Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N.CO.[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:14](O)=[O:15])[CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][S:20](=[O:25])(=[O:24])[CH2:19]1.C[N:27](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:14]([NH2:27])=[O:15])[CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][S:20](=[O:25])(=[O:24])[CH2:19]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc(Br)cc2c(CC3CCCS(=O)(=O)C3)c[nH]c12
Agent: F[B-](F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1cc(Br)cc2c(CC3CCCS(=O)(=O)C3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
A solution of NH3/MeOH (40 mL) was added to a mixture of 5-bromo-3-((1,1-dioxo-tetrahydro-2H-thiopyran-3-yl)methyl)-1H-indole-7-carboxylic acid (1.30 g, 0.0034 mol), TEA (0.68 g, 0.0067 mol), and TBTU (2.16 g, 0.067 mol) in DCM (30 mL). The resulting mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was washed with water and extracted with DCM (2×100 mL). The organic layers were dried, filtered, concentrated under reduced pressure, and purified by chromatography eluting with a mixture of DCM:MeOH (60:1), giving 0.94 g (72.5%) of the title compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.[Li]CCCC.[CH2:21]([O:23][C:24]1[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH:25]=1)[CH3:22].CN(C)P(N(C)C)(N(C)C)=O.I[CH2:43][CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]>O1CCCC1>[CH2:21]([O:23][C:24]1[CH2:29][CH2:28][CH:27]([CH2:43][CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:51])([CH3:53])[CH3:52])([CH3:48])[CH3:49])[C:26](=[O:30])[CH:25]=1)[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCCI
Reactant: CCOC1=CC(=O)CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC1=CC(=O)C(CCCO[Si](C)(C)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 51.9 %

Procedure:
To a lithium diisopropylamide (LDA) solution [prepared from diisopropylamine (3.82 mL, 27 mmol) and nBuLi (7.26 mL of a 2.5M solution in hexanes, 18 mmol) in tetrahydrofuran (THF, 12 mL) at 0° C.] at −78° C. was added 3-ethoxy-2-cyclohexen-1-one (2.64 mL, 18 mmol) in THF (6 mL), dropwise, over 40 min. After stirring for an additional 30 min at −78° C., hexamethyl phosphoramide (HMPA, 3.16 mL, 18 mmol) was added followed by the dropwise addition of 3-iodo-1-tert -butyldimethylsiloxypropane (5.45 g, 18 mmol) in THF (8 mL). The resultant mixture was allowed to warm to rt, stirred for 6 h and then quenched by the addition of water (10 mL). The reaction mixture was then partitioned between dichloromethane (DCM, 100 mL) and sat. NH4Cl (40 mL). The aqueous phase was extracted with DCM (3×50 mL), the organic phases combined and washed with brine (50 mL), dried over anhydrous MgSO4 and reduced to dryness. The resultant syrup was purified by flash column chromatography (hexanes/EtOAc 8/2) to yield 2 as a pale yellow oil (2.92 g, 51.2%). Rf 0.21 (hexanes/EtOAc 8/2); 1H NMR (300 MHz, CDCl3) δ 5.26 (1H, s), 3.83 (2H, q, J=7.0 Hz), 3.59 (1H, t, J=6.5 Hz), 3.58 (H, t, J=6.5 Hz), 2.38 (2H, t, J=6.2 Hz), 2.20-1.99 (2H, m), 1.85-1.35 (5H, m), 1.31 (3H, t, J=7.0 Hz), 0.84 (s, 9H), 0.00 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 201.6, 176.7, 102.3, 64.2, 63.4, 45.0, 30.5, 28.0, 26.4, 26.0 (×2), 18.4, 14.2, −5.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([C:13]2[C:14](Cl)=[N:15][CH:16]=[CH:17][CH:18]=2)=O)[NH:8][CH:7]=1)=[O:5])[CH3:2].O.[NH2:21][NH2:22]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:22][N:21]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c(C(=O)c2cccnc2Cl)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 80 °C

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-carboxylic acid ethyl ester (1.2 g, 4.32 mmol) and hydrazine hydrate (6.27 mL) in ethanol (50 mL) was heated at 80° C. for 24 hours. The reaction was concentrated and the residue was neutralized to pH 7 with 1N HCl, extracted with ethyl acetate. The combined ethyl acetate was dried, concentrated and purified on a silica gel column to give the titled compound as a white solid.
