Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21](=[O:30])/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([CH:22]1[C:21](=[O:30])[O:13][C:12]2[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:9][C:8]=2[CH:1]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: O=C1NC(c2ccccc2F)=N/C1=C\c1ccccc1
Product: O=C1Oc2[nH]c(-c3ccccc3F)nc2C(c2ccccc2)C1Cc1ccccc1
Reaction time: 72 h
Yield: 65 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2-fluorophenyl)-1H-imidazol-5(4H)-one and trans-cinnamaldehyde. After 72 h, the unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 5h as an off-white solid (78 mg, 65%). Analytical data for 5 h: 1H NMR (500 MHz, CDCl3) δ 9.32 (d, J=8.4 Hz, 1H), 8.21 (td, J=8.0, 1.9 Hz, 1H), 7.36-7.21 (m, 8H), 7.12-7.05 (m, 3H), 7.02-6.99 (m, 2H), 4.09 (d, J=6.8 Hz, 1H), 3.62 (ddd, J=10.2, 6.8, 4.6 Hz, 1H), 3.37 (dd, J=14.9, 4.5 Hz, 1H), 2.43 (dd, J=14.8, 10.2 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 169.1, 159.5 (d, JCF=244.7 Hz), 148.8, 138.0, 137.5, 137.2, 130.1 (d, JCF=8.9 Hz), 129.2, 129.0, 128.6, 128.5 (d, JCF=3.0 Hz), 128.2, 128.0, 126.7, 125.2 (d, JCF=2.9 Hz), 117.0 (d, JCF=10.2 Hz), 115.8 (d, JCF 22.3 Hz), 110.3 (d, JCF=3.3 Hz), 47.4, 38.4, 32.7; IR (film) cm−1 1771, 1632, 1614, 1528, 1467, 1454, 1428, 1122, 1106, 1073, 909, 762, 732, 698; LRMS (ESI): Mass calcd for [M+H]+ C25H20FN2O2: 399.1. found 399.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 5% IPA/3% MeOH/hexanes 0.5 mL/min, 280 nm), Rt1 (minor)=53.0, Rt2 (major)=63.6 min; er=98:2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[CH3:23][CH:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:26]([NH:27][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[CH2:25][CH:24]([CH3:28])[CH3:23]
Reactant: CC(C)CCN
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
4-Nitrobenzene-1-sulfonyl chloride (1.5 g, 6.57 mmol) was dissolved in dichloromethane (30 ml) and cooled to 0° C. followed by addition of diisopropylethylamine (2.293 ml, 13.13 mmol). 3-Methylbutan-1-amine (0.926 ml, 7.88 mmol) was dissolved in 5 ml dichloromethane and added via syringe. After the addition, the mixture was allowed to warm to room temperature for 3 hours. The solution was diluted with aqueous sodium bicarbonate and extracted twice with dichloromethane. The organics were combined, dried over magnesium sulfate, filtered and concentrated. Chromatography provided the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]([C:20]1[CH:32]=[CH:31][C:23]([CH:24]=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=1)[CH2:16][CH2:17][O:18][CH3:19])=O)(C)(C)C>>[CH3:19][O:18][CH2:17][CH2:16][NH:15][C:20]1[CH:32]=[CH:31][C:23]([CH:24]=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C=Cc1ccc(N(CCOC)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C=Cc1ccc(NCCOC)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
Trifluoroacetic acid (3 ml) was added to ethyl 4-[N-tert-butoxycarbonyl-N-(2-methoxyethyl)amino]cinnamate (932 mg) in ice water bath and stirred for 15 minutes at same temperature. The solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting to a mixture of n-hexane and ethyl acetate (3:1) and recrystallized from a mixture of n-hexane and ethyl acetate to give ethyl 4-(2-methoxyethylamino)cinnamate (470 mg) as crystals. mp: 49.9-53.4° C.
