Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34]/[CH:35]=[CH:36]/[CH:37]1[CH2:39][CH2:38]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:34]/[CH:35]=[CH:36]/[CH:37]2[CH2:39][CH2:38]2)=[CH:24][CH:25]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: BrC/C=C/C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OC/C=C/C4CC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 3 h

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (37 mg, 0.097 mmol) in 1.5 ml of DMF was added Cs2CO3 (48 mg, 0.146 mmol) and (E)-(3-bromoprop-1-enyl)cyclopropane (intermediate BY) (50 mg) at room temperature. After stirring for 3 h, the reaction was quenched with 2 ml of ice water. The mixture was extracted 3× with ethyl acetate (5 ml), and the combined organic layers were washed 2× with water (5 ml) and brine, dried over Na2SO4, concentrated, and purified by preparative LC-MS to obtain compound BZ (8.6 mg). 1H NMR (CD3OD, 400 MHz): δ 7.37˜7.33 (2H, m), 7.30˜7.27 (1H, dd, J=8.2, 2 Hz), 7.11˜7.09 (2H, d, J=8.8 Hz), 6.82˜6.79 (2H, d, J=8.8 Hz), 5.77˜5.70 (1H, dt, J=15.2, 6 Hz), 5.39˜5.33 (1H, dd, J=15.2, 8.8 Hz), 4.43˜4.41 (2H, dd, J=6.4, 1.0 Hz), 4.10 (1H, d, J=9.6 Hz), 4.08˜3.98 (2H, dd, J=23.6, 15.2 Hz), 3.90˜3.87 (1H, m), 3.72˜3.67 (1H, m), 3.49˜3.39 (3H, m), 3.31˜3.27 (1H, m), 1.47˜1.45 (1H, m), 0.76˜0.71 (2H, m), 0.41˜0.37 (2H, m); MS ESI (m/z) 461 (M+H)+, calc. 460.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=1.[CH2:12]([O:14][C:15](=[O:27])[C:16]1[CH:26]=[C:23]([O:24][CH3:25])[C:21]([OH:22])=[C:18]([O:19][CH3:20])[CH:17]=1)[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:12]([O:14][C:15](=[O:27])[C:16]1[CH:17]=[C:18]([O:19][CH3:20])[C:21]([O:22][CH2:2][C:3]2[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=2)=[C:23]([O:24][CH3:25])[CH:26]=1)[CH3:13]
Reactant: CCOC(=O)c1cc(OC)c(O)c(OC)c1
Reactant: Cc1nc(C)c(CBr)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OC)c(OCc2nc(C)c(C)nc2C)c(OC)c1
Temperature: 90 °C
Yield: 61.6 %

Procedure:
Adding 2-bromomethyl-3,5,6-trimethylpyrazine (0.44 g, 0.002 mol), syringic acid ethyl ester (0.54 g, 0.0024 mol), anhydrous potassium carbonate (0.72 g, 0.005 mol), and DMF (20 mL) into a 100 mL three-necked bottle in turn, wherein the solution appears orange and turbid, irradiating with incandescent lamp, heating to 90° C., stifling to react for 12 hours, TLC [V(petroleum ether):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.7, Rf of product=0.5), and the reaction solution appears deep yellow, filtering to obtain orange filtrate, adding 30 mL water, extracting with chloroform (3×30 mL), incorporating the chloroform layer and wishing with water (2×20 mL), drying with anhydrous sodium sulfate, recycling chloroform under reduced pressure to obtain a light yellow oily matter, separating with a silica column, wherein eluant is V(cyclohexane):V(ethyl acetate)=3:1, collecting product, recycling the solution under reduced pressure to obtain 0.45 g light yellow 4-((3,5,6-trimethylpyrazine-2-yl)methoxyl)-3,5-dimethoxybenzoic acid ethyl ester, a yield is 61.6%, m.p. 121.7-123.2° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]4[C:23]5[CH:35]=[CH:34][CH:33]=[N:32][C:24]=5[NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:21]4=[N:20][C:19]=3[C:36]3[CH:41]=[CH:40][C:39]([O:42]CC4C=CC=CC=4)=[CH:38][CH:37]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CO.[Pd]>[OH:42][C:39]1[CH:38]=[CH:37][C:36]([C:19]2[N:20]=[C:21]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[NH:25][C:24]4[N:32]=[CH:33][CH:34]=[CH:35][C:23]=4[N:22]3[C:18]=2[C:15]2[CH:16]=[CH:17][C:12]([C:8]3([NH:7][C:6](=[O:50])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:9][CH2:10][CH2:11]3)=[CH:13][CH:14]=2)=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(OCc5ccccc5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of tert-butyl[1-(4-{2-[4-(benzyloxy)phenyl]-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl}phenyl)cyclobutyl]carbamate (236 mg, 0.36 mmol) in THF (10 mL) and MeOH (20 mL) was added 10%-Pd/C (100 mg). The reaction mixture was stirred under atomospheric hydrogen at room temperature for 19 hours. The reaction mixture was filtered through Celite and concentrated. The title compound was gave 125 mg as a white solid. LCMS: 572 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.ClC1C=CC(C(Cl)=O)=C(OC)C=1.