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)(Cl)Cl.CO>[C:1]1([CH2:7][S:8]([C:9]2[NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(CSc2nc3cnccc3[nH]2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=S(Cc1ccccc1)c1nc2cnccc2[nH]1
Reaction time: 0.75 h

Procedure:
To a chilled (0°-5° C.) solution of 3.3 g (0.014 mol) of 2-[[(phenyl)methyl]thio]-1H-imidazo[4,5-c]pyridine in 50 mL of chloroform and 5 mL of methanol was added dropwise a solution containing 2.78 g (0.014 mol) of m- chloroperoxybenzoic acid in 50 mL of chloroform. The reaction mixture was then stirred at room temperture for 45 minutes. Approximately one half of the chloroform was removed in a rotary evaporator and the reaction mixture was then poured into 200 mL of ether. The reaction mixture was cooled in ice. The precipitate that formed was collected and amounted to 1.78 g. The product was suspended in aqueous 10% sodium bicarbonate solution, filtered and was air dried overnight. The product amounted to 1.39 g. An analytical sample (m.p. 190°-193° C.) was obtained by recrystallization from ethanol.
Reaction SMILES: [C:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([N+:14]([O-])=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([NH2:14])=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc([N+](=O)[O-])c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)n1nc(N)c2ccccc21
Yield: 64.2 %

Procedure:
A mixture of 1-tert-butyl-3-nitro-1 H-indazole (3.0 g, 14 mmol) and Pd/C (1 g) in MeOH (50 mL) was hydrogenated (1 atm) at RT for 2 h. The reaction mixture was filtered and the filtrate was concentrated and purified by chromatography to give 1-tert-butyl-1 H-indazol-3-ylamine (1.7 g, 68% yield). 1H NMR (400 MHz, DMSO-d4): δ 7.67 (m, 1 H), 7.52 (m, 1 H), 7.19 (m, 1 H), 6.89 (m, 1 H), 5.32 (s, 2 H), 1.58 (s, 9 H); MS (ESI) m/z: 190.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][C@@H:21]2[C@@H:26]3[CH2:27][C@@H:23]([CH:24]=[CH:25]3)[C@@H:22]2[C:28]([NH2:30])=[O:29])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:13]=2)=[N:6][CH:7]=1.[C:31]([NH:34][CH2:35][C:36](O)=[O:37])(=[O:33])[CH3:32].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.C([O-])(O)=O.[Na+]>[C:31]([NH:34][CH2:35][C:36]([N:17]1[CH2:16][CH2:15][CH:14]([N:12]2[CH:13]=[C:9]([NH:8][C:5]3[N:4]=[C:3]([NH:20][C@@H:21]4[C@@H:26]5[CH2:27][C@@H:23]([CH:24]=[CH:25]5)[C@@H:22]4[C:28]([NH2:30])=[O:29])[C:2]([Cl:1])=[CH:7][N:6]=3)[CH:10]=[N:11]2)[CH2:19][CH2:18]1)=[O:37])(=[O:33])[CH3:32]
Reactant: CC(=O)NCC(=O)O
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Nc3cnn(C4CCNCC4)c3)ncc2Cl)[C@H]2C=C[C@@H]1C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CC(=O)NCC(=O)N1CCC(n2cc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)cn2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(1S,2S,3R,4R)-3-(5-Chloro-2-(1-(piperidin-4-yl)-1H-pyrazol-4-ylamino)pyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide (85 mg, 0.20 mmol), N-acetylglycine (26 mg, 0.22 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (76 mg, 0.40 mmol) and 1-hydroxybenzotriazole hydrate (61 mg, 0.40 mmol) were taken up in N,N-dimethylformamide (1 mL), and N-methylmorpholine (0.11 mL, 1.0 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours, then diluted with NaHCO3 solution (30 mL). The mixture was extracted with ethyl acetate (3×20 mL), and the extracts were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography, using a 12 g silica cartridge and eluting with a gradient from 0 to 8% methanol/CH2Cl2 over 30 minutes at a flow rate of 30 mL/minutes, yielding the desired product. 