Reaction SMILES: [O:1]1[C:5]([CH3:12])([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]1[CH2:3][OH:4].[OH:13][CH2:14][CH2:15][NH:16][CH3:17]>C1(C)C=CC=CC=1>[OH:13][CH2:14][CH2:15][N:16]([CH3:17])[CH:2]([C:5]([CH3:12])([OH:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][OH:4]
Reactant: CC(C)CCCC1(C)OC1CO
Reactant: CNCCO
Solvent: Cc1ccccc1
Product: CC(C)CCCC(C)(O)C(CO)N(C)CCO
Yield: 85 %

Procedure:
A solution of 17.2 g of 2,3-epoxy-3,7-dimethyl-1-octanol, 15.0 g of (2-hydroxyethyl)methylamine and 20 ml of toluene was refluxed for 4 hours. After the reaction was completed, the reaction mixture was distilled under reduced pressure to give 21.0 g (yield 85%) of 2-[(2hydroxyethyl)methylamino]-3,7-dimethyl-1,3-octanediol Compound (60)]. The physical constants of Compound (60) are as follows.
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ncccc1[N+](=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccnc1CBr
Temperature: 25 °C
Yield: 37.3 %

Procedure:
2,2′-azobis(isobutyronitrile) (2.7 g, 16.4 mmol) was added to a solution of 2-methyl-3-nitropyridine (12.97 g, 92.6 mmol) prepared in Step 1 and N-bromosuccinimide (23.06 g, 130 mmol) in carbon tetrachloride (100 ml) and then the reaction mixture was refluxed for 3 days. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (100 ml) and then washed with a saturated sodium bicarbonate solution and a saturated sodium thiosulfate solution. The organic layer was dried on anhydrous magnesium sulfate and then purified with silica gel column chromatography (dichloromethane/n-hexane=2/1, v/v) to give 7.5 g of the titled compound as brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([SH:12])=[N:6][C:5]=2[NH:4][CH:3]=1.[OH-].[Na+].[Cl:15][C:16]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:17]=1[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)=[O:19]>CO.COCCOC>[Cl:15][C:16]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:17]=1[C:18]([C:20]1[CH:21]=[CH:22][C:23]([CH2:24][S:12][C:7]2[NH:8][C:9](=[O:11])[C:10]3[C:2]([CH3:1])=[CH:3][NH:4][C:5]=3[N:6]=2)=[CH:26][CH:27]=1)=[O:19]
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Reactant: Cc1c[nH]c2nc(S)[nH]c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CO
Product: Cc1c[nH]c2nc(SCc3ccc(C(=O)c4ccc(Cl)cc4Cl)cc3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.9 %

Procedure:
In methanol (18.7 ml) was suspended 5-methyl-2-mercapto-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.36 g) followed by addition of 1N-sodium hydroxide (7.88 ml) for dissolution. Then, under ice-cooling, a solution of 4-(2,4-dichlorobenzoyl)benzyl bromide (3.09 g) in DME (8 ml) was added dropwise. The mixture was stirred at room temperature for 4 hours and the resulting crystalline precipitate was collected by filtration and rinsed with water. The crystals were further rinsed with 50% ethanol/water, methanol and ether, dried, and recrystallized from DME (1,2-dimethoxyethane) to provide the title compound (2.03 g). 1H-NMR (DMSO-d6) δ: 2.23(3H,s), 4.48(2H,s), 6.65(1H,s), 7.53(1H,d,J=8.2Hz), 7.59(1H,dd,J=1.6,8.8Hz), 7.64(2H,d,J=8.4Hz), 7.69(2H,d,J=8.4Hz), 7.80(1H,d,J=1.6Hz), 11.40(1H,s), 11.96(1H,s).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C:11]3=[CH:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO.O>[C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C:11]3=[CH:12][CH2:13][C@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@H]3C4=CC[C@H](C(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@H]3C4=CC[C@@H](C(C)=O)[C@@]4(C)CC[C@@H]32)C1