[Al+3].[Cl-].[Cl-].[Cl-].[N:29]1([C:34]2[CH:38]=[CH:37][NH:36][C:35]=2[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:47][CH3:48])=[O:40])[CH:33]=[CH:32][CH:31]=[CH:30]1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1.O=S(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:30]2[N:29]([C:34]3[CH:38]=[CH:37][NH:36][C:35]=3[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[O:47][CH3:48])=[O:40])[CH:33]=[CH:32][CH:31]=2)=[O:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(=O)O
Reactant: COc1ccccc1C(=O)c1[nH]ccc1-n1cccc1
Agent: COc1cc(Cl)ccc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1ccccc1C(=O)c1[nH]ccc1-n1cccc1C(=O)c1ccc(Cl)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
Into a solution of 4-chloro-2-methoxybenzoic acid (125 mg, 0.67 mmol, 1.2 eq.) in benzene (1.5 mL), SOCl2 (1.5 mL) was added at room temperature and the resulting solution was refluxed for 2 h. The reaction mixture was concentrated under vacuum to generate 4-chloro-2-methoxybenzoyl chloride which was used directly in the next step without purification. A solution of 4-chloro-2-methoxybenzoyl chloride in DCM (2 mL) was added to a slurry of AlCl3 (96 mg, 1.3 eq.) in DCM (2.5 mL) at 0° C. and then a solution of (e) (150 mg, 0.56 mmol, 1.0 equiv) in DCM (1.5 mL) was added dropwise. The resulting solution was allowed to warm to room temperature and stirred overnight. A saturated solution of NaHCO3 (10 mL) and DCM (10 mL) was then added and the resulting mixture was stirred for 1 h, and then filtered though Celite®. The mixture was extracted with DCM (2×10 mL), the organic layer was dried over anhydrous Na2SO4, and purified by flash column chromatography (hexanes:EtOAc) to afford 172 mg of (h) as a white solid, 70% yield. 1H NMR (400 MHz, CDCl3) δ 9.83 (s, 1H), 7.22-7.14 (m, 2H), 7.12 (d, J=7.8 Hz, 1H), 7.04 (t, J=3.0 Hz, 1H), 6.95-6.88 (m, 2H), 6.73-6.63 (m, 3H), 6.31 (dd, J=4.0, 1.7 Hz, 1H), 6.27 (t, J=2.8 Hz, 1H), 5.83 (dd, J=4.0, 2.6 Hz, 1H), 3.77 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16]C(OCC)=O)[CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.[CH3:24][Mg]Br.[NH4+].[Cl-].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>CCOCC.O.CCOC(C)=O>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:32]([CH3:31])([OH:34])[CH3:24])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1.[F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:32]([OH:34])([CH3:31])[CH3:24])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCN1CCC(c2nsc3cc(F)ccc23)CC1
Reactant: C[Mg]Br
Agent: O=C(O)/C=C/C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(O)CCN1CCC(c2nsc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
To a stirred solution, under N2, of ethyl 3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propionate (3.1 g, 9 mmol), in TIF (100 ml) was added, dropwise, methylmagnesium bromide (9.0 ml, 27 mmol of a 3M solution in ether). The reaction was stirred at ambient temperature for 16 hours and then a saturated solution NH4Cl was added dropwise, with cooling. The reaction was further diluted with H2O, and after extractive workup of the aqueous mixture with EtOAc, 2.8 g of a waxy solid resulted. The solid was dissolved in EtOAc and 3.0 g of fumaric acid was added, and 5.0 g of a fumarate salt was collected, which was contaminated with unreacted fumaric acid. The crude salt was recrystallized from MeOH--Et2O, and then from DMF to afford 1.6 g (45.7%) of the desired compound as a hemifumarate, m.p.=237°-239° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])CC[CH2:5]2.O[C:19]1C=CC(CCC(OCC)=O)=C(C)C=1C>>[OH:1][C:2]1[CH:11]=[C:10]([CH3:19])[C:9]([CH2:8][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]([CH3:5])[CH:3]=1
Reactant: CCOC(=O)CC1CCCc2cc(O)ccc21
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: CCOC(=O)CCc1c(C)cc(O)cc1C

Procedure:
Similar reaction routes used for the synthesis of (514) was used to synthesize the intermediate ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate (570) (1.2 g, 89.3%) as a white solid.
