Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[CH:7]([N:8](C(=O)C)[CH2:9][N:10](C(=O)C)[C:11]=2Cl)[N:6]([C@@H:20]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]2[OH:22])[CH2:5]1)(=O)C.[CH3:29][NH:30][CH2:31][CH:32]=[CH:33][CH3:34].C(N(CC)CC)C>C(O)(C)C>[CH3:29][N:30]([CH2:31][CH:32]=[CH:33][CH3:34])[C:11]1[C:12]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=[CH:9][N:10]=1)[C@@H:20]1[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]1[OH:22]
Reactant: CC=CCNC
Reactant: CC(=O)N1CN(C(C)=O)C2C(=C1Cl)N(C(C)=O)CN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC=CCN(C)c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 8 h
Yield: 70 %

Procedure:
7.3 g. triacetyl-6-chloro-9-(β-D-ribofuranosyl)-purine, 2.1 g. methyl-but-2-enylamine and 2.8 ml. triethylamine were heated under reflux for 2 hours in 100 ml. isopropanol. After cooling, the reaction mixture was mixed with 200 ml. diethyl ether, extracted twice with water and the organic phase evaporated to dryness in a vacuum. The residue was dissolved in 100 ml. 25% methanolic ammonia and then left to stand overnight at ambient temperature. The solution was thereafter evaporated and the residue obtained was recrystallized from water. 4.1 g. (70% of theory) N(6)-methyl-N(6)-but-2-enyl-adenosine were obtained; m.p. 160° - 162° C.
Reaction SMILES: S(=O)(=O)(O)O.C(OC[O:10][C:11]1[CH:12]=[C:13]([CH:31]=[C:32]([CH2:34][O:35]COCC)[CH:33]=1)[CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]([CH3:30])[CH2:23][CH2:24][CH2:25][C:26]([CH3:29])([OH:28])[CH3:27])[CH:19]=[CH:20][CH:21]=1)C>CO.C1COCC1>[OH:28][C:26]([CH3:27])([CH3:29])[CH2:25][CH2:24][CH2:23][CH:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][C:13]1[CH:12]=[C:11]([OH:10])[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=1)[CH3:30]
Reactant: CCOCOCc1cc(COc2cccc(C(C)CCCC(C)(C)O)c2)cc(OCOCC)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(CCCC(C)(C)O)c1cccc(OCc2cc(O)cc(CO)c2)c1

Procedure:
In a manner similar to Example 1(j), by reacting 0.4 ml of concentrated sulphuric acid in 5 ml of methanol with 860 mg (1.8 mmol) of 6-[3-(3-ethoxymethoxy-5-ethoxymethoxymethylbenzyloxy)phenyl]-2-methylheptan-2-ol in 5 ml of methanol and 5 ml of THF, after purification on a silica column (ethyl acetate 60-heptane 40), a colourless oil (m=510 mg. Y=79%) is obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>>[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:17]
Reactant: CNCCC#Cc1ccccn1
Reactant: O=C(Cl)c1ccccc1F
Product: CN(CCC#Cc1ccccn1)C(=O)c1ccccc1F
Yield: 32 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2-fluorobenzoyl chloride (59 mg, 0.37 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 28 mg of 2-fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 32%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[Br:11][C:12]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:15]=[CH:14][C:13]=1[N:21]([C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]2)[CH:27]=[C:26]([CH3:37])[N:25]=1)[CH2:22][CH3:23].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Br:11][C:12]1[CH:17]=[C:16]([CH:18]([CH3:19])[CH3:20])[CH:15]=[CH:14][C:13]=1[N:21]([C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][C:33]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)([OH:36])[CH2:32][CH2:31]2)[CH:27]=[C:26]([CH3:37])[N:25]=1)[CH2:22][CH3:23]
Reactant: CCN(c1nc(C)cc(N2CCC(=O)CC2)n1)c1ccc(C(C)C)cc1Br
Reactant: c1ccoc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN(c1nc(C)cc(N2CCC(O)(c3ccco3)CC2)n1)c1ccc(C(C)C)cc1Br
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 55.8 %