Procedure:
A solution of 10.0 g of 3β-acetoxy-5β-pregn-14-en-20-one (Bach, G. et al. Can. J. Chem. 1968, 46, 733) and K2CO3 (25.0 g) in MeOH/water (160 mL/80 mL) was stirred at room temperature for 2 hrs; the organic solvent was evaporated to dryness under reduced pressure and the aqueous suspension obtained was extracted with CH2Cl2 ; the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure; the crude 3β-acetoxy-5β,17α-pregn-14-en-20-one obtained was used for the next step without further purification. A solution of the crude intermediate and p-toluensulphonyl hydrazide (11.1 g) in AcOH (300 mL) was stirred at room temp. for 12 hrs. To this solution NaBH4 (7.8 g) was added portionwise; after 2 hrs the reaction mixture was poured in water/ice and the aqueous suspension obtained was extracted with AcOEt and neutralised with 0.1 N NaOH: the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 1/1 as eluant to give 7.0 g of 3β-acetoxy-5β,17α-pregn-14-ene as a white solid.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].O.[OH-].[Na+].[CH:14]([N:17]=[C:18]=[O:19])([CH3:16])[CH3:15]>CC(C)=O>[CH:14]([NH:17][C:18](=[O:19])[NH:10][C:8](=[NH:9])[O:7][CH3:6])([CH3:16])[CH3:15]
Reactant: COC(=N)N
Reactant: CC(C)N=C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COC(=N)NC(=O)NC(C)C
Reaction time: 3 h

Procedure:
To 114 parts of 2-methylpseudourea sulfate in 400 parts of water at 0°C is added 106 parts of 50% sodium hydroxide, followed by 400 parts of acetone, and 51 parts of isopropyl isocyanate. The reaction mixture is allowed to come to room temperature in 3 hrs. The organic solvent is then evaporated under vacuum, the aqueous residue saturated with sodium chloride, and the mixture extracted with methylene chloride. The organic extract is dried and the methylene chloride evaporated to yield 78 parts of methyl 4-isopropylallophanimidate, m.p. 64°-67°C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH3:4].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C@H:21]([CH3:25])[C:22](O)=[O:23])[CH:15]=[CH:14]2.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(#N)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C@H:21]([CH3:25])[C:22]([O:1][CH2:2][C:3]([CH2:7][OH:8])([CH3:4])[CH2:5][OH:6])=[O:23])[CH:15]=[CH:14]2
Reactant: CC(CO)(CO)CO
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc2cc([C@H](C)C(=O)OCC(C)(CO)CO)ccc2c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 65.4 %

Procedure:
To a stirred solution of 1,1,1-tris(hydroxymethyl)ethane (13.1 g, 109 mmol), (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 5.00 g, 21.7 mmol), 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (4.80 g, 25 mmol), and N,N-dimethylaminopyridine (DMAP, 20 mg, catalytic amount) in acetonitrile (200 mL) was added triethylamine (4.2 mL, 30 mmol). The reaction mixture was stirred at ambient temperature for 25 hours, filtered, and the filtrate was concentrated to dryness. The residue was diluted with EtOAc, washed with 1N HCl (2×), saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The resulting material was purified by crystallization (2×) from EtOAc/Hexanes (1:3 v:v) to give the title compound (4.72 g, 66% yield) as white flakes. Mp 105° C. 