1H NMR (400 MHz, DMSO-D6) ppm 1.42 (d, J=8.9 Hz, 1H) 1.73-1.86 (m, 2H) 1.88 (s, 3H) 2.01-2.08 (m, 2H) 2.13 (d, J=8.9 Hz, 1H) 2.55 (d, J=7.9 Hz, 1H) 2.76 (s, 1H) 2.87 (s, 1H) 2.93-3.14 (br m, 4H) 3.96 (d, J=5.2 Hz, 2H) 4.17 (t, J=7.9 Hz, 1H) 4.29-4.38 (m, 1H) 6.25 (dd, J=5.8, 3.1 Hz, 1H) 6.34 (dd, J=5.7, 2.9 Hz, 1H) 6.73-7.03 (br, 1H) 7.34-7.52 (br, 1H) 7.47 (d, J=7.6 Hz, 1H) 7.54 (s, 1H) 7.57-7.65 (br s, 1H) 7.75 (s, 1H) 7.84 (s, 1H) 8.69 (s, 1H); MS (ESI(+)) m/e 528 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6](=[N:8][OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>>[OH:9][N:8]([CH:6]1[CH2:7][C:2]([CH3:12])([CH3:1])[NH:3][C:4]([CH3:11])([CH3:10])[CH2:5]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:8]([OH:9])[CH:6]1[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3][C:2]([CH3:12])([CH3:1])[CH2:7]1
Reactant: CC1(C)CC(=NO)CC(C)(C)N1
Reactant: BrCCCCCCBr
Product: CC1(C)CC(N(O)CCCCCCN(O)C2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1

Procedure:
from 2,2,6,6-tetramethylpiperidin-4-one oxime and 1,6-dibromohexane
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH2:35][CH:34]([CH:38]=O)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH2:35][CH:34]([CH:38]=[C:1]([Br:5])[Br:2])[CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(C=C(Br)Br)C1
Reaction time: 24 h
Yield: 8.7 %

Procedure:
To a mixture of CBr4 (1.63 g, 4.92 mmol) and PPh3 (1.29 g, 4.92 mmol 9 in DCM (25 ml) was added 1 g (4.69 mmol) 3-Formyl-piperidine-1-carboxylic acid tert-butyl ester (commercially available) at room temperature. The reaction mixture was stirred at R.T for 24 h and the solvent was removed. The crude product was purified by flash chromatography (cyclohexane/AcOEt 90/10) to afford 0.15 g (9%) of 3-(2,2-Dibromo-vinyl)-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: FC1C=CC(C=NO)=CC=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:22]3[C:23](=[O:27])[CH2:24][CH2:25][CH2:26][C:21]=3[O:20][N:19]=2)=[CH:14][CH:13]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:36][CH2:37][CH2:38][CH2:39]I>C1COCC1.O>[Cl:36][CH2:37][CH2:38][CH2:39][CH:24]1[C:23](=[O:27])[C:22]2[C:18]([C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=3)=[N:19][O:20][C:21]=2[CH2:26][CH2:25]1
Reactant: O=C1CCCc2onc(-c3ccc(F)cc3)c21
Reactant: ClCCCI
Agent: CC(C)[N-]C(C)C
Agent: ON=Cc1ccc(F)cc1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2c(-c3ccc(F)cc3)noc2CCC1CCCCl
Temperature: -78 °C

Procedure:
In a similar manner to that of Examples 7a-d starting with 4-fluorobenzaldehyde oxime, the starting ketone is prepared. In 170 ml anhydrous THF was dissolved 4.0 g 6,7-dihydro-3-(4-fluorophenyl)-1,2-benzisoxazol-4(5H)-one under nitrogen atmosphere with stirring. The solution was cooled to -78° C. and 17.3 ml lithium diisopropylamide (1.50 molar in cyclohexane) was added dropwise. The resulting solution was stirred for ten minutes at -78° C. and 2.2 ml 1-chloro-3-iodopropane was added. Upon warming to room temperature, the reaction mixture was poured into water and the layers were then separated. The aqueous phase was extracted twice with dichloromethane and once with ether. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Column chromatography on silica gel (start with 10% dichloromethane in hexane and gradually increase polarity to 100% dichloromethane) gave 4.2 g of 5-(3-chloropropyl)-6,7-dihydro-3-(4-fluorophenyl)-1,2-benzisoxazol-4-(5H)-one.