 36 mmol) in THF (350 mL) cooled to 0° C. was added a 1M solution of tetrabutylammonium fluoride in THF (40 mmol, 40 mL). The reaction was diluted with water and extracted two times with EtOAc. The combined organic extractions were washed with water, dried over MgSO4 and concentrated onto silica gel. The crude material was purified by column chromatography to give the desired product (6.4 g, 78%). 1H NMR (400 MHz, d6-DMSO) δ 11.00 (s, 1H), 7.36-7.30 (m, 3H), 4.19 (s, 1H), 2.17 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10](Br)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Nc1ccc(Cc2ccccc2)cc1Br
Product: Nc1ccc(Cc2ccccc2)cc1-c1ccc(Cl)cc1

Procedure:
4-benzyl-2-bromo-aniline and 4-chlorobenzene boronic acid were combined to form 4-benzyl-2-(4-chlorophenyl)aniline.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[C@H:8]2[CH2:9][O:10][CH2:11][C@H:7]2[O:6][N:5]=1>FC(F)(F)C(O)=O.O>[O:6]1[C@@H:7]2[CH2:11][O:10][CH2:9][C@@H:8]2[C:4]([CH:3]=[O:2])=[N:5]1
Reactant: COC(OC)C1=NO[C@@H]2COC[C@H]12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=CC1=NO[C@@H]2COC[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
A solution of (3aS,6aS)-rel-3-dimethoxymethyl-3a,4,6,6a-tetrahydro-furo[3,4-d]isoxazole (35.3 mmol) in trifluoroacetic acid (30 ml) was treated with water (1.3 ml). The mixture was stirred at room temperature for 30 minutes. For the workup, the reaction mixture was diluted with water (100 ml) and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulphate and evaporated. The crude product was purified by chromatography on silica gel using a 5:1-mixture of dichloromethane and heptane as the eluent. The (3aS,6aS)-rel-3a,4,6,6a-tetrahydro-furo[3,4-d]isoxazole-3-carbaldehyde (4.79 g, 96% yield) was obtained as a yellow oil. MS: m/z=144.0 [M+H]+.
Reaction SMILES: II.C(Br)C.Br[C:7]1[CH:19]=[CH:18][C:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:9][CH:8]=1.[CH3:20][N:21]([CH3:38])[CH2:22][CH2:23][CH2:24][N:25]1[CH:30]=[CH:29][C:28]([C:31](N(OC)C)=[O:32])=[CH:27][C:26]1=[O:37]>C1COCC1>[CH3:38][N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][N:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:32])[C:7]2[CH:19]=[CH:18][C:10]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)=[CH:9][CH:8]=2)=[CH:27][C:26]1=[O:37]
Reactant: CON(C)C(=O)c1ccn(CCCN(C)C)c(=O)c1
Reactant: Brc1ccc(OC2CCCCO2)cc1
Agent: II
Solvent: CCBr
Solvent: C1CCOC1
Product: CN(C)CCCn1ccc(C(=O)c2ccc(OC3CCCCO3)cc2)cc1=O
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
Mg (440 mg, 3.5 eq) was added to a 3-neck round bottom flask containing 50 mL anhydrous THF, and the mixture was heated to 55° C. Iodine chips (2 grains) were added in one lot followed by 0.1 mL ethyl bromide. 2-(4-Bromophenoxy)-tetrahydro-2H-pyran (4.0 g, 3.0 eq) was dissolved in 30 mL anhydrous THF, and 3 mL of this solution was added at once to the Mg-THF suspension. The reaction was initiated after 30 min and reflux started. the remaining solution of 2-(4-bromophenoxy)-tetrahydro-2H-pyran was added dropwise maintaining the reflux temperature over 5 min. After addition, the reaction mixture was further reflux for 2 h., cooled to rt, 1-(3-(dimethylamino)propyl)-N-methoxy-N-methyl-2-oxo-1,2-dihydro-pyridine-4-carboxamide (1.4 g, 1.0 eq) in 20 mL THF was added dropwise at rt, stirred at rt for 30 min., quenched with sat NH4Cl (aq), and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product (1.6 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=9.2 Hz, 2H), 7.48 (d, J=6.8 Hz, 1H), 7.11 (d, J=9.2 Hz, 2H), 6.75 (d, J=1.6 Hz, 1H), 6.44 (dd, J=6.8 Hz, 2.0 Hz, 1H), 5.55 (t, J=2.8 Hz, 1H), 4.05 (t, J=7.2 Hz, 2H), 3.82-3.88 (m, 1H), 3.62-3.66 (m, 1H), 2.32 (t, J=6.4 Hz, 2H), 2.24 (s, 6H), 1.88-2.08 (m, 5H), 1.62-1.74 (m, 4H).
Reaction SMILES: C([O:8][C:9]1[C:14]2[N:15]([CH3:18])[CH:16]=[N:17][C:13]=2[CH:12]=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:11]2[CH:10]=[C:9]([OH:8])[C:14]3[N:15]([CH3:18])[CH:16]=[N:17][C:13]=3[CH:12]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(-c2cc(OCc3ccccc3)c3c(c2)ncn3C)cc1OC
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(-c2cc(O)c3c(c2)ncn3C)cc1OC
Reaction time: 8 h