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=2.0 Hz, 1H), 7.69 (d, J=2.5 Hz, 1H), 7.66 (s, 1H), 7.39 (dd, J=8.5, 1.7 Hz, 1H), 7.17-7.10 (m, 2H), 4.25 (d, J=11.3 Hz, 1H), 4.09 (d, J=11.3 Hz, 1H), 3.90 (s, 3H), 3.88 (q, J=7.1 Hz, 1H), 3.46-3.25 (m, 4H), 2.65-2.55 (m, 2H), 1.60 (d, J=7.1 Hz, 3H), 0.67 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 175.8, 157.7, 135.3, 133.8, 129.2, 128.9, 127.3, 126.0, 119.2, 105.6, 67.7, 67.5, 66.8, 55.3, 45.6, 40.9, 18.1, 16.7. LRMS (API-TIS) m/z 350.2 ((M+NH4)+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[CH2:9][CH2:8]1.[C:23]([OH:32])(=[O:31])[CH:24]([CH:26]([C:28]([OH:30])=[O:29])[OH:27])[OH:25]>CO.O>[C:28]([C@@H:26]([C@H:24]([C:23]([OH:32])=[O:31])[OH:25])[OH:27])([OH:30])=[O:29].[C:28]([C@@H:26]([C@H:24]([C:23]([OH:32])=[O:31])[OH:25])[OH:27])([OH:30])=[O:29].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[NH:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:11][CH2:12]1
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: c1ccc(N2CCN(Cc3nc4ccccc4[nH]3)CC2)nc1
Solvent: O
Solvent: CO
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O

Procedure:
2-[(4-Pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole (4.00 g, 13.6 mmol) in methanol (20 mL) and H2O (20 mL) was treated with (L) tartaric acid (4.09 g, 27.2 mmol). The resulting solid was filtered, washed with methanol (10 mL), and dried under reduced pressure to provide the title compound as a solid. Elemental analysis calc'd for C25H31N5O12: C, 50.59; H, 5.26; N, 11.80; O, 32.35. Found: C, 50.48; H 5.27; N, 11.78; O, 32.41. DSC: sharp endotherm at 206° C.
Reaction SMILES: [C:1]12([C:11]3[C:19]4[O:18][CH2:17][O:16][C:15]=4[CH:14]=[C:13](Br)[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)=O.CC(C)=O.[Li]CCCC.C([O:36][B:37](OC(C)C)[O:38]C(C)C)(C)C>C1COCC1.CCCCCC>[C:1]12([C:11]3[CH:12]=[C:13]([B:37]([OH:38])[OH:36])[CH:14]=[C:15]4[O:16][CH2:17][O:18][C:19]=34)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cc2c(c(C34CC5CC(CC(C5)C3)C4)c1)OCO2
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: OB(O)c1cc2c(c(C34CC5CC(CC(C5)C3)C4)c1)OCO2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 65.5 %

Procedure:
To a solution of 4-(1-adamantyl)-6-bromobenzo[1,3]dioxole (2.10 g, 6.26 mmol) in THF (11 mL) at −78° C. (dry ice/acetone bath) under argon was added 1.6 M n-BuLi (10.0 mmol) in hexane (6.26 mL) in one portion. This mixture was stirred at −78° C. for 15 min. Tri(isopropyl)borate (4.30 mL, 18.8 mmol) was added, and the resulting solution was stirred at −78° C. for 20 min more before being allowed to warm to room temperature with stirring overnight. The mixture was quenched with 1 N HCl (40 mL) and then extracted with EtOAc (100 and 40 mL). The combined organic extracts were washed with brine and dried. Solvents were removed at reduced pressure, and the residue was washed with hexane and dried to give 1.23 g (65%) of 3-(1-adamantyl)-4,5-methylenedioxyphenylboronic acid as a cream solid, mp 258-261° C. IR 3231, 2903, 2849, 1343, 1164 cm−1; 1H NMR δ (CDCl3) 1.81 (bs, 6H, AdCH2), 2.13 (bs, 9H, AdCH2 and AdCH), 6.02 (s, 2H, CH2), 7.48 (s, 1H, 6-ArH), 7.75 ppm (s, 1H, 2-ArH).