Reaction SMILES: [O:1]=[C:2]([OH:14])[C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([C:11]([OH:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18](S(O)(=O)=O)=[CH:17][CH:16]=1>C[Re](=O)(=O)=O.C(O)CCCCCC>[O:1]=[C:2]([O:14][CH2:25][CH2:15][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([C:11]([O:13][CH2:25][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C(=O)O
Agent: C[Re](=O)(=O)=O
Solvent: CCCCCCCO
Product: CCCCCCCOC(=O)[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C(=O)OCCCCCCC
Temperature: 150 °C
Reaction time: 12 h

Procedure:
In one specific embodiment of the present disclosure, 20 ml of 1-heptanol, 1 mmol of galactaric acid, 0.05 mmol of methyltrioxorhenium catalyst, and 0.05 mmol of para-toluenesulfonic acid were poured into a 50 cc reactor. The temperature in the reactor was then raised to 150° C. and the reaction was performed for 12 hours, maintaining the reactor temperature at 150° C. to obtain diheptyl galactarate.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][N:14]=1>CO>[N:16]1[CH:17]=[CH:18][C:13]([CH:12]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])=[N:14][CH:15]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccncn1
Solvent: CO
Product: O=C1c2ccccc2C(=O)C1c1ccncn1

Procedure:
7.87 g (53.1 mmol) phthalic acid anhydride and 22 ml (0.24 mol) 4-methylpyrimidine are stirred for 1 h at 140° C. and for 4 h at 210° C. The reaction mixture is then stirred with 15 ml methanol, filtered, and the residue washed with methanol. Further product is obtainable by evaporating the filtrate and stirring the residue with water m.p.: 168-169° C.); Anal. calc.(C13H8N2O2) C, 69.64%; H, 3.60%; N, 12.49%; found C, 69.8%; H 3.7%; N, 12.4%; FAB MS (M+H)+=225.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17](=[O:25])(=[O:24])[NH:18][C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC>C1COCC1>[CH3:16][C:8]1[N:9]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[S:11][C:7]=1[C:6]1[CH:5]=[C:4]([S:17]([NH:18][C:19]2[NH:23][N:22]=[N:21][N:20]=2)(=[O:24])=[O:25])[S:3][CH:2]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Nc3nnn[nH]3)sc2Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)Nc3nnn[nH]3)c2)s1
Temperature: -70 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
N-{5-[2-Bromo-5-(1H-tetrazol-5-ylsulfamoyl)-thiophen-3-yl]-4-methyl-thiazol-2-yl}-acetamide obtained in Step I as described above (220 mg; 0.37 mmol; 1 eq), is dissolved in anhydrous THF (20 ml). The reaction mixture is cooled down to −70° C. and put under nitrogen. n-Butyllithium (1.9 ml; 1.6 M; 2.99 mmol; 8 eq) is added dropwise. The reaction is stirred 2 hours and is quenched with water. Solvents are evaporated and the resulting crude product is purified by preparative HPLC, affording Compound (41) as a beige solid (8.5 mg; 6%).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].O.[C:6]([C:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)#[CH:7].C(N(CC)CC)C>C(Cl)Cl>[N:14]([C:8]1([CH2:6][CH3:7])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[C:1]=[S:2]
Reactant: C#CC1(N)CCCCC1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC1(N=C=S)CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thiophosgene (140 g) was dissolved in 250 ml methylene chloride and 250 ml water was added. To the two-phase system was added dropwise a solution of 1-ethynyl-1-amino-cyclohexane (123 g) and triethylamine (101 g) in 250 ml methylene chloride. The mixture was cooled to prevent refluxing. The mixture was stirred at room temperature for two hours, phase separated, and the organic phase was collected. This layer was dried (MgSO4) and stripped, and the residue was dissolved in diethyl ether, filtered and stripped to yield a dark brown oil. A small portion of the oil was purified on a silica gel column (3×10 cm) with hexane elution to yield 1-isothiocyano-1-ethyl-cyclohexane (A), 5.9 g.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:30](C(OC(C)(C)C)=O)[CH3:31])[N:25]=2)=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:5]([Si](C(C)C)(C(C)C)C(C)C)[CH:6]=1.O1CCCC1.O.C(=O)([O-])O.[Na+]>Cl.O1CCOCC1>[Br:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH3:31])[N:25]=2)=[C:4]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[NH:5][CH:6]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c(-c2ccnc(N(C)C(=O)OC(C)(C)C)n2)c1-c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CNc1nccc(-c2c(Br)c[nH]c2-c2ccc(F)cc2)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