Procedure:
To a solution of 136 mg of furan in 1 ml of tetrahydrofuran was added dropwise 0.9 ml of a 1.63M n-hexane solution of n-butyl lithium under cooling at −15° C. over 10 minutes, followed by stirring at 5° C. for 20 minutes. To the reaction mixture was added dropwise a solution of 432 mg of 2-[N-(2-bromo-4-isopropylphenyl)-N-ethylamino]-6-methyl-4-(4-oxopiperidin-1-yl)pyrimidine in 2 ml of tetrahydrofuran over 10 minutes while cooling to −15° C., followed by stirring at −15° to 0° C. for 30 minutes. After stirring at room temperature for 1 hour, a saturated aqueous solution of ammonium chloride was added thereto dropwise under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated ammonium chloride aqueous solution, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to give 279 mg of 2-[N-(2-bromo-4-isopropylphenyl)-N-ethylamino]-4-[4-(furan-2-yl)-4-hydroxypiperidin-1-yl]-6-methylpyrimidine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][CH:8]=[N:7][C:6]=1[CH3:10].[C:11](OCC)(=[O:13])[CH3:12]>>[C:11]([C:8]1[S:9][C:5]([CH2:4][CH2:3][O:2][CH3:1])=[C:6]([CH3:10])[N:7]=1)(=[O:13])[CH3:12]
Reactant: CCOC(C)=O
Reactant: COCCc1scnc1C
Product: COCCc1sc(C(C)=O)nc1C

Procedure:
From 5-(2-methoxyethyl)-4-methylthiazole and ethyl acetate, following the procedure of Preparation 1.
Reaction SMILES: C([Li])CCC.[CH:6]1([C:9]#[CH:10])[CH2:8][CH2:7]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C@@:21]23[C:27]([CH3:29])([CH3:28])[C@@:24]([CH3:30])([CH2:25][CH2:26]2)[C:23](=[O:31])[O:22]3)=[O:20])=[C:14]([C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH:13]=1>O1CCCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C@@:21]23[C:27]([CH3:28])([CH3:29])[C@@:24]([CH3:30])([CH2:25][CH2:26]2)[C:23](=[O:31])[O:22]3)=[O:20])=[C:14]([C@@:32]([OH:37])([C:10]#[C:9][CH:6]2[CH2:8][CH2:7]2)[C:33]([F:34])([F:35])[F:36])[CH:13]=1
Reactant: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1C(=O)C(F)(F)F)OC2=O
Reactant: C#CC1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F)OC2=O
Reaction time: 0.5 h