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](=S)[NH2:23])C1C=CC=CC=1.CI.[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH:37][NH2:38])=O)=[CH:30][CH:29]=1.CO>C(#N)C>[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]2[NH:23][C:22]([C:10]3[N:11]=[C:12]4[N:17]([C:18](=[O:19])[C:9]=3[OH:8])[CH2:16][CH2:15][O:14][C:13]4([CH3:21])[CH3:20])=[N:38][N:37]=2)=[CH:30][CH:29]=1
Reactant: NNC(=O)Cc1ccc(F)cc1
Reactant: CC1(C)OCCn2c1nc(C(N)=S)c(OCc1ccccc1)c2=O
Solvent: CC#N
Solvent: CO
Solvent: CI
Product: CC1(C)OCCn2c1nc(-c1nnc(Cc3ccc(F)cc3)[nH]1)c(O)c2=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a slurry of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbothioamide (0.04 g, 0.116 mmol, 1.0 equiv) in acetonitrile (1.2 mL) under a nitrogen atmosphere, was added MeI (0.011 mL, 0.174 mmol, 1.5 equiv). The reaction was heated at 50° C. (oil bath) for 1 h. The reaction was then cooled to ambient temperature and concentrated in vacuo. 2-(4-Fluorophenyl)acetohydrazide (0.058 g, 0.35 mmol, 3 equiv) was then added to the residue followed by methanol (1 mL) and the slurry was heated at 70° C. (oil bath). After stirring 1 h, the reaction was cooled to ambient temperature and concentrated in vacuo. DMF (1 mL) was added to the residue and the solution was heated at 150° C. (oil bath) for 3.5 h. The reaction was then cooled to ambient temperature and stirred 3 d. The reaction was heated at 140° C. (oil bath) for 2 h. The reaction was cooled to ambient temperature and concentrated in vacuo. The residue was added to a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×2). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo. The crude product was purified by reverse phase preparatory HPLC to provide the title compound (0.021 g, 49% yield) as a gray solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.99 (s, 2H), 7.21-7.39 (m, 2H), 7.00 (t, J=8.69 Hz, 2H), 4.17 (s, 2H), 4.05 (s, 4H), 1.62 (s, 6H); LCMS (ES+, (M+H)+) m/z 372.16.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH2:20][CH3:21])[C:12]2=[O:22])=[O:10])[CH2:3][CH2:2]1.[CH3:23]O[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]2[O:35][CH2:34]2)=[CH:27][CH:26]=1>>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH:20]([CH3:23])[CH3:21])[C:12]2=[O:22])=[O:10])[CH2:3][CH2:2]1.[O:35]1[CH:33]([CH2:32][O:31][C:28]2[CH:27]=[CH:26][CH:25]=[CH:30][CH:29]=2)[CH2:34]1
Reactant: CCn1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Reactant: COc1ccc(OCC2CO2)cc1
Product: CC(C)n1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Product: c1ccc(OCC2CO2)cc1

Procedure:
The procedure given in Example 104 was followed using 3-ethyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and glycidyl 4-methoxyphenyl ether as a reactant, instead of 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 1,2-epoxy-3-phenoxypropane, to give the title compound.