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][C:16]([OH:23])=[CH:17][CH:18]=3)[CH2:13][C:12]=2[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:24][C:25]([F:51])([F:50])[O:26][C:27]([F:49])([F:48])[C:28]([F:47])([F:46])[O:29][C:30]([F:45])([F:44])[C:31]([F:43])([F:42])[O:32][C:33]([F:41])([F:40])[CH2:34][O:35][CH2:36][CH2:37][CH2:38]Cl.FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)COCCCBr>>[CH2:1]([O:9][C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:38][CH2:37][CH2:36][O:35][CH2:34][C:33]([O:32][C:31]([F:42])([F:43])[C:30]([F:44])([F:45])[O:29][C:28]([F:46])([F:47])[C:27]([F:48])([F:49])[O:26][C:25]([F:51])([F:50])[F:24])([F:41])[F:40])=[CH:17][CH:18]=3)[CH2:13][C:12]=2[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)COCCCCl
Reactant: CCCCCCCCOc1ccc2c(c1)Cc1cc(O)ccc1-2
Agent: FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)COCCCBr
Product: CCCCCCCCOc1ccc2c(c1)Cc1cc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)ccc1-2

Procedure:
The title compound was prepared essentially as in Example 1 by combining 2-octyloxy-7-hydroxyfluorene (1.0 g, 3.2 mmol) with a mixture of 3-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propyl chloride and 3-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propyl bromide (total 1.62 g, 3.3 mmol, 80:20 mole ratio). The reaction mixture was quenched by addition of water, and the resulting crude product was recrystallized from ethanol and further purified by Kugelrohr distillation (188° C. at 0.01 torr) to provide a yield of 0.84 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1.[Br:14]Br.O>C(O)(=O)C>[Br:14][CH:8]1[C:7](=[O:12])[C:6]2[CH:13]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[S:11][CH2:10][CH2:9]1
Reactant: O=C1CCCSc2ccc(F)cc21
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2cc(F)ccc2SCCC1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7-Fluoro-2,3,4,5-tetrahydro-1-benzothiepin-5-one (1 equivalent) was dissolved in glacial acetic acid and stirred at room temperature. Bromine (2.5 equivalents) was added to the above mixture dropwise and stirring continued at room temperature for 4 hours. Water was added to the reaction mixture and the mixture was then extracted with 2×25 ml ethyl acetate. The combined ethyl acetate extracts were washed with water, saturated sodium bicarbonate, and water. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford a solid which was re-crystallized from ethyl acetate/hexane 1:1 v/v to afford 4-bromo-7-fluoro-2,3,4,5-tetrahydro-1-benzothiepin-5-one: 1H NMR (CDCl3) δ 7.55 (dd, 1H, J=2.7, 9.0 Hz), 7.44 (dd, 1H, J=8.7, 5.1 Hz), 7.11 (Apparent dt, 1H, J=2.7, 4.8 Hz), 5.34 (dd, 1H, J=5.7, 10.2 Hz), 3.20–2.50 (m, 4H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH3:6])[CH3:5].[H-].[Na+].[OH:9][CH2:10][C@@H:11]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:21](=[O:23])[CH3:22].[NH4+].[Cl-]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-].CCOC(C)=O>[CH3:5][N:4]([CH3:6])[CH2:3][CH2:2][O:9][CH2:10][C@@H:11]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:21](=[O:23])[CH3:22]
Reactant: CC(=O)N1Cc2ccccc2C[C@H]1CO
Reactant: CN(C)CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1Cc2ccccc2C[C@H]1COCCN(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