Procedure:
To a solution of 7-(benzyloxy)-5-(3,4-dimethoxyphenyl)-1-methyl-1H-benzo[d]imidazole 2.52 (106 mg) in ethanol (4 mL) was added Pd/C (10% wet). The mixture was stirred at 1 atm H2 overnight. LCMS showed some starting material was still remaining, another 50 mg of Pd/C (10% wet) was added and after 1 h under H2 (balloon), the reaction mixture was diluted with ethanol and filtered through celite and washed with ethanol. The filtrate was then concentrated and purified by flash chromatography (SiO2, 1% MeOH/EtOAc to 30% MeOH/EtOAc) to afford 5-(3,4-dimethoxyphenyl)-1-methyl-1H-benzo[d]imidazol-7-ol 2.53.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:2].[C:18](OCC)(=[O:20])[CH3:19]>C(O)C.[Pd]>[NH:9]([C:7]1[CH:6]=[CH:5][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]([C:1]#[N:2])[CH:8]=1)[C:18]([CH3:19])=[O:20]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1-c1ccccc1
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Nc1ccc(-c2ccccc2)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Cyano-4-nitrobiphenyl (0.067 moles, 15.0 g.) was dissolved in 100 ml ethyl acetate/100 mi ethanol and hydrogenated at 40 psi over 3.0 g of 10% palladium on carbon. The catalyst was removed by filtering though celite. The solvents were removed in vacuo. The residue was dissolved in 175 ml of methylene chloride. Acetic anhydride (15 ml) was added. The reaction was stirred at room temperature for 30 minutes and poured over ice. The organic layer was dried, concentrated, and then purified by HPLC over silica gel eluted with a gradient of 0-10% ethyl acetate in chloroform. (MS)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[NH2:26][C@@H:27]([C@H:32]([OH:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl.CN(C=O)C>[OH:34][C@H:32]([CH3:33])[C@H:27]([NH:26][C:16]([C@@H:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:18])[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)[C@@H](C)O
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
Compound 8 (5.0 g, 20.08 mmol) was dissolved in CH2Cl2 (50 mL), NMM (2.43 mL, 22.08 mmol) and IBCF (2.74 mL, 23.09 mmol) were added and stirred at −15° C. for 30 minutes under inert atmosphere. A mixture of (2S,3R)-methyl 2-amino-3-hydroxybutanoate (2.93 g, 22.08 mmol) and NMM (2.43 mL, 22.08 mmol) in DMF (15 mL) were added drop wise at −15° C. The resultant reaction mixture was stirred at RT for 3 h. It was diluted with DCM (200 mL) and the organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude was purified by silica gel column chromatography eluting with 30% EtOAc/Hexane to afford compound 9 (3.1 g, 42%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:14]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=O)[C:13]([C:25](O)=[O:26])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:28]([NH2:31])[CH2:29][NH2:30].C(Cl)Cl.O>ClCCCl>[Si:1]([O:8][CH2:9][C:10]1[N:14]2[CH2:15][C:16]3([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[NH:31][CH2:28][CH2:29][N:30]3[C:25](=[O:26])[C:13]2=[CH:12][CH:11]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: NCCN
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)O)n1CC(=O)c1ccc(Cl)cc1
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccc2n1CC1(c3ccc(Cl)cc3)NCCN1C2=O
Yield: 42 %

Procedure:
5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid (˜70% pure, 268 mg, 0.46 mmol) was stirred at reflux in 1,2-dichloroethane with ethane-1,2-diamine (938 mL) for 18 h. The resultant suspension was concentrated in vacuo to give a residue. The mixture was treated with CH2Cl2 (30 mL) and water (30 mL) to form an emulsion that was filtered through a filter system. The organic layer was then separated. The aqueous layer was extracted with further CH2Cl2 (2×30 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a waxy solid. Purification by flash column chromatography (Biotage SP4, 4 g cartridge, 0-5% MeOH gradient in CH2Cl2) gave 8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-10a-(4-chlorophenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]-pyrazin-5-one as a off-white solid (85%, yield 42%). 1H NMR (400 MHz, MeOD): δ−0.11 (s, 3H), −0.04 (s, 3H), 0.79 (s, 9H), 2.79 (dt, 1H, J 12.2, 8.2 Hz), 3.32-3.37 (m, 1H), 3.51 (ddd, 1H, J 11.0, 7.9, 3.1 Hz), 3.71-3.79 (m, 1H), 4.20 (d, 1H, J 12.5 Hz), 4.44 (d, 1H, J 13.2 Hz), 4.56 (d, 1H, J 13.2 Hz), 4.76 (d, 1H, J 12.5 Hz), 6.05 (d, 1H, J 3.8 Hz), 6.77 (d, 1H, J 3.8 Hz), 7.25-7.35 (m, 4H).
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[S:7][N:6]=1)(=O)=O.[CH2:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH:10]1([C:8]2[S:7][N:6]=[C:5]([O:20][CH2:16][C:17]#[C:18][CH3:19])[N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CS(=O)(=O)c1nsc(C2CCCCC2)n1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1nsc(C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
200 mg of 3-methylsulfonyl-5-cyclohexyl-1,2,4-thiadiazole and 63 mg of 2-butyn-1-ol were dissolved in 2 g of N,N-dimethylformamide, 39 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 30 minutes under ice-cooling and for 1 hour at room temperature. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 79 mg of 5-cyclohexyl-3-(2-butynyloxy)-1,2,4-thiadiazole (hereinafter referred to as the present invention compound (1)).