Procedure:
2.5 M n-Butyllithium (14.8 mL, 37.16 mmol) was added slowly to a solution of cyclopropyl acetylene (2.46 g, 37.16 mmol) in tetrahydrofuran (20 mL) in an ice-salt-bath under argon, and then (1S,4R)-N-(4-chloro-2-(2,2,2-trifluoroacetyl)phenyl)-4,7,7-trimethyl-3-oxo-2-ox abicyclo[2.2.1]heptane-1-carboxamide(9, 5 g, 12.39 mmol) was added. The reaction mixture was stirred for 0.5 hour. The reaction was quenched with 10% citric acid aqueous, the mixture was extracted with ethyl acetate and the two layers were separated. The organic layer was evaporated to dryness to give crude oil which was further crystallized with ethyl acetate and petroleum ether to give (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10) as a white or off-white powder. 1H NMR spectrum of the product was identical to that of Example 5.
Reaction SMILES: [C:1]([NH:20][C:21]1[NH:25][N:24]=[CH:23][C:22]=1[C:26]#[N:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:29]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[N:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[C:42]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH:43]=3)[C:38]2=[O:51])[C:30]=1[CH:31]=[O:32].C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[C:47]([C:42]1[CH:43]=[C:44]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:51])[N:37]([C:33]1[C:30]([CH:31]=[O:32])=[C:29]([N:24]3[CH:23]=[C:22]([C:26]#[N:27])[C:21]([NH:20][C:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[N:25]3)[CH:36]=[CH:35][CH:34]=1)[N:46]=[CH:45]2)([CH3:50])([CH3:48])[CH3:49]
Reactant: N#Cc1cn[nH]c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1ccc2c(=O)n(-c3cccc(Br)c3C=O)ncc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C#N)c(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3C=O)ncc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To degassed DMF (1.5 mL) were added 5-(tritylamino)-1H-pyrazole-4-carbonitrile (1.36 g, 3.89 mmol), 2-bromo-6-(6-tert-butyl-1-oxophthalazin-2(1H)-yl)benzaldehyde (1.0 g, 2.6 mmol), copper (I) iodide (494 mg, 2.6 mmol) and potassium carbonate (717 mg, 5.19 mmol). The reaction was inerted five times by alternating vacuum and a nitrogen purge and then heat to 100° C. (external); for 8 hr. TLC the following morning showed trace amounts of starting materials. The reaction was diluted with EtOAc (50 mL) and through a pad of diatomaceous earth. The pad was rinsed with additional EtOAc (50 mL) and concentrated in vacuo. The crude material was bound to silica column and purified over a 40 g silica gel cartridge, eluting the column with a 20-40% EtOAc/hexanes, isocratic hold for 5 minutes, then 40-100% EtOAc/hexanes gradient over 20 minutes. The product containing fractions were combined and concentrated to give 1-[3-(6-tert-Butyl-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-3-(trityl-amino)-1H-pyrazole-4-carbonitril (632 mg, 37%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1I.[CH:15]([Sn](CCCC)(CCCC)CCCC)=[CH2:16]>ClC(Cl)C.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[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[CH:15]=[CH2:16]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(Cl)Cl
Product: C=Cc1c(C(=O)OC)nc(Cl)c(F)c1N
Temperature: 70 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoro-3-iodopicolinate (7.05 g, 21.33 mmol, prepared as described in Epp et al., WO 2013003740 A1) and vinyl tri-n-butyl tin (7.52 mL, 25.6 mmol) were suspended in dichloroethane (71.1 mL) and the mixture was degassed with Argon for 10 min. Bis(triphenylphosphine)palladium(II) chloride (1.497 g, 2.133 mmol) was then added and the reaction mixture was stirred at 70° C. overnight (clear orange solution). The reaction was monitored by GCMS. After 20 h, the reaction mixture was concentrated, adsorbed onto Celite™, and purified by column chromatography (SiO2, hexanes/ethyl acetate gradient) to afford the title compound as a light brown solid (3.23 g, 65.7%): mp 99-100° C.; 1H NMR (400 MHz, CDCl3) δ 6.87 (dd, J=18.1, 11.6 Hz, 1H), 5.72 (dd, J=11.5, 1.3 Hz, 1H), 5.52 (dd, J=18.2, 1.3 Hz, 1H), 4.79 (s, 2H), 3.91 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −138.79 (s); EIMS m/z 230.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:28])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2([OH:27])[CH2:19][CH2:18][N:17](CC3C=CC=CC=3)[CH2:16][CH2:15]2)=[CH:8][CH:7]=1.[H][H]>[Pd].CO>[OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:28])[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C:14]2([OH:27])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: O=C(NCCO)c1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: O=C(NCCO)c1ccc(OCC2(O)CCNCC2)cc1
Yield: 90.5 %

Procedure:
A mixture of 23 parts of N-(2-hydroxyethyl)-4-[[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]methoxy]benzamide and 200 parts of methanol was hydrogenated at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 16 parts (90.5%) of N-(2-hydroxyethyl)-4-[(4-hydroxy-4-piperidinyl)methoxy]benzamide as an oily residue (int. 81).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([NH:15][CH2:16][C:17]([NH2:19])=[O:18])[C:8]([O:10]C(C)(C)C)=[O:9]>C(O)(=O)C>[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([NH:15][CH2:16][C:17]([NH2:19])=[O:18])[C:8]([OH:10])=[O:9]
Reactant: CC(C)(C)OC(=O)C(NCC(N)=O)c1cccs1
Agent: Cl
Solvent: CC(=O)O
Product: NC(=O)CNC(C(=O)O)c1cccs1

Procedure:
Gaseous HCl is passed into a cooled solution of 2.4 g of the compound from Example 4 in 25 ml of glacial acetic acid until saturated. The mixture is allowed to reach room temperature while stirring. The precipitate which forms is filtered off with suction, washed with a little methanol and dried. Yield: 2.0 g melting point 206° C. (decomposition)
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=2[N:3]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:25])[C:18]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:25])[C:18]=1[N:19]1[CH2:24][CH2:23][N:22]([C:2]2[NH:6][C:5]3[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=3[N:3]=2)[CH2:21][CH2:20]1
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Reactant: Cc1ccc2nc(Cl)[nH]c2c1
Product: Cc1ccc2nc(N3CCN(c4c(Cl)cncc4Cl)CC3)[nH]c2c1