Reaction SMILES: [OH-].[K+].[C:3]1(=[O:10])[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4]1.Cl[CH2:12][C:13](=[O:15])[CH3:14]>O.C(O)C>[O:15]=[C:13]([CH3:14])[CH2:12][CH:4]1[C:5](=[O:9])[CH2:6][CH2:7][CH2:8][C:3]1=[O:10]
Reactant: CC(=O)CCl
Reactant: O=C1CCCC(=O)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)CC1C(=O)CCCC1=O

Procedure:
A solution of potassium hydroxide (23.58 g, 20.0 g corrected for assay, 357 mmol) in water (36 mL) at r.t. was added to a solution of 1,3-cyclohexanedione (39.97 g, 356 mmol) in ethanol (144 mL) with stirring (exothermic addition). After stirring for 15 mins at 20° C., redistilled chloroacetone (37.62 g, 33.9 g corrected for assay, 366 mmol) was added in one portion and the reaction mixture stirred for 20 h at 20° C. The inorganic by products were removed by filtration, washing the filter cake with ethanol (40 mL) and the filtrates were combined to provide 2-(2-oxo-propyl)cyclohexane-1,3-dione as a solution in aqueous ethanol. To this solution were added glycine ethyl ester hydrochloride (54.73 g, 392 mmol) and anhydrous sodium acetate (32.19 g, 392 mmol). The reaction mixture was heated to reflux (75° C. internal temperature) for 1 h then cooled to 20° C. and stirred for 19 h. The mixture was heated to reflux (internal temperature 75° C.) and water (116 mL) added, then cooled to 20° C. over 30 mins. A small amount of 2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)-acetic acid, ethyl ester was added as a seed (10 mg) and, after a few minutes, crystallization of the product was observed. The slurry was stirred for 30 mins, then cooled to 5° C. and stirred for 18 h. The solid was collected by filtration, washed with water (2×80 mL) followed by tert-butyl methyl ether (2×80 mL) and then dried in vacuo at 40° C. for 20 h to provide ethyl(2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)acetate as a pale yellow crystalline solid, 41.77 g (49.8% yield). MP 105.1 to 105.4° C. Assay by 1H-NMR 99.3% w/w. Purity by GC 100 area %.
Reaction SMILES: [C:1]1([C:7]2[N:12]3[CH:13]=[N:14][C:15]([C:16]([NH2:18])=[O:17])=[C:11]3[NH:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[S:20]>O1CCCC1.[H-].[Na+]>[C:1]1([C:7]2[N:12]3[C:11]4[N:10]([C:19](=[S:20])[NH:18][C:16](=[O:17])[C:15]=4[N:14]=[CH:13]3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NC(=O)c1ncn2c1NCC=C2c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c(=S)n2c3c1ncn3C(c1ccccc1)=CC2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 1.0 g of 1,2-dihydro-4-phenylimidazo[1,5-a]pyrimidine-8-carboxamide (prepared as described in Example 29) in 30 ml of dry tetrahydrofuran cooled to -78° C. in a dry ice acetone bath was added in one portion 360 mg of sodium hydride (60% dispersion in mineral oil). The reaction mixture was stirred at -78° C. for 30 minutes then 817 mg of 1,1'-thiocarbonyldiimidazole was added in one portion and the mixture was stirred at -78° C. for 3 hours then allowed to warm slowly to room temperature and was stirred at room temperature for 36 hours. The reaction mixture was quenched with water and neutralized with 5% hydrochloric acid. The aqueous solution was extracted with chloroform. The organic layer was separated and evaporated in vacuo to give the product of the example as a yellow solid, mp 316°-317° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH:18]([OH:20])[CH3:19])[S:17][C:13]=2[N:12]2[C:21]([CH3:24])=[N:22][N:23]=[C:11]2[CH2:10][N:9]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1>[ClH:1].[C:25]([O:20][CH:18]([C:16]1[S:17][C:13]2[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]=2[CH:15]=1)[CH3:19])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nnc2n1-c1sc(C(C)O)cc1C(c1ccccc1Cl)=NC2
Solvent: c1ccncc1
Product: Cc1nnc2n1-c1sc(C(C)OC(=O)c3ccccc3)cc1C(c1ccccc1Cl)=NC2
Product: Cl
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a solution of 1 g of 4-(2-chlorophenyl)-2-(1-hydroxyethyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine dissolved in 20 ml of pyridine is added 0.4 g of benzoyl chloride under ice-cooling and then stirred overnight. After completion of the reaction, the mixture is concentrated under reduced pressure and the residue is dissolved in 30 ml of ethyl acetate. The solution is washed with 5% aqueous sodium hydrogencarbonate solution and sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering off, the filtrate is concentrated under reduced pressure and the oily residue is subjected to chromatography on silica gel and eluted with chloroform-methanol (100:1-100:3). The objective fraction is concentrated under reduced pressure to give 0.4 g of 2-(1-benzoyloxyethyl)-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine.hydrochloride, melting at 180°14 193° C. with decomposition.