To 2-chloro-N,N-dimethylethanamine (63 mg, 0.59 mmol) in DMF (1.0 mL) was added NaH (156 mg, 3.90 mmol, 60% suspension in mineral oil) at 0° C. After stirring for 20 min at 0° C., (S)-1-(3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (40 mg, 0.20 mmol) was added, and the resulting suspension was stirred at room temperature for 10 min. TBAI (7 mg, 0.019 mmol) was then added, and the reaction mixture was heated at 70° C. for 1.5 h. The mixture was then poured into sat. aq. NH4Cl solution and EtOAc. The layers were separated, and the organic layer was washed with sat. aq. NH4Cl solution. The aqueous layer was extracted with EtOAc (3×), and the combined organics were washed with sat. aq. NaCl solution and dried over Na2SO4. Filtration and concentration in vacuo provided a crude oil which was triturated with hexanes (3×) to give the title compound (29 mg, 54%) as a pale yellow oil. MS(ESI+) m/z 206.1 (M+H)+.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([OH:15])[CH:14]=1)OCCC)#[N:2].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][NH2:25]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([OH:15])[CH:14]=1)=[N:25][CH2:24][CH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[Cl:16])#[N:2]
Reactant: CCCOC(=NC#N)c1cncc(O)c1
Reactant: NCCc1ccccc1Cl
Solvent: CO
Product: N#CNC(=NCCc1ccccc1Cl)c1cncc(O)c1
Reaction time: 4 h
Yield: 41.8 %

Procedure:
To a solution of propyl N-cyano-5-hydroxy-3-pyridinecarboximidate (0.26 g) in methanol (5 ml) was added 2-(2-chlorophenyl)ethylamine (0.22 g, 1.4 mmol), and the mixture was stirred for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue obtained was extracted with chloroform (50 ml×3). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200, 30 g; eluted with chloroform:methanol=50:1) and further crystallized from diethyl ether to give the title compound (0.16 g, 0.53 mmol) as colorless crystals. (Yield starting from 3-cyano-5-hydroxypyridine 15%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH:9]=O.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]([C:23](=[S:25])[NH2:24])[CH:19]1[C:26]1[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[N:27]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1>COCCOC>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]([C:23]2[S:25][CH:8]=[CH:9][N:24]=2)[CH:19]1[C:26]1[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[N:27]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Cc1cc(C2C(C(N)=S)CCN2C(=O)OC(C)(C)C)nc(-n2ccnc2)n1
Reactant: O=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: COCCOC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(C2C(c3nccs3)CCN2C(=O)OC(C)(C)C)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
Potassium carbonate (700 mg, 5.20 mmol) and 2-chloroacetaldehyde (400 mg, 5.20 mmol) were added sequentially to a solution of 2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-3-thiocarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg, 1.04 mmol) in DME (10 mL) at rt under an atmosphere of N2. The reaction mixture was stirred at room temperature for 16 h then filtered under vacuum. The filtrate was concentrated and the residue dissolved in DME (10 mL) prior to cooling to 0° C. Trifluoroacetic anhydride (655 mg, 3.12 mmol) and pyridine (575 mg, 7.28 mmol) were added and reaction mixture was stirred at rt for 4 h. The mixture was concentrated and the residue was diluted with DCM (20 mL). The solution was washed with water (2×30 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified using column chromatography (DCM to 9:1 DCM/MeOH) to afford 2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-3-thiazol-2-yl-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil (200 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][CH2:9][C:10]1[C:15]2[CH:16]=[C:17]([C:19]([O:21]CC)=[O:20])[O:18][C:14]=2[C:13]([O:24][CH3:25])=[CH:12][CH:11]=1.Cl>O1CCOCC1.CO.[OH-].[Na+]>[Cl:26][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][CH2:9][C:10]1[C:15]2[CH:16]=[C:17]([C:19]([OH:21])=[O:20])[O:18][C:14]=2[C:13]([O:24][CH3:25])=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc2c(CCc3c(Cl)cncc3Cl)ccc(OC)c2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(CCc2c(Cl)cncc2Cl)c2cc(C(=O)O)oc12