Procedure:
The benzoimidazole from step (b) above (0.287 g, 1.73 mmol) and 1-(3,5-dichloropyridin-4-yl)piperazine (0.4 g, 1.73 mmol, Maybridge) reacted under the conditions of Example 1d to give the title compound as a white solid. M.p. 251-254° C. MS (ESI, pos. ion) m/z: 362 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:15])[C@H:12]([OH:14])[CH3:13])[CH2:6][CH2:5]1)[CH3:3].CN(C=O)C.[F:21][C:22]([F:55])([F:54])[C:23]1[CH:24]=[C:25]2[C:31]([C:32]3[C:37]([C:38]#[N:39])=[CH:36][N:35]=[C:34](S(C)(=O)=O)[N:33]=3)=[CH:30][N:29](S(C3C=CC(C)=CC=3)(=O)=O)[C:26]2=[N:27][CH:28]=1.[OH-].[Li+]>C1COCC1>[C:38]([C:37]1[C:32]([C:31]2[C:25]3[C:26](=[N:27][CH:28]=[C:23]([C:22]([F:54])([F:21])[F:55])[CH:24]=3)[NH:29][CH:30]=2)=[N:33][C:34]([NH:1][C@@H:2]([C@H:4]2[CH2:5][CH2:6][C@H:7]([NH:10][C:11](=[O:15])[C@H:12]([OH:14])[CH3:13])[CH2:8][CH2:9]2)[CH3:3])=[N:35][CH:36]=1)#[N:39]
Reactant: C[C@@H](O)C(=O)N[C@H]1CC[C@H]([C@@H](C)N)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H](O)C(=O)N[C@H]1CC[C@H]([C@@H](C)Nc2ncc(C#N)c(-c3c[nH]c4ncc(C(F)(F)F)cc34)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Trans-(R)—N-(4-((R)-1-aminoethyl)cyclohexyl)-2-hydroxypropanamide (45 mg, 0.21 mmol) was dissolved in THF (6 mL) and DMF (2 mL) and stirred over 4 Å molecular sieves for 10 minutes. 4-(5-(trifluoromethyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (131.9 mg, 0.2100 mmol) was added. The reaction mixture was stirred under nitrogen at ambient temperature for 18 hours. The molecular sieves was removed by filtration and washed with EtOAc. The filtrate was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue dissolved in tetrahydrofuran (6 mL). Lithium hydroxide (840.0 μL of 1 M, 0.8400 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The crude mixture was partitioned between ethyl acetate and brine. The organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (19 mg, 18% yield).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([O:16]C)=O)[CH2:3]1.[CH3:18][NH2:19]>CO>[CH3:18][NH:19][C:14]([CH:4]1[CH2:3][C:2](=[O:1])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5]1)=[O:16]
Reactant: CN
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Solvent: CO
Product: CNC(=O)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 100 °C
Yield: 88.4 %

Procedure:
A mixture of 100 g (0.43 mole) of methyl 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate [J. Org. Chem., 26, 1519 (1961)], 500 ml methanol and 100 g (3.2 mole) of methylamine was heated at 100° C. in a pressure reactor for 16 hours. The reaction mixture was cooled and the ammonia and methanol were removed under reduced pressure. The residue was taken up in dichloromethane and washed 3×100 ml 1N sodium hydroxide. The organic layer was dried over magnesium sulfate and the solvent removed at reduced pressure to give 88.3 g of N-methyl-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide as a white solid, mp 82.5°-83.0° C.
Reaction SMILES: [C:1]1([S:7][C:8]2[C:13]([CH2:14]O)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)[Cl:18]>CC#N>[Cl:18][CH2:14][C:13]1[C:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccnc1Sc1ccccc1
Solvent: CC#N
Product: ClCc1cccnc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2-Phenylsulfanyl-pyridin-3-yl)-methanol (20 mg, 0.09 mmol) obtained in Step B was dissolved in CH3CN (20 mL), and SOCl2(13 uL, 0.18 mmol) was added dropwise thereto at 0° C. The mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1.S(Cl)([Cl:17])=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([Cl:17])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Product: O=C(Cl)c1ccc(-c2ccccn2)s1