472 mg (0.782 mmol) of 4-bromo-3-[2-(N-t-butoxycarbonyl-N-methylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)-1-triisopropylsilyl-1H-pyrrole [prepared as described in step (vi) above] were dissolved in 10 of ml tetrahydrofuran, 0.98 ml (3.91 mmol) of a 4N solution of hydrogen chloride in dioxane were added to the solution, and the resulting mixture was stirred for 3 hours at 50° C. At the end of this time, water was added to the reaction mixture and then it was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. This was extracted with ethyl acetate, and the organic extract was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using a 7:3 by volume mixture of hexane and ethyl acetate as the eluant to afford 202 mg (yield 74%) of the title compound as a pale brown amorphous solid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][C:11]1[N:12]=[CH:13][NH:14][C:15]=1[Cl:16]>C(Cl)(Cl)Cl>[C:1]1([NH:7][C:8]([N:14]2[C:15]([Cl:16])=[C:11]([CH3:10])[N:12]=[CH:13]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1nc[nH]c1Cl
Solvent: ClC(Cl)Cl
Product: Cc1ncn(C(=O)Nc2ccccc2)c1Cl
Temperature: 42 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Using a procedure similar to that described in Example 1, 59.5 g of phenyl isocyanate were added dropwise to 58.5 g of 4-methyl-5-chloroimidazole in 250 ml of chloroform. During the addition, the temperature increased to 42° C. Refluxing was then carried out for 2 hours, after which the solution was cooled with ice, and the precipitate which separated out was filtered off under suction, washed with chloroform and dried to give 80 g (67.9%) of 1-N-phenylcarbamyl-4-methyl-5-chloroimidazole of melting point 112.3°-114.4° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][S:14][CH2:15][C:16]([OH:18])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.S(Cl)(Cl)=O.[OH-].[Na+].[NH2:25][CH2:26][C:27]([OH:29])=[O:28].Cl>C1C=CC=CC=1.O.O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][S:14][CH2:15][C:16]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)CSCCCCc1ccc2c(c1)OCO2
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(O)CNC(=O)CSCCCCc1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
1.4 g of [{(1,3-benzodioxol-5-yl)butyl}thio]acetic acid was dissolved in 10 ml of benzene, followed by the addition of 0.8 ml of thionyl chloride. The obtained mixture was heated under reflux for 1.5 hours and concentrated in a vacuum to obtain a residue. Separately, 0.43 g of sodium hydroxide was dissolved in 4 ml of water, followed by the addition of 0.8 g of glycine to obtain a mixture. The above residue was dissolved in a small amount of tetrahydrofuran to obtain a solution. This solution was dropwise added to the above mixture under cooling with ice/water. The obtained mixture was stirred for 30 minutes, followed by the addition of water. The mixture was acidified with concentrated hydrochloric acid and extracted with chloroform. The organic layer was dried over magnesium sulfate and distilled to remove the solvent. Thus, a brown oil was obtained. This oil was crystallized from isopropyl ether to obtain 1.0 g of the title compound as a light brown crystal.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([O:29][CH3:30])[CH:21]=1.[C:31]([NH:35][C:36](=[O:50])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:38]=1)([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>ClCCl>[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:47]2[CH2:46][CH2:45][N:44]([CH2:43][C:39]3[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=3)[C:36]([NH:35][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:50])[CH2:49][CH2:48]2)=[O:26])=[C:22]([O:29][CH3:30])[CH:21]=1
Reactant: COc1cc(N)ccc1C(=O)O
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N)ccc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (12.91 g, 20.2 mmol, 12.91 mL) was added dropwise to a solution of 4-amino-2-methoxybenzoic acid (1.70 g, 10.1 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (3.07 g, 11.2 mmol) and triethylamine (3.08 g. 30.3 mmol, 4.23 mL) in dichloromethane. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and the residue was taken up with ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic phase was concentrated under vacuum to afford the title compound (1.39 g). MS (ESI) m/z 425.4 [M+H]+