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
Ethyl 4-[2-(3,5-dichloro-4-pyridyl)ethyl]-7-methoxybenzofuran-2-carboxylate (1.9 g) was dissolved in dioxane (20 ml)-methanol (5 ml), and 1 N aqueous NaOH (15 ml) as added thereto. The mixture was returned to room temperature and stirred for 30 minutes. After 1 N aqueous HCl was dropwise added thereto under cooling on ice, the precipitated crystals were collected by filtration and washed with water to give Compound N (1.72 g, 97%) as colorless crystals.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:9]=1[CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]2[N:16]=[C:17]([NH2:19])[S:18][C:14]=2[CH:13]=1>N1C=CC=CC=1>[Cl:7][C:8]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:9]=1[CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]2[N:16]=[C:17]([NH:19][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:6])[S:18][C:14]=2[CH:13]=1
Reactant: O=C(O)C1CC1
Reactant: Nc1nc2ccc(OCc3c(Cl)cccc3Cl)cc2s1
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccc(OCc3c(Cl)cccc3Cl)cc2s1)C1CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
add 23 mg of cyclopropanecarboxylic acid to a solution of 70 mg of 6-[(2,6-dichlorobenzyl)oxy]-1,3-benzothiazol-2-amine in 1.5 cm3 of anhydrous pyridine. After stirring for one hour at around 20° C., the reaction mixture is concentrated to dryness under reduced pressure (0.2 kPa). The residue is taken up in 25 cm3 of water, then the mixture obtained is extracted three times with 20 cm3 of dichloromethane. The combined organic phases are washed twice with 20 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. After purification of the residue by silica-column flash chromatography [eluent: dichloromethane/methanol (92/8 by volume)], we obtain 51 mg of N-{6-[(2,6-dichlorobenzyl)oxy]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide in the form of a cream-coloured powder, which has the following characteristics:
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].CC1C=C(O)C=CC=1O.[C:17]([O:22][CH2:23][CH2:24][N:25]=[C:26]=[O:27])(=[O:21])[C:18]([CH3:20])=[CH2:19]>C1(C)C=CC=CC=1>[C:17]([O:22][CH2:23][CH2:24][NH:25][C:26]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])=[O:27])(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: OCCNCCO
Reactant: C=C(C)C(=O)OCCN=C=O
Agent: Cc1cc(O)ccc1O
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCCNC(=O)N(CCO)CCO
Reaction time: 1.75 h

Procedure:
A one liter flask, under a N2 blanket, was charged with 105 gm of diethanolamine (1 mole) and 20 mg of methylhydroquinone. One molar of 2-isocyanatoethyl methacrylate (IEM) containing 2 ml of DBTDL (2% solution in toluene) was dropped slowly in the flask with moderate stirring over a period of 105 minutes, while the temperature was maintained at 20° to 25° C. with an ice-bath. The resulting viscous solution was stirred for an additional 60 minutes at 20° C. and then discharged. The product showed no NCO absorption in the IR spectrum and the NMR spectrum was consistent with the proposed structure. Gas chromatography also indicated the purity of the product to be greater than 95%. Additional inhibitor was added (to a total of 250 ppm) and the diol was stored in a freezer.