Procedure:
A mixture of 1.0 g of 5-(2-pyridinyl)thiophene-2-carboxylic acid and 5 ml of thionyl chloride is refluxed for 2.5 hours. The mixture is concentrated to dryness under vacuum. Toluene is added (2 times) and the solvent removed under vacuum to give the product as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].[H-].[Na+].I[CH3:21].O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]([CH3:21])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCc1ccccc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCc1ccccc1Br)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A solution of tert-butyl [2-(2-bromophenyl)ethyl]carbamate (810 mg, 2.7 mmol) in dry THF (2.0 mL) was transferred to a flask with a suspension of sodium hydride (65 mg, 2.7 mmol) in dry THF (2.0 mL) under an atmosphere of argon. The mixture was stirred for 15 min at room temperature and 10 min at 60° C. Iodomethane (0.19 mL, 2.97 mmol) was added with a syringe. After 4 h the reaction mixture was poured into water and extracted with EtOAc (×3). The organic phases were combined and washed with brine and dried with MgSO4. The crude product was purified by chromatography eluting with petroleum ether/EtOAc 10:1 to afford the title compound as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[C:9](OC)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=[O:2].[NH2:12][NH2:13].O>CN(C=O)C>[CH:7]1[CH:6]=[N:5][C:4]2[N:1]([OH:2])[N:12]=[N:13][C:9]=2[CH:8]=1
Reactant: NN
Reactant: COc1cccnc1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: On1nnc2cccnc21
Reaction time: 24 h
Yield: 52.1 %

Procedure:
To 13.58 g of 2-nitro-3-methoxypyridine was added 26.4 mL of 95% hydrazine, 10.4 mL of water and 15.3 mL of DMF. The mixture was carefully warmed to about 70° on a hot plate. Spontaneous warming then set in, the temperature rising to about 80° as the solid dissolved. The solution was set aside for 24 hr and then evaporated from a water bath with the aid of a water aspirator to remove excess hydrazine and water. The dark green residue was cooled in an ice bath, diluted with 50 mL of water and acidified to Congo Red with concentrated hydrochloric acid (ca. 17 ml). A yellow-straw-colored solid separated and was filtered and washed with a little cold water to give 6.25 g (52.1%) of HOAt upon recrystallization from 75 mL of water gave 5.46 g (45.5%) of nearly colorless crystals, mp 216°-217° 1H NMR (CDCl3-DMSO-d6): δ 7.35 (dd, 1, β-H), 8.3 (dd, 1, γ-H), 8.66 (dd, 1, α-H); Jα,β=4.2 Hz, Jβ,γ=8.2 Hz, Jα,γ=1.6 Hz. Evaporation of the filtrate gave an additional 0.14 g of the pure hydroxy compound so the total yield was 5.6 g (46.7%).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[CH3:8].[CH3:9][C:10]1[N:15]=[C:14]([SH:16])[N:13]=[C:12]([OH:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:9][C:10]1[N:15]=[C:14]([S:16][CH2:2][C:3]2[S:7][CH:6]=[N:5][C:4]=2[CH3:8])[N:13]=[C:12]([OH:17])[CH:11]=1
Reactant: Cc1ncsc1CCl
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(O)nc(SCc2scnc2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of 5-(chloromethyl)-4-methyl-1,3-thiazole (887 mg, 4.9 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (600 mg, 4.2 mmol), and potassium carbonate (2.1 g, 15 mmol) in acetone (30 mL) was stirred at room temperature overnight. The solid material was removed by filtration. The filtrate was recovered and evaporated, co-evaporated with EtOAc (20 mL) and dried in vacuo. The solid residue was treated with diethyl ether (30 mL). The solid product was recovered by filtration, washed with diethyl ether (2×15 mL) and hexanes (1×15 mL), and dried in vacuo, affording 6-methyl-2-{[(4-methyl-1,3-thiazol-5-yl)methyl]sulfanyl}pyrimidin-4-ol (1.0 g, 93% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.91 (s, 3H), 2.34 (s, 3H), 4.31 (s, 2H), 5.32 (s, 1H), 8.73 (s, 1H); M+254. The product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.O[CH:26]([C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C1C=CN=CC=1)C.CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][C:22]([O:24][CH:26]([C:33](=[O:40])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:23])=[CH:19][CH:20]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CC(=O)O)cc1
Reactant: COC(=O)CCC(O)C(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)CCC(OC(=O)Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.3 %

Procedure:
A mixture of [4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]acetic acid (1.00 g), methyl 4-hydroxy-5-oxo-5-phenylpentanoate (687 mg), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (water-soluble carbodiimide; hereinafter to be referred to as WSC) (711 mg), 4-(N,N-dimethylamino)pyridine (75.5 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 18 hrs, and the reaction mixture was poured into 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]acetoxy-5-oxo-5-phenylpentanoate (1.44 g, yield 88%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).