Reaction SMILES: [CH2:1]([N:8]1[C:13]([CH3:15])([CH3:14])[CH2:12][O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH2:12][C:13]1([CH3:15])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)COCC(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COCCN1Cc1ccccc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
4-Benzyl-5,5-dimethyl-3-morpholinone (4.45 g) was added to an ice-cooled suspension of lithium aluminum hydride (0.77 g) in dried tetrahydrofuran (20 ml) under nitrogen atmosphere. After 5 hours of stirring at 50° C., the reaction mixture was cooled below 5° C., and water (0.36 ml), 12% sodium hydroxide aqueous solution (0.36 ml) and water (1 ml) were added thereto successively. After 30 minutes of stirring, the mixture was filtrated through Celite® pad, and the pad was washed with ethyl acetate. The filtrate and washing were combined and the whole was dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate. The fractions containing the objective compound were collected and evaporated under reduced pressure to give 4-benzyl-3,3-dimethylmorpholine as an oil. The obtained oil and ammonium formate (5.7 g) were dissolved into a mixed solvent of ethanol (35 ml) and water (5 ml), and the whole was stirred under reflux for 1 hour under nitrogen atmosphere. After cooling, the mixture was filtrated through Celite® pad. The filtrate was evaporated under reduced pressure. The residue was dissolved into methanol and 4N hydrogen chloride in ethyl acetate solution was added-thereto. The whole mixture was evaporated and the residue was triturated with a mixture of ethanol and n-hexane (1:1). The resulting crystals were collected by filtration and washed with a mixed solvent of ethanol and n-hexane (1:1) to give colorless crystals of 3,3-dimethylmorpholine hydrochloride (1.56 g).
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:6]=[C:7]([CH2:17][N:18]2C(=O)C3C(=CC=CC=3)C2=O)[CH:8]=[N:9][C:10]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]>CO>[Cl:4][C:5]1[CH:6]=[C:7]([CH2:17][NH2:18])[CH:8]=[N:9][C:10]=1[O:11][CH2:12][C:13]([F:14])([F:15])[F:16]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc(OCC(F)(F)F)c(Cl)c1
Agent: NN
Solvent: O
Solvent: CO
Product: NCc1cnc(OCC(F)(F)F)c(Cl)c1
Temperature: 50 °C
Reaction time: 20 h
Yield: 111.3 %

Procedure:
Hydrazine monohydrate (0.04 mL, 0.84 mmol) is added to a solution of 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (210 mg, 0.56 mmol, Step-3) in methanol (10 mL) and stirred for 20 hours at 50° C. After removal of the solvent, the residue is poured into 2 M aqueous sodium hydroxide solution (10 mL) and extracted with DCM (30 mL×3) and dried over sodium sulfate, and concentrated in vacuo to give 0.15 g (>99% yield) of the title compound as colorless oil. This material is used for the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:23])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])[C:6]=2[CH:5]=[C:4]([NH2:24])[CH:3]=1.Br[CH2:26][CH2:27][O:28][CH2:29][CH2:30]Br.CCN(C(C)C)C(C)C>C(O)CO.O>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:23])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[C:13]=3[CH3:22])[C:6]=2[CH:5]=[C:4]([N:24]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:3]=1
Reactant: BrCCOCCBr
Reactant: Cc1c(Cn2c(C)nc3c(Br)cc(N)cc32)cccc1C(F)(F)F
Solvent: OCCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cn2c(C)nc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 20 h
Yield: 79.4 %

Procedure:
A mixture of 7-bromo-2-methyl-3-(2-methyl-3-(trifluoromethyl)benzyl)-3H-benzo[d]imidazol-5-amine (45 g, 113 mmol), 1-bromo-2-(2-bromoethoxy)ethane (39 g, 169 mmol) and DIPEA (21 g, 169 mmol) in ethylene glycol (700 mL) was stirred at 100° C. for 20 h. It was cooled to rt, and diluted with water (300 mL) and extracted with DCM (300 mL×4). The combined organic layers were washed with brine, dried over sodium sulphate and evaporated. The residue was combined with previous batch prepared similarly and purified by column chromatography (eluted with petroleum ether/ethyl acetate=1/1) to give the product (42 g, 55%) as a yellow solid; LC/MS: MS (ES+) m/e 468 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.36 (s, 3H), 2.53 (s, 3H), 3.06 (t, J=4.5 Hz, 4H), 3.70 (t, J=4.5 Hz, 4H), 5.53 (s, 2H), 6.32 (d, J=7.8 Hz, 1H), 6.99 (d, J=1.5 Hz, 1H), 7.10 (d, J=